Netter's Atlas of Neuroscience [4 ed.] 0323756549, 9780323756549

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NETTER’S ATLAS OF NEUROSCIENCE 4th Edition David L. Felten, MD, PhD

Associate Dean of Clinical Sciences University of Medicine and Health Sciences New York, New York

M. Kerry O’Banion, MD, PhD

Professor and Vice Chair Department of Neuroscience Del Monte Neuroscience Institute Director of the Medical Scientist Training Program University of Rochester School of Medicine Rochester, New York

Mary Summo Maida, PhD

Adjunct Professor of Neuroscience Department of Neuroscience Del Monte Neuroscience Institute University of Rochester School of Medicine Rochester, New York

Illustrations by

Frank H. Netter, MD Contributing Illustrators James A. Perkins, MFA, CMI, FAMI Carlos A.G. Machado, MD John A. Craig, MD

1600 John F. Kennedy Blvd. Ste. 1600 Philadelphia, PA 19103-­2899 NETTER’S ATLAS OF NEUROSCIENCE, FOURTH EDITION

ISBN: 978-­0-­323-­75654-­9

Copyright © 2022 by Elsevier, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein. Permission for Netter Art figures may be sought directly from Elsevier’s Health Science Licensing Department in Philadelphia, PA: phone 1-­800-­523-­1649, ext. 3276, or (215) 239-­3276; or email [email protected].

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyright © 2016, 2010, 2003 by Elsevier, Inc. Library of Congress Control Number: 2021932599

Senior Content Strategist: Elyse O’Grady Senior Content Development Specialist: Marybeth Thiel Publishing Services Manager: Catherine Jackson Senior Project Manager/Specialist: Carrie Stetz Design Direction: Patrick Ferguson Printed in Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1

ABOUT THE AUTHORS DAVID L. FELTEN, MD, PhD, is currently Associate Dean of Clinical Sciences at the

University of Medicine and Health Sciences. He counsels and advised MD candidates to assist them in passing the USMLE clinical board exams (Step 2 CK and CS) and the basic sciences board exam (Step 1). He was formerly Vice President for Research and Medical Director of the Research Institute at William Beaumont Health System in Royal Oak, Michigan and the Founding Associate Dean for Research at Oakland University William Beaumont School of Medicine. He previously served as Dean of the School of Graduate Medical Education at Seton Hall University in South Orange, New Jersey; the Founding Executive Director of the Susan Samueli Center for Integrative Medicine and Professor of Anatomy and Neurobiology at the UC Irvine School of Medicine; the Founding Director of the Center for Neuroimmunology at Loma Linda School of Medicine; and the Kilian J. and Caroline F. Schmitt Professor and Chair of the Department of Neurobiology and Anatomy, and Director of the Markey Charitable Trust Institute for Neurobiology and Neurodegenerative Diseases and Aging at the University of Rochester School of Medicine in Rochester, New York. He received a bachelor of science degree from Massachusetts Institute of Technology and MD and PhD degrees (Anatomy, Institute of Neurological Sciences) from the University of Pennsylvania School of Medicine. Dr. Felten carried out pioneering studies of autonomic innervation of lymphoid organs and neural-­immune signaling that underlie the mechanistic foundations for psychoneuroimmunology and many aspects of integrative medicine. Dr. Felten is the recipient of numerous honors and awards, including the prestigious John D. and Catherine T. MacArthur Foundation Prize Fellowship, two simultaneous NIH MERIT awards from the National Institutes of Mental Health and the National Institute on Aging, an Alfred P. Sloan Foundation Fellowship, an Andrew W. Mellon Foundation Fellowship, a Robert Wood Johnson Dean’s Senior Teaching Scholar Award, the Norman Cousins Award in Mind-­Body Medicine, the Building Bridges of Integration Award from the Traditional Chinese Medicine Would Foundation, and numerous teaching awards. Dr. Felten co-­authored the definitive scholarly text in the field of neural-­immune interactions, Psychoneuroimmunology (Academic Press, 3rd edition, 2001) and was a founding co-­ editor of the major journal in the field, Brain, Behavior and Immunity, with Drs. Robert Ader and Nicholas Cohen of the University of Rochester School of Medicine. He also is the author of three editions of Netter’s Neuroscience Flash Cards (fourth edition now in process) and, with Dr. Mary Maida, the first edition of Netter’s Neuroscience Coloring Book. Dr. Felten is the author of more than 210 peer-­reviewed journal articles and reviews, many on links between the nervous system and immune system. His work has been featured on Bill Moyer’s PBS series and book, “Healing and the Mind,” “20/20,” and many other media venues. He served for over a decade on the National Board of Medical Examiners, including Chair of the Neurosciences Committee for the US Medical Licensure Examination. He has served on many Study Sections for the National Institutes of Health. Dr. Felten was named one of the “30 Most Influential Neuroscientists Alive Today” by Online Psychology Degree Guide, 2017.

M. KERRY O’BANION, MD, PhD, is Professor and Vice Chair of the Department of

Neuroscience, member of the Del Monte Neuroscience Institute, and Director of the Medical Scientist Training Program at the University of Rochester School of Medicine in Rochester, New York. He received a bachelor of science degree and medical and doctoral degrees from the University of Illinois at Champaign-­Urbana. As a postdoctoral fellow at the University of Rochester, Dr. O’Banion cloned cyclooxygenase-­2 and discovered its critical role in mediating inflammation.

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About the Authors Dr. O’Banion has worked for more than 25 years in the field of neuroinflammation, with particular interests in how cytokines mediate disease pathology. His current work, funded by NIH and NASA, focuses on possible beneficial effects of modulating inflammation in Alzheimer disease, the persistent effects elicited by brain irradiation, and the potential risk of neurodegenerative disease in individuals exposed to cosmic radiation. Dr. O’Banion has authored over 120 peer-­reviewed journal articles and reviews on these and other topics. Since 1997, Dr. O ‘Banion has co-­directed the Medical Neural Science course (now called Mind, Brain, and Behavior I) at the University of Rochester School of Medicine, a role he assumed from Dr. Felten. Dr. O’Banion also helped design and direct Mind, Brain, and Behavior II, a basic science course that accompanies medical clerkships in neurology and psychiatry for third-­year medical students. He has been program director of the University of Rochester MSTP since 2000 and has served on multiple national committees related to medical and doctoral training.

MARY E.S. MAIDA, PhD, divides her time among research, teaching, mentoring future

medical scientists, mentoring future entrepreneurs, and leading a company she founded focused on translational research. She is an adjunct faculty member of the Department of Neuroscience at the University of Rochester School of Medicine, as well as an annually invited MBA Mentor for Entrepreneurship at the University of Rochester Simon School of Business. During her academic training she received bachelor of science degrees in microbiology/immunology, as well as finance and operations management. She returned to academic medicine as a nontraditional student after having raised her children, commencing at the University of Miami School of Medicine and subsequently at the University of Rochester School of Medicine, where she completed a master of science degree in neurobiology and anatomy, and a doctoral degree in molecular neuroscience under the mentorship of Drs. M. Kerry O ‘Banion, John Olschowka, Richard Phipps, and Denise Figlewicz. Because her return to medical and basic sciences training resumed after she raised her children, her interest turned from microbiology/immunology to the broader field of neuroimmunology, which seeks to pinpoint how the CNS and immune systems are intricately involved in a delicate and elaborate dance of connectivity, everyday cross-­talk, more elaborate communication when pathogens or damage is involved, give-­and-­take vs. give-­and-­go between the two systems (and among other systems), and many more descriptions than words can adequately capture. Dr. Maida has received several honors and awards across many disciplines, including Outstanding Alumni of Distinction Award from Excelsior College, New York State Hall of Distinction Award, Partners in Lifelong Learning Award, Greater Rochester Excellence in Achievement Technology Award, Winning Mentor for Mark Ain Business Competition, 43North Semifinalist distinction, and winning finalist in several open invitation awards. A firm proponent of fostering and living the spirit-­mind-­body relationship that clearly underlies optimal neural-­immune health, Dr. Maida is devoted to her family, her Catholic faith, and the privilege of being a Eucharistic Minister. She is honored to be a community volunteer and board member for The EquiCenter, which provides equine therapy and other programs for US military veterans, developmentally and physically disabled children, and their families. She is a member of the board of trustees for Daystar Kids, which provides early education and respite care for medically fragile children and their families. Dr. Maida also serves as a board member for Boots on the Court, which brings weekend tennis fun to military bases across the United States. She has founded a scholarship fund at Excelsior College, named in honor of her parents. Dr. Maida is a fun-­loving and enthusiastic competitor in tennis, pickleball, golf, cross-­fitness training, and equestrianism and a lover of the arts as a patron, musician, and active performer.

DEDICATION In memory of Walle J.H. Nauta, MD, PhD, Institute Professor of Neuroscience at the Massachusetts Institute of Technology A distinguished, brilliant, and pioneering neuroscientist An outstanding and inspirational teacher A kind, supportive, insightful, and gracious mentor An incredible role model and human being and To my wife, Mary E.S. Maida, PhD A wonderful wife, partner, and friend My inspiration and motivation A superb researcher, teacher, scientific innovator, and business leader A woman who has it all—brains, beauty, kindness, and accomplishment David L. Felten In memory of Teresa Bellofatto, Joe Summo, Robert Summo, and Nicholas Summo Beloved family and friends who faced overwhelming health challenges with determination and an unwaivering joy for life. Daily, they demonstrated the strength of the human spirit and unshakable human kindness, even in the face of daunting physiological challenges. They taught us that it is possible to live life fully, to laugh, and to be the best version of humanity in spite of the absence of a cure. May their memory forever inspire us to strive for a better understanding of the molecular, physiological, and systemic mechanisms that underlie health and disease. David L. Felten Mary E.S. Maida

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Dedication

In memory of Fred Coyner and Nellie Rogers, sweet souls changed in old age, who turned my attention to brain dysfunction and neuroscience research, and To my parents, Terry O’Banion and Mary Rogers, who both served as educators, teaching me the values of service in the name of learning and inspiring me to pursue my love of nature despite the piles of fossils, the stench of chemistry experiments, and some small fires they may still not know about, and To my spouse, Dorothy Petrie, also an educator, for her love, her unconditional support through late nights and weekends of writing and looming deadlines, and her consistent reminder that the opportunity to do science is a gift to be shared with all. M. Kerry O’Banion In honor of my mother, Mary D. Summo, MS, who endlessly gave her love, time, talent, intellect, and wise advice to the 6 of us, her children, and her 10 grandchildren, and still does to this very day. Thank you, Mom. and In memory of my father, Dr. Anthony J. Summo, a true Renaissance man who embraced and promoted the reality of psychobiology, biopsychology, and PTSD well before they became accepted into mainstream medicine. And whose Ciba-­Geigy Netter “green books” with the flip-­over acetate pages sitting on our living room coffee table fascinated me and formed the basis of my love for science and medicine, and To my husband, David L. Felten, MD, PhD, and my sons ­Michael and Matthew Maida, without whose love, encouragement, and support I would never be the woman I am ­today. In the spirit and words of our ancestors’ family motto: Avanti! Sempre Avanti! Mary E.S. Maida

ACKNOWLEDGMENTS For decades, Dr. Frank Netter’s beautiful and informative artwork has provided the visual basis for understanding anatomy, physiology, and relationships of great importance in medicine. Generations of physicians and healthcare professionals have “learned from the master” and have carried Dr. Netter’s legacy forward through their own knowledge and contributions to patient care. There is no way to compare Dr. Netter’s artwork to anything else because it stands in a class of its own. For many decades, the Netter Collection volume on the nervous system has been a flagship for the medical profession and for students of neuroscience. It was a great honor to provide the framework, organization, and new information for the updated first, second, and third editions, and now the fourth edition, of Netter’s Alas of Neuroscience. The opportunity to make a lasting contribution to the next generation of physicians and healthcare professionals is perhaps the greatest honor anyone could receive. I also gratefully acknowledge Walle J.H. Nauta, MD, PhD, whose inspirational teaching of the nervous system at MIT contributed to the organizational framework for this atlas. Professor Nauta always emphasized the value of an overview; the plates in the beginning of Section II, Regional Neurosciences, on the conceptual organization of sensory, motor, and autonomic systems, especially reflect his approach. I am particularly honored to contribute to these updated editions of Netter’s Atlas of Neuroscience because I first learned neurosciences as an undergraduate in Professor Nauta’s laboratory at MIT through his personal mentorship, masterful insights, and explanations—using the first Nervous System “green book” volume by Dr. Frank Netter. It is my hope that continuing generations of students can benefit from the legacy of this wonderful teacher and great scientist. I thank our outstanding artist and medical illustrator, James Perkins, MS, MFA, for his clear, creative, and beautiful contributions to this revised atlas. Jim is an excellent anatomist, with great insights for bringing otherwise complex systems and mechanisms into understandable illustrations. His accomplishments have received wide acclaim and many awards. Special thanks go to the outstanding editors at Elsevier Clinical Solutions: Marybeth Thiel, Senior Content Development Specialist, Elyse O’Grady, Senior Content Strategist, and Carrie Stetz, Senior Project Manager. They helped guide the process of the fourth edition and gave us the latitude to introduce new components, such as the new molecular plates (especially in Chapter 1 ), new additions to forebrain anatomy, a new chapter on Global Neurological Functions, and new clinical correlations. I also acknowledge and thank my friend, colleague, and co-­author of this atlas, Kerry O’Banion. His insights, spanning from the molecular details to the systemic interactions of neural systems, are amazing. For more than 30 years we have had the privilege of working together, both in teaching and research arenas. As one of the premier experts on brain inflammation and a highly knowledgeable molecular neurobiologist, his expertise has been invaluable. Continuing thanks also go to Ralph Jozefowicz, MD, the consummate neurology educator. It was a delight to work with him in the University of Rochester medical neurosciences course and to learn from him through his amazing insights into clinical neurology, and his ability to make those insights come alive for the benefits of both his students and colleagues. And finally, to my wife Mary (Mary E.S. Maida), I again thank you for your unwavering love and your support and encouragement to continue this challenging project, and for your patience with the long hours and seemingly endless clutter of papers and folders you tolerated along the way. Your expertise as a molecular neuroscientist and your outstanding ability to take complex plates and explanations and help to clarify and re-­express them in understandable terms for the readers has been a valuable addition. David L. Felten

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Acknowledgments First, I thank David Felten not only for the opportunity to contribute to this fourth edition but also for his long-­standing support, encouragement, and friendship. Second, I thank Ralph Jozefowicz, MD, Professor of Neurology at the University of Rochester, who together with David Felten served as outstanding mentors for how to teach neuroscience. Finally, I am indebted to my professional colleagues and students, past and current, for the opportunity to learn new things as we pursue science together. M. Kerry O’Banion To this very day, I remember my fascination with the original Netter “green books” that sat prominently displayed on the coffee table in the living room of my childhood home. I would sit for hours turning each page, which added another colorful layer to the beauty and intricacy of the human body’s anatomy and physiology—and day after day trying to recall what I saw, let along make sense of it all. These original tomes that contained the original illustrations of Dr. Frank Netter in part formed the basis of my interest in, and pursuit of, science and medicine. I thank my parents, Dr. Anthony J. and Mary D. Summo, for having provided us with such an enriched environment at home and for encouraging and allowing us to pursue our dreams. I thank the University of Rochester School of Medicine and Dentistry Graduate Program in Neuroscience for providing me the opportunity to pursue my dreams as a nontraditional student. I also extend my deepest gratitude to my mentors M. Kerry O’Banion, MD, PhD, John Olschowka, PhD, Richard Phipps, PhD, and Denise Figlewicz, PhD, whom I have the privilege to know as friends as well as research colleagues. Finally, I express my deepest gratitude to my husband, David Felten, and to my sons Michael and Matthew Maida—my biggest cheerleaders in life—who help me achieve far more than I believe I am capable of achieving and who adeptly help to keep my immune system healthy with the daily dose of humor and laughter we share. Mary E.S. Maida

PREFACE As in the three prior editions, Netter’s Atlas of Neuroscience, 4th edition, combines the richness and beauty of Dr. Frank Netter’s illustrations with key information about the many regions and systems of the brain, spinal cord, and periphery. Jim Perkins and John Craig have contributed outstanding illustrations to complement the original Netter illustrations. The first edition included cross-­sectional illustrations through the spinal cord and brainstem, as well as coronal and axial (horizontal) sections. The second edition built on the first edition with several additional illustrations and extensive new imaging using computed tomography (CT), magnetic resonance imaging (MRI), both T1-­ and T2-­weighted, positron emission tomography (PET) scanning, functional MRI (fMRI), and diffusion tensor imaging (DTI), which provides pseudocolor images of central axonal commissural, association, and projection pathways. Full-­plate MRIs were included for direct side-­by-­side comparisons with Dr. John Craig’s illustrations of the brainstem cross sections and axial and coronal sections. More than 200 “clinical boxes” were added to offer succinct clinical discussions of the functional importance of key topics. These clinical discussions were intended to assist the reader in bridging the anatomy and physiology depicted in each relevant plate to important related clinical issues. The third edition added many new components. Chapter 1, in the Overview section, “Neurons and Their Properties,” was extensively revised and reorganized. Approximately 15 new plates on molecular and cellular topics such as astrocytes, microglia, oligodendrocytes, axonal transport, growth and trophic factors, nuclear transcription factors, neuronal stem cell biology, and others were added. Almost 50 new plates were added throughout the atlas. Many of these plates reflect Jim Perkins’ outstanding ability to represent molecular and cellular concepts in lucid and beautiful form. We added histological cross sections of the spinal cord and brainstem to match the previous illustrations. We also added brainstem sections illustrating the major vascular syndromes of the medulla, pons, and midbrain. Many photomicrographs were introduced to plates throughout the atlas to add clarity to the illustrations. The third edition received three book awards: (1) Highly Commended, British Medical Association (2017); (2) Award of Merit, Association of Medical Illustrators (2016); and (3) Top 10 Neuroscience Textbooks (#2), Wiki Award (2018). This fourth edition of this Atlas adds significant components that were not present in earlier editions, and are often are minimally covered in other sources. The Systemic Neurosciences Section has a new chapter, Chapter 17, Global Brain Functions. This chapter includes several plates on dementias, neuropsychiatric disorders, traumatic brain injury (TBI) and chronic traumatic encephalopathy (CTE), aphasias, nondominant hemispheric functions and dysfunctions, brain substrates of addictive behaviors, consciousness and coma, and aging and the nervous system. Chapter 16, on Autonomic-­Hypothalamic-­Limbic Systems, includes new plates on circumventricular organs and their functions, hypothalamic regulation of sleep, bed nucleus of the stria terminalis, insular cortex, prefrontal cortex, and the functional role of major limbic and cortical regions. xi

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Preface

Several other new plates include molecular techniques for studying neurons, genetic models for studying neurons and their diseases, normal pressure hydrocephalus, postnatal and adult neurogenesis, fetal alcohol syndrome, endogenous opioid systems, endogenous cannabinoid systems, somatosensory nuclei neuronal organization (dorsal column and thalamic nuclei), mechanisms of migraine headaches, neural mechanisms of swallowing (central and peripheral), surgical approaches to movement disorders, and others. The fourth edition retains the organization of the previous three editions: (I) Overview, (II) Regional Neurosciences, and (III) Systemic Neurosciences. Further subdivisions in these sections into component chapters aides in ease of use. We have provided succinct figure legends to point out some of the major functional aspects of each illustration, particularly as they relate to problems that a clinician may encounter in the assessment of a patient with neurological symptoms. We believe that it is important for an atlas of the depth and clarity of Netter’s Atlas of Neuroscience to let the illustrations provide the focal point for learning, not long and detailed written explanations that constitute a full textbook in itself. However, the figure legends, combined with the excellent illustrations and the clinical discussions, provide content for a thorough understanding of the basic components, organization, and functional aspects of the region or system under consideration. Netter’s Atlas of Neuroscience, 4th edition provides a comprehensive view of the entire nervous system, including the peripheral nerves and their target tissues, central nervous system, ventricular system, meninges, cerebral vascular system, developmental neuroscience, and neuroendocrine regulation. We have provided substantial but not exhaustive details and labels to permit the reader to understand the basics of human neuroscience, including the nervous system information usually presented in medical neurosciences courses, the nervous system components of anatomy courses, and neural components of physiology courses in medical school. We are confronted with an era of rapid changes in healthcare and exploding knowledge in all fields of medicine, particularly with the continuing revolution in molecular biology. Medical school curricula are under enormous pressure to add more and more non-­basic sciences components. It has become dangerously tempting to emphasize high-­ technology tests, readouts, imaging, and automated EMR drop-­down menus as a substitute for the real foundations of medical practice—the history and the physical examination. Many medical schools strive to “decompress” the intensity of teaching and to incorporate more problem-­based and small group teaching exercises (which we applaud), with a goal of hastening students into clinical experiences. In the long run, much of the additional information crammed into the medical curriculum has come at the expense of the basic sciences, particularly anatomy, physiology, histology, and embryology. We believe that there is a fundamental core of knowledge that every physician must know. It is not sufficient for a medical student to learn only 3 of the 12 cranial nerves, their functional importance, and their clinical applications, as “representative examples,” in order to further reduce the length of basic sciences courses. Although medical students are always anxious to get

into the clinics and see patients, they need a substantial fund of knowledge to be even marginally competent, particularly if they strive to apply evidence-­based practice, instead of rote memory, to patient care. ORGANIZATION OF NETTER’S ATLAS OF NEUROSCIENCE The Overview section of the atlas is a presentation of the basic components and organization of the nervous system, a “view from 30,000 feet”; this view is an essential foundation for understanding the details of regional and systemic neurosciences. The Overview includes chapters on neurons and their properties, an introduction to the forebrain, brainstem and cerebellum, spinal cord, meninges, ventricular system, cerebral vasculature, and developmental neuroscience. The Regional Neurosciences section provides the structural components of the peripheral nervous system, the spinal cord, the brainstem and cerebellum, and the forebrain (diencephalon and telencephalon). We begin in the periphery and move from caudal to rostral. The peripheral nervous system section includes details about the somatic and autonomic innervation of peripheral nerves; we do not leave the learner at the boundary of CNS and PNS, and hope that they can find out about peripheral and autonomic nerves from a gross anatomy course. This detailed regional understanding is necessary to diagnose and understand the consequences of a host of lesions whose localization depends on regional knowledge—this includes strokes, local effects of tumors, injuries, specific demyelinating lesions, inflammatory reactions, a host of neuropathies, and many other localized problems. In this section many of the clinical correlations assist the reader in integrating a knowledge of the vascular supply with the consequences of infarcts (e.g., brainstem syndromes), which requires a detailed understanding of brainstem anatomy and relationships. The Systemic Neurosciences section evaluates the sensory systems, motor systems (including cerebellum and basal ganglia, acknowledging that they also are involved in many other spheres of activity besides motor), autonomic-­hypothalamic-­limbic systems (including neuroendocrine), and global neural functions and dysfunctions, now named as a fourth section. We have organized each sensory system, when appropriate, with a sequential presentation of reflex channels, cerebellar channels, and lemniscal channels, reflecting Professor Nauta’s conceptual organization of sensory systems. For the motor systems, we begin with lower motor neurons and then show the various systems of upper motor neurons followed by cerebellum and basal ganglia, whose major motor influences are ultimately exerted through regulation of upper motor neuronal systems. For the autonomic-­hypothalamic-­ limbic system, we begin with the autonomic preganglionic and postganglionic organization and then show brainstem and hypothalamic regulation of autonomic outflow, and finally limbic and cortical regulation of the hypothalamus and autonomic outflow The newly added Chapter 17 addresses global functions and dysfunctions of the nervous system. The systemic neurosciences constitute the basis for carrying out and interpreting the neurological examination. We believe that it is necessary for a student of neuroscience to understand both regional organization and systemic organization. Without this dual understanding, clinical

Preface

evaluation of a patient with a neurological problem would be incomplete. In a discipline as complex as the neurosciences, the acquisition of a solid organization and understanding of the major regions and hierarchies of the nervous system is not just a “nice idea” or a l­uxury—it is essential. The fact that this approach has been stunningly successful for our students in a course organized and taught for 35 years by both authors of the first edition (David L. Felten, MD, PhD, and Ralph F. Jozefowicz, MD), and by M. Kerry ­O’Banion, MD, PhD, and Ralph F. Jozefowicz, MD, for more than 15 years is an added benefit but is not why we organized this Atlas as we have. A working competence for students in basic and clinical

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neuroscience, and its value for delivering outstanding patient care, are always the main focus of our efforts. We truly value success in this arena. Knowledgeable and highly competent students are the finest outcome of our teaching that we could ever achieve. We hope that our students will come to appreciate both the beauty and the complexity of the nervous system and be inspired to contribute to the knowledge and functional application to patients of this greatest biological and medical frontier, which constitutes the substrate for human behavior and our loftiest human aspirations and endeavors. David L. Felten

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ABOUT THE ARTISTS FRANK H. NETTER, MD was born in 1906 in New York City. He studied art at the

Art Students League and the National Academy of Design before entering medical school at New York University, where he received his medical degree in 1931. During his student years, Dr. Netter ‘s notebook sketches attracted the attention of the medical faculty and other physicians, allowing him to augment his income by illustrating articles and textbooks. He continued illustrating as a sideline after establishing a surgical practice in 1933, but he ultimately opted to give up his practice in favor of a full-­time commitment to art. After service in the United States Army during World War II, Dr. Netter began his long collaboration with the CIBA Pharmaceutical Company (now Novartis Pharmaceuticals). This 45-­year partnership resulted in the production of the extraordinary collection of medical art so familiar to physicians and other medical professionals worldwide. In 2005, Elsevier, Inc. purchased the Netter Collection and all publications from Icon Learning Systems. There are now more than 50 publications featuring the art of Dr. Netter available through Elsevier, Inc. (in the US: www.us.elsevierhealth.com/Netter; outside the US: www.elsevierhealth.com). Dr. Netter’s works are among the finest examples of the use of illustration in the teaching of medical concepts. The 13-­book Netter Collection of Medical Illustrations, which includes the greater part of the more than 20,000 paintings created by Dr. Netter, became and remain one of the most famous medical works ever published. Dr. Netter’s Atlas of Human Anatomy, first published in 1989, presents the anatomical paintings from the Netter Collection. Now translated into 16 languages, it is the anatomy atlas of choice among medical and health professions students the world over. The Netter illustrations are appreciated not only for their aesthetic qualities, but, more important, for their intellectual content. As Dr. Netter wrote in 1949, “. . . clarification of a subject is the aim and goal of illustration. No matter how beautifully painted, how delicately and subtly rendered a subject may be, it is of little value as a medical illustration if it does not serve to make clear some medical point.” Dr. Netter’s planning, conception, point of view, and approach are what inform his paintings and what makes them so intellectually valuable. Frank H. Netter, MD, physician and artist, died in 1991. Learn more about the physician-­artist whose work has inspired the Netter Reference collection: http://www.netterimages.com/artist/netter.htm.

CARLOS MACHADO, MD was chosen by Novartis to be Dr. Netter’s successor. He con-

tinues to be the main artist who contributes to the Netter Collection of medical illustrations. Self-­taught in medical illustration, cardiologist Carlos Machado has contributed meticulous updates to some of Dr. Netter’s original plates and has created many paintings of his own in the style of Netter as an extension of the Netter collection. Dr. Machado’s photorealistic expertise and his keen insight into the physician/patient relationship inform his vivid and unforgettable visual style. His dedication to researching each topic and subject he paints places him among the premier medical illustrators at work today. Learn more about his background and see more of his art at: http://www.netterimages. com/artist/machado.htm.

JAMES A. PERKINS, CMI, FAMI is Professor of Medical Illustration at Rochester Institute of Technology (RIT) where he teaches courses in anatomy, digital illustration, and scientific visualization. He is a Board Certified Medical Illustrator and Fellow of the Association of Medical Illustrators.

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About The Artists An expert in visualizing biological processes, Professor Perkins has illustrated more than 40 medical textbooks, particularly in the areas of pathology, physiology, and molecular biology. For more than 20 years, he has been the sole illustrator of the “Robbins” series of pathology texts published by Elsevier, including the flagship of the series, Robbins and Cotran Pathologic Basis of Disease. He has been a contributor to the Netter Collection since 2001, creating most of the new art for Netter’s Atlas of Human Physiology, Netter’s Illustrated Pharmacology, and Netter’s Atlas of Neuroscience and contributing to many other titles. Professor Perkins received a bachelor degree in biology and geology from Cornell University and studied vertebrate paleontology and anatomy at the University of Texas and University of Rochester. He received a Master of Fine Arts degree in medical illustration from RIT and spent several years working in medical publishing and the medical legal exhibit field before returning to RIT to join the faculty. Learn more about his background and see more of his art at: http://www.netterimages.com/artist/perkins.htm

CONTENTS

Section I  OVERVIEW OF THE NERVOUS SYSTEM 1 Neurons and Their Properties �������������������������������������������� 3 Anatomical and Molecular Properties ������������������������������������������ 4 Electrical Properties �������������������������������������������������������������������� 23 Neurotransmitter and Signaling Properties �������������������������������� 38

2 Skull and Meninges ����������������������������������������������������������� 47 3 Brain ����������������������������������������������������������������������������������� 53 4 Brainstem and Cerebellum ����������������������������������������������� 73 5 Spinal Cord ������������������������������������������������������������������������ 78 6 Ventricles and the Cerebrospinal Fluid ���������������������������� 85 7 Vasculature ������������������������������������������������������������������������ 94 Arterial System ��������������������������������������������������������������������� 95 Venous System ������������������������������������������������������������������� 119 8 Developmental Neuroscience ����������������������������������������� 128

Section II  REGIONAL NEUROSCIENCE 9 Peripheral Nervous System �������������������������������������������� 161 Introduction and Basic Organization ���������������������������������������� 162 Somatic Nervous System ��������������������������������������������������������� 180 Autonomic Nervous System ����������������������������������������������������� 204

10 Spinal Cord ���������������������������������������������������������������������� 239 11 Brainstem and Cerebellum ��������������������������������������������� 254 Brainstem Cross-­Sectional Anatomy ��������������������������������������� Cranial Nerves and Cranial Nerve Nuclei ��������������������������������� Reticular Formation ������������������������������������������������������������������ Cerebellum ��������������������������������������������������������������������������������

255 270 287 291 xvii

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Contents

12 Diencephalon ������������������������������������������������������������������� 294 13 Telencephalon ������������������������������������������������������������������ 299

Section III  SYSTEMIC NEUROSCIENCE 14 Sensory Systems ������������������������������������������������������������� 361 Somatosensory Systems ���������������������������������������������������������� Trigeminal Sensory System ������������������������������������������������������ Sensory System for Taste ��������������������������������������������������������� Auditory System ����������������������������������������������������������������������� Vestibular System ��������������������������������������������������������������������� Visual System ���������������������������������������������������������������������������

362 372 376 378 385 388

15 Motor Systems ���������������������������������������������������������������� 401 Lower Motor Neurons ��������������������������������������������������������������� Upper Motor Neurons ��������������������������������������������������������������� Cerebellum �������������������������������������������������������������������������������� Basal Ganglia ����������������������������������������������������������������������������

402 405 420 427

16 Autonomic-­Hypothalamic-­Limbic Systems��������������������� 434 Autonomic Nervous System ����������������������������������������������������� Hypothalamus and Pituitary������������������������������������������������������ Limbic System �������������������������������������������������������������������������� Olfactory System ����������������������������������������������������������������������

435 437 465 479

Section IV  GLOBAL BRAIN FUNCTIONS 17 Global Brain Functions����������������������������������������������������� 483

VIDEO CONTENTS 3.­1 Sagittal Brain 3.­2 Axial DT Imaging with Color Depiction of Pathways 6.­1 Axial Sections with Surface Anatomy 6.2 Brain: High-­Resolution Axial T2 7.1 Circle of Willis: Left to Right 7.­2 Circle of Willis: Head to Foot 7.­3 Carotid Artery: Left to Right 7.­4 Carotid Artery: Head to Foot 7.­5 Brain: Magnetic Resonance Venogram, Left to Right 7.­6 Brain: Magnetic Resonance Venogram, Head to Foot   13.­1 Axial Brain   13.­2 Coronal Brain  13.­3 Brain: Axial from Axial, Rotation Left to Right  13.­4 Brain: Sagittal from Sagittal, Rotation Left to Right

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Section I OVERVIEW OF THE

NERVOUS SYSTEM

1.  Neurons and Their Properties Anatomical and Molecular Properties Electrical Properties Neurotransmitter and Signaling Properties 2.  Skull and Meninges 3. Brain 4.  Brainstem and Cerebellum 5.  Spinal Cord 6.  Ventricles and the Cerebrospinal Fluid 7. Vasculature Arterial System Venous System 8.  Developmental Neuroscience

1

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1

NEURONS AND THEIR PROPERTIES



Anatomical and Molecular Properties

1.24 Action Potentials

1.1 Neuronal Structure

1.25 Propagation of the Action Potential

1.2 3D Neuronal Structure and Neurohistology

1.26 Node of Ranvier and Conduction Velocity

1.3 Neuronal Ultrastructure

1.27 Classification of Peripheral Nerve Fibers by Size and Conduction Velocity

1.4 Types of Synapses 1.5 Neuronal Cell Types 1.6 Molecular Techniques for Studying Neurons 1.7 Genetic Models for Studying Neurons and Their Disorders

1.28 Electromyography and Conduction Velocity Studies 1.29 Presynaptic and Postsynaptic Inhibition 1.30 Spatial and Temporal Summation

1.8 Glial Cell Types

1.31 Normal Electrical Firing Patterns of Cortical Neurons and the Origin and Spread of Seizures

1.9 Astrocyte Biology

1.32 Electroencephalography

1.10 Microglial Biology

1.33 Types of Electrical Discharges in Generalized Seizures and Sites of Action of Antiseizure Medications

1.11 Oligodendrocyte Biology 1.12 Neuronal Growth Factors and Trophic Factors

1.34 Visual and Auditory Evoked Potentials

Neurotransmitter and Signaling Properties

1.13 Stem Cells in the CNS: Intrinsic and Extrinsic Mechanisms



1.14 Stem Cell Therapy

1.35 Synaptic Morphology

1.15 Blood-­Brain Barrier

1.36 Mechanisms of Molecular Signaling in Neurons

1.16 Inflammation in the CNS

1.37 Neurotransmitter Release

1.17 Axonal Transport in the CNS and PNS

1.38 Multiple Neurotransmitter Synthesis, Release, and Signaling from Individual Neurons

1.18 Myelination of CNS and PNS Axons 1.19 Development of Myelination and Axon Ensheathment

1.39 Neuronal Signal Transduction: Local Regulation of Synaptic Strength at an Excitatory Synapse



1.40 Neuronal Signal Transduction: Regulation of Nuclear Signaling

Electrical Properties

1.20 Neuronal Resting Potential 1.21 Neuronal Membrane Potential and Sodium Channels

1.41 Glucocorticoid Regulation of Neurons and Apoptosis 1.42 Chemical Neurotransmission

1.22 Graded Potentials in Neurons 1.23 Mechanisms of Excitatory Postsynaptic Potentials and Inhibitory Postsynaptic Potentials

3

4

Overview of the Nervous System

Dendrites Dendritic spines (gemmules) Rough endoplasmic reticulum (Nissl substance) Ribosomes Mitochondrion Nucleus

Axon

Nucleolus Axon hillock Initial segment of axon Neurotubules Golgi apparatus Lysosome Cell body (soma) Axosomatic synapse Glial (astrocyte) process Axodendritic synapse

ANATOMICAL AND MOLECULAR PROPERTIES 1.1 NEURONAL STRUCTURE Neuronal structure reflects the functional characteristics of the individual neuron. Incoming information is projected to a neuron mainly through axonal terminations on the cell body and dendrites. These synapses are isolated and are protected by astrocytic processes. The dendrites usually make up the greatest surface area of the neuron. Some protrusions from dendritic branches (dendritic spines) are sites of specific axodendritic synapses. Each specific neuronal type has a characteristic dendritic branching pattern called the dendritic tree, or dendritic arborizations. The neuronal cell body varies from a few micrometers (μm) in diameter to more than 100 μm. The neuronal cytoplasm contains extensive rough endoplasmic reticulum (rough ER), reflecting the massive amount of protein synthesis necessary to maintain the neuron and its processes. The Golgi apparatus is involved in packaging potential signal molecules for transport and release. Large numbers of mitochondria are necessary to meet the huge energy demands of neurons, particularly those related to the maintenance of ion pumps and membrane potentials. Each neuron has a single (or occasionally no) axon, usually emerging from the cell body or occasionally from a dendrite (e.g., some hippocampal CA neurons). The cell body tapers to the axon at the axon hillock, followed by the initial segment of the axon, which contains the Na+ channels, the first site where action potentials are initiated. The axon extends for a variable distance from the cell body (up to 1 m or more). An axon larger than 1 to 2 μm in diameter is insulated by a sheath of myelin provided by oligodendroglia in the central nervous system (CNS) or Schwann cells in the peripheral nervous system (PNS). An axon may branch into more than 500,000 axon

terminals and may terminate in a highly localized and circumscribed zone (e.g., primary somatosensory axon projections used for fine discriminative touch) or may branch to many disparate regions of the brain (e.g., noradrenergic axonal projections of the locus coeruleus). A neuron whose axon terminates at a distance from its cell body and dendritic tree is called a macroneuron or a Golgi type I neuron; a neuron whose axon terminates locally, close to its cell body and dendritic tree, is called a microneuron, a Golgi type II neuron, a local circuit neuron, or an interneuron. There is no typical neuron because each type of neuron has its own specialization. However, pyramidal cells and lower motor neurons are commonly used to portray a so-­called typical neuron. CLINICAL POINT Neurons require extraordinary metabolic resources to sustain their functional integrity, particularly that related to the maintenance of membrane potentials for the initiation and propagation of action potentials. Neurons require aerobic metabolism for the generation of adenosine triphosphate (ATP) and have virtually no ATP reserve, so they require continuous delivery of glucose and oxygen, generally in the range of 15% to 20% of the body’s resources, which is a disproportionate consumption of resources. During starvation, when glucose availability is limited, the brain can shift gradually to using beta-­hydroxybutyrate and acetoacetate as energy sources for neuronal metabolism; however, this is not an instant process and is not available to buffer acute hypoglycemic episodes. An ischemic episode of even 5 minutes, resulting from a heart attack or an ischemic stroke, can lead to permanent damage in some neuronal populations such as pyramidal cells in the CA1 region of the hippocampus. In cases of longer ischemia, widespread neuronal death can occur. Because neurons are postmitotic cells, except for a small subset of interneurons, dead neurons are not replaced. One additional consequence of the postmitotic state of most neurons is that they are not sources of tumor formation. Brain tumors derive mainly from glial cells, ependymal cells, and meningeal cells.   

5

Neurons and Their Properties

Dendrites

Purkinje neurons

A. Spinal cord lower motor neuron.

Nissl substance (rough endoplasmic reticulum) stains purple. The nucleolus is stained in the clear nucleus. Cresyl violet stain.

B. Cerebellar Purkinje neurons.

Large dendrites branch from the cell body. Intraneuronal neurofibrils and background neural processes (neuropil) stain densely. Silver stain.

Axon

Axon

Dendrite

Dendrite

C. Spinal cord neuron. Many large dendrites emerge from the cell body, and the smaller axon extends from the large neuron at the 3 o'clock position. Ink stain.

D. Reticular formation neuron. Heavy metal impregnation of selective neurons revealing the cell body and all processes. Golgi stain.

G. Superior mesenteric-celiac ganglion. Immunohistochemical stain demonstrating the presence of interleukin-2 receptors in these neurons.

H. Superior mesenteric-celiac ganglion. Acetylcholinesterase (AChE) histochemical stain demonstrating the presence of this enzyme, which cleaves acetylcholine to choline and acetyl coenzyme A.

Neuronal cell bodies

Interface

E. Spinal cord ventral horn. Neuronal F. Superior mesenteric-celiac cell bodies and the tangle of axons and dendrites seen in the neuropil of the ventral horn. The interface between gray matter and white matter is conspicuous. Cajal stain.

ganglion. Glyoxylic acid fluorescence histochemistry demonstrating noradrenergic cell bodies.

Parenchyma Astrocytes

End feet

Vasculature

I. Neurons in superior

mesenteric-celiac ganglion stained with fluorogold, which has been transported retrogradely from an injection site into immune tissue innervated by NA fibers from these NA ganglion cells in a rat.

J. Immunocytes in the marginal zone K. CNS astrocytes with processes of the spleen. In-situ hybridization demonstrating the presence of corticotropin-releasing factor (CRF) gene in these darkly staining nonneuronal cells. CRF is an important releasing factor secreted by neurons into the hypophyseal portal system in the hypothalamus. CRF also is present in, and secreted by, nonneuronal cells in the immune system.

extending into the gray matter and “end feet” extending to the surface of CNS blood vessels with a blood-brain barrier. Silver stain.

L. Axons from NA sympathetic

postganglionic neurons innervating the vasculature and parenchyma (T lymphocyte zone and marginal zone) of the spleen. Immunohistochemical stain for tyrosine hydroxylase (TH), the rate-limiting enzyme for the synthesis of catecholamines from tyrosine.

Myelin sheaths

M. Same NA axons as in part L. Stained for norepinephrine with glyoxylic acid fluorescence histochemistry.

N. Same NA axons as in part M, with O. Myelinated fascicles in a

added injection of gel ink (dark blue) peripheral nerve cut in cross-section. to demonstrate the vasculature. Gel Osmic acid stain reveals myelinated ink also is picked up by macrophages axons but not unmyelinated axons. in the marginal zone.

1.2 3D NEURONAL STRUCTURE AND NEUROHISTOLOGY

Nodes of Ranvier

P. Axons in a peripheral nerve cut in

longitudinal section. Oil red O stain demonstrating longitudinal axons surrounded by myelin sheaths (light-colored areas), with conspicuous appositions of sheaths at nodes of Ranvier.

 

6

Overview of the Nervous System

Reprinted with permission from Felten DL, Peterson RG, McConnell J, Wood JG. X-ray analytical electron microscopy of central serotonergic neurons. J Histochem Cytochem 30(8):774–779, 1982.  

1.3 NEURONAL ULTRASTRUCTURE Neuron of nucleus raphe obscurus, standard transmission electron microscopy. The nucleolus (nc) is prominent and the chromatin is dispersed throughout the nucleus (n). The bounding nuclear envelope (ne) follows an uneven contour. Within the cytoplasm of the cell body are Nissl bodies (nb) with their characteristic lamellar organization of rough endoplasmic reticulum, scattered ribosomes, arrays of Golgi apparatus (ga), mitochondria

(m), and dense particles (large arrows). These dense particles demonstrate the presence of serotonin when stained with chromium and examined with x-­ray analytical electron microscopy. Axon terminals (a) synapse on the neuronal membrane. A small somatic spine (s) is present near one of these synapses. This specimen was fixed in 4% glutaraldehyde, osmicated, and stained with uranyl acetate and lead citrate. Bar = 1 um. Original magnification × 15,000.

7

Neurons and Their Properties

Glial process

Dendrite or cell body

Axon

C. Dendritic crest synapse

Axon

Dendrite

B. Dendritic spine synapse

matic synapse

Dendrite

A. Simple axodendritic or axoso-

Dendritic spine (gemmule) Axon

D. Simple synapse plus

E. Combined axoaxonic and

F. Varicosities (“boutons en passant”)

Dendrite

axodendritic synapse

Dendrite

axoaxonic synapse

Dendrite or cell body

I. Serial synapse G. Dendrodendritic synapse

J. Cerebellar glomerulus

Dendrodendritic synapse

Dendrite

Dendrite

Dendrite

H. Reciprocal synapse

Dendrite or cell body

K. Inner plexiform layer of retina Ganglion cell

Granule cell dendrites Glial capsule Golgi cell axon

Bipolar cell axon Müller cell (supporting)

Golgi cell dendrite Mossy cell axon

1.4 TYPES OF SYNAPSES A synapse is a site where an arriving action potential, through excitation-­secretion coupling involving Ca2+ influx, triggers the release of one or more neurotransmitters into the synaptic cleft (typically 20 μm across). The neurotransmitter acts on receptors on the target neuronal membrane, altering the membrane potential from its resting state. These postsynaptic potentials are called graded potentials. Most synapses carrying information toward a target neuron terminate as axodendritic or axosomatic synapses. Specialized synapses, such as reciprocal synapses or complex arrays of synaptic interactions, provide specific regulatory control over the excitability of their target neurons. Dendrodendritic synapses aid in the coordinated firing of groups of related neurons such as the phrenic nucleus neurons that cause contraction of the diaphragm.

Amacrine cell processes

 

CLINICAL POINT The configurations of the synapses of key neuronal populations in particular regions of the brain and of target cells in the periphery determine the relative influence of that input. At the neuromuscular junction, a sufficient amount of acetylcholine is usually released by an action potential in the motor axon to guarantee that the muscle end plate potential reaches threshold and initiates an action potential. In contrast, the neuronal inputs into reticular formation neurons and many other types of neurons require either temporal or spatial summation to allow the target neuron to reach threshold; this orchestration involves coordinated multisynaptic regulation. In some key neurons such as lower motor neurons (LMNs), input from brainstem upper motor neurons (UMNs) is directed mainly through spinal cord interneurons and requires extensive summation to activate the LMNs; in contrast, direct monosynaptic corticospinal UMNs input onto some LMNs, such as those regulating fine finger movements, terminate close to the axon hillock/initial segment; and can directly initiate an action potential in the LMNs. Some complex arrays of synapses among several neuronal elements, such as those seen in the cerebellum and retina, permit modulation of key neurons by both serial and parallel arrays of connections, providing lateral modulation of neighboring neuronal excitability.   

8

Overview of the Nervous System Peripheral nervous system (PNS)

Central nervous system (CNS)

Bipolar cell of cranial nerve VIII

Multipolar (pyramidal) cell of cerebral motor cortex

Unipolar cell of sensory ganglia of cranial nerves V, VII, IX, or X

Associational, commissural, and thalamic endings Astrocyte

Satellite cells Interneurons Blood vessel

Striated (somatic) muscle

Muscle spindle Unipolar sensory cell of spinal dorsal root ganglion

Multipolar somatic motor cell of nuclei of cranial nerves III, IV, V, VI, VII, IX, X, XI, or XII

Interneuron

Multipolar cell of caudal brain motor centers

Renshaw interneuron (feedback) Myelinated somatic motor fiber of spinal nerve

Myelinated afferent fiber of spinal nerve

Multipolar visceral motor (autonomic) cell of spinal cord Autonomic preganglionic (sympathetic or parasympathetic) nerve fiber Myelin sheath Autonomic postganglionic neuron of sympathetic or parasympathetic ganglion Satellite cells Unmyelinated nerve fiber Schwann cells

Myelin sheath

Myelin sheath Red: Motor neurons, preganglionic autonomic neuron Blue: Sensory neuron Purple: CNS neurons Gray: Glial and neurilemmal cells and myelin Note: Cerebellar cells not shown here

Myelin sheath Schwann cells

Motor end plate with Schwann cell cap Striated (voluntary) muscle

Satellite cells

Astrocyte

Oligodendrocyte

Multipolar somatic motor cell of anterior horn of spinal cord Nissl substance Astrocyte Collateral

Free nerve endings (unmyelinated fibers) Encapsulated ending Specialized ending

Motor end plate

Corticospinal (pyramidal) fiber Axodendritic ending Axosomatic ending Axoaxonic ending

Schwann cell Myelinated fibers

Endings on cardiac muscle or nodal cells Beaded varicosities and endings on smooth muscle and gland cells

1.5 NEURONAL CELL TYPES Local interneurons and projection neurons demonstrate characteristic size, dendritic arborizations, and axonal projections. In the CNS (denoted by dashed lines), glial cells (astrocytes, microglia, oligodendroglia) provide support, protection, and maintenance of neurons. Schwann cells and satellite cells provide these functions in the PNS. The primary sensory neurons (blue) provide sensory transduction of incoming energy or stimuli into electrical signals that are carried into the CNS. The neuronal outflow from the CNS is motor (red) to skeletal muscle fibers via neuromuscular junctions, or is autonomic preganglionic (red) to autonomic ganglia, whose neurons innervate cardiac muscle, smooth muscle, secretory glands, metabolic cells, or cells of the immune system. Neurons other than primary sensory neurons, LMNs, and preganglionic autonomic neurons are located in the CNS in the brain (enclosed by upper dashed lines) or spinal cord (enclosed by lower dashed lines). Neurons and glia are not drawn to scale.

Unmyelinated fibers Free nerve endings Encapsulated ending Muscle spindle

 

CLINICAL POINT Neuronal form and configuration provide evidence of the role of that particular type of neuron. Dorsal root ganglion cells have virtually no synapses on the cell body; the sensory receptor is contiguous with the initial segment of the axon to permit direct activation of the initial segment upon reaching a threshold stimulus. This arrangement provides virtually no opportunity for centrifugal control of the initial sensory input; rather, control and analysis of the sensory input occurs in the CNS. Purkinje neurons in the cerebellum have huge planar dendritic trees, with activation occurring via hundreds of parallel fibers and the background excitability influenced by climbing fiber control. This type of array allows network modulation of Purkinje cell output, via neurons of the deep cerebellar nuclei, to UMNs, a control mechanism that permits fine-­grained, ongoing adjustments to smooth and coordinated motor activities. Small interneurons in many regions have local and specialized functions that have local circuit connections, whereas large isodendritic neurons of the reticular formation receive widespread, polymodal, nonlocal input, which is important for general arousal of the cerebral cortex and consciousness. Damage to these key neurons may result in coma. LMNs and preganglionic autonomic neurons receive tremendous convergence upon their dendrites and cell bodies to orchestrate the final pattern of activation of these final common pathway neurons through which the peripheral effector tissues are signaled and through which all behavior is achieved.   

Neurons and Their Properties

Immunohistochemistry

9

In situ hybridization

Chromogenic Colorless substrate

Brightly colored product

Bound enzyme (e.g., horseradish peroxidase) Antibody Target molecule

Fluorescence UV light Fluorophore (e.g., fluorescein, rhodamine, GFP)

Chromogenic, fluorescent, or radiolabeled marker

Antibody Target molecule

DNA or RNA strand

“Omics” (genomics, transcriptomics, proteomics, etc.)

Complementary nucleotide probe

Clustering of data points reveals differences in gene expression between cell types or at different times in one cell type

Single-cell RNA sequencing (scRNA-seq)

Gene group B

Cell 1

Cell 2

Viral tracers

Isolate individual cells

Viral DNA or RNA

Cell 1

Cell 2

Gene group A Lyse cells, purify mRNA

Reverse transcribe Add unique nucleic acid mRNA to cDNA “bar codes” Synaptic propagation of virus Anterograde

Amplify cDNA, sequence, and analyze data

Retrograde Viral vector (herpes, adeno-associated Intracerebroventricular, intravitreal, virus, rabies, etc.) genetically modified intramuscular, intravascular, or to encode fluorescent marker other mode of delivery Chemogenetics Viral vector delivers gene for a DREADD (designer Optogenetics receptor exclusively Activated activated by designer by CNO drug) to specific cell types

DREADD, often a G-protein-coupled receptor, activated by a designer drug (e.g., clozapine-N-oxide or CNO)

Gene codes for DREADD

Viral vector delivers gene for a lightactivated protein

Light

Light-activated protein, often a light-gated ion channel

 

1.6 MOLECULAR TECHNIQUES FOR STUDYING NEURONS Multiple molecular approaches are used to investigate neurons and their complex interactions. Traditional methods localize specific proteins or mRNA species using immunohistochemistry and in situ hybridization, respectively. New technologies (OMICS) can tag RNA from single cells to investigate patterns of gene expression and their changes in disease states. Some viruses can transduce specific cell types, particularly neurons, and provide precise and efficient means to express molecules in the nervous system.

This technology is used to (1) label neuronal pathways, including transsynaptic connections, and (2) deliver engineered G-­protein-­ coupled receptors or light-­sensitive ion channels to modulate neural function directly with exogenous stimuli. Viral vectors are being developed for gene replacement or gene targeting in human disease; some of these therapies are already approved, such as a treatment for spinal muscular atrophy.

10

Overview of the Nervous System

Transgenic Mouse Models of Human Disease Transgenic mouse

Gene of Reporter of interest gene expression (e.g., Green Fluorescent Protein) Knockout and knockin mouse

Genetic material injected into male pronucleus of fertilized egg Knockout

Functional gene replaced with non-functional copy Embryonic stem cells harvested from blastocyst of a mouse with a certain coat color (e.g., white)

Knockin

Implantation of embryo into hormonally induced “pseudo-pregnant” female

Modified stem cells inserted into blastocyst of a mouse with a different coat color (e.g., gray)

Novel gene inserted

Chimeric mouse with mix of coat colors and mix of modified and wild type genes

Viral or non-viral delivery of guide RNAs and Cas9 enzyme in vivo Cre-Lox Technology Cre recombinase is an enzyme that recombines short DNA segments between two target sequences called LoxP. Cre and LoxP are derived from the bacteriophage P1 virus, which uses them to insert its DNA into the host cell genome.

Guide RNA

DNA breaks Novel gene inserted at DNA breaks

Cre transgenic mouse Cre

Cre Cre enzyme

Breeding

LoxP Gene of LoxP interest

LoxP transgenic mouse LoxP Gene of LoxP interest

Cre-LoxP hybrid transgenic mouse

Overexpression of APP

Presenilins involved in cleaving APP into Aβ

Hyperphosphorylation of tau protein

Cre can be modified to require activation (e.g., by tamoxifen)

Depending on the orientation of LoxP sites, Cre may cause insertion, deletion, inversion, or translocation of target gene, generating new strains of knockout, knockin, and transgenic mice.

Plaque formation: Aβ surrounded by a tangle of neurites and tau protein

Transgenic Disease Model – Alzheimer’s Disease

Transgeneic mouse with overexpression of amyloid-β (Aβ) precursor protein (APP), mutant presenilin proteins, and/or mutant tau protein

If modified cells are incorporated into germline (ova and sperm), subsequent breeding can yield pure strains of genetically modified mice

Cas9 enzyme

CRISPR-Cas9 knockin mouse Mouse DNA

Transgenic offspring. Fluorescence indicates location of gene expression

Overproduction of Aβ, forming plaques

Atrophy of cerebral cortex and hippocampus. Cognitive deficits measured with mazes, object recognition, and other tests

Tau

Breakdown of microtubules, releasing tau

Tau protein deposits in nerve cells

Y-maze

 

1.7 GENETIC MODELS FOR STUDYING NEURONS AND THEIR DISORDERS Genetic manipulation of mammalian DNA, initially in mice, is a powerful experimental tool to explore the effect of the introduction or deletion of specific genes. Transgenic mice, in which a new gene or set of genes is introduced, are widely used in models of human disease. Gene function or disease phenotypes can also be investigated using knockout or knockin technologies, which have been made increasingly efficient by the discovery

of systems such as CRISPR-­Cas9. This system provides direct, targeted gene insertion or deletion. Other genetic technologies such as Cre-­Lox, adapted from bacteriophages, provide methods for cell-­specific expression or deletion of genes, depending on which cells express Cre, as well as temporal control of expression or deletion with the use of modified Cre, which can be activated by a drug or hormone. The latter approach is especially useful for avoiding the impact of genetic manipulation during development.

Neurons and Their Properties

11

Ventricle

Ependyma

Microglial cell

Tanycyte

Neuron Oligodendrocyte

Axon Astrocyte Astrocyte foot processes

Pia mater

Capillary

Perivascular pericyte

 

1.8 GLIAL CELL TYPES Astrocytes provide structural isolation of neurons and their synapses and provide ionic (K+) sequestration, trophic support, and support for growth and signaling functions to neurons. Oligodendroglia (oligodendrocytes) provide myelination of axons in the CNS. Microglia are scavenger cells that participate in phagocytosis, inflammatory responses, cytokine and growth factor

secretion, and some immune reactivity in the CNS. Perivascular cells participate in similar activities at sites near the blood vessels. Schwann cells provide myelination, ensheathment, trophic support, and actions that contribute to the growth and repair of peripheral neurons. Activated T lymphocytes normally can enter and traverse the CNS for immune surveillance for a period of approximately 24 hours.

12

Overview of the Nervous System Non-overlapping, 3D polyhedral domains

“Bushy” processes fill space within 3D domains

Astrocyte Physiology Metabolic support of neurons: - Provide lactate to neurons - Glycogenesis Ionic balance: - K+ buffering - pH balance Neural growth factors Glial scar formation

100-200µm

Neuron (not to scale) Lactate K+

Synapse

Insulation of synapse Gap junctions between adjacent astrocytes forming a syncytium

Ionic balance

Arteriole

K+

Endothelial cell Astrocyte end-foot processes: - Ensheath arterioles and capillaries - Water transport via aquaporin 4 - Release “gliotransmitters” (glutamate, ATP, adenosine, etc.) - Regulate formation of endothelial tight junctions? End-foot - Regulate vasodilation and processes cerebral blood flow?

Glutamine

Vascular smooth muscle cell

Glutamate and GABA reuptake

Astrocyte processes: - Surround and insulate synapses - Ionic balance (K+ and pH buffering) - Glutamate and GABA reuptake from synapse - Inactivation of glutamate to glutamine and recycling of glutamine

  1.9 ASTROCYTE BIOLOGY Astrocytes are the most abundant glial cells in the CNS. They arise from neuroectoderm and are intimately associated with neural processes, synapses, vasculature, and the pial-­glial membrane investing the CNS. Astrocytes in gray matter are called protoplasmic astrocytes, and in white matter are called fibrous astrocytes. The somas vary in diameter from a few micrometers to 10 or more micrometers. Astrocytes are arrayed in nonoverlapping 3D polyhedral domains of 100–200 μm across (up to 400 μm in hominids). Structurally, astrocytic processes interdigitate, forming a syncytium to protect synapses (as close as 1 μm to these structures). Astrocytic endfeet associate with vascular endothelial cells

and associated smooth muscle cells. Astrocytic processes invest the entire pial membrane from the inside. Physiologically, astrocytic processes affect ion balance (sequester K+), transport water via aquaporin 4 channels, uptake and recycle glutamate and gamma-aminobutyric acid (GABA), provide metabolic support to neurons, and can become reactive after CNS injury and lay down glial scar tissue. Astrocytes also can release growth factors and bioactive molecules (termed gliotransmitters) such as glutamate, ATP, and adenosine. In development, specialized astrocytes, called radial glia, provide a scaffold for orderly neural migrations in the CNS. Astrocytes are able to transfer mitochondria to neurons damaged by a stroke.

13

Neurons and Their Properties “Resting” Microglia Microglial processes constantly sample local environment

Microglial processes make frequent contact (~once per hour) with synapses and sense synaptic activity

Neuron (not to scale)

Response to injury or pathogens Cell injury, apoptosis

Pathogens

DAMPs

PAMPs (bacterial LPS, viral RNA, etc.)

ATP from damaged cells

Ion flux

Toll-like receptors (TLRs) NF-B, MAPK

NOD-like receptors (NLRs) Caspase-1 Pro-IL-1β Pro-IL-18

Nucleus

IL-1β IL-18

Synapse remodeling and removal (”synaptic stripping”) plays a role in synaptic plasticity

K+

Purinergic receptorregulated channels ACTIVATION

Activated Microglia

Ameboid shape Processes fewer, shorter, thicker Release signaling molecules

Interleukins, cytokines

Interaction with T cells may determine microglia phenotype (M1, M2)

T cell Antigen presentation Phagocytosis of pathogens and cellular debris

1.10 MICROGLIAL BIOLOGY Microglial cells are mesenchymal cells derived from yolk sac that come to reside in the CNS. They are a unique resident population with the capacity for self-­renewal. Microglia provide constant surveillance of the local microenvironment, with processes moving back and forth up to 1.5 μm/min. Microglial processes can grow and shrink up to 2–­3 μm/min. They have a territory 15–30 μm wide, with little overlap with each other. Resting microglia have soma of 5–­6 μm diameter, and activated micro­ glia are ameboid in appearance, with soma of approximately 10 μm diameter. Microglia can carry out phagocytosis of debris and apoptotic cells, remodel and remove synapses in developing and adult CNS, and respond to injury or pathogens. Microglia have receptors

Release of: - Reactive oxygen species (•O2–) - Reactive nitrogen species (NO) - Proinflammatory cytokines (IL-1, IL-6, TNF-) - Matrix metalloproteinases - Neurotrophic factors (NGF, TGF-, neurotrophin-4/5, GDNF, FGF)

 

for multiple types of stimuli, such as ATP (indicator of local damage), toll-­like receptors (TLRs) that respond to molecules released from dying cells (DAMPS: damage-­associated molecular patterns) or pathogens (PAMPS: pathogen associated molecular patterns) such as LPS on gram-­negative bacteria, or double-­ stranded RNA in viruses. Reactive microglia produce reactive oxygen species (ROS), reactive nitrogen species (RNS, such as NO), proinflammatory cytokines (IL-­1β , IL-­6, TNF-­α), matrix metalloproteinases (MMPs), and neurotrophic factors (such as NGF, TGF-β, neurotrophin 4/5, GDNF, FGF). Such signal molecules from activated microglia can affect neurons and astrocytes, inducing dysfunction. Recent evidence suggests that peripheral macrophages can transfer mitochondria to assist primary sensory neurons in inflamed tissue.

14

Overview of the Nervous System Oligodendrocyte Maturation Functional activity in neurons triggers myelination by oligodendrocyte precursor cells (OPCs) “Myelinate me” signals may include ATP, K+, glutamate, GABA, cell adhesion molecules

NG2+ OPC

Oligodendrocyte Physiology Adjacent segments of axons are myelinated by different oligodendrocytes

An individual oligodendrocyte myelinates an average of 30 axons

Myelin Sheath Monocarboxylate Transporter 1 (MCT1) delivers lactate, pyruvate, ketone bodies from oligodendrocyte to axons through the myelin sheath Node of Ranvier

Na+ channels Mitochondria Fused layers of oligodendrocyte Minute masses of cytoplasm cell membrane wrapped around trapped between fused axon of central nervous system layers of cytoplasm

1.11 OLIGODENDROCYTE BIOLOGY Oligodendrocytes are neuroectodermally derived glial cells that have the major role of myelinating central axons. The trigger for myelination may include associated axonal size and signal molecules (such as ATP, K+, glutamate, GABA, and some cell adhesion molecules). Each oligodendrocyte can myelinate individual intermodal segments of an average of 30 separate axons (as high as 60 axons); adjacent internodal segments are myelinated by different oligodendrocytes. This pattern of central myelination leaves periodic nodes of Ranvier bare, with sodium channels, at which action potentials (APs)

 

are reinitiated as they travel down the myelinated axon and its branches (called saltatory conduction). Oligodendrocytes can be attacked by antibodies directed at specific oligodendrocyte proteins in multiple sclerosis, leading to oligodendrocyte death and axonal dysfunction. Oligodendrocyte precursor cells can replicate following such insults and remyelinate the denuded central axon segments. Oligodendrocyte membranes possess monocarboxylate transporter 1 (MCT 1), which can deliver lactate, pyruvate, and ketone bodies to the axon. Oligodendrocyte precursor cells (OPCs) are present in the adult CNS and have NG2 and PDGFα receptors.

15

Neurons and Their Properties I. Growth (e.g., neuronal differentiation, axonal outgrowth)

Neuron

Growth factors

Target tissue

Axonal outgrowth

II. Autocrine and paracrine signaling between and among neurons

Neuron

Autocrine signaling

Paracrine signaling

Signaling inhibits apoptosis, promotes neuron survival, maintains synapses

III. Reciprocal signaling (e.g., neuromuscular junction) Maintenance of neuron (e.g., GDNF)

Neuron

Muscle Maintenance of muscle (e.g., agrin)

Growth Factor

Source

Receptor

Critical for:

NGF

Skin, hippocampus?

TrkA, p75

BDNF

Many sites

TrkB, p75

NT3

Golgi tendon organs and muscle spindles Multiple sites Muscle Muscle? Muscle Muscle

TrkC, p75

Cutaneous nociceptive neurons (small DRG neurons) Sympathetic neurons Basal forebrain cholinergic neurons (not the only factor required) Synaptic plasticity In periphery, BDNF KO mice show loss of vestibular ganglion neurons Loss of proprioceptive sensory neurons in DRG No gamma motorneurons; mice die at birth No robust phenotype Partial loss of muscles KO of CNTFR partial loss of muscles, but CNTF KO no loss due to LIF working Partial loss of muscles Embryonic lethal (required for angiogenesis)

NT4 GDNF CNTF IGF-1 VEGF

TrkB, p75 Grf1, Ret CNTFR, gp130 IGFR-1, IGFR-2 Flk-1, Flt-1, Flt-4

NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; NT3 and NT4, neurotrophic 3 and 4; GDNF, glial cell line–derived neurotrophic factor; CNTF, ciliary neurotrophic factor; IGF-1, insulin-like growth factor 1; VEGF, vascular endothelial growth factor; Trk, tyrosine kinase; KO, knock out; LIF, leukemia inhibitory factor

1.12 NEURONAL GROWTH FACTORS AND TROPHIC FACTORS Neuronal growth factors and trophic factors are signal molecules produced by neurons, glia, and target tissues that can influence neuronal differentiation, growth of neurites, establishment of contacts for signaling, maintenance of neural contacts with their

 

central or peripheral targets, and other functions. These factors act through specific receptors and can induce the production of specific molecules, such as agrin for the maintenance of nicotinic cholinergic receptors at the neuromuscular junction. Several identified growth factors, along with their sourced receptors and possible roles, are provided in the table above.

16

Overview of the Nervous System Superior horn of lateral ventricle

Subventricular zone (SVZ) of lateral ventricle

Inferior horn of lateral ventricle

Dentate gyrus of Subgranular zone (SGZ) hippocampus of dentate gyrus

I. Subventricular zone (SVZ) of lateral ventricle Radial glia-like Transient amplifying cells (B cells) cells (C cells) Asymmetric division

SVZ

Neuroblasts migrate into olfactory bulb

Neuroblasts

Olfactory memory Olfactory fear-conditioning Pheromone-linked behavior

Ependyma Ventricle

Olfactory bulb

II. Subgranular zone (SGZ) of dentate gyrus Type I radial glia-like cells

Hilus SGZ

Type II progenitor cells

Neuroblast

Asymmetric division

Immature Mature granule neuron cell neuron

Spatial and episodic memory Object recognition memory Emotional regulation

Granule cell layer Molecular layer

III. Oligodendrocyte progenitor cells (OPCs)

OPCs widely distributed throughout adult brain and spinal cord (~5% of all cells in CNS)

Myelin turnover Myelin repair NG2+ OPC

  1.13 STEM CELLS IN THE CNS: INTRINSIC AND EXTRINSIC MECHANISMS Embryogenesis involves the proliferation of stem cells, followed by differentiation and migration of the resultant cell types. In the CNS, neuronal stem cells, derived from the neural tube, persist in the subventricular (or subependymal) zone of the lateral ventricles (I). Waves of neuronal proliferation, differentiation, and migration occur during prenatal CNS development. After birth, stem cells in the subventricular zone continue to proliferate and

produce granule cells (neurons) for many brain regions; this process is driven by postnatal environmental stimuli. Throughout adulthood radial glial-­like cells, in the subgranular zone of the dentate gyrus, give rise to neuroblasts that contribute new granule cell neurons (II). In addition, oligodendroglial progenitor cells throughout the CNS can proliferate and then differentiate into mature oligodendrocytes (III). This process can occur after a demyelinating lesion and helps to remyelinate CNS axons (e.g., after a multiple sclerosis lesion).

17

Neurons and Their Properties

1. Induced pluripotent stem cells OSKM cocktail of transcription factors (Oct4, Sox2, Klf4, c-Myc) delivered by viral vectors, plasmids, mRNA, etc. Oct4

Sox2 Klf4

Additional transcription factors

c-Myc

Peripheral neurons Cortical neurons GABAergic neurons Glutamatergic neurons Dopaminergic neurons etc. Astrocytes

Differentiated somatic cells (e.g., skin fibroblasts)

2. Spinal cord injury

Induced pluripotent stem cells Neural stem cells (iPSCs) self-assemble into rosettes, mimicking neural tube formation in the CNS Traumatic injury

Acute Phase (1–14 days)

Descending upper motor neuron axon

3. Transplant of exogenous stem cells

Human embryo

Oct4 Sox2 Klf4 c-Myc

Human induced pluripotent stem cells (hiPSC)

Glial scar formation by activated astrocytes Inhibition of axonal regeneration by chondroitin sulfate proteoglycans and myelin-associated proteins

Transplant during subacute phase (7–14 days)

Human embryonic stem cells (hESC)

Skin Bone marrow Umbilical cord blood

Chronic Phase (>14 days)

Severed axons Distal segments degenerate Vascular changes Ischemia Edema Lipid peroxidation Inflammation Inflammatory cytokines Excitatory neurotransmitters Free radicals Loss of oligodendrocytes Demyelination

Ascending secondary sensory axon

Oligodendrocytes

Embryoid bodies

Neurospheres

(3D aggregates of stem cells)

(free floating clusters of neural stem cells)

Direct benefit: Differentiation of neurons, astrocytes, oligodendrocytes Indirect benefit: Trophic support Substrate for axonal growth Modulate inflammation

4. In situ modulation of endogenous spinal cord stem cells Two populations of endogenous stem cells:

Proliferation of ependymal stem cells Infusion of fibroblast growth factor-2 (FGF-2) with or without epidermal growth factor (EGF)

Ependymal cells Cells scattered around central canal throughout parenchyma

1.14 STEM CELL THERAPY Recent approaches to stem cell therapy after a spinal cord injury are depicted here. 1. Induced pluripotent stem cells can be generated from somatic cells (e.g., skin biopsy) and differentiated into neural lineage cells for therapy. 2. The pathologic process of spinal cord injury shows acute and chronic responses. 3. Use of exogenous

Enhanced oligodendrocyte differentiation and maturation in parenchyma

 

stem cells transplanted during the subacute phase leads to differentiation of neurons and glia, and trophic support and modulation of inflammation. 4. In situ modulation of endogenous stem cells uses infusion of growth factors. These approaches remain experimental but offer possible applications of knowledge derived from stem cell biology to treat devastating conditions such as spinal cord injury.

18

Overview of the Nervous System

Cell membrane

Basement membrane

Tight junction proteins

Cytoplasm

Red blood cell Astrocyte foot processes

Capillary lumen

Perivascular pericyte

Perivascular macrophage Tight junction

Capillary endothelial cell

Astrocyte

  1.15 BLOOD-­BRAIN BARRIER The blood-­brain barrier (BBB) is the cellular interface between the blood and the CNS. It serves to protect the brain from unwanted intrusion by many large molecules and potentially toxic substances and to maintain the interstitial fluid environment to ensure optimal functioning of the neurons and their associated glial cells. The major cellular basis for the BBB consists of the capillary endothelial cells, which have an elaborate network of tight junctions; these tight junctions restrict access by many large molecules, including many drugs, to the CNS. Endothelial cells in the CNS also exhibit a low level of pinocytotic activity across the cell, providing selected specific carrier systems for the transport of essential substrates of energy production and amino acid metabolism into the CNS. Astrocytic endfoot processes abut the endothelial cells and their basement membranes; these processes help to transfer important metabolites from the blood to neurons and can influence the expression of some specific gene products in the endothelial cells. These astrocytic processes also can remove excess K+ and some neurotransmitters from the interstitial fluid.

CLINICAL POINT The BBB, anatomically consisting mainly of the capillary tight junctions of the vascular endothelial cells, serves to protect the CNS from the intrusion of large molecules and potentially damaging agents from the peripheral circulation. The neurons need protection of their ionic and metabolic environment, which is aided by glial cells and the BBB. There are selected areas (windows on the brain) where the BBB is not present, such as the median eminence, the area postrema, the organum vasculosum of the lamina terminalis, and others, and where specialized cells can sample the peripheral circulation and can initiate corrective brain mechanisms to protect the neuronal environment. The presence of the BBB presents a challenge for pharmacotherapy aimed at the CNS; many antibiotics and other agents will not penetrate the BBB and must be coupled to a carrier molecule that does cross or must be injected intrathecally. In some pathological circumstances, such as the presence of a brain tumor, neuronal degeneration resulting from a neurodegenerative disease, the presence of a high concentration of a solute, or a stroke, the BBB is disrupted extensively, exposing the internal CNS milieu to molecules in the peripheral circulation. Therapeutic strategies now are being tested that will achieve transport of desired pharmacotherapeutic agents across the BBB and will protect the brain from unwanted disruption of the BBB in pathological circumstances.   

19

Neurons and Their Properties I. Response to intrinsic damage (acute stroke, trauma, bacterial infection, etc.) A. Rapid inflammatory response Tissue damage DAMPs

B. Delayed inflammatory response Cytokines, chemokines

Breakdown of blood-brain barrier

TLRs

PAMPs

C. Healing

ROS, RNS

Pathogens

Neuronal Activated microglia Ingestion of pathogens Recruitment of and cellular debris peripheral blood dysfunction elements (macrophages, neutrophils, T cells) and loss

Conversion of astrocytes from supportive role to scar formation

II. Response to extrinsic stimuli Inflammatory Mediators

Activation of local microglia Extrinsic inflammatory stimuli such as infection and chronic disease (e.g., CVD, arthritis) acting via: 1. Crossing blood-brain barrier 2. Action on endothelium to produce prostaglandins 3. Peripheral stimulation of the sensory part of the vagus n.

Cytokines, chemokines, PGE2, ROS, RNS

PGE2

Cytokines/chemokines: IL-1 TNF- CCL2 TGF- ROS (e.g., superoxide) RNS (e.g., NO) Prostaglandins (e.g., PGE2)

Neuronal dysfunction and loss

Recruitment of peripheral blood elements

III. Response to intrinsic proteinopathy or neurodegenerative process (e.g., Alzheimer’s disease) A plaque

Ingestion of amyloid- (A) and tau

Astrocyte reactivity and loss

Age-related “priming” of microglia

Activated microglia; little or no recruitment of peripheral blood elements

Cytokines, chemokines

Tau neurofibrillary tangles

Production of excess A and tau

1.16 INFLAMMATION IN THE CNS Inflammatory responses in the CNS occur under several different conditions. I. Inflammatory response to intrinsic damage such as stroke, trauma, or infection involves an acute inflammatory response, a delayed inflammatory response, and a healing phase. II. Response to extrinsic inflammatory stimuli such as infection and chronic disease usually involves a host

Slow, chronic inflammation with progressive synaptic dysfunction and loss of neurons

 

of inflammatory mediators crossing the blood-­brain barrier, triggering release of prostaglandins and central neuronal dysfunction and loss. III. Response to intrinsic proteinopathy or neurodegenerative processes such as aberrant amyloid-β plaque or tau neurofibrillary tangles in Alzheimer’s disease is a slow, chronic inflammatory response that leads to synaptic dysfunction and neuronal loss.

20

Overview of the Nervous System

I. Fast Anterograde Axonal Transport 100–400 mm/day in a saltatory fashion (start-stop-start) Cargo includes: - Synaptic vesicles and synaptic vesicle precursors - Mitochondria and other membrane organelles - Integral membrane proteins - Secretory polypeptides - Neurotransmitters - Elements of smooth endoplasmic reticulum

Vesicle

Kinesin

Membrane organelles

Nucleus

Microtubule

II. Fast Retrograde Axonal Transport 200–270 mm/day Cargo includes: - Endosomes - Damaged mitochondria and other organelles - Elements of smooth endoplasmic reticulum - Regulatory signals (growth factors and neurotrophins) - Viruses and toxins (e.g., tetanus, herpes simplex, rabies, polio)

Microtubule

Nucleus

Dynein

Damaged organelles

Endosome

III. Slow Axonal Transport (Anterograde Only) Different substances move at two different speeds: Slow component a (SCa) 0.2–2.5 mm/day (rate of neurite elongation) - Microtubules - Neurofilaments - Cytoskeletal proteins (e.g., - and -tubulin) Slow component b (SCb) 5.0–6.0 mm/day - Cytosolic proteins - Clathrin - Calmodulin - Soluble enzymes and other proteins

Neurofilaments move on their own or carried along microtubules

Short segments of microtubules carried by dynein

Nucleus

Pre-assembly of microtubule segments

 

1.17 AXONAL TRANSPORT IN THE CNS AND PNS Intracellular organelles and molecules are transported both away from the cell body down the axon (anterograde transport) and toward the cell body from the axon (retrograde transport). I. Fast anterograde transport moves vesicles, organelles, membrane proteins, neurotransmitter elements, and smooth endoplasmic reticulum components at a rate of 100–­400 mm/day in a stop-­start fashion, using kinesin as a transport mechanism. II. Fast retrograde transport returns endosomes, damaged organelles, growth factors and trophic factors, and some viruses and toxins at a rate of 200–­270 mm/day, using dynein as a transport mechanism.

Fast anterograde and retrograde transport mechanisms have been exploited in experimental neuroanatomical studies using labeled compounds (e.g., horseradish peroxide, fluorogold) for retrograde tract tracing and radiolabeled proteins for anterograde tract tracing. III. Slow anterograde transport carries microtubules, neurofilaments, and some cytoskeletal proteins at 0.2–2.5 mm/ day (slow component a) and other enzymes and proteins at 5.0–­6.0 mm/day (slow component b). This slow transport process is the rate-­limiting factor governing axonal recovery after injury or insult; recovery usually proceeds (if it occurs at all) at approximately 1 mm/day.

Neurons and Their Properties CENTRAL NERVOUS SYSTEM

21

PERIPHERAL NERVOUS SYSTEM

Sensory neuron cell body

Satellite cells

Pia mater

Oligodendrocyte

Schwann cells associated with myelin sheaths of myelinated axons

Capillary Astrocyte

Boutons of association neurons synapsing with preganglionic autonomic neuron of brainstem or spinal cord

Oligodendrocyte

Boutons of association neurons synapsing with somatic motor neurons of brain or spinal cord

Schwann cells associated with myelin sheaths of myelinated axons

Postganglionic neuron of sympathetic or parasympathetic ganglion

Satellite cells

Node of Ranvier

Axons terminating on motor end plates of striated (voluntary) muscle

  1.18 MYELINATION OF CNS AND PNS AXONS Central myelination of axons is provided by oligodendroglia. Each oligodendroglial cell can myelinate a single segment of several separate central axons. In the PNS, sensory, motor, and preganglionic autonomic axons are myelinated by Schwann cells. A Schwann cell myelinates only a single segment of one axon. Unmyelinated sensory and autonomic postganglionic autonomic axons are ensheathed by a Schwann cell, which provides a single enwrapping arm of cytoplasm around each of several such axons. The space between adjacent myelin segments of an axon is called a node of Ranvier; this site of axon membrane contains sodium channels and allows the reinitiation of action potentials in the course of propagation down the axon, a process called saltatory conduction.

CLINICAL POINT The integrity of the myelin sheath is essential for proper neuronal function in both the CNS and the PNS. Disruption of the myelin sheath around axons in either system results in the inability of the formerly myelinated axons to carry out their functional activities. In the CNS, the myelin sheath of central axons can be attacked in an autoimmune disease such as multiple sclerosis, resulting in a variety of symptoms, such as blindness, diplopia caused by discoordinated eye movements, loss of sensation, loss of coordination, paresis, and others. This condition may occur episodically, with intermittent remyelination occurring as the result of oligodendroglia proliferation and remyelination. In the PNS, a wide variety of insults, including exposure to toxins and the presence of diabetes or autoimmune Guillain-­ Barré syndrome, result in peripheral axonal demyelination, which is manifested mainly as sensory loss and paralysis or weakness. Remyelination also can occur around peripheral axons, initiated by the Schwann cells. Clinically, the status of axonal conduction is assessed by examining sensory evoked potentials in the CNS and by conduction velocity studies in the PNS.   

22

Overview of the Nervous System SHEATH AND SATELLITE CELL FORMATION

A. Two postganglionic autonomic neurons of a sympathetic or parasympathetic ganglion Endings of preganglionic autonomic neuron synapsing with cell bodies of postganglionic neurons

Axons ending on gland or smooth (involuntary) muscle or cardiac muscle cells

Satellite cells

Schwann sheath of Schwann cell surrounding unmyelinated axons of two neurons

B. Somatic or visceral sensory neuron of a spinal ganglion or sensory ganglion of cranial nerves V, VII, IX, or X 1. During development Neuron endings of central process within spinal cord or brainstem

2. Mature

Dividing satellite cell

Neuron cell body

Dividing Schwann cell

Neuron endings of peripheral process within an organ

Satellite cells Nodes Node

Schwann sheath surrounding a myelinated axon

C. Unmyelinated axons

Axon

Neurilemmal cell

Periaxonal space

of peripheral neurons

(sensory, somatic motor or visceral motor) being surrounded by cytoplasm of a neurilemmal (Schwann) cell

D. Myelinated axon of peripheral neuron (sensory, somatic motor or visceral motor) being surrounded by a wrapping of cell membrane of a neurilemmal (Schwann) cell

Axons

Axon

Neurilemmal cell

Axons

E. Myelinated axons of CNS neurons

being surrounded by a wrapping of cell membrane of an oligodendrocyte. Unmyelinated axons of CNS neurons are left unprotected.

Axon Oligodendrocyte

  1.19 DEVELOPMENT OF MYELINATION AND AXON ENSHEATHMENT Myelination requires a cooperative interaction between the neuron and its myelinating support cell. Unmyelinated peripheral axons are invested with a single layer of Schwann cell cytoplasm. When a peripheral axon at least 1 to 2 μm in diameter triggers myelination, a Schwann cell wraps many layers of tightly packed cell membrane around a single segment of that axon. In the CNS,

an oligodendroglia cell extends several arms of cytoplasm, which then wrap multiple layers of tightly packed membrane around a single segment of each of several axons (or occasionally two autonomic preganglionic axons). Although myelination is a process that occurs most intensely during development, Schwann cells may remyelinate peripheral axons following injury, and oligodendroglial cells may proliferate and remyelinate injured or demyelinated central axons in diseases such as multiple sclerosis.

Neurons and Their Properties

Extracellular fluid

+

Membrane

+

23

Axoplasm

– – –

Na

+ Diffu sio n +

– –

+ ATP

anspo

ADP

rt

ti Ac ve

tr

+

Na

Mitochondrion

ATPase

+ + K

D

n sio iffu

+

K

– – –

+ Diffusion

Cl

+

Cl

–

+ +

–

+

gNa1

Protein _ (anions)

–

Resistance

ENa 50

mV

EK 90 mV

gK100

ECl 70 mV

gCl50 to 150 +

RMP –70 mV

–

ELECTRICAL PROPERTIES 1.20 NEURONAL RESTING POTENTIAL Cations (+) and anions (–­) are distributed unevenly across the neuronal cell membrane because the membrane is differentially permeable to these ions. The uneven distribution depends on the forces of charge separation and diffusion. The permeability of the membrane to ions changes with depolarization (toward 0) or hyperpolarization (away from 0). The typical neuronal resting potential is approximately –­90 mV with respect to the extracellular fluid. The extracellular concentrations of Na+ and Cl–­ of 145

Equivalent circuit diagram; g is ion conductance across the membrane

 

and 105 mEq/L, respectively, are high compared to the intracellular concentrations of 15 and 8 mEq/L. The extracellular concentration of K+ of 3.5 mEq/L is low compared to the intracellular concentration of 130 mEq/L. The resting potential of neurons is close to the equilibrium potential for K+ (as if the membrane were permeable only to K+). Na+ is actively pumped out of the cell in exchange for inward pumping of K+ by the Na+-­K+-­ATPase membrane pump. Equivalent circuit diagrams for Na+, K+, and Cl−­, calculated using the Nernst equation, are illustrated in the lower diagram.

24

Overview of the Nervous System

A. The movement of ions across the cell membrane is dependent upon both concentration and electrostatic forces. Ions flow from high concentrations to lower concentrations as depicted by the flow of K+ ions from inside the cell, where the concentration is high, to outside the cell, where the concentrations is lower. Na+ Cl–

Cl–

Cl–

Na+

Na+

K+ ions flow from the extracellular environment, which is positive in relationship to the intracellular space, which is negative. Both concentration and electrostatic forces determine flow of ions. The equilibrium potential for the ion is the membrane potential at which a particular ion does not diffuse through the membrane in either direction. Na+

Na+

Cl– K+

Cl–

Na+

B. Ions are attracted to charges of the opposite polarity. In this example,

K+

Cl–

Extracellular

Na+ +

+

+

+

–

X– K

–

–

X– X–

K+

–

+

+

+

–

–

–

–

–

–

X–

X–

X–

K+

X–

+

X–

X–

K+

+

Electrical potential difference moves K+ into cell

Concentration gradient moves K+ out of cell

+

+

K+

K+

+

K

X–

Intracellular

Three states of the sodium channel. C. In the resting state, no ion flow occurs due to closure of the activation gate. D. When the membrane begins to depolarize, the activation channel opens and ion flow occurs. E. As the cell becomes depolarized, the inactivation gate closes and no further ion flow occurs. Only when the cell repolarizes does the sodium channel return to the resting state.

C. Resting (closed) Na+

+

+

–

–

–

Activation gate

D. Activated (open)

Na+

Na+

E. Inactivated (closed)

Na+

Na+

Na+

Na+

–

–

+

+

–

–

–

–

+

+

+

+

+

Depolarization

Inactivation gate

Na+

+

Na+

–

–

–

–

+

+

+

+

+

+

Na+ Na+

+

+

–

–

+

+

Inactivation gate closes Repolarization

 

1.21 NEURONAL MEMBRANE POTENTIAL AND SODIUM CHANNELS Illustrations of ion flow contributing to the neuronal resting potential and three states of the sodium channel in neuronal excitability.

Neurons and Their Properties

25

Chemical Synaptic Transmission Excitatory

A. Ion movements

Inhibitory Synaptic vesicles in synaptic bouton Presynaptic membrane

+ –

+ –

Na+ + –

K+

+ –

+ –

Transmitter substances

+ –

Synaptic cleft

Cl–

+ –

+ –

+ –

+ –

K+

Postsynaptic membrane At inhibitory synapse, transmitter substance released by an impulse increases permeability of postsynaptic membrane to K+ and Cl– but not Na+. K+ moves out of postsynaptic cell.

When impulse reaches excitatory synaptic bouton, it causes release of a transmitter substance into synaptic cleft. This increases permeability of postsynaptic membrane to Na+ and K+. More Na+ moves into postsynaptic cell than K+ moves out, due to greater electrochemical gradient.

Synaptic bouton

+ –

+ –

– +

+ –

Resultant net ionic current flow is in a direction that tends to depolarize postsynaptic cell. If depolarization reaches firing threshold at the axon hillock, an impulse is generated in postsynaptic cell.

+ –

+ –

+ –

+ –

Potential (mV)

Potential (mV)

–70

–70

0

8 12 16 msec Current flow and potential change

+ –

Resultant ionic current flow is in a direction that tends to hyperpolarize postsynaptic cell. This makes depolarization by excitatory synapses more difficult—more depolarization is required to reach threshold.

B. EPSPs, IPSPs, and current flow

–65

+ –

0

4

msec 8

12

16

–75 Current flow Potential change

4

Current flow and potential change

  1.22 GRADED POTENTIALS IN NEURONS A, Ion movements. Excitatory and inhibitory neurotransmissions are processes by which released neurotransmitter, acting on postsynaptic membrane receptors, elicits a local or regional perturbation in the membrane potential: (1) toward 0 (depolarization, excitatory postsynaptic potential; EPSP) via an inward flow of Na+ caused by increased permeability of the membrane to positively charged ions; or (2) away from 0 (hyperpolarization, inhibitory postsynaptic potential; IPSP) via an inward flow of Cl−­ and a compensatory outward flow of K+ caused by increased membrane permeability to Cl–­. Following the action of neurotransmitters on

the postsynaptic membrane, the resultant EPSPs and IPSPs exert local influences that dissipate over time and distance but contribute to the overall excitability and ion distribution in the neuron. It is unusual for a single excitatory input to generate sufficient EPSPs to bring about depolarization of the initial segment of the axon above threshold so that an action potential is fired. However, the influence of multiple EPSPs, integrated over space and time, may sum to collectively reach threshold. IPSPs reduce the ability of EPSPs to bring the postsynaptic membrane to threshold. B, EPSPs, IPSPs, and current flow. EPSP-­and IPSP-­induced changes in postsynaptic current (red) and potential (blue).

26

Overview of the Nervous System A. Postsynaptic neuron at which several presynaptic afferent fibers terminate. Fibers colored in pink convey excitatory information across the synaptic cleft to the postsynaptic neuron, whereas the inhibitory fiber is blue and conveys inhibitory information to the postsynaptic neuron. Inhibitory fiber Excitatory fiber

Na+

Presynaptic neuron

Ca2+

Ca2+ Na+

Ca2+

Na+

Presynaptic GABAergic neuron Na+

Ca2+

GABA

Glutamate Na+ Cl–

Mg2+ Postsynaptic neuron

K+

Ca2+

Na+

NMDA receptor Na+

Ca2+

AMPA receptor Na+ EPSP

B. Excitatory fiber. At the excitatory synaptic cleft, glutamate is released. Glutamate passes across the cleft and acts as an agonist at the AMPA and NMDA ionotropic receptor. The excitatory neurotransmitters signal the AMPA channel to open, permitting the inflow of Na+. This results in depolarization in the membrane potential so that the difference in potential across the membrane is shifted toward the positive, i.e., depolarization. With depolarization, there is a release of Mg2+ from the NMDA receptor, permitting Na+ and Ca2+ ions to enter the postsynaptic neuron. An excitatory postsynaptic potential (EPSP) is generated.

=

Na+

Presynaptic GABAergic neuron Na+

Decreased GABA K+ Cl–

Mg2+ Postsynaptic neuron Na+

C. Inhibitory fiber. The inhibitory neurotransmitters, principally GABA, act on IPSP GABA receptors in the postsynaptic neuron membrane, permitting the entry of Cl– ions, shifting the membrane potential to a more negative potential, i.e., hyperpolarization. An inhibitory postsynaptic potential (IPSP) is generated. In normal synaptic transmission, there is a balance between excitatory and inhibitory neurotransmitters so that the summation of EPSP and IPSP maintains the polarization of the membrane at a level below the threshold at which bursts of firing occur, termed the resting potential. +

Ca2+

Na+

Ca2+

Na+

Summated potential

EPSP

Na+

Increased glutamate

K+

Cl–

Ca2+

Ca2+

GABAB receptor

Postsynaptic neuron

Na+

Presynaptic neuron

Ca2+

GABAA receptor

NMDA receptor Ca2+

AMPA receptor Na+ Summated potential

EPSP +

= IPSP

D. Increase in glutamate EPSP. With an increase in excitatory neurotransmitters, the postsynaptic neuron membrane becomes more positive, producing an increase in EPSP. The summation of the excitatory and inhibitory signals moves across the threshold value, and an action potential occurs.

 

1.23 MECHANISMS OF EXCITATORY POSTSYNAPTIC POTENTIALS AND INHIBITORY POSTSYNAPTIC POTENTIALS

GABAA receptor Postsynaptic neuron

GABAB receptor

K+

Cl– Summated potential

EPSP +

= IPSP

E. Decrease in IPSP. When there is a decrease in inhibitory neurotransmitters, the IPSP decrease and the postsynaptic neuron membrane becomes more positive. The summation of the excitatory and inhibitory signals moves across the threshold value and an action potential is fired.

Neurons and Their Properties

27

Membrane potential (mV)

20 Action potential

0

Na conductance

K conductance

70 msec 0

0.5

Extracellular fluid

Na

K

Cl 

 

Na

 

K

 

Cl 40

 

 Stimulus current

Stimulus current produces depolarization 

Stim.

Na

K

1.0

Membrane

 

 

 

 

 

 

Axoplasm

Na

Na

K

K

Cl   20   At firing level Na conductance greatly increases, giving rise to strong inward Na current, leads to explosive positive feedback with depolarization increasing Na conductance Cl



20

 

 

 

 

Cl  75 

Na  K  Cl

Cl  

K



 Cl 

Na

K conductance increases, causing repolarization; Na conductance returns to normal

K

K

  

 

Na 



 

75

 Na 

Cl

 









Equivalent circuit diagrams

 

1.24 ACTION POTENTIALS Action potentials (APs) are all-­or-­nothing, nondecremental, electrical potentials that allow an electrical signal to travel for very long distances (a meter or more) and trigger neurotransmitter release through electrochemical coupling (excitation-­ secretion coupling). APs are usually initiated at the initial segment of axons when temporal and spatial summation of EPSPs cause sufficient excitation (depolarization) to open Na+ channels, allowing the membrane to reach threshold. Threshold is the point at which Na+ influx through these Na+ channels

cannot be countered by efflux of K+. When threshold is reached, an action potential is fired. As the axon rapidly depolarizes during the rising phase of the AP, the membrane increases its K+ conductance, which then allows efflux of K+ to counter the rapid depolarization and bring the membrane potential back toward its resting level. Once the action potential has been initiated, it rapidly propagates down the axon by reinitiating itself at each node of Ranvier (myelinated axon) or adjacent patch of membrane (unmyelinated axon) by locally bringing that next zone of axon membrane to threshold.

28

Overview of the Nervous System

Intracellular potential –60 mV Repolarizing (K+) current

Extracellular potential +1 mV

Depolarizing (Na+) current

Membrane Axoplasm

Refractory Impulse

1

Membrane Extracellular potential –5 mV

Intracellular potential +20 mV

Refractory

2

Impulse

Extracellular potential +1 mV

Intracellular potential –75 mV

Refractory

3

Impulse

+20 0-

Intracellular potential (mV) –70 -

Extracellular potential (mV)

Resting potential 1 2

3

+1 0 --

–5 -

1.0 msec

  1.25 PROPAGATION OF THE ACTION POTENTIAL When an AP is initiated at a specific site of the axonal membrane (usually the initial segment), the inward flow of Na+ alters the extracellular ion environment, causing a local flow of charge from adjacent regions of the axon. This induces a depolarized state in the adjacent node of Ranvier (myelinated axon) or patch of axonal membrane (unmyelinated axon), bringing that region to threshold and resulting in the reinitiation of the action potential. The presence of myelination along axonal segments results in the reinitiation of the action potential at the next node, thus hastening the velocity of conduction of the AP. The resultant appearance of the AP skipping from node to node down the axon is called saltatory conduction.

CLINICAL POINT An action potential is an explosive reversal of the neuronal membrane potential that takes place because of an increase in Na+ conductance induced by depolarization, usually due to the cumulative effects of graded potentials from incoming neurotransmitters; this explosive reversal is followed later by an increase in K+ conductance, restoring the membrane back toward the resting potential. This process normally takes place at the initial segment of an axon. The conduction of an AP down a myelinated axon, saltatory conduction, requires the reinitiation of the AP at each bare patch of axonal membrane, a node of Ranvier. The reinitiation of the AP occurs because of a voltage change at the next node brought about by passive current flow from the AP at its present site. If several nodes distal to the site of AP propagation are blocked with a local anesthetic, preventing Na+ conductance, then the AP will die, or cease, because the closest fully functional, nonblocked node is too far from the point of AP propagation to reach threshold by means of passive current flow. This mechanism of blocking reinitiation of the action potential at nodes of Ranvier underlies the use of the -­caine derivatives, as in novocaine and xylocaine, for local anesthesia during surgical and dental procedures.   

Neurons and Their Properties

29

A. Anatomic organization of myelinated nerve fibers and its subdivisions Node of Ranvier

Neuron

Internode

Juxtaparanode

Paranode

Node

Myelin

Paranode

Juxtaparanode

Internode

Gliomedin TAG-1 NF-155

CASPR-2 K+ voltage-gated channels

NF-186

Contactin-1 CASPR-1

Na+ voltage-gated channels

K+ voltage-gated channels

GM1 ganglioside Myelin

B. Myelinated fibers

Site where action potential is reinitiated













Impulse 









 Axolemma

























Node of Ranvier Myelin sheath     





































































































































C. Unmyelinated fibers

Axoplasm











 

1.26 NODE OF RANVIER AND CONDUCTION VELOCITY A, Intra-axonal and membrane components of an axon associated with Na+ and K+ ion channels. B, The speed of propagation increases with larger axonal diameter and in the presence of a

myelin sheath. In myelinated axons the AP is propagated from node to node by saltatory conduction. C, The AP travels down the unmyelinated axon by depolarizing adjacent patches of membrane, leading to reinitiation of the action potential.

30

Overview of the Nervous System

120

Myelinated fibers Efferent

110 100

Alpha motor neuron axons to extrafusal striated (somatic) muscle fibers (motor end plates)

Afferent

Conduction velocity (meters/sec)

90 80 70 60 50 40 30

Gamma motor neuron axons to intrafusal fibers of spindles in striated muscle

Group I (A fibers): Ia from primary muscle spindle endings: proprioception; lb from Golgi tendon organs: proprioception

Autonomic preganglionic (group B) fibers Group II (A fibers) from secondary endings of muscle spindles: proprioception; from specialized receptors in skin and deep tissues: touch, pressure

Autonomic postganglionic (group C) fibers

Group III (A fibers) from free and from some specialized endings in muscle and joints: pain; from skin: sharp pain, heat, cold, and some touch and pressure; also many visceral afferents

20 10

Unmyelinated fibers Group IV (C fibers) from skin and muscle: slow burning pain; also visceral pain 5

10

15

20

Fiber diameter (µm)

 

1.27 CLASSIFICATION OF PERIPHERAL NERVE FIBERS BY SIZE AND CONDUCTION VELOCITY Unmyelinated peripheral nerve fibers (1 to 2 μm in diameter) conduct APs slowly (1 to 2 m/sec) because propagation requires reinitiation of the AP at each adjacent patch of axonal membrane along the entire course of the axon. These peripheral fibers are called group IV fibers. Myelinated peripheral nerve fibers (2 to 20+ μm in diameter) conduct APs rapidly (2 to 120+ m/sec) because propagation is aided by the distant spacing of nodes of Ranvier resulting from the successive internodal myelin sheaths. The larger diameter axons conduct APs the most rapidly. Clinical conduction-­velocity studies can document the conduction velocity of successive classes of myelinated peripheral nerve fibers (group I, II, and III fibers), and they provide evidence of normal or altered nerve conduction and possibly function. Conduction velocity is measured by placing a stimulating electrode at a specific site (in the popliteal fossa) where a current can initiate APs in axons in a specific nerve. Recording electrodes are placed at

a distant site, where muscle contractions can be measured and where the time delay of conduction of APs in axons can be measured. The classification system of myelinated nerve fibers in the figure is accompanied by descriptions of the functional types of axons included in each group. CLINICAL POINT Peripheral axons larger than approximately 2 μm in diameter trigger the process of myelination by adjacent Schwann cells. Peripheral axons of different sizes subserve different functions and are subject to damage by a variety of separate insults. Thus, small-­fiber neuropathies, such as leprosy, damage pain and temperature sensation (via small-­diameter axons) and can affect these modalities without concomitant damage to discriminative touch, LMN function, or Ia afferent reflex activity. In contrast, damage to large-­diameter axons, as seen in demyelinating neuropathies, can result in flaccid paralysis with loss of tone and reflexes (motor axons) and loss of fine, discriminative sensation (sensory axons) without loss of autonomic functions or loss of pain and temperature sensation, which are carried in part by small unmyelinated axons.   

Neurons and Their Properties

31

Electrodiagnostic Studies in Compression Neuropathy Electromyography (EMG)

Bipolar recording needle

Nerve impulse (action potential)

EMG of dorsal interosseous muscle (ulnar innervation)

First dorsal interosseous muscle

Normal Action potential Needle insertion

Abnormal Fibrillation

EMG detects and records electric activity or potentials within muscle in various phases of voluntary contraction

Voltage

Time Increased threshold Normal threshold

Normal amplitude Decreased amplitude

Normal latency Increased latency

Conduction = Difference in elbow and wrist latency velocity Distance between electrodes Increased threshold for Stimulation depolarization, increased at wrist latency, and decreased Motor conduction velocity suggest (recording compression neuropathy electrodes) Voltage

Distance

Fasciculation

Compression–induced denervation produces abnormal spontaneous potentials

Nerve conduction studies Stimulating electrode Stimulation at elbow

Denervation positive waves

Maximal contraction

Sensory (recording electrodes)

Nerve conduction studies evaluate ability of nerve to conduct electrically evoked action potentials. Sensory and motor conduction stimulated and recorded

 

1.28 ELECTROMYOGRAPHY AND CONDUCTION VELOCITY STUDIES Electromyography detects and records electrical activity within muscles in various phases of voluntary contraction. These studies are useful for diagnosing myopathies and axonal damage in

neuropathies. Nerve conduction velocity studies assess the ability of nerves (especially myelinated nerve fibers) to conduct electrically evoked APs in sensory and motor axons. Conduction velocity studies are particularly helpful in evaluating damage to myelinated axons.

32

Overview of the Nervous System

Presynaptic Inhibition I (Inhibitory fiber)

E (Excitatory fiber)

Postsynaptic Inhibition E (Excitatory fiber)

Motor neuron Motor neuron

I (Inhibitory fiber)

Axon

Axon

mV +20 mV

A. Only E fires 90 mV spike in E terminal

90 mV

A′. Only E fires

EPSP in motor neuron

–70 –60

EPSP in motor neuron

–60 –70

–70

B. Only I fires

Long-lasting partial depolarization in E terminal

B′. Only I fires –60 –70

Motor neuron hyperpolarized –70

No response in motor neuron

–80

–70

C. I fires before E Partial depolarization of E terminal reduces spike to 80 mV, thus releasing less transmitter substance

Smaller EPSP in motor neuron

+20 80 mV

–70 –60 –70

C′. I fires before E Depolarization of motor neuron less than if only E fires

–60 –70 –80

 

1.29 PRESYNAPTIC AND POSTSYNAPTIC INHIBITION Inhibitory synapses modulate neuronal excitability. Presynaptic inhibition (left) and postsynaptic inhibition (right) are shown in relation to a motor neuron. Postsynaptic inhibition causes local

hyperpolarization at the postsynaptic site. Presynaptic inhibition involves the depolarization of an excitatory axon terminal, which decreases the amount of Ca2+ influx that occurs with depolarization of that excitatory terminal, thus reducing the resultant EPSP at the postsynaptic site.

Neurons and Their Properties

Excitatory fibers

mV

Excitatory fibers

Axon

Axon Inhibitory fibers

A. Resting state: motor nerve cell shown with synaptic boutons of excitatory and inhibitory nerve fibers ending close to it

Excitatory fibers

mV

B. Partial depolarization: impulse from one excitatory fiber has

caused partial (below firing threshold) depolarization of motor neuron

Excitatory fibers

mV –70

–70

Axon

Axon Inhibitory fibers

Inhibitory fibers

C. Temporal excitatory summation: a series of impulses in one

excitatory fiber together produce a suprathreshold depolarization that triggers an action potential

Excitatory fibers

mV –70

–70

Inhibitory fibers

33

mV

D. Spatial excitatory summation: impulses in two excitatory fibers cause two synaptic depolarizations that together reach firing threshold, triggering an action potential

Excitatory fibers

–70

–70

Axon Inhibitory fibers

E. Spatial excitatory summation with inhibition: impulses from

two excitatory fibers reach motor neuron but impulses from inhibitory fiber prevent depolarization from reaching threshold

mV

Axon Inhibitory fibers

E. (continued): motor neuron now receives additional excitatory

impulses and reaches firing threshold despite a simultaneous inhibitory impulse; additional inhibitory impulses might still prevent firing

Axon(s) activated in each scenario

 

1.30 SPATIAL AND TEMPORAL SUMMATION A, In the resting state, the resting potential of the membrane reflects the balance of negative and positive charges and the diffusion of ion species. B, Neurons receive multiple excitatory and inhibitory inputs. Stimulation of a neuron by an excitatory neurotransmitter from an incoming nerve fiber results in partial depolarization of that neuron. C, Temporal summation occurs when a series of subthreshold EPSPs in one excitatory fiber produce an AP in the postsynaptic cell. This occurs because the EPSPs are

superimposed on each other temporally before the local region of membrane has completely returned to its resting state. D, Spatial summation occurs when subthreshold impulses from two or more synapses trigger an AP because of synergistic interactions. E, Both temporal and spatial summation can be modulated by simultaneous inhibitory input. Inhibitory and excitatory neurons use a wide variety of neurotransmitters, whose actions depend on the ion channels opened by the ligand-receptor interactions.

34

Overview of the Nervous System

Origin and Spread of Seizures A. Normal firing pattern of cortical neurons Thalamus –

–

E +

+

P

Recurrent inhibitory circuit

P

Cerebral cortex

+

+

I

Single stimulus

–

+

P

+

–

P

+

E

+ –

+

+

– Substantia nigra Corpus striatum

+

+ E

Action potentials (nonsynchronous)

Normal activation of cortical neurons (P) modulated by excitatory (E) and inhibitory (l) feedback circuits.

B. Epileptic firing pattern of cortical neurons

P

Depolarization field potential –

High frequency

Repetitive stimuli

–

–

Recurrent excitatory circuit

P

–

–

E

+

+

+

+

+

+

Depressed inhibition

P

Excitatory pathways between cerebral cortex and thalamus modulated by tonic midbrain inhibitory stimuli.

Cortex

+

+

+

P +

I + +

+

–

+ –

+

E –

Depolarization extracellular K+ –

P

+

– Increased excitation

P

+

Substantia nigra Corpus striatum

+ E

Thalamus

Burst firing action potentials (hypersynchronous)

Repetitive cortical activation potentiates excitatory transmission and depresses inhibitory transmission, creating self-perpetuating excitatory circuit (burst) and facilitating excitation (recruitment) of neighboring neurons.

Cortical bursts to corpus striatum and thalamus block inhibitory projections and create self-perpetuating feedback circuit.

 

1.31 NORMAL ELECTRICAL FIRING PATTERNS OF CORTICAL NEURONS AND THE ORIGIN AND SPREAD OF SEIZURES The collective electrical activity of the cerebral cortex can be monitored by electroencephalography (EEG). Normal cortical electrical activity reflects the summation of excitatory and inhibitory actions, which is modulated through feedback circuits.

Thalamic inputs to the cortex can drive electrical excitability; the midbrain can provide inhibitory control over this process. Repetitive cortical activation can dampen inhibition, enhance excitatory feedback circuits, and recruit repetitive excitatory circuitry in adjacent cortical neurons. These self-­perpetuating excitatory feedback circuits can initiate and spread seizure activity.

Neurons and Their Properties A.

35

B. Electrode placement and lead identification

Fp2

Fp1

F8

F7 A1

T3

F3

Fz

F4

C3

Cz C4

P3

Pz

P4

T5 O1

A2 T4

T6

O2

Odd numbers, left side Even numbers, right side z locations, midline

C. EEG in normal awake person, eyes closed Fp1–F3 F3–C3



Fp2–F4 F4–C4

 

E. Fp1–F7

F3–A1 F4–A2 C4–A2 P3–A1 P4–A2 O1–A1

C4–P4 P4–O2

D.

C3–A1

C3–P3 P3–O1

Normal sleep

O2–A2 Sleep spindles



Right temporal tumor

Fp1–F7

F7–T3

F7–T3

T3–T5

T3–T5

T5–O1

T5–O1

Fp2–F8

Fp2–F8

F8–T4

F8–T4

T4–T6

T4–T6

T6–O2

Epilepsy

F.

T6–O2 Right temporal  activity

Left temporal spikes

  1.32 ELECTROENCEPHALOGRAPHY EEG permits the recording of the collective electrical activity of the cerebral cortex as a summation of activity measured as a difference between two recording electrodes. Recording electrodes (leads) are placed on the scalp on at least 16 standard sites, and recordings of potential differences between key electrodes are obtained. The principal waveforms recorded in the EEG are alpha (9 to 10 Hz, occipital location, predominant activity in adults, awake in resting state with eyes closed), beta (20 to 25 Hz, frontal and precentral locations, prominent in wakefulness, seen in light sleep), delta (2 to 2.5 Hz, frontal and central location, not

prominent in wakefulness, generalized in deep sleep and coma or toxic states), and theta (5 to 6 Hz, central location, constant and not prominent when awake and active, sometimes generalized when drowsy). Electrode placement is shown in part B. Examples are provided of a normal EEG taken when the patient is awake with eyes closed (C) and when sleeping normally (D). Abnormal patterns of activity can be seen in the presence of tumors (E) and in seizures (F); for example, the spike-­and-­wave appearance in a generalized tonic-­clonic seizure (generalized fast repetitive spikes and generalized spikes and slow waves, respectively) and a 3 Hz spike-­and-­wave EEG in the case of an absence seizure.

36

Overview of the Nervous System Ictal discharge

Potential difference (mV)

Spike

Paroxysmal depolarization shift (PDS)

Spike-wave

Tonic phase

Clonic phase

0 -20 100 ms

-40 -60

1 sec

-80

A. Paroxysmal depolarization shift (PDS) is a cellular marker of epilepsy and consists of a large depolarization of a group of neurons with action potentials, as indicated by the vertical lines on the large depolarization. The PDS is followed by repolarization. The PDS and repolarization correspond to a spike and wave on the EEG. A seizure occurs when there is a massive depolarization of cells without intervening periods of repolarization. This would correspond to the tonic phase of the seizure. As inhibition increases during the seizure, there is a cycle of PDS followed by repolarization. This corresponds to the clonic phase of the seizure. Voltage-gated Carbamazepine calcium channel Gabapentin Ca2+ Lamotrigine Levetiracetam Oxcarbazepine Phenytoin Potassium Topiramate channel

Excitatory presynaptic neuron Ca2+

Voltage-gated sodium channel Na

Carbamazepine Oxcarbazepine Felbamate Lacosamide Lamotrigine Phenytoin Rufinamide Topiramate Zonisamide

+

Na+

K+

Ezogabine

Levetiracetam

K+ Glutamate release Felbamate Postsynaptic neuron

Topiramate

Na+

NMDA receptor Ca2+ Na+

AMPA receptor

B. Examples of molecular targets of antiepileptic drugs that reduce excitability. This may occur through blockage of calcium, sodium, and potassium channels or through reducing ion flow through NMDA and AMPA receptors. Levetiracetam binds to synaptic vesicles, which may lead to reduced neurotrasnmiter release. GABA

GABA Glia

GABA-T

Succinic semialdehyde

Valproate Vigabatrin Tiagabine

GABA-T Succinic semialdehyde

GABA transporter

GABA

Benzodiazepines Barbituates

Postsynaptic neuron

Inhibitory presynaptic neuron

GABAA receptor

Zn2+

Levetiracetam displaces zinc to increase inhibitory Cl– current

Cl–

C. Examples of molecular targets of antiepileptic drugs that enhance inhibition. Drugs may increase amount of GABA postsynaptically by blocking GABA uptake or increase intracellular GABA by reducing degradation of GABA. Enhancing chloride flow through the GABA receptor is a common mechanism of inhibitory drugs, such as barbiturates and benzodiazepines. Levetiracetam displaces zinc from the GABA receptor, which results in increased chloride currents.

 

1.33 TYPES OF ELECTRICAL DISCHARGES IN GENERALIZED SEIZURES AND SITES OF ACTION OF ANTISEIZURE MEDICATIONS

Illustrations of types of electrical discharges in generalized seizures and the sites of action for antiseizure medications that reduce excitability or that enhance inhibition.

Neurons and Their Properties

37

A. Visual Evoked Potential Alternating checkerboard pattern displayed

Amplitude

P1

N2

N1

Retina

Optic nerve

Optic chiasm

Latency

Primary visual cortex

Optic tract Lateral geniculate nucleus

B. Brainstem Auditory Evoked Potential I

Medial geniculate body

III VI

VII

VII VI

Lateral lemniscus Series of clicks or tones

II

V

Amplitude

Acoustic area of temporal lobe cortex

IV

Cochlear division of Cochlea vestibulocochlear nerve

Inferior colliculus

Latency

Nucleus of lateral lemniscus

V

Midbrain Dorsal cochlear nucleus

I III IV

Ventral cochlear nucleus

Medulla oblongata

II Superior olivary complex

 

1.34 VISUAL AND AUDITORY EVOKED POTENTIALS Electrophysiological recordings can be used to evaluate the intactness of specific sensory systems, including the visual system and the auditory system. A, Visual evoked potentials. The visual stimulus is often an alternating flashing checkerboard (2 Hz), with recording done over the primary visual cortex in the midline. The normal latencies for recordings are 70 msec for N1 (negative 1), 100 msec for P1 (positive 1), and 140 msec for N2 (negative 2). Damage to the retino-­geniculo-­calcarine pathway

may result in altered latencies and amplitudes. B, Brainstem auditory evoked responses or potentials (BAERs). The auditory stimulus is a series of clicks or tones, with recording done over the temporal lobe auditory cortex. Seven distinctive peak latencies occur: I. distal auditory nerve; II. proximal auditory nerve; III. cochlear nuclei; IV. superior olivary complex; V. nucleus of the lateral lemniscus; VI. inferior colliculus; and VII. medial geniculate nucleus. Altered latencies and amplitudes may indicate damage or disruption to the auditory pathway at specific sites.

38

Overview of the Nervous System A. Schematic of synaptic endings Numerous boutons (synaptic knobs) of presynaptic neurons terminating on a motor neuron and its dendrites Dendrite Neurofilaments Axon hillock Neurotubules Initial segment Axon Node

Axon (axoplasm) Axolemma

Myelin sheath Dendrites

B. Enlarged section of bouton

Mitochondria Glial process Synaptic vesicles Synaptic cleft

Presynaptic membrane (densely staining) Postsynaptic membrane (densely staining) Postsynaptic cell

C. Electron micrograph of axo-dendritic synapses.

D. Electron micrograph of axo-dendritic synapses and dendro-dendritic appositions.

 

NEUROTRANSMITTER AND SIGNALING PROPERTIES 1.35 SYNAPTIC MORPHOLOGY Synapses are specialized sites where neurons communicate with each other and with effector or target cells. A, A typical neuron that receives numerous synaptic contacts on its cell body and associated dendrites. The contacts are derived from both myelinated and unmyelinated axons. Incoming myelinated axons lose their myelin sheaths, exhibit extensive branching, and terminate as synaptic boutons (terminals) on the target (in this example, motor) neuron. B, An enlargement of an axosomatic terminal. Chemical neurotransmitters are packaged in synaptic vesicles. When an action potential invades the terminal region, depolarization triggers Ca2+ influx into the terminal, causing numerous synaptic vesicles to fuse with the presynaptic membrane, releasing their packets of neurotransmitter into the synaptic cleft. The neurotransmitter can bind to receptors on the postsynaptic membrane, resulting in graded excitatory or inhibitory postsynaptic potentials or in neuromodulatory effects on intracellular signaling systems in the target cell. There is sometimes a mismatch between the site of release of a neurotransmitter and the location of target neurons possessing receptors for the neurotransmitter (can be immediately adjacent or at a distance). Many nerve terminals can release multiple neurotransmitters; the process is regulated by gene activation and by the frequency and duration of axonal

activity. Some nerve terminals possess presynaptic receptors for their released neurotransmitters. Activation of these presynaptic receptors regulates neurotransmitter release. Some nerve terminals also possess high-­affinity uptake carriers for transport of the neurotransmitters (e.g., dopamine, norepinephrine, serotonin) back into the nerve terminal for repackaging and reuse.

CLINICAL POINT Synaptic endings, particularly axodendritic and axosomatic endings, terminate abundantly on some neuronal cell types such as LMNs. The distribution of synapses, based on a hierarchy of descending pathways and interneurons, orchestrates the excitability of the target neuron. If one of the major sources of input is disrupted (such as the corticospinal tract in an internal capsule lesion, which may occur in an ischemic stroke) or if damage has occurred to the collective descending UMN pathways (as in a spinal cord injury), the remaining potential sources of input can sprout and occupy regional sites left bare because of the degeneration of the normal complement of synapses. As a result, primary sensory inputs from Ia afferents and other sensory influences, via interneurons, can take on a predominant influence over the excitability of the target motor neurons, leading to a hyperexcitable state. This may account in part for the hypertonic state and hyperreflexic responses to stimulation of primary muscle spindle afferents (muscle stretch reflex) and of flexor reflex afferents (nociceptive stimulation). Recent studies indicate that synaptic growth, plasticity, and remodeling can continue into adulthood and even into old age.   

CENTRAL NERVOUS SYSTEM NEUROTRANSMITTERS, RECEPTORS, AND DRUG TARGETS Voltage-gated ion channels

“IONOTROPIC” RECEPTORS

Ion Pore

4 subunits

Voltage-gated K+ channel (extracellular view)

Ligand-gated ion channels

“IONOTROPIC” RECEPTORS

Ion 5 subunits (1 removed to show pore)

Ligand

GABA receptor

“METABOTROPIC” RECEPTORS Ligand

G protein–coupled receptors Receptor tyrosine kinases Others

G proteins, enzymes (e.g., tyrosine kinases) Muscarinic cholinergic receptor

Second messenger pathways

Select CNS Neurotransmitters and Neuromodulators Acetylcholine Adenosine AMP, ADP, ATP Anandamide Aspartate Bombesin Bradykinin Calcitonin gene–related peptide (CGRP) Cholecystokinin Cytokines

Dopamine Eicosanoids Endothelins Epinephrine FMRF-amide-related peptides GABA Galanin Gastrin Glutamate Glutamine

  1.36 MECHANISMS OF MOLECULAR SIGNALING IN NEURONS Types of molecular signaling in neurons are shown, including ionotropic receptors (both voltage-­gated ion channels and ligand-­ gated channels) and metabotropic receptors.

Glycine Histamine Neuropeptide Y Neurosteroids Neurotensin NO (nitric oxide) Norepinephrine Opioid peptides (endorphins, enkephalins, dynorphins)

Oxytocin Somatostatin Substance P (tachykinins) Taurine Vasoactive intestinal polypeptide (VIP) Vasopressin

Membrane potential difference (mV)

A. Action potential 40 30 20 10 0 –10 –20 –30 –40 –50 –60 –70

B. Ligand-gated channels

Ligand-gated Na+ channel

Ca2+ Na+

Action potential

K+ Ca2+

Na+

Na+ conductance

SNARE complex

K+

K+ conductance

Na+

Ca2+

Ca2+

C. Metabotropic receptors

Na+ Excitatory neurotransmitter

Presynaptic autoreceptor Ca2+

Na+

Postsynaptic receptor (e.g., NE receptor)

K+ Ca2+

Na+

Excitatory neurotransmitter (e.g., NE)

K+ Ca2+

Cellular response

Ca2+ High–affinity uptake carrier Uptake of circulating epinephrine

Reuptake of synaptic NE

Vasculature

  1.37 NEUROTRANSMITTER RELEASE A, Major ion conductances are triggered by an action potential (AP). B, Their effects on neurotransmitter (NT) release as related to ligand-­gated channels influencing postsynaptic excitability. NT is packaged in synaptic vesicles; these vesicles, in response to nerve terminal depolarization and Ca2+ influx, merge with the nerve terminal membrane through a mechanism involving the SNARE complex. Through this mechanism of docking proteins, membrane fusion, and NT exocytosis, multiple vesicles simultaneously release their NT content, called quantal release, allowing postsynaptic stimulation. SNARE proteins represent a large superfamily of soluble NSF (N-­ethylmaleimide-­sensitive factor) attachment protein receptors that are composed of four alpha helices that mediate vesicle fusion and exocytosis. C, Metabotropic receptors responding to nerve terminal depolarization with SNARE complex–­ mediated vesicle membrane fusion and exocytosis. Both postsynaptic and presynaptic receptors bind with NT (in this case norepinephrine, NE) and transduce the receptor-­ligand binding into intracellular signaling. The presynaptic receptor can modulate nerve terminal excitability and subsequent NT release. The postsynaptic receptor can modulate

postsynaptic excitability and the postsynaptic membrane responsiveness to other NTs. High-­affinity uptake carriers remove NE from the synaptic cleft back into the nerve terminal for repackaging into synaptic vesicles. This NE uptake carrier also can take up epinephrine (E) from the circulation. Uptaken E also is repackaged into the NE synaptic vesicles and is preferentially released on subsequent nerve terminal depolarization. This E substitute-­NT mechanism provides augmented receptor activation (especially beta receptor activation by E) during sympathetic responses. CLINICAL POINT Botulinum toxin (BOTOX) is a proteolytic enzyme that cleaves SNARE proteins in nerve terminals, preventing vesicle fusion with the nerve terminal membrane and release of NT. Hence, nerve APs do not result in NT release; for muscles targeted by cholinergic motor end plates, botulinum toxin results in muscle paralysis. Deliberate clinical use of this toxin can alleviate muscle spasm in spasmodic torticollis, dystonia, and other conditions of excess chronic muscle contraction. This toxin is also used cosmetically to reduce or eliminate the appearance of facial skin wrinkles through selective paralysis of facial muscles.   

Neurons and Their Properties Co-Localization and Release Norepinephrine Norepinephrine axon

Neuropeptide Y CNS PNS Motor axon

ACh

Glut

Neuromuscular junction

Non-Linearity of Release Action potential

B

Action potential

B

Action potential

B

Neurotransmitter DA NE (sympathetics) NE (locus coeruleus) SP Serotonin (5-HT) CRF GHRH ACh Met-enkephalin

Cotransmitters Glutamate, neurotensin, CCK or multiples + calbindin Neuropeptide Y, somatostatin Galanin CGRP (calcitonin gene-related peptide) Glutamate, GABA GABA DA, GABA VIP Oxytocin (in magnocellular neurons of hypothalamus)

Fiber Type Motor axon Medial habenula Arcuate nucleus Mossy fibers Dorsal horn neurons Striatal neurons

Colocalized neurotransmitters ACh at neuromuscular junction, glutamate in SC ACh, glutamate DA, GABA, many others GABA, glycine Met-enkephalin, GABA Met-enkephalin, GABA

41

A

A

A A A

A receptor

A

B receptor

A A A A A A B

A receptor

B receptor

A A A

B

A receptor

B B B B B

B receptor

Diminishing release at high frequency due to: 1. Depletion of vesicles 2. Depletion of extracellular Ca2+

Neurotransmitter–Receptor Mismatch Classic model

A receptor A The closest B receptor may be several neurons away

Mismatch

A receptor

B receptor

B

  1.38 MULTIPLE NEUROTRANSMITTER SYNTHESIS, RELEASE, AND SIGNALING FROM INDIVIDUAL NEURONS Many, perhaps most, nerve terminals co-­localize and release multiple neurotransmitters (NTs), each presumably packaged in its own synaptic vesicles. Major co-­localized NTs, sorted by transmitter and by fiber type, are presented in the table. Some authors have noted as many as seven or more NTs present in a single type of nerve terminal. It should be noted that some NTs are present in the presynaptic cytoplasm and are not released by quantal (vesicle-­based) release. Some NTs are packaged in vesicles in the cell body and transported by axonal transport (e.g., neuropeptides), while other NTs are synthesized and/or packaged locally in the nerve terminals (e.g., amino acids, monoamines).

NT release is usually nonlinear, with some NTs diminishing their quantal release at higher action potential (AP) frequencies, while other co-­localized NTs (especially some neuropeptides) are released only at much higher AP frequencies. A further phenomenon affecting the functional consequence of NT release is the frequent NT-­receptor mismatch. Some NTs are released into a synaptic cleft and immediately activate receptors on the postsynaptic site (e.g., ACh at the neuromuscular junction). However, some NTs, when released, have no local receptors with which to interact, except at distant sites. Hence, NT-­receptor activation in these circumstances may occur only during particularly robust or prolonged NT transmitter release.

42

Overview of the Nervous System

Presynaptic terminal

Group II/III mGluR

Glu BDNF Ca2+ Group I mGluR

TrkB

P

IP3

PLCγ1

P

AMPAR NMDAR

Gq

P Ca2+

P

Na+

Ca2+

P

P

Na+

Phosphorylation enhances AMPAR conductance P

ER

Ca2+ IP3R

Ca2+

Calmodulin

Recruitment and stabilization of AMPAR at synapse

Phosphorylation of CaMKII

 

1.39 NEURONAL SIGNAL TRANSDUCTION: LOCAL REGULATION OF SYNAPTIC STRENGTH AT AN EXCITATORY SYNAPSE Glutamate released at excitatory synapses can bind to several different classes of receptors including ligand regulated ion channels for sodium (α-­amino-­3-­hydroxy-­5-­methyl-­4-­isoxazolepropionic acid receptor; AMPAR) and calcium (N-­ methyl-­ D-­ aspartate receptor; NMDAR), as well as several types of G ­protein–coupled metabotropic glutamate receptors (mGluRs). Repeated firing at such synapses results in modulation of synaptic strength through several mechanisms, including increased levels of the second messenger Ca2+ via NMDAR, which enhances AMPAR action by activation of a calcium-­calmodulin kinase II (CaMKII)-dependent pathway, resulting in AMPAR phosphorylation and increased

AMPAR recruitment and stabilization. Group I mGluR are generally found on postsynaptic sites and can further increase synaptic strength by Gq-­mediated activation of phospholipase C gamma 1 (PLCy1), leading to production of inositol 1,4,5-­triphosphate (IP3) and release of calcium from endoplasmic reticulum (ER) stores by activation of the inositol 1,4,5-­triphosphate receptor (IP3R). In contrast, groups II and III mGluRs, which are typically present on presynaptic sites, lead to decreased release of glutamate via their G ­protein–coupled second messengers, resulting in feedback inhibition of the process. Other factors such as brain-­ derived neurotrophic factor (BDNF) can modulate glutamatergic signaling by activating tropomyosin receptor kinase B (TrkB), resulting in activation of PLCγ1- and IP3-­dependent calcium release from the ER.

Neurons and Their Properties

43

Presynaptic terminal

BDNF

Ca2+

Glu

Na+ DA AMPAR

NMDAR

TrkB

P

D1 receptor

Adenylyl cyclase

PLCγ1 Ca2+

Na+

cAMP

ATP

Propagation of signals from dendrite to nucleus P ER

P

Inactive PKA

P IP 3 cAMP Ca2+

IP3R Ras

MAPK

Calmodulin RSK

CaMKK

P

P

P P Transcription Factors: CREB c-Fos c-Jun NF-κB GR Others

Active PKA

CaMKIV MAPK

Active PKA

RSK P P

Other pathways

Nucleus

CREB

CBP TBP POL2

CRE

TRANSCRIPTION: Arc, Dynorphin, Homer, Fos, FosB, MKP-1, Narp, BDNF, nNOS, others

TATA

  1.40 NEURONAL SIGNAL TRANSDUCTION: REGULATION OF NUCLEAR SIGNALING In addition to short-­term modulation of individual synapses, increased excitatory neuron firing can lead to changes in gene expression through several mechanisms. In particular, increased calcium levels arising from NMDAR activation and BDNF binding to TrkB can activate calcium calmodulin kinase IV (CaMKIV), leading to phosphorylation and activation of the cAMP response element-­binding protein (CREB) transcription factor, which recruits critical transcriptional elements such as CREB-­binding protein (CBP), TATA-­binding protein (TBP), and RNA polymerase II (POL2) to genes with cAMP response elements (CRE), ultimately leading to transcription of factors

related to synaptic plasticity. CREB can also be phosphorylated by cAMP-­dependent activation of protein kinase A (PKA), providing a mechanism for modulation of gene transcription by G p­ rotein–coupled receptors such as dopamine 1–­like receptors (D1 receptor). Activation of growth factor receptors such as TrkB can also result in Ras-­dependent activation of the mitogen-activated protein kinase (MAPK) pathway, ultimately leading to phosphorylation of CREB by a MAPK/ribosomal s6 kinase (RSK) dimer. In addition to CREB, many other transcription factors can be activated to influence neuronal gene expression including c-­Fos, c-­Jun, nuclear factor kappa B (NF-­ κB), and steroid hormone receptors such as the glucocorticoid receptor (GR; see Fig. 1.41).

44

Overview of the Nervous System Hypothalamic-Pituitary Axis (HPA)

CHRONIC STRESS Hypothalamus CRH

Anterior pituitary ACTH OH O

Adrenal cortex

Hippocampus

Granule cell

HO

OH

O

Cortisol

NFκB hsp90

GR

Blocks inflammatory transcription factors (e.g., NF-κB) Dentate gyrus

Anti-inflammatory effects

Cytosol Transcription

Nucleus

GRE

Decreased neuron proliferation and differentiation; Increased apoptosis Decreased dendritic branching and spine density Loss of hippocampal-HPA regulation Loss of diurnal regulation of glucocorticoid release Possible link to anxiety, depression, and other disorders

  1.41 GLUCOCORTICOID REGULATION OF NEURONS AND APOPTOSIS Glucocorticoid production is controlled by the hypothalamic-­ pituitary-­adrenal (HPA) axis in which hypothalamic corticotropin-releasing hormone (CRH) stimulates cells in the anterior pituitary via the hypophyseal-­portal circulation to produce adrenocorticotropic hormone (ACTH). ACTH, in turn, stimulates the adrenal cortices to produce the glucocorticoid hormone cortisol. Cortisol interacts with glucocorticoid receptors (GR) in the cytoplasm of some neurons to effect dissociation from chaperone proteins such as heat shock protein (hsp) 90 and translocation to the nucleus, where the activated GR interacts with glucocorticoid response elements (GREs) to effect gene transcription. Cortisol acts on many body tissues to promote metabolic and antiinflammatory effects, in the latter case by blocking inflammatory transcription factors such as nuclear factor κB (NF-­κB). Under normal

conditions, the HPA axis is regulated by feedback at several levels, including regulation of CRH release via the hippocampus, resulting in normal diurnal regulation of systemic cortisol levels. In the hippocampus, low to moderate levels of cortisol provide optimal memory acquisition and consolidation by supporting synaptic plasticity. However, under conditions of chronic stress, sustained high levels of cortisol can negatively affect hippocampal neurons, particularly the granule cells of the dentate gyrus, resulting in decreased neurogenesis, decreased dendritic complexity, and cell death via apoptosis. Hippocampal cell loss and dysfunction can lead to loss of hippocampal control over cortisol release, resulting in loss of normal diurnal release patterns, which is seen in old age and in diseases such as Alzheimer’s. Such changes have also been linked to psychiatric disorders. Loss of diurnal cortisol rhythms also contributes to metabolic dysfunction and truncal obesity in the periphery.

Neurons and Their Properties

Amino acid synapse

Catecholamine synapse Glutamate

Presynaptic receptor

Serotonin synapse

Tyrosine TH L-Dopa ALAAD

Tryptophan TrH 5-OH-tryptophan

Presynaptic receptor

Dopamine

ALAAD 5-OH-tryptamine (serotonin)

DBH Returned to Krebs cycle

Norepinephrine

Into terminal Uptake

Metabolism

Metabolism

Astrocyte

Receptor

Metabolism Diffusion

High-affinity uptake carrier

High-affinity uptake carrier

Metabolism Diffusion

Receptor

Receptor

Returned to Krebs cycle

Peptide synapse

Peptide synthesized in cell body

Acetylcholine synapse

Acetyl CoA from glucose metabolism Choline ChAT Acetylcholine

Peptidases

Receptor

 

1.42  CHEMICAL NEUROTRANSMISSION

See next page.

Acetylcholinesterase rapidly hydrolyzes ACh Receptor

45

46

Overview of the Nervous System

1.42 CHEMICAL NEUROTRANSMISSION (CONTINUED) AMINO ACID SYNAPSE

Amino acids used by a neuron as neurotransmitters are compartmentalized for release as neurotransmitters in synaptic vesicles. The amino acid glutamate (depicted in this diagram) is the most abundant excitatory neurotransmitter in the CNS. Following release from synaptic vesicles, some glutamate binds to postsynaptic receptors. Released glutamate is inactivated by uptake into both pre-­and postsynaptic neurons, where the amino acid is incorporated into the Krebs cycle or reused for a variety of functions. Glutamate also is taken up and recycled in the CNS by astrocytes.  CATECHOLAMINE SYNAPSE

Catecholamines are synthesized from the dietary amino acid tyrosine, which is taken up competitively into the brain by a carrier system. Tyrosine is synthesized into L-­dopa by tyrosine hydroxylase (TH), the rate-­limiting synthetic enzyme. Additional conversion into dopamine takes place in the cytoplasm via aromatic L-­amino acid decarboxylase (ALAAD). Dopamine is taken up into synaptic vesicles and stored for subsequent release. In noradrenergic nerve terminals, dopamine beta-­hydroxylase (DBH) further hydroxylates dopamine into norepinephrine in the synaptic vesicles. In adrenergic nerve terminals, norepinephrine is methylated to epinephrine by phenolethanolamine N-­methyl transferase (PNMT). Following release, the catecholamine neurotransmitter binds to appropriate receptors (dopamine and alpha-­and beta-­ adrenergic receptors) on the postsynaptic membrane, altering postsynaptic excitability, second messenger activation, or both. Catecholamines also can act on presynaptic receptors, modulating the excitability of the presynaptic terminal and influencing subsequent neurotransmitter release. Catecholamines are inactivated by presynaptic reuptake (high-­affinity uptake carrier) and, to a lesser extent, by metabolism (monoamine oxidase deamination and catechol-­O-­methyltransferase) and diffusion.  SEROTONIN SYNAPSE

Serotonin is synthesized from the dietary amino acid tryptophan, taken up competitively into the brain by a carrier system. Tryptophan is synthesized to 5-­ hydroxytryptophan (5-­ OH-­ tryptophan) by tryptophan hydroxylase (TrH), the rate-­limiting synthetic enzyme. Conversion of 5-­ hydroxytryptophan to 5-­hydroxytryptamine (5-­HT, serotonin) takes place in the cytoplasm by means of ALAAD. Serotonin is stored in synaptic vesicles. Following release, serotonin can bind to receptors on the postsynaptic membrane, altering postsynaptic excitability, second messenger activation, or both. Serotonin also can act on presynaptic receptors (5-­HT receptors), modulating the excitability of the presynaptic terminal and influencing subsequent

neurotransmitter release. Serotonin is inactivated by presynaptic reuptake (high-­affinity uptake carrier) and to a lesser extent by metabolism and diffusion.  PEPTIDE SYNAPSES

Neuropeptides are synthesized from prohormones, large peptides synthesized in the cell body from mRNA. The larger precursor peptide is cleaved posttranslationally to active neuropeptides, which are packaged in synaptic vesicles and transported anterogradely by the process of axoplasmic transport. These vesicles are stored in the nerve terminals until released by appropriate excitation-­secretion coupling induced by an action potential. The neuropeptide binds to receptors on the postsynaptic membrane. In the CNS, there is often an anatomic mismatch between the localization of peptidergic nerve terminals and the localization of cells possessing membrane receptors responsive to that neuropeptide, suggesting that the amount of release and the extent of diffusion may be important factors in neuropeptide neurotransmission. Released neuropeptides are inactivated by peptidases.  ACETYLCHOLINE (CHOLINERGIC) SYNAPSE

Acetylcholine (ACh) is synthesized from dietary choline and acetyl coenzyme A (CoA), derived from the metabolism of glucose by the enzyme choline acetyltransferase (ChAT). ACh is stored in synaptic vesicles; following release, it binds to cholinergic receptors (nicotinic or muscarinic) on the postsynaptic membrane, influencing the excitability of the postsynaptic cell. Enzymatic hydrolysis (cleavage) by acetylcholine esterase rapidly inactivates ACh.

CLINICAL POINT Synthesis of catecholamines in the brain is rate limited by the availability of the precursor amino acid tyrosine; synthesis of serotonin, an indoleamine, is rate limited by the availability of the precursor amino acid tryptophan. Tyrosine and tryptophan compete with other amino acids—phenylalanine, leucine, isoleucine, and valine—for uptake into the brain through a common carrier mechanism. When a good protein source is available in the diet, tyrosine is present in abundance, and robust catecholamine synthesis occurs; when a diet lacks sufficient protein, tryptophan is competitively abundant compared with tyrosine, and serotonin synthesis is favored. This is one mechanism by which the composition of the diet can influence the synthesis of serotonin as opposed to catecholamine and influence mood and affective behavior. During critical periods of development, if low availability of tyrosine occurs because of protein malnourishment, central noradrenergic axons cannot exert their trophic influence on cortical neuronal development such as the visual cortex; stunted dendritic development occurs, and the binocular responsiveness of key cortical neurons is prevented. Thus, nutritional content and balance are important to both proper brain development and ongoing affective behavior.   

2

SKULL AND MENINGES

2.1 Interior View of the Base of the Adult Skull 2.2 F  oramina in the Base of the Adult Skull 2.3 B  ony Framework of the Head and Neck 2.4 S  chematic of the Meninges and Their Relationships to the Brain and Skull 2.5 Hematomas

47

48

Overview of the Nervous System

Frontal bone Sulcus of superior sagittal sinus Frontal crest Sulcus for anterior meningeal vessels Foramen cecum Internal surface of orbital part Ethmoid bone Crista galli Cribriform plate Sphenoid bone Lesser wing Anterior clinoid process Greater wing Sulcus for middle meningeal vessels (frontal branches) Body Jugum Prechiasmatic sulcus Tuberculum sellae Sella Hypophyseal fossa turcica Posterior clinoid process Dorsum sellae Groove for internal carotid artery Temporal bone Squamous part Petrous part Sulcus of lesser petrosal nerve Sulcus of greater petrosal nerve Cartilage of auditory tube Arcuate eminence Sulcus of superior petrosal sinus Sulcus of sigmoid sinus

Anterior cranial fossa

Middle cranial fossa

Posterior cranial fossa

Parietal bone Sulcus for middle meningeal vessels (parietal branches) Mastoid angle Occipital bone Basilar part Sulcus of inferior petrosal sinus Sulci for posterior meningeal vessels Condyle Sulcus of transverse sinus Sulcus of occipital sinus Internal occipital crest Internal occipital protuberance Sulcus of superior sagittal sinus

2.1 INTERIOR VIEW OF THE BASE OF THE ADULT SKULL The anterior, middle, and posterior cranial fossae house the anterior frontal lobe, temporal lobe, and cerebellum and brainstem, respectively. The fossae are separated from each other by bony structures

and dural membranes. A swelling of the brain or the presence of mass lesions can selectively exert pressure within an individual fossa. The perforated cribriform plate allows the olfactory nerves to penetrate into the olfactory bulb, a site where head trauma can result in the tearing of the penetrating olfactory nerve fibers.

49

Skull and Meninges

Foramen cecum

Vein to superior sagittal sinus

Anterior ethmoidal foramen

Anterior ethmoidal artery, vein and nerve

Foramina of cribriform plate

Olfactory nerve bundles

Posterior ethmoidal foramen

Posterior ethmoidal artery, vein and nerve

Optic canal

Optic (II) nerve Ophthalmic artery

Superior orbital fissure

Oculomotor (III) nerve Trochlear (IV) nerve Ophthalmic nerve Abducens (VI) nerve Superior ophthalmic vein

Foramen rotundum

Maxillary nerve

Foramen ovale

Mandibular nerve Accessory meningeal artery Lesser petrosal nerve (occasionally)

Foramen spinosum

Middle meningeal artery and vein Meningeal branch of mandibular nerve

Foramen of Vesalius (inconstant)

Small emissary vein

Foramen lacerum

Internal carotid artery Internal carotid nerve plexus

Hiatus of canal of Hiatus of canal of

Lesser petrosal nerve Greater petrosal nerve

Internal acoustic meatus

Facial (VII) nerve Vestibulocochlear (VIII) nerve Labyrinthine artery

Vestibular aqueduct

Endolymphatic duct

Mastoid foramen (inconstant)

Emissary vein Branch of occipital artery

Jugular foramen

Inferior petrosal sinus Glossopharyngeal (IX) nerve Vagus (X) nerve Accessory (XI) nerve Sigmoid sinus Posterior meningeal artery

Condylar canal (inconstant)

Emissary vein Meningeal branch of ascending pharyngeal artery

Hypoglossal canal

Hypoglossal (XII) nerve

Foramen magnum

Medulla oblongata Meninges Vertebral arteries Spinal roots of accessory nerves

2.2 FORAMINA IN THE BASE OF THE ADULT SKULL The foramina in the base of the skull allow major nerves and blood vessels to course through the skull. Pressure, traction, and masses can damage structures traversing these small spaces that snugly confine the structures.

 

CLINICAL POINT The foramina of the skull are narrow openings that allow the passage of nerves and blood vessels. Under normal circumstances, there is enough room for comfortable passage of these structures without traction or pressure. However, with the presence of a tumor at a foramen, the passing structures can be compressed or damaged. For example, a tumor at the internal acoustic meatus can result in ipsilateral facial and vestibuloacoustic nerve damage, and a tumor at the jugular foramen can result in damage to the glossopharyngeal, vagus, and spinal accessory nerves.   

50

Overview of the Nervous System

Temporal bone Sphenoid bone Temporal fossa Zygomatic arch Condylar process of mandible Mandibular notch Coronoid process of mandible Lateral pterygoid plate (broken line) Hamulus of medial pterygoid plate (broken line) Pterygomandibular raphe (broken line)

Mastoid process External acoustic meatus Mandible

Ramus Angle Body

Atlas (C1) Styloid process Axis (C2) Stylomandibular ligament

Stylohyoid ligament Hyoid bone Spine of sphenoid bone Foramen spinosum Foramen ovale

C3 vertebra

Body Lesser horn Greater horn

C7 vertebra

Epiglottis Thyroid cartilage Cricoid cartilage Trachea

T1 vertebra

1st rib

Sphenopalatine foramen Pterygopalatine fossa Choanae (posterior nares)

Tuberosity of maxilla Infratemporal fossa Alveolar process of maxilla

Lateral plate Medial plate of pterygoid process Hamulus Pyramidal process of palatine bone

2.3 BONY FRAMEWORK OF THE HEAD AND NECK The skull provides bony protection for the brain. The spine, consisting of vertebrae and their intervertebral disks, provides bony

 

protection for the spinal cord. The spine and skull articulate at the foramen magnum, where the C1 vertebral body (the atlas) abuts the occipital bone.

51

Skull and Meninges

Arachnoid granulation

Venous lacuna Skin Galea aponeurotica Epicranium Calvaria Dura mater (outer and inner layers) Subdural space (potential) Arachnoid Subarachnoid space Pia mater Cerebral hemisphere Superior sagittal sinus

Epidural space (potential)

Arachnoid granulation Arachnoid granulation indenting skull (foveola) Venous lacuna

Arachnoid

Dura mater (outer layer) Dura mater (inner layer)

Subarachnoid space

Inner layer of dura mater Falx cerebri

Inferior sagittal sinus

Pia mater

Middle meningeal artery and vein

 

2.4 SCHEMATIC OF THE MENINGES AND THEIR RELATIONSHIPS TO THE BRAIN AND SKULL The meninges provide protection and support for neural tissue in the central nervous system. The innermost membrane, the pia mater, adheres to every contour of neural tissue, including sulci, folia, and other infoldings. It adheres tightly to glial endfoot processes of astrocytes; this association is called the pial-­glial membrane. The arachnoid mater, a fine, lacy membrane external to the pia, extends across the neural sulci and foldings. The space between these two membranes is the subarachnoid space, a space into which the cerebrospinal fluid flows, providing buoyancy and protection for the brain. Arteries and veins run through the subarachnoid space to and from the central nervous system. The rupture of an arterial aneurysm in a cerebral artery results in a subarachnoid hemorrhage. The dura mater, usually adherent to the inner arachnoid, is a tough protective outer membrane. It splits into two layers in some locations to provide channels, the venous sinuses, for return flow of the venous blood. The arachnoid granulations, one-­ way valves, extend from the subarachnoid space into the venous sinuses, especially the superior sagittal sinus, allowing cerebrospinal fluid to

drain into the venous blood and return to the heart. Blockage of these arachnoid granulations (e.g., in acute purulent meningitis) can result in increased intracranial pressure. Cerebral arteries and veins traverse the subarachnoid space. The veins, called bridging veins, drain into the dural sinuses. As they enter the sinus, these bridging veins are subject to tearing in cases of head trauma. If there is atrophy in the brain, as occurs with age, these veins may tear with relatively minor head trauma; in younger adults, more severe head trauma is needed to tear these bridging veins. Such tearing permits venous blood to accumulate in the subdural space as it dissects the inner dura from the arachnoid. This process may be gradual (chronic subdural hematoma) in older individuals or may be abrupt (acute subdural hematoma) with severe head trauma. A sub-­dural hematoma, especially when it occurs acutely, may be life-­threatening as the result of increased intracranial pressure caused by accompanying edema and by the accumulation of the blood in the hematoma itself. The dura is closely adherent to the inner table of the skull. A skull fracture may tear a branch of the middle meningeal artery, permitting arterial blood to dissect the dura from the skull, resulting in an epidural hematoma.

52

Overview of the Nervous System

Temporal Fossa Hematoma Shift of normal midline structures

Skull fracture crossing middle meningeal artery

Compression of posterior cerebral artery

Shift of brainstem to opposite side may reverse lateralization of signs by tentorial pressure on contralateral pathways

Herniation of temporal lobe under tentorium cerebelli

Herniation of cerebellar tonsil Compression of oculomotor (III) nerve leading to ipsilateral pupil dilation and third cranial nerve palsy

Compression of corticospinal and associated pathways, resulting in contralateral hemiparesis, deep tendon hyperreflexia, and Babinski’s sign

Acute Subdural Hematoma Subfrontal Hematoma Frontal trauma: headache, poor cerebration, intermittent disorientation, anisocoria

Posterior Fossa Hematoma Occipital trauma and/or fracture: headache, meningismus, cerebellar and cranial nerve signs, Cushing’s triad Section showing acute subdural hematoma on right side and subdural hematoma associated with temporal lobe intracerebral hematoma (“burst” temporal lobe) on left

2.5 HEMATOMAS Epidural hematomas occur with trauma or skull fractures that tear meningeal arteries (especially middle meningeal artery branches). Blood from the tear dissects the outer layer of the dura from the skull, forming a space-­occupying mass in what was normally only a potential space. The hematoma may compress adjacent brain tissue, producing localized signs, and may also cause herniation of distant brain regions across the free edge of the tentorium cerebelli (a transtentorial herniation) or across the falx cerebri (a subfalcial herniation). Such herniation may produce changes in consciousness, breathing, and blood pressure, and altered motor, pupillary, and other neurological

 

signs. It may be fatal. Severe head trauma in an adult may tear bridging veins that lead from the brain through the subarachnoid space and into the dural sinuses, especially the superior sagittal sinus. The subsequent venous bleeding dissects the arachnoid membrane from the inner layer of the dura, and the blood accumulates as a subdural hematoma. The subdural space is normally only a potential space. Some of the proteins and other solutes in the hematoma attract edema, adding fluid accumulation to the hematoma and further exacerbating the space-­occupying nature of the bleed. A subdural hematoma also may be associated with bleeding directly into the brain, an intracerebral hematoma.

3

BRAIN

3.1 Surface Anatomy of the Forebrain: Lateral View 3.2 Lateral View of the Forebrain: Functional Regions 3.3 Lateral View of the Forebrain: Brodmann’s Areas 3.4 Anatomy of the Medial (Midsagittal) Surface of the Brain in Situ 3.5 Anatomy of the Medial (Midsagittal) Surface of the Brain, With Brainstem Removed 3.6 Medial Surface of the Brain 3.7 Anatomy of the Basal Surface of the Brain, With the Brainstem and Cerebellum Removed 3.8 Basal Surface of the Brain: Functional Areas and Brodmann’s Areas

3.11 Brain Imaging: Magnetic Resonance Imaging, Axial and Sagittal T2-­Weighted Images 3.12 Positron Emission Tomography Scanning 3.13 Horizontal Brain Sections Showing the Basal Ganglia 3.14 Major Limbic Forebrain Structures 3.15 Corpus Callosum 3.16 Color Imaging of the Corpus Callosum by Diffusion Tensor Imaging 3.17 Hippocampal Formation and Fornix 3.18 Thalamic Anatomy 3.19 Thalamic Nuclei

3.9 Brain Imaging: Computed Tomography Scans, Coronal and Sagittal 3.10 Brain Imaging: Magnetic Resonance Imaging, Axial and Sagittal T1-­Weighted Images

53

54

Overview of the Nervous System Central sulcus Precentral gyrus Precentral sulcus Frontal (F), frontoparietal (FP) and temporal (T) opercula

Superior (superomedial) margin of cerebrum Postcentral gyrus Postcentral sulcus Supramarginal gyrus Superior parietal lobule Intraparietal sulcus

Superior frontal gyrus

Inferior parietal lobule

Superior frontal sulcus

Angular gyrus Middle frontal gyrus

Parietooccipital sulcus Transverse occipital sulcus

Inferior frontal sulcus Inferior frontal gyrus

FP F

Calcarine fissure

T

Occipital pole

Frontal pole Anterior ramus Ascending ramus Posterior ramus Temporal pole Superior temporal gyrus Superior temporal sulcus Middle temporal gyrus Inferior temporal sulcus Parietal lobe

Lunate sulcus (inconstant) Inferior (inferolateral) margin of cerebrum

Lateral (sylvian) fissure

Preoccipital notch

Inferior temporal gyrus

Frontal lobe Occipital lobe

Central sulcus of insula Temporal lobe

Circular sulcus of insula Insula



3.1 SURFACE ANATOMY OF THE FOREBRAIN: LATERAL VIEW The convolutions of the cerebral cortex permit a large expanse of cortex to be compactly folded into a small volume, an adaptation particularly prominent in primates. Major dependable landmarks separate the forebrain into lobes; the lateral (sylvian) fissure separates the temporal lobe below from the parietal and frontal lobes above, and the central sulcus separates the parietal and frontal lobes from each other. Several of the named gyri are associated with specific functional activities, such as the precentral gyrus (motor cortex) and the postcentral gyrus (primary sensory cortex). Some gyri, such as the superior, middle, and inferior frontal and temporal gyri, serve as anatomical landmarks of the cerebral cortex. The insula, the fifth lobe of the cerebral cortex, is deep to the outer cortex and can be seen by opening the lateral fissure.

Short gyri Limen Long gyrus

CLINICAL POINT Some functional characteristics of the cerebral cortex, such as long-term memory and some cognitive capabilities, cannot be localized easily to a particular gyrus or region of cortex. However, other functional capabilities are regionally localized. For example, the inferior frontal gyrus on the left contains the neuronal machinery for expressive language capabilities; the occipital pole, particularly along the upper and lower banks of the calcarine fissure, is specialized for visual processing from the retino-­geniculo-­calcarine system. Some very discrete lesions in further processing sites such as vision-­related regions of the temporal lobe can result in specific deficits, such as agnosia for the recognition of faces or the inability to distinguish animate objects. This knowledge provides some clues about how feature extraction in sensory systems might be achieved in neuronal networks.   

Brain

Central sulcus

Supplemental motor cortex

Superior parietal lobule

Primary motor cortex Frontal eye fields

Premotor cortex

Primary somatosensory cortex Wernicke's

Primary trigeminal region of

Broca's area motor cortex

55

Secondary area somatosensory cortex somatosensory cortex Primary Auditory cortex

Multisensory association areas of cortex

Visual association areas of cortex

Primary visual cortex

Lateral fissure

 

3.2 LATERAL VIEW OF THE FOREBRAIN: FUNCTIONAL REGIONS Some circumscribed regions of the cerebral hemisphere are associated with specific functional activities, including the motor cortex, the supplemental and premotor cortices, the frontal eye fields, the primary sensory cortex, and other association regions of the sensory cortex. Part of the auditory cortex is visible at the inferior edge of the lateral fissure (the transverse temporal gyrus of H ­ eschl). Part of the visual cortex is visible at the occipital pole. Language areas of the left hemisphere include Broca’s area (expressive language) and Wernicke’s area (receptive language). Damage to these cortical regions results in loss of specific functional capabilities. There is some overlap between functional areas and named gyri (e.g., the motor cortex and the precentral gyrus), but there is no absolute concordance.

CLINICAL POINT Some specific regions (gyri) of the cerebral cortex, such as the precentral gyrus (primary motor cortex) and the postcentral gyrus (primary somatosensory cortex), demonstrate topographic organization. Thus, information from the contralateral hand and arm is localized laterally, the body is represented more medially, and the lower extremity is represented along the midline and over the edge into the paracentral lobule. The face and head are represented in far lateral regions of these gyri, just above the lateral fissure. This has important functional implications; damage to selected regions such as the midline territory, which is supplied with blood from the anterior cerebral artery, results in somatosensory loss and paresis in the contralateral lower extremity, while sparing the upper extremity.   

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Overview of the Nervous System Central sulcus

3,1,2

6

6

7

3,1,2

4

46 4 45

41 42 11 11

11

19

22

10

37 22

19

22

18 18

37 21

38

19

39

44

47

19

40

40

3,1,2

7

39

40

9

10

7

5

6

8

9

10

5

4

8 9

4

6

37

21

19

18

17

37 20

38 20

Lateral fissure

Central sulcus

Parietal lobe

Frontal lobe

Occipital lobe

Lateral fissure Temporal lobe Pons

Lateral cerebellar hemisphere

Medulla

  3.3 LATERAL VIEW OF THE FOREBRAIN: BRODMANN’S AREAS Brodmann’s areas of the cerebral cortex have unique architectural characteristics in terms of the thickness and layering of the cerebral cortex; this knowledge is based on histological observations originally made by Korbinian Brodmann in 1909. His numbering of cortical areas is still used as a shorthand for describing the functional

regions of the cortex, particularly those related to sensory functions. Some overlap exists among functional areas. For example, the motor cortex is area 4; the primary sensory cortex includes areas 3, 1, and 2; and the primary visual cortex is area 17. In this lateral view, the lateral surface of the spinal cord, medulla, and caudal pons can be seen, as well as the lateral surface of the cerebellum. The temporal lobe overlies the more rostral portions of the brainstem.

Brain

Cingulate gyrus

57

Precentral sulcus Central (rolandic) sulcus Paracentral lobule Corpus callosum Precuneus

Cingulate sulcus Medial frontal gyrus Sulcus of corpus callosum Fornix

Superior sagittal sinus Choroid plexus of 3rd ventricle

Septum pellucidum Interventricular foramen (of Monro)

Parieto-occipital sulcus Stria medullaris of thalamus Cuneus

Interthalamic adhesion Thalamus

Calcarine cortex (upper bank)

Anterior commissure

Habenular commissure Calcarine sulcus (fissure) Lingual gyrus Calcarine cortex (lower bank)

Hypothalamic sulcus Subcallosal (parolfactory) area Paraterminal gyrus

AP

Gyrus rectus

Pineal gland Straight sinus (in tentorium cerebelli)

Lamina terminalis Optic recess

Great cerebral vein (of Galen) Posterior (epithalamic) commissure

Optic chiasm Tuber cinereum

Superior and inferior colliculi Cerebellum Superior medullary velum

Mammillary body Pituitary gland (anterior and posterior) Midbrain

Pons

Medulla oblongata

Cerebral aqueduct (of Sylvius)

4th ventricle and choroid plexus Inferior medullary velum

 

3.4 ANATOMY OF THE MEDIAL (MIDSAGITTAL) SURFACE OF THE BRAIN IN SITU The entire extent of the neuraxis, from the spinomedullary junction through the brainstem, diencephalon, and telencephalon, is visible in a midsagittal section. The corpus callosum, a major commissural fiber bundle interconnecting the two hemispheres, is a landmark separating the cerebral cortex above from the thalamus, fornix, and subcortical forebrain below. The ventricular system, including the interventricular foramen (of Munro); the third ventricle (diencephalon); the cerebral aqueduct (midbrain); and the fourth ventricle (pons and medulla), is visible in a midsagittal view. This subarachnoid fluid system provides internal (the ventricular system) and external (cerebrospinal fluid in the subarachnoid space) protection to the brain and also may serve as a fluid transport system for important regulatory molecules. The thalamus serves as a gateway to the cortex. The hypothalamic proximity to the median eminence (tuber cinereum) and the pituitary gland reflects the

important role of the hypothalamus in regulating neuroendocrine function. A midsagittal view also reveals the midbrain colliculi, sometimes called the visual (superior) and auditory (inferior) tecta. See Video 3.1. CLINICAL POINT The right and left hemispheres are interconnected by commissural fiber bundles. The largest is the corpus callosum, which interconnects all lobes with their counterparts. The anterior commissure interconnects regions of the temporal lobes. When these commissural fiber bundles are disconnected (split brain), the hemispheres do not know what their counterparts are doing, and inputs to one hemisphere cannot produce an appropriate response from the opposite hemisphere. With a split brain, only a more generalized recognition of mood states occurs between the two hemispheres, presumably communicated through interconnections between lower structures, such as the diencephalon and brainstem.   

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Overview of the Nervous System

Cingulate gyrus Mammillothalamic fasciculus Mammillary body

Genu Rostrum Body Splenium

Uncus

Cuneus

Optic (II) nerve

Calcarine sulcus (fissure) Lingual gyrus

Olfactory tract

Body Crus Column

Collateral sulcus Rhinal sulcus Medial occipitotemporal gyrus Occipitotemporal sulcus Lateral occipitotemporal gyrus

of corpus callosum

of fornix

Fimbria of hippocampus Dentate gyrus Parahippocampal gyrus

 

3.5 ANATOMY OF THE MEDIAL (MIDSAGITTAL) SURFACE OF THE BRAIN, WITH BRAINSTEM REMOVED When the brainstem is removed, a midsagittal view reveals the C-­shaped course of the fornix, extending from the hippocampal formation in the temporal lobe to the septum and

hypothalamus. Temporal lobe structures, such as the parahippocampal cortex, the dentate gyrus and fimbria of the hippocampus, and the uncus (olfactory cortex) also are visible. In the hypothalamus, the caudal mammillary bodies and the interconnecting pathway to the thalamus, the mammillothalamic tract, are revealed.

Brain Primary motor cortex

59

Precentral sulcus

Limbic cingulate cortex

Paracentral lobule

Supplemental motor cortex

Somatosensory association cortex

Parietal

Frontal

Limbic

Corpus callosum Occipital Visual association cortex

Thalamus

Primary visual cortex

Calcarine fissure

Pituitary gland Pons

Cerebellum

Medulla oblongata

A. Lobes and functional areas

6

3 12 7

4

8 9 32

7

31

24

23

33

19 18

10 32 12

17 25

18 17

B. Brodmann’s areas

 

3.6 MEDIAL SURFACE OF THE BRAIN A, Lobes and functional areas. The cingulate cortex is labeled the limbic lobe, reflecting its association with other limbic forebrain structures and with hypothalamic control of the autonomic nervous system. Functional areas of the cortex, particularly those involved with vision, are best seen on a midsagittal view. The sensory and motor cortices associated with the lower extremities are located medially and are supplied with blood by the anterior cerebral artery. This region

is selectively vulnerable to specific vascular (anterior cerebral artery infarct) and mass (parasagittal meningioma) lesions that result in contralateral motor and sensory deficits of the lower extremity. B, Brodmann’s areas of the cerebral cortex are labeled on this midsagittal view of the brain. The major regions are the primary (17) and associative (18, 19) visual cortices and the continuation of areas 4 (motor) and areas 3, 1, and 2 (primary sensory) onto the paracentral lobule in the midline.

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Overview of the Nervous System Cerebral longitudinal fissure

Frontal pole Straight gyrus

Genu of corpus callosum Olfactory bulb

Olfactory sulcus

Lamina terminalis

Orbital sulcus Orbital gyri

Olfactory tract Optic chiasm

Lateral (sylvian) fissure

Optic (II) nerve Pituitary gland

Inferior temporal sulcus

Temporal pole Inferior temporal gyrus

Optic tract Anterior (rostral) perforated substance Tuber cinereum Mammillary body Posterior perforated substance Cerebral peduncles (crus cerebri)

Rhinal sulcus

Lateral geniculate body Lateral occipitotemporal gyrus

Substantia nigra Medial geniculate body

Occipitotemporal sulcus

Red nucleus Pulvinar

Medial occipitotemporal gyrus

Superior (cranial) colliculus

Collateral sulcus

Cerebral aqueduct (of Sylvius)

Parahippocampal gyrus

Splenium of corpus callosum

Lingual gyrus

Apex of cuneus

Uncus

Occipital pole

Calcarine sulcus (fissure)

Cerebral longitudinal fissure

Cingulate gyrus

  3.7 ANATOMY OF THE BASAL SURFACE OF THE BRAIN, WITH THE BRAINSTEM AND CEREBELLUM REMOVED Removal of the brainstem and cerebellum by a cut through the midbrain exposes the underlying cerebral cortex, the base of the diencephalon, and the basal forebrain. Basal hypothalamic landmarks, from caudal to rostral, include the mammillary bodies, tuber cinereum, pituitary gland, and optic chiasm. The proximity of the pituitary to the optic chiasm is important because bitemporal hemianopsia can result from optic chiasm fiber damage, often an early sign of a pituitary tumor. The genu and splenium of the corpus callosum are revealed in this view. In the cross-­section of the midbrain, the superior colliculus, cerebral aqueduct, periaqueductal gray, red nucleus, substantia nigra, and cerebral peduncles are shown.

CLINICAL POINT The olfactory bulb and tract send connections directly into limbic forebrain structures, such as the uncus (the primary olfactory cortex), amygdala, and other limbic regions. This is the only sensory system with direct access to forebrain structures without prior screening through the diencephalon. This reflects the evolutionary importance of olfaction to functions vital for survival, such as detection of food, defense, and reproduction. Olfactory damage can alter emotional behavior. In addition, complex partial seizures involving the temporal lobe frequently are accompanied by an olfactory aura. Changes in olfactory function and gene expression may be among the earliest signs of Alzheimer’s disease. The optic nerve, chiasm, and tract can be seen extending toward the lateral geniculate body (nucleus), the pulvinar, and the superior colliculus. Optic nerve damage can result in ipsilateral blindness; optic chiasm damage can result in bitemporal visual field deficits; and optic tract damage can result in contralateral hemianopsia. Additional visual input from the optic tract enters the hypothalamus and ends in the suprachiasmatic nucleus. This visual input conveys information of total light flux and exposure, permitting visual influence over diurnal rhythms such as the cortisol rhythm. Disruption of this diurnal input can produce altered production of hormones such as melatonin, and metabolic consequences such as the propensity for abdominal obesity resulting from disruption of the diurnal cortisol rhythm.   

Brain

Brodmann’s areas

61

Structures Olfactory bulb Executive anticipatory cortical function 10

Olfactory tract

Temporal pole

11

10

Optic chiasm Optic nerve (II) (cut) Hypophysis (pituitary gland)

11 38

Optic tract

Olfactory cortex (uncus) 34 20

Mammillary body 28 Multisensory association areas

20 36

37

19 18 17

Visual association cortex

Primary visual cortex

 

3.8 BASAL SURFACE OF THE BRAIN: FUNCTIONAL AREAS AND BRODMANN’S AREAS This view provides information about the medial temporal lobe on the left side of the brain, especially cortical regions associated

with the hippocampal formation, the amygdaloid nuclei, and the olfactory system. On the right side of the brain, Brodmann’s areas are noted.

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Overview of the Nervous System

A. Coronal view Superior sagittal sinus Skull Cortical gyrus Subarachnoid space Lateral ventricle Thalamus Third ventricle

Cortical gyri Subarachnoid space Skull Parietal lobe Corpus callosum Frontal lobe Lateral ventricle Occipital lobe Thalamus Midbrain Pons Cerebellum Medulla Cisterna magna

B. Sagittal view

 

3.9 BRAIN IMAGING: COMPUTED TOMOGRAPHY SCANS, CORONAL AND SAGITTAL A and B, Computed tomography (CT) is an x-­ray-­based imaging approach that is used to view the brain, particularly when looking for differences in tissue density such as the presence of blood. The use of spiral (helical) scanners can quickly provide

access to views of slices through the brain at a desired thickness. CT delineates soft tissue, fluid, and bone and can be used with contrast to image blood vessels or to reveal the presence of a tumor caused by a disrupted blood-­brain barrier, which allows leakage of the contrast agent into the surrounding extracellular space of the brain.

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63

A. Axial view Cortical gyrus Insular cortex Cortical white matter Genu, corpus callosum Frontal pole, lateral ventricle Head of caudate nucleus Putamen Columns, fornix Globus pallidus Internal capsule Thalamus Hippocampal formation Temporal pole, lateral ventricle Optic radiations Cingulate cortex Corpus callosum Lateral ventricle Fornix Thalamus Colliculi Midbrain Hypothalamus Pons Cerebellum Medulla Cisterna magna Subarachnoid space Spinal cord

B. Sagittal view

  3.10 BRAIN IMAGING: MAGNETIC RESONANCE IMAGING, AXIAL AND SAGITTAL T1-­WEIGHTED IMAGES A, Axial view. B, Sagittal view. Magnetic resonance imaging (MRI) uses short bursts (radiofrequency pulses) of electromagnetic waves that are sent into the magnet and are absorbed by protons in the tissues of the patient in the scanner. The pulses cause alignment of the protons as the result of raised energy levels that is followed by a relaxation phase in which the protons return to a lower energy level. During the relaxation process, a detector records the emitted energy, and a computer provides a uniform image of the scanned tissue. The intervals (milliseconds) between the pulses (repetition time, TR) and the intervals

between the collection times of the emitted energy (echo time, TE) provide various contrast information, which are indicated by contrast weighting. Short TR and TE intervals result in Tl-­ weighted images, whereas longer TR and TE intervals result in T2-­weighted images. The Tl-­weighted images are particularly useful for viewing normal brain structures and are particularly useful for viewing the brainstem and the cervical and thoracic spinal cord. The ventricular system and subarachnoid space in T1-­weighted images appear dark. The T2-­weighted images are particularly useful for revealing pathology, such as infarcts, tumors, edema, and demyelination. A contrast agent such as gadolinium can be used to delineate a tumor because of its ability to leak across the blood-­brain barrier.

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Overview of the Nervous System

A. Axial view Subarachnoid space Cortical gyrus Cortical white matter Insular cortex Genu, corpus callosum Head, caudate nucleus Frontal pole, lateral ventricle Putamen Columns, fornix Internal capsule

Thalamus Hippocampal formation Temporal pole, lateral ventricle Optic radiations Cingulate cortex Corpus callosum Site of lateral ventricle Fornix Thalamus Subarachnoid space Colliculi Midbrain Pons Cerebellum Medulla Cisterna magna Subarachnoid space Spinal cord

B. Sagittal view

 

3.11 BRAIN IMAGING: MAGNETIC RESONANCE IMAGING, AXIAL AND SAGITTAL T2-­WEIGHTED IMAGES A, Axial view. B, Sagittal view. T2-­weighted images are particularly useful for imaging the ventricular system and the cisterns

of cerebrospinal fluid. The ventricular system and subarachnoid space in T2-­weighted images appear white.

Brain

65

 

3.12 POSITRON EMISSION TOMOGRAPHY SCANNING Positron emission tomography (PET) scanning is designed to assess the distribution of tracers labeled with positron-emitting nuclides, such as carbon-­11 (11C), nitrogen-­13 (13N), oxygen-­15 (15O), and fluorine-­18 (18F). Fluorodeoxyglucose (FDG), a glucose analogue labeled with 18F, can cross the blood-­brain barrier. The metabolic products of FDG become immobile and trapped where the molecule is first used, thereby permitting FDG to be used to map glucose uptake in the brain.

This is a valuable tool for investigating subtle physiological processes related to neurological diseases. The distribution of FDG can be localized and reconstructed using standard tomographic techniques that show the tracer distribution throughout the body or brain. In this example of axial, sagittal, and coronal views, the transmission measurement and correction was performed immediately following PET acquisition using a 16-­slice CT unit. The PET and CT images were automatically fused by anatomical coregistration software (shown as colored images).

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Overview of the Nervous System B

A

Genu of corpus callosum Septum pellucidum Head of caudate nucleus Column of fornix Anterior limb Genu Posterior limb

Internal capsule

Insular cortex Putamen Globus pallidus Internal and external segments 3rd ventricle External capsule Extreme capsule Claustrum Habenula

I E

Lentiform nucleus

Tail of caudate nucleus Choroid plexus of lateral ventricle Hippocampus and fimbria

Crus of fornix

Posterior (occipital) horn of lateral ventricle

Splenium of corpus callosum

Pineal gland

B

A

Cleft for internal capsule Caudate nucleus

Body Thalamus

Head Levels of sections

A B Lentiform nucleus (globus pallidus medial to putamen)

Pulvinar Medial geniculate body Lateral geniculate body Tail of caudate nucleus

Amygdaloid body

Schematic illustration showing interrelationship of thalamus, lentiform nucleus, caudate nucleus, and amygdaloid body (viewed from side).

  3.13 HORIZONTAL BRAIN SECTIONS SHOWING THE BASAL GANGLIA Two levels of horizontal sections through the forebrain reveal the major anatomical features and the relationships among the basal ganglia, the internal capsule, and the thalamus (schematically shown in the lower illustration). The caudate nucleus is a C-­shaped structure that sweeps from the frontal lobe into the temporal lobe; a horizontal section passes through this nucleus in two distinct places (head and tail). The anterior limb, genu, and posterior limb of the internal capsule contain major connections into and out of the cerebral cortex. The head and body of the caudate are medial to the anterior limb, whereas the thalamus is medial to the posterior limb. These relationships are important for understanding imaging studies and for understanding the involvement of specific functional systems in vascular lesions or strokes. The internal and external segments of the globus pallidus are located medial to the putamen. The external capsule, claustrum, extreme capsule,

and insular cortex, from medial to lateral, are located lateral to the putamen. The fornix, also a C-­shaped bundle, is sectioned in two sites, the crus and the column. CLINICAL POINT The basal ganglia (caudate nucleus, putamen, and globus pallidus) form characteristic anatomical relationships with the internal capsule. The head and body of the caudate nucleus are found medial to the anterior limb; the thalamus is found medial to the posterior limb; and the globus pallidus and putamen are found lateral to the anterior and posterior limbs. Basal ganglia disorders are characterized by movement disorders, although emotional and cognitive symptoms also are seen. Some movement disorders involve actual degeneration of basal ganglia and related structures; these disorders include Huntington’s chorea and degeneration of the head of the caudate nucleus as well as Parkinson’s disease and degeneration of the dopaminergic pars compacta of substantia nigra. Other movement disorders involve altered inhibitory and excitatory activity of specific portions of basal ganglia circuitry; reordering this circuitry may require pharmacologic treatment, therapeutic ablation procedures, or deep brain stimulation.   

Brain Anterior nucleus of thalamus

67

Interthalamic adhesion Fornix

Interventricular foramen

Stria terminalis Anterior commissure

Stria medullaris Habenula

Cingulate gyrus Indusium griseum Corpus callosum Septum pellucidum Precommissural fornix Septal nuclei Subcallosal area Paraterminal gyrus Hypothalamus

Lamina terminalis Olfactory

bulb tract medial stria lateral stria

Anterior perforated substance Optic chiasm Calcarine sulcus (fissure)

Postcommissural fornix Mammillary body and mammillothalamic tract

Gyrus fasciolaris Dentate gyrus

Median forebrain bundle

Fimbria of hippocampus Hippocampus

Amygdaloid body (nuclei)

Parahippocampal gyrus

Interpeduncular nucleus

Descending connections to reticular and tegmental nuclei of brainstem (dorsal longitudinal fasciculus)

Uncus Fasciculus retroflexus

  3.14 MAJOR LIMBIC FOREBRAIN STRUCTURES The term limbic is derived from limbus, meaning ring. Many of these structures and their pathways in the limbic system form a ring around the diencephalon. They are involved in emotional behavior and individualized interpretations of external and internal stimuli. The hippocampal formation and its major pathway, the fornix, curve into the anterior pole of the diencephalon, forming precommissural (to the septum) and postcommissural (to the hypothalamus) connections in relation to the anterior commissure. The amygdaloid nuclei give rise to several pathways; one, the stria terminalis, extends in a C-­shaped course around the diencephalon into the hypothalamus and basal forebrain. The olfactory tract communicates directly with several limbic forebrain areas; it is the only sensory system to entirely bypass the thalamus and terminate directly in cortical and subcortical zones of the telencephalon. Connections from the septal nuclei to the habenula (stria medullaris thalami) connect the limbic forebrain to the brainstem. The amygdaloid nuclei and hippocampus (shaded) are deep to the cortex.

CLINICAL POINT Many of the limbic forebrain structures are connected with the hypothalamus by C-­shaped structures, such as the hippocampus and the fornix, and with the amygdala and the stria terminalis. The amygdala has additional direct connections into the hypothalamus via the ventral amygdalofugal pathway. The amygdaloid nuclei receive multimodal sensory information from cortical regions and provide context for this input, particularly emotions related to fear responses. Bilateral amygdaloid damage results in the loss of the fear response and also in failure to recognize facial responses of fear in others. The hippocampal formation processes abundant information from the temporal lobe, subiculum, and entorhinal cortex and sends connections through the fornix to the hypothalamus and septal nuclei, with subsequent connections through the thalamus to the cingulate cortex. These structures are part of the so-­called Papez circuit. The hippocampal formation is particularly vulnerable to ischemia; damage bilaterally results in the inability to consolidate new information into long-­term memory. A common pattern may be observed in older persons who forget who has talked with them minutes before or forget what they had for breakfast (or even whether they had breakfast) but can recall details from the past that have some degree of accuracy.   

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Overview of the Nervous System

Cerebral longitudinal fissure Genu of corpus callosum Indusium griseum (on upper surface of corpus callosum) Medial longitudinal striae Lateral longitudinal striae Body of corpus callosum Splenium of corpus callosum Frontal forceps (forceps minor)

A. Anatomy of the corpus callosum: horizontal view

Indusium griseum

Commissural fibers Medial longitudinal stria Lateral longitudinal stria

B. Schematic view of the lateral extent of major components

Occipital forceps (forceps major)

 

3.15 CORPUS CALLOSUM A, Anatomy of the corpus callosum, horizontal view. The corpus callosum, the major fiber commissure between the hemispheres, is a conspicuous landmark in imaging studies. It is viewed from above after dissection of tissue just dorsal to its upper surface. Horizontal cuts taken deeper (more ventrally) section the genu anteriorly and the splenium posteriorly (see Fig. 3.13). B,

Schematic view of the lateral extent of major components. Many of the commissural fibers of the corpus callosum, particularly the forceps of commissural fibers that interconnect frontal areas with each other and occipital areas with each other, extend rostrally and caudally, respectively, after crossing the midline. These interconnections allow communication between the hemispheres for coordinated activity of these two “separate” hemispheres.

Brain

69

Lateral corpus callosum fibers radiating to cortical gyri

Lateral fibers of corpus callosum

Midline fibers, body of corpus callosum

Genu

Midline fibers, genu of corpus callosum

Cortical association fibers Splenium

A. Axial view B. Oblique sagittal view Forceps minor

Genu

Body

Lateral fibers of corpus callosum Splenium

Forceps major

C. Axial view

 

3.16 COLOR IMAGING OF THE CORPUS CALLOSUM BY DIFFUSION TENSOR IMAGING A–­C, Diffusion-­weighted imaging (DWI), also called diffusion tensor imaging (DTI), provides unique information about tissue viability, architecture, and cellular function. In many tissues, restricted water diffusion is isotropic or independent of direction. In structured tissues, such as cerebral white matter and peripheral nerves, diffusion is anisotropic because of cellular arrangements. By using diffusion sensitivity that projects in multiple directions, such diffusion can be evaluated in the form of a tensor. Tensor field calculations for six or more diffusion-­weighted

measurements are based on an analytical solution of the Stejskal and Tanner diffusion equation system. Diffusion tensor imaging permits reconstruction of axonal tracts in brain and spinal cord; the three-­dimensional architecture of the white matter tracts can be traced based on eigenvectors of the diffusion tensor. To discriminate fiber bundles that radiate in different directions, a color scheme is adopted in which green represents eigenvectors pointing in anteroposterior directions; red represents eigenvectors radiating in left-­right directions; and blue represents eigenvectors pointing in the superoinferior direction. In these images of the corpus callosum, components of this major commissural bundle are represented in red. See Video 3.­2.

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Overview of the Nervous System

A. Dissection of the hippocampal formation and fornix Genu of corpus callosum Septum pellucidum Head of caudate nucleus Columns of fornix Stria terminalis Body of fornix Pes hippocampus Thalamus Uncus Crura of fornix Parahippocampal gyrus Dentate gyrus Fimbria of hippocampus Hippocampus Commissure of fornix Splenium of corpus callosum Lateral ventricle Calcar avis Posterior (occipital) horn of lateral ventricle

C. Hippocampal formation in coronal section B. 3D Reconstruction of the fornix Columns of fornix

Fimbria of hippocampus CA3 Optic tract

Body of fornix Commissure of fornix Crura of fornix

Tail of caudate nucleus Choroid plexus

Amygdaloid nuclei CA2

Hippocampal sulcus Subiculum Dentate gyrus

Lateral ventricle

Hippocampus Mammillary bodies Amygdaloid bodies

Alveus of hippocampus Hippocampus with fimbria

CA1

Entorhinal cortex

 

3.17 HIPPOCAMPAL FORMATION AND FORNIX In this dissection, the cortex, white matter, and corpus callosum have been removed. The lateral ventricles have been opened, and the head of the caudate nucleus and the thalamus have been dissected away quite close to the midline, allowing a downward view of the full extent of the hippocampal formation, including the dentate gyrus and the associated fornix. This view reveals the relationship between the hippocampus proper and the dentate gyrus. The two limbs of the fornix sweep upward medially, eventually running side by side at their most dorsal position, just beneath the corpus callosum. The full extent of this arching,

C-­shaped bundle is shown in the left lower image. The hippocampal formation occupies a large portion of the temporal pole of the lateral ventricle. The dentate gyrus is adjacent to subcomponents of the cornu ammonis (CA) regions of the hippocampus proper (the CA1 and CA3 regions), the subiculum, and the entorhinal cortex). Pyramidal neurons in the CA1 region are particularly sensitive to ischemic damage, and their counterparts in the CA3 region are sensitive to damage from high levels of corticosteroids (cortisol). Damage to pyramidal cells in both regions that has been caused by ischemia and/or high levels of corticosteroids is synergistic.

Brain

71

Interventricular foramen Corpus callosum (cut) Cut edge of tela choroidea of 3rd ventricle 3rd ventricle Choroid plexus Internal cerebral vein Superior thalamostriate vein (vena terminalis)

Head of caudate nucleus Septum pellucidum Columns of fornix Anterior tubercle Stria terminalis Interthalamic adhesion

Pes hippocampi Inferior horn of lateral ventricle Dentate gyrus Collateral eminence Hippocampus Fimbria of hippocampus

Lamina affixa Stria medullaris Habenular trigone Pulvinar (lifted) Lateral geniculate body Medial geniculate body Brachium of superior colliculus

Posterior commissure Brachium of inferior colliculus Habenular commissure Pineal gland

Superior colliculus Inferior colliculus

Collateral trigone Cerebellum Calcar avis Posterior horn of lateral ventricle

Calcarine sulcus (fissure)

 

3.18 THALAMIC ANATOMY The thalamus is viewed from above. The entire right side of the brain, just lateral to the thalamus, has been removed, the head of the caudate nucleus has been sectioned, the corpus callosum and all tissue dorsal to the thalamus have been removed, and the third ventricle has been opened from its dorsal surface. The pineal gland is present in the midline, just caudal to the third ventricle; it produces melatonin, a hormone that helps regulate

circadian rhythms, sleep, and immune responses. The superior and inferior colliculi are shown, depicting the dorsal surface of the midbrain. On the left, the temporal horn of the lateral ventricle, with the hippocampal formation, has been exposed to show the relationship of these structures to the thalamus. The terminal vein and choroid plexus accompany the stria terminalis along the lateral margin of the thalamus. The stria medullaris runs along the medial surface of the dorsal thalamus.

72

Overview of the Nervous System

3rd ventricle Interthalamic adhesion Internal medullary lamina

MD

LP

Mi

rnal

Inte

M

n

dli

Intralaminar nuclei

)

ian

ed

m e(

l dia Me llary edu

lam ina

Pulvinar

a

lamin

m

VA

LD

LP

VPL

VL

3rd ventricle

CM

VI

VP

M

VP

M

VP

Reticular nucleus of thalamus

L

VP

External medullary lamina

Pulvinar Lateral geniculate body Thalamic nuclei

Midline (median) nuclei

Schematic section through thalamus (at level of broken line shown in figure at right)

CM LD LP M MD VA VI VL VP VPL VPM

Centromedian Lateral dorsal Lateral posterior Medial group Medial dorsal Ventral anterior Ventral intermedial Ventral lateral Ventral posterior (ventrodorsal) Ventral posterolateral Ventral posteromedial

Medial geniculate body

Schematic representation of thalamus

(external medullary lamina and reticular nuclei removed)

Lateral cell mass Medial cell mass Anterior cell mass

 

3.19 THALAMIC NUCLEI The thalamus is subdivided into nuclear groups (medial, lateral, and anterior) that are separated by medullary (white matter) lamina. Many of these thalamic nuclei are “specific” thalamic nuclei that are reciprocally connected with discrete regions of the cerebral cortex. Some nuclei, such as those embedded within the internal medullary lamina (intralaminar nuclei such as the centromedian and parafascicular nuclei) and the outer, lateral shell nucleus (reticular nucleus of the thalamus), have very diffuse, nonspecific associations with the cerebral cortex.

CLINICAL POINT Thalamic syndrome (posterolateral thalamic syndrome, or Dejerine-­ Roussy syndrome) results from obstruction of the thalamogeniculate arterial supply to the region of the thalamus where the ventral posterolateral nucleus is located. Initially, all sensation is lost in the contralateral body, epicritic more completely than protopathic. Commonly, severe spontaneous pain occurs contralaterally, described as stabbing, burning, or tearing pain; it is diffuse and persistent. Even light stimulation can evoke such pain (hyperpathia), and other sensory stimuli or emotionally charged situations can result in these painful sensations. Even when the threshold for pain and temperature sensation (protopathic sensations) is elevated, the thalamic pain may be present; it is called analgesic dolorosa. If the vascular lesion includes the subthalamic nucleus or associated basal ganglia circuitry, the patient may also experience hemiballismus (or choreiform or athetoid) movements in addition to the sensory deficits.   

4

BRAINSTEM AND CEREBELLUM

4.1 Brainstem Surface Anatomy: Posterolateral View 4.2 B  rainstem Surface Anatomy: Anterior View 4.3 C  erebellar Anatomy: External Features 4.4 C  erebellar Anatomy: Internal Features

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74

Overview of the Nervous System

Posterolateral View Thalamus

Pulvinar

Optic tract Pineal gland

Lateral geniculate body Medial geniculate body

Brachia of superior and inferior colliculi

Cerebral peduncle Trochlear (IV) nerve

Superior colliculi

Pons

Inferior colliculi

Trigeminal (V) nerve Superior cerebellar peduncle

Superior medullary velum

Middle cerebellar peduncle Vestibulocochlear (VIII) nerve

Medial eminence

Facial (VII) nerve Rhomboid fossa of 4th ventricle

Inferior cerebellar peduncle Vestibular area

Facial colliculus

Olive

Cuneate tubercle

Hypoglossal (XII) nerve Glossopharyngeal (IX) and vagus (X) nerves

Gracile tubercle

Hypoglossal trigone

Dorsal roots of 1st spinal nerve (C1)

Vagal trigone

Fasciculus cuneatus



Accessory (XI) nerve

Fasciculus gracilis

4.1 BRAINSTEM SURFACE ANATOMY: POSTEROLATERAL VIEW The entire telencephalon, most of the diencephalon, and the cerebellum are removed to reveal the dorsal surface of the brainstem. The three cerebellar peduncles (superior, middle, and inferior) are sectioned and the cerebellum removed. The dorsal roots provide input into the spinal cord, and the cranial nerves provide input into and receive output from the brainstem. The fourth nerve (trochlear) is the only cranial nerve to exit dorsally from the brainstem. The tubercles and trigones on the floor of the fourth ventricle are named for nuclei just beneath them. The superior and inferior colliculi form the dorsal surface of the midbrain, and the medial and lateral geniculate bodies (nuclei), associated with auditory and visual processing, respectively, are shown at the caudalmost region of the diencephalon.

CLINICAL POINT The facial colliculus is an elevation on the floor of the fourth ventricle in the pons under which is located the abducens nucleus (cranial nerve VI) and the axons of the facial nerve nucleus (VII), which arc around the abducens nucleus. A tumor or other lesion on one side of the floor of the fourth ventricle may induce symptoms related to cranial nerves VI and VII, including (1) ipsilateral paralysis of lateral gaze (lateral rectus) and medial gaze (resulting from damage to interneurons of the abducens nucleus, whose axons ascend to the nucleus of CN III via the medial longitudinal fasciculus), and (2) ipsilateral facial palsy resulting from damage to the axons in the genu of the facial nerve. The cerebellar peduncles convey the cerebellar afferent and efferent fibers. The superior peduncle conveys the major efferents to the red nucleus and thalamus (especially the ventrolateral nucleus), whereas the inferior peduncle conveys the major efferents to the vestibular and reticular nuclei. The middle peduncle conveys the cortico-­ pontocerebellar fibers. Afferents enter the cerebellum especially through the inferior peduncle but also through the superior peduncle. Damage to the lateral hemisphere of the cerebellum or its associated peduncles results in ipsilateral symptoms, including limb ataxia, mild hypotonia, dysmetria (misjudgment of distance), decomposition of movement (especially movement involving several joints), intention tremor (with movement), dysdiadochokinesia (inability to perform rapid alternating movements), and inability to dampen movements appropriately (rebound phenomena).   

75

Brainstem and Cerebellum

Insula Olfactory tract

Anterior View

Anterior perforated substance

Optic chiasm

Mammillary body

Infundibular stalk

Temporal lobe

Tuber cinereum

Oculomotor (III) nerve

Optic tract

Trochlear (IV) nerve

Cerebral peduncle

Pons

Posterior perforated substance in interpeduncular fossa

Trigeminal (V) nerve

Lateral geniculate body

Facial (VII) nerve

Abducens (VI) nerve

Vestibulocochlear (VIII) nerve Basilar groove

Flocculus Choroid plexus of 4th ventricle at foramen of Luschka

Middle cerebellar peduncle Olive

Glossopharyngeal (IX) nerve

Pyramid

Vagus (X) nerve Hypoglossal (XII) nerve

Ventral roots of 1st spinal nerve (C1)

Accessory (XI) nerve

Pyramidal decussation

  4.2 BRAINSTEM SURFACE ANATOMY: ANTERIOR VIEW The left temporal lobe is dissected to show the anterior (ventral) surface of the brainstem. The cerebral peduncles, direct caudal extensions of the posterior limbs of the internal capsules, carry corticospinal and corticobulbar fibers from the internal capsule to the spinal cord and brainstem, respectively. The decussation of the pyramids marks the boundary between the caudal medulla and the cervical spinal cord. Cranial nerve XI (accessory) is associated with the lateral margin of the upper cervical spinal cord. Cranial nerves XII (hypoglossal), X (vagus), and IX (glossopharyngeal) emerge from the ventrolateral margin of the medulla. Cranial nerves VI (abducens), VII (facial), and VIII (vestibulocochlear) emerge from the boundary between the medulla and the pons. Cranial nerve V (trigeminal) emerges from the lateral margin of the upper pons. Cranial nerve III (oculomotor) emerges from the interpeduncular fossa in the medial portion of the caudal midbrain. The optic nerve, chiasm, and tract (cranial nerve II) and the olfactory tract (cranial nerve I) are not peripheral nerves; they are central nervous system tracts that were identified as cranial nerves by anatomists in centuries past. CLINICAL POINT The oculomotor nerve (III) emerges from the ventral surface of the brainstem in the interpeduncular fossa, at the medial edge of the cerebral peduncle. In conditions of increased intracranial pressure in

the anterior and middle cranial fossa, such as that caused by a tumor, edema from injury, or other space-­occupying lesions, the brainstem can herniate through the tentorium cerebelli, a rigid wing of dura. The resultant transtentorial herniation can compress the third nerve on one side (ipsilateral fixed and dilated pupil resulting from parasympathetic disruption and paralysis of medial gaze resulting from motor fiber disruption) and compress the cerebral peduncle on that same side, resulting in contralateral hemiparesis. The medullary pyramids contain the descending corticospinal tract fibers from the ipsilateral cerebral cortex, particularly from the motor and premotor cortex. The major crossing of the corticospinal tract takes place in the decussation of the pyramids (80%), producing the crossed, descending, lateral corticospinal tract in the spinal cord. An infarct in the upper reaches of the anterior spinal artery or the paramedian branches of the vertebral artery can result in damage to the ipsilateral pyramid (contralateral hemiparesis); to the ipsilateral medial lemniscus (contralateral loss of epicritic somatosensory sensations such as fine, discriminative touch, vibratory sensation, and joint position sense); and the ipsilateral hypoglossal nerve (cranial nerve XII; paralysis of the ipsilateral tongue, which deviates toward the weak side when protruded). This condition is called Dejerine’s syndrome. The hemiparesis is not spastic and is characterized by mild loss of tone, loss of fine hand movements, and a plantar extensor response (Babinski’s sign). It appears that isolated damage to the pyramids does not result in spasticity. Damage to other descending systems, from either the motor-­related cortices or other upper motor neurons in the brainstem, must accompany pyramidal tract damage to produce spasticity. Thus, the term pyramidal tract syndrome, when used to describe spastic hemiplegia, is a misnomer and is anatomically incorrect.   

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Overview of the Nervous System

Anterior cerebellar notch

Superior Surface

Anterior lobe Quadrangular lobule

Central lobule V e r m i s

Culmen Superior vermis Declive Folium

P a r a v e r m i s

Primary fissure Horizontal fissure Simplex lobule Middle lobe

Lateral hemisphere

Postlunate fissure Superior semilunar lobule Horizontal fissure

Posterior cerebellar notch

Inferior semilunar lobule

Inferior Surface Central lobule Superior vermis

Anterior lobe Ala of central lobule Superior

Lingula

Middle

Cerebellar peduncles

Inferior

Superior medullary velum

Flocculonodular lobe

Flocculus 4th ventricle

Posterolateral fissure

Inferior medullary velum

Retrotonsillar fissure

Nodule Inferior vermis

Middle lobe

Uvula

Tonsil Biventral lobule Secondary (postpyramidal) fissure

Pyramid Tuber

Posterior cerebellar notch Prepyramidal fissure

Horizontal fissure Inferior semilunar lobule

 

4.3 CEREBELLAR ANATOMY: EXTERNAL FEATURES These color-­coded illustrations show the superior (dorsal) surface and the inferior (ventral) surface of the cerebellum. The cerebellar peduncles are cut to provide this view. The ventral surface of the cerebellum is the roof of the fourth ventricle. The anterior, middle, and flocculo-­nodular lobes of the cerebellum are traditional anatomic subdivisions with well-­described syndromes derived from lesions. The vermis, paravermis, and lateral hemispheres are cerebellar cortical zones that have specific projection relationships with deep cerebellar nuclei (vermis with fastigial nucleus and lateral vestibular nucleus; paravermis with globose and emboliform nuclei; lateral hemispheres with dentate nucleus), which, in turn, provide neuronal feedback to specific upper motor neuronal systems that regulate specific types of motor responses. These

relationships are key to understanding how the major upper motor neuronal systems are coordinated for specific functional tasks. CLINICAL POINT The anterior lobe of the cerebellum (paleocerebellum) receives extensive input from the proprioceptors of the body, particularly the limbs, via the spinocerebellar tracts. This region is particularly important for coordination of the lower limbs. The anterior cerebellum also helps to regulate tone in the limbs via connections to the lateral vestibular nucleus. In some alcoholic patients, the anterior lobe of the cerebellum shows selective cortical degeneration. The patient shows a wide-­based stance and gait with some ataxia but little involvement of dysarthria or oculomotor dysfunction. The gait tends to be stiff-legged, probably reflecting disinhibition of the extensor-­dominant lateral vestibular nucleus. Typically, heel to shin testing is not severely impaired when the patient is tested while lying down. Few treatment options are available.   

77

Brainstem and Cerebellum

Cerebral peduncle

Decussation of superior cerebellar peduncles

Medial longitudinal fasciculus 4th ventricle Superior cerebellar peduncle

Superior medullary velum Fastigial nucleus

Lingula

Globose nuclei

Cerebellar cortex

Dentate nucleus

Vermis

Emboliform nucleus

Section in plane of superior cerebellar peduncle

Purkinje cell layer White matter zone Molecular layer

Granular cell layer

Molecular layer

External surface Cerebellar architecture. The infolding of cerebellar folia demonstrates the architecture of the cerebellar cortex. Cresyl violet stain. Dendritic trees

Molecular layer Dendritic trees

Basket cell arborizations Purkinje cells Granular cell layer

Purkinje cells

Granular cell layer Cerebellar cortex. Purkinje cells with their huge planar dendritic trees arborizing into the molecular layer. Basket cell arborizations surrounding the Purkinje cell bodies. Granular cell layer with granule cells and Golgi cells. The molecular layer contains outer stellate cells and basket cells. Cajal stain–fiber stain.

4.4 CEREBELLAR ANATOMY: INTERNAL FEATURES The major internal subdivisions of the cerebellum are shown in this transverse section. The outer zone, the cerebellar cortex (three-­layered), is infolded to form numerous folia. Deep to the folia is the white matter, carrying afferent and efferent fibers associated with the cerebellar cortex. Deep to the white matter are the deep cerebellar nuclei, cell groups that receive most of the output from the cerebellar cortex via Purkinje cell axon projections. The

Cerebellar cortex. Purkinje cells send their dendritic trees into the molecular layer. Densely packed granule cells sit deep to the Purkinje cells in the granular layer. Cresyl violet stain with phase contrast microscopy.

 

deep cerebellar nuclei also receive collaterals from mossy fiber and climbing fiber inputs to the cerebellum. These direct afferent inputs to the deep nuclei provide a coarse adjustment for their output to upper motor neurons, whereas the loop of afferent input through the cerebellar cortex back to the deep nuclei provides fine adjustments for their output to upper motor neurons. The cerebellar peduncles are interior to the deep nuclei; these massive fiber bundles interconnect the cerebellum with the brainstem and the thalamus.

5

SPINAL CORD

 5.1 Spinal Column: Bony Anatomy 5.2 Lumbar Vertebrae: Radiography 5.3 Spinal Cord: Gross Anatomy in Situ 5.4 The Spinal Cord: Its Meninges and Spinal Roots 5.5 Spinal Cord: Cross-­Sectional Anatomy in Situ 5.6 Spinal Cord: White and Gray Matter

Spinal Cord



Anterior View

Left Lateral View

Posterior View

Atlas (C1)

Atlas (C1)

Axis (C2)

Axis (C2)

C7

C7

T1

T1

T12 L1

79

T12 Intervertebral disc

Body

L1 Spinous process Transverse process Lamina Pedicle L5

L5

Sacrum (S1–5) Sacrum (S1–5)

Coccyx

5.1 SPINAL COLUMN: BONY ANATOMY Anterior, lateral, and posterior views of the bony spinal column show the relationships of the intervertebral discs with the vertebral bodies. The discs’ proximity to the intervertebral foramina provides an anatomical substrate for understanding the possible impingement of a herniated nucleus pulposus on spinal

Coccyx

roots. Such impingement can cause excruciating, radiating pain if dorsal roots are involved and can cause loss of motor control of affected muscles if ventral roots are involved. In the adult, the spinal cord extends caudally only as far as the L1 vertebral body, leaving the lumbar cistern (the subarachnoid space) accessible for withdrawal of cerebrospinal fluid.

80

Overview of the Nervous System

Anteroposterior Radiograph

Lateral Radiograph T12

L1 SA

L2

IA

IN

D SN

T

L3

B

P

P

T

P I

IA

SA L4 L

S

S

L

L5

S1 SF

B IA L P S SA SF T

SF

Body of L3 vertebra Inferior articular process of L1 vertebra Lamina of L4 vertebra Pedicle of L3 vertebra Spinous process of L4 vertebra Superior articular process of L1 vertebra Sacral foramen Transverse process of L3 vertebra

S2

D Intervertebral disc space I Intervertebral foramen IA Inferior articular process of L3 vertebra IN Inferior vertebral notch of L2 vertebra P Pedicle of L3 vertebra S Spinous process of L4 vertebra SA Superior articular process of L4 vertebra SN Superior vertebral notch of L3 vertebra Note: The vertebral bodies are numbered

 

5.2 LUMBAR VERTEBRAE: RADIOGRAPHY These lumbar radiographs show the lumbar spine in an anteroposterior view and a lateral view. The vertebral bodies, with their spinous and transverse processes, are visible, and the spaces occupied by the intervertebral discs are uniform and symmetrical in

a normal radiograph. A herniated disc may show a disruption of that symmetry. However, the presence of lumbar radiculopathy and a herniated disc is not always accompanied by radiographic abnormalities.

Spinal Cord

81

C1 1st cervical nerve Cervical enlargement C7 8th cervical nerve T1 1st thoracic nerve Spinal dura mater Filaments of nerve root

T12 Lumbosacral enlargement 12th thoracic nerve L1 1st lumbar nerve Conus medullaris Cauda equina L5 5th lumbar nerve S1 1st sacral nerve Filum terminale 5th sacral nerve Coccygeal nerve Coccyx

  5.3 SPINAL CORD: GROSS ANATOMY IN SITU The posterior portions of the vertebrae have been removed to show the posterior (dorsal) surface of the spinal cord. Cervical and lumbosacral enlargements of the spinal cord reflect innervation of the limbs. The spinal cord extends rostrally through the foramen magnum, continuous with the medulla. The conus medullaris is located under the L1 vertebral body. The longitudinal growth of the spinal column exceeds that of the spinal cord, causing the spinal cord to end considerably more rostrally in the adult than in the newborn. The associated nerve roots traverse a considerable distance through the subarachnoid space, particularly more caudally in the lumbar cistern, to reach the appropriate intervertebral foramina of exit. In the lumbar cistern, this collection of nerve roots is called the cauda equina (horse’s tail). The lumbar cistern is a large reservoir of subarachnoid space from which cerebrospinal fluid can be withdrawn. The filum terminale helps to anchor the spinal cord caudally to the coccyx.

CLINICAL POINT In the adult, the spinal cord ends at the level of the L1 vertebral body, and the roots extend caudally in the cauda equina to exit in the appropriate intervertebral foramina. As a consequence, a large lumbar cistern is filled with cerebrospinal fluid (CSF); from this cistern, samples can be drawn in a spinal tap with little risk for neurological damage by the needle. Analysis of CSF is a vitally important part of neurological assessment in many conditions, such as infections, bleeds, inflammatory conditions, some degenerative conditions, and other disorders. The CSF is commonly analyzed for color and appearance, viscosity, cytology, and the presence of red and white blood cells, protein, and glucose. It should be noted that in some conditions in which intracranial pressure is elevated, withdrawal of CSF from the lumbar cistern may encourage brainstem herniation through the foramen magnum.   

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Overview of the Nervous System

Posterior View Rami communicans Dura mater Dorsal root Dorsal root (spinal) ganglion Arachnoid Mesothelial septum in posterior median sulcus Subarachnoid space Pia mater (overlying spinal cord) Filaments of dorsal root Denticulate ligament

Anterior View Gray matter Lateral funiculus

Filaments of dorsal root White matter Dorsal root Dorsal root (spinal) ganglion Spinal nerve Ventral root Filaments of ventral root Anterior median fissure Anterior funiculus

  5.4 THE SPINAL CORD: ITS MENINGES AND SPINAL ROOTS The upper illustration is a posterior (dorsal) view of the spinal cord showing both intact and reflected meninges. The pia adheres to every contour of the spinal cord surface. The arachnoid membrane extends over these contours and adheres to the overlying dura, a very tough, fibrous, and protective membrane. These meninges extend outward to the nerve roots. The denticulate ligaments are fibrous structures that help to anchor the spinal cord in place. The posterior spinal arteries supply the dorsal spinal cord with blood and run just medial to the dorsal root entry zone. The lower illustration shows an anterior (ventral) view of the spinal cord with the meninges stripped away. Both the dorsal and the ventral roots consist of a convergence of rootlets that provide a continuous dorsal and ventral array of rootlets along the entire longitudinal extent of the spinal cord.

CLINICAL POINT Groups of contiguous dorsal and ventral spinal rootlets converge to form the major dorsal and ventral roots associated with each level of the spinal cord. Herniation of an intervertebral disc, usually resulting from a flexion injury, may cause the nucleus pulposus to extrude in a posterolateral direction and impinge on a dorsal root. The L5–S1 and L4–L5 discs are most commonly involved in the lower extremities, and the C6–C7, C5–C6, and C4–C5 discs in the upper extremities. Sharp, radiating pain in the territory of the nerve root is the most common symptom. In some disc herniations, a specific muscle-­stretch reflex may be absent or diminished. When there is compression of a dorsal root, there will not be a corresponding nerve root territory in which anesthesia is present, unlike in a branch lesion of the trigeminal nerve; the dorsal roots send sensory axons to at least three dermatomal segments and have sufficient overlap that an isolated root lesion is unlikely to produce complete anesthesia in that territory. Compression of a ventral root because of disc herniation is less common than that of a dorsal root; it may be accompanied by significant weakness in the muscles supplied by that ventral root.   

Spinal Cord A. Section through thoracic vertebra

Vertebral body

83

Epidural space (with epidural fat) Dura mater

Sympathetic ganglion

Arachnoid

Ventral root

Subarachnoid space

Rami communicans

Pia mater (adherent to spinal cord)

Dorsal root Dorsal root (spinal) ganglion Spinal nerve Ventral ramus (intercostal nerve)

Dorsal ramus Spinous process

B. Section through lumbar vertebra

Sympathetic ganglion Ramus communicans Ventral root Spinal nerve Ventral ramus (contributes to lumbar plexus) Filum terminale

Dorsal root (spinal) ganglion

Dorsal ramus Cauda equina

Dorsal root

  5.5 SPINAL CORD: CROSS-­SECTIONAL ANATOMY IN SITU A, The spinal cord in the spinal canal is surrounded by meninges. Dorsal and ventral roots course through the intervertebral foramina. The epidural space, with its associated fat, is sometimes used for the infusion of anesthetics, for example, for pain relief during childbirth. Arteries and veins are associated with the spinal nerves and nerve roots. Some segmental arteries provide crucial anastomotic channels for blood flow from the aorta to augment flow from the anterior and posterior spinal arterial systems, which cannot sustain the entire spinal cord; surgical procedures affecting blood flow through the aorta may affect the spinal cord. The sympathetic chain ganglia (paravertebral), important for fight-­or-­flight responses, lie adjacent to the vertebral body ventrally. The dorsal and ventral rami of the spinal nerves provide innervation to specific regions. The spinous process of the vertebral body extends dorsally, where it can be palpated by physical exam. B, The subarachnoid space of a lumbar vertebra, containing the filum terminale and roots of the cauda equina.

CLINICAL POINT The dorsal and ventral roots travel through the adjacent subarachnoid space and join to form the peripheral nerves. These nerve roots and resultant nerves are sometimes the targets of acute autoimmune inflammatory demyelinating conditions (polyradiculoneuropathy), called Guillain-­Barré syndrome (GBS). GBS is an acute, progressive, symmetrical weakness that usually progresses from distal to proximal in the limbs and may result in total paralysis of all musculature, including respiratory musculature, occurring over the course of hours to days. The weakness is often accompanied by paresthesias in the distal extremities. GBS is commonly preceded by an infectious process, such as Campylobacter jejuni enteritis, Epstein-­Barr syndrome, or cytomegaloviral infections, or by Mycoplasma pneumoniae, which presumably triggers the autoimmune attack on peripheral myelin. Most patients with GBS recover through a remyelinating process, which may take a year or more, although at least 10% are left with severe deficits, and a small percent of individuals die.   

84

Overview of the Nervous System A. Sections through spinal cord at various levels C5

T2

T8

L1

L3

S1 S3

B. Principal fiber tracts of spinal cord (composite) Ascending pathways Descending pathways Fibers passing in both directions Anterior white commissure

Fasciculus gracilis

Lateral (crossed) corticospinal (pyramidal) tract

Fasciculus cuneatus

Rubrospinal tract

Dorsolateral fasciculus (of Lissauer)

Lateral (medullary) reticulospinal tract

Posterior (dorsal) spinocerebellar tract

Anterior or medial (pontine) reticulospinal tract

Spinothalamic tract and spinoreticular tract Anterior (ventral) spinocerebellar tract

Vestibulospinal tract

Spino-olivary tract

Tectospinal tract

Fasciculus proprius

Anterior (uncrossed) corticospinal tract

Medial longitudinal fasciculus

 

5.6 SPINAL CORD: WHITE AND GRAY MATTER A, Seven representative spinal cord levels. The images depict their relative sizes and the variability in the amount of gray matter at each level. Levels associated with the limbs have greater amounts of gray matter. White matter increases in absolute amount from caudal to rostral, reflecting the level-­by-­level addition of ascending tracts and the termination of descending tracts. B, The gray matter consists of dorsal and ventral horns, and in the T1–L2 segments, there is an intermediolateral cell column (lateral horn) where preganglionic sympathetic neurons reside. The white matter is subdivided into dorsal, lateral, and ventral funiculi, each containing multiple tracts (fasciculi, bundles). The tracts conveying pain and temperature information rostrally travel in the anterolateral funiculus, the spinothalamic/spinoreticular system. Fine discriminative sensation is conveyed through the dorsal funiculus. The major descending upper motor neuronal tract, the corticospinal tract, travels mainly in the lateral funiculus, with a component present in the medial part of the anterior funiculus. Dorsal root entry zones and ventral root exit zones are present at each cross-­sectional level.

CLINICAL POINT The spinal cord levels show considerable variation in the size of the dorsal and ventral horns. The cervical and lumbosacral enlargements reflect the large number of sensory, intermediate, and motor neurons necessary for the afferent and efferent innervation of the limbs. The lower motor neurons (LMNs) in these enlargements are particularly vulnerable to poliovirus. Acute poliomyelitis results in the death of some LMNs, with resultant denervation of corresponding muscles, atrophy, flaccid paralysis, and loss of tone and reflexes. Remaining LMNs that survive the viral infection may sprout axons to reoccupy the sites on skeletal muscles left denuded by death of their original LMNs. These remaining LMNs then possess larger motor units (innervate more muscle fibers per cell body); this extra burden may account for some of the later degeneration and weakness seen in postpolio syndrome many decades after the acute disease. Polio is unusual in the United States and Western countries because of widespread vaccination programs, but still occurs in some developing nations. The ascending and descending tracts are clustered in specific zones of the dorsal (posterior), lateral, and ventral (anterior) funiculi. Some regions of these funiculi are selectively vulnerable to vitamin B12 (cobalamin) deficiency; impairment of methylmalonyl-­CoA mutase results in damage to myelinated fibers. Pernicious anemia may precede neurological symptoms by months or years. Damage involves the dorsal funiculi and components of the lateral funiculi. Dorsal column damage is accompanied by paresthesias of the feet and legs and often of the hands and arms, with sensory ataxia and broad-­based gait; by loss of vibratory sensation, joint position sense, and fine discriminatory touch; and by Romberg’s sign. Lateral funiculus damage is accompanied by spastic paraparesis with increased tone and muscle stretch reflexes and plantar extensor responses. Early recognition of this condition and treatment with B12 can lead to rapid reversal and recovery.   

6

VENTRICLES AND THE CEREBROSPINAL FLUID

 6.1 V  entricular Anatomy 6.2 V  entricular Anatomy in Coronal Forebrain Section 6.3 A  natomy of the Fourth Ventricle: Posterior View With Cerebellum Removed 6.4 A  natomy of the Fourth Ventricle: Lateral View 6.5 M  agnetic Resonance Imaging of the Ventricles: Axial and Coronal Views 6.6 C  irculation of the Cerebrospinal Fluid 6.7 H  ydrocephalus and Shunting of the Cerebrospinal Fluid 6.8 N  ormal Pressure Hydrocephalus

85

86

Overview of the Nervous System



Ventricles of Brain

Right lateral ventricle Anterior (frontal) horn Body Inferior (temporal) horn Posterior (occipital) horn

Left lateral ventricle

Cerebral aqueduct (of Sylvius) 4th ventricle

Left lateral aperture (foramen of Luschka) Left interventricular foramen (of Monro)

Left lateral recess

3rd ventricle Median aperture (foramen of Magendie)

Optic recess Interthalamic adhesion Infundibular recess

CSF Composition

Pineal recess Suprapineal recess

CSF

Blood plasma

140–145

135–147

K (mEq/L)

3

3.5–5.0

Cl (mEq/L)

115–120

95–105

HCO3 (mEq/L)

20

22–28

Glucose (mg/dL)

50–75

70–110

0.05–0.07

6.0–7.8

7.3

7.35–7.45

Na (mEq/L)

Protein (g/dL) pH

6.1 VENTRICULAR ANATOMY The lateral ventricles are C-­shaped, reflecting their association with the developing telencephalon as it sweeps upward, back, and then down and forward as the temporal lobe. The position of the lateral ventricles in relation to the head and body of the caudate nucleus is an important radiological landmark in a variety of conditions, such as hydrocephalus, caudate atrophy in Huntington’s disease, and shifting of the midline with a tumor. Cerebrospinal fluid (CSF) flows through the interventricular foramen of Monro into the

narrow third ventricle, then into the cerebral aqueduct and the fourth ventricle. Blockage of flow in the aqueduct can precipitate internal hydrocephalus, with swelling of the ventricles rostral to the site of blockage. The escape sites where CSF can flow into expanded regions of the subarachnoid space called cisterns are the medial foramen of Magendie and the lateral foramina of Luschka. These foramina are additional sites where blockage of CSF flow can occur. The choroid plexus, extending into the ventricles, produces the CSF. See Videos 6.1 and 6.2.

Ventricles and the Cerebrospinal Fluid

87

Corpus callosum Right lateral ventricle Body of caudate nucleus Choroid plexus of lateral ventricle Stria terminalis Right thalamostriate vein Body of fornix Tela choroidea of 3rd ventricle Choroid plexus of 3rd ventricle Thalamus Putamen _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Globus pallidus (internal [i] and external [e] segments) e i

Lentiform nucleus

Internal capsule 3rd ventricle Hypothalamus Tail of caudate nucleus Optic tract Choroid plexus of lateral ventricle Inferior (temporal) horn of lateral ventricle Fimbria of hippocampus

Coronal section of brain (posterior view; arrow in left interventricular foramen)

Hippocampus Dentate gyrus Subiculum Parahippocampal cortex

Ependyma

Pia mater

Entorhinal cortex

 

6.2 VENTRICULAR ANATOMY IN CORONAL FOREBRAIN SECTION A coronal section through the diencephalon shows the bodies of the lateral ventricles, the narrow interventricular foramina of Munro, and the midline third ventricle. The flow of CSF is from

the lateral ventricles into the third ventricle. The choroid plexus protrudes into both the lateral and third ventricles and produces CSF. The temporal (inferior) pole of the lateral ventricle and its associated choroid plexus are shown in the temporal lobe.

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Overview of the Nervous System

Posterior View

3rd ventricle

Habenular trigone

Pulvinar

Lateral Medial

Pineal gland Superior colliculus

Superior cerebellar peduncle

Inferior colliculus

Median sulcus

Trochlear (IV) nerve

Locus coeruleus area

Superior medullary velum

Medial eminence

Superior Cerebellar peduncles

Geniculate bodies

Sulcus limitans

Middle

Facial colliculus

Inferior

Vestibular area

Lateral recess

Dentate nucleus

Superior fovea

Tenia of 4th ventricle

Striae medullares Hypoglossal nerve trigone

Obex

Inferior fovea

Gracile tubercle Tuberculum cinereum (spinal tract of trigeminal nerve) Cuneate tubercle Vagal trigone

Posterior median sulcus Fasciculus cuneatus Fasciculus gracilis

 

6.3 ANATOMY OF THE FOURTH VENTRICLE: POSTERIOR VIEW WITH CEREBELLUM REMOVED The rhomboid-­ shaped fourth ventricle extends through the pons and medulla. The foramina of Magendie and Luschka must remain patent for proper flow of the CSF into the cisterns. Bilaterally symmetrical protrusions, depressions, and sulci on the floor of the fourth ventricle define the underlying anatomy of brainstem regions, such as the hypoglossal, vagal, and vestibular

areas. Vital brainstem centers for cardiovascular, respiratory, and metabolic functions just below the floor of the fourth ventricle can be damaged by tumors in the region. The lateral margins of the fourth ventricle are embraced by the huge cerebellar peduncles interconnecting the cerebellum with the brainstem and diencephalon. These anatomical relationships are important when interpreting imaging studies in the compact brainstem regions where the diagnosis of tumors and vascular lesions is challenging.

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Median Sagittal Section Habenular commissure

Body of fornix Choroid plexus of 3rd ventricle

Pineal gland Splenium of corpus callosum

Interventricular foramen (of Monro)

Great cerebral vein (of Galen)

Thalamus Anterior commissure

Cerebral aqueduct (of Sylvius)

Lamina terminalis

Lingula

Posterior commissure

Central lobule Culmen

Mammillary body

Vermis

Declive

Optic chiasm

Folium

Oculomotor (III) nerve

Tuber

Superior colliculus

Superior medullary velum

Inferior colliculus Pons

Inferior medullary velum

Medial longitudinal fasciculus 4th ventricle

Choroid plexus of 4th ventricle

Medulla (oblongata) Tonsil

Pyramid

Median aperture (of Magendie)

Uvula

Pyramidal decussation

Vermis

Nodule

Central canal of spinal cord

 

6.4 ANATOMY OF THE FOURTH VENTRICLE: LATERAL VIEW In a midsagittal section, the rhomboid shape of the fourth ventricle is shown. Rostrally, the narrow cerebral aqueduct leads into the fourth ventricle; caudally, the foramen of Magendie provides for escape of CSF into a cistern of the subarachnoid space. CSF normally does not flow through the central canal of the spinal cord. The dorsal surface of the brainstem is on the floor of the fourth ventricle, the cerebral peduncles form the lateral boundaries, and the medullary velum and cerebellum form the roof of the fourth ventricle. The choroid plexus is present in the fourth ventricle. In the diencephalon, the shallow depression of the third ventricle and the interventricular foramen of Munro are shown. CLINICAL POINT The choroid plexus is the site of production of CSF in the lateral, third, and fourth ventricles. Even subtle changes in equilibrium between CSF production and absorption can result in altered intraventricular

pressure and intracranial pressure. Hydrocephalus is most commonly caused by obstruction of outflow (internal hydrocephalus) or failure of appropriate absorption into the venous sinuses (external hydrocephalus). Occasionally, alterations in CSF production by the choroid plexus may occur. Inflammation of the choroid plexus or a papilloma can lead to hypersecretion hydrocephalus. In contrast, damage to the choroid plexus by radiation, trauma, or meningitis or secondary to lumbar puncture may result in diminished CSF production (hypoliquorrhea), with resultant long-­lasting and persistent headache that is responsive to change in posture. The CSF escapes from the ventricular system from the medial foramen of Magendie and the lateral foramina of Luschka of the fourth ventricle. These apertures must remain unobstructed in order to allow CSF to escape into the subarachnoid space, bathe the CNS, and then be absorbed into the venous sinuses through the arachnoid granulations. The foramen of Magendie is the most important of these apertures; it may become obstructed by tonsillar herniation into the foramen magnum as the result of Arnold-­Chiari malformation; by a cerebellar tumor; or by an intraventricular tumor that obstructs the lower portion of the fourth ventricle. Such an obstruction at this lower level results in expansion of the entire ventricular system, including the fourth, third, and lateral ventricles.   

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Overview of the Nervous System

Subarachnoid space

Frontal pole, lateral ventricle

Interventricular foramen of Monro

Third ventricle

Temporal pole, lateral ventricle

A. Axial view

Subarachnoid space Frontal pole, lateral ventricle

Interventricular foramen of Monro

Third ventricle Temporal pole, lateral ventricle Cisterns around brainstem

B. Coronal view

 

6.5 MAGNETIC RESONANCE IMAGING OF THE VENTRICLES: AXIAL AND CORONAL VIEWS A and B, These T2-­weighted magnetic resonance images of the brain in axial and coronal sections demonstrate major components of the ventricular system (in white) and some cisternal

structures. Both the frontal and temporal poles of the lateral ventricles are visible. Figure 3.11 also illustrates a T2-­weighted midsagittal image, revealing the midsagittal ventricular system and related cisterns.

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91

Choroid plexus of lateral ventricle

Bridging veins

Superior sagittal sinus Subarachnoid space

Supracallosal cistern Dura mater

Arachnoid granulations

Arachnoid

Chiasmatic cistern Choroid plexus of 3rd ventricle Interpeduncular cistern Cerebral aqueduct (of Sylvius) Prepontine cistern Lateral aperture (foramen of Luschka) Choroid plexus of 4th ventricle Dura mater Arachnoid Subarachnoid space

Cistern of great cerebral vein Cerebellomedullary cistern (cisterna magna) Median aperture (foramen of Magendie)

 

6.6 CIRCULATION OF THE CEREBROSPINAL FLUID CSF flows internally through the ventricles, from lateral ventricles to the third ventricle to the cerebral aqueduct to the fourth ventricle. The CSF passes through several points where blockage or obstruction could precipitate internal hydrocephalus and increased intracranial pressure. CSF flow from the fourth ventricle into the cisterns of the subarachnoid space, surrounding the brain and spinal cord, provides the external protective cushioning and buoyancy to protect underlying central nervous system tissue from minor trauma. Some cisterns such as

the lumbar cistern provide sites for withdrawal of CSF (lumbar puncture). The CSF is absorbed from the subarachnoid space into the venous drainage through the arachnoid granulations by a process driven by the pressure of flow through these one-­way valves. Disruption of this drainage results in external hydrocephalus. Thus, production, flow, and absorption of CSF must be in precise balance. The flow of the CSF in the ventricles also can act as a fluid delivery system for downstream influences of specific mediators (e.g., prostaglandins, interleukins) and represents an internal paracrine communication channel for some structures close to the ventricles.

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Overview of the Nervous System

B. Section through brain showing marked dilation of lateral and 3rd ventricles

A. Clinical appearance in advanced hydrocephalus

C. Potential lesion sites in obstructive hydrocephalus 1. Interventricular foramina (of Monro) 2. Cerebral aqueduct (of Sylvius) 3. Lateral apertures (of Luschka) 4. Median aperture (of Magendie) Lateral ventricle

1

1

Reservoir at end of cannula implanted beneath galea permits transcutaneous needle puncture for withdrawal of CSF or introduction of antibiotic medication or dye to test patency of shunt

Drainage tube may be introduced into internal jugular vein and then into right atrium via neck incision, or may be continued subcutaneously to abdomen 3rd ventricle

4th ventricle

Cannula inserted into anterior horn of lateral ventricle through trephine hole in skull

One-way, pressure-regulated valve placed subcutaneously to prevent reflux of blood or peritoneal fluid and control CSF pressure

2

3

3

D. Shunt procedure for hydrocephalus

Drainage tube is most often introduced into peritoneal cavity, with extra length to allow for growth of child

4

E. Head measurement is of

value in diagnosis, especially in early cases, and serial measurements will indicate progression or arrest of hydrocephalus

 

6.7 HYDROCEPHALUS AND SHUNTING OF THE CEREBROSPINAL FLUID Hydrocephalus presents as enlargement of the ventricles and increased intracranial pressure. In infants, whose cranial bones have not fused, head size may enlarge, with bulging fontanelles (A). Hydrocephalus due to obstruction, which blocks outflow of the CSF and produces enlarged ventricles above the site of obstruction (B). C shows potential lesion sites in obstructive

hydrocephalus. Nonobstructive hydrocephalus occurs because of diminished absorption of CSF into the venous sinuses via the arachnoid granulations; its etiology may be due to infection (e.g., acute purulent meningitis), hemorrhage (intraventricular or subarachnoid), trauma, or tumor spread. A frequent surgical approach to hydrocephalus is the placement of a shunt, draining CSF into the internal jugular vein or the peritoneal cavity (D).

Ventricles and the Cerebrospinal Fluid

93

B. Ventricles distended, compressing brain tissue

A. Masked facies Speech terse, abbreviated, telegraphic; difficulty in persevering—noted in counting backward 20..19...18......17...........16 Stooped posture

Fades out

Incontinence Magnetic gait; wide based with short steps as if feet glued to floor

C. Shunting may potentially relieve symptoms but may cause hemorrhage along cannula tract, brain edema, subdural hematoma, and infection.

Subdural hematoma Pus

Hemorrhage

D. Axial FLAIR images demonstrate moderate

enlargement of the third and lateral ventricles, more normal sulcal pattern, and patchy periventricular increased T2 changes.

 

6.8 NORMAL PRESSURE HYDROCEPHALUS Normal pressure hydrocephalus is a syndrome in older adults associated with neurological signs and symptoms and enlarged ventricles (B, C, D) in the absence of increased intracranial pressure. The increased ventricular size is not attributable to brain atrophy (B, C, D). The condition may occur slowly, over the course of a year or more. The enlarged ventricles may compress frontal white matter.

Clinical manifestations of normal pressure hydrocephalus include progressive dementia, stooped posture, “glue-­ footed gait,” and urinary incontinence. Shunting may relieve some of the symptoms but has the risk of infection, bleeds, and brain edema (C). The etiology of normal pressure hydrocephalus may be degeneration of arachnoid granulations and diminished CSF absorption.

7

VASCULATURE

Arterial System

7.18 Vertebrobasilar Arterial System

7.1 Meningeal Arteries: Relationship to Skull and Dura

7.19 Angiographic Anatomy of the Vertebrobasilar System

7.2 Arterial Supply to the Brain and Meninges

7.20 Occlusive Sites of the Vertebrobasilar System

7.3 Common Sites of Cerebrovascular Occlusive Disease

7.21 Vascular Supply to the Hypothalamus and the Pituitary Gland

7.4 Internal Carotid and Ophthalmic Artery Course and Cavernous Sinus Fistula 7.5 Arterial Distribution to the Brain: Basal View 7.6 Arterial Distribution to the Brain: Cutaway Basal View Showing the Circle of Willis 7.7 Arterial Distribution to the Brain: Frontal View With Hemispheres Retracted

7.22 Arterial Blood Supply to the Spinal Cord: Longitudinal View 7.23 Anterior and Posterior Spinal Arteries and Their Distribution 7.24 Arterial Supply to the Spinal Cord: Cross-­Sectional View

Venous System

7.8 Arterial Distribution to the Brain: Coronal Forebrain Section

7.25 Meninges and Superficial Cerebral Veins

7.9 Types of Strokes

7.26 Veins: Superficial Cerebral, Meningeal, Diploic, and Emissary

7.10 Lacunar Infarcts 7.11 Schematic of Arteries to the Brain 7.12 Circle of Willis: Schematic Illustration and Vessels in Situ

7.27 Venous Sinuses 7.28 Deep Venous Drainage of the Brain

7.13 Intracranial Aneurysms and Subarachnoid Hemorrhage

7.29 Deep Venous Drainage of the Brain: Relationship to the Ventricles

7.14 Arterial Distribution to the Brain: Lateral and Medial Views

7.30 Carotid Venograms: Venous Phase

7.15 Territories of the Cerebral Arteries

7.31 Magnetic Resonance Venography: Coronal and Sagittal Views

7.16 Magnetic Resonance Angiography: Frontal and Lateral Views 7.17 Angiographic Anatomy of the Internal Carotid Circulation

7.32 Venous Drainage of the Brainstem and the Cerebellum 7.33 Venous Drainage of the Spinal Cord

Vasculature

95

 Arachnoid granulations Parietal (posterior) and frontal (anterior) branches of middle meningeal artery

Opening of superior cerebral vein Venous lacuna

Middle meningeal artery

Superior sagittal sinus Dura mater

Anterior meningeal artery (from anterior ethmoidal artery)

Mastoid branch of occipital artery

Anterior and posterior meningeal branches of vertebral artery Mastoid branch of occipital artery

Meningeal branches of ascending pharyngeal artery Tentorial branch (cut) and dorsal meningeal branch of meningohypophyseal trunk Middle and accessory meningeal arteries Meningeal branch of posterior ethmoidal artery Anterior meningeal artery (from anterior ethmoidal artery) Internal carotid artery and its meningohypophyseal trunk (in phantom) Middle meningeal artery Accessory meningeal artery Superficial temporal artery Maxillary artery Posterior auricular artery Occipital artery External carotid artery

ARTERIAL SYSTEM 7.1 MENINGEAL ARTERIES: RELATIONSHIP TO SKULL AND DURA Meningeal arteries are found in the outer portion of the dura; they supply it with blood. They also help to supply blood to adjacent skull and have some anastomoses with cerebral arteries. The skull has grooves, or sulci, for the meningeal vessels. This relationship reflects an important functional consequence of skull fractures.

Fractures can rip a meningeal artery (usually the middle meningeal artery) and allow arterial blood to accumulate above the dura. Such an epidural hematoma is a space-­occupying mass and can produce increased intracranial pressure and risk for herniation of the brain, particularly across the free edge of the tentorium cerebelli. Even very fine fractures can have this dangerous consequence.

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Overview of the Nervous System

Left middle meningeal artery

Right and Ieft middle cerebral arteries

Right and Ieft posterior cerebral arteries

Right and Ieft anterior cerebral arteries Anterior communicating artery

Right and Ieft superior cerebellar arteries

Right ophthalmic artery Right posterior communicating artery

Basilar artery Mastoid branch of Ieft occipital artery

Cavernous sinus

Left internal auditory (labyrinthine) artery

Right deep temporal artery

Posterior meningeal branch of Ieft ascending pharyngeal artery

Right maxillary artery Right middle meningeal artery

Right and Ieft anterior inferior cerebellar arteries

Right superficial temporal artery

Right and Ieft posterior inferior cerebellar arteries

Right external carotid artery

Posterior meningeal branches of right and Ieft vertebral arteries

Right facial artery Right lingual artery

Anterior meningeal branch of right vertebral artery

Carotid body Right superior laryngeal artery

Right posterior auricular artery Right occipital artery

Right superior thyroid artery

Right internal carotid artery

Thyroid cartilage

Right ascending pharyngeal artery

Right common carotid artery

Right carotid sinus Right vertebral artery

Right inferior thyroid artery

Transverse process of C6

Right internal thoracic artery

Right deep cervical artery Brachiocephalic trunk

Right thyrocervical trunk Right costocervical trunk Right subclavian artery

 

7.2 ARTERIAL SUPPLY TO THE BRAIN AND MENINGES The internal carotid artery (ICA) and the vertebral artery ascend through the neck and enter the skull to supply the brain with blood. The tortuous bends and sites of branching (such as the bifurcation of the common carotid artery into the internal and external carotids) produce turbulence of blood flow and are sites where atherosclerosis can occur. The bifurcation of the common carotid is particularly vulnerable to plaque formation and occlusion, threatening the major anterior part of the brain with ischemia, which would result in a stroke. The ICA passes through the cavernous sinus, a site where carotid-­cavernous fistulae can occur, resulting in damage to the extraocular and trigeminal cranial nerves, which also pass through this sinus. Studies of blood flow through these arteries are important diagnostic tools. Magnetic resonance arteriography and Doppler flow studies have, for most purposes, replaced the older dye studies for performing cerebral angiography.

CLINICAL POINT The paired carotid arteries and vertebral arteries supply the brain and part of the spinal cord with blood. The carotids supply the anterior circulation, including most of the forebrain except for the occipital lobe and inferior surface of the temporal lobe. The bifurcation of the common carotid artery is a common site of plaque formation in atherosclerosis, leading to gradual occlusion of blood flow to the forebrain on the ipsilateral side. Early warnings can be seen in the form of transient ischemic attacks, forerunners of a full-­blown stroke. The best treatment is prevention, with exercise, proper diet and weight control, and careful regulation of lipid levels and other contributing factors such as inflammatory mediators. In cases in which severe and symptomatic occlusion has occurred as the result of atherosclerotic plaque, carotid endarterectomy can be performed to remove the plaque and attempt to open up more robust flow to the anterior circulation. Carefully performed controlled studies have established criteria that determine which patients can best benefit from this surgical procedure as opposed to more conservative medical treatment. Current studies are investigating the use of carotid stents to enhance blood flow to the brain.   

Vasculature

97

Middle cerebral artery origin Basilar artery Anterior cerebral artery origin

Fourth segment of vertebral artery

Siphon portion of internal carotid artery

Carotid bifurcation

First segment of vertebral artery Proximal subclavian artery

 

7.3 COMMON SITES OF CEREBROVASCULAR OCCLUSIVE DISEASE Atherosclerosis is the most common cause of internal carotid disease, accounting for many cerebral ischemic events, particularly in the elderly. Atherosclerotic plaques are formed by deposition of circulating lipids and the accumulation of fibrous tissue in the subintimal layer of large and medium arteries, exacerbated by the presence of inflammatory mediators and shearing forces from hypertension. Plaque formation particularly occurs at arterial branch points, where turbulence is maximal. Disruption of the endothelial surface can result in thrombus formation, platelet aggregation, and production of emboli,

which are carried upstream into end branches of the vascular system. In addition to genetic factors, predisposing risks for atherosclerotic plaque formation include smoking, type 2 diabetes, hypertension, and hypercholesterolemia. Illustrated here are the most common sites for atherosclerosis in the cerebral circulation, including the bifurcation of the common carotid artery and origin of the internal carotid artery, carotid siphon, main stems of the middle and anterior cerebral arteries, proximal subclavian artery, first segment of the vertebral artery, fourth segment of the vertebral artery, and basilar artery.

98

Overview of the Nervous System Cavernous sinus Internal carotid artery Ophthalmic artery Vidian nerve Maxillary nerve Carotid plexus Great superficial petrosal nerve Nervus intermedius

A. Internal carotid and ophthalmic artery course: lateral view

Facial nerve

Internal carotid artery Carotid nerve Superior cervical ganglion

Spheno-palatine ganglion

B. Cavernous sinus fistula

Superior and inferior ophthalmic veins Rupture of internal carotid artery into cavernous sinus (greatly dilated) Superior petrosal sinus

Supraorbital vein Supratrochlear vein Angular vein Pulsating exophthalmos Chemosis

Dilation of retinal veins, papilledema, and progressive loss of vision Retromandibular (posterior facial) vein Internal carotid artery Internal jugular vein

Facial (anterior facial) vein Pterygoid plexus

 

7.4 INTERNAL CAROTID AND OPHTHALMIC ARTERY COURSE AND CAVERNOUS SINUS FISTULA The ophthalmic artery is the first major branch of the ICA. It supplies the eyeball, ocular muscles, and adjacent structures with blood. This artery is commonly involved in the first phases of clinical recognition of cerebro-­vascular disease. Because of its position as the first branch of the ICA, emboli from atherosclerotic plaques that are found at sites such as the bifurcation of the common carotid artery may travel through the ophthalmic artery, resulting in a transient ischemic attack with the symptom of fleeting blindness (amaurosis fugax) in the affected eye.

The carotid artery may rupture into the cavernous sinus, forming a carotid-­cavernous fistula. This occurs mainly from trauma, but also from a ruptured intracavernous aneurysm or an infection. This syndrome is characterized by pulsating exophthalmos from engorged superior and inferior ophthalmic veins, conspicuous diplopia, damage to an extraocular nerve (III, IV, and VI), visual loss from flow changes in the central retinal artery, headache, and chemosis (edema of the conjunctiva). This condition does not resolve spontaneously and requires surgical intervention, usually involving selective occlusion of the fistula with the carotid artery remaining intact.

Vasculature

99

Anterior communicating artery Anterior cerebral artery

Circle of Willis (dotted outline)

Recurrent artery (of Heubner) Internal carotid artery Medial and lateral lenticulostriate arteries Middle cerebral artery Lateral orbitofrontal artery Ascending frontal (candelabra) branch Anterior choroidal artery Posterior communicating artery Posterior cerebral artery Superior cerebellar artery Basilar artery and pontine branches Internal auditory (labyrinthine) artery Anterior inferior cerebellar artery Vertebral artery Anterior spinal artery Posterior inferior cerebellar artery Posterior spinal artery

 

7.5 ARTERIAL DISTRIBUTION TO THE BRAIN: BASAL VIEW The anterior circulation (middle and anterior cerebral arteries; MCAs, ACAs) and the posterior circulation (the vertebrobasilar system and its end branch, the posterior cerebral artery; PCA) and their major branches are shown. The right temporal pole is removed to show the course of the MCA through the lateral fissure. The circle of Willis (the paired ACAs, MCAs, and PCAs and the anterior and two posterior communicating arteries) surrounds the basal hypothalamic area. The circle of Willis appears to allow free flow of blood around the anterior and posterior circulation of both sides but usually it is not sufficiently patent to allow bypass of an occluded zone. See Video 7.­1.

CLINICAL POINT The vertebrobasilar system supplies blood to the posterior circulation of the brain, including most of the brainstem, part of the diencephalon, and the occipital and inferior temporal lobes of the forebrain. The paired PCAs are the end arteries of the vertebrobasilar system. An infarct in the PCAs (top of the basilar infarct) results in damage to the ipsilateral occipital lobe, including both the upper and lower banks of the calcarine fissure. Functionally, this infarct affecting one side results in contralateral blindness, called contralateral homonymous hemianopia. There may be macular sparing if the MCA has some anastomoses with the posterior cerebral circulation.   

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Overview of the Nervous System

Anterior communicating artery Recurrent artery (of Heubner) Anterior cerebral artery Middle cerebral artery Posterior communicating artery Anterior choroidal artery Optic tract Cerebral peduncle Lateral geniculate body Posterior medial choroidal artery Posterior lateral choroidal artery Choroid plexus of lateral ventricle Medial geniculate body Pulvinar Lateral ventricle

 

7.6 ARTERIAL DISTRIBUTION TO THE BRAIN: CUTAWAY BASAL VIEW SHOWING THE CIRCLE OF WILLIS The circle of Willis and the course of the choroidal arteries are shown. The arteries supplying the brain are end arteries and do not have sufficient anastomotic channels with other arteries to sustain blood flow in the face of disruption. The occlusion of an artery supplying a specific territory of the brain results in functional damage that affects the performance of structures deprived of adequate blood flow. See Video 7.­2.

CLINICAL POINT Obstruction of the MCA near its origin is relatively unusual compared with obstruction or infarcts in selected branches, but it demonstrates the full range of blood supply of this critical artery. Obstruction near the origin usually results from embolization, not from atherosclerotic or thrombotic lesions. It causes contralateral hemiplegia (resolving to spastic), contralateral central facial palsy (lower face), contralateral hemianesthesia, contralateral homonymous hemianopia, and global aphasia if the left hemisphere is involved. Additional problems with anosognosia (inability to recognize a physical disability), contralateral neglect, and spatial disorientation may occur.   

Vasculature

101

Frontal View with Hemispheres Retracted, Tilted for a View of the Ventral Brainstem Paracentral artery

Corpus callosum Medial and lateral lenticulostriate arteries

Frontal branches

Lateral orbitofrontal artery

Pericallosal artery Callosomarginal artery

Ascending frontal (candelabra) branch

Frontopolar artery Anterior and posterior parietal branches Anterior cerebral arteries

Precentral (prerolandic) and central (rolandic) branches

Medial orbitofrontal artery Recurrent artery (of Heubner)

Angular branch Temporal branches (posterior, middle, anterior)

Internal carotid artery

I

Middle cerebral artery and branches, deep in lateral cerebral (sylvian) fissure

Anterior choroidal artery

II IV

III

Anterior communicating artery

V

Posterior communicating artery

VII VIII

VI

IX XII X

Superior cerebellar artery Anterior inferior cerebellar artery Posterior spinal artery

Posterior cerebral artery Basilar artery Internal auditory (labyrinthine) artery Vertebral artery Posterior inferior cerebellar artery

XI Anterior spinal artery

 

7.7 ARTERIAL DISTRIBUTION TO THE BRAIN: FRONTAL VIEW WITH HEMISPHERES RETRACTED With the hemispheres retracted, the course of the ACAs and their distribution along the midline are visible. This artery supplies blood to the medial zones of the sensory and motor cortex, which are associated with the contralateral lower extremity; an ACA stroke thus affects the contralateral lower limb. With the lateral fissure opened up, the MCA is seen to course laterally and to give branches to the entire convexity of the hemisphere. End-­branch infarcts of the MCA affect the contralateral upper extremity and, if on the left, also affect language function. More proximal MCA infarcts affecting the MCA distribution to the internal capsule can cause full contralateral hemiplegia with drooping of the contralateral lower face; this results from damage to corticospinal and other corticomotor fibers traveling in the posterior limb of the internal capsule and damage to corticobulbar fibers traveling in the genu of the internal capsule.

CLINICAL POINT The ACA branches from the internal carotid as it splits from the middle cerebral artery. It supplies a medial strip of the forebrain with blood. ACA occlusion is usually caused by embolization, although an anterior communicating artery aneurysm, vasospasm resulting from a subarachnoid hemorrhage, or subfalcial herniation can occlude this artery. If the ACA is occluded distal to the recurrent artery of Heubner, it results in contralateral spastic paresis and sensory loss in the lower extremity. A more proximal lesion involving the recurrent artery of Heubner may involve the upper body and limb as well. In addition, there may be internal sphincter weakness of the urinary bladder, frontal release signs, and conjugate deviation of the eyes toward the side of the lesion (damage to frontal eye fields with unopposed deviation from the intact side).   

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Overview of the Nervous System

Coronal Section through the Head of the Caudate Nucleus

Frontal horn of lateral ventricle Corpus striatum (head of the caudate and putamen) Medial and lateral lenticulostriate arteries

Falx cerebri

Callosomarginal arteries and Pericallosal arteries (branches of anterior cerebral arteries)

Limen of insula

Insula Precentral (prerolandic), central (rolandic) and parietal branches Lateral cerebral (sylvian) fissure

Temporal branches

Temporal lobe

Middle cerebral artery

Internal carotid artery

Body of corpus callosum Internal capsule (anterior limb)

Septum pellucidum

Rostrum of corpus callosum Anterior cerebral arteries Recurrent artery (of Heubner) Anterior communicating artery Optic chiasm

 

7.8 ARTERIAL DISTRIBUTION TO THE BRAIN: CORONAL FOREBRAIN SECTION The MCA is the major continuation of the ICA. The MCA travels through the lateral fissure, supplying branches both to deep structures and to the convexity of the cerebral cortex. The lenticulostriate arteries, sometimes called the arteries of stroke, are thin

branches of the MCA that penetrate into the basal ganglia and internal capsule regions of the forebrain. A stroke in this territory produces a classic contralateral hemiplegia (spastic), often worse in the upper extremity, contralateral anesthesia on the body, and aphasia (if on the left side).

Vasculature

Ischemic

Diagnosis of Stroke Stroke

103

Hemorrhagic

Thrombosis Infarct

Clot in carotid artery extends directly to middle cerebral artery Subarachnoid hemorrhage (ruptured aneurysm)

Embolism Infarct

Clot fragment carried from heart or more proximal artery Hypoxia Infarcts

Intracerebral hemorrhage (hypertensive) Hypotension and poor cerebral perfusion: border zone infarcts, no vascular occlusion

 

7.9 TYPES OF STROKES There are two types of strokes, ischemic and hemorrhagic. The ischemic strokes include thrombotic strokes, embolic strokes, and hypoxic strokes. The hemorrhagic strokes include subarachnoid hemorrhages (ruptured aneurysm) and intracerebral hemorrhages (hypertensive strokes or bleeds associated with anticoagulant medication).

CLINICAL POINT There are three main categories of central nervous system (CNS) ischemia. Thrombotic ischemia (atherosclerosis, plaque buildup) is a local problem of narrowed lumen, leading to significantly reduced blood flow, which ultimately leads to a clot that totally obstructs the artery. Embolic ischemia is caused by clots from a downstream source (cardiac, aortic, proximal arterial) that move distally and block flow in the arterial site where they lodge. Hypoxic or hypotensive ischemia, from cardiac dysfunction or cardiac arrest or from significant bleeding, severe dehydration, or shock, results in inadequate perfusion of the brain and inadequate delivery of oxygen and glucose to neurons.   

104

Overview of the Nervous System

Myelin-stained brain section showing extensive demyelination

Small (100-µm) artery within brain parenchyma showing typical pathologic changes secondary to hypertension. Vessel lumen almost completely obstructed by thickened media and enlarged to about 3 times normal size. Pink-staining fibrinoid material within walls.

Lacunar infarcts in base of pons interrupting some corticospinal (pyramidal) fibers. Such lesions cause mild hemiparesis.

Multiple bilateral lacunes and scars of healed lacunar infarcts in thalamus, putamen, globus pallidus, caudate nucleus, and internal capsule. Such infarcts produce diverse symptoms.

 

7.10 LACUNAR INFARCTS Lacunar infarcts are occlusive lesions of small deep arteries, penetrating arteries that arise perpendicular to their main artery of origin. Susceptible arteries include the lenticulostriate penetrating arteries from the middle cerebral artery, branches of the recurrent artery of Heubner (a branch of the anterior cerebral artery), thalamogeniculate branches from the posterior cerebral artery,

and penetrating paramedian branches of the basilar artery, especially in the pons. These infarcts are frequently the consequence of hypertension. Lacunar infarcts produce circumscribed areas of ischemic damage of 20 mm or less. The most common sites include the putamen and globus pallidus, the pons, the thalamus, the caudate nucleus, and the internal capsule and corona radiata. Such infarcts do not occur in the cerebral cortex or cerebellum.

Vasculature

Anterior cerebral artery

1 Anterior communicating artery

Middle cerebral artery

Ophthalmic artery

Posterior communicating artery Caroticotympanic branch of internal carotid artery

3

Posterior cerebral artery

3

2

3

Supraorbital artery 1

Dorsal nasal artery

3

Anterior tympanic artery

Middle meningeal artery

Middle meningeal artery Maxillary artery

1 1

4

Basilar artery

Posterior inferior cerebellar artery

Supratrochlear artery Lacrimal artery

Superior cerebellar artery

Anterior inferior cerebellar artery

105

4

5

5

5

5 5

Common carotid artery 5

Facial artery

Lingual artery

Anterior spinal artery Spinal segmental medullary branches Vertebral artery

Ascending cervical artery Inferior thyroid artery

Posterior auricular artery

Ascending pharyngeal artery

Superior thyroid artery

Vertebral artery

Superficial temporal artery

Occipital artery

External carotid artery Internal carotid artery

5

Angular artery

5

Thyrocervical trunk

Common carotid artery Deep cervical artery Transverse cervical artery Suprascapular artery Supreme intercostal artery Costocervical trunk

Subclavian artery Brachiocephalic trunk

Arch Aorta

Descending Ascending

Subclavian artery Internal thoracic artery

Anastomoses 1 Right–Left 2 Carotid–Vertebral 3 Internal carotid–External carotid 4 Subclavian–Carotid 5 Subclavian–Vertebral

 

7.11 SCHEMATIC OF ARTERIES TO THE BRAIN This schematic diagram shows the entire layout of the arterial blood supply to the brain, including anastomoses. The circle of Willis is present in the upper central portion of this schematic.

The relative separation of the anterior (MCA, ACA) and posterior (vertebrobasilar system, PCA) circulation is evident in this diagram. See Videos 7.­3 and 7.­4.

106

Overview of the Nervous System Vessels Dissected Out: Inferior View Anterior cerebral artery (A2 segment)

Medial striate artery (recurrent artery of Heubner) Anteromedial central (perforating) arteries

Anterior communicating artery

Hypothalamic artery

Anterior cerebral artery (A1 segment)

Anterolateral central (lenticulostriate) arteries

Ophthalmic artery Internal carotid artery Middle cerebral artery

Superior hypophyseal artery

Posterior communicating artery

Inferior hypophyseal artery

Posterior cerebral artery (P2 segment) (P1 segment)

Anterior choroidal artery Thalamotuberal (premammillary) artery Posteromedial central (perforating) artery

Superior cerebellar artery

Thalamoperforating artery

Basilar artery

Posteromedial central (paramedian) arteries

Pontine arteries

Labyrinthine (internal acoustic) artery

Anterior inferior cerebellar artery Vertebral artery

Vessels in Situ: Inferior View Anterior cerebral artery

Anterior communicating artery Optic chiasm

Hypothalamic artery Internal carotid artery

Cavernous sinus

Superior hypophyseal artery

Infundibulum (pituitary stalk) and long hypophyseal portal veins

Middle cerebral artery

Adenohypophysis (anterior lobe of pituitary gland) Inferior hypophyseal artery

Neurohypophysis (posterior lobe of pituitary gland)

Posterior communicating artery Efferent hypophyseal veins

Posteromedial central (perforating) arteries

Posterior cerebral artery

Superior cerebellar artery Basilar artery

  7.12 CIRCLE OF WILLIS: SCHEMATIC ILLUSTRATION AND VESSELS IN SITU The circle of Willis surrounds the optic tracts, pituitary stalk, and basal hypothalamus. It includes the three sets of paired cerebral arteries plus the anterior communicating artery, interconnecting the ACAs, and the posterior communicating arteries, interconnecting the MCAs and PCAs. The free flow of arterial blood through the communicating arteries usually is insufficient to perfuse the brain adequately in the face of an occlusion to a major cerebral artery; the circle of Willis is fully patent and functional for free flow through the communicating arteries in only approximately 20% of individuals. The circle of Willis is the most common site of cerebral aneurysms.

CLINICAL POINT Saccular, or berry, aneurysms account for more than 80% of all intracranial aneurysms; they are outpouchings of cerebral arteries that probably form over a relatively short period of time (days to weeks). The most likely site of these berry aneurysms is at the junctions of arteries in the circle of Willis. Rupture of the aneurysm results in arterial bleeding into the cerebrospinal fluid (subarachnoid hemorrhage), which produces an acute, excruciating headache, nausea, vomiting, signs of meningeal irritation, and sometimes loss of consciousness. A sudden subarachnoid hemorrhage may be immediately fatal. Autopsy studies show that most cerebral aneurysms never rupture. Untreated ruptured aneurysms have approximately a onethird likelihood of rebleeding within 2 months, sometimes with fatal results; other sequelae are cerebral infarction and vasospasm of the affected vessel. Treatment sometimes involves clipping the aneurysm or occluding it with coils or balloons.   

Vasculature

107

A. Distribution of congenital cerebral aneurysms Anterior cerebral 30% Distal anterior cerebral 5% Anterior communicating 25% Internal carotid 30% Ophthalmic 4% Anterior circulation 85% Posterior communicating 18% Bifurcation 4% Anterior choroidal 4% Middle cerebral 25% Posterior cerebral 2% (Posterior communicating and distal posterior cerebral) Basiliar 10% Bifurcation 7%

Posterior circulation 15%

Basilar trunk 3% Vertebral—posterior inferior cerebellar 3%

B. Aneurysm of middle cerebral artery C. Aneurysm of anterior cerebralanterior communicating arteries

D. Aneurysm of posterior inferior cerebellar artery

 

7.13 INTRACRANIAL ANEURYSMS AND SUBARACHNOID HEMORRHAGE Saccular (berry) aneurysms are outpouchings of major arteries, often associated with the circle of Willis (85%) or with sites experiencing turbulent blood flow. Many individuals (2–5%) have such aneurysms that never rupture or bleed. The distribution of aneurysms and their clinical manifestations are show in the diagram above. Ruptured aneurysms are the most common cause of spontaneous subarachnoid hemorrhage. The wall of the berry aneurysm

may be thin due to the lack of a second layer of internal elastic lamina, leading to a risk of rupture. An aneurysm may grow in size during adulthood, but the neck of the aneurysm emerging from the parent artery is usually small and does not grow. Rupture of the aneurysm into the subarachnoid space produces an acute, excruciating headache (“the worst headache of my life”), nausea, vomiting, signs of meningeal irritation, and loss of consciousness. It may be rapidly fatal. Treatment involves clipping the aneurysm to prevent it from bleeding or occluding it with coils or a balloon.

108

Overview of the Nervous System

Anterior parietal branch

Posterior parietal branch

Central (rolandic) branch

Angular branch

Precentral (prerolandic) branch

Terminal cortical branches of Ieft posterior cerebral artery

Ascending frontal (candelabra) branch Terminal cortical branches of anterior cerebral arteries Lateral orbitofrontal artery

Posterior temporal branches

Left middle cerebral artery Anterior temporal branches

Left anterior cerebral artery Anterior communicating artery Right anterior cerebral artery Left internal carotid artery

A. Lateral view Pericallosal artery Internal frontal branches

Paracentral artery

Posterior Middle Anterior

Precuneal artery Right posterior cerebral artery Posterior pericallosal artery

Callosomarginal artery

Parietooccipital branch

Frontopolar artery

Posterior temporal branch Right anterior cerebral artery

Anterior temporal branch Calcarine branch

Medial orbitofrontal artery Anterior communicating artery Recurrent artery (of Heubner) Right internal carotid artery

Posterior communicating artery

B. Medial view

 

7.14 ARTERIAL DISTRIBUTION TO THE BRAIN: LATERAL AND MEDIAL VIEWS A, The MCA sends named branches along the surface of the hemispheric convexity into the frontal and parietal lobes and into the anterior and middle regions of the temporal lobes. Occlusion disrupts sensory and motor functions in the contralateral body, especially the upper extremity, or in the entire contralateral body if the blood supply to the internal capsule is affected. B, The ACA distributes to the midline region of the frontal and parietal lobes. Occlusion disrupts sensory and motor functions in the contralateral lower extremity. The PCA distributes to the occipital lobe and the inferior surface of the temporal lobe. Occlusion disrupts mainly visual functions in the contralateral visual field.

CLINICAL POINT The MCA is a continuation of the ICA, extending through the lateral fissure to supply branches to the convexity of the hemisphere and penetrating branches. Cerebrovascular “strokes” appear in several forms. Approximately one third are atherosclerotic/sclerotic strokes (usually preceded by a transient ischemic attack); about one third are embolic strokes; close to 20% are lacunar (small distal) infarcts; 10% are cerebral hemorrhages; and a small percent are ruptured aneurysms or arteriovenous malformations. Lacunar infarcts are small infarcts (between 3 to 4 μm and 2 cm in diameter) in small penetrating vessels supplying the putamen, caudate, internal capsule, thalamus, pons, and cerebral white matter. They occur most commonly as atherosclerosis-­ related infarcts, particularly in the presence of hypertension or diabetes. Symptoms are determined by which region of the brain is involved; they can include weakness, hemiplegia, contralateral loss of sensation, ataxia, and other symptoms.   

Vasculature

109

Anterior cerebral artery

Middle cerebral artery

Posterior cerebral artery

 

7.15 TERRITORIES OF THE CEREBRAL ARTERIES The specific midline and lateral territories of distribution of the ACA, MCA, and PCA illustrate the exclusive zones supplied by

these major arteries and make particularly clear the watershed zones at the junctions of the major cerebral arteries.

110

Overview of the Nervous System

Anterior cerebral artery Internal carotid artery Middle cerebral artery

Posterior cerebral artery

Basilar artery Vertebral artery

A. Axial view Branches of middle cerebral artery Middle cerebral arteries Internal carotid arteries

B. Lateral view

Posterior cerebral artery Basilar artery Vertebral arteries

Midline portion, anterior cerebral artery Middle cerebral artery Anterior cerebral artery Basilar artery

Internal carotid artery Vertebral artery

Common carotid artery

Subclavian artery Brachiocephalic trunk Aortic arch

C. Coronal full vessel view

  7.16 MAGNETIC RESONANCE ANGIOGRAPHY: FRONTAL AND LATERAL VIEWS A, Axial view. B, Lateral view. C, Coronal full vessel view. The technique of magnetic resonance angiography (MRA) exploits the properties of macroscopic blood flow to render images of cerebral blood vessels. Depending on the technique, the blood signal can be made to appear dark or bright; with conventional spin-­echo pulse sequences, the blood vessels appear dark, and with gradient-­echo pulse sequences, the blood vessels appear bright. There are two types of MRA that are defined mainly by

the two fundamental flow effects in magnetic resonance: time-­ of-­flight phenomena based on magnitude effects and phase contrast phenomena, based on phase-­shift effect. The MRAs in these images were made by using the technique that exploits signal enhancement due to the effects of time of flight. Positive flow contrast is generated by inflow effects, whereas the background (stationary tissue) is saturated by the rapid, repeated application of the radiofrequency pulses; thus the blood signal is higher than that of stationary tissue.

Vasculature

111

Cerebral Angiography Lateral projection

Pericallosal artery

Multiple branches of middle cerebral artery

Callosomarginal artery Parieto-occipital and Anterior cerebral artery

Frontopolar artery

Medial orbitofrontal artery

Ophthalmic artery

Posterior temporal branches of Posterior cerebral artery Posterior communicating artery

Supraclinoid, Cavernous, Petrous, and Cervical segments of internal caroid artery

Frontal projection

Right anterior cerebral artery Anterior choroidal artery Left anterior cerebral artery Medial and lateral lenticulostriate arteries Anterior communicating artery Middle cerebral artery Frontopolar artery Ophthalmic artery Supraclinoid, Cavernous, Petrous, and Cervical segments of internal carotid artery

  7.17 ANGIOGRAPHIC ANATOMY OF THE INTERNAL CAROTID CIRCULATION The top plate is an angiogram that is a lateral view of the ICA circulation after injection of a radiopaque contrast agent into the ICA. The major branches of the ICA, particularly the ACA and MCA, are delineated. The bottom plate is an angiogram that

is a frontal view of the ICA circulation after injection of a radiopaque contrast agent into the common carotid artery. The major branches of this arterial system are delineated. MRA is used commonly to investigate the status of the cerebral arteries, but angiography with contrast agents can provide excellent anatomical details for teaching purposes.

112

Overview of the Nervous System Arteries of Posterior Cranial Fossa

Crura of fornix

Lateral and medial geniculate bodies of left thalamus

choroid plexuses of lateral ventricles

Right Left

Posterior horn of right lateral ventricle Right and left pulvinars

Septum pellucidum Corpus callosum

Splenium of corpus callosum

Anterior cerebral arteries Longitudinal (interhemispheric) fissure

Right posterior pericallosal artery

Heads of caudate nuclei

Parieto-occipital and Calcarine branches of right posterior cerebral artery

Thalamogeniculate arteries Medial and lateral lenticulostriate arteries

Left superior colliculus

Anterior choroidal artery

Superior vermian artery Posterior medial choroidal artery (to choroid plexus of 3rd ventricle)

Anterior cerebral artery Optic (II) nerve and ophthalmic artery Middle cerebral artery Thalamoperforating arteries

III

Left posterior cerebral artery with anterior and posterior temporal branches

V

Posterior communicating artery

VIII

Left internal carotid artery Superior cerebellar artery

Posterior lateral choroidal artery

IV

VI

Lateral marginal branch of superior cerebellar artery

VII

Basilar artery

IX X

Pontine branches Left internal auditory (labyrinthine) artery

Inferior vermian artery (in phantom) Choroidal point and choroidal artery to 4th ventricle

XI

Anterior inferior cerebellar artery

Tonsillohemispheric branches

Posterior inferior cerebellar artery

Outline of 4th ventricle (broken line)

Anterior meningeal branch of vertebral artery

Posterior meningeal branch of vertebral artery Left posterior spinal artery

Left vertebral artery

Anterior spinal artery

 

7.18 VERTEBROBASILAR ARTERIAL SYSTEM The vertebral arteries unite at the midline to form the basilar artery. Medial penetrating branches extend into medial zones of the brainstem, supplying wedgelike territories. Infarcts in these branches can produce “alternating hemiplegias,” resulting in contralateral motor deficits (corticospinal system damage above the decussation of the pyramids), and ipsilateral brainstem/cranial nerve signs and symptoms. The vertebral and basilar arteries also give rise to larger short and long circumferential branches, such as the posterior inferior cerebellar artery (PICA), the anterior inferior cerebellar artery (AICA), and the superior cerebellar artery (SCA). Strokes in these arterial territories generally produce a constellation of ipsilateral brainstem sensory, motor, and autonomic symptoms and contralateral somatosensory symptoms. For example, an infarct in the vertebral artery or the PICA can result in loss of pain and temperature sensation on the contralateral body and the ipsilateral face. The end branch of the basilar artery is the PCA, which distributes to the visual cortex and inferior temporal lobe. Occlusion results in contralateral hemianopsia.

CLINICAL POINT The vertebrobasilar system gives rise to several types of arterial branches. Those located most medially are the paramedian branches. An infarct in such a branch commonly involves ipsilateral damage to a cranial nerve and its function as well as contralateral hemiplegia because of involvement of the corticospinal tract before it decussates on its way to the spinal cord. These infarcts are known as alternating hemiplegias. The short and long circumferential arteries distribute into more lateral territories, and infarcts commonly result in a complex mixture of sensory, motor, and autonomic symptoms, as seen in the lateral medullary syndrome resulting from an infarct in the vertebral artery or the PICA on one side.   

Vasculature

113

Arteries of Posterior Cranial Fossa Vertebral Angiograms: Arterial Phase

A. Lateral projection

Posterior lateral choroidal arteries

Posterior pericallosal artery

Superior cerebellar arteries

Parieto-occipital

Posterior cerebral arteries

Posterior temporal

Thalamoperforating arteries

Inferior vermian artery

Posterior communicating arteries

Tonsillohemispheric branches

Basilar artery Anterior inferior cerebellar artery

B. Frontal projection

Branches of posterior cerebral artery

Calcarine

Posterior inferior cerebellar artery Vertebral artery

Posterior cerebral arteries Superior cerebellar arteries

Anterior inferior cerebellar arteries Basilar artery

Inferior vermian branches of Right and left posterior inferior cerebellar arteries and Left hemispheric branch of left posterior inferior cerebellar artery

Vertebral artery

 

7.19 ANGIOGRAPHIC ANATOMY OF THE VERTEBROBASILAR SYSTEM These figures show angiograms of both lateral and frontal views of the vertebrobasilar (posterior) circulation after injection of a

radiopaque contrast agent into the vertebral artery. The major arterial branches of this system are delineated.

114

Overview of the Nervous System

Posterior cerebral artery

Internal carotid artery Middle cerebral artery

SCA

Posterior communicating artery

Basilar artery

Thalamoperforating arteries to medial thalamus

Pons AICA

Thalamoperforating arteries to lateral thalamus

Vertebral artery

Superior cerebellar artery

Medulla

Basilar artery and obstruction

PICA

Anterior inferior cerebellar artery

Dura

Vertebral artery

Anterior spinal artery Intracranial obstruction of vertebral artery proximal to origin of posterior inferior cerebellar artery (PICA) may be compensated by preserved flow from contralateral vertebral artery. If PICA origin is blocked, lateral medullary syndrome (shown above) may result. Clot also may extend to block anterior spinal artery branch, causing hemiplegia, or embolization to basilar bifurcation may cause “top of basilar” syndrome.

Posterior cerebral artery

C

A

Areas supplied by posterior cerebral arteries (blue) and clinical manifestations of infarction

Posterior cerebral arteries SCA Pons

Medial thalamus and midbrain Hypersomnolence Small, nonreactive pupils Bilateral third cranial nerve palsy Behavioral alterations Hallucinosis

Paramedian and short circumferential penetrating branches Basilar artery (occluded) AICA Medulla Vertebral arteries PICA Anterior spinal artery Collateral circulation via superior cerebellar (SCA), anterior inferior cerebellar (AICA), and posterior inferior cerebellar (PICA) arteries may partially compensate for basilar occlusion. Basilar artery has paramedian, short circumferential and long circumferential (AICA) and (SCA) penetrating branches. Occlusion of any or several of these branches may cause pontine infarction. Occlusion of AICA or PICA may also cause cerebellar infarction.

Lateral thalamus and posterior limb of internal capsule Hemisensory loss Hippocampus and medial temporal lobes Memory loss Splenium of corpus callosum Alexia without agraphia

D

Calcarine area Hemianopsia (or bilateral blindness if both posterior cerebral arteries occluded)

B

 

7.20 OCCLUSIVE SITES OF THE VERTEBROBASILAR SYSTEM A, Arteries of the base of the brainstem, illustrating a vertebral artery/PICA occlusion, and a top of the basilar syndrome. B, Arteries of the brainstem in lateral view, showing potential collateral

circulation among paramedian branches and short and long circumferential branches. C, Vertebrobasilar arterial system with posterior cerebral artery end branches, illustrating a top of the basilar occlusion. D, The territories of brain supplied by the posterior cerebral arteries and the possible functional consequences of occlusion.

Vasculature

115

Hypothalamic vessels

Primary plexus of hypophyseal portal system Long hypophyseal portal veins

Anterior branch Posterior branch

Short hypophyseal portal veins

Superior hypophyseal artery (from internal carotid artery or posterior communicating artery)

Artery of trabecula

Capillary plexus of infundibular process

Trabecula

Posterior lobe Efferent vein to cavernous sinus Anterior lobe Secondary plexus of hypophyseal portal system Stalk

Anterior lobe Posterior lobe

Cavernous sinus

Efferent vein to cavernous sinus Lateral branch and Medial branch of Inferior hypophyseal artery (from the internal carotid artery)

Efferent vein to cavernous sinus

Internal carotid artery Posterior communicating artery Superior hypophyseal artery Portal veins Lateral hypophyseal veins Inferior hypophyseal artery Posterior lobe veins

Inferior aspect

  7.21 VASCULAR SUPPLY TO THE HYPOTHALAMUS AND THE PITUITARY GLAND The superior hypophyseal arteries (from the ICA or the posterior communicating artery) supply the hypothalamus and infundibular stalk and anastomose with branches of the inferior hypophyseal artery (from the ICA). A unique aspect of this arterial distribution is the hypophyseal portal system, whose primary plexus derives from small arterioles and capillaries that then send branches into the anterior pituitary gland. This plexus allows neurons producing hypothalamic releasing factors and inhibitory factors to secrete these factors into the hypophyseal portal system, which delivers a very high concentration directly into the secondary plexus in the anterior pituitary. Thus, anterior pituitary cells are bathed in releasing and inhibitory factors in very high concentrations. This private vascular communication channel allows the hypothalamus to exert fine control, both directly and through feedback, over the secretion of anterior pituitary hormones.

CLINICAL POINT The primary hypophyseal portal system coalesces into long hypophyseal portal veins that give rise to a secondary hypophyseal plexus. This arrangement allows the secretion of releasing and inhibitory factors from nerve endings, whose cell bodies are located in the hypothalamus and other structures, into a private vascular portal system, to be delivered to the pituicytes in the anterior pituitary gland in extraordinarily high concentrations. The ultimate CNS control of the releasing and inhibitory factors profoundly influences neuroendocrine secretion and its downstream effects on both target endocrine organs and the entire body. For example, corticotrophin-releasing hormone or factor induces the release of adrenocorticotropic hormone from the anterior pituitary, which is released into the systemic circulation and activates the adrenal cortex to release cortisol and other steroid hormones. This hypothalamo-­pituitary-­adrenal system helps to regulate glucose metabolism, insulin secretion, immune responses, adipose distribution, and a host of other vital functions. The corticotrophin-releasing hormone neurons are under extensive regulatory control by neural inputs, hormonal feedback, and inflammatory mediators; these neurons help to orchestrate stress reactivity for the organism as a whole.   

116

Overview of the Nervous System

Posterior View

Anterior View

Posterior inferior cerebellar artery

Posterior cerebral artery Superior cerebellar artery

Posterior spinal arteries

Basilar artery Anterior inferior cerebellar artery

Vertebral artery

Posterior inferior cerebellar artery

Posterior radicular arteries

Anterior spinal artery Vertebral artery Anterior radicular arteries

Cervical vertebrae

Deep cervical artery Ascending cervical artery

Ascending cervical artery Deep cervical artery

Subclavian artery

Subclavian artery Anterior radicular artery

Posterior radicular arteries Posterior intercostal artery Posterior intercostal arteries Thoracic vertebrae

Artery of Adamkiewicz (major anterior radicular artery)

Anterior radicular artery

Posterior radicular arteries

Lumbar artery Anastomotic loops to posterior spinal arteries

Lumbar arteries Lumbar vertebrae Anastomotic loops to anterior spinal artery Lateral sacral (or median sacral) artery

Lateral sacral (or median sacral) artery

Sacrum

 

7.22 ARTERIAL BLOOD SUPPLY TO THE SPINAL CORD: LONGITUDINAL VIEW The major arterial blood supply to the spinal cord derives from the anterior spinal artery and the paired posterior spinal arteries, both branches of the vertebral artery. The actual blood flow through these arteries, derived from the posterior circulation, is inadequate to maintain the spinal cord caudally beyond the cervical segments. Radicular arteries, deriving from the aorta, provide

major anastomoses with the anterior and posterior spinal arteries and supplement the blood flow to the spinal cord. The largest of these anterior radicular arteries, often from the L2 region, is the artery of Adamkiewicz. Impaired blood flow through these critical radicular arteries, especially during surgical procedures that involve abrupt disruption of blood flow through the aorta, can result in spinal cord infarct.

Vasculature

117

Arteries of Cervical Cord Exposed from the Rear

Basilar artery Posterior inferior cerebellar artery Vertebral artery Anterior spinal artery Spinal ramus Posterior spinal artery Posterior radicular artery Pre-laminar branch

Anterior spinal artery Post-central branch Anterior central artery Spinal ramus Neural branch Anterior radicular artery Posterior radicular artery Internal spinal arteries Posterior central artery Pre-laminar branch Posterior spinal artery

Arteries of Spinal Cord Diagrammatically Shown in Horizontal Section

 

7.23 ANTERIOR AND POSTERIOR SPINAL ARTERIES AND THEIR DISTRIBUTION The anterior and posterior spinal arteries travel in the subarachnoid space and send branches into the spinal cord. The anterior spinal artery sends alternating branches into the anterior median fissure to supply the anterior two thirds of the spinal cord. Occlusion of one of these branches can result in ipsilateral flaccid paralysis in muscles supplied by the affected segments, ipsilateral spastic paralysis below the affected level (resulting

from upper motor neuron axonal damage), and contralateral loss of pain and temperature sensation below the affected level (resulting from damage to the anterolateral spinothalamic/­ spinoreticular system). The posterior spinal artery branches supply the dorsal third of the spinal cord. Occlusion affects the ipsilateral perception of fine discriminative touch, vibratory sensation, and joint position sense below the level of the lesion (resulting from damage to fasciculi gracilis and cuneatus, the dorsal columns).

118

Overview of the Nervous System Posterior spinal arteries Anterior spinal artery Anterior radicular artery Posterior radicular arteries Branch to vertebral body and dura mater Spinal branch Dorsal ramus of posterior intercostal artery Posterior intercostal arteries Paravertebral anastomosis Prevertebral anastomosis Aorta

Section through Thoracic Spine Right posterior spinal artery Peripheral branches from pial plexus Central branches to right side of spinal cord

Central branches to left side of spinal cord Left posterior spinal artery

Anterior radicular artery

Zone supplied by penetrating branches from pial plexus

Pial arterial plexus

Zone supplied by central branches Zone supplied by both central branches and branches from pial plexus

Posterior radicular artery

Anterior spinal artery

Posterior radicular artery Anterior radicular artery

Schema of Arterial Distribution

Pial arterial plexus

  7.24 ARTERIAL SUPPLY TO THE SPINAL CORD: CROSS-­SECTIONAL VIEW The major contribution to the arterial blood supply of the spinal cord below the cervical segments derives from the radicular arteries (top). This intercostal blood supply also distributes to adjacent bony and muscular structures. The penetrating vessels supplying the spinal cord derive from central branches of the anterior spinal artery and from a pial plexus of vessels that surround the exterior of the spinal cord.

CLINICAL POINT Alternating branches arise from the anterior spinal artery into the anterior two thirds of the spinal cord. Following an infarct in the anterior spinal artery, acute radiating leg pain is experienced. Depending on the level of insult, acute flaccid paraparesis or quadraparesis occurs, resolving to spastic paraparesis or quadraparesis with hyperreflexia as the result of the upper motor neuron lesion resulting from damage to the bilateral lateral funiculi. Only at the level of the infarct, where lower motor neurons are lost, does flaccid paralysis remain, along with hyporeflexia. Bilateral plantar extensor responses are seen. Bilateral loss of pain and temperature sensation is seen because of ischemia to the anterolateral territory of the spinothalamic/spinoreticular protopathic system. Descending fibers for control of the bladder and bowel travel in the lateral funiculus and are damaged by an anterior artery infarct. In a lesion of the anterior spinal artery above the T1 level, bilateral damage to descending central sympathetic fibers regulating T1 intermediolateral cell column outflow produces bilateral Horner’s syndrome, with bilateral ptosis, myosis, and anhidrosis.   

Vasculature

Galea aponeurotica Pericranium

Calvaria

Arachnoid granulation

119

Superior sagittal sinus Emissary vein

Tributary of superficial temporal vein

Skin

Falx cerebri

Cerebral hemisphere

Diploic vein

Pia mater

Epidural space (potential)

Superior cerebral vein

Dura mater Subdural space

Cerebral artery Arachnoid Subarachnoid space

 

VENOUS SYSTEM 7.25 MENINGES AND SUPERFICIAL CEREBRAL VEINS The superior sagittal sinus and other dural sinuses receive venous blood from a variety of veins, including superficial cerebral veins draining blood from the cortical surface, meningeal veins draining blood from the meninges, diploic veins draining blood from channels located between the inner and outer tables of the calvaria, and emissary veins, which link the venous sinuses and diploic veins with veins on the surface of the skull. These channels do not have valves and permit free communication between these venous systems and the venous sinuses. This is a significant factor in the possible spread of infections from foci outside the cranium to the venous sinuses. Recent studies demonstrate a lymphatic drainage network for the meningeal system.

CLINICAL POINT Arachnoid granulations act as one-­way valves that convey cerebrospinal fluid into the dural sinus, channeling it back into the venous circulation. The cerebral veins also extend across the subarachnoid space and enter into the superior sagittal sinus. With severe head trauma, these bridging veins can be torn, with resultant venous bleeding into the subdural space; this bleed dissects the dura from the arachnoid and becomes a space-­occupying mass. It also brings about cerebral edema and swelling. Acute subdural hematomas can be life-­threatening, especially in young individuals with head trauma. Chronic subdural hematomas often occur in the elderly with relatively minor trauma; the bridging veins tear because of some mild atrophy of the underlying hemisphere, making the course of the bridging veins more extended and more vulnerable to tearing. Slow accumulation of subdural blood eventually can result in increased intracranial pressure with headache, lethargy, confusion, seizures, and focal neurological abnormalities. Surgical drainage is often performed for large subdural hematomas, whereas small hematomas usually regress naturally in the elderly.   

120

Overview of the Nervous System

Scalp, Skull, Meningeal, and Cerebral Blood Vessels Superior sagittal sinus Diploic vein

Arachnoid Cerebral vein penetrating subdural space to enter sinus (bridging veins) granulation Dura mater (two layers)

Emissary vein Frontal and parietal tributaries of superficial temporal vein Frontal and parietal branches of superficial temporal artery Arachnoid granulation indenting skull (foveola) Venous lacuna Inferior sagittal sinus

Epidural space (potential) Arachnoid Subarachnoid space Pia mater Middle meningeal artery and vein Deep middle and superficial temporal arteries and veins

Thalamostriate and internal cerebral veins Deep and superficial middle cerebral veins

Diploic and Emissary Veins of Skull Parietal emissary vein Frontal diploic vein

Posterior temporal diploic vein Occipital emissary vein Occipital diploic vein

Anterior temporal diploic vein

Mastoid emissary vein

 

7.26 VEINS: SUPERFICIAL CEREBRAL, MENINGEAL, DIPLOIC, AND EMISSARY Venous blood drains from the skull, the meninges, and the cerebral cortex into the superior sagittal sinus and other dural sinuses. This is a point of vulnerability where potential infections and

contamination from the more superficial venous drainage networks can be allowed into the central venous sinus channels.

Vasculature

121

Optic (II) nerve Intercavernous (circular) sinus and pituitary gland Internal carotid artery Cavernous sinus Sphenoparietal sinus Superficial middle cerebral vein Oculomotor (III) nerve Trochlear (IV) nerve Trigeminal (V) nerve Middle meningeal vein Abducens (VI) nerve Superior petrosal sinus Petrosal vein Facial (VII) nerve and nervus intermedius Vestibulocochlear (VIII) nerve Glossopharyngeal (IX) nerve Vagus (X) nerve Jugular foramen Sigmoid sinus Accessory (XI) nerve Hypoglossal (XII) nerve Transverse sinus Great cerebral vein (of Galen) Opening of an inferior cerebral vein

Falx cerebri (cut) Superior ophthalmic vein Basilar plexus

Cavernous sinus

Tentorial artery

Superior and inferior petrosal sinuses

Tentorium cerebelli Straight sinus Falx cerebri (cut) Confluence of sinuses Superior sagittal sinus Falx cerebri Inferior sagittal sinus Great cerebral vein (of Galen) Sphenoparietal sinus Intercavernous sinus Superior petrosal sinus Straight sinus Inferior petrosal sinus Sigmoid sinus Jugular foramen Transverse sinus Confluence of sinuses Occipital sinus

  7.27 VENOUS SINUSES The falx cerebri and tentorium cerebelli, protrusions of fused inner and outer dural membranes, confine the anterior, middle, and posterior fossae of the skull. Outer (superior sagittal) and inner (inferior sagittal) venous channels, found in split layers of the dura, drain blood from the superficial and deep regions of the central nervous system, respectively, into the jugular veins. The great cerebral vein of Galen and the straight sinus merge with the transverse sinus into the confluence of sinuses to drain the deep, more posterior regions of the central nervous system. Infection can be introduced into the cerebral circulation through these sinuses. Venous sinus thrombosis can cause stasis (a backup of the venous pressure), which results in inadequate perfusion of the regions where drainage should occur. The protrusions of dura, such as the tentorium cerebelli and falx cerebri, are tough, rigid membranes through which portions of the brain can herniate when intracranial pressure increases.

CLINICAL POINT Venous sinus thrombosis commonly occurs with infection. Cavernous sinus thrombosis can occur as the result of infection in the paranasal sinuses or middle ear or following a furuncle in the region of the face. Anterior cavernous sinus thrombosis can result in severe pain and headache, ipsilateral visual loss, exophthalmos (protrusion of the eyeball), edema of the eyeball (chemosis), and palsies of the extraocular nerves (III, IV, VI) and V1 (ophthalmic division) that traverse the sinus. This lesion can expand to cause hemiparesis and can involve the interconnected cavernous sinus of the other side, the superior petrosal sinuses, and other venous structures. The petrosal sinuses can undergo a process of thrombosis caused by the spread of infection in the middle ear. An inferior petrosal sinus thrombosis may cause damage to the VI (abducens) nerve; a superior petrosal sinus thrombosis can result in damage to the semilunar ganglion, producing facial pain. If the transverse sinus is thrombosed, cranial nerve deficits in nerves IX, X, and XI may occur.   

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Overview of the Nervous System Longitudinal fissure Anterior cerebral veins Rostrum of corpus callosum Septum pellucidum Anterior septal vein Head of caudate nucleus Anterior terminal (caudate) vein Caudate veins Interventricular foramen (of Monro) Columns of fornix Thalamostriate vein Superior choroidal vein and choroid plexus of lateral ventricle Thalamus Tela choroidea of 3rd ventricle Direct lateral vein Posterior terminal (caudate) vein Internal cerebral veins Basal vein (of Rosenthal) Great cerebral vein (of Galen) Inferior sagittal sinus Straight sinus Tentorium cerebelli Transverse sinus Confluence of sinuses Superior sagittal sinus

A. Dissection from Above Uncal vein Anterior cerebral vein Superficial middle cerebral vein (draining to sphenoparietal sinus) Deep middle cerebral vein Cerebral peduncle

Inferior cerebral veins

Basal vein (of Rosenthal) Lateral geniculate body Medial geniculate body Pulvinar Splenium of corpus callosum Great cerebral vein (of Galen)

B. Dissection from Below

Inferior anastomotic vein (of Labbé)

 

7.28 DEEP VENOUS DRAINAGE OF THE BRAIN A, This superior view of the thalamus and basal ganglia reveals the venous drainage of deeper forebrain regions into the posterior venous sinuses. B, This basal view of the brain with the brainstem

removed illustrates the drainage of forebrain and mesencephalic venous blood into the great cerebral vein of Galen, heading toward the straight sinus.

Vasculature

Subependymal Veins Superior choroidal vein Caudate veins Lateral ventricle Thalamostriate vein Anterior terminal (caudate) vein Anterior septal vein Genu of corpus callosum

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Veins on lateral wall of ventricle Veins on medial wall and floor of ventricle All other veins

Posterior septal vein Direct lateral vein Posterior terminal (caudate) vein (posterior part of thalamostriate vein) Internal cerebral vein Medial atrial vein Lateral atrial vein Splenium of corpus callosum Inferior sagittal sinus Posterior pericallosal vein Internal occipital vein Great cerebral vein (of Galen) Post horn of lateral ventricle

Interventricular foramen (of Monro)

Straight sinus

Superior thalamostriate veins Anterior commissure Interthalamic adhesion 3rd ventricle Anterior cerebral vein Optic chiasm Deep middle cerebral vein Inferior thalamostriate veins Basal vein (of Rosenthal) Inferior horn of lateral ventricle

Cerebellum 4th ventricle Median aperture (of Magendie) Lateral aperture (of Luschka)

Posterior mesencephalic vein Hippocampal and inferior ventricular veins Cerebral aqueduct

 

7.29 DEEP VENOUS DRAINAGE OF THE BRAIN: RELATIONSHIP TO THE VENTRICLES Subependymal regions of the central nervous system drain venous blood into the inferior sagittal sinus superiorly or into the great cerebral vein of Galen inferiorly, both of which drain into the straight sinus. Occlusion of a vein in this region causes a blockage of drainage and a backup of perfusion, with resultant ischemia of the tissue in the regions of drainage.

CLINICAL POINT Venous thrombosis can occur following an infectious process, especially in the nearby sinuses, middle ear, or adjacent facial areas. Non-­ infectious causes of venous thrombosis include dehydration, cancer, polycythemia vera and other hyperviscosity syndromes, inflammatory conditions, and other disorders. The symptoms vary according to the affected focal territory and the spread of the underlying pathological process; they include severe headache, nausea and vomiting, weakness and sensory losses, sometimes aphasia, and sometimes coma.   

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Overview of the Nervous System Subependymal and Superficial Veins Opacified A. Lateral projection Caudate vein

Posterior terminal (caudate) vein Superior anastomotic vein (of Trolard)

Anterior terminal (caudate) vein

Superior sagittal sinus Inferior sagittal sinus

Internal cerebral vein Great cerebral vein (of Galen)

Straight sinus

Anterior septal vein Thalamostriate vein

Internal jugular vein

Transverse sinus Inferior anastomotic vein (of Labbé) Basal vein (of Rosenthal)

Superior choroidal vein

B. Frontal projection

Superior sagittal sinus

Thalamostriate vein

Superficial cortical veins Straight sinus Transverse sinus

Internal cerebral vein

Internal jugular vein Basal vein (of Rosenthal)

Great cerebral vein (of Galen)

7.30 CAROTID VENOGRAMS: VENOUS PHASE These lateral and anterior venous-­phase angiograms illustrate the superior sagittal sinus, the inferior sagittal sinus, and the great cerebral vein of Galen draining into the straight sinus, the

 

transverse sinus, the basal vein of Rosenthal, and the internal jugular, through which the venous blood of the brain drains back to the heart. See Video 7.­5.

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Superior sagittal sinus

Transverse sinus Sigmoid sinus Internal jugular vein

A. Coronal view

Cerebral veins Superior sagittal sinus Internal cerebral vein Great vein of Galen Basal vein of Rosenthal Straight sinus

Confluence of sinus

Transverse sinus

B. Lateral view

  7.31 MAGNETIC RESONANCE VENOGRAPHY: CORONAL AND SAGITTAL VIEWS Magnetic resonance venography uses the same principles of flow imaging used in MRA (see Fig. 7.16). The flow of venous blood in the brain is relatively slow and steady compared to the flow of arterial blood. Gradient echo sequences are sensitive to flow but are not sensitive to direction of flow. To distinguish arterial flow from venous flow, a presaturation slab must be applied

downstream below the heart or upstream above the heart prior to placing imaging slices. In a typical magnetic resonance venography of the head, a saturation slab is placed at the level of the carotid bifurcation, and traveling saturation is placed inferiorly to the slice. Multiple two-­dimensional thin slices are placed nearly perpendicular to the vessels. A, Coronal view. B, Sagittal view. These images illustrate the major cerebral veins and sinuses of the brain. See Video 7.­6.

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Overview of the Nervous System

Parts of cerebellum

Left superior and inferior colliculi

L CL C D F

Left pulvinar

Basal vein (of Rosenthal)

Right thalamus

Posterior mesencephalic vein

TU P U N T

lingula central lobule culmen declive folium

tuber pyramid uvula nodule tonsil

Internal cerebral veins

Medial geniculate body

Splenium of corpus callosum

Lateral mesencephalic vein Cut surface of left thalamus Lateral geniculate body Optic tract Inferior thalamostriate vein Anterior cerebral vein

Great cerebral vein (of Galen) Inferior sagittal sinus Superior cerebellar vein (inconstant) Superior vermian vein Straight sinus Falx cerebri

Optic (II) nerve Deep middle cerebral vein

C

Superior sagittal sinus

C

CL

F

L

Anterior pontomesencephalic vein Trigeminal (V) nerve Petrosal vein (draining to superior petrosal sinus) Transverse pontine vein Vestibulocochlear (VIII) nerve

Tentorium cerebelli (cut) Intraculminate vein Preculminate vein

D TU P

N

Confluence of sinuses

U

Left transverse sinus Inferior vermian vein

T

Falx cerebelli (cut) and occipital sinus Inferior cerebellar hemispheric vein

Facial (VII) nerve Anterior medullary vein

Precentral vein Left lateral brachial vein Inferior retrotonsillar vein

Vein of lateral recess of 4th ventricle Superior, middle, and inferior cerebellar peduncles 4th ventricle

Superior retrotonsillar vein Posterior spinal vein

Anterior spinal vein

 

7.32 VENOUS DRAINAGE OF THE BRAINSTEM AND THE CEREBELLUM The venous drainage of the cerebellum and the brainstem is anatomically diverse. The veins of the posterior fossa drain the cerebellum and brainstem. The superior group drains the superior cerebellum and upper brainstem posteriorly into the great cerebral vein of Galen and the straight sinus or laterally into the transverse and superior petrosal sinuses. The anterior, or petrosal, group drains the anterior brainstem, the superior and inferior surfaces of the cerebellar hemispheres, and the lateral regions associated with the fourth ventricle into the superior petrosal sinus. The posterior, or tentorial, group drains the inferior portion of

the cerebellar vermis and the medial portion of the superior and inferior cerebellar hemispheres into the transverse sinus or the straight sinus. CLINICAL POINT The confluence of sinuses occurs at the junction of the posterior fossa and the occipital lobe. The superior sagittal sinus drains into this confluence of sinuses as the blood flows ultimately toward the jugular vein. The most common sinus thrombosis is that of the superior sagittal sinus. Thrombosis in the posterior portion of this sinus results in headache, increased intracranial pressure with resultant papilledema (after 24 hours), and often a diminished state of consciousness or coma.   

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127

Veins of Spinal Cord and Vertebrae

Anterior external venous plexus Posterior external venous plexus Anterior internal venous plexus Intervertebral vein Basivertebral vein

Anterior external venous plexus

Anterior internal venous plexus

Basivertebral vein Anterior and posterior radicular veins Anterior spinal vein Anterior central vein

Basivertebral vein

Posterior internal venous plexus

Anterior internal venous plexus

Intervertebral vein

Posterior external venous plexus

Intervertebral vein Anterior radicular vein Posterior radicular vein Internal spinal veins Pial venous plexus Posterior central vein Posterior spinal vein Posterior internal venous plexus

 

7.33 VENOUS DRAINAGE OF THE SPINAL CORD An external and internal plexus of veins extends along the entire length of the vertebral column, forming a series of venous rings with extensive anastomoses around each vertebra. Blood from the spinal cord, the vertebrae, and the ligaments drains into these plexuses. Changes in intrathoracic pressure and cerebrospinal fluid pressure can be conveyed through these venous plexuses, affecting the venous volume. Ultimately, these venous plexuses drain through the intervertebral veins into vertebral, posterior intercostal, subcostal, and lumbar and lateral sacral veins.

CLINICAL POINT A venous plexus is present in the epidural space surrounding the spinal cord, along with epidural fat. This epidural space is wide enough for the insertion of a catheter and infusion of local anesthesia. The local anesthesia is absorbed into this plexus and diffuses into the adjacent spinal cord, producing profound analgesia at and below the level of the infusion. This technique of epidural anesthesia often is used for analgesia in childbirth and also for a variety of surgeries in which epidural anesthesia is preferable to general anesthesia.   

8

DEVELOPMENTAL NEUROSCIENCE

8.1 Formation of the Neural Plate, Neural Tube, and Neural Crest

8.16 Comparison of 5½-­Week and Adult Central Nervous System Regions

8.2 Neurulation

8.17 Alar And Basal Plate Derivatives in the Brainstem

8.3 Neural Tube Development and Neural Crest Formation

8.18 Adult Derivatives of the Forebrain, Midbrain, and Hindbrain

8.4 Development of Peripheral Axons

8.19 Cranial Nerve Primordia

8.5 Somatic Versus Splanchnic Nerve Development

8.20 Cranial Nerve Neuron Components

8.6 Limb Rotation and Dermatomes

8.21 Development of Motor and Preganglionic Autonomic Nuclei in the Brainstem and Spinal Cord

8.7 Neural Proliferation and Differentiation: Walls of the Neural Tube

8.22 Development of the Eye and Orbit

8.8 Neural Tube and Neural Crest Derivatives

8.23 Development of the Ear

8.9 Early Brain Development: The 28-­Day-­Old Embryo

8.24 Development of the Pituitary Gland

8.10 Early Brain Development: The 36-­Day-­Old Embryo

8.25 Development of the Ventricles

8.11 Early Brain Development: The 49-­Day-­Old Embryo and the 3-­Month-­Old Embryo

8.26 Development of the Fourth Ventricle

8.12 Forebrain Development: 7 Weeks Through 3 Months 8.13 The 6-­Month and 9-­Month Central Nervous Systems 8.14 Neurogenesis and Cell Migration in the Developing Neocortex 8.15 Postnatal and Adult Neurogenesis

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8.27 Neural Tube Defects 8.28 Defects of the Brain and Skull 8.29 Fetal Alcohol Syndrome

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Oropharyngeal membrane Lens placode Olfactory placode

Notochord

Hypophysis

Paraxial column Intermediate column Appearance of the neural plate Lateral plate

Optic area

Forebrain Midbrain Hindbrain Neural crest Neural plate forming neural tube Somite

Axial rudiment Spinal cord Neural crest

Intermediate mesoderm Intraembryonic coelom

Developmental fates of local regions of ectoderm of embryonic disc at 18 days

Notochord

8.1 FORMATION OF THE NEURAL PLATE, NEURAL TUBE, AND NEURAL CREST The neural plate, neural tube, and neural crest form at the 18-­ day stage of embryonic development. The underlying notochord induces the neural plate, and a midline neural groove forms.

The elevated lateral margins become the neural folds, tissue destined to become the neural crest with future contributions to many components of the peripheral nervous system (PNS). At this very early stage of embryonic development, these neural precursors are vulnerable to toxic insult and other forms of damage.

130

Overview of the Nervous System Future neural crest Ectoderm

Neural plate of forebrain

Neural plate

Level of section Neural groove Neural groove Neural folds 2.0 mm

Future neural crest

Neural fold

Level of section 1st occipital somite

Primitive streak

Embryo at 20 days (dorsal view)

Neural plate of forebrain Neural crest Neural groove

Level of section

2.3 mm

Neural folds

Fused neural folds

1st cervical somite

Caudal neuropore Embryo at 21 days (dorsal view)

  8.2 NEURULATION In the 21– or 22-­day-­old-­embryo, the neural plate, with its midline neural groove, thickens and begins to fold and elevate along either side, allowing the two lateral edges to fuse at the dorsal midline to form the completed neural tube. The central canal, the site of the future development of the ventricular system, is in the center of the neural tube. This process of neurulation continues both caudally and rostrally. Disruption can occur because of failure of full neural tube formation caudally (spina bifida) or rostrally (anencephaly).

CLINICAL POINT As the neural plate forms into a neural tube, the process of neurulation results in fused neural folds, starting centrally and moving both caudally and rostrally. Failure of the neural tube to close results in dysraphic defects, with altered development of associated muscles, bone, skin, and meninges. If the anterior neuropore fails to form, anencephaly results, with failure of the brain to develop, accompanied by facial defects. This condition is lethal. Failure of the posterior (caudal) neuropore to close results in spina bifida, with failure of the vertebral arches to fuse. A saccular protrusion from the lumbar region may contain meninges (meningocele) or meninges and spinal cord (meningomyelocele). Meningomyelocele is often accompanied by paraparesis, bowel and bladder dysfunction, sensory disruption at the level of the lesion, motor dysfunction in the lower extremities, and accompanying hydrocephalus or Arnold-­Chiari malformation, requiring a ventriculo-­peritoneal or ventriculo-­jugular shunt.   

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131

The neural tube will form the brain and spinal cord, the two components of the central nervous system (CNS). The neural crest will give rise to all of the neurons whose cell bodies are located outside the CNS in the peripheral nervous system (PNS), consisting of nerves, ganglia, and plexuses. Ectoderm Neural crest Fused neural folds Derivatives of the neural tube include: Neurons of the CNS Supporting cells of the CNS Lower motor neurons of the CNS Preganglionic autonomic neurons of the CNS

Level of section

2.6 mm

1st occipital somite

1st cervical somite Neural tube Sulcus limitans

1st thoracic somite

Derivatives of the neural crest include: Sensory neurons in the PNS Postganglionic autonomic neurons Schwann (neurolemma) cells Adrenal medulla cells Head mesenchyme Melanocytes in the skin Arachnoid and pia mater of meninges (dura mater from mesoderm)

Embryo at 24 days

Caudal neuropore

(dorsal view)

Dorsal spinal ganglion

Ectoderm

Spinal cord Sympathetic trunk ganglion

Sensory neuron of dorsal spinal ganglion

Neural crest

Aorta

Neural tube (spinal cord)

Preaortic sympathetic ganglion

Notochord

4th week

Cortical primordium of suprarenal gland

Visceral motor neuron of sympathetic ganglion

Chromaffin cell, suprarenal medulla cell

Mesonephros

Dorsal mesentery

Germinal epithelium of future gonad

Gut

Serosal lining (peritoneum) of abdominal celom (peritoneal cavity)

6th week

 

8.3 NEURAL TUBE DEVELOPMENT AND NEURAL CREST FORMATION The dorsal and ventral halves of the neural tube are separated by the sulcus limitans, an external protrusion from the central canal that demarcates the alar plate above from the basal plate below. This important landmark persists at some sites in the adult ventricular system. The alar plate is the source of generation of many neurons with sensory function. The basal plate is the source of generation of many neurons with motor or autonomic function in the spinal cord and the brainstem. The neural crest cells at the edge of the neural folds unite and become a dorsal crest, with the neural crest above the neural tube. The neural tube and neural crest separate from the originating ectoderm.

CLINICAL POINT The neural crest gives rise to a wide variety of neural elements of the PNS, including primary sensory neurons, postganglionic autonomic neurons, Schwann cells, adrenal medullary chromaffin cells, pia and arachnoid cells, melanocytes, and some mesenchyme of the head. A failure of the neural crest to develop and migrate properly is seen in Hirschsprung’s disease (congenital megacolon), in which sensory signals from the colon are absent, and in familial dysautonomia, in which autonomic symptoms (cardiovascular dysfunction, gastrointestinal dysfunction) and sensory deficits (especially pain and temperature sensation) are present.   

132

Overview of the Nervous System

Differentiation and Growth of Neurons at 26 Days Neural crest Spinal cord (thoracic part)

Ependymal layer Mantle layer Marginal layer Motor neuroblasts growing out to terminate on motor end plates of striated (voluntary) muscle

Differentiation and Growth of Neurons at 28 Days (right side of diagram shows newly acquired neurons only) Spinal cord (thoracic part)

Sensory cells from neural crest Commissural neuron Association neuron Ventral funiculus Growing to dorsal surface of body Growing to lateral and ventral surfaces of body

Migrating neuroblasts from neural crest (postganglionic, sympathetic)

Growing to viscera of body

Differentiation and Growth of Neurons at 5 to 7 Weeks (right side of diagram shows neurons acquired since 28th day only) Dorsal (sensory) root Dorsal (sensory) ganglion Ventral (motor) root

Dorsal funiculus Association neuron Preganglionic, sympathetic, and motor neurons Lateral funiculus Postganglionic sympathetic neurons (derived from neural crest) growing to end on smooth (involuntary) muscle and sweat glands

Dorsal ramus of spinal nerve Ventral ramus of spinal nerve Sympathetic trunk

White ramus communicans Gray ramus communicans

Branch to thoracic viscera Splanchnic nerve

Postganglionic sympathetic neurons innervating thoracic viscera

Sympathetic trunk (chain) ganglion Sympathetic trunk Collateral sympathetic trunk ganglion (celiac, superior, and inferior mesenteric) Sensory neuron of abdominal viscera (cell body in dorsal ganglion)

Preganglionic sympathetic axons extending to innervate sympathetic chain ganglion Postganglionic sympathetic neurons (derived from neural crest) innervating glands and smooth (involuntary) muscle

 

8.4 DEVELOPMENT OF PERIPHERAL AXONS Peripheral axon development is a complex process of central and peripheral neurite extension, trophic and chemotactic factors, and axonal guidance and maintenance by innervated target tissues. Dorsal root ganglion cells are bipolar; a peripheral axonal process is associated with simple or complex sensory receptor cells, and a central axonal process extends into the central nervous system (CNS) to form connections with secondary sensory neurons. The lower motor neurons send motor axons to the developing skeletal muscles through the ventral roots or motor cranial nerves, forming neuromuscular junctions as sites of synaptic connectivity.

Motor neurons that fail to establish such contact with skeletal muscles die. Central preganglionic axons exit in the ventral roots and terminate on sympathetic ganglion cells in the sympathetic chain or collateral ganglia or on parasympathetic intramural ganglia near the organs innervated. Postganglionic axons form connections with target tissues, including smooth muscle, cardiac muscle, secretory glands, some metabolic cells (hepatocytes, fat cells), and cells of the immune system in parenchymal zones of many lymphoid organs. Sensory, motor, and autonomic symptoms can occur in peripheral neuropathies based on disruption of these connections.

Developmental Neuroscience

Neural crest

133

Sensory neuroblast grows into dorsal horn and viscera

Neural tube Dorsal root ganglion Dermatomyotome

Splanchnic nerve

Sympathetic chain ganglion (sympathetic for spinal nerves) Collateral ganglion (sympathetic for visceral arteries) Gut Enteric plexus ganglia (parasympathetic input for muscle and glands)

Gut Motor neuroblasts form primitive axons, which migrate into ganglia and then innervate viscera

Migration of neural crest cells forms peripheral ganglia of autonomic nervous system

Autonomic Development Autonomic nervous system mostly innervates splanchnopleure (viscera) Dorsal root

Motor neuroblasts form primitive axons and enter skeletal muscle of body wall

Ventral root Epaxial muscles Dorsal ramus

Posterior cutaneous nerve

Ventral ramus Posterior division Anterior division

Epaxial muscles

Hypaxial muscles (extensors of limb)

Dorsal ramus Ventral ramus

Hypaxial muscles in thoracic and abdominal wall Hypaxial muscles (flexors of limb)

Lateral cutaneous nerve

Hypaxial muscles (flexors of arm and shoulder) Anterior cutaneous nerve

Somatic Development Somatic nervous system innervates somatopleure (body wall)

 

8.5 SOMATIC VERSUS SPLANCHNIC NERVE DEVELOPMENT Somatopleure and splanchnopleure constitute the embryonic basis for the subdivision of the PNS into spinal (somatic) nerves and splanchnic (autonomic) nerves. The somatopleure develops from ectoderm and the somatic portion of lateral plate mesoderm. Somite hypoblasts migrate into somatopleure to form the

lateral and ventral aspects of the body wall, including the limbs. Splanchnopleure, derived from endoderm and lateral plate mesoderm, give rise to visceral organs. The ventral rami migrate into somatopleure, and splanchnic nerves grow into splanchnopleure. Thoracic and lumbar splanchnic nerves have sympathetic and visceral sensory axonal components. Pelvic splanchnic nerves (S2– S4) have parasympathetic and visceral sensory axonal components.

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Overview of the Nervous System

Changes in ventral dermatome pattern (cutaneous sensory nerve distribution) during limb development

C3 C4 C5 C6 C7 C8 T1 T2 Upper limb

L2 L3 L4 L5 S1 S2 S3 At 4 weeks

Thumb

Lower limb

Preaxial border

C7 C8

Palmar surface

Postaxial border

Preaxial border Big toe Palmar surface Postaxial border

Preaxial border C7 C8

Upper limb Postaxial border

C3 C4 C5 C6 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5 S1 S2 S3

At 7 weeks

C6

Preaxial border

C3 C4 C5

L5

Lower limb

T1 T2

L4 S1

Postaxial border

L3

L2

S2

S3

At 5 weeks

Thumb

C3 C4

Preaxial border

C5

C7 C8

T1 T2

C6

Palmar surface Postaxial border

Dorsal surface Postaxial border S1

L5

L4

L3

L2 S2

Preaxial border Big toe

S3

At 8 weeks

 

8.6 LIMB ROTATION AND DERMATOMES Rotation of the lower limb results in a reversal of the preaxial and postaxial borders, producing a spiral arrangement of dermatomes. Spinal nerve segments on the anterior surface of the lower extremity extend medially and inferiorly; the great toe (hallux) is supplied

by nerves from a more rostral dermatome (L4) than the little toe (S1). The lower extremity is an extension of the trunk, and the most caudal dermatomes (sacral and coccygeal) supply the perineum, not the foot. Cervical dermatomes maintain a relatively orderly distribution to the upper extremity with minimal rotation.

Developmental Neuroscience

Migrating neuroblasts

135

Pia mater

Central canal Ependymal zone

Migrating neuroblasts Internal limiting membrane

Mantle zone (gray matter)

Marginal zone (white matter)

B. Spinal cord at 3 months

External limiting membrane

Migrating neuroblasts

Pial cell

Pia mater

Marginal layer

C. Cerebellar hemisphere at 3 months

A. Neural tube at 5 weeks

Molecular layer

Mantle layer

Future white matter

Migrating neuroblasts

External granular cell layer

Ependymal layer

Mantle zone

Golgi cell and internal granular cell layer

Ependymal zone

Purkinje cell layer

4th ventricle

Pia mater

Lateral ventricle

Ependymal zone

Mantle zone

D. Cerebral hemisphere at 3 months

Future white matter

Primordial cortex

Molecular layer

Marginal zone

 

8.7 NEURAL PROLIFERATION AND DIFFERENTIATION: WALLS OF THE NEURAL TUBE Early in development (5 weeks), neuroblasts in the ependymal layer lining the central canal move back and forth from the ependymal surface to the pial surface, replicating as they go. Neural migration follows distinctive patterns in different regions of the neural tube. In the spinal cord, neurons migrate into the inner mantle zone, leaving the outer marginal zone as a site for axonal pathways. In the cerebellar cortex, some neurons

migrate to an outer location on the outer pial surface as an external granular layer, from which granular cells then migrate inward to synapse with other neurons present in deeper layers of the cerebellar cortex. In the cerebral cortex, neurons migrate to the outer zone, where the gray matter (neuronal cell bodies) remains on the surface, external to the white matter (nerve fibers). These developmental patterns reflect the anatomical organization of the mature structures, their blood supply, and their vulnerability to injury by tumors, vascular insults, trauma, and other disorders.

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Overview of the Nervous System

Cel

ls d

eriv

ed

Bipolar cell of ganglia of cranial nerve VIII Unipolar sensory cell of dorsal spinal ganglia and sensory ganglia of cranial nerves V, VII, IX and X

Multipolar visceral motor postganglionic cell of sympathetic and parasympathetic ganglia

from

neu

ral

cre

st

Chromaffin cell of adrenal medulla Pia mater cell

Arachnoid cell

Migrating neuroblasts Bipolar neuroblast Neural crest

Microglial cell Wandering neural crest cell

Neural tube epithelial cell Neural tube

Satellite and neurilemmal (Schwann) cells

Glioblast

Adventitial cell of capillary Cells of multiple origin

Ependymal cell Migrating glioblast

Migrating neuroblast

Multipolar neuroblast of spinal cord and brain

Specialized central neurons, RF, other

Oligodendroglial cell

At birth Protoplasmic

Fibrous

Astrocytes Dendrites

Dendrites

Mature

Association and commissural cells of spinal cord and brain Axon Multipolar somatic motor cell of ventral column of spinal cord and motor nuclei of cranial nerves III through VII and IX through XII

Axon Multipolar somatic motor control (pyramidal) cell of cerebral cortex and other projectional cells

Multipolar visceral motor preganglionic (sympathetic and parasympathetic) cell of spinal cord and brain

m

s ell

ne

e

riv

de

ro df

e

ub

lt

a ur

C

  8.8 NEURAL TUBE AND NEURAL CREST DERIVATIVES Neural tube ependymal cells give rise to neuroblasts, from which the neurons of the CNS are derived. They also give rise to the glioblasts, from which the mature ependymal cells, astrocytes, and oligodendroglia are derived. Microglia, the “scavenger cells” of the CNS, are derived mainly from mesodermal precursors. Cells of glial origin are the predominant cells that give rise to CNS tumors. The neural crest cells give rise to many peripheral neural

structures, including primary sensory neurons, postganglionic autonomic neurons of both the sympathetic and parasympathetic systems, adrenal medullary chromaffin cells, pial and arachnoid cells, Schwann cells (the supporting cells of the PNS), and some other specialized cell types. Neural crest cells can be damaged selectively in some disorders (e.g., familial dysautonomias) and also can give rise to specific tumor cell types such as pheochromocytomas. Most microglial cells are derived from specialized mesenchymal cells infiltrating from the yolk sac.

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Central nervous system at 28 days Midbrain (mesencephalon)

Forebrain (prosencephalon)

Hindbrain (rhombencephalon)

Optic vesicle

Cephalic flexure

3.6 mm

Cervical flexure

Spinal cord

Forebrain

Hypothalamic sulcus

Alar (roof) plate

Forebrain (prosencephalon) Midbrain (mesencephalon)

Optic vesicle

Sulcus limitans Hindbrain (rhombencephalon) Opening of right optic vesicle

Alar (roof) plate Basal plate

In these sections:

Hindbrain

Sulcus limitans Basal plate

Spinal cord

Alar plate Basal plate

Midbrain

Spinal cord

Sagittal section

Frontal section (ventral to sulcus limitans)

 

8.9 EARLY BRAIN DEVELOPMENT: THE 28-­DAY-­ OLD EMBRYO Some components of the neural tube expand differentially, resulting in bends or flexures that separate the neural tube into caudal to rostral components. The cervical flexure caudally and the cephalic flexure rostrally result from the differential expansion. Three regions of rapid cellular proliferation develop: the forebrain (prosencephalon) rostrally, the mesencephalon (midbrain) in the middle, and the hindbrain (rhombencephalon) caudally. The ventricular system bends and expands to accommodate the increasing neural growth. An outgrowth from the caudal part of the prosencephalon extends from the future diencephalon to become the optic cup, giving rise to the future retina and its central connections.

CLINICAL POINT The optic vesicle develops from the prosencephalon, specifically the future diencephalon. As a consequence, the neuroretina is actually a central neural derivative and not a peripheral neural crest derivative. Therefore, the retina is supplied with CNS vasculature, and the ganglion cells of the retina (projecting into the optic nerve, chiasm, and tract) are actually CNS axons myelinated by oligodendroglia and surrounded by subarachnoid space and its cerebrospinal fluid. As a CNS tract, the optic nerve is subject to central demyelinating lesions as seen in multiple sclerosis. The retinal vasculature is the only CNS vasculature that is directly observable by ophthalmoscopy.   

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Overview of the Nervous System

Sagittal section Cranial nerve VII (facial) (sensory and motor)

Metencephalon (cerebellum, pons)

Hindbrain (metencephalon)

Cranial nerve VI (abducens) (motor) Cranial nerve V (trigeminal) (sensory and motor)

Forebrain (prosencephalon)

Cranial nerve III (oculomotor) (motor)

1.0 mm

Coccygeal nerve (sensory and motor)

4th ventricle Central canal

Mesencephalon

Spinal cord

Cerebral aqueduct

Diencephalon Hypothalamic sulcus

3rd ventricle Opening of right telencephalic vesicle

Diencephalon

Infundibulum

Thin root of myelencephalon (medulla oblongata)

Sulcus limitans

Cranial nerve X (vagus) (sensory and motor)

Midbrain (mesencephalon)

Optic cup

Basal plate

Cranial nerve IX (glossopharyngeal) (sensory and motor)

Cranial nerve IV (trochlear) (motor)

Telencephalic vesicle

Alar plate

Cranial nerve VIII (vestibulocochlear) (sensory)

4th ventricle

Cranial nerve XI (accessory) (motor)

Hindbrain (myelencephalon)

Cranial nerve XII (hypoglossal) (motor)

Infundibulum Opening of right optic stalk Lamina terminalis

Frontal section (ventral to sulcus limitans)

Lamina terminalis

3rd ventricle Telencephalic vesicle Lateral ventricle Alar plate

1st cervical nerve (sensory and motor)

3rd ventricle Optic stalk Optic cup

1st sacral nerve (sensory and motor)

Infundibular recess Diencephalon Mesencephalon Cerebral aqueduct Basal plate Metencephalon (cerebellum, pons)

1st thoracic nerve (sensory and motor)

Central Nervous System: Cranial and Spinal Nerves at 36 Days

4th ventricle Myelencephalon (medulla oblongata)

Sensory neurons and ganglia from neural crest In sagittal and frontal sections:

4th ventricle

Alar (roof) plate

Spinal cord

Basal plate

Central canal

Rhombencephalon

1st lumbar nerve (sensory and motor)

 

8.10 EARLY BRAIN DEVELOPMENT: THE 36-­DAY-­ OLD EMBRYO By day 36, the prosencephalon begins to expand rapidly as the future diencephalon (thalamus and hypothalamus) and telencephalon (basal ganglia, limbic forebrain, olfactory system, and cerebral cortex). This rapid growth is accompanied by the formation of the thin third ventricle for the diencephalon and the

C-­shaped lateral ventricles from the rostral end of the original central canal for the telencephalon. The rhombencephalon further develops into two distinct regions, the metencephalon (future pons and cerebellum) and the myelencephalon (future medulla). Distinct spinal nerves and cranial nerves begin to form as sensory and motor neurons differentiate and begin to connect with their appropriate targets in the periphery.

Developmental Neuroscience

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Central nervous system at 49 days Cephalic flexure

Metencephalon (cerebellum, pons)

Mesencephalon

Roof of 4th ventricle

Mammillary body

Myelencephalon (medulla oblongata)

Epiphysis (pineal gland) 17.0 mm

Diencephalon Telencephalon

Cervical flexure

Telencephalic vesicle (cerebral hemisphere)

Pontine flexure Spinal cord

Olfactory lobe (paleocortex) Optic cup Infundibulum (pituitary stalk)

Central nervous system at 3 months Cerebral hemisphere (neocortex)

Mesencephalon

Outline of diencephalon (overgrown by cerebral hemispheres) Cerebellum (metencephalon) Olfactory lobe (paleocortex) Medulla oblongata (myelencephalon)

Optic nerve (cranial nerve II)

78.0 mm

Hypophysis (pituitary gland) Cervical enlargement of spinal cord

Pons (metencephalon)

Lumbosacral enlargement of spinal cord

  8.11 EARLY BRAIN DEVELOPMENT: THE 49-­DAY-­OLD EMBRYO AND THE 3-­MONTH-­OLD EMBRYO By 49 days of age, the diencephalon and telencephalon differentiate into distinct components: the thalamus dorsally and the hypothalamus ventrally from the diencephalon and the olfactory lobe, basal ganglia, limbic forebrain structures, and cerebral cortex from the telencephalon. The metencephalon (pons) and myelencephalon (medulla) develop further and fold, separated by the pontine flexure. Between 49 days and 3 months, massive development of the telencephalon overrides and covers the diencephalon. The cerebellum forms from the rhombic lips of the metencephalon as neurons travel dorsally to overlie the future pons and eventually most of the brainstem. The mesencephalon

expands dorsally, forming the superior and inferior colliculi (quadrigeminal bodies). The continuing growth of the spinal cord as it connects with peripheral tissues in the developing limbs forms the cervical and lumbosacral enlargements.

CLINICAL POINT The process by which the prosencephalon gives rise to the diencephalon and telencephalon is termed prosencephalization. A failure of this process to form the two hemispheres results in holoprosencephaly, with a single large forebrain ventricle, a poorly developed diencephalon, and aberrant development of telencephalic structures. This severe defect in forebrain formation is also accompanied by severe facial malformations.   

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Overview of the Nervous System

Telencephalon at 71/2 Weeks (transverse section)

Forebrain at 7 Weeks (transverse section) Choroidal vein and artery Telencephalic vesicle (cerebral hemisphere; neopallium)

Roof of median telocele (3rd ventricle) Lateral telocele (lateral ventricle)

Choroidal vein and artery Telencephalic vesicle (cerebral hemisphere; neopallium)

Roof of 3rd ventricle Hippocampus (archipallium) Lateral ventricle Choroid plexus

Opening between lateral and median teloceles (interventricular foramen)

Ependymal layer Mantle layer Marginal layer

Median telocele (3rd ventricle)

Interventricular foramen

Ependymal layer Mantle layer Marginal layer Anterior lobe of hypophysis (pituitary gland)

Corpus striatum (basal ganglion) 3rd ventricle Infundibulum (pituitary stalk)

Telencephalon at 2 1/2 Months (right anterior view)

Forebrain at 2 Months (coronal section; anterior view)

Right cerebral hemisphere (neopallium, cut edge) Epiphysis (pineal gland) Cerebral hemisphere (neopallium, cut edge)

Diencephalon Roof of 3rd ventricle

Left cerebral hemisphere (neopallium) Hippocampus (archipallium)

Hippocampus (archipallium)

Choroid plexus protruding into right lateral ventricle along choroid fissure

Choroid plexus Choroid fissure

Corpus striatum (basal ganglion)

Thalamus Corpus striatum (basal ganglion) 3rd ventricle Optic (nerve) stalk

Lateral ventricle

Fornix Anterior commissure Lamina terminalis Olfactory lobe (paleopallium) 3rd ventricle

Opening of cavity of right olfactory lobe

Interventricular foramen

Olfactory lobes (paleopallium)

Lamina terminalis

Right Cerebral Hemisphere at 3 Months (medial aspect) Corpus callosum Commissure of fornix (hippocampal commissure)

Interventricular foramen

Medial surface of right cerebral hemisphere (neopallium) Choroidal vessels passing to choroid plexus, which protrudes into right lateral ventricle along choroid fissure Hippocampus (archipallium) Stria terminalis Thalamus (cut surface) Line of division between diencephalon and telencephalon

Cerebral Hemispheres at 3 Months (coronal section) Falx cerebri

Dura mater

Ependymal layer Mantle layer Marginal layer

Superior sagittal sinus Inferior sagittal sinus Lateral ventricle Ependymal-pial covering of choroid plexus

Neopallial cortex

Choroidal vein and artery

Hippocampal cortex Corpus striatum (basal ganglia)

Internal capsule Anterior commissure

Caudate nucleus Lenticular nucleus

Interventricular foramen Optic recess of 3rd ventricle

Choroid plexus of roof of 3rd ventricle

 

8.12 FOREBRAIN DEVELOPMENT: 7 WEEKS THROUGH 3 MONTHS Neurons of the developing telencephalon move rostrally, dorsally, and then around the diencephalon in a C shape toward the anterior pole of the temporal lobe. The hippocampal formation forms in a dorsal and anterior position and migrates in a C-­shaped course into the anterior temporal lobe. The amygdala develops in a similar manner, giving rise to the stria terminalis pathway in a C shape. The lateral ventricles follow the same C-­shaped

developmental process anatomically. The caudate nucleus also extends around the telencephalon in a C-­shaped pattern, with the large head of the nucleus remaining anterior and the much smaller body and tail following as a thinner C-­shaped structure that ends ventrally adjacent to the temporal horn of the lateral ventricle. The corpus callosum and anterior commissure connect the two hemispheres. The internal capsule funnels centrally in the core of the forebrain on either side; the posterior limb continues caudally as the cerebral peduncle.

Developmental Neuroscience Brain at 6 months

141

8.0 mm

Central (rolandic) sulcus

Frontal lobe of left cerebral hemisphere

Parietal lobe Insula (island of Reil) in lateral (sylvian) sulcus

Parieto-occipital sulcus Occipital lobe

Olfactory bulb

Cerebellum Temporal lobe Medulla oblongata Pons Spinal cord

Pyramid

Brain at 9 months (birth) 10.5 mm Central (rolandic) sulcus

Precentral (motor) gyrus Precentral sulcus

Postcentral (sensory) gyrus

Frontal lobe

Postcentral sulcus

Left cerebral hemisphere Parieto-occipital sulcus Lateral (sylvian) sulcus Parietal lobe

Insula (island of Reil)

Occipital lobe

Olfactory bulb

Cerebellum

Temporal lobe Pons

Medulla oblongata

Pyramid Spinal cord

Olive

  8.13 THE 6-­MONTH AND 9-­MONTH CENTRAL NERVOUS SYSTEMS At 6 months, the brainstem has differentiated into the medulla, pons, and midbrain, with the developing cerebellum overlying them dorsally. Even though the diencephalon is rapidly developing, the overlying telencephalon shows massive growth rostrally, then caudally, downward, and forward into the temporal lobe. From 6 to 9 months of age, the cerebral cortex forms its characteristic convolutions with gyri and sulci, and the cerebellar cortex forms its distinctive folds, the folia. Within the forebrain, the major components of the basal ganglia, the limbic forebrain structures (i.e., the amygdala and hippocampal formation), the olfactory system, and the cerebral cortex develop rapidly. Most neurons are present at birth; some populations of granular cells in the cerebellum, the dentate gyrus of the hippocampus, and the

cerebral cortex form postnatally in response to environmental stimuli. The in utero and postnatal environments provide major influences on neural development and function. CLINICAL POINT The cerebral cortex develops through an orderly process of cell proliferation from the ventricular zone and then the subventricular zone, with proper cell migration and interconnectivity extending through prenatal life and well into postnatal life. A failure of proper cell proliferation and migration of cortical neurons can result in the failure of proper formation of gyri and sulci, giving a smooth cortical surface appearance called lissencephaly. In some situations, gyri can be unusually small (microgyria) or unusually large (pachygyria). These developmental defects may be accompanied by profound neural deficits and intellectual disability.   

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Overview of the Nervous System

Cerebral cortex

Pial surface

MZ Ventricle

CP

PP MZ SP CP IZ SVZ VZ

Preplate Marginal zone Subplate Cortical plate Intermediate zone Subventricular zone Ventricular zone

Neurons migrate along radial glial cells

MZ

SP Basal progenitors

PP

IZ

Neuron Neuron SVZ

VZ

Neuroepithelial cells

Radial glial cells

Ventricle

Development of cerebral cortex over time

 

8.14 NEUROGENESIS AND CELL MIGRATION IN THE DEVELOPING NEOCORTEX During the earliest phases of cortical development, neuroepithelial progenitor cells, with processes extending from the cell body to the inner ventricular surface and the outer pial surface, replicate. They form some neurons that populate the preplate region and also generate the radial glial cells. The radial glial cells maintain their contact with the ventricular and pial surfaces and give rise to postmitotic cortical neurons. These neurons migrate toward the cortical surface along the radial glial processes and populate the cortical plate. Cortical neurons accumulate in the cortical plate region in an inside-­out fashion, with earliest generated neurons located deepest and latest generated neurons located more superficially. These neurons differentiate to form association neurons (cortical-­cortical connections) and projection neurons (to deeper subcortical structures). Most of the subplate neurons die, although some remain and differentiate into local (interstitial) interneurons. Cortical granule cells proliferate from the subependymal zone and migrate both tangentially and radially into the cortical architecture. These neurons undergo abundant proliferation and migration postnatally in response to environmental stimuli. These complex processes of neurogenesis, proliferation, migration, differentiation,

and integration into complex circuitry (intrinsic, projection, and association), followed by extensive postnatal dendritic and axonal maturation and connectivity, leave cortical development vulnerable to a variety of insults and disruptions. CLINICAL POINT The neonatal environment exerts significant influences over postnatal proliferation and migration of granule cells, as well as synaptic connectivity and neuronal maturation. During critical developmental periods, a stressful environment can adversely impact the future reactivity of the major stress axes, the sympathoadrenal system, and the hypothalamo-­pituitary-­adrenal (HPA) system. In animal models, where careful controls are possible, the stress of maternal separation can lead to heightened reactivity in adulthood in these stress axes with elevated catecholamine and glucocorticoid secretion, elevated inflammatory mediators, and diminished components of immune reactivity. In observations in humans, where carefully controlled environments are not readily achievable, observations of children raised with neglectful or stressful environments also demonstrate greater reactivity of the stress axes, greater likelihood of cardiac disease and type 2 diabetes, and greater incidence of psychosocial disorders in later life. These observations in humans show greater variability than those seen in well-­controlled animal models.   

Developmental Neuroscience

Cerebral cortex neurogenesis

Pial surface

143

Cerebral cortex

MZ

Body of lateral ventricle

CP

Basal progenitors

Neurons migrate along radial glial cells

IZ Thalamus SVZ

Neuron VZ

Radial glial cell

Inferior horn of lateral ventricle Hippocampus

Lateral ventricle Pial surface EGL disappears ~age 1.5 yr

EGL

ML

PL Granule cell progenitors migrate to EGL

Granule cells migrate back to IGL

Radial glial cell

Mature granule cell

IGL

VZ

Floor of fourth ventricle Cortex of cerebellum

Cerebellar cortex neurogenesis

MZ CP IP SVZ VZ EGL ML PL IGL

Marginal zone Cortical plate Intermediate zone Subventricular zone Ventricular zone External granule layer Molecular layer Purkinje layer Inner granule layer

Fourth ventricle

Level of section (midthalamus)

 

8.15 POSTNATAL AND ADULT NEUROGENESIS In the neonate, granule cells proliferate and migrate into key neural structures, including the cerebellar cortex, the hippocampus, and the cerebral cortex, in response to postnatal stimuli. Phenomena such as sensory stimuli (external touch) and an enriched environment (affecting balance and cerebellar development, exploratory behavior, maternal interactions) can influence the proliferation, migration, and placement of granule cells into complex synaptic circuitry. This plate illustrates the granule cell process in neonatal cerebellum and cortex. The CNS does not have

a full complement of neurons at birth, especially granule cells, and the neonatal environment plays a critical role in brain development, as demonstrated by the early studies of Joseph Altman and Shirley Bayer. More recently, this process of neuronal proliferation, migration, and neuronal replacement has been demonstrated in the adult hippocampus, including in aging. Cells from the subventricular zone of the adjacent ventricle contribute new neurons to the granule cell layer of the hippocampus, a phenomenon of synaptic plasticity that occurs throughout the life span, as shown by Fred “Rusty” Gage of the Salk Institute.

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Overview of the Nervous System

5 1/2 weeks (transverse section)

Spinal Cord

Mature (transverse section) Central canal

Central canal Sensory Ependymal layer Mantle layer Marginal layer Motor Sulcus limitans

Dorsal alar plate (sensory and coordinating) Ventral basal plate (motor)

Dorsal gray column (horn) Tracts (white matter) Lateral gray column (horn) Ventral gray column (horn) Tracts (white matter)

Medulla Oblongata

5 1/2 weeks (transverse section) Roof plate 4th ventricle Dorsal alar plate Ependymal (sensory and layer coordinating) Mantle layer Marginal Ventral basal layer plate (motor) Sulcus limitans 5 1/2 weeks (transverse section)

Location of sensory coordinating nuclei (gray matter) Location of motor control nuclei (gray matter)

Mesencephalon

Mature (transverse section) Vestibular nuclei Nucleus tractus solitarius (nucleus of the solitary tract) 4th ventricle Dorsal (motor) nucleus of the vagus Hypoglossal nucleus Tracts (white matter) Nucleus ambiguus Inferior olivary nucleus Pyramid Mature (transverse section) Superior colliculus

Tectum

Cerebral aqueduct Ependymal Tegmentum layer

Dorsal alar plate (sensory and coordinating)

Mantle layer Marginal layer Sulcus limitans

Ventral basal plate (motor)

Diencephalon

Cerebral aqueduct Tracts (white matter) Oculomotor nucleus Nucleus of Edinger-Westphal

Base

Red nucleus Cerebral peduncle

Diencephalon and Telencephalon

Mature (transverse section) Choroid plexus (projecting into lateral ventricle along choroid fissure) Body of caudate nucleus (basal ganglion) Corpus callosum Internal capsule Corpus striatum (basal ganglion) Claustrum (basal ganglion) Insula Lateral sulcus Temporal lobe of cerebral hemisphere Thalamus (from alar plate) HypoCerebral cortex (gray matter) thalamus Tracts (white matter) Amygdaloid body (nuclei) Hypothalamic (limbic forebrain) sulcus Line of fusion between Mammillary recess Mammillary bodies diencephalon and telencephalon

Septum pellucidum Fornix Choroid plexus in Roof plate roof of 3rd ventricle 3rd ventricle Interthalamic Ependymal layer adhesion Mantle layer (bridging 3rd Marginal ventricle) layer

5 1/2 weeks (transverse section)

Dorsal part of alar plate (thalamus)

Ventral part of alar plate (hypothalamus)

 

8.16 COMPARISON OF 5½-­WEEK AND ADULT CENTRAL NERVOUS SYSTEM REGIONS The relatively large ventricular system at 5½ weeks becomes comparatively smaller as the process of neuronal growth occurs. In adults, the central canal of the spinal cord becomes virtually obliterated and does not convey cerebrospinal fluid (CSF). The fourth ventricle opens up laterally; the sulcus limitans demarcates motor nuclei (medially) and sensory nuclei (laterally). The cerebral aqueduct remains very small. The third

ventricle narrows down to a slit. The lateral ventricles expand massively into a C-­shape. The basal plate forms motor and autonomic structures whose axons leave the CNS. The alar plate forms sensory derivatives in the spinal cord and brainstem and structures that migrate ventrally (the inferior olivary complex, the pontine nuclei, and the red nucleus). The rhombic lips, an alar derivative of the metencephalon, give rise to the entire cerebellum. The diencephalon and telencephalon are also alar plate derivatives.

Developmental Neuroscience

Superior colliculus Tegmentum Reticular formation Substantia nigra Temporopontine fibers Crus cerebri

Corticospinal and corticonuclear fibers Frontopontine fibers

145

Cerebral aqueduct Central gray matter Medial geniculate body (nucleus) Oculomotor nucleus Medial longitudinal fasciculus Medial, spinal and trigeminal lemnisci Nucleus of Edinger-Westphal Red nucleus Oculomotor (III) nerve

Section through midbrain at level of superior colliculi Superior medullary velum Superior cerebellar peduncle Ventral (anterior) spinocerebellar tract Medial longitudinal fasciculus Reticular formation Middle cerebellar peduncle Pontocerebellar fibers Corticopontine fibers Corticospinal and corticonuclear fibers

4th ventricle Mesencephalic Principal sensory Motor

Nuclei of trigeminal nerve

Motor nucleus of VII (facial) nerve Lateral lemniscus Medial, spinal, and trigeminal lemnisci Trigeminal (V) nerve and ganglion Median raphe

Section through pons at level of trigeminal nerves Inferior medullary velum Choroid plexus of 4th ventricle Lateral cuneate nucleus Inferior cerebellar peduncle Dorsal (posterior) spinocerebellar tract Ventral (anterior) spinocerebellar tract Spinal lemniscus (spinothalamic tracts) Medial longitudinal fasciculus Medial lemniscus

4th ventricle Vestibular nuclei Dorsal vagal nucleus Solitary tract nucleus Spinal tract and spinal nucleus of trigeminal nerve Hypoglossal nucleus Vagus (X) nerve Nucleus ambiguus Pyramid

Inferior olivary nuclei Hypoglossal (XII) nerve

Section through medulla oblongata at level of inferior olivary nuclei Central canal Hypoglossal nucleus Dorsal (posterior) spinocerebellar tract Spinothalamic tracts Ventral (anterior) spinocerebellar tract Medial lemniscus Pyramid

Fasciculus gracilis Gracile nucleus Fasciculus cuneatus Cuneate nucleus Spinal tract and spinal nucleus of trigeminal nerve Internal arcuate fibers Decussation of the medial lemniscus

Section through medulla oblongata at level of decussation of lemnisci Spinal tract and spinal nucleus of trigeminal nerve Dorsal (posterior) spinocerebellar tract Ventral horn Ventral (anterior) spinocerebellar tract Spinothalamic tracts Pyramid and anterior corticospinal fibers

Fasciculus gracilis Gracile nucleus Fasciculus cuneatus Dorsal horn Lateral corticospinal tract Pyramidal decussation

Section through medulla oblongata at level of pyramidal decussation

  8.17 ALAR AND BASAL PLATE DERIVATIVES IN THE BRAINSTEM The general pattern of alar and basal plate derivatives seen in the spinal cord continues into the brainstem. The alar plate derivatives shown in red are the sensory nuclei (the rhombic lip

from which the cerebellum is derived) and nuclei that migrate ventrally to form such structures as the inferior olivary nuclei, the pontine nuclei, the red nucleus, and others. The basal plate derivatives shown in blue are the motor and preganglionic autonomic nuclei.

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Overview of the Nervous System

Adult derivatives of brain primordia

Cerebral hemispheres (telencephalon) Olfactory bulbs (CN I) (telencephalon) Thalamus/3rd ventricle (diencephalon) Optic chiasm (CN II) (diencephalon)

CN III CN IV

Pineal gland (diencephalon) Neurohypophysis (diencephalon) Tectum/aqueduct (mesencephalon) Pons (metencephalon) 4th ventricle (metencephalon) Cerebellum (metencephalon)

Adult neural structures derived from embryonic primordia

CN V CN VI

CN VII CN VIII CN IX CN X CN XI

Medulla oblongata (myelencephalon) CN XII

Spinal cord

Sagittal view

Dorsal view

Adult derivatives of the forebrain, midbrain, and hindbrain Cerebral hemispheres (neocortex) Olfactory cortex (paleocortex) Hippocampus (archicortex) Basal ganglia/corpus striatum Lateral and 3rd ventricles

Nerves: Olfactory (I)

Optic cup/nerves Thalamus Hypothalamus Mammillary bodies Part of 3rd ventricle

Optic (II)

Mesencephalon

Tectum (superior, inferior colliculi) Cerebral aqueduct Red nucleus Substantia nigra Crus cerebelli

Oculomotor (III) Trochlear (IV)

Metencephalon

Pons Cerebellum

Trigeminal (V) Abducens (VI) Facial (VII) Acoustic (VIII) Glossopharyngeal (IX) Vagus (X) Hypoglossal (XI)

Telencephalon Forebrain Diencephalon

Midbrain

Hindbrain

Medulla oblongata Myelencephalon

 

8.18 ADULT DERIVATIVES OF THE FOREBRAIN, MIDBRAIN, AND HINDBRAIN The telencephalon has four major components: the cerebral cortex, the limbic forebrain structures, the basal ganglia, and the olfactory system. The diencephalon consists of two major structures: the thalamus and hypothalamus and two smaller structures, the epithalamus and subthalamus. The thalamus has extensive interconnections with the cerebral cortex and serves as a gateway to the telencephalon. The hypothalamus receives extensive input from the limbic forebrain and a variety of brainstem and visceral sensory sources and regulates neuroendocrine and visceral autonomic functions. The midbrain consists of the colliculi,

the tegmentum, and the cerebral peduncles. The colliculi convey visual (superior) and auditory (inferior) information to higher regions of the brain and to brainstem and reflex pathways. The tegmentum houses important motor, sensory, and autonomic structures and plays a crucial role in consciousness and sleep. The cerebral peduncles are caudal continuations of the posterior limb of the internal capsule and play a particularly important role in motor functions. The cerebellum plays an important role in coordinating movement, posture, locomotion, and equilibrium. The medulla and pons integrate the sensory, motor, and autonomic functions of the body via extensive connections through the cranial nerves, to which the spinal cord inputs contribute.

Developmental Neuroscience

Ophthalmic division of trigeminal nerve (V1)

Preotic somitomeres

Sensory for orbit, nose, and forehead

Postotic somites

IV

Otic ganglion (V3)

Accessory nerve XI relates to somitic mesenchyme by arch 6

VIII III

Ciliary ganglion (V1)

V

Pterygopalatine ganglion (V2)

VI

Otic vesicle VII

IX

X

II

Lens placode

XII

Optic cup Submandibular ganglion (V3) I

Head mesenchyme

Olfactory placode

XI Chorda tympani Taste to anterior 2/3 of tongue and parasympathetic to salivary glands Heart bulge

Pharyngeal arches and their nerves:

Tympanic nerve

Arch 1—trigeminal nerve (V) Maxillary part of arch 1— maxillary nerve (trigeminal, V2) Mandibular part of arch 1— mandibular nerve (trigeminal, V3) Pretrematic branch— ophthalmic nerve (trigeminal, V1) Arch 2—facial nerve (VII) Pretrematic branch—chorda tympani Arch 3—glossopharyngeal nerve (IX) Pretrematic branch—tympanic nerve Arch 4—vagus nerve (X) Arch 6—vagus nerve (X)

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Visceral sensory for middle ear and parasympathetic for parotid gland

Somite primordia and their nerves: Preotic somitomeres—oculomotor nerve (III) trochlear nerve (IV) abducens nerve (VI) Postotic somites—hypoglossal nerve (XII) Somitic mesenchyme—accessory nerve (XI)

Parasympathetic and visceral sensory branch from X for foregut and midgut

Ectodermal structures and their nerves: Olfactory placode—olfactory nerve (I) Optic cup—optic nerve (II) Otic placode—vestibulocochlear nerve (VIII)

 

8.19 CRANIAL NERVE PRIMORDIA The 12 pairs of cranial nerves exit the developing brain in sequence, except for cranial nerve XI, which exits most caudally. Cranial nerves I and II are CNS tracts, not peripheral nerves. The cranial nerves relate to surface placodes, head somites, or the pharyngeal arches, and they innervate all of the structures and

tissues that derive from them. The vagus nerve supplies arches 4 and 6. Although the otic, ciliary, pterygopalatine, and submandibular ganglia are associated anatomically with branches of the trigeminal nerve, these ganglia contain postganglionic neurons of the parasympathetic nervous system, receiving inputs from preganglionic neurons whose axons travel with CNs III, VII, and IX.

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Overview of the Nervous System

Special sensory and somatomotor cranial nerve components Nerve

Primordium innervated

Neuron components

Olfactory (I) Optic (II) Vestibulocochlear (VIII)

Olfactory placode Optic cup Otic placode

Special sensory (olfaction) Special sensory (vision) Special sensory (hearing and balance)

Oculomotor (III)

Preotic somitomere

Trochlear (IV) Abducens (VI) Hypoglossal (XII) Accessory (XI)

Preotic somitomere Preotic somitomere Postotic somites Somitic mesenchyme by arch 6

Somatomotor to extraocular eye muscles Parasympathetics to ciliary ganglion (for pupil constrictor and ciliary muscle) Somatomotor to superior oblique muscle Somatomotor to lateral rectus muscle Somatomotor to tongue muscles Somatomotor to sternocleidomastoid and trapezius muscles

Pharyngeal arch cranial nerve components Nerve

Arch

Neuron components

Trigeminal (V)

1

General sensory (face, orbit, nasal, and oral cavities) Branchiomotor (muscles of mastication, tensor tympani, tensor veli palatini)

Facial (VII)

2

Branchiomotor (muscles of facial expression, stylohyoid, posterior digastric, stapedius) Special sensory (taste to anterior two thirds of tongue) Parasympathetic to pterygopalatine and submandibular ganglia (for lacrimal glands, nasal mucosa, and salivary glands)

Glossopharyngeal (IX)

3

Visceral sensory to pharynx Branchiomotor to stylopharyngeus Parasympathetic to otic ganglion (for the parotid gland) Special sensory (taste to posterior tongue; carotid body and sinus)

Vagus (X)

4 and 6

Branchiomotor (pharynx and larynx) Visceral sensory (larynx, foregut below pharynx and midgut) General sensory to external acoustic meatus Parasympathetics (enteric ganglia of foregut and midgut) Special sensory (taste in laryngopharynx; carotid body and sinus)

Reprinted with permission from Cochard L. Netter’s Atlas of Human Embryology, Updated Edition. Philadelphia: Elsevier, 2012. 

8.20 CRANIAL NERVE NEURON COMPONENTS The pharyngeal arch nerves of the head and neck consist of several neuronal types. Most have branchiomotor neurons for skeletal muscles derived from arch mesenchyme, visceral sensory neurons for the inner endodermal linings of the arches (larynx and pharynx), and general sensory neurons for surface ectoderm

or lining of the stomodeum. The somites give rise to extraocular muscles and intrinsic muscles of the tongue. The placodes and optic cup relate to the special sensory organs of the head. Cranial nerves III, VII, IX, and X have preganglionic parasympathetic components that innervate ganglia distant from their nerves of origin.

Developmental Neuroscience

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CN III (GVE) Somatic (GSE)

CN III (GSE)

CN III CN IV CN VI

CN XII CN XI

Parasympathetic (GVE)

Branchiomotor (SVE)

CN III CN VII CN IX CN X

CN V CN VII CN IX CN X

1

Rhombomeres

CN IV (GSE)

2

CN V (SVE)

3

CN VII (SVE)

Pharyngeal arches

CN VII (GVE) I Parasympathetic (GVE) column

CN VI (GSE) CN IX (GVE)

4

CN IX (SVE)

5

Branchiomotor (SVE) column

CN XII (GSE) Somatomotor (GSE) column

CN X (SVE) II

CN X (GVE) 6 7

III 8

Ventral horn Lateral horn

Note: GSE  General somatic efferent GVE  General visceral efferent SVE  Special visceral efferent

IV Dorsal horn

Spinal cord

 

8.21 DEVELOPMENT OF MOTOR AND PREGANGLIONIC AUTONOMIC NUCLEI IN THE BRAINSTEM AND SPINAL CORD Gray matter columns develop in the spinal cord for somatic lower motor neurons (ventral horn) and preganglionic autonomic neurons (lateral horn). These columns extend rostrally into the brainstem, maintaining the same general positional

relationship to each other but organized into a series of separate but aligned nuclei. A third group of nuclei develops in the rhombencephalon as branchiomotor neurons supplying pharyngeal arch muscles. Both the somatic motor and the branchiomotor neurons are classified as lower motor neurons and have axons exiting the CNS to synapse on skeletal muscle fibers.

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Overview of the Nervous System

Surface ectoderm Neuroectoderm (forebrain) Mesenchyme Optic cup Lens placode Lens vesicle

Optic vesicle

Mesenchymal condensation forms outer layers of globe (cornea and sclera) Hyaloid artery

Inner layer of optic vesicle (visual retina) Outer layer of optic vesicle (pigmented retina [epithelium]) Hyaloid vessels regress prior to birth

Anterior chamber

Optic cup

Hyaloid artery Internal carotid artery

Early eye develops as neuroectodermal outpouching (optic vesicle) of primitive forebrain and thickening of adjacent surface ectoderm (lens placode) Eyelid primordia

Optic stalk

Lens placode invaginates to form the lens vesicle. The optic vesicle invaginates to form a double-layered optic cup that surrounds the lens vesicle and hyaloid vessels Orbicularis oculi (2nd pharyngeal arch) Conjunctiva (surface ectoderm)

Extraocular muscles (preotic somitomeres) Sclera (mesenchyme) Choroid (mesenchyme)

Corneal epithelium (surface ectoderm) Cornea (mesenchyme) Anterior chamber Lens (surface ectoderm) Iris (neuroectoderm) Visual retina (neuroectoderm)

Fusion of visual retina and pigmented retinal epithelium

Pigmented retina (epithelium) (neuroectoderm)

Optic nerve (neuroectoderm)

Primordium Optic cup

Derivative Retina, optic nerve, ciliary and iris epithelium, and pupil constrictor and dilator muscles

Related nerve Optic nerve (II)

Head mesenchyme Somites Surface ectoderm

Cornea, sclera, meninges, choroid, ciliary muscle and connective tissue, and iris connective tissue Extraocular eye muscles Eyelid epidermis, conjunctiva, lacrimal gland

2nd pharyngeal arch

Orbicularis oculi muscle

Ophthalmic nerve (V1) III, IV, and VI Ophthalmic nerve (V1) Facial nerve (VII)

Lens placode

Lens

 

8.22 DEVELOPMENT OF THE EYE AND ORBIT The retina and optic nerve develop as a double-­layered extension of the neural tube, the optic cup. This extension surrounds the lens vesicle of surface origin and has a ventral groove to accommodate blood vessels. The iris and ciliary body are formed in part from optic cup epithelium. The two layers of the optic cup never

fully fuse and can be separated in the case of a retinal detachment. Connective tissues of mesodermal origin include the sclera, cornea, and vascular choroid layer. The extraocular muscles derive from somitomeres. The epidermis of the eyelids develops from surface ectoderm and is continuous with the conjunctiva and corneal epithelium.

Developmental Neuroscience

Otic vesicle

Endolymphatic appendage

Endolymphatic sac Endolymphatic duct

Endolymphatic appendage Condensing mesenchyme

151

Pars superior

Pars inferior

Pars superior Pars inferior

Ossicle condensations

Developing external auditory meatus Meatal plug

Tubotympanic recess

A

B

28 days

C

29 days

Developing semicircular canals

Endolymphatic sac

Regressing cells

32 days

Semicircular canals: Anterior Posterior

Cranial nerve VIII

Tympanic cavity

Lateral

Incus

Stapes Malleus

le

ric

Ut

Ampulla Ductus reuniens

Eardrum Saccule

Meatal plug Developing cochlear duct

Tympanic cavity Cochlear duct

Auditory tube

D

Late 5th week

E

9th month

Reprinted with permission from Schoenwolf G, Bleyl S, Brauer P, et al. Larsen’s Human Embryology, 4th ed. Philadelphia: Elsevier, 2008.

 

8.23 DEVELOPMENT OF THE EAR The ear consists of the outer component (the auricle, external auditory meatus to the eardrum); the middle component (the ossicles [malleus, incus, stapes]); and the inner component (the

bony and membranous labyrinths, the cochlea, and the semicircular canals). The outer ear derives from the first pharyngeal groove, the middle ear from the first pharyngeal pouch, and the inner ear from the otic placode.

152

Overview of the Nervous System

Infundibular process Brain

Infundibular process

Oral ectoderm Rathke’s pouch Mesoderm

Stomodeum

Rathke’s pouch

1. Beginning formation of Rathke’s pouch and infundibular process

2. Neck of Rathke’s pouch constricted by growth of mesoderm

3. Rathke’s pouch “pinched off”

Median eminence

Pars tuberalis Infundibulum

Cleft

Pars nervosa Pars intermedia Sphenoid sinus 4. Pinched-off segment conforms to neural process, forming pars distalis, pars intermedia, and pars tuberalis

Pars distalis (pars glandularis) 5. Pars tuberalis encircles infundibular stalk (lateral surface view)

6. Mature form

Pituitary hormones From the anterior lobe (pars distalis)

From the posterior lobe (pars nervosa)

Follicle-stimulating hormone (FSH)

Thyroid-stimulating hormone (TSH)

Vasopressin

Luteinizing hormone (LH)

Adrenocorticotropic hormone (ACTH)

Oxytocin

Prolactin

Growth hormone (GH)

 

8.24 DEVELOPMENT OF THE PITUITARY GLAND The pituitary gland develops from outgrowth of two separate primordia. The anterior lobe (adenohypophysis) derives from the roof of the stomodeum and encircles the base of the posterior lobe (neurohypophysis). The posterior lobe derives from the brain and possesses axonal processes from the hypothalamus that secrete oxytocin and vasopressin into the general circulation.

The anterior lobe contains pituicytes that respond to releasing and inhibitory factors from neurons of the brain that are delivered through a private vascular channel, the hypophyseal-­portal system, and secreted into this circulation are hormones such as follicle-­ stimulating hormone, luteinizing hormone, prolactin, thyroid-­stimulating hormone, adrenocorticotropic hormone, and growth hormone.

Developmental Neuroscience Frontal section (ventral to sulcus limitans) at 36 days

153

Ependymal lining of cavities of brain at 3 months

Lamina terminalis 3rd ventricle

Telencephalic vesicle

Optic stalk

3rd ventricle

Optic cup Infundibular recess Diencephalon

Cerebral aqueduct

Rhombencephalon

Interventricular foramen (of Monro)

Lateral ventricle

Alar plate

Mesencephalon Basal plate

Metencephalon (cerebellum, pons) Metacoele (4th ventricle)

Right lateral ventricle

Left lateral ventricle

3rd ventricle Infundibular recess (on ventral surface) Cerebral aqueduct (of Sylvius) Lateral aperture of 4th ventricle (of Luschka) in lateral recess Median aperture of 4th ventricle (of Magendie) in roof

Myelencephalon (medulla oblongata)

Spinal cord

4th ventricle

Central canal of spinal cord

Central canal

Ependymal lining of cavities of brain at 9 months (birth) Right lateral ventricle

Anterior horn of left lateral ventricle in frontal lobe

Region of invagination of choroid plexus along choroid fissure of lateral ventricle

Central part of left lateral ventricle Suprapineal recess of 3rd ventricle

Right interventricular canal (of Monro)

Pineal recess Inferior horn of left lateral ventricle in temporal lobe

Foramen in 3rd ventricle for interthalamic adhesion

Posterior horn of left lateral ventricle in occipital lobe

Thalamic impression Optic recess of 3rd ventricle

Superior recess of 4th ventricle

Infundibular recess

Left lateral aperture (of Luschka) of 4th ventricle

Region of invagination of choroid plexus along choroid fissure of lateral ventricle

Median aperture (of Magendie) of 4th ventricle

Cerebral aqueduct (of Sylvius)

Central canal of spinal cord

  8.25 DEVELOPMENT OF THE VENTRICLES The rapid growth of the brainstem and the forebrain alters the uniform appearance of the ventricles. The C-­shaped lateral ventricles follow the growth of the telencephalon, with limited access into the third ventricle through the interventricular foramen of Monro. The narrow cerebral aqueduct remains very small in the upper mesencephalon and opens into the rhomboid-­shaped and expanding fourth ventricle. The foramina of Magendie (medial) and Luschka (lateral) in the fourth ventricle allow flow from the ventricular system into the developing cisterns of the subarachnoid space. CSF reenters the venous system through the arachnoid granulations, one-­way valves that allow drainage from the subarachnoid space into the dural (venous) sinuses, especially the superior sagittal sinus.

CLINICAL POINT The C-­shaped form of the ventricular system follows from the development of the primary brain vesicles, with the flexures and disproportionate neural development. The lateral ventricles are associated with the telencephalon, the third ventricle with the diencephalon, the cerebral aqueduct with the mesencephalon, and the fourth ventricle with the rhombencephalon (metencephalon [pons] and myelencephalon [medulla]). The foramina of Magendie and Luschka, which allow for the escape of CSF into the subarachnoid space, are already patent at the end of the first trimester. An obstruction of internal CSF flow results in internal hydrocephalus. A common site for such an obstruction is atresia of the cerebral aqueduct, with enlarged third and lateral ventricles. Another site of possible obstruction occurs with Dandy-Walker syndrome, a malformation of the fourth ventricle that includes atresia of the foramina of Magendie and Luschka, internal hydrocephalus of the entire ventricular system, hypoplasia of the cerebellum, and posterior fossa cyst formation.   

154

Overview of the Nervous System

5½ weeks

Roof plate Ependymal layer

Dorsal alar plate (sensory and coordinating)

4th ventricle

Mantle layer Marginal layer Sulcus limitans Mantle layer

Ventral basal plate (motor)

Marginal layer

3½ months

Choroidal artery and vein

Ependymal roof of 4th ventricle

Choroid plexus Sulcus limitans

Ependymal floor of 4th ventricle Lateral recess of 4th ventricle

4th ventricle

Lateral aperture Marginal layer Mantle layer Marginal layer

Mature

Choroidal vessels

Ependymal floor of 4th ventricle

4th ventricle

Choroid fissure of roof of 4th ventricle Vestibular nuclei Lateral recess of 4th ventricle Choroid plexus protruding through lateral aperture of 4th ventricle

Descending (spinal) nucleus of V

Nucleus ambiguus Olive Pyramid

Nucleus tractus solitarius Dorsal motor nucleus of X Hypoglossal (XII) nucleus Raphe nuclei Inferior olivary nucleus

 

8.26 DEVELOPMENT OF THE FOURTH VENTRICLE The expansion of the fourth ventricle from the original central canal of the rhombencephalon into its mature form is a complex process. The sulcus limitans is conspicuous early in development (5½ weeks), and the original lateral walls expand outward and lie down horizontally (3½ months) as the roof plate expands to both sides. As a result, the sulcus limitans becomes a landmark

at the dorsal boundary of the medulla on the floor of the fourth ventricle, separating the motor structures medially from the sensory structures laterally. The lateral aperture of the fourth ventricle (the foramen of Luschka) opens into the subarachnoid space. In their mature form (bottom illustration), these paired lateral apertures are major channels between the internal and external circulation of the CSF and must remain open to prevent internal hydrocephalus.

Developmental Neuroscience

Spinal bifida occulta

155

Dermal sinus

Dural sac Cauda equina

Sinus with squamous plug

Fat pad overlying spina bifida occulta. Tuft of hair or only skin dimple may be present, or there may be no external manifestation. Dermal sinus also present in this case (arrow )

Types of spina bifida aperta with protrusion of spinal contents

Meningocele

Meningomyelocele

Arnold-Chiari syndrome decompression

 

8.27 NEURAL TUBE DEFECTS Spina bifida occurs when a vertebral arch fails to develop; the neural tube cannot move below the surface, and somite sclerotome cells cannot migrate over it to complete the vertebral arch. The spinal cord may be exposed on the surface (myeloschisis), which involves severe functional deficits or death and a high likelihood of infection. A protrusion may form, usually in the lumbar region, into which spinal cord and nerve roots

may protrude (meningomyelocele) or in which CSF is present (meningocele). When these defects are repaired, the brainstem may herniate (Arnold-­ Chiari malformation), and extensive functional deficits may be present, such as loss of bladder and bowel function and loss of motor function and sensation in the lower extremities. In its most benign form, spina bifida occulta may be manifested by a small sinus or a tuft of hair at the site of defect.

156

Overview of the Nervous System

Occipital encephalocele

Frontal encephalocele

Anencephaly

 

8.28 DEFECTS OF THE BRAIN AND SKULL Defects of the rostral portion of the neural tube involve the brain and skull. If the occipital bone or other midline bones fail to ossify, meninges and possibly brain tissue may protrude into a sac (encephalocele). If the rostral (cranial) neuropore fails to close, the brain and much of the skull fail to develop (anencephaly) and

the tissue that is present is exposed to the external environment. This condition is incompatible with life. The Arnold-­Chiari malformation may occur with or without spina bifida such as in a meningomyelocele; in this malformation, the tonsils of the cerebellum herniate through the foramen magnum and can disrupt vital brainstem functions, resulting in death.

Developmental Neuroscience

157

Microcephaly Ptosis Short palpebral fissures Long smooth philtrum

Appearance of infant

Thin vermilion border

Atrial septal defect Ventricular septal defect

Alcohol consumption in excess of 3 oz/day during pregnancy is considered ’’high risk.’’ Although identifiable effects are seldom seen with consumption less than 1 oz/day, there is no assurance of safety at that level. Weight

Cardiac and skeletal anomalies are common

Intellectual disability

Ptosis

Height

Abnormal palmar crease

Strabismus

Head circumference

Short palpebral fissures

Long, smooth philtrum Dental caries and malocclusion

Developmental deficiency is common. Prognosis is most influenced by degree of maternal alcohol consumption, extent and severity of malformation pattern, including growth retardation.

Thin vermilion border Appearance in older child

 

8.29 FETAL ALCOHOL SYNDROME Ethanol is among the most potent teratogens to the developing fetus. Prenatal alcohol exposure leads to a broad range of adverse effects collectively termed fetal alcohol spectrum disorders (FASD). The most severe consequence of maternal alcohol abuse, particularly binge drinking, is fetal alcohol syndrome (FAS). Both FASD and FAS are completely preventable by maternal abstinence. FASD And FAS are characterized by significant and irreversible effects on the unborn infant during intrauterine embryonic and fetal development, including growth retardation, microencephaly, CNS impairment, and neurodevelopmental abnormalities affecting cognition, thereby leading to learning disabilities, hyperactivity, and other behavioral-­social deficits. Long-­term CNS dysfunction is caused by structural damage to the developing brain such as reduced volume of white matter and

gray matter, agenesis or significant malformation of the corpus callosum, and diminished volume of the cerebellum, caudate nucleus, hippocampus, and parietal and frontotemporal lobes. Related neurodevelopmental anomalies include growth stature deficits, below-­average head circumference, and characteristic facial aberrations such as ptosis, broad philtrum, thin upper lip, and short palpebral fissures. Alcohol readily crosses the placenta during all stages of in utero development, all of which are equally critical and vulnerable. Underlying mechanisms of the broad spectrum of alcohol-­induced damage include overproduction and imbalance of cellular oxidative stress/free radical scavenging; alterations in the cell cycle, cellular proliferation, and migration; interference in cell signaling pathways and gene expression; epigenetic modifications; and activation of cellular necrosis and apoptosis.

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Section II REGIONAL

NEUROSCIENCE

9. Peripheral Nervous System Introduction and Basic Organization Somatic Nervous System Autonomic Nervous System 10. Spinal Cord 11. Brainstem and Cerebellum Brainstem Cross-Sectional Anatomy Cranial Nerves and Cranial Nerve Nuclei Reticular Formation Cerebellum 12. Diencephalon 13. Telencephalon

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9

PERIPHERAL NERVOUS SYSTEM



Introduction and Basic Organization

9.1 Schematic of the Spinal Cord with Sensory, Motor, and Autonomic Components of Peripheral Nerves 9.2 Anatomy of a Peripheral Nerve 9.3 Nerve Compression and Pressure Gradients 9.4 Peripheral Nerve Injury and Degeneration in a Compression Neuropathy 9.5 Relationship of Spinal Nerve Roots to Vertebrae 9.6 Lumbar Disc Herniation: L4–­L5 and L5–­S1 9.7 Sensory Channels: Reflex and Cerebellar 9.8 Sensory Channels: Lemniscal 9.9 Motor Channels: Basic Organization of Lower and Upper Motor Neurons 9.10 Autonomic Channels 9.11 Cutaneous Receptors 9.12 Pacinian Corpuscles 9.13 Interoceptors 9.14 Skin and Its Nerves 9.15 The Neuromuscular Junction and Neurotransmission 9.16 Physiology of the Neuromuscular Junction 9.17 Major Structures and Proteins in the Normal Neuromuscular Junction 9.18 Neuroeffector Junctions Somatic Nervous System 9.19 Dermatomal Distribution 9.20 Cutaneous Distribution of Peripheral Nerves 9.21 Cutaneous Nerves of the Head and Neck 9.22 Cervical Plexus in Situ 9.23 Cervical Plexus 9.24 Phrenic Nerve 9.25 Thoracic Nerves 9.26 Brachial Plexus 9.27 Dermatomes of the Upper Limb 9.28 Cervical Disc Herniation 9.29 Cutaneous Innervation of the Upper Limb 9.30 The Scapular, Axillary, and Radial Nerves Above the Elbow 9.31 Radial Nerve in the Forearm 9.32 Musculocutaneous Nerve 9.33 Median Nerve 9.34 Carpal Tunnel Syndrome 9.35 Ulnar Nerve 9.36 Lumbar Plexus 9.37 Sacral and Coccygeal Plexuses 9.38 Femoral and Lateral Femoral Cutaneous Nerves 9.39 Obturator Nerve

9.40 Sciatic and Posterior Femoral Cutaneous Nerves 9.41 Tibial Nerve 9.42 Common Peroneal Nerve

Autonomic Nervous System

9.43 General Schema 9.44 Autonomic Innervation of the Immune System and Metabolic Organs 9.45 Reflex Pathways 9.46 Cholinergic and Adrenergic Synapses 9.47 Schematic of Cholinergic and Adrenergic Distribution to Motor and Autonomic Structures 9.48 Autonomic Distribution to the Head and Neck: Medial View 9.49 Autonomic Distribution to the Head and Neck: Lateral View 9.50 Schematic of Autonomic Distribution to the Head and Neck 9.51 Autonomic Distribution to the Eye 9.52 Autonomic Innervation of the Nasal Cavity 9.53 Schematic of the Pterygopalatine and Submandibular Ganglia 9.54 Schematic of the Otic Ganglion 9.55 Innervation of the Limbs 9.56 Thoracic Sympathetic Chain and Splanchnic Nerves 9.57 Innervation of the Tracheobronchial Tree 9.58 Innervation of the Heart 9.59 Abdominal Nerves and Ganglia 9.60 Nerves of the Esophagus 9.61 Innervation of the Stomach and Proximal Duodenum 9.62 Nerves of the Stomach and Duodenum 9.63 Innervation of the Small and Large Intestines 9.64 Nerves of the Small Intestine 9.65 Nerves of the Large Intestine 9.66 Enteric Nervous System: Longitudinal View 9.67 Enteric Nervous System: Cross-­Sectional View 9.68 Autonomic Innervation of the Liver and Biliary Tract 9.69 Autonomic Innervation of the Pancreas 9.70 Schematic of Innervation of the Adrenal Gland 9.71 Innervation of the Adrenal Gland 9.72 Autonomic Pelvic Nerves and Ganglia 9.73 Nerves of the Kidneys, Ureters, and Urinary Bladder 9.74 Innervation of the Kidneys and Upper Ureter 9.75 Innervation of the Urinary Bladder and Lower Ureter 9.76 Innervation of the Male Reproductive Organs 9.77 Innervation of the Female Reproductive Organs

161

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Regional Neuroscience

 Sensory Motor Preganglionic sympathetic Postganglionic sympathetic Dorsal column

Dorsal root Pacinian corpuscle

Dorsal root ganglion Vascular smooth muscle, sweat glands, and arrector pili muscles in skin

Dorsal ramus Skeletal muscle Ventral ramus Gray ramus communicans Ventral root Sympathetic chain ganglion Free endings

Splanchnic nerve

White ramus communicans Sympathetic chain

Collateral sympathetic ganglion Skeletal muscle

Neuroeffector junctions on smooth muscle, cardiac muscle, secretory glands, metabolic cells, immune cells

Sensory neuron of abdominal viscera

INTRODUCTION AND BASIC ORGANIZATION 9.1 SCHEMATIC OF THE SPINAL CORD WITH SENSORY, MOTOR, AND AUTONOMIC COMPONENTS OF PERIPHERAL NERVES Peripheral nerves consist of axons from primary sensory neurons, lower motor neurons (LMNs), and preganglionic and postganglionic autonomic neurons. The primary sensory axons have sensory receptors (transducing elements) at their peripheral (distal) ends, contiguous with the initial segment of the axon. The proximal portion of the axon enters the central nervous system (CNS) and terminates in secondary sensory nuclei associated with reflex, cerebellar, and lemniscal channels. LMNs in the anterior horn of the spinal cord send axons via the ventral (anterior) roots to travel in peripheral nerves to skeletal muscles, with which they form neuromuscular junctions. The autonomic preganglionic neurons send axons via the ventral roots to terminate in autonomic ganglia or in the adrenal medulla. Postganglionic neurons send axons into splanchnic or peripheral nerves and form neuroeffector junctions

Preganglionic sympathetic neurons passing to synapse in another sympathetic chain ganglion

with smooth muscle, cardiac muscle, secretory glands, metabolic cells, and cells of the immune system. Splanchnic nerves convey preganglionic axons to collateral sympathetic ganglia in the abdomen and pelvis viscera, postganglionic axons to the thoracic viscera, and sensory axons from the viscera. CLINICAL POINT Peripheral nerves form through the union of dorsal and ventral roots and by subsequent branching, similar to the process that occurs through the brachial plexus. The resultant terminal peripheral nerves contain limited categories of axonal types, including LMN axons (both alpha and gamma), primary sensory axons (both myelinated and unmyelinated), and autonomic axons (mainly postganglionic sympathetic axons). Destructive lesions in peripheral nerves may cause flaccid paralysis of innervated skeletal muscles (with loss of tone and denervation atrophy), loss of some or all aspects of somatic sensation in the innervated territory, and some autonomic dysfunction resulting from loss of sympathetic innervation (e.g., vasodilation and lack of sweating). An irritative lesion of a peripheral nerve is usually manifested as pain radiating to the innervated territory.   

Peripheral Nervous System

163

Compression

Longitudinal vessels Outer epineurium Inner epineurium

Fascicle

Nerve fiber bundles Traction Epineurial coat provides some protection against compression. Spiral configuration of nerve fiber bundles within fascicles provides some protection from traction.

Fascicle Perineurium Nerve fibers (axons)

Intact axons

Axons undergoing dissolution

Degenerating axons Axons Myelin Peripheral nerve in longitudinal section, demonstrating the longitudinal array of axons (densely stained), with segments surrounded by myelin (clear areas). Fiber stain.

Peripheral nerve undergoing Wallerian degeneration following an insult. Some axons at the top are relatively intact. Other axons on the bottom are starting to degenerate, and a group of axons in the middle are forming globules of axons and myelin remnants, and are undergoing dissolution (see Plate 9.4 for full description of this process). Osmic acid myelin stain.

  9.2 ANATOMY OF A PERIPHERAL NERVE A peripheral nerve is made up of unmyelinated and myelinated axons, the connective sheaths with which they are associated, and local blood vessels, the vasa nervorum. Unmyelinated axons are surrounded by the cytoplasm of Schwann cells, called Schwann cell sheaths. Each individual segment of a myelinated axon is enwrapped by a myelin sheath, provided by an individual Schwann cell. The bare space between each myelin sheath is called a node of Ranvier and is the site on the membrane where sodium channels are present and is also the site of initiation or

reinitiation of the action potential. Endoneurium is loose, supportive, connective tissue that is found between individual axons within a fascicle. Fascicles of multiple axons are enwrapped by a sheath of supportive cells and collagenous connective tissue; this perineurium functions as a blood-­nerve barrier and helps to protect the axons from local diffusion of potentially damaging substances. This perineurial barrier can be disrupted in neuropathic conditions such as diabetic neuropathy. The epineurium is the outermost layer of supportive connective tissue that enwraps the entire nerve.

164

Regional Neuroscience Myelinated nerve fiber Median nerve in carpal tunnel

Node of Ranvier Internode Axon

Arterial pressure Capillary pressure

Asymmetric distortion of internodes

Intrafascicular pressure Venous pressure Extraneural pressure >

>

>

Chronic compression

>

Fascicle Arteries enter fascicle at right angles

Veins exit fascicle obliquely, theoretically leaving them more vulnerable to mild compression

Pressure gradient necessary for adequate intrafascicular circulation

  9.3 NERVE COMPRESSION AND PRESSURE GRADIENTS With chronic compression of a nerve, such as median nerve entrapment in carpal tunnel syndrome, internodes of large myelinated axons are distorted (accompanied by repeated demyelination and remyelination), and both ischemia and endoneurial edema occur. Endoneurial edema can induce venous congestion

and increase fluid pressure, resulting in metabolic, physiologic, and anatomic damage and dysfunction of the affected peripheral nerves. Affected axons exhibit impaired axoplasmic transport, both anterograde and retrograde. Diabetes increases the susceptibility of peripheral nerves to entrapment, with endoneurial edema and impaired axoplasmic transport. Chronic compression can lead to degeneration of the affected axons.

Peripheral Nervous System Severe acute compression

Normal Patent vessels Normal epineurium

165

Severe chronic compression Vascular compression and ischemia

Thickened epineurium

Axon Patent microtubules Compression of nerve with thinned myelin and closed microtubules

Myelin sheath Thinned myelin in compressed area Distortion of myelin or demyelination and axonal degeneration Normal motor neuron

Sunderland classification of nerve injury Cell body Axon

Epineurium Perineurium Endoneurium Myelin sheath Motor neuron undergoing central chromatolysis

Normal

First Second Third Fourth Fifth degree degree degree degree degree (neurapraxia) (axonotmesis) Classification of nerve injury by degree of involvement of various neural layers

  9.4 PERIPHERAL NERVE INJURY AND DEGENERATION IN A COMPRESSION NEUROPATHY If a peripheral nerve is compressed or damaged, a series of reactions takes place within the neurons whose axons have been damaged and in the supportive tissue. At the site of the injury, axonal damage and thinning of the myelin or frank demyelination can occur. Distal to the site of the injury, the peripheral portion of the axon can degenerate (called Wallerian degeneration), resulting in the breaking up and dissolution of the peripheral axon. The Schwann cells responsible for myelinating the degenerating axons also break up and degenerate. However, the basement membrane remains intact, providing a scaffold through which future regenerating axons can be directed. The

Motor neuron permanently impaired

central (proximal) portion of the neuron can undergo changes called central chromatolysis. The Nissl bodies (endoplasmic reticulum) break up into individual ribosomes, the cell body swells, and the neuron shifts its metabolism to structural and reparative synthetic products that attempt to save the neuron and permit it to try to recover from the injury. If successful, this process gradually reverses, and the neuron begins to sprout a peripheral axonal extension, seeking to reattach to the target from which it was disrupted. The Schwann cells proliferate and generate new myelin sheaths around the regrowing axon, but the intersegmental distances of the new myelin sheath are shorter than the original distances and the myelin sheath is thinner; thus, the regenerated axon shows a slower conduction velocity than the original intact axon.

166

Regional Neuroscience

Base of skull Cervical enlargement

Lumbar enlargement

C1 C1 C2 C2 C3 C3 C4 C4 C5 C5 C6 C6 C7 C7 C8 T1 T1 T2 T2 T3 T3 T4 T4 T5 T5 T6 T6 T7 T7 T8 T8 T9 T9 T10 T10 T11 T11 T12 T12 L1 L1 L2 L2 L3

Internal terminal filum (pial part)

L4

L3

C1 spinal nerve exits above C1 vertebra

L4 L4 L5

C8 spinal nerve exits below C7 vertebra (there are 8 cervical nerves but only 7 cervical vertebrae) S1 S2

Lumbar disc protrusion does not usually affect nerve exiting above disc. Lateral protrusion at disc level L4–5 affects L5 spinal nerve, not L4 spinal nerve. Protrusion at disc level L5–S1 affects S1 spinal nerve, not L5 spinal nerve L4

L5 L5 Cauda equina S1

L4

S2

L5

S2

L4

Conus medullaris (termination of spinal cord)

L5

External terminal filum (pial part)

L5

S3

Sacrum S1

S4 S5

S3 Termination of dural sac S4 S5 Coccygeal nerve

Coccygeal nerve

Cervical nerves Thoracic nerves Coccyx Lumbar nerves Sacral and coccygeal nerves

Medial protrusion at disc level L4–5 rarely affects L4 spinal nerve but may affect L5 spinal nerve and sometimes S1–4 spinal nerves.

  9.5 RELATIONSHIP OF SPINAL NERVE ROOTS TO VERTEBRAE The dorsal (posterior) and ventral (anterior) roots of the spinal cord segments extend from the spinal cord as peripheral axons, invested initially with meninges. As the axons enter the peripheral nervous system, they become associated with Schwann cells for myelination and support. The roots exit through the intervertebral foramina, compact openings between the vertebrae where herniated discs (nucleus pulposus) may impinge on the nerve roots and produce sensory or motor symptoms. Sensory and motor axons travel with the dorsal and ventral rami of peripheral nerves. Autonomic preganglionic axons (myelinated) course from the ventral roots into the white (preganglionic) rami communicans and synapse in autonomic ganglia. The ganglion cells give rise to postganglionic axons (unmyelinated) that course through the gray rami communicans and join the peripheral nerves.

CLINICAL POINT The longitudinal growth of the spinal column outstrips the longitudinal growth of the spinal cord; as a consequence, the spinal cord in adults ends adjacent to the L1 vertebral body. Nerve roots heading for intervertebral foramina below L1 extend caudally through the subarachnoid space in the lumbar cistern, forming the cauda equina. Damage to the cauda equina can occur as the result of tumors, such as ependymomas and lipomas, or of a prolapsed intervertebral disc. It is common for symptoms to occur gradually and be irregular because of the ample room in the lumbar cistern for nerve roots to move. Radicular pain often is experienced in a sciatic distribution, with progressive loss of sensation in radicular patterns. A more caudal location of the obstructing mass may lead to loss of sensation in regions of sacral innervation in the perineal (saddle) zone. Loss of bowel, bladder, and erectile function also may occur. More rostral lesions may result in flaccid paralysis of the legs.   

Peripheral Nervous System

Cross section showing compression of nerve root

Nucleus pulposus Nerve root

Characteristic posture in left-sided lower lumbar disk herniation

Dura Surgical exposure of lower lumbar disk herniation

Clinical features of herniated lumbar nucleus pulposus Level of herniation

Pain

Numbness

Weakness

Atrophy

L3 L4 L5 L5

S

L4–5 disk; 5th lumbar nerve root L4 L5 S

L5–S1 disk; 1st sacral nerve root

Over sacroiliac joint, hip, lateral thigh and leg

Over sacroiliac joint, hip, posterolateral thigh and leg to heel

Dorsiflexion of great toe and foot; difficulty walking on Lateral leg, heels; foot first 3 toes drop may occur

Back of calf, lateral heel, foot to toe

 

9.6 LUMBAR DISC HERNIATION: L4–­L5 AND L5–­S1 Characteristics and clinical manifestation of lower lumbar disc herniations at L4–­L5 and L5–­S1.

Minor

Reflexes

Changes uncommon in knee and ankle jerks, but internal hamstring reflex diminished or absent

Plantar flexion of foot and great toe may be affected; Ankle jerk difficulty diminished walking on toes Gastrocnemius or absent and soleus

167

168

Regional Neuroscience A. Sensory Channels—Reflex Central nervous system

Peripheral nervous system Primary sensory cell body Polysynaptic (flexor) reflex

Unmyelinated

Monosynaptic muscle stretch reflex

Myelinated

Interneuron

Free endings

Interneuron Muscle spindle Lower motor neuron

Lower motor neuron Skeletal muscle

B. Sensory Channels—Cerebellar Central nervous system

Peripheral nervous system

Granular cell in cerebellum

Spinocerebellar tract enters cerebellum via inferior or superior cerebellar peduncle

Primary sensory neuron cell body in dorsal root ganglion

Primary sensory axon (supplies muscle spindle, Golgi tendon organ, cutaneous sites)

Secondary sensory neuron in spinal cord (e.g., Clarke‘s nucleus) or brainstem (e.g., lateral cuneate nucleus) Muscle spindle

  9.7 SENSORY CHANNELS: REFLEX AND CEREBELLAR Primary sensory axons communicate with secondary sensory neurons in reflex, cerebellar, and lemniscal channels, carrying transduced information from the periphery into the CNS. A, The reflex channels interconnect primary sensory axons with anterior horn cells (LMNs) through one or more synapses to achieve unconscious reflex motor responses to sensory input. These responses can be elicited in an isolated spinal cord devoid of connections from the brain. The monosynaptic reflex channels connect primary sensory Ia axons from muscle spindles, via the dorsal roots, directly with LMNs involved in muscle stretch reflex contraction; this is the only monosynaptic reflex seen in the human CNS. Polysynaptic reflex channels are directed particularly toward flexor (withdrawal) responses through one or more interneurons to produce coordinated patterns of muscle

activity to remove a portion of the body from a potentially damaging or offending stimulus. This polysynaptic channel can spread ipsilaterally and contralaterally through many segments. B, Primary somatosensory axons carrying unconsciously processed information from muscles, joints, tendons, ligaments, and cutaneous sources enter the CNS via dorsal roots and synapse with secondary sensory neurons in the spinal cord or caudal brainstem. These secondary sensory neurons convey information, initially derived from the periphery, to the ipsilateral cerebellum via spinocerebellar pathways. The dorsal and ventral spinocerebellar pathways carry information from the lower body (T6 and below). The rostral spinocerebellar tract and the cuneocerebellar tract carry information from the upper body (above T6). Polysynaptic indirect spinocerebellar pathways (spino-­olivocerebellar and spino-­reticulo-­cerebellar tracts) also are present.

Peripheral Nervous System

169

Sensory Channels—Lemniscal Central nervous system

Peripheral nervous system Dorsal root

Primary sensory cortex neurons

Nucleus VPL (ventral posterolateral)

Round cell bodies of the dorsal root ganglion, devoid of dendrites. Many darkly stained axons course through the ganglion and form the dorsal root. Cajal stain; fiber stain.

Tertiary sensory neurons in thalamus

Axons

Medial lemniscus Neurons Spinothalamic tract Crosses in caudal medulla Crosses in anterior white commissure Dorsal horn (spinal cord)

Secondary sensory neurons in spinal cord or brainstem

High magnification of dorsal root ganglion primary sensory neurons and axons. Cajal stain.

Nuclei gracilis and cuneatus

Primary sensory neurons in dorsal root ganglion

Fasciculi gracilis and cuneatus Large myelinated

Pacinian corpuscle

Small myelinated

  9.8 SENSORY CHANNELS: LEMNISCAL Primary sensory axons carrying sensory information destined for conscious perception arise from receptors in superficial and deep tissue. These axons enter the CNS via the dorsal roots and terminate on secondary sensory nuclei in the spinal cord or brainstem. Secondary sensory axons from these nuclei cross the midline (decussate), ascend as lemniscal pathways, and terminate in the contralateral thalamus. These specific thalamic nuclei then project to specific regions of the primary sensory cortex, where fine-­grained analysis of incoming, consciously perceived sensory information takes place. Somatosensory information is directed into two sets of channels, protopathic and epicritic. The epicritic information (fine, discriminative sensation; vibratory sensation; joint position sense) is transduced by primary sensory neurons (dorsal root ganglion cells) that send myelinated axons to neurons in the medulla, the nucleus gracilis (lower body, T6 and below), and the nucleus cuneatus (upper body, above T6). Nuclei gracilis and cuneatus give rise to the medial lemniscus, a crossed secondary sensory pathway that terminates in the ventral posterolateral (VPL) nucleus of the thalamus. This thalamic nucleus has reciprocal projections with cortical neurons in the postcentral gyrus (Brodmann’s areas 3, 1, and 2). This entire epicritic somatosensory system is highly

topographically organized, with each region of the body represented in each nucleus and axonal pathway. The protopathic information (pain, temperature sensation, light moving touch) is transduced by primary sensory neurons (dorsal root ganglion cells) that project mainly via small myelinated and unmyelinated axons to neurons in the dorsal horn of the spinal cord. These spinal cord neurons give rise to the spinothalamic tract (spinal lemniscus), a secondary sensory pathway that terminates in separate neuronal sites in the VPL nucleus of the thalamus. This portion of the VPL nucleus communicates mainly with the primary sensory cortex (SI) and a secondary area of somatosensory cortex (SII) posterior to the lateral postcentral gyrus. Some unmyelinated nociceptive protopathic axons that terminate in the dorsal horn of the spinal cord interconnect with a cascade of spinal cord interneurons that project mainly into the reticular formation of the brainstem (the spinoreticular pathway). This more diffuse pain system is processed through nonspecific thalamic nuclei with projections to somatosensory cortices and more widespread regions of cortex. This system can result in the perception of excruciating, long-­lasting pain that may exceed the duration and intensity of direct peripheral stimuli. Chronic activation of this system can result in chronic neuropathic pain, persisting and reinforced by central mechanisms.

170

Regional Neuroscience Peripheral nervous system

Central nervous system

Endoplasmic reticulum

Cortical upper motor neuron

Cell bodies

Corticospinal tract

Brainstem upper motor neuron (red nucleus, superior colliculus, vestibular nuclei, reticular nuclei)

Lower motor neurons showing large cell bodies and extensive Nissl substance (endoplasmic reticulum). Cresyl violet stain.

Brainstem upper motor neuron tracts

Apical dendrite Pyramidal neuron

(all) Interneurons

Basolateral dendrites (some)

Lower motor neurons (spinal cord and brainstem) Large pyramidal neuron with a typical branching apical dendrite and multiple basolateral dendrites (BD) and their branches. Fiber stain. Skeletal muscle

 

9.9 MOTOR CHANNELS: BASIC ORGANIZATION OF LOWER AND UPPER MOTOR NEURONS LMNs are found in the anterior horn of the spinal cord and in motor cranial nerve nuclei in the brainstem. Their axons exit via the ventral roots or cranial nerves to supply skeletal muscles. LMN synapses with muscle fibers form neuromuscular junctions and release the neurotransmitter acetylcholine, which acts on nicotinic receptors on the skeletal muscle fibers. A motor unit consists of an LMN, its axon, and the muscle fibers the axon innervates. LMNs are regulated and

coordinated by groups of upper motor neurons (UMNs) found in the brain. Brainstem UMNs regulate basic tone and posture. Cortical UMNs (from corticospinal and corticobulbar tracts) regulate consciously directed, or volitional, movements. Cortical UMNs also have extensive connections with brainstem UMNs and may help to coordinate their activities. The cerebellum and basal ganglia aid in the coordination of movement and in pattern selection, respectively, via connections with UMNs; the cerebellum and basal ganglia do not connect with LMNs directly.

Peripheral Nervous System

Central nervous system

171

Peripheral nervous system

Limbic forebrain structures (e.g., amygdaloid nucleus, some cortical areas)

Hypothalamus

Hypothalamus

Brainstem nuclei and “centers” Hypophyseal portal system

Anterior pituitary hormones

Sensory neuron in dorsal root ganglion

Preganglionic sympathetic neuron Intermediolateral cell column in lateral horn of spinal cord (T1–L2)

Reflex connections

Target tissue Sympathetic ganglion cell

  9.10 AUTONOMIC CHANNELS Preganglionic neurons for the sympathetic nervous system (SNS) are found in the lateral horn (intermediolateral cell column) of the thoracolumbar (T1–­L2) spinal cord (thoracolumbar system). Preganglionic neurons for the parasympathetic nervous system (PsNS) are found in nuclei of cranial nerves (CNs) III, VII, IX, and X and in the intermediate gray matter of the spinal cord between S2 and S4 (the craniosacral system). Preganglionic axons exit the CNS via cranial nerves or ventral roots and terminate in chain ganglia or collateral ganglia (the SNS) or in intramural ganglia in or near the organ innervated (the PsNS). Postganglionic autonomic axons innervate smooth muscle, cardiac muscle, secretory glands, metabolic cells (e.g., liver, fat cells), and cells of the immune system. The SNS is

a fight-­or-­flight system that responds to emergency demands. The PsNS is a homeostatic, reparative system active in more quiescent activities and in digestive and eliminative functions. Preganglionic responses are coordinated by autonomic UMN equivalents from the brainstem (autonomic centers), the hypothalamus, and the limbic forebrain structures. Inputs that affect visceral functions or elicit emotional responsiveness, originating from sensory inputs or from the brain (including the cerebral cortex), are conveyed through these central autonomic regulatory systems, which help to coordinate appropriate autonomic responses. These central autonomic regulatory systems coordinate autonomic responses that affect both visceral functions and neuroendocrine outflow from the pituitary gland.

172

Regional Neuroscience

Glabrous skin Dermal papilla

Hairy skin Sweat gland

Hair

Epidermis

Hair follicle Merkel‘s disc

Krause’s end bulb

Free nerve ending Free nerve ending Sebaceous gland Meissner‘s corpuscle Nerve plexus around hair follicle

Pacinian corpuscle

Free nerve ending Merkel‘s disc

Ruffini terminals

Pacinian corpuscle

Basement membrane Axon terminal Lobulated nucleus

Desmosomes

Mitochondrion Schwann cell

Merkel cell

Basal epithelial cells

Cross section

Cytoplasmic protrusion

Mitochondria

Axon

Expanded axon terminal

Schwann cells Granulated vesicles

Schwann cell

Detail of Merkel’s disc

Detail of free nerve ending

 

9.11 CUTANEOUS RECEPTORS Cutaneous receptors are found at the distal ends of the primary sensory axon; they act as dendrites, in which threshold stimuli lead to the firing of an action potential at the initial segment of the primary sensory axon. Although specific types of sensory receptors are thought to code for consciously perceived modalities, there is not an exact correlation. Glabrous skin and hairy skin contain a wide variety of sensory receptors for detecting mechanical, thermal, or nociceptive (consciously perceived as painful) stimuli applied on the body surface. These receptors include bare nerve endings (nociception, thermal sensation)

and encapsulated endings. The latter include pacinian corpuscles (rapidly adapting mechanoreceptors for detecting vibration or brief touch), Merkel’s discs (slowly adapting mechanoreceptors for detecting maintained deformation or sustained touch on the skin), Meissner’s corpuscles (rapidly adapting mechanoreceptors for detecting moving touch), Ruffini endings (slowly adapting mechanoreceptors for detecting steady pressure applied to hairy skin), hair follicle receptors (rapidly adapting), and Krause end bulbs (possibly thermoreceptors). The initial segment of the primary sensory axon is immediately adjacent to the sensory receptor.

Peripheral Nervous System

173

Axon

Pacinian corpuscle cross-section. Cell stain Pressure

To amplifier

Generator potential

Axon 1st node Myelin sheath

Action potential

Pacinian corpuscle longitudinal section, enwrapped by layers of lamellae. Small supporting cells are interspersed among the lamellae.

Lamellated capsule Central core Unmyelinated axon terminal

A. Sharp “on and off” changes in pressure at start and end of pulse applied to lamellated capsule are transmitted to central axon and provoke generator potentials which in turn may trigger action potentials; there is no response to a slow change in pressure gradient. Pressure at central core and, accordingly, generator potentials are rapidly dissipated by viscoelastic properties of capsule. (Action potentials may be blocked by pressure at a node or by drugs) Pressure To amplifier Generator potential B. In absence of capsule, axon responds to slow as well as to rapid changes in pressure. Generator potential dissipates slowly, and there is no “off” response

Action potential Pressure Na+ + +

+

+

+

+

+

+

+

+

+

+ +

+ + Pressure applied to axon terminal directly or via capsule causes increased permeability of membrane to Na+, thus setting up ionic generator current through 1st node +

+

+

+

+

+

+

+

+

+

+

+

+ +

+

If resultant depolarization at 1st node is great enough to reach threshold, an action potential appears which is propagated along nerve fiber

  9.12 PACINIAN CORPUSCLES Pacinian corpuscles are mechanoreceptors that transform mechanical force or displacement into action potentials in large-­diameter primary sensory axons. The mechanical stimulus is modified by the viscoelastic properties of the contributing lamellae of the pacinian corpuscle and the associated accessory

cells. An action potential results when a generator potential of sufficient magnitude to bring the initial segment of the axon to threshold is elicited. The onset and cessation of mechanical deformation enhance ionic permeability in the axon, optimizing the physiological response of the pacinian corpuscle to vibratory stimuli.

174

Regional Neuroscience

Vagus (X) nerve

Carotid body and carotid sinus

Superior cervical sympathetic trunk ganglion

Glossopharyngeal (IX) nerve Carotid sinus nerve

Retromandibular and facial veins

Veins from carotid body Lingual vein External carotid artery Internal jugular vein Carotid body Internal carotid artery

Artery to carotid body Superior thyroid artery

Carotid sinus

Common carotid artery

Carotid body Synaptic ending

Nerve fibers

Carotid sinus Intima

Type II (sheath) cells

Media Adventitia Free nerve endings

Nerve fibers

Thin elastic media

Fibroblast

Capillaries

Basement membrane

Type I (glomus) cells

Encapsulated endings

Endothelial cells

 

9.13 INTEROCEPTORS Interoceptors, including internal nociceptors, chemoreceptors, and stretch receptors, inform the CNS about the internal state of the body. The carotid body, a specialized chemoreceptor for detecting carbon dioxide (in a hypoxic state) or, to a lesser extent, low blood pH resulting in increased respiration, is associated with afferent axons of CN IX that project to the

caudal nucleus solitarius in the medulla. The carotid sinus, a thin-­walled region of the carotid artery, contains encapsulated and bare nerve endings that act as stretch receptors. These stretch receptors respond to increased arterial pressure as baroreceptors, send primary afferents to the caudal nucleus solitarius via CN IX, and elicit reflex bradycardia and a decrease in blood pressure.

Peripheral Nervous System

175

Meissner’s corpuscle Free nerve endings

Pore of sweat gland

Hair shaft

Stratum corneum

Melanocyte Arrector muscle of hair

Stratum lucidum Stratum granulosum Stratum spinosum

Cuticle Hair follicle

Internal sheath

Epidermis

Sebaceous gland

Stratum basale

External sheath Glassy membrane Dermal papilla (of papillary layer)

Connective tissue layer

Dermis

Reticular layer

Hair cuticle

Sweat gland

Subcutaneous tissue

Hair matrix

Papilla of hair follicle

Pacinian corpuscle Artery Vein Sensory nerves Elastic fibers Skin ligaments (retinacula cutis)

Subcutaneous artery and vein Cutaneous nerve

Motor (autonomic) nerve

 

9.14 SKIN AND ITS NERVES The skin is supplied with a variety of receptor types (see Fig. 9.11) that transduce slowly and rapidly adapting mechanical stimuli and deformation into electrical impulses in primary afferent fibers. The bare nerve endings are associated mainly with nociceptors, peripheral arborizations of unmyelinated axons. Some nociceptors and thermoreceptors are associated with small myelinated axons. These axons collectively contribute somatosensory information to the spinothalamic/spinoreticular lemniscal system for protopathic sensation. The more complex encapsulated receptors contribute

somatosensory information to the dorsal column/medial lemniscal system for epicritic sensation and are associated with larger myelinated axons. Noradrenergic postganglionic sympathetic nerve fibers form dense nerve networks around the hair follicules and can secrete high concentrations of NE during significant stress; the NE can activate beta2-­adrenergic receptors. Bing Zhang and colleagues from Harvard recently reported that excessive release of NE can cause melanocyte stem cell depletion, and under extreme conditions may account for graying of hair, or even lead to hair turning white in a short time period of extreme stress.

176

Regional Neuroscience Synaptic trough (cross section) Schwann cell Sarcolemma Axon terminal

Axoplasm Axolemma Mitochondria Synaptic vesicles

Active zone Schwann cell process Acetylcholine receptor sites

Neurilemma Axoplasm

Synaptic cleft Folds of sarcolemma Sarcoplasm

Schwann cell Mitochondria Basement membrane

Axons

Nucleus of Schwann cell Presynaptic membrane Active zone

Motor end plates

Synaptic vesicles Synaptic trough

Motor end plates at the end of motor axons, forming neuromuscular junctions with skeletal muscle fibers. Cajal stain fiber stain. Basement membrane

Myofibrils

Sarcolemma Synaptic cleft

Nucleus of muscle cell

Postsynaptic membrane Junctional fold Sarcoplasm Acetylcholine receptor sites

  9.15 THE NEUROMUSCULAR JUNCTION AND NEUROTRANSMISSION Axons of LMNs that synapse on skeletal muscle form expanded terminals called neuromuscular junctions (motor end plates). The motor axon loses its myelin sheath and expands into an extended terminal that resides in a trough in the muscle fiber and is covered by a layer of Schwann cell cytoplasm. The postsynaptic membrane is thrown into secondary folds. When an action potential invades the motor terminal, several hundred vesicles simultaneously release their acetylcholine (ACh) into the synaptic cleft. The ACh binds to nicotinic receptors on the muscle sarcolemma, initiating a motor endplate potential, which is normally of sufficient magnitude to result in the firing of a muscle action potential, leading to contraction of the muscle fiber. A single muscle fiber has only one neuromuscular junction, but a motor axon may innervate multiple muscle fibers.

CLINICAL POINT An action potential that invades the motor end plate results in a calcium-­mediated simultaneous release of multiple quanta (vesicles) of ACh. This released ACh acts on nicotinic cholinergic receptors on the postjunctional membrane, normally resulting in a muscle contraction (excitation-­contraction coupling). In myasthenia gravis, antibodies against the cholinergic nicotinic receptors greatly reduce the number of active receptors available for stimulation by released ACh. The size and number of ACh quanta appear to be normal. As a consequence, there is easy fatigability of involved muscles with repeated attempts at contraction. Ocular, facial, and bulbar muscles are the most likely to be affected by this disease, with resultant ptosis, drooping face, diplopia with strabismus, and dysarthria, dysphonia, and dysphagia. Limb muscles (mainly proximal) are involved only in advanced myasthenia gravis. The muscles do not show wasting and atrophy because they are not denervated; muscle stretch reflexes are elicitable.   

Peripheral Nervous System

+

Sarcolemma

177

Sarcoplasm

_

+

Basement membrane Synaptic cleft

_

Schwann cell

+

_

Axon terminal

+

+ _

+

+

Ca2+ binds to site at active zone of presynaptic of ACh from vesicles

+

_

+ _

+

+

ACh receptors

+

_ AChE

_

+ _

+ _

_

_

+

+

+ _

+

ACh

+

K+

_

_

Choline acetyltransferase

+

Na+

+

Na +

_

+ _

ACh

CoA

_

+ _

K+ + _

_

Junctional fold

Acetyl-

Electric impulse

_

nd

_

+

K+

cho

_

Mito

_

+ Na+ _

Ca++

rion

+

+

+ _

+ _

_

_

Ca2+

Axon

+ _

Postsynaptic membrane

_

Axolemma

Myelin sheath

Electric impulses cause channels to open in presynaptic membrane, permitting Ca2+ to enter nerve terminal

_

Electric impulse propagated along axon by inflow of Na+ and outflow of K+

+

+ _

+

+

+ _

Choline + _

Choline_ +

_

+

_

_

+

_

Acetylcholine (ACh) formed in nerve terminal from acetate derived from acetyl CoA of mitochondria plus choline, catalyzed by choline acetyltransferase. ACh enters synaptic vesicles.

+

+

_

Acetylcholinesterase (AChE) promptly degrades ACh into acetate and choline, thus terminating its activity Choline reenters nerve terminal to be recycled

Na+

_

+

K+

_

+

Electric impulse traverses sarcolemma to transverse tubules, where it causes release Ca2+ from sarcoplasmic reticulum, thus initiating muscle contraction

ACh attaches to receptors of postsynaptic membrane at apex of junctional folds, causing channels to open for inflow of Na+ and outflow of K+, which results in depolarization and initiation of electric impulse (action potential)

 

9.16 PHYSIOLOGY OF THE NEUROMUSCULAR JUNCTION This process is called excitation-­contraction coupling; that is, mechanisms by which a motor action potential initiates the

release of acetylcholine, activating nicotinic cholinergic receptors on the muscle membrane, initiating muscle contraction.

178

Regional Neuroscience MOTOR AXON TERMINAL

Extracellular matrix Laminin Agrin SYNAPTIC CLEFT

Acetylcholine receptor

  





Laminin

-Dystroglycan -Dystroglycan MuSK MUSCLE CELL

Rapsyn

Utrophin

SECONDARY CLEFT

Actin

Na channel

Representation of the normal neuromuscular junction, adult acetylcholine receptor in the postsynaptic muscle membrane and other important associated proteins

  9.17 MAJOR STRUCTURES AND PROTEINS IN THE NORMAL NEUROMUSCULAR JUNCTION Motor axons innervate skeletal muscle fibers through a series of interactions that include the nerve traveling along a laminin substrate, an important trimeric protein family helping to establish the basal lamina of the basement membrane of the neuromuscular junction (NMJ). Muscle-­specific kinase (MuSK) is a receptor tyrosine kinase that is required to form the NMJ; it signals through casein kinase 2 (CK2), Dok-­7, and rapsyn to form and maintain the NMJ and to orchestrate clustering of ACh receptors (AChRs) at the NMJ. Agrin, a glycoprotein secreted by the growing end of the motor axon, binds to MuSK and aids in this process. Laminin-­alpha4 acts as a presynaptic organizer and binds to agrin, which acts as a postsynaptic organizer. These molecules are necessary to maintain the appositions of the presynaptic and postsynaptic specializations of the NMJ. Utrophin forms a link between the extracellular matrix and the thin helical filaments of F-­actin, part of the contractile machinery of the muscle fiber, along with myosin, and helps keep the actin filaments from depolymerizing. Utrophin and dystroglycans (dystrophin-­ associated glycoproteins), which

also bind to the F-­actin filaments, also serve as agrin receptors and aid in the clustering of AChRs at the postsynaptic site of the NMJ. CLINICAL POINT Muscular dystrophies (MDs) are genetic muscular disorders characterized by progressive skeletal muscle weakness and dysfunction, defects in muscle proteins (e.g., dystrophins), and associated physiologic and anatomic problems such as scoliosis. There are multiple forms of muscular dystrophy. Duchennes muscular dystrophy, the most common form of MD in children, affecting mainly males, is a recessive mutation of the dystrophin gene on the short arm of the X chromosome affecting skeletal muscle and some other structures (gastrointestinal system, brain, heart, endocrine system). The cytoskeleton of muscles is impaired because of the absence of dystrophin and dystrophin-­related complexes. Muscle wasting occurs, often in the presence of the accumulation of fat and fibrous connective tissue (pseudohypertrophy). Muscle weakness can be accompanied by heart and respiratory failure. Standard therapy is occupational therapy and physiotherapy. However, a new approach involving molecular therapy is currently being explored. Antisense oligonucleotides (AONs) have been designed that bind to the complementary sequences of mRNA, skipping the affected exon and inducing partially functional isoforms of dystrophin in skeletal muscles. Before widespread use of AONs occurs, further refinement of delivery and effectiveness of this treatment is needed.   

Peripheral Nervous System A. Smooth muscle

B. Gland (submandibular)

C. Lymphoid tissue (spleen)

Sympathetic terminal ending Mucous cells Varicosity Schwann Schwann cell cell cap cap enclosing nerve axons

Smooth muscle cells (cut) Schwann cell cap enclosing nerve axons Terminal endings

179

Smooth muscle cells

Blood vessel lumen Adventitial zone neuroeffector junction

T cell

Varicosities

Schwann cell cap Smooth muscle cells

D. Noradrenergic (NA) postganglionic sympathetic

nerve fibers supplying thoracic fat cells near the thymus. Glyoxylic acid fluorescence histochemistry (9.18 D-I). Nerve fibers and terminals appear turquoise.

Serous cells Varicosity Schwann cell cap enclosing Parasympathetic nerve axons terminal ending

Sympathetic terminals among T lymphocytes in periarteriolar lymphoid sheath

E. NA postganglionic sympathetic nerve fibers supplying the submandibular gland and its duct (F).

Artery Periarteriolar lymphatic sheath Marginal sinus

H. NA nerve fibers in the splenic white pulp (see G), showing the central artery in a longitudinal expanse.

G. NA postganglionic sympathetic nerve fibers

surrounding the central artery of the white pulp, shown in cross-sectional view, and fibers also present among T lymphocytes in the periarteriolar lymphatic sheath and along arrays of antigen-presenting cells along the marginal sinus.

I. NA nerve fibers in the splenic white pulp (see H) in an experimental setting in which a mouse was treated with a high dose of cyclophosphamide, which temporarily mobilizes T lymphocytes and other immunocytes to leave the spleen, significantly diminishing the cellularity of the white pulp. The NA nerve fibers accommodate to the changing structure and cellularity of the splenic white pulp, and remain associated with the same compartments, with the consequence of greater density of nerve terminals, and more compact distribution in the white pulp. With recovery from the treatment and repopulation of the white pulp, the appearance of NA terminals, and their distribution and density, return to the normal picture (H).

  9.18 NEUROEFFECTOR JUNCTIONS Autonomic postganglionic axons form neuroeffector junctions with cardiac muscle, smooth muscle (A), secretory glands (B), metabolic cells such as hepatocytes and fat cells, and cells of the immune system (C). These nerve endings use mainly norepinephrine for the SNS and acetylcholine for the PsNS. These endings do not form classic CNS or motor endplate synapses; instead, they terminate as neuroeffector junctions, releasing neurotransmitter

into interstitial spaces. This permits a widespread diffusion of the neurotransmitter as a paracrine secretion, initiating postsynaptic responses on cells with appropriate receptors (including many types of cells of the immune system). Some close appositions also are found, such as SNS endings on lymphocytes. Not all smooth muscle cells are innervated by neuroeffector junctions; they are coupled by gap junctions and can contract together when the innervated smooth muscle cell contracts.

180

Regional Neuroscience

C2 C3 C4 C5

C2 C3 C4 C5 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10

C6

C7 C8 T1 C6

C5 C8

C7

C8

T11 T12 L1 S2, 3

C6

T1

C6 C8

C7

C7

T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5

S1 S2

C8 S3 S4

L2

S1

S5

L3

S2 L5

L4

L1 L2 L3

L5

S1 S2

L4 S1

S1

L5

L5

Levels of Principal Dermatomes C5 C5, 6, 7 C8; T1 C6 C6, 7, 8 C8 T4

L4

L4

Clavicles Lateral parts of upper limbs Medial sides of upper limbs Thumb Hand Ring and little fingers Level of nipples

T10 T12 L1, 2, 3, 4 L4, 5; S1 L4 L5; S1, 2 S1 S2, 3, 4

Level of umbilicus Inguinal or groin regions Anterior and inner surfaces of lower limbs Foot Medial side of great toe Outer and posterior sides of lower limbs Lateral margin of foot and little toe Perineum

 

SOMATIC NERVOUS SYSTEM 9.19 DERMATOMAL DISTRIBUTION A dermatome is the cutaneous area supplied by a single spinal nerve root; the cell bodies are located in dorsal root ganglia. The spinal nerve roots are distributed to structures according to their associations with spinal cord segments. The nerve roots supplying neighboring dermatomes overlap. Thus, sectioning or dysfunction of a single dorsal root produces hypoesthesia (diminished sensation), not anesthesia (total loss of sensation), in the region supplied predominantly by that dermatome, as shown in the figure. Dermatomal anesthesia requires damage to at least three dorsal roots: the central dorsal root and the roots above and below it.

In contrast, an irritative lesion such as a herniated intervertebral disc may produce sharp, radiating pain within the distribution of the affected dermatome. As the limb buds for the lower extremities develop, they draw out the nerve roots that correspond with their mesodermal cores and ectodermal coverings. The developing lower limbs rotate medially around a longitudinal axis, with a resultant oblique orientation of the dermatomes. The L1 and L2 dermatomes can be found in sites adjacent to S2 and S3 dermatomes because of the intervening segments migrating into more distal parts of the lower limbs. Knowledge of dermatomes is important for localizing peripheral nerve root lesions and distinguishing them from peripheral nerve lesions.

Peripheral Nervous System

181

Ophthalmic branch of trigeminal (V) n. Ophthalmic branch of trigeminal (V) n.

Greater occipital (C2)

Maxillary branch of trigeminal (V) n.

Lesser occipital (C2, 3)

Mandibular branch of trigeminal (V) n.

Great auricular (C2, 3)

Great auricular (C2, 3)

Posterior div. of cervical nn.

Cutaneous cervical (C2, 3)

Supraclavicular (C3, 4)

Supraclavicular (C3, 4)

Axillary (C5, 6)

Axillary (C5, 6) Dorsal antebrachial cutaneous (C5–T1) Medial brachial cutaneous (C8, T1)

Thoracic nerves Lat. div.

Ant. div.

Dorsal antebrachial cutaneous (C5–T1) Thoracic nerves Post. div.

Medial brachial cutaneous (C8, T1)

Lat. div.

Intercostobrachial (T2)

Intercostobrachial (T2)

Lateral antebrachial cutaneous (C5–7)

Lateral antebrachial cutaneous (C5–7)

Medial antebrachial cutaneous (C8, T1)

Medial antebrachial cutaneous (C8, T1)

Radial (C5–T1)

Radial (C5–T1) Ulnar (C8, T1)

Median (C5–T1)

Median (C5–T1)

Ulnar (C8, T1) Iliohypogastric (L1)

IIiohypogastric (L1)

Lateral femoral cutaneous (L2, 3)

Genitofemoral (L1, 2) Ilioinguinal (L1)

Posterior femoral cutaneous (S1–3)

Lateral femoral cutaneous (L2, 3)

Obturator (L2–4)

Femoral (L2–4)

Femoral (L2–4)

Obturator (L2–4)

Common peroneal (L4–S2)

Common peroneal (L4–S2)

Saphenous (L3, 4)

Saphenous (L3, 4)

Superficial peroneal (L4–S1)

Superficial peroneal (L4–S1)

Sural (S1, 2)

Sural (S1, 2)

Calcaneal (S1, 2)

Deep peroneal (L4, 5)

Medial plantar (L4, 5)

Lateral plantar (S1, 2)

Lateral plantar (S1, 2) Anterior aspect

Posterior aspect

 

9.20 CUTANEOUS DISTRIBUTION OF PERIPHERAL NERVES Peripheral nerves distribute sensory processes and endings to specific surface regions of the body. These sites may be innervated

by a nerve with contributions from several dermatomes. A nerve lesion can leave the site of cutaneous distribution devoid of all sensation (anesthetic). Sites of innervation by specific nerves vary from person to person.

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From ophthalmic division of trigeminal nerve (V1)

Auricular branch of vagus nerve (X)

Supraorbital nerve Supratrochlear nerve Palpebral branch of lacrimal nerve Infratrochlear nerve External nasal branch of anterior ethmoidal nerve

Medial branches of dorsal rami of cervical spinal nerves Greater occipital nerve (C2) 3rd occipital nerve (C3)

From maxillary division of trigeminal nerve (V2)

From 4th, 5th, 6th, and 7th nerves in succession below

Infraorbital nerve Zygomaticofacial nerve Zygomaticotemporal nerve

Branches from cervical plexus

From mandibular division of trigeminal nerve (V3) Mental nerve

Great auricular nerve (C2, 3) Transverse cervical nerve (C2, 3)

Buccal nerve

Supraclavicular nerves (C3, 4)

Auriculotemporal nerve

Ophthalmic nerve (V1)

Trigeminal nerve (V)

Lesser occipital nerve (C2, 3)

Maxillary nerve (V2)

Mandibular nerve (V3)

 

9.21 CUTANEOUS NERVES OF THE HEAD AND NECK Cutaneous nerves of the head and neck derive from dorsal rami of cervical spinal nerves, from branches from the cervical plexus, and from all three divisions of the trigeminal nerve (CN V).

Dorsal rami of cervical spinal nerves

Note: Auricular branch of vagus nerve to external acoustic meatus and small area on posteromedial surface of auricle

Branches from cervical plexus

Peripheral Nervous System

183

Great auricular nerve

Parotid gland Facial artery and vein

Lesser occipital nerve

Submandibular gland

Sternocleidomastoid muscle (cut, turned up)

Mylohyoid muscle

Stylohyoid muscle

Hypoglossal nerve (XII)

Digastric muscle (posterior belly)

Digastric muscle (anterior belly) Lingual artery

C2 spinal nerve (ventral ramus)

External carotid artery

Accessory nerve (XI)

Internal carotid artery

C3 spinal nerve (ventral ramus)

Thyrohyoid muscle

Levator scapulae muscle

Superior thyroid artery

Middle scalene muscle

Omohyoid muscle (superior belly) (cut) Ansa cervicalis

Superior root Inferior root

Anterior scalene muscle C5 spinal nerve (ventral ramus)

Sternohyoid muscle

Superficial cervical artery

Sternothyroid muscle

Phrenic nerve Omohyoid muscle (inferior belly) (cut)

Internal jugular vein Common carotid artery Inferior thyroid artery Vagus nerve (X)

Brachial plexus Dorsal scapular artery Suprascapular artery

Vertebral artery Thyrocervical trunk Subclavian artery and vein

Cervical plexus: schema

(S = gray ramus from superior cervical sympathetic ganglion)

Hypoglossal nerve (XII)

To geniohyoid muscle

Accessory nerve (XI)

S

Great auricular nerve C1

S

Lesser occipital nerve C2

To thyrohyoid muscle

To rectus capitis lateralis, longus capitis, and rectus capitis anterior muscles

Communication to vagus nerve Transverse cervical nerves To omohyoid muscle (superior belly) Ansa cervicalis

Superior root Inferior root

S

S

C3

C4

To longus capitis and longus colli muscles

To sternothyroid muscle To sternohyoid muscle To omohyoid muscle (inferior belly) Supraclavicular nerves

 

9.22 CERVICAL PLEXUS IN SITU This diagram of the cervical plexus in situ and the schema below demonstrate the distribution of branches from the C1–­C4 nerve roots into the associated peripheral nerves and branches to the innervated muscles.

To scalene and levator scapulae muscles Phrenic nerve

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Greater occipital nerve (from dorsal ramus of C2)

Accessory (XI) nerve Lesser occipital nerve Hypoglossal (XII) nerve C1 Geniohyoid muscle Thyrohyoid muscle Superior root (descendens hypoglossi) of ansa cervicalis Inferior root (descendens cervicalis) of ansa cervicalis

Sternocleidomastoid muscle (upper end) Great auricular nerve

C2

C3

C4

Nerves to anterior and lateral rectus capitis muscles, and longus capitis and longus colli muscles Nerves to longus capitis, longus colli and levator scapulae muscles Trapezius muscle Nerves to longus colli, scalenus anterior and scalenus medius muscles

Transverse cervical nerve C5 Omohyoid muscle

Communication to brachial plexus

Sternothyroid muscle Sternohyoid muscle Ansa cervicalis (ansa hypoglossi) Phrenic nerve Sternocleidomastoid muscle (lower end) Supraclavicular nerves (medial, intermediate and lateral) Motor fibers Sensory fibers Proprioceptive fibers

 

9.23 CERVICAL PLEXUS The cervical plexus lies deep to the sternocleidomastoid muscle. Its branches convey motor fibers to many cervical muscles and to the diaphragm. Its sensory fibers convey exteroceptive information from parts of the scalp, neck, and chest as well as proprioceptive information from muscles, tendons, and joints. Sympathetic sudomotor and vasomotor fibers travel with this plexus to blood vessels and glands. The superficial branches perforate the cervical fascia to supply cutaneous structures; the deep branches supply mainly muscles and joints.

CLINICAL POINT The cervical plexus is formed from the anterior primary rami of C1–­ C4, deep to the sternocleidomastoid muscle and in front of the scalenus medius and levator scapulae muscles. Sensory branches include the greater and lesser occipital nerves, great auricular nerve, cutaneous cervical nerves, and supraclavicular nerves. The motor branches include the ansa hypoglossi, branches to scalenus medius and levator scapulae muscles, the phrenic nerve, and branches to the spinal accessory nerve. Lesions of the cervical plexus are uncommon, usually resulting from trauma, mass lesions, or as sequelae to surgery such as carotid endartectomy. Involvement of motor branches results in disruption of muscular function, such as shoulder elevation and head rotation and flexion with spinal accessory nerve damage. Involvement of sensory branches results in loss of cutaneous sensation or in pain and paresthesias in regions of the head or neck supplied by these branches.   

Peripheral Nervous System

Ventral rami

C3

C3

C4

C4

C5

C5

Anterior scalene muscle

185

Ventral rami

Anterior scalene muscle

Right common carotid artery Brachial plexus

Brachial plexus Right phrenic nerve

Left phrenic nerve

Right subclavian artery

Left subclavian artery

Right vagus (X) nerve

Left common carotid artery

Internal thoracic artery

Left vagus (X) nerve

Brachiocephalic trunk

Internal thoracic artery Thoracic cardiac nerves

Right pericardiacophrenic artery

Left pericardiacophrenic artery

Superior vena cava

Left recurrent laryngeal nerve

Pericardial branch of phrenic nerve

Root of left lung

Root of right lung Diaphragmatic pleura (cut ) Mediastinal pleura

Phrenicoabdominal branches of phrenic nerves (to inferior surface of diaphragm)

Mediastinal pleura

Phrenic nerves (motor and sensory)

Lower intercostal nerves (sensory only to peripheral portion of diaphragm)

Innervation of diaphragm

  9.24 PHRENIC NERVE The left and right phrenic nerves are the motor nerves that supply both sides of the diaphragm from the C3, C4, and C5 ventral roots. The phrenic nerve also contains many sensory nerve fibers that supply the fibrous pericardium, the mediastinal pleura, and central areas of the diaphragmatic pleura. Sympathetic postganglionic nerve fibers also travel with this nerve. Coordinated contraction of the diaphragm relies on central control of firing of LMNs through dendrite bundles in the spinal cord.

CLINICAL POINT The phrenic nerves derive from the C3–­C5 ventral roots and provide the motor supply to the diaphragm. Lesions of the phrenic nerve usually occur in the mediastinum, not the cervical plexus. Pathological processes, such as enlarged mediastinal nodes, aortic aneurysms, mediastinal tumors, sequelae of surgery, and demyelination from Guillain-­Barré syndrome, can damage these nerves. Unilateral damage to the phrenic nerve results in paralysis of the diaphragm on the ipsilateral side, which can usually be tolerated at rest but not following exertion. Bilateral phrenic nerve damage results in diaphragmatic paralysis with extreme dyspnea and hypoventilation.   

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Spinal nerve trunk

Trapezius muscle Collateral branch of intercostal nerve

Erector spinae muscle

Spinal ganglion

Subcostal muscles

Medial and lateral branches of dorsal ramus

Dorsal root Ventral root

External intercostal muscle Internal intercostal muscle

Intercostal nerve (ventral ramus)

Innermost intercostal muscle Latissimus dorsi muscle

Meningeal branch

Serratus anterior muscle

Costotransverse ligaments

Thoracic splanchnic nerves

Window cut in innermost intercostal muscle Internal intercostal muscle

Sympathetic trunk

Rami communicans (gray and white)

Posterior intercostal membrane on external intercostal muscle

Transversus abdominis muscle Rectus abdominis muscle

Costal cartilage

Anterior cutaneous branches of intercostal nerve

Collateral branch rejoining main anterior cutaneous branch Communicating branch Slip of origin of diaphragm

Lateral cutaneous branch and anterior cutaneous branch of intercostal nerve

Internal intercostal muscle External intercostal muscle and membrane External oblique muscle

Linea alba

 

9.25 THORACIC NERVES The 12 pairs of thoracic nerves are derived from dorsal and ventral roots of their corresponding segments. These nerves do not form plexuses; they distribute cutaneous branches to the thoracic dermatomes and send other sensory fibers to deeper muscular structures, vessels, periosteum, parietal pleura, the peritoneum, and breast tissue. The thoracic nerves also send motor fibers to

muscles of the thoracic and abdominal wall and carry preganglionic and postganglionic sympathetic nerve fibers into and out of the sympathetic chain. Muscles of the thoracic and abdominal wall, supplied by these nerves, act as accessory respiratory muscles and may assist in breathing in times of dyspnea or phrenic nerve impairment.

Peripheral Nervous System

Dorsal scapular nerve; C5

Suprascapular nerve; C5, 6

3 Ventral divisions 3 Dorsal divisions

Contribution from C4

5 Roots (ventral rami)

3 Trunks

To phrenic nerve; C5

187

Dorsal ramus

C5

To subclavius muscle; C5, 6

3 Cords

C6

r

erio

Sup

Terminal branches

dle

Lateral pectoral nerve; C5, 6, 7

(2 from each cord) Musculocutaneous nerve; C(4), 5, 6, 7 Axillary nerve; C5, 6

C7 Mid

ior

fer

l

a er

t

La

C8

In

r

rio

ste

Po

Long thoracic nerve; C5, 6, 7

Subscapular nerves; C5, 6

1st rib

ial

Radial nerve; C5, 6, 7, 8; T1

Med

T1

Contribution from T2 To longus colli and scalene muscles; C5, 6, 7, 8 1st intercostal nerve

Medial pectoral nerve; C8; T1

Median nerve; C(5), 6, 7, 8; T1

Medial cutaneous nerve of forearm; C8; T1 Medial cutaneous nerve of arm; T1

Some contributions inconstant

Thoracodorsal nerve; C6, 7, 8 Ulnar nerve; C(7), 8; T1

Supraclavicular Branches

From plexus roots To longus colli and scalene muscles Dorsal scapular Branch to phrenic Long thoracic From superior trunk Suprascapular To subclavius muscle

Infraclavicular Branches C5, 6, 7, 8 C5 C5 C5, 6, 7 C5, 6 C5, 6

From lateral cord C5, 6, 7 Lateral pectoral Musculocutaneous C(4), 5, 6, 7 C(5), 6, 7 Lateral root of median From medial cord C8; T1 Medial pectoral Medial cutaneous nerve of arm T1 Medial cutaneous nerve of forearm C8; T1

  9.26 BRACHIAL PLEXUS The brachial plexus is formed by the union of the ventral roots of C5 through C8 plus T1, with a smaller contribution from C4. Sensory and sympathetic fibers also distribute in the brachial plexus. The roots give rise to three trunks, three ventral and three dorsal divisions, three cords as well as numerous terminal branches, the peripheral nerves. This plexus is vulnerable to birth injury (superior plexus paralysis), which causes paralysis of the deltoid, biceps, brachial, and brachioradialis muscles, with sparing of the hands, and causes sensory loss over the deltoid area and radial aspect of the forearm and hand. Pressure by a cervical rib can cause inferior plexus injury (C8, T1 injury), which results in paralysis of small hand muscles and flexors of the hand, with ulnar sensory loss and possible Horner’s syndrome. CLINICAL POINT Lesions in the upper brachial plexus, particularly those affecting C5 and C6 contributions, can be caused by traction from a difficult

Infraclavicular Branches

Ulnar Medial root of median From posterior cord Upper subscapular Lower subscapular Axillary (circumflex humeral) Thoracodorsal Radial

C(7), 8; T1 C8; T1 C5, 6, (7) C5, 6 C5, 6 C5, 6 C5, 6, 7, 8

birth, including displacement of the head to the opposite side and depression of the shoulder on the same side (Erb-­Duchenne palsy); by radiation damage; from congenital causes; and by tumors. Such lesions may result in paresis of shoulder abduction and external rotation and in paresis of elbow flexion caused by damage to the motor nerve supply to the deltoid, supraspinatus, infraspinatus, biceps, supinator, and brachioradialis muscles. The arm hangs down and is rotated medially; the forearm is pronated. The biceps and brachioradialis muscle stretch reflexes are absent. Sensory loss is experienced over the deltoid region and along the radial side of the forearm. Lesions of the lower brachial plexus, particularly those affecting C8 and T1 contributions, can result from traction on an abducted arm, a breech delivery (Dejerine-­Klumpke paralysis), an apical lung tumor, a cervical rib, radiation damage, or a tumor. These lesions result in paralysis of finger flexion and paralysis of all the small muscles of the hand; a claw hand results. Sensory loss is present along the ulnar surface of the forearm and hand. Ipsilateral Horner’s syndrome is sometimes seen due to damage to T1 preganglionic outflow to the superior cervical ganglion, with resultant ptosis, miosis, and hemianhydrosis.   

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Note: Schematic demarcation of dermatomes shown as distinct segments. There is actually considerable overlap between adjacent dermatomes. C2 C3

C6

Anterior view

C5

C6

C7

C4

T1

C5 T1

C8

C8

C2

C3 C4 C5

C6

Posterior view

C7

C6

C8 T1

C7 C8

 

9.27 DERMATOMES OF THE UPPER LIMB Because of the distribution of nerve fibers in the brachial plexus and the interchange of sensory and motor fibers through the trunks, divisions, and cords, the orderly segmental distribution of cervical dermatomes is obscured to some degree.

However, the arrangement of dermatomes in the upper limb is explicable embryologically as limb buds extend. The more proximal dermatomes are elongated strips located along the outer sides of the limbs, whereas the more distal dermatomes are found medially.

Peripheral Nervous System

189

Spurling maneuver: hyperextension and flexion of neck ipsilateral to the side of lesion cause radicular pain in neck and down the affected arm

Herniated disk compressing nerve root

Level

Motor signs (weakness)

Reflex signs

Sensory loss

Deltoid C5

None

Biceps brachii Biceps brachii C6

Weak or absent reflex Triceps brachii Triceps brachii

C7

Weak or absent reflex Interossei

C8

None

  9.28 CERVICAL DISC HERNIATION Cervical disc herniation is a common neurologic process, often caused by age-­related vertebral deterioration and processes other than trauma (a major cause of lumbar disc herniation). The initial manifestation of cervical disc herniation often is radiating pain

(radiculopathy). Cervical nerve roots 5, 6, and 7 emerge above their related vertebral body, while cervical nerve root 8 emerges between vertebrae C7 and T1. This plate illustrates characteristics of cervical disc herniation, including motor, sensory, and reflex manifestations.

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Anterior (palmar) view

Posterior (dorsal) view Supraclavicular nerves (from cervical plexus – C3, 4)

Supraclavicular nerves (from cervical plexus – C3, 4)

Axillary nerve Superior lateral cutaneous nerve of arm (C5, 6)

Axillary nerve Superior lateral cutaneous nerve of arm (C5, 6)

Radial nerve Posterior cutaneous nerve of arm (C5, 6, 7, 8) Inferior lateral cutaneous nerve of arm Posterior cutaneous nerve of forearm (C[5], 6, 7, 8)

Radial nerve Inferior lateral cutaneous nerve of arm (C5, 6) Intercostobrachial nerve (T2) and medial cutaneous nerve of arm (C8, T1, 2) Lateral cutaneous nerve of forearm (C5, 6 [7]) (terminal part of musculocutaneous nerve)

Radial nerve Superficial branch (C6, 7, 8)

Medial cutaneous nerve of forearm (C8, T1)

Lateral cutaneous nerve of forearm (C5, 6, [7]) (terminal part of musculocutaneous nerve)

Ulnar nerve (C8, T1) Palmar branch

Palmar digital branches

Dorsal branch and dorsal digital branches

Radial nerve Superficial branch and dorsal digital branches (C6, 7, 8)

Proper palmar digital branches

Median nerve Palmar branch and palmar digital branches (C6, 7, 8)

Median nerve Proper palmar digital branches

Note: Division is variable between ulnar and radial innervation on dorsum of hand and often aligns with middle of 3rd digit instead of 4th digit as shown.

 

9.29 CUTANEOUS INNERVATION OF THE UPPER LIMB The cutaneous innervation of the limb derives from the musculocutaneous, axillary, radial, median, and ulnar nerves. These nerves are the terminal branches of the brachial plexus. Unlike the distributions of the dorsal nerve roots, the cutaneous sensory

distributions of these peripheral nerves to the upper limb do not overlap. Thus, a peripheral nerve injury or compression results in a zone of anesthesia corresponding to its distribution. Irritative lesions result in pain and paresthesias that occur in the same corresponding distribution.

Peripheral Nervous System Suprascapular nerve

Dorsal scapular nerve

Supraspinatus muscle Levator scapulae muscle (supplied also by branches from C5 and C6)

191

Dorsal Scapular Nerve (C5), Suprascapular Nerve (C5, C6), Axillary Nerve (C5, C6) and Radial Nerve (C5, C6, C7, C8; T1) Above Elbow (viewed from behind) Deltoid muscle

Teres minor muscle

Axillary nerve Rhomboideus minor muscle

Upper lateral cutaneous nerve of arm

Rhomboideus major muscle

Radial nerve

Lower lateral cutaneous nerve of arm Infraspinatus muscle Teres major muscle

Posterior cutaneous nerve of forearm

Lower subscapular nerve Posterior cutaneous nerve of arm (branch of radial nerve in axilla)

Lateral intermuscular septum

Brachialis muscle (lateral part) Long head Triceps brachii muscle

Lateral head

Brachioradialis muscle

Medial head Extensor carpi radialis longus muscle Triceps tendon Medial epicondyle

Extensor carpi radialis brevis muscle

Olecranon Anconeus muscle Extensor digitorum muscle Extensor carpi ulnaris muscle

  9.30 THE SCAPULAR, AXILLARY, AND RADIAL NERVES ABOVE THE ELBOW The dorsal scapular nerve (C5) supplies the levator scapulae and rhomboid muscles; it aids in elevation and adduction of the scapula toward the spinal column. A nerve lesion leads to lateral displacement of the vertebral border of the scapula and to rhomboid atrophy (difficult to detect). The suprascapular nerve (C5–­C6) supplies the supraspinatus and infraspinatus muscles; it aids in lifting and in outward rotation of the arm. A lesion results in weakness in the first 15 degrees of abduction and in external rotation of the arm. The axillary nerve (C5–­ C6) supplies the deltoid and teres minor muscles; it aids in abduction of the arm to the horizontal and in outward rotation

of the arm. A lesion may be caused by dislocation of the shoulder joint or a fracture of the surgical neck of the humerus and results in deltoid atrophy, in weakness in abduction from 15 degrees to 90 degrees, and in loss of cutaneous sensation over the lower half of the deltoid. The radial nerve (C5–­C8) in the upper arm supplies the triceps, anconeus, brachioradialis, extensor carpi radialis, extensor digitorum, and supinator muscles and aids in the extension and flexion of the elbow. A lesion may be caused by a fracture of the midshaft of the humerus that affects the nerve within the spiral groove and leads to paralysis of extension and flexion of the elbow and of supination of the forearm. The wrist and fingers cannot be extended, and wrist drop occurs.

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Radial nerve

Radial Nerve in Forearm (C5, C6, C7, C8; T1) (viewed from behind and slightly laterally)

Superficial branch Deep terminal branch Lateral epicondyle Anconeus muscle Brachioradialis muscle Extensor carpi radialis longus muscle Supinator muscle Extensor carpi radialis brevis muscle Extensor carpi ulnaris muscle

Extensor supinator group of muscles

Extensor digitorum muscle and extensor digiti minimi muscle Extensor indicis muscle Extensor pollicis longus muscle Abductor pollicis longus muscle Extensor pollicis brevis muscle Posterior interosseous nerve (deep branch of radial nerve) Superficial branch of radial nerve

From axillary nerve

Upper lateral cutaneous nerve of arm

Lower lateral cutaneous nerve of arm

From radial nerve

Posterior cutaneous nerve of arm Posterior cutaneous nerve of forearm

Dorsal digital nerves

Superficial branch of radial nerve Cutaneous innervation from radial and axillary nerves

 

9.31 RADIAL NERVE IN THE FOREARM In the forearm, the radial nerve (C6–­C8) supplies motor fibers to the (1) extensor carpi radialis, (2) extensor digitorum, (3) extensor digiti V, (4) extensor carpi ulnaris, (5) supinator, (6) abductor pollicis longus, (7) extensor pollicis brevis and longus, and (8) extensor indicis proprius muscles. It supplies the posterior upper arm, an

elongated zone of the posterior forearm, and the posterior hand, thumb, and lateral 2½ fingers. A lesion results in paralysis of extension and flexion of the elbow, paralysis of supination of the forearm, paralysis of extension of the wrist and fingers, and paralysis of abduction of the thumb, as well as loss of sensation over the radial aspect of the posterior forearm and the dorsum of the hand.

Peripheral Nervous System

193

Musculocutaneous Nerve (C5, C6, C7) (only muscles innervated by musculocutaneous nerve are depicted)

Musculocutaneous nerve

Medial Posterior Lateral cords of brachial plexus

Coracobrachialis muscle Medial cutaneous nerves of forearm and arm Biceps brachii muscle (turned back )

Ulnar nerve Median nerve Radial nerve

Brachialis muscle

Axillary nerve Articular branch

Lateral cutaneous nerve of forearm

Anterior branch

Posterior branch

Cutaneous innervation

 

9.32 MUSCULOCUTANEOUS NERVE The musculocutaneous nerve (C5–­C6) supplies the biceps brachii, coracobrachialis, and brachialis muscles; it aids in flexion of the upper and lower arm, supination of the lower arm, and elevation and adduction of the arm. The nerve supplies sensory

innervation to the lateral forearm. A lesion may be caused by a fracture of the humerus and results in the wasting of the muscles supplied, weakness of flexion of the supinated arm, and loss of sensation on the lateral forearm.

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Median Nerve (C6, C7, C8; T1) (only muscles innervated by median nerve are depicted)

Musculocutaneous nerve Medial

Median nerve

Posterior Pronator teres muscle (humeral head)

Lateral cords of brachial plexus

Articular branch

Medial cutaneous nerve of arm

Flexor carpi radialis muscle

Medial cutaneous nerve of forearm

Palmaris longus muscle

Axillary nerve Radial nerve

Pronator teres muscle (ulnar head)

Ulnar nerve

Flexor digitorum superficialis muscle (turned up ) Flexor digitorum profundus muscle (lateral portion supplied via anterior interosseous nerve; medial portion by ulnar nerve) Anterior interosseous nerve Flexor pollicis longus muscle Pronator quadratus muscle

Cutaneous innervation

Palmar branch

Thenar muscles

Abductor pollicis brevis Opponens pollicis Flexor pollicis brevis (superficial head; deep head supplied by ulnar nerve)

Flexor retinaculum Anastomotic branch to ulnar nerve

1st and 2nd lumbrical muscles

Branches to dorsum of middle and distal phalanges

Common Proper

Palmar digital nerves

 

9.33 MEDIAN NERVE The median nerve (C5–T1) supplies motor fibers to the (1) flexor carpiradialis, (2) pronatorteres, (3) palmaris longus, (4) flexor digitorum superficialis and profundus, (5) flexor pollicis longus, (6) abductor pollicis brevis, (7) flexor pollicis brevis, (8) opponens pollicis brevis, and (9) lumbrical muscles of the index and middle fingers. It supplies sensory innervation to the palm and adjacent thumb, the

index and middle fingers, and the lateral half of the fourth finger. A lesion (caused by carpal tunnel syndrome) results in weakness in flexion of the fingers, abduction and opposition of the thumb, and loss of sensation or painful sensation in the radial distribution in the hand (thumb, index finger, middle finger, and half of the fourth finger). Pain in that distribution often radiates back to the wrist. A higher lesion also produces weakness in pronation of the forearm.

Peripheral Nervous System

195

Median nerve Palmar cutaneous branch of median nerve

Transverse carpal ligament

Ulnar nerve in Guyon’s canal

Thenar muscles Abductor pollicis brevis

Flexor tendons in carpal tunnel

Opponens pollicis Carpal tunnel

Transverse carpal ligament (roof of carpal tunnel) Median nerve in carpal tunnel

Flexor pollicis brevis (superficial head)

1st and 2nd lumbrical muscles

Digital nerves

Activities or medical conditions that increase contents and pressure within tunnel may result in nerve compression.

Distribution of branches of median nerve in hand

Long-term compression can result in thenar muscle weakness and atrophy.

Thenar atrophy

Sensory distribution of median nerve

 

9.34 CARPAL TUNNEL SYNDROME The median nerve travels through the carpal tunnel in the wrist. The carpal tunnel is a tightly confined space restricted by the presence of the transverse carpal ligament. Repetitive movements of the wrist (e.g., repeated computer activity), chronic extension of the wrist (e.g., bicycling), and even sleeping with the wrist bent can compress the median nerve in the carpal tunnel. The mechanism of damage to the nerve may be direct compression on the nerve and also may involve an accompanying reduction in blood flow to the nerves through the vasa nervorum. This

produces a painful neuropathy characterized by tingling and paresthesias or pain (sometimes severe) on the median side of the palm and in the thumb, the index finger, the middle finger, and the adjacent half of the fourth finger, often radiating back to the wrist. The pain is severe enough to awaken the patient. There also may be weakness in the innervated muscles with atrophy in the thenar eminence. Nerve conduction velocity studies show slowing of motor and sensory axons. An electromyogram may show denervation of innervated muscles such as the abductor pollicis brevis.  

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Ulnar Nerve (C8; T1)

Ulnar nerve (no branches above elbow)

(only muscles innervated by ulnar nerve are depicted)

Articular branch (behind medial condyle)

Flexor digitorum profundus muscle (medial portion only; lateral portion supplied by anterior interosseous branch of median nerve)

Cutaneous innervation

Flexor carpi ulnaris muscle (drawn aside )

Dorsal branch Palmar branch Superficial branch

Flexor pollicis brevis muscle (deep head only; superficial head and other thenar muscles supplied by median nerve)

Deep branch

Palmaris brevis Abductor digiti minimi

Adductor pollicis muscle

Flexor digiti minimi brevis

Hypothenar muscles

Opponens digiti minimi Common palmar digital nerve Anastomotic branch to median nerve Palmar and dorsal interossei muscles 3rd and 4th lumbrical muscles (turned down ) Proper palmar digital nerves (dorsal digital nerves are from dorsal branch) Branches to dorsum of middle and distal phalanges

9.35 ULNAR NERVE The ulnar nerve (C8–­T1) supplies motor fibers to the (1) flexor carpi ulnaris, (2) flexor digitorum profundus, (3) adductor pollicis, (4) abductor digiti V, (5) opponens digiti V, (6) flexor digiti brevis V, (7) interosseus dorsal and palmar, and (8) lumbrical muscles of the fourth and little fingers. It supplies sensory innervation to the dorsal and palmar medial surfaces of the hand for the little finger and the medial half of the fourth

finger. A lesion results in wasting of hand muscles; weakness of wrist flexion and ulnar deviation of the hand; weakness of abduction and adduction of fingers, known as claw hand (hyperextension of the fingers at metacarpophalangeal joints and flexion at the interphalangeal joints); and loss of sensation in the ulnar distribution in the hand (dorsal and palmar surfaces of the medial hand, the little finger, and the adjacent half of the fourth finger).

Peripheral Nervous System

Schema

197

T12

Subcostal nerve (T12) White and gray rami communicans

L1

Iliohypogastric nerve L2

Ilioinguinal nerve Genitofemoral nerve

L3

Ventral rami of spinal nerves

Lateral cutaneous nerve of thigh Gray rami communicans

L4

Muscular branches to psoas and iliacus muscles L5

Femoral nerve Accessory obturator nerve (often absent)

Obturator nerve

Anterior division Posterior division

Lumbosacral trunk

White and gray rami communicans Diaphragm (cut)

Subcostal nerve (T12)

Subcostal nerve (T12) Sympathetic trunk

Iliohypogastric nerve

L1

Ilioinguinal nerve

Iliohypogastric nerve

L2

Transversus abdominis muscle

Ilioinguinal nerve

L3

Quadratus lumborum muscle

Genitofemoral nerve (cut)

Psoas major muscle

L4

Gray rami communicans

Lateral cutaneous nerve of thigh

Genitofemoral nerve

Femoral nerve

Iliacus muscle

Obturator nerve

Lateral cutaneous nerve of thigh

Psoas major muscle (cut)

Femoral nerve Genital branch and Femoral branch of genitofemoral nerve

Lumbosacral trunks Inguinal (Poupart’s) ligament

Obturator nerve

 

9.36 LUMBAR PLEXUS The lumbar plexus is formed from the anterior primary rami of the L1 through L4 roots within the posterior substance of the psoas muscle. The L1 (and some of L2) root forms the iliohypogastric and ilioinguinal nerves and the genitofemoral nerves. These nerves contribute innervation to the transverse and the oblique abdominal muscles. The remaining roots form the femoral, obturator, and lateral femoral cutaneous nerves. Lesions in the lumbar plexus are unusual because of the protection of the plexus within the psoas muscle. Such lesions result in weakness of hip flexion, weakness of adduction of the thigh and extension of the leg, and decreased sensation on the anterior thigh and leg.

CLINICAL POINT A lumbar plexopathy results in characteristic weakness and sensory losses in nerve roots L2–­L4 and involves the distribution of both the obturator and femoral nerves. The most characteristic motor losses are weakness of hip flexion and adduction and weakness of extension of the leg. The motor loss can sometimes occur as the principal finding in a plexopathy but must be distinguished from radiculopathy. Sensory loss over the anterior (and medial) aspect of the thigh may or may not be seen. The patellar reflex usually is diminished. Some lumbar plexopathies present with a patchy motor loss in one or both legs; sometimes the cause is very clear, as in postradiation lumbar plexopathy following treatment of a retroperitoneal tumor or nodes, or in a plexopathy that accompanies pregnancy. And sometimes the cause is not clear and may include an ischemic diabetic plexopathy, a tumor with infiltration, vasculitis, or trauma. Lumbar plexopathies are usually distinguished from radiculopathies because the latter are painful and are accompanied by a nerve root distribution.   

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Regional Neuroscience L4

Lumbosacral trunk

Schema

Anterior division Posterior division

L5

Gray rami communicans

S1

Superior gluteal nerve

S2 Inferior gluteal nerve

Pelvic splanchnic nerves (parasympathetic to inferior hypogastric [pelvic] plexus)

S3

Nerve to piriformis

S4 Tibial nerve Sciatic nerve

Coccygeal nerve

S5

Anococcygeal nerve

Common fibular (peroneal) nerve

Perineal branch of 4th sacral nerve Nerve to levator ani and (ischio-)coccygeus muscles Pudendal nerve

Nerve to quadratus femoris (and inferior gemellus) Nerve to obturator internus (and superior gemellus)

Perforating cutaneous nerve Posterior cutaneous nerve of thigh Sympathetic trunk

Lumbosacral trunk Psoas major muscle

Gray rami communicans

L5

Superior gluteal artery and nerve

L4

Obturator nerve

Pelvic splanchnic nerves (cut) (parasympathetic to inferior hypogastric [pelvic] plexus)

S1

Iliacus muscle S2

Inferior gluteal artery Nerve to quadratus femoris

S3

Internal pudendal artery

S4 S5

Nerve to obturator internus Pudendal nerve

Co

Obturator internus muscle Superior pubic ramus Piriformis muscle (Ischio-)coccygeus muscle

Sacral splanchnic nerves (cut) (sympathetic to inferior hypogastric [pelvic] plexus)

Nerve to levator ani muscle Levator ani muscle

Topography: medial and slightly anterior view of hemisected pelvis

  9.37 SACRAL AND COCCYGEAL PLEXUSES The sacral and coccygeal plexuses are formed from the roots of the L4–­S4 segments, located anterior to the piriformis muscle. The major branches include the superior (L4–­S1) and inferior (L5–­S2) gluteal nerves, the posterior femoral cutaneous nerve (S1–­S3), the sciatic nerve (L4–­S3) and its tibial and common peroneal divisions, and the pudendal nerve (S2–­S4). The pudendal nerve supplies the perineal and sphincter muscles, which aid in closing the sphincters of the bladder and the rectum. Lesions of the sacral plexus result in weakness of the posterior thigh and muscles of the leg and feet, with decreased sensation in the posterior thigh and a perianal/saddle location.

CLINICAL POINT Sacral plexopathies usually present as weakness and loss of sensation in the distribution of the gluteal, tibial, and peroneal nerves. The leg weakness can be significant; it includes weakness of hip extension and abduction, weakness of flexion of the leg, and weakness of ankle movements (plantarflexors and dorsiflexors). Weakness may occur in the gluteal muscles if the plexopathy involves more proximal regions of the plexus. Sensory loss can occur in the posterior region of the thigh, the anterolateral and posterior leg, and the plantar surface and dorsolateral portion of the foot. Saddle sensory loss may or may not be present. Some autonomic involvement also may occur, with vascular changes and trophic alterations characteristic of autonomic damage.   

Peripheral Nervous System

Lateral femoral cutaneous nerve Femoral nerve Obturator nerve

T12 L1 L2 L3 L4

Lumbar plexus

199

Femoral Nerve (L2, L3, L4) and Lateral Femoral Cutaneous Nerve (L2, L3)

Lumbosacral trunk

lliacus muscle Psoas major muscle (lower part) Articular twig Sartorius muscle (divided)

Quadriceps femoris

Pectineus muscle

Lateral femoral cutaneous nerve

Rectus femoris muscle (divided )

Anterior cutaneous branches of femoral nerve

Vastus intermedius muscle

Sartorius muscle (divided )

Vastus medialis muscle Saphenous nerve Vastus lateralis muscle

Articularis genus muscle

Infrapatellar branch of saphenous nerve

Medial crural cutaneous branches of saphenous nerve

Cutaneous innervation Note: Only muscles innervated by the femoral nerve are shown.

  9.38 FEMORAL AND LATERAL FEMORAL CUTANEOUS NERVES The femoral nerve (mainly L2–­L4) innervates the iliopsoas, sartorius, and quadriceps femoris muscles. It contributes to flexion and outward rotation of the hip, flexion and inward rotation of the lower leg, and extension of the lower leg around the knee joint. It supplies sensory fibers to the anterior thigh and to the anterior and medial surface of the leg and foot. A lesion results in weakness of extension of the leg and flexion of the hip and leg,

with quadriceps atrophy, and in loss of sensation in territories of sensory distribution. The lateral femoral cutaneous nerve supplies sensation to the skin and fascia of the anterior and lateral surfaces of the thigh to the level of the knee. Compression of the nerve at the inguinal ligament or near the surface (caused by a tight-­fitting garment) may result in loss of sensation or paresthesias and pain on the anterior and lateral surfaces of the ipsilateral thigh.

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Obturator Nerve (L2, L3, L4) L1 L2

Lumbar plexus

L3 lliohypogastric nerve

L4

llioinguinal nerve Lumbosacral trunk Genitofemoral nerve Lateral femoral cutaneous nerve Femoral nerve Obturator nerve

Posterior branch

Obturator externus muscle

Articular branch

Adductor brevis muscle Adductor longus muscle (divided )

Anterior branch Posterior branch

Adductor magnus muscle (partly supplied by sciatic nerve)

Cutaneous branch Gracilis muscle Articular branch to knee joint

Hiatus of adductor canal

Cutaneous innervation Note: Only muscles innervated by the obturator nerve are shown.

 

9.39 OBTURATOR NERVE The obturator nerve (L2–­L4) supplies the pectineus, adductor (longus, brevis, and magnus), gracilis, and external obturator muscles. This nerve controls adduction and rotation of the thigh. A small cutaneous zone on the internal thigh is supplied

by sensory fibers. A lesion of the obturator nerve results in weakness of adduction of the thigh and a tendency to abduct the thigh in walking. There also is weakness of external rotation of the thigh. A small zone of anesthetic skin on the medial thigh is present.

Peripheral Nervous System Sciatic Nerve (L4, L5; S1, S2, S3) and Posterior Femoral Cutaneous Nerve (S1, S2, S3)

Posterior femoral cutaneous nerve Inferior cluneal nerve Perineal branches

201

Greater sciatic foramen Sciatic nerve Common peroneal segment of sciatic nerve

Tibial segment of sciatic nerve Long head (divided) of biceps femoris muscle Adductor magnus muscle (also supplied by obturator nerve) Semitendinosus muscle

Short head of biceps femoris muscle

Cutaneous innervation

Long head (divided) of biceps femoris muscle

Common peroneal nerve

Semimembranosus muscle Tibial nerve

Articular branch Posterior femoral cutaneous nerve

Articular branch Plantaris muscle

Lateral sural cutaneous nerve

Medial sural cutaneous nerve

Peroneal communicating branch Common peroneal nerve (via lateral sural cutaneous nerve)

Gastrocnemius muscle Sural nerve Soleus muscle

Superficial peroneal nerve

Tibial nerve

From sciatic nerve

Medial calcaneal branches

Sural nerve Lateral calcaneal branches

Medial and lateral plantar nerves Lateral dorsal cutaneous nerve

Tibial nerve (via medial calcaneal branches)

  9.40 SCIATIC AND POSTERIOR FEMORAL CUTANEOUS NERVES The sciatic nerve is formed from the roots of the L4–­S3 segments. The superior and inferior gluteal nerves branch proximally, just before the sciatic nerve’s formation. The superior gluteal nerve (L4–­S1) supplies the gluteus medius and minimus, tensor fascia lata, and piriformis muscles. It contributes to abduction and inward rotation and some outward rotation of the thigh, and to flexion of the upper leg at the hip. The inferior gluteal nerve (L4–­ S1) supplies the gluteus maximus, obturator internus, gemelli, and quadratus muscles. It contributes to extension of the thigh at the hip and to outward rotation of the thigh. A lesion results

in difficulty climbing stairs and rising from a sitting position. The sciatic nerve proper supplies the biceps femoris, semitendinosus, and semimembranosus muscles (hamstrings) and regulates flexion of the lower leg. Because it branches into the tibial and common peroneal nerves, major lesions of the sciatic nerve result in weakness of leg flexion, weakness of all muscles below the knee, and loss of sensation in the posterior thigh, posterior and lateral aspects of the leg, and sole of the foot. Such lesions may result from a fracture of the pelvis or femur, nerve compression, a herniated disc, or diabetes. The posterior femoral cutaneous nerve (S1–­S3) supplies sensory innervation to the posterior thigh, lateral part of the perineum, and lower portion of the buttock.

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Tibial Nerve (L4, L5; S1, S2, S3) Tibial nerve

Common peroneal nerve

Medial sural cutaneous nerve (cut) From tibial nerve Articular branches Plantaris muscle

Articular branch Lateral sural cutaneous nerve (cut)

Medial calcaneal branches (S1, 2) Medial plantar nerve (L4, 5) Lateral plantar nerve (S1, 2)

Sural nerve (S1, 2)

Gastrocnemius muscle Nerve to popliteus muscle

Saphenous nerve (L3, 4)

Popliteus muscle

Cutaneous innervation of sole

Crural interosseous nerve Soleus muscle Flexor digitorum longus muscle Tibialis posterior muscle

Medial and lateral calcaneal branches Flexor retinaculum (cut) Tibial nerve Medial plantar nerve to: Flexor digitorum brevis muscle Abductor hallucis muscle

Flexor hallucis longus muscle Sural nerve (cut)

Lateral calcaneal branch

Medial calcaneal branch Flexor retinaculum (cut)

Flexor hallucis brevis muscle 1st lumbrical muscle, Articular branch, Cutaneous branches, Proper plantar digital nerves

9.41 TIBIAL NERVE The tibial nerve (L4–­S2) supplies innervation to (1) the gastrocnemius and soleus muscles (the main plantar flexors of the foot), (2) the tibialis posterior (plantar flexion and inversion), (3) the flexor digitorum longus (plantar flexor and toe flexor), (4) the flexor hallucis longus (plantar flexor and great toe flexor), and (5) the muscles of the foot, including the abductor digiti minimi pedis, flexor digiti minimi, adductor hallucis, interosseous, and third and fourth lumbrical muscles. Sensory branches supply the skin over the lateral calf, foot, heel, and small toe (sural nerve) and the medial aspect of the heel and the sole of the foot (tibial nerve). A lesion can occur because of compression in the tarsal tunnel, a tumor, or diabetes; it results in weakness of plantar flexion and inversion of the foot, weakness of toe flexion, and loss of sensation in the lateral calf and the plantar region of the foot.

Lateral plantar nerve to: Quadratus plantae muscle, Abductor digiti minimi muscle Deep branch to: 1st, 2nd, 3rd plantar interossei muscles; 2nd, 3rd, 4th lumbrical muscles; Adductor hallucis muscle, articular branches Superficial branch to: Flexor digiti minimi brevis muscle, 4th interossei muscles, Proper plantar digital nerves, cutaneous branches

  CLINICAL POINT The tibial nerve in the popliteal fossa can be used for evaluation of conduction velocity and of specific reflexes. This nerve may be directly stimulated by electrical current. Surface recording electrodes are placed over a distal innervated muscle, and the nerve is stimulated in one or more places, resulting in an indirect evaluation of motor conduction velocity and the muscle response to tibial nerve stimulation. Sensory conduction velocity evaluation is a bit more straightforward; the stimulating electrode is placed at a distal site, and compound action potentials are recorded over at least two proximal sites. A more complex evaluation of reflexes involves evaluation of the muscle stretch (monosynaptic) reflex. With recording electrodes placed over the distal muscle (triceps surae), the tibial nerve is gradually stimulated first by weak and then by stronger electrical current in the popliteal fossa. The first axons that are stimulated are the Ia afferents, which conduct action potentials into the spinal cord and excite the homonymous LMN, whose axon then sends action potentials down to the innervated muscle. This is a long-­latency response, called the H wave or H reflex because it involves both the sensory and the motor arms of the muscle stretch reflex. As current strength is increased, the LMN axon is finally stimulated directly, and the muscle response (direct muscle activation) occurs and with a far shorter latency. This H reflex evaluation is useful in assessment of axonal neuropathies and demyelinating neuropathies.   

Peripheral Nervous System

Common peroneal nerve (in phantom)

203

Common Peroneal Nerve (L4, L5; S1, S2) Lateral sural cutaneous nerve (in phantom)

Tendon of biceps femoris muscle

Articular branches

Common peroneal nerve

Anterior tibial recurrent branch

Head of fibula

Extensor digitorum longus muscle

Peroneus longus muscle

Deep peroneal nerve Tibialis anterior muscle

Cutaneous innervation

Superficial peroneal nerve

Branches of lateral sural cutaneous nerve

Extensor digitorum longus muscle

Peroneus longus muscle

Peroneus brevis muscle

Extensor hallucis longus muscle

Medial dorsal cutaneous nerve Intermediate dorsal cutaneous nerve

Superior extensor retinaculum

Inferior extensor retinaculum (cut) Lateral dorsal cutaneous nerve (branch of sural nerve)

Lateral sural cutaneous nerve Lateral branch of deep peroneal nerve to: Extensor hallucis brevis muscle and Extensor digitorum brevis muscle

Superficial peroneal nerve

Deep peroneal nerve Medial branch of deep peroneal nerve

Sural nerve

Proper dorsal digital nerves Proper dorsal digital nerves

  9.42 COMMON PERONEAL NERVE The common peroneal nerve (L4–­S1) branches into the deep peroneal nerve, supplying (1) the tibialis anterior (foot dorsiflexion and inversion), (2) the extensor hallucis longus (foot dorsiflexion and great toe extension), (3) the extensor digitorum longus (extension of the toes and foot dorsiflexion), and (4) the extensor digitorum brevis muscles (extension of toes) and the superficial peroneal nerve, which supplies the peroneus longus

and brevis muscles (plantar flexion and foot eversion). Sensory branches supply the lateral aspect of the leg below the knee and the skin on the dorsal surface of the foot. This nerve may be damaged by compression, a fracture at the head of the fibula, or diabetes, resulting in weakness of dorsiflexion and eversion of the foot, weakness of toe extension (dorsiflexion), and loss of sensation in the lateral aspect of the lower leg and the dorsum of the foot.

204

Regional Neuroscience Oculomotor (III) nerve Facial (VII) nerve

Intracranial vessels

Glossopharyngeal (IX) nerve

Eye

Ciliary ganglion

Medulla oblongata

Lacrimal gland

Vagus (X) nerve

Pterygopalatine ganglion

C1 C2

Sublingual and submandibular glands

Otic ganglion

C3 Submandibular ganglion

Gray

C4 C5 C6 C7 C8

Peripheral cranial blood vessels Larynx Trachea Bronchi and lungs

T1 Sweat gland

T2 Heart

T3 T4

T7 T8 T9

Stomach

L sp esse la r Lo nc th sp we hn or la st ic aci nc th ne c hn or rv ic ac e i ne c rv e

T6

Hair follicle

Greater thoracic Celiac splanchnic nerve ganglion

Rami c o gray a mmunican nd wh tes ite

T5

Peripheral vessel

Shown for only 1 segment

T10 T11

Liver Gallbladder Bile ducts

er

L2 L3 Gray

Superior hypogastric plexus Hypogastric nerves

L5 Sympathetic fibers preganglionic postganglionic preganglionic postganglionic

S1

Antidromic conduction

Adrenal glands Brown fat Kidneys

Intestines

Inferior mesenteric ganglion

Lymphoid organs Distal colon

Bladder

S2 S3 S4 S5 Coccyx

ic

Lumbar splanchnic nerves

L1

L4

Pancreas

S ga up. ng m lio ese n nt

T12

Parasympathetic fibers

Parotid gland

Pelvic splanchnic nerves Sympathetic trunk

External genitalia

Inferior hypogastric (pelvic) plexus

AUTONOMIC NERVOUS SYSTEM 9.43 GENERAL SCHEMA The autonomic nervous system is a two-­neuron chain. The preganglionic neuron arises from the brainstem or spinal cord and synapses on postganglionic neurons in the sympathetic chain or collateral ganglia (sympathetic) or on intramural ganglia (parasympathetic) near the organ innervated. The sympathetic division, derived from neurons in the T1–­L2 lateral horn, prepares the body for fight-­or-­ flight mobilization for emergency responses. The parasympathetic division, derived from neurons in the brainstem (CNs III, VII, IX, and X) and the sacral spinal cord (S2–­S4 intermediate gray), regulates reparative, homeostatic, and digestive functions. These autonomic systems achieve their actions through innervations of smooth muscle, cardiac muscle, secretory (exocrine) glands, metabolic cells

  (hepatocytes, fat cells), and cells of the immune system. Normally, both autonomic divisions work together to regulate visceral activities such as respiration, cardiovascular function, digestion, and some endocrine functions. CLINICAL POINT Pure autonomic failure is a gradual deterioration of sympathetic postganglionic neurons; it occurs in middle-­aged individuals and is observed more commonly in men than in women. This syndrome includes neurogenic orthostatic hypotension (syncope or dizziness when standing), inability to sweat, urinary tract dysfunction, erectile dysfunction, and retrograde ejaculation. Pure autonomic failure can be present without evidence of involvement of the CNS. Catecholamine challenge results in robust reactivity in target organs caused by denervation hypersensitivity.   

Peripheral Nervous System

205

Preganglionic sympathetic Postganglionic sympathetic Preganglionic parasympathetic Postganglionic parasympathetic Thymus

CN X (Vagus)

C1

Cervical lymph nodes

C2 C3

Upper limb bone marrow

C4 C5 C6 C7 C8

Sympathetic chain ganglia Brown fat

T1 T2

Pulmonary MALT

T3 T4 T5 T6

Celiac and aorticorenal ganglia

T7

Liver and hepatocytes

T8 Splanchnic nerves

T9 T10

Spleen Superior and inferior mesenteric ganglia

T11 T12

Mesenteric lymph nodes

L1 L2

GALT (e.g., Peyer's patches) with parasympathetic intramural ganglia

L3 L4 L5 S1

Inguinal lymph nodes

S2 S3 S4 S5 Co

9.44 AUTONOMIC INNERVATION OF THE IMMUNE SYSTEM AND METABOLIC ORGANS The autonomic nervous system innervates the vasculature, smooth muscle tissue, and parenchyma of organs of the immune system mainly through the sympathetic division. In the bone marrow and thymus, sympathetic fibers modulate cell proliferation, differentiation, and mobilization. In the spleen and lymph nodes, sympathetic fibers modulate innate immune reactivity and the magnitude and timing of acquired immune responses, particularly the choice of cell-­mediated (Th1 cytokines) as opposed to humoral (Th2 cytokines) immunity. Autonomic nerve fibers

Lower limb bone marrow

  regulate immune responses and inflammatory responses in the mucosa-­associated lymphoid tissue (MALT) in the lungs, the gut-­associated lymphoid tissue (GALT), and the skin. Extensive neuropeptidergic innervation, derived from both the autonomic nervous system and the primary sensory neurons, also is present in the parenchyma of lymphoid organs. Many subsets of lymphoid cells express cognate receptors for catecholamines (alpha and beta receptor subsets) and neuropeptides; the expression of these neurotransmitter receptors is highly regulated by both lymphoid and neural molecular signals. Postganglionic sympathetic nerve fibers also directly innervate hepatocytes and fat cells. Th, T helper cells.

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Regional Neuroscience Dorsal root Sympathetic trunk

Thoracic part of spinal cord Spinal ganglion

Sympathetic trunk ganglion

Spinal nerve to vessels and glands of skin

Ventral root Recurrent meningeal branch (to spinal meninges and spinal perivascular plexuses) Nonnociceptive Sympathetic trunk ganglion

White ramus communicans

Thoracic splanchnic nerve

Gray ramus communicans

Vagus (X) nerve Viscus

Celiac ganglion

Sympathetic trunk ganglion

Nociceptive

Enteric plexus Nociceptive Superior mesenteric ganglion

Sympathetic fibers

Parasympathetic fibers

preganglionic

preganglionic

postganglionic

postganglionic

  9.45 REFLEX PATHWAYS Autonomic reflex pathways consist of a sensory (afferent) component, interneurons in the CNS, and autonomic efferent components that innervate the peripheral tissue responding to the afferent stimulus. The afferents can be either autonomic (e.g., from the vagus nerve) and processed by brainstem nuclei such as the nucleus solitarius; or they can be somatic (e.g., nociception) and processed by spinal cord neurons. The preganglionic sympathetic or parasympathetic neurons are activated through interneurons to produce a reflex autonomic response (e.g., contraction of vascular smooth muscle to alter blood pressure and increase heart rate and contractility). The efferent connectivity can be relayed via splanchnic or somatic nerves because of the complexity of autonomic efferent pathways.

Afferent fibers to spinal cord Afferent fibers to brainstem

CLINICAL POINT Autonomic reflex pathways are vital for maintenance of homeostasis. Sensory signals associated with standing result in vascular constriction induced by sympathetic neurons to maintain blood pressure, prevent pooling of blood in the lower extremities, and maintain appropriate perfusion of the brain and other vital organs. Nociceptive stimulation may result in reflex elevation of heart rate, blood pressure, and other characteristics of sympathetic activation. Stimulation of the perioral region, particularly in an infant during feeding, activates a parasympathetic state to enhance digestion and diminish sympathetic activation, thereby promoting growth and development. Problems can arise when autonomic reflexes are disrupted, or when hyperactivation of reflex pathways elevates either parasympathetic or sympathetic activity. In such circumstances, there is often a counterpart activation of the other system, as when paradoxical parasympathetic activation leads to compensatory sympathetic activation. This can increase the likelihood of problems such as arrhythmia or even cardiac arrest.   

Peripheral Nervous System

Salivary glands

Glossopharyngeal (IX) nerve

Medulla oblongata

207

Trachea and bronchi Vagus (X) nerve

Heart Cervical sympathetic truck ganglia Striated muscle

Thoracolumbar part of spinal cord

Sweat glands White ramus communicans

Gray ramus communicans

Hair follicles

Celiac ganglion

Peripheral arterioles

Visceral arterioles

Superior mesenteric ganglion

Gastrointestinal tract Adrenal gland

Sacral part of spinal cord

Inferior mesenteric ganglion

Ganglion cells

Pelvic splanchnic nerves

Bladder

Cholinergic ganglion cells (parasympathetic postganglionic) in intramural ganglia in the heart. Acetylcholinesterase (AChE) stain.

C Cholinergic synapse A Adrenergic synapse

Sympathetic fibers

Parasympathetic fibers

preganglionic

preganglionic

Somatic fibers

postganglionic

postganglionic

Antidromic conduction Axons

Postganglionic parasympathetic cholinergic nerve fibers (axons) ending along cardiac atrial muscle cells. AChE stain.

  9.46 CHOLINERGIC AND ADRENERGIC SYNAPSES The autonomic nervous system is a two-­neuron chain. All preganglionic neurons, sympathetic and parasympathetic, use ACh as the principal neurotransmitter in synapses on ganglion cells. These cholinergic (C) synapses activate mainly nicotinic receptors on the ganglion cells. Postganglionic parasympathetic neurons use ACh at synapses with target tissue, activating mainly

muscarinic receptors. Postganglionic sympathetic neurons use mainly norepinephrine (adrenergic responses; A), to activate both alpha and beta receptors on target tissues. Although ACh and norepinephrine are the principal neurotransmitters used by autonomic neurons, many colocalized neuropeptides and other neuromediators are also present, including neuropeptide Y, substance P, somatostatin, enkephalins, histamine, glutamate, and others.

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Regional Neuroscience

Central nervous system

Peripheral nervous system

Lower motor neurons

C

N

Skeletal muscle

 or 

Sympathetic chain ganglion

C

N

A

 or 

Collateral ganglion

C

Sympathetics T1–L2

A

N

Target tissue Adrenal

C

N

Epinephrine Norepinephrine

Chromaffin cell

Intramural ganglion

C

Paraympathetics (cranial and sacral)

N

C

M

Target tissue Synapses

Receptors

A Adrenergic

 or 

C Cholinergic

N M

Alpha or beta adrenergic Nicotinic Muscarinic

 

9.47 SCHEMATIC OF CHOLINERGIC AND ADRENERGIC DISTRIBUTION TO MOTOR AND AUTONOMIC STRUCTURES All preganglionic neurons of both the SNS and the PsNS use ACh as their neurotransmitter. All ganglion cells possess mainly nicotinic receptors for fast response to cholinergic release from preganglionic axons. However, additional muscarinic receptors and dopamine receptors on ganglion cells help to mediate longer term

excitability. The postganglionic sympathetic nerves use mainly norepinephrine as their neurotransmitter and target structures in the periphery possessing different subsets of alpha and beta adrenergic receptors for response to norepinephrine. Some postganglionic nerve fibers to sweat glands use ACh as their neurotransmitter. Postganglionic parasympathetic nerves use ACh as their neurotransmitter and target structures in the periphery possessing mainly muscarinic receptors for response to ACh.

Peripheral Nervous System

Sensory root Trigeminal (V) nerve Motor root Ganglion Internal carotid artery and plexus Facial (VII) nerve

Greater petrosal nerve Deep petrosal nerve Nerve of pterygoid canal Oculomotor (III) nerve Maxillary nerve Ophthalmic nerve Nasociliary nerve

Vestibulocochlear (VIII) nerve

209

Nasociliary nerve root Sympathetic root of ciliary ganglion Oculomotor nerve root Ciliary ganglion Long and short ciliary nerves Pterygopalatine nerves

Glossopharyngeal (IX) nerve Vagus (X) nerve

Posterior lateral nasal nerves

Pterygopalatine ganglion Mandibular nerve

Otic ganglion

Internal carotid nerve

Greater and lesser palatine nerves

Chorda tympani

Lingual nerve

Superior laryngeal nerve

Submandibular ganglion

Superior cervical sympathetic trunk ganglion Vagus (X) nerve Internal carotid artery Cervical sympathetic trunk Superior cervical cardiac branch of vagus nerve

Pharyngeal plexus Maxillary artery and plexus External carotid artery and plexus

Inferior alveolar nerve Middle meningeal artery and plexus Facial artery and plexus

Carotid sinus branch of glossopharyngeal nerve Carotid sinus Common carotid artery and plexus Superior cervical sympathetic cardiac nerve

  9.48 AUTONOMIC DISTRIBUTION TO THE HEAD AND NECK: MEDIAL VIEW Autonomic nerve distribution to the head and neck includes components of both the SNS and the PsNS. The parasympathetic components are associated with CNs III (ciliary ganglion), VII (pterygopalatine, submandibular ganglia), and IX (otic ganglion). The vagus nerve and its associated ganglia do not innervate effector tissue in the head and neck, although they are present in the neck. Sympathetic components are associated with the superior cervical ganglion and, to a lesser extent, the middle cervical ganglion. The geniculate ganglion (CN VII), petrosal ganglion (CN IX), and nodose ganglion (CN X) process taste information. They are sometimes thought of as autonomic afferents, but they are not components of the autonomic efferent nervous system. CLINICAL POINT The oculomotor (III nerve) parasympathetic distribution to the eye forms a vital link in one of the most important reflexes in neurology, the pupillary light reflex. Light shone into one eye provides an afferent signal that is processed by the retina, resulting in ganglion cell activation and axonal projections to the pretectum on both sides. The pretectum, through direct and contralateral connections via the posterior commissure, stimulates the nucleus of Edinger-­Westphal bilaterally.

This system, via connections in the ciliary ganglion, distributes to the pupillary constrictor muscle, resulting in constriction of the ipsilateral (direct) and contralateral (consensual) pupils. The pupillary light reflex is particularly important in someone with a head injury, intracranial bleed, or space-­occupying mass in whom possible brain herniation is suspected. The third nerve may be trapped and compressed against the free edge of the tentorium cerebelli, resulting in failure of the ipsilateral pupil to constrict and disruption of the pupillary light reflex The superior cervical ganglion (SCG) is the most rostral component of the sympathetic chain. It supplies structures in the head and neck, including the pupillary dilator muscle, blood vessels, sweat glands, pineal gland, thymus gland, and superior tarsal (Müller’s) muscle. The T1–­T2 intermediolateral cell column in the spinal cord (preganglionic sympathetic neurons) innervates the SCG; this ganglion then distributes noradrenergic fibers to the pupillary dilator muscle, resulting in dilation of the pupil. When CN III is damaged (e.g., by compression during transtentorial herniation), the actions of the sympathetic SCG are unopposed, resulting in a fixed (unresponsive to the pupillary light reflex), dilated pupil. In circumstances in which the SCG or its central innervation is damaged (e.g., apical lung tumor, Horner’s syndrome), the ipsilateral pupil cannot dilate and the pupil is constricted (miotic). A pupil that constricts when light is shone into one eye and paradoxically appears to dilate when light is shone into the other eye (swinging flashlight test) indicates an afferent (CN II) defect, with the paradoxical dilation occurring as the result of recovery from the initial constriction because of the unresponsiveness of the damaged CN II.   

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Regional Neuroscience

Internal carotid nerve

Glossopharyngeal (IX) nerve

C1

Vagus (X) nerve (cut) Superior cervical sympathetic trunk ganglion C2

Pharyngeal plexus Superior pharyngeal branch of vagus nerve External carotid artery and plexus Superior laryngeal nerve Internal carotid artery and carotid sinus branch of glossopharyngeal nerve

C3 C4

Carotid body

Gray rami communicans

Carotid sinus Superior cervical cardiac branch of vagus nerve

C5

Superior cervical sympathetic cardiac nerve

C6

Phrenic nerve Middle cervical sympathetic trunk ganglion Common carotid artery and plexus

C7

Middle cervical sympathetic cardiac nerve Vertebral ganglion Vertebral artery and plexus

C8

Recurrent laryngeal nerve Cervicothoracic (stellate) ganglion Ansa subclavia Vagus (X) nerve (cut) Inferior cervical sympathetic cardiac nerve Subclavian artery

9.49 AUTONOMIC DISTRIBUTION TO THE HEAD AND NECK: LATERAL VIEW The parasympathetic nerve fibers to the head and neck regulate pupillary constriction and accommodation for near vision (CN III, ciliary ganglion to pupillary constrictor muscle and ciliary muscle), tear production (CN VII, pterygopalatine ganglion to lacrimal glands), and salivation (CN VII, submandibular ganglion to submandibular and sublingual glands and CN IX, otic ganglion to parotid gland). The sympathetic nerve fibers to the head and neck derive mainly from the SCG, with synapses to the pupillary dilator muscle, sweat glands, vascular smooth muscle, and the thymus gland. CLINICAL POINT Blood flow to the brain, derived from the two internal carotid arteries and the two vertebral arteries, is highly regulated. The brain requires moment-­to-­moment delivery of oxygen and glucose to maintain cerebral activity and generate the adenosine triphosphate needed for the

Thoracic sympathetic and vagal cardiac nerves

  high energy demands of neurons. Blood flow to the brain is autoregulated; several levels of superimposed control derive from metabolic and neural regulatory systems. (1) Autoregulation may be based on smooth muscle responsiveness to stretch and on endothelial cell response to vasoactive secretory products. (2) Superimposed on autoregulation is metabolic control, which is based on blood gases (oxygen, carbon dioxide) and on metabolic products stimulated by neuronal activity (nitric oxide, adenosine, lactate, some ions). (3) A third level of regulation derives from neural regulation. The superior cervical ganglion sends noradrenergic (colocalized with neuropeptide Y) sympathetic vasoconstrictor fibers along the vasculature, and the sphenopalatine ganglion sends acetylcholinergic (colocalized with vasoactive intestinal peptide; VIP) vasodilator fibers along the vasculature. The trigeminal ganglion also distributes substance P (colocalized with calcitonin gene-­ related peptide) vasodilator fibers along the vasculature; these fibers can be activated by pain. Some central regions, such as the fastigial nucleus of the cerebellum and the rostral ventrolateral medulla, can regulate the activation of some of these neural circuits to the cerebral vasculature, influencing blood flow to the brain.   

Peripheral Nervous System

Central nervous system

Peripheral nervous system

Parasympathetics Nucleus of Edinger-Westphal

Superior salivatory nucleus

Inferior salivatory nucleus

211

Ciliary ganglion

Pupillary constrictor muscle Ciliary muscle

Pterygopalatine ganglion

Lacrimal glands Nasal mucosal glands

Submandibular ganglion

Submandibular gland Sublingual gland

Otic ganglion

Parotid gland

Cranial nerve III

Cranial nerve VII

Cranial nerve IX

Pupillary dilator muscle Sympathetics

Superior cervical ganglion

T1–T2 Intermediolateral cell column

Sweat glands and vascular smooth muscle in head and neck

  9.50 SCHEMATIC OF AUTONOMIC DISTRIBUTION TO THE HEAD AND NECK Autonomic innervation to the head and neck is derived from parasympathetic neurons in the brainstem, including the nucleus of Edinger-­Westphal (CN III), the superior salivatory nucleus (CN VII), and the inferior salivatory nucleus (CN IX), and from sympathetic neurons in the T1–­T2 intermediolateral cell column in the spinal cord. The associated ganglia and target (effector) tissue are illustrated.

CLINICAL POINT The superior and inferior salivatory nuclei provide important parasympathetic regulatory control over salivation. The superior salivatory nucleus innervates (via CN VII) the submandibular ganglion, which supplies the submandibular and sublingual glands; the inferior salivatory nucleus innervates (via CN IX) the otic ganglion, which supplies the parotid gland. These parasympathetic fibers stimulate secretion of saliva. In addition, sympathetic innervation from the superior cervical ganglion activates contraction of the myoepithelial cells of the salivary ducts. Salivation is important as an initial phase of the digestion process; it prepares food for swallowing, aids in speaking, and contains mediators and immunoglobulins that provide an initial protective barrier against potentially dangerous organisms that gain access to the oral cavity.   

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Regional Neuroscience

From hypothalamus Oculomotor nerve root of ciliary ganglion (motor)

Short ciliary nerves

Oculomotor (III) nerve

Edinger-Westphal nucleus Pretectum

Ciliary ganglion I

aI

Vi

Dilator of pupil Sphincter of pupil Ciliary muscle

Descending nucleus of trigeminal nerve (V) Ophthalmic nerve Trigeminal ganglion

Nasociliary nerve Optic (II) nerve Long ciliary nerve Nasociliary nerve root of ciliary ganglion Ophthalmic artery

Middle ear

Internal carotid plexus

Internal carotid artery Thoracic part of spinal cord

Superior cervical sympathetic trunk ganglion Gray ramus communicans 1st thoracic sympathetic trunk ganglion Sympathetic fibers Preganglionic Postganglionic

White ramus communicans T1

Parasympathetic fibers Preganglionic Postganglionic Afferent fibers T2 Pupillary light reflex pathway Descending pathway

 

9.51 AUTONOMIC DISTRIBUTION TO THE EYE Parasympathetic preganglionic nerve fibers from the Edinger-­ Westphal nucleus innervate the ciliary ganglion, which supplies the ciliary muscle (aiding in accommodation to near vision) and the pupillary constrictor muscle (constricting the pupil). Sympathetic preganglionic nerve fibers from the T1–T2 intermediolateral cell column innervate the superior cervical ganglion, which supplies the dilator muscle of the pupil.

T3

The pupillary light reflex is a major reflex in neurological testing. The afferent limb is activated by light shone in either eye via CN II and processed through the pretectum to the Edinger-­ Westphal nucleus on both sides (via the posterior commissure); the efferent limb consists of autonomic parasympathetic outflow to the pupillary constrictor muscles of both sides.

Peripheral Nervous System

213

Superior salivatory nucleus (parasympathetic) Facial nerve (VII) Geniculum Greater petrosal nerve (parasympathetic) Deep petrosal nerve (sympathetic) Nerve (vidian) of pterygoid canal Maxillary nerve (V2) entering foramen rotundum Pterygopalatine ganglion in pterygopalatine fossa Lateral and medial posterior superior nasal branches in pterygopalatine fossa Infraorbital nerve Posterior superior and inferior lateral nasal nerves (cut ends)

Medulla oblongata

Tympanic cavity Internal carotid nerve Internal carotid artery

Spinal cord

Sympathetic trunk

Greater and lesser palatine nerves

Posterior superior alveolar nerves

Superior cervical ganglion

Maxillary sinus

Nasopalatine nerve

Postganglionic fibers to vessels (sympathetic) and glands (parasympathetic) of nasal cavity, maxillary sinus, and palate

T1 T2

Preganglionic parasympathetic fibers

T3

Postganglionic parasympathetic fibers Preganglionic sympathetic fibers Presynaptic sympathetic cell bodies in intermediolateral nucleus (lateral horn) of gray matter

9.52 AUTONOMIC INNERVATION OF THE NASAL CAVITY Parasympathetic preganglionic neurons in the superior salivatory nucleus innervate the pterygopalatine ganglion. Sympathetic

Postganglionic sympathetic fibers

 

preganglionic neurons from the T1–­T2 intermediolateral cell column innervate the SCG. The pterygopalatine ganglion supplies secretory glands, and the SCG supplies blood vessels with postganglionic nerve fibers in the nasal cavity, maxillary sinus, and palate.

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Regional Neuroscience

Trigeminal ganglion Deep petrosal nerve

Ophthalmic nerve (V1) Mandibular nerve (V3)

Greater petrosal nerve

Otic ganglion

Chorda tympani nerve

Lingual nerve

Trigeminal nerve (V)

Maxillary nerve (V2)

Facial nerve (VII) (intermediate nerve)

Nerve (vidian) of pterygoid canal Pterygopalatine ganglion

Superior salivatory nucleus

Lacrimal gland

Descending palatine nerves

Pharyngeal nerve

Posterior nasal nerves

Maxillary artery Internal carotid nerve Glossopharyngeal nerve (IX)

Palatine nerves

Superior cervical sympathetic ganglion

Greater Lesser

Sympathetic trunk T1 and T2 spinal nerves Thoracic spinal cord

Submandibular ganglion

Dorsal root Sublingual gland Submandibular gland Facial artery Lingual artery

White

Gray

Rami communicans Internal carotid artery

Ventral root

Sympathetic preganglionic cell bodies in intermediolateral nucleus (lateral horn) of gray matter

External carotid artery and plexus Common carotid artery

 

9.53 SCHEMATIC OF THE PTERYGOPALATINE AND SUBMANDIBULAR GANGLIA The pterygopalatine and submandibular ganglia, innervated by the superior salivatory nucleus via CN VII, supply the lacrimal

Sympathetic preganglionic fibers Sympathetic postganglionic fibers Parasympathetic preganglionic fibers Parasympathetic postganglionic fibers

glands and nasal mucosal glands as well as the submandibular and sublingual salivary glands, respectively, with postganglionic parasympathetic cholinergic nerve fibers.

Peripheral Nervous System

215

Trigeminal ganglion

Mandibular nerve (V3)

Lesser petrosal nerve

Otic ganglion

Chorda tympani nerve Ophthalmic nerve (V1)

Trigeminal nerve (V)

Maxillary nerve (V2)

Facial nerve (VII) Glossopharyngeal nerve (IX)

Auriculotemporal nerve

Inferior salivatory nucleus

Superficial temporal artery

Pons

Parotid gland

Maxillary artery Medulla oblongata

Tympanic plexus

Tympanic nerve (Jacobson)

Inferior alveolar nerve

Inferior ganglion (IX)

Lingual nerve

Superior cervical sympathetic ganglion Sympathetic trunk T1 and T2 spinal nerves

Thoracic spinal cord

External carotid artery Dorsal root Internal carotid artery

Common carotid artery White Sympathetic presynaptic fibers Sympathetic postsynaptic fibers Parasympathetic presynaptic fibers Parasympathetic postsynaptic fibers

Gray

Rami communicans

9.54 SCHEMATIC OF THE OTIC GANGLION The otic ganglion, innervated by the inferior salivatory nucleus via CN IX, supplies the parotid salivary gland with postganglionic parasympathetic cholinergic nerve fibers.

 

Ventral root

Sympathetic preganglionic cell bodies in intermediolateral nucleus (lateral horn) of gray matter

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Regional Neuroscience

Internal carotid nerve Cervical sympathetic trunk ganglia Cervical cardiac nerves Gray ramus communicans

Brachial plexus White ramus communicans

Upper thoracic sympathetic trunk ganglia

Thoracic sympathetic cardiac and aortic nerves

Intercostal nerves

Lower thoracic sympathetic trunk ganglia

Thoracic splanchnic nerves

Upper lumbar sympathetic trunk ganglia

Fibers direct to vessels

Lower lumbar and sacral sympathetic trunk ganglia

Sympathetic fibers

Sympathetic rami to lumbar and sacral plexuses and nerves to lower limb

preganglionic postganglionic

  9.55 INNERVATION OF THE LIMBS Autonomic innervation to the limbs derives from the SNS. Preganglionic sympathetic nerve fibers from the thoracolumbar intermediolateral cell column supply sympathetic chain ganglia. These ganglia send postganglionic noradrenergic nerve fibers through the gray rami communicans into the peripheral nerves to

supply vascular smooth muscle (vasomotor fibers), sweat glands (sudomotor fibers), and arrector pili muscles associated with hair follicles (pilomotor fibers). Smooth muscle fibers of blood vessels in the viscera also are supplied with postganglionic sympathetic nerve fibers.

Peripheral Nervous System

Cervicothoracic (stellate) ganglion

217

Cervicothoracic (stellate) ganglion

Ansa subclavia Cervical cardiac nerves (sympathetic and vagal)

Right sympathetic trunk Cervical cardiac nerves (sympathetic and vagal)

Left vagus nerve (cut )

Thoracic sympathetic cardiac nerves

Left recurrent laryngeal nerve

Right vagus nerve (cut )

Thoracic cardiac nerves (sympathetic and vagal)

Thoracic vagal branches to pulmonary and cardiac plexuses

Branches to anterior and posterior pulmonary plexuses

5th intercostal nerve (anterior ramus of 5th thoracic spinal nerve) Cardiac plexus Gray and white rami communicans

Left sympathetic trunk Thoracic aorta plexus

5th thoracic sympathetic trunk ganglion Right greater thoracic splanchnic nerve

Esophageal plexus

Sympathetic branch to esophageal plexus

Left greater thoracic splanchnic nerve

Thoracic duct Left lesser thoracic splanchnic nerve

Thoracic aortic plexus

Anterior vagal trunk

Right lesser thoracic splanchnic nerve

Diaphragm (pulled down)

Right lowest thoracic splanchnic nerve Diaphragm (pulled down) Azygos vein (cut) Inferior vena cava (cut)

9.56 THORACIC SYMPATHETIC CHAIN AND SPLANCHNIC NERVES The sympathetic chain is a collection of sympathetic ganglia that receive input from the thoracolumbar preganglionic nerve fibers derived from the spinal cord. The ganglia, interconnected by nerve trunks, are located in a paravertebral array from the neck to the coccygeal region. Postganglionic noradrenergic nerve fibers from the sympathetic chain supply effector tissue in the periphery. Some preganglionic nerve fibers do not synapse as they travel through the sympathetic chain. They continue along the splanchnic nerves to synapse in collateral ganglia, which supply noradrenergic innervation to effector tissue in the viscera.

  CLINICAL POINT The sympathetic chain (paravertebral ganglia) extends from the neck to the pelvis, whereas collateral (prevertebral) ganglia are present along the great vessels and distribute to internal target organs. These ganglia are supplied by preganglionic cholinergic fibers from the T1–­L2 intermediolateral cell column (lateral horn), the chain ganglia via white rami communicans, and the collateral ganglia via splanchnic nerves. A spinal cord crush injury above the T1 level damages the central regulation of the sympathetic preganglionic neurons and the parasympathetic S2–­S4 preganglionic neurons. Initially the patient experiences a spinal shock syndrome, with hypotension (worse on standing), loss of sweating, loss of piloerection, paralysis of bladder function (neurogenic bladder), gastric dilation, and paralytic ileus. As the process of spinal cord injury resolves to a permanent state and spinal shock recedes, the autonomic equivalent of spasticity (hyperresponsiveness) may result, accompanied by spikes in blood pressure and a spastic bladder.   

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Regional Neuroscience

From hypothalamic and higher centers

Vagus nerve (X) (cholinergic; efferent to smooth muscle and glands; afferent from aorta, tracheobronchial mucosa, and alveoli) Glossopharyngeal nerve (IX)

Descending tracts in spinal cord

Superior cervical sympathetic ganglion

Superior laryngeal nerve

Sympathetic nerves (adrenergic) T1 T2 Thoracic spinal cord T3

Larynx A

Carotid sinus

C

C

Carotid body A C

Common carotid artery

Cough receptors A

T4

T5

Afferent nerves from nose and sinuses (via trigeminal [V] and glossopharyngeal [IX] nerves) may also initiate reflexes in airways

A

Arch of aorta

C A C

Sympathetic trunk A Sympathetic fibers Preganglionic Postganglionic

C

Pulmonary plexus

Cough receptors

C

Parasympathetic fibers Preganglionic Postganglionic Afferent fibers A Adrenergic terminals (norepinephrine and/or epinephrine) C Cholinergic terminals (acetylcholine)

A C

Irritant receptors

A C Stretch receptors (Hering-Breuer reflex)

 

9.57 INNERVATION OF THE TRACHEOBRONCHIAL TREE Both sympathetic (noradrenergic) and parasympathetic (cholinergic) innervation supplies smooth muscle of the tracheobronchial tree. Sympathetics derive from the sympathetic chain, and parasympathetics derive from vagal autonomic input to local intramural ganglia. Sympathetic influences result in bronchodilation and parasympathetic influences result in bronchoconstriction. Some

medications for asthma use a sympathomimetic compound; others use a parasympathetic blocker. Additional neuropeptidergic innervation, some as colocalized or independent autonomic fibers and some as primary afferent fibers, also distributes along the epithelium and among the alveoli, where they can influence innate immune reactivity and the production of inflammatory mediators.

Peripheral Nervous System Dorsal vagal nucleus

219

Solitary tract nucleus

Medulla oblongata

Superior cervical sympathetic trunk ganglion

Vagus nerves Superior cervical sympathetic cardiac nerve Superior cervical vagal cardiac branches Middle cervical sympathetic trunk ganglion Middle cervical sympathetic cardiac nerve

Inferior cervical vagal cardiac branches

Vertebral ganglion

Ascending connections

Ansa subclavia Cervicothoracic (stellate) ganglion

T1

Ventral ramus of T1 (intercostal nerve) T2 Inferior cervical sympathetic cardiac nerve T3 2nd thoracic sympathetic trunk ganglion T4 Thoracic vagal cardiac branch

White rami communicans

4th thoracic sympathetic trunk ganglion Gray ramus communicans Sympathetic fibers Preganglionic Postganglionic

Parasympathetic fibers Preganglionic Postganglionic

Afferent fibers

Afferent fibers

  9.58 INNERVATION OF THE HEART Sympathetic noradrenergic nerve fibers (derived from chain ganglia) and parasympathetic cholinergic nerve fibers (derived from cardiac intramural ganglia innervated by the vagus nerve) supply the atria, ventricles, sinoatrial node, and atrioventricular node and bundle. Sympathetic noradrenergic nerve fibers also distribute along the great vessels and the coronary arteries. Sympathetic fibers increase the force and rate of cardiac contraction, increase cardiac output, and dilate the coronary arteries. Parasympathetic fibers decrease the force and rate of cardiac contraction and decrease cardiac output. CLINICAL POINT Both sympathetic noradrenergic and parasympathetic cholinergic vagal postganglionic fibers innervate the heart. Cardiovascular autonomic

Thoracic sympathetic cardiac nerves Cardiac plexus

neuropathies sometimes occur in diabetes and other disorders. Vagal nerve damage can result in sustained tachycardia; excessive vagal activity can provoke bradycardia, atrial fibrillation or flutter, ventricular fibrillation, or paroxysmal tachycardia. Loss of sympathetic innervation of the heart results in severe exercise intolerance, painless myocardial ischemia, cardiomyopathy, and possibly sudden death. In studies of cardiac failure, the increased reflex drive on sympathetic cardiac nerves in an attempt to increase cardiac output results in accelerated release of norepinephrine, which produces highly toxic oxidative metabolites (free radicals) that are taken up by the noradrenergic nerve endings (through the high-­affinity uptake carriers) and produce a dying-­back sympathetic neuropathy, leaving the heart further denervated. In experimental models in dogs, either a norepinephrine-­specific uptake inhibitor (desmethylimipramine) or potent antioxidants (vitamins C and E) can prevent this free radical autodestructive process.   

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Regional Neuroscience

Right sympathetic trunk Thoracic duct

Anterior and posterior vagal trunks

Right greater and lesser thoracic splanchnic nerves

Celiac plexus and ganglia

Right phrenic nerve

Left greater and lesser thoracic splanchnic nerves

Right inferior phrenic artery and plexus

Superior mesenteric ganglion

Right greater and lesser thoracic splanchnic nerves

Left aorticorenal ganglion

Right adrenal plexus

Left lowest thoracic splanchnic nerve

Right aorticorenal ganglion

Left sympathetic trunk Right lowest thoracic splanchnic nerve

Intermesenteric (abdominal aortic) plexus

Right renal artery and plexus

Inferior mesenteric ganglion Inferior mesenteric artery and plexus

Right sympathetic trunk Gray and white rami communicans

Left colic artery and plexus

Cisterna chyli Left common iliac artery and plexus

3rd lumbar sympathetic trunk ganglion

Superior rectal artery and plexus

Gray ramus communicans

Superior hypogastric plexus (presacral nerve)

Lumbar splanchnic nerves Right ureter and plexus

Hypogastric nerves to right and left inferior hypogastric (pelvic) plexuses

Right testicular artery and plexus Sacral part of right sympathetic trunk

Left sacral plexus

  9.59 ABDOMINAL NERVES AND GANGLIA Abundant sympathetic nerves are present in the abdomen and pelvis and are associated with innervation of the gastrointestinal and urogenital systems, associated vessels, the peritoneum, and the adrenal gland. The lumbar portion of the sympathetic chain and its branches and the splanchnic nerves and their collateral ganglia (celiac, superior and inferior mesenteric, hepatic, aorticorenal, adrenal, superior hypogastric, and others) innervate smooth muscle, glands, lymphoid tissue, and metabolic cells in the abdomen and pelvis. Most of the collateral ganglia (plexuses) also contain parasympathetic contributions from the vagus nerve and associated ganglia.

CLINICAL POINT The collateral ganglia (celiac, superior and inferior mesenteric, hepatic, aorticorenal, adrenal, superior hypogastric) and the lumbar sympathetic chain supply sympathetic innervation to the abdomen and pelvis. Parasympathetic vagal fibers and their associated intramural ganglia provide parasympathetic innervation. The importance of this innervation is illustrated by the relatively unusual disorder known as dysautonomic polyneuropathy, which is a postganglionic polyneuropathy of both sympathetic and parasympathetic nerves, most likely the result of autoimmune reactivity. The affected individual develops orthostatic hypotension, unresponsive pupillary light reflexes, paralytic ileus and constipation, bladder dysfunction, and diminished sweating, peripheral vasoconstriction, and piloerection.   

Peripheral Nervous System

Anterior view

221

Superior ganglion of vagus nerve Superior cervical sympathetic ganglion Inferior ganglion of vagus nerve

Esophagus

Pharyngeal branch of vagus nerve Vagus nerve (X)

Recurrent laryngeal nerves

Superior laryngeal nerve Cervical sympathetic trunk Middle cervical sympathetic ganglion

Right recurrent laryngeal nerve

Cervical (sympathetic and vagal) cardiac nerves Vertebral ganglion of cervical sympathetic trunk Ansa subclavia

Ansa subclavia

Branch to esophagus and recurrent nerve from stellate ganglion Cervicothoracic (stellate) ganglion 3rd intercostal nerve Gray and white rami communicans 3rd thoracic sympathetic ganglion Thoracic sympathetic trunk

Right greater splanchnic nerve

Left recurrent laryngeal nerve

Cardiac plexus Pulmonary plexuses Esophageal plexus (anterior portion) Branches to esophageal plexus from sympathetic trunk, greater splanchnic nerve and thoracic aortic plexus Left greater splanchnic nerve

Sympathetic fibers along left inferior phrenic artery

Anterior vagal trunk

Branch of posterior vagal trunk to celiac plexus

Principal anterior vagal branch to lesser curvature of stomach

Greater splanchnic nerve

Esophageal plexus (posterior portion)

Vagal branch to hepatic plexus via lesser omentum

Vagal branch to fundus and body of stomach

Posterior vagal trunk

Vagal branch to celiac plexus

Sympathetic fibers along esophageal branch of left gastric artery

Celiac plexus and ganglia

 

9.60 NERVES OF THE ESOPHAGUS The sensory stimuli that initiate swallowing derive mainly from CN IX (some also from CNs V and X) and are mediated through nucleus solitarius in the medulla. Food passes through the cricopharyngeal sphincter at the proximal esophagus; this sphincter is controlled by the vagal nerve fibers derived from the dorsal motor nucleus of CN X. Movement of food through the esophagus is regulated by vagal nerve fibers derived from the dorsal motor

Posterior view

Thoracic (vagal and sympathetic) cardiac branches

Vagal branch to fundus and cardiac part of stomach

Posterior vagal branch to lesser curvature

nucleus of CN X, which synapse on neurons within the myenteric plexus of the esophagus. This plexus directly controls peristalsis through the esophagus by alternately relaxing and then contracting the muscles of the esophagus. Food then moves into the stomach through the lower esophageal sphincter, which relaxes when nitric oxide and VIP are released from some neurons of the myenteric plexus.

222

Regional Neuroscience

Left 7th thoracic sympathetic trunk ganglion

Right 6th thoracic sympathetic trunk ganglion

Esophageal plexus

7th intercostal nerve

Aortic plexus

White and gray rami communicans

Left greater thoracic splanchnic nerve

Spinal ganglion and ventral root of 8th thoracic spinal nerve

Posterior vagal trunk and celiac branch

Right greater and lesser thoracic splanchnic nerves

Anterior vagal trunk and celiac branch

Left gastric artery Celiac ganglia and plexus

Splenic artery Short gastric arteries

Celiac trunk

Right lowest thoracic splanchnic nerve Common hepatic artery Right gastric artery Superior mesenteric ganglion Aorticorenal ganglia Left gastroepiploic artery

Renal artery

Gastroduodenal artery Right gastroepiploic artery Superior mesenteric artery Inferior pancreaticoduodenal artery

Sympathetic fibers

Parasympathetic fibers

Preganglionic

Preganglionic

Postganglionic

Postganglionic

Afferent fibers

  9.61 INNERVATION OF THE STOMACH AND PROXIMAL DUODENUM The stomach and proximal duodenum receive abundant sympathetic innervation from the celiac and superior mesenteric ganglia and, to a lesser extent, from the thoracic sympathetic trunk ganglia. The celiac and superior mesenteric ganglia receive their preganglionic input from the greater and lesser thoracic splanchnic nerves. Parasympathetic fibers distribute to the stomach and proximal duodenum from the celiac branches of the vagus nerve. Sympathetic fibers decrease peristalsis and secretomotor activities. Parasympathetic fibers increase peristalsis and secretomotor

activity (such as gastrin and hydrochloric acid) and relax associated sphincters. CLINICAL POINT Diabetic neuropathy may be accompanied by delayed gastric emptying. The patient may experience nausea and vomiting, premature satiety, and large fluctuations in blood glucose. Weight loss may be noted. Approaches for treatment include parasympathetic agonists that stimulate gastric emptying and dopamine antagonists that remove the dopaminergic inhibition of gastric emptying. Delayed gastric emptying may also be accompanied by dysfunction of esophageal motility, resulting in dysphagia.   

Peripheral Nervous System Right and left inferior phrenic arteries and plexuses Anterior and posterior layers of lesser omentum

223

Hepatic branch of anterior vagal trunk Anterior vagal trunk Celiac branch of posterior vagal trunk

Branch from hepatic plexus to cardia via lesser omentum

Celiac branch of anterior vagal trunk Left gastric artery and plexus

Right greater thoracic splanchnic nerve

Vagal branch from hepatic plexus to pyloric part of stomach Hepatic plexus Right gastric artery and plexus

Anterior gastric branch of anterior vagal trunk Left greater splanchnic nerve Left lesser splanchnic nerve Splenic artery and plexus Celiac ganglia and plexus Plexus on gastro-omental (gastroepiploic) arteries Superior mesenteric artery and plexus Plexus on inferior pancreaticoduodenal artery Plexus on first jejunal artery Plexus on anterior superior and anterior inferior pancreaticoduodenal arteries (posterior pancreaticoduodenal arteries and plexuses not visible in this view)

  9.62 NERVES OF THE STOMACH AND DUODENUM Parasympathetic and sympathetic nerve fibers distribute to the stomach and proximal duodenum through specific splanchnic nerves and branches of the vagus nerve. Sympathetic fibers decrease peristalsis and secretomotor activities. Parasympathetic fibers increase peristalsis and secretomotor activity (such as gastrin and hydrochloric acid) and relax associated sphincters. CLINICAL POINT Obesity may occur for a variety of reasons. The stomach expands, neural satiety signals do not provide effective feedback to the brain, and compulsive eating can overcome normal appetitive control mechanisms. In situations in which diet and exercise are ineffective for weight control and when diabetes and other serious comorbidities are life-­threatening for a morbidly obese individual, bariatric surgery is an option. The Roux-­en-­Y gastric bypass procedure takes the distal

90% of the stomach, the duodenum, and approximately 20 cm of the proximal jejunum off-­line; the digestive tract then consists of the esophagus and a very small proximal stomach pouch that is connected with the remaining jejunum (the off-­line jejunum is anastomosed farther downstream). This procedure markedly reduces the stomach’s capacity, slows gastric emptying, and produces deliberate partial malabsorption. Long-­term data indicate extensive and permanent weight loss in many subjects (more than 70% of needed weight loss) and common reversal of diabetes, hypertension, sleep apnea, and many of the comorbid conditions that accompany morbid obesity. In addition, a striking alteration in the secretion of a variety of gastrointestinal hormones, inflammatory mediators, and other mediators has been noted. Autonomic and somatic neural signals are altered, central setpoints related to appetitive behavior are reset, and changes in morbidity and mortality rates have been observed. The Roux-­en-­Y procedure is not without risks and complications, and chronic supplementation of nutrients such as calcium, iron, and B vitamins is required. Underlying psychopathology may lead to circumvention of the effectiveness of the procedure.   

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Medulla oblongata

Thalamus

Sympathetic efferents Parasympathetic efferents Somatic efferents Afferents (and CNS connections) Indefinite paths

Hypothalamus (red—sympathetic, blue—parasympathetic) Dorsal nucleus of vagus Dorsal root ganglion T9

Vagus nerve (X) Sympathetic trunk Gray ramus communicans White ramus communicans

Celiac ganglia

Greater thoracic splanchnic nerve Aorticorenal ganglion Lesser thoracic splanchnic nerve

Celiac trunk Superior mesenteric ganglion

T10

Thoracolumbar cord

T11 T12

T12 to L1 Least thoracic splanchnic nerve

Superior mesenteric artery Intermesenteric nerves Inferior mesenteric ganglion

L1

L1 and L2

L2 L3 L4

Lumbar splanchnic nerves

Inferior mesenteric artery Superior hypogastric plexus

L5 Hypogastric nerves S1 Sacral cord

T9 to T10

S2 S3

Sacral (sympathetic) splanchnic nerves

T10 to T12 T10 to T12

Superior rectal artery Inferior hypogastric (pelvic) plexus

S4

Inferior rectal nerve

Pelvic splanchnic nerves (nervi erigentes) Pudendal nerve

9.63 INNERVATION OF THE SMALL AND LARGE INTESTINES Autonomic innervation of the small and large intestines is ­supplied by extrinsic sympathetic and parasympathetic fibers. Sympathetic innervation derives from the T5–­L2 intermediolateral cell column of the spinal cord and distributes to collateral ganglia (superior and inferior mesenteric, celiac). Parasympathetic innervation derives from the vagus nerve and from the S2–­S4 intermediate gray of the spinal cord; it distributes to intramural ganglia and plexuses via CN X and pelvis splanchnic nerves. Sympathetic

L1 and L2

 

nerve fibers generally decrease peristalsis and secretomotor functions (i.e., decreased fluid secretion). Parasympathetic nerve fibers generally increase peristalsis, relax involuntary sphincters, and increase secretomotor activities. The extrinsic innervation of the intestines is integrated with the intrinsic (enteric) innervation. Autonomic gastrointestinal neuropathies such as those seen in diabetes most commonly result in constipation, requiring treatment with pharmacological agents and high-­fiber agents. However, diabetic diarrhea also is common and may require treatment to slow secretomotor function.

Peripheral Nervous System

Recurrent branch of left inferior phrenic artery and plexus to esophagus Anterior vagal trunk Posterior vagal trunk Hepatic branch of anterior vagal trunk (courses in lesser omentum, removed here) Celiac branches of anterior and posterior vagal trunks Inferior phrenic arteries and plexuses Left gastric artery and plexus Hepatic plexus Greater splanchnic nerves Right gastric artery and plexus (cut) Celiac ganglia and plexus Gastroduodenal artery and plexus Lesser splanchnic nerves Least splanchnic nerves Aorticorenal ganglia Superior mesenteric ganglion Intermesenteric (aortic) plexus Inferior pancreaticoduodenal arteries and plexuses Superior mesenteric artery and plexus Middle colic artery and plexus (cut) Right colic artery and plexus Ileocolic artery and plexus Superior mesenteric artery and plexus Peritoneum (cut edge) Mesenteric branches Mesoappendix (contains appendicular artery and nerve plexus)

 

9.64 NERVES OF THE SMALL INTESTINE This figure shows the anatomy of the extrinsic innervation of the small intestine by the splanchnic and vagal nerves and their associated plexuses.

225

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Regional Neuroscience

Anterior vagal trunk and hepatic branch Posterior vagal trunk

Marginal artery and plexus Esophagus Left inferior phrenic artery and plexus

Celiac branches of anterior and posterior vagal trunks

Left gastric artery and plexus

Right inferior phrenic artery and plexus

Left greater splanchnic nerve

Right greater splanchnic nerve Celiac ganglia and plexus

Left suprarenal plexus

Right lesser and least splanchnic nerves

Left lesser and least splanchnic nerves

Right aorticorenal ganglion

Left aorticorenal ganglion

Superior mesenteric ganglion

Left renal artery and plexus Middle colic artery and plexus

1st left lumbar splanchnic nerve

Inferior pancreaticoduodenal arteries and plexuses

Left lumbar sympathetic trunk Intermesenteric (aortic) plexus

Right colic artery and plexus

Left colic artery and plexus

Ileocolic artery and plexus

Inferior mesenteric ganglion, artery, and plexus

Cecal and appendicular arteries and plexuses

Sigmoid arteries and plexuses

Right internal iliac artery and plexus (cut)

Superior hypogastric plexus

Sacral sympathetic trunk

Superior rectal artery and plexus

Right sacral plexus Pelvic splanchnic nerves

Right and left hypogastric nerves

Middle rectal artery and plexus Right inferior hypogastric (pelvic) plexus Vesical plexus Rectal plexus Urinary bladder

 

9.65 NERVES OF THE LARGE INTESTINE This figure shows the anatomy of the extrinsic innervation of the large intestine by the splanchnic and vagal nerves and their associated plexuses.

Rectosigmoid artery and plexus Nerves from inferior hypogastric (pelvic) plexuses to sigmoid colon, descending colon, and left colic (splenic) flexure

Peripheral Nervous System

Subserous plexus

Longitudinal intramuscular plexus

227

Myenteric plexus lying on longitudinal muscular layer. Fine secondary bundles crossing meshes (duodenum of guinea pig, Champy-Coujard, osmic stain,  20)

Myenteric (Auerbach’s) plexus

Circular intramuscular plexus

Submucosal (Meissner’s) plexus

Group of multipolar neurons, type II, in ganglion of myenteric plexus (ileum of cat, Bielschowsky, silver stain,  200)

Periglandular plexus

Lumen

Submucous plexus (ascending colon of guinea pig, stained by Golgi impregnation,  20)

Mucosa and mucosal glands Muscularis mucosae Glands Submucosa Circular muscle layer Intermuscular stroma Longitudinal muscle Subserous connective tissue

  9.66 ENTERIC NERVOUS SYSTEM: LONGITUDINAL VIEW The enteric nervous system is made up of approximately 100 million neurons arranged principally in submucosal (Meissner’s) and myenteric (Auerbach’s) plexuses; it provides intrinsic innervation to the small and large intestines. Neurons of this system interconnect with one another and with neuronal processes of the autonomic nervous system, although most neuronal components of this network are free of autonomic influence. The enteric plexuses regulate peristaltic responses (which can proceed without extrinsic innervation), pacemaker activity, and other automated secretory processes. The myenteric plexus controls primarily motility;

Visceral peritoneum

the submucosal plexus controls primarily fluid secretion and absorption. More than 20 distinct neurotransmitters have been identified in enteric neurons (e.g., ACh, substance P, serotonin, VIP, somatostatin, nitric oxide). ACh and substance P are excitatory to smooth muscle, whereas VIP and nitric oxide are inhibitory. Extrinsic autonomic innervation helps to coordinate these enteric plexuses and circuits; optimal functioning of the gastrointestinal tract requires coordinated interactions among endocrine, paracrine, and neurocrine mediators. Disturbance of extrinsic innervation by a neuropathy can result in disorders of motility such as constipation or diarrhea.

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Regional Neuroscience Vagus nerves Preganglionic sympathetic Postganglionic sympathetic Preganglionic parasympathetic Postganglionic parasympathetic Intrinsic enteric neurons Afferents

Sympathetic chain T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2

S2 S3 S4

Vagus nerves

Splanchnic nerves

Celiac or superior mesenteric ganglia

Celiac ganglion

Mesenteric nerves following blood vessels Superior mesenteric ganglion Inferior mesenteric ganglion

Mesentery

Pelvic nerves Serosa Longitudinal muscle Myenteric plexus Circular muscle Submucous plexus

Postganglionic sympathetic NA nerve fibers in the myenteric plexus of the jejunum. GA fluorescence histochemistry counterstained with ethidium bromide to reveal the architecture of this area.

Muscularis mucosae Mucosa

  9.67 ENTERIC NERVOUS SYSTEM: CROSS-­ SECTIONAL VIEW In the myenteric and the submucosal plexuses, some neurons are innervated by sympathetic nerve fibers from the sympathetic chain and collateral ganglia and by vagal or pelvic splanchnic parasympathetic nerve fibers; other neurons are independent of autonomic regulation. Autonomic postganglionic nerve fibers and intrinsic neuropeptidergic nerve fibers also supply macrophages, T lymphocytes, plasma cells, and other cells of the immune system with innervation. This provides a regulatory network that modulates the host defenses of the gastrointestinal tract and the immune reactivity of gut-associated lymphoid tissue.

CLINICAL POINT The intrinsic neuronal clusters that form the enteric nervous system derive from the neural crest. If these neural crest derivatives fail to migrate properly into the colon, as occurs in a developmental abnormality called Hirschsprung’s disease (chronic megacolon), the intrinsic circuitry for peristalsis, pacemaker activity, and other gut functions cannot occur. The vagus nerve and sympathetic innervation from the pelvic splanchnic nerves cannot coordinate the activity of the colon in the absence of its enteric components. Therefore, megacolon (intestinal obstruction) results from absent peristalsis and loss of smooth muscle tone of the colon. Distention and hypertrophy of the colon may ensue.   

Peripheral Nervous System

229

T7

Sympathetic fibers Preganglionic Postganglionic

Dorsal root ganglion

T8

Parasympathetic fibers Preganglionic Postganglionic

T9

Afferent fibers T10

Left greater thoracic splanchnic nerve

Right greater thoracic splanchnic nerve Posterior vagal trunk Right phrenic nerve

Anterior vagal trunk

Common areas of referred pain in biliary diseases

Diaphragm Phrenic ganglion Anterior vagal trunk Celiac ganglia

Splenic artery

Anterior hepatic plexus Posterior hepatic plexus

Hepatic triad Portal vein branch Bile duct Hepatic artery branch

Aorta Common hepatic artery Gastroduodenal artery and plexus

Sphincter ampullae

  9.68 AUTONOMIC INNERVATION OF THE LIVER AND BILIARY TRACT Sympathetic nerve fibers to the liver derive from T7–­T10 of the spinal cord and distribute mainly via the celiac ganglion and its associated plexus. Parasympathetic nerve fibers to the liver derive from the abdominal vagus nerve. Postganglionic noradrenergic sympathetic nerve fibers end directly adjacent to hepatocytes; norepinephrine released from these nerve fibers initiates glycogenolysis and hyperglycemia for fight-­or-­flight responses and induces gluconeogenesis. Autonomic innervation helps to regulate vascular, secretory, and phagocytic processes in the liver. The gallbladder, especially the sphincter ampullae and the sphincter of the choledochal duct, is also supplied by autonomic nerve fibers. The sympathetic nerve fibers cause contraction of the sphincters and dilation of the gallbladder; the parasympathetic

nerve fibers cause opening of the sphincters and contraction of the gallbladder. CLINICAL POINT Postganglionic sympathetic noradrenergic nerves to the liver can trigger glycogenolysis and gluconeogenesis, providing glucose as fuel for sympathetic arousal. Chronic activation of the SNS, with increased secretion of norepinephrine, can drive glucose levels, provoke insulin secretion, increase free radical formation, increase platelet aggregation, and initiate other actions that are beneficial in an emergency but problematic when present chronically. These connections may be one route by which chronic stressors intersect with metabolic syndrome, diminish antiviral and antitumor immunity, and increase the risk for a variety of chronic diseases, including hypertension, cardiovascular disease and stroke, some cancers, and type II diabetes. Autonomic neuropathy to the gallbladder can result in atonic smooth muscle responses, with the development of gallstones (especially in individuals with hypercholesterolemia) and diarrhea.   

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T5 T6

Right sympathetic trunk

Spinal sensory (dorsal root) ganglion Left sympathetic trunk Thoracic part of spinal cord

T7

Right greater thoracic splanchnic nerve

T8

Posterior vagal trunk

Left greater splanchnic nerve Anterior vagal trunk

T9

Common areas of pancreatic pain

Celiac ganglia Splenic artery

Celiac trunk

Superior mesenteric ganglion Superior mesenteric artery and plexus

Sympathetic fibers Presynaptic Postsynaptic

Schema of intrinsic nerve supply

Parasympathetic fibers Presynaptic Postsynaptic Afferent fibers

  9.69 AUTONOMIC INNERVATION OF THE PANCREAS Secretion by the pancreas is under both neural and endocrine control. Pancreatic exocrine glands and endocrine cells (islets of Langerhans) are innervated by parasympathetic subdiaphragmatic vagal nerve fibers via intramural ganglia and by sympathetic nerve fibers derived from T5–­T9 intermediolateral spinal cord gray via the celiac ganglion. Although only a small anatomical component of the pancreas (1%), the endocrine pancreas secretes several vital endocrine products, including glucagon (a fuel-­mobilizing hormone), insulin (a fuel-­storing hormone), somatostatin (a suppressor of glucagons and insulin secretion),

and pancreatic polypeptide (an inhibitor of the secretion of enzymes and HCO3−­, the bicarbonate ion, by the exocrine pancreas). ACh supplied by the parasympathetic fibers stimulates insulin secretion by islet cells, and norepinephrine secretion by the sympathetic fibers (as well as epinephrine by the adrenal medulla) inhibits insulin secretion from the islet cells. ACh stimulates a variety of hormones. Secretin acts on ductal cells of the pancreas to stimulate secretion of fluid with a high HCO3−­ content. Cholecystokinin is secreted by I cells in response to fats in the duodenum and upper jejunum and acts on acinar cells to stimulate the secretion of enzymes.

231

Peripheral Nervous System

Intermediolateral cell column (lateral horn of gray matter) T10

Medulla

Cortex

Abdominopelvic splanchnic nerves (presynaptic fibers)

T11

Celiac, aorticorenal and renal ganglia T12

Postganglionic fibers supply blood vessels

L1

Spinal cord

Sympathetic trunk

Preganglionic cholinergic nerve fibers ramify around cells of the medulla Norepinephrine (20%) and epinephrine (80%) secreted into the general circulation

Suprarenal gland (adrenal gland)

 

9.70 SCHEMATIC OF INNERVATION OF THE ADRENAL GLAND Sympathetic preganglionic nerve fibers from neurons in the T10–­ L1 intermediolateral cell column pass through the sympathetic

chain, travel in splanchnic nerves, and directly innervate adrenal medullary chromaffin cells. These chromaffin cells are of neural crest origin and function as sympathetic ganglion cells.

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Regional Neuroscience

Preaortic ganglia

CH2–CH–COOH NH2

es

nic

ch

Sympathetic trunk

n pla

rv ne

OH

S

Adrenal medulla

OH CH–CH2–NH

Adrenal cortex

T10 T11 T12 L1

OH

CH3 OH

Epinephrine

OH

Con stim version by c ulated ortis ol

OH

++++

Nor

+ +

epin

++++ ++

Cortisol

eph

Epin

eph

rine

rine

CH3O

CH3 OH OH O CH–C–OH

CH3O

OH OH CH–CH2–NH2

CH3O

OH

OH

Dopamine

OH CH–CH2–NH2 OH

Norepinephrine

++++ +

OH CH–CH2–NH

CH2–CH2–NH2

+++

+

Blood pressure Increased elevation cardiac output

Tyrosine

++++

Glucose

BMR elevation

Bronchial dilation; intestinal inhibition

Epinephrine 20 µg/24 h Metanephrine 400 µg/24 h

Kidney

++++

Glycogen Glycogenolysis; hyperglycemia CNS excitability +++

Neutrophilia Eosinopenia

Vanillylmandelic acid 6 mg/24 h

Lipolysis

++

Normetanephrine 900 µg/24 h Norepinephrine 80 µg/24 h

+++

+++

  9.71 INNERVATION OF THE ADRENAL GLAND The adrenal medullary chromaffin cells act as modified sympathetic ganglion cells, which are innervated by preganglionic sympathetic nerve fibers from T10 to L1 intermediolateral cells of the spinal cord. An adrenal portal system conveys blood directly from the adrenal cortex to the adrenal medulla. Cortisol, derived from action of the hypothalamopituitary-­adrenal axis, bathes the chromaffin cells in very high concentrations, inducing the enzyme phenylethanolamine-­N-­methyl-­transferase, which is responsible for the synthesis of epinephrine. Approximately 70% to 80% of the adrenal medullary output of catecholamines is epinephrine;

the remaining output is norepinephrine. Both epinephrine and norepinephrine can be taken up into sympathetic postganglionic noradrenergic nerve terminals at any site throughout the body by the high-­affinity uptake carrier and can be subsequently released. A sympathetic arousal response that generates the secretion of epinephrine from the adrenal medulla will therefore provide altered catecholamine content (higher epinephrine) because of high-­affinity uptake in nerve terminals throughout the body; subsequent release of this epinephrine modifies the usual sympathetic balance of alpha versus beta receptor stimulation on target organs for a brief period.

Peripheral Nervous System

233

2nd lumbar sympathetic trunk ganglion Intermesenteric (abdominal aortic) plexus Gray and white rami communicans

Inferior mesenteric ganglion

L2

Lumbar splanchnic nerves Right sympathetic trunk and its 3rd lumbar ganglion L3

Inferior mesenteric artery and plexus

Gray rami communicans Superior hypogastric plexus (presacral nerve) L4

Superior rectal artery and plexus

Right and left hypogastric nerves

Nerves from inferior hypogastric plexuses to sigmoid and descending colon

1st sacral sympathetic trunk ganglion

Right ureter and ureteral plexus

Gray rami communicans L5

Seminal vesicle Sacral part of sympathetic trunk

Ductus deferens

S1

Sacral plexus

S2 S3 S4 S5 Vesical plexus

Pelvic splanchnic nerves (sacral parasympathetic outflow)

Inferior rectal plexus Prostatic plexus

Pudendal nerve

Cavernous plexus Dorsal nerve of penis

Right inferior hypogastric (pelvic) plexus

  9.72 AUTONOMIC PELVIC NERVES AND GANGLIA Sympathetic nerve fibers supply the pelvis through the sympathetic trunk ganglia and the superior hypogastric plexus. These fibers travel along visceral and vascular nerves to the colon, ureters, and great vessels, such as the inferior mesenteric and common iliac vessels. Parasympathetic nerve fibers arise from the S2–­S4 intermediate gray of the spinal cord and travel via the pelvic splanchnic nerves to distribute with the branches of the inferior hypogastric plexus. The parasympathetic ganglia are intramural, in or adjacent to the wall of the organ innervated.

CLINICAL POINT The pelvic nerves and ganglia contain both sympathetic and parasympathetic components. The sympathetic trunk ganglia and superior hypogastric plexus distribute sympathetic nerve fibers to pelvic viscera, and S2–­S4 intermediate gray neurons send pelvic splanchnic nerves via the inferior hypogastric plexuses to end in intramural ganglia that supply the pelvic viscera. Of particular functional importance is the autonomic distribution to the bladder and reproductive organs. Lesions in these pelvic autonomic nerves can occur with diabetes, demyelinating diseases, and mass lesions. Damage to pelvic parasympathetic nerves can produce a flaccid bladder with overflow incontinence and can cause erectile impotence in males. It should be noted that both parasympathetic and sympathetic autonomic nerves play roles in sexual function. Parasympathetic nerves are essential for proper erectile function, and sympathetic nerves play a role in ejaculation and may also contribute to erectile function; beta-­adrenergic blockers sometimes have the side effect of erectile dysfunction.   

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Regional Neuroscience

Anterior vagal trunk Posterior vagal trunk Greater splanchnic nerve Celiac ganglia and plexus Lesser splanchnic nerve Superior mesenteric ganglion Least splanchnic nerve Aorticorenal ganglion Renal plexus and ganglion 2nd lumbar splanchnic nerve Renal and upper ureteric branches from intermesenteric plexus Intermesenteric (aortic) plexus Testicular (ovarian) artery and plexus Inferior mesenteric ganglion Sympathetic trunk and ganglion Middle ureteric branch Superior hypogastric plexus Sacral splanchnic nerves (branches from upper sacral sympathetic ganglia to hypogastric plexus) Gray ramus communicans Hypogastric nerves Sacral plexus Pudendal nerve Pelvic splanchnic nerves Inferior hypogastric (pelvic) plexus with periureteric loops and branches to lower ureter Rectal plexus Vesical plexus Prostatic plexus

 

9.73 NERVES OF THE KIDNEYS, URETERS, AND URINARY BLADDER This schematic demonstrates the nerves that distribute to the kidneys, ureters, and urinary bladder.

Peripheral Nervous System

Solitary tract nucleus

Sympathetic fibers Preganglionic Postganglionic

Dorsal vagal nucleus Medulla oblongata

Parasympathetic fibers Preganglionic Postganglionic Afferent fibers

235

Vagus (X) nerve Spinal ganglion

Gray ramus communicans

Descending fibers Ascending fibers T10

White ramus communicans

Spinal cord (T10 to L1) T11

Ventral ramus of T11 (intercostal nerve)

T12 Lesser thoracic splanchnic nerve

Sympathetic trunk ganglia L1

Lowest thoracic splanchnic nerve Celiac plexus

1st lumbar splanchnic nerve

Aorticorenal ganglion Renal ganglion

Renal artery and plexus

Intermesenteric plexus

Superior hypogastric plexus (presacral nerve)

Hypogastric nerve Sacral plexus

S2 S3

Pelvic splanchnic nerves

Inferior hypogastric (pelvic) plexus

S4

  9.74 INNERVATION OF THE KIDNEYS AND UPPER URETER Sympathetic innervation of the kidneys and upper ureter arises from the T10–­L1 intermediolateral cell column preganglionic neurons in the spinal cord and travels through lower thoracic and upper lumbar splanchnic nerves to synapse in the celiac or aorticorenal ganglia. Noradrenergic postganglionic fibers travel in fascicles that accompany the upper ureteric, renal, pelvic, calyceal, and segmental branches of the renal vessels. Parasympathetic nerve fibers are distributed to renal ganglia by the vagus nerve

and pelvic splanchnic nerves via a longer course through other plexuses. The sympathetic nerve fibers stimulate renin secretion (and the renin-angiotensin-­aldosterone system), decrease the glomerular filtration rate, stimulate proximal tubule and collecting duct sodium chloride reabsorption (further elevating blood pressure), and stimulate contraction of the ureters. Parasympathetic nerve fibers cause relaxation of smooth muscle in the pelvis, the calyces, and the upper ureter and, when accompanied by decreased sympathetic activation, may lead to a decrease in blood pressure.

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Regional Neuroscience

Ascending fibers

Descending fibers

Spinal ganglion

Sympathetic fibers Preganglionic Postganglionic

Ventral root Gray ramus communicans

Renal ganglion

Parasympathetic fibers Preganglionic Postganglionic

Aorticorenal ganglion

L1

Somatic motor fibers Renal artery and plexus

L2

Lumbar part of spinal cord

Celiac ganglion

Afferent fibers

2nd lumbar spinal nerve White ramus communicans

Sympathetic trunk

1st and 2nd lumbar splanchnic nerves

Intermesenteric plexus Inferior mesenteric ganglion

Ureter Superior hypogastric plexus (presacral nerve)

Ascending fibers

Descending fibers

Hypogastric nerves

Gray rami communicans

Inferior hypogastric (pelvic) plexus

S2

Urinary bladder

Sacral splanchnic nerves

S3

Vesical plexus

S4

Sacral part of spinal cord

Prostatic plexus

Sacral plexus

Pelvic splanchnic nerves Pudendal nerve

  9.75 INNERVATION OF THE URINARY BLADDER AND LOWER URETER The sympathetic innervation of the bladder and lower ureter derives mainly from the L1–­L2 preganglionic neurons in the spinal cord and travels through sacral splanchnic nerves to the hypogastric plexus. Parasympathetic innervation derives from the S2–­S4 intermediate gray of the spinal cord and distributes to intramural ganglia in the wall of the bladder via pelvic splanchnic nerves. Sympathetic nerve fibers relax the detrusor muscle and contract the trigone and the internal sphincter. Parasympathetic nerve fibers contract the detrusor muscle and relax the trigone and the internal sphincter, thus stimulating emptying of the

Sphincter urethrae in deep perineal space between layers of urogenital diaphragm

Bulbospongiosus muscle

bladder. Sensory nerves also are present in the bladder; when the bladder is stretched because it is full, these nerves can initiate the sensation of the need to empty the bladder. CLINICAL POINT Parasympathetic nerve damage, particularly in diabetic neuropathy, results in initial problems of incomplete emptying of the bladder, dribbling, and urinary stasis sufficient to increase the likelihood of infection. Later in the course of parasympathetic damage, a flaccid bladder with incomplete emptying and incontinence can occur. Sensory neuropathy also can result in an enlarged bladder caused by incomplete emptying because of the inability of the patient to sense fullness and by the decreased sense of urgency for urination.   

Peripheral Nervous System Sympathetic trunk and ganglia Greater splanchnic nerve (T5–9) T10 Gray ramus communicans

237

Celiac ganglia

Superior mesenteric ganglion

T11 White ramus communicans

Left aorticorenal ganglion

T12 Lesser splanchnic nerve Least splanchnic nerve

Renal ganglion

L1 Upper lumbar splanchnic nerves L2

Intermesenteric (aortic) plexus

L3

Inferior mesenteric ganglion

Gray ramus communicans Testicular artery and plexus

L4

Superior hypogastric plexus

Testicular artery and plexus

Hypogastric nerves

Ductus deferens and plexus Inferior extent of peritoneum Pelvic splanchnic nerves

Sacral plexus

S1

Ductus deferens and plexus

S1

S2 S2 S3 S4

S3

S5

S5

Pelvic splanchnic nerves Sacral plexus

S4

Pudendal nerve

Pudendal nerve Inferior hypogastric (pelvic) plexus

Posterior nerves Sympathetic Presynaptic of penis fibers Postsynaptic Epididymis Parasympathetic Presynaptic fibers Postsynaptic Testis Afferent fibers

Vesical plexus Prostatic plexus (Greater and lesser) cavernous nerves of penis

  9.76 INNERVATION OF THE MALE REPRODUCTIVE ORGANS Sympathetic innervation to the male reproductive organs derives from T10–­L2 intermediolateral cell column neurons and reaches the hypogastric plexus via thoracic and upper lumbar splanchnic nerves. Parasympathetic innervation derives from the S2–­S4 intermediate gray of the spinal cord and travels to the inferior hypogastric plexus via pelvic splanchnic nerves. Sympathetic nerve fibers cause contraction of the vas deferens and prostatic capsule and contract the sphincter to the bladder, which prevents retrograde ejaculation. Sympathetic nerve fibers also contribute to vascular responses in the penile corpora cavernosa that are related to erection; beta-­receptor blockade can result in erectile dysfunction. Parasympathetic nerve fibers regulate the vascular

dilation that initiates and maintains penile erection. Sympathetic and parasympathetic nerve fibers must work together to optimize sexual and reproductive function. CLINICAL POINT Parasympathetic nerve damage may lead to autonomic erectile dysfunction. Some individuals taking beta blockers might have similar responses. However, erectile function also depends extensively on psychological, perceptive, and sensory factors in addition to the need for coordinated autonomic function. Pharmacological compounds that enhance erectile function influence vascular responses through the production of nitric oxide to promote erection; these drugs may interact adversely with alpha blockers used to treat benign prostatic hypertrophy and other conditions, resulting in hypotensive responses that are potentially fatal.   

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Regional Neuroscience

Sympathetic trunk and ganglion

T5 Celiac ganglia and plexus

T6 Gray ramus communicans White ramus communicans

Aorticorenal ganglia

Greater splanchnic nerve

Superior mesenteric ganglion

Lesser splanchnic nerve Least splanchnic nerve

T11

T11

T12

Intermesenteric (aortic) plexus

Sympathetic trunk

L1

L1 Lumbar splanchnic nerves

Inferior mesenteric ganglion

L3 spinal nerve (anterior ramus) L4 Ovarian artery and plexus Uterine (fallopian) tube Uterus Note: Pain from intraperitoneal pelvic viscera (e.g., uterine contractions) goes via uterovaginal and pelvic plexuses, hypogastric nerves, superior Ovary Cervix hypogastric plexus, lower aortic plexus, lower lumbar S1 splanchnic nerves, S2 sympathetic trunk from L4 to L5 to spinal nerves T11, 12. Pain from subperitoneal pelvic S3 viscera (e.g., cervical S4 dilation and upper Vagina S5 vagina) goes via pelvic splanchnic nerves to S2, 3, 4. Afferent fibers from lower vagina and perineum go via pudendal nerves to S2, 3, 4.

L4 Superior hypogastric plexus Hypogastric nerves

S1

S2 S3

Inferior extent of peritoneum Uterovaginal and inferior hypogastric (pelvic) plexuses Pelvic splanchnic nerves Sacral plexus Sympathetic Preganglionic fibers Postganglionic

S4 S5

Parasympathetic fibers Pudendal nerve

Preganglionic Postganglionic Afferent fibers

 

9.77 INNERVATION OF THE FEMALE REPRODUCTIVE ORGANS Autonomic nerves supplying the female reproductive organs have origins similar to those supplying their male counterparts. Sympathetic nerves can stimulate contraction of the uterus, but the extent of this action is determined also by hormonal receptor responsiveness and neurotransmitter receptor expression. Sympathetic nerve fibers also supply the vaginal arteries, the vestibular

glands, and erectile tissue. Parasympathetic nerve fibers supply the muscular and mucous coats of the vagina and urethra, stimulate the erectile tissue of the vestibular bulb and corpora cavernosa of the clitoris, and supply the vestibular glands. Autonomic neuropathy affecting the nerves to female reproductive organs may result in dry, atrophic vaginal walls with very little lubrication, resulting in dyspareunia (painful intercourse).

10

SPINAL CORD

10.1 Cytoarchitecture of the Spinal Cord Gray Matter 10.2 Spinal Cord Levels: Cervical, Thoracic, Lumbar, and Sacral 10.3 Spinal Cord Levels: Cervical, Thoracic, Lumbar, and Sacral (Continued) 10.4 Spinal Cord Levels: Cervical, Thoracic, Lumbar, and Sacral (Continued) 10.5 Spinal Cord Levels: Cervical, Thoracic, Lumbar, and Sacral (Continued) 10.6 Spinal Cord Histological Cross Sections 10.7 Spinal Cord Histological Cross Sections (Continued) 10.8 Spinal Cord Imaging 10.9 Spinal Cord Syndromes 10.10 Syringomyelia 10.11 Spinal Cord Lower Motor Neuron Organization and Control 10.12 Spinal Somatic Reflex Pathways 10.13 Muscle and Joint Receptors and Muscle Spindles 10.14 The Muscle Stretch Reflex and Its Central Control via Gamma Motor Neurons

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Nuclear cell columns

Laminae of Rexed

Nucleus posterior marginalis (marginal zone) Substantia gelatinosa (lamina II) Nucleus proprius of posterior horn Nucleus dorsalis; Clarke‘s column (T1-L3) II

Lateral basal nucleus

III IV

Spinal reticular zone

V

Intermediolateral cell column; sympathetic preganglionic neurons (T1-L2)

VI X

Intermediomedial cell column; parasympathetic preganglionic neurons (S2-4)

VII IX

VIII IX

Flexors Motor neurons to limbs (cervical and lumbar enlargements of cord)

I

IX

Extensors Distal part of limb Proximal part of limb

Motor neurons to trunk and neck (C1-3 and T2-12)

10.1 CYTOARCHITECTURE OF THE SPINAL CORD GRAY MATTER The spinal cord gray matter is located centrally in the interior of the spinal cord in a butterfly pattern. The gray matter is subdivided into three horns: (1) the dorsal horn, a site of major sensory processing; (2) the intermediate gray with a lateral horn, a site where preganglionic sympathetic (thoracolumbar) and parasympathetic (sacral) neurons reside and where interneuronal processing occurs; and (3) the ventral horn, a site where lower motor neurons (LMNs) reside and where converging reflex and descending control of LMNs occurs. Neuronal cell groups appear homogeneous in some regions of gray matter, intermixed with a presence of some discrete nuclei (e.g., Clarke’s nucleus, substantia gelatinosa). Laminae of Rexed, an alternative system of cytoarchitectural classification established in the 1950s, subdivides the spinal cord gray matter into 10 laminae. This system is used extensively for the dorsal horn and the intermediate gray, laminae I–VII, particularly in conjunction with anatomical details of nociceptive processing and for some reflex and cerebellar processing. Although these laminae have distinctive characteristics at each segmental level, they show some similarities across segmental levels. The absolute amount of spinal cord gray is more extensive in the cervical and lumbosacral enlargements of the spinal cord, which correspond to zones associated with limb innervation, than it is in upper cervical, thoracic, and sacral regions.

CLINICAL POINT Classical descriptions of secondary sensory processing in the spinal cord describe neurons of lamina I (marginal zone) and lamina V of the dorsal horn as cells of origin for crossed projections into the spinothalamic/anterolateral system for the processing of pain and temperature sensation (protopathic modalities). Primary sensory large-­diameter axons, carrying information about fine discriminative touch, vibratory sensation, and joint position sense (epicritic modalities), enter through the dorsal root entry zone and travel rostrally into the dorsal column system, bypassing synapses in the spinal cord; these axons terminate in their secondary sensory nuclei, gracilis and cuneatus, in the caudal medulla. According to this scheme, pure dorsal column lesions should result in the total loss of epicritic sensation on the ipsilateral side of the body below the level of the lesion. However, such lesions result in diminution of these epicritic sensations or in the inability to discriminate vibratory sensations of different frequencies, but not in the total loss of these modalities. Only with additional damage to the dorsolateral part of the lateral funiculus is profound loss of epicritic sensation observed. This is because additional dorsal horn neurons receive primary sensory input related to epicritic sensation and send ipsilateral projections into the dorsolateral funiculus, providing additional contributions to lemniscal processing of fine discriminative modalities. In addition, some large-­diameter primary axons of the epicritic dorsal column system send collaterals into nociceptive processing zones in the spinal cord, where they can alter pain thresholds and dampen nociception. These collaterals are activated by rubbing an area of the body that has just sustained a potentially painful injury and also are a major mechanism of pain control from dorsal column stimulation.   

Spinal Cord

Second cervical level

241

Fasciculus gracilis Fasciculus cuneatus

Dorsolateral fasciculus (Lissauer's zone) Substantia gelatinosa

Dorsal spinocerebellar tract

Nucleus proprius

Rostral spinocerebellar tract Lateral corticospinal tract Rubrospinal tract

Spinal accessory nucleus

Ventral spinocerebellar tract Anterolateral system (Spinothalamic tract and spinoreticular tract)

Anterior horn

Lateral (medullary) reticulospinal tract Lateral vestibulospinal tract Medial (pontine) reticulospinal tract Anterior corticospinal tract

Anterior white commissure Medial longitudinal fasciculus (with medial vestibulospinal tract, interstitiospinal tract, and tectospinal tract)

Seventh cervical level

Descending monoamine axons (noradrenergic, serotonergic) Descending fibers from hypothalamus and brainstem to spinal cord

Fasciculus gracilis Fasciculus cuneatus

Dorsolateral fasciculus (Lissauer's zone) I

Dorsal spinocerebellar tract

Marginal zone Substantia gelatinosa

II III

Nucleus proprius

IV

Rostral spinocerebellar tract

V

Lateral corticospinal tract

VI

Rubrospinal tract

Intermediate gray

VII Ventral spinocerebellar tract Anterolateral system (Spinothalamic tract and spinoreticular tract)

IX

X Lower motor neurons in anterior horn

IX VIII

Lateral (medullary) reticulospinal tract Lateral vestibulospinal tract Medial (pontine) reticulospinal tract

Anterior white commissure Medial longitudinal fasciculus Anterior corticospinal tract

 

10.2 SPINAL CORD LEVELS: CERVICAL, THORACIC, LUMBAR, AND SACRAL The organization of the gray matter into laminae of Rexed is retained throughout the spinal cord. The dorsal and ventral horns are larger and wider at levels of the cervical and lumbosacral enlargements. The lateral horn is present from L1 to T2. Some nuclei are found only in circumscribed regions, such as the intermediolateral cell column with preganglionic sympathetic neurons (T1–­L2 lateral horn), Clarke’s nucleus (C8–­L2), and the parasympathetic preganglionic nucleus (S2–­S4).

The white matter increases in absolute amount from caudal to rostral. The dorsal columns contain only fasciculus gracilis below T6; fasciculus cuneatus is added laterally above T6. The spinothalamic/spinoreticular anterolateral system increases from caudal to rostral. The descending upper motor neuron (UMN) pathways diminish from rostral to caudal. The lateral corticospinal pathway loses more than half of its axons as they synapse in the cervical segments; this tract then diminishes in size as it extends caudally.

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Regional Neuroscience Second thoracic level

Fasciculus gracilis Fasciculus cuneatus

Dorsolateral fasciculus (Lissauer's zone)

Dorsal spinocerebellar tract Marginal zone Lateral corticospinal tract

Substantia gelatinosa Nucleus proprius

Rubrospinal tract

Nucleus dorsalis of Clarke Lateral horn

Ventral spinocerebellar tract

Intermediolateral cell column

Anterolateral system (Spinothalamic tract and spinoreticular tract)

Lower motor neurons in anterior horn

Lateral (medullary) reticulospinal tract Lateral vestibulospinal tract

Anterior white commissure Medial longitudinal fasciculus

Medial (pontine) reticulospinal tract

Anterior corticospinal tract

Eighth thoracic level

Fasciculus gracilis

Dorsolateral fasciculus (Lissauer's zone)

Dorsal spinocerebellar tract

I

Lateral corticospinal tract

II III IV

Rubrospinal tract

VI

Marginal zone Substantia gelatinosa Nucleus proprius

V

Nucleus dorsalis of Clarke

VII Ventral spinocerebellar tract Anterolateral system (Spinothalamic tract and spinoreticular tract)

Descending monoamine axons (noradrenergic, serotonergic) Descending fibers from hypothalamus and brainstem to spinal cord

Lateral horn

X

IX

Intermediolateral cell column Lower motor neurons in anterior horn

VIII

Lateral (medullary) reticulospinal tract Lateral vestibulospinal tract

Anterior white commissure Medial longitudinal fasciculus

Medial (pontine) reticulospinal tract

Anterior corticospinal tract

  10.3 SPINAL CORD LEVELS: CERVICAL, THORACIC, LUMBAR, AND SACRAL (CONTINUED) CLINICAL POINT Damage to the lateral funiculus of the cervical spinal cord caused by demyelination, trauma, ischemia, or other causes can lead to disruption of (1) the descending lateral corticospinal tract and rubrospinal tract, resulting in ipsilateral spastic (long-­term result) hemiplegia below the level of the lesion, and (2) the descending axons from the hypothalamus to the preganglionic sympathetic neurons in the intermediolateral cell column at the T1 and T2 segments of the cord. These preganglionic neurons supply the superior cervical ganglion, which provides postganglionic noradrenergic sympathetic innervation to the ipsilateral head. Disruption of these descending axons in the lateral

funiculus or at any point distal in the sympathetic pathway can result in Horner’s syndrome, which consists of ipsilateral ptosis (because of effects on the superior tarsal muscle), miosis (because of effects on the pupillary dilator muscle), and anhidrosis (less sweat gland activity). Trauma that damages one entire side of the spinal cord at the cervical level produces the same symptoms (ipsilateral spastic paralysis with brisk reflexes and ipsilateral Horner’s syndrome) and also causes (1) flaccid paralysis of ipsilateral muscles innervated by LMNs damaged by the trauma, (2) loss of epicritic sensation (fine discriminative touch, vibratory sensation, joint position sense) ipsilaterally below the level of the trauma because of damage to the dorsal column and dorsolateral funiculus axons, and (3) loss of pain and temperature sensation contralaterally below the level of the lesion because of damage to the anterolateral system (spinothalamic/spinoreticular system). This collection of neurological deficits resulting from a hemi­section lesion to the spinal cord is called a Brown-­Séquard lesion.   

Spinal Cord

First lumbar level

243

Fasciculus gracilis

Dorsolateral fasciculus (Lissauer's zone) Marginal zone Substantia gelatinosa Nucleus proprius

Dorsal spinocerebellar tract Lateral corticospinal tract

Nucleus dorsalis of Clarke

Rubrospinal tract

Lateral horn

Ventral spinocerebellar tract

Intermediolateral cell column

Anterolateral system (Spinothalamic tract and spinoreticular tract)

Lower motor neurons in anterior horn

Lateral (medullary) reticulospinal tract Lateral vestibulospinal tract Medial (pontine) reticulospinal tract

Anterior white commissure Medial longitudinal fasciculus Anterior corticospinal tract

Third lumbar level

Descending monoamine axons (noradrenergic, serotonergic) Descending fibers from hypothalamus and brainstem to spinal cord

Fasciculus gracilis

Dorsolateral fasciculus (Lissauer's zone) I Dorsal spinocerebellar tract

II

III IV

Lateral corticospinal tract

V

Rubrospinal tract

Ventral spinocerebellar tract

Marginal zone Substantia gelatinosa Nucleus proprius Nucleus dorsalis of Clarke

VI VII

IX

Anterolateral system (Spinothalamic tract and spinoreticular tract)

X VIII

IX

Lower motor neurons in anterior horn

IX

Lateral (medullary) reticulospinal tract Lateral vestibulospinal tract Medial (pontine) reticulospinal tract

Anterior white commissure Medial longitudinal fasciculus Anterior corticospinal tract

  10.4 SPINAL CORD LEVELS: CERVICAL, THORACIC, LUMBAR, AND SACRAL (CONTINUED) CLINICAL POINT The central canal of the spinal cord is ordinarily a closed remnant of former neural tube development and in the adult does not convey or produce cerebrospinal fluid. However, a developmental defect may result in the formation of a syrinx in the central canal region of the spinal cord, either alone or in the presence of an obstruction of the foramen magnum (with Arnold-­Chiari malformation). This condition, called syringomyelia, occurs mainly at a lower cervical or a

thoracic level. The distinguishing feature is destruction of the axons in the anterior white commissure, resulting in a dissociated sensory loss of pain and temperature sensation at the levels of the syrinx, with preservation of epicritic sensation (dorsal columns and the dorsolateral funiculus are usually preserved). If the syrinx extends laterally, it most likely will involve adjacent LMNs; this manifests as segmental weakness and muscle atrophy. Larger lesions may extend into the lateral funiculus and damage the descending UMN systems (the corticospinal and rubrospinal tracts), causing ipsilateral spastic paresis below the level of the lesion. Syringomyelia is sometimes accompanied by kyphoscoliosis and pain in the region of the neck and arms. The syrinx may extend to the brainstem (syringobulbia) and produce damage to lower brainstem structures.   

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First sacral level

Fasciculus gracilis

Dorsolateral fasciculus (Lissauer's zone) Marginal zone Substantia gelatinosa

Dorsal spinocerebellar tract

Nucleus proprius

Lateral corticospinal tract Rubrospinal tract

Intermediate gray

Ventral spinocerebellar tract Anterolateral system (Spinothalamic tract and spinoreticular tract)

Lower motor neurons in anterior horn

Lateral (medullary) reticulospinal tract Lateral vestibulospinal tract Medial (pontine) reticulospinal tract

Anterior white commissure Medial longitudinal fasciculus Anterior corticospinal tract

Third sacral level

Fasciculus gracilis

Descending monoamine axons (noradrenergic, serotonergic) Descending fibers from hypothalamus and brainstem to spinal cord

Dorsolateral fasciculus (Lissauer's zone) I

II

Dorsal spinocerebellar tract Lateral corticospinal tract

V

Rubrospinal tract VII Ventral spinocerebellar tract Anterolateral system (Spinothalamic tract and spinoreticular tract)

Marginal zone Substantia gelatinosa Nucleus proprius

III IV

IX

VI

Sacral parasympathetic nucleus

X

VIII IX

IX Lower motor neurons in anterior horn

Lateral (medullary) reticulospinal tract Lateral vestibulospinal tract Medial (pontine) reticulospinal tract

  10.5 SPINAL CORD LEVELS: CERVICAL, THORACIC, LUMBAR, AND SACRAL (CONTINUED) CLINICAL POINT A severe spinal cord crush injury damages local neurons and disrupts both the ascending and the descending tracts. Such a lesion at the lumbar level causes flaccid paralysis of muscles (with loss of tone and muscle stretch reflexes) at the damaged levels as the result of LMN injury and spastic paralysis of muscles (with increased tone and muscle stretch reflexes, possible clonus, and extensor plantar responses) in muscles supplied by LMNs below the level of the lesion as the result of damage to the UMN axons in the lateral funiculus. All

Anterior white commissure Medial longitudinal fasciculus Anterior corticospinal tract

sensation is lost below the level of the lesion because of disruption of both dorsal column and anterolateral axons, although some protopathic sensation may remain present, even in the case of a very extensive lesion. A severe crush injury also damages descending axons in both lateral funiculi that help to regulate bowel function, bladder function, and sexual function. The patient initially shows spinal shock syndrome, with unresponsive bowel and bladder; after recovery from spinal shock, a spastic bladder (small, stimulated to empty by reflex, with incontinence) occurs. In addition, voluntary control over erectile function in males is lost, but reflex erection caused by specific sensory stimuli may occur. Severe crush injury at higher levels (cervical) also can disrupt descending axons that regulate sympathetic outflow, resulting in dysregulated blood pressure, Horner’s syndrome, and other autonomic symptoms.   

Spinal Cord

Dorsal Dorsal root root entry zone

Posterior spinal artery

245

Fasciculus Fasciculus gracilis cuneatus

Lissauer’s zone (dorsolateral fasciculus) Marginal zone

Lateral corticospinal tract

Substantia gelatinosa

Dorsal spinocerebellar tract

Nucleus proprius

Rubrospinal tract

Intermediate gray

Spinothalamic/spinoreticular tracts

Anterior horn with lower motor neurons

Ventral spinocerebellar tract

Anterior (ventral) root

Anterior Anterior Anterior Anterior Reticulospinal/ median spinal corticospinal white vestibulospinal fissure artery tract commissure tract zone Dorsal root

Fasciculus gracilis

Lissauer’s zone Marginal zone

Dorsal spinocerebellar tract

Substantia gelatinosa

Lateral corticospinal tract

Nucleus proprius

Rubrospinal tract

Lateral horn with intermediolateral cell column

Spinothalamic/spinoreticular tracts

Nucleus dorsalis of Clarke

Ventral spinocerebellar tract

Anterior (ventral) horn with lower motor neurons

Anterior Reticulospinal/ Anterior white corticospinal vestibulospinal commissure tract tracts

  10.6 SPINAL CORD HISTOLOGICAL CROSS SECTIONS Cross sections through the spinal cord at levels C7 and T7 prepared with a Weigert stain. Major gray matter and white matter zones are labeled. CLINICAL POINT Combined systems degeneration (subacute combined degeneration) is a degeneration of the dorsal columns and lateral funiculi, frequently in the lower cervical and thoracic cord. Demyelination is the

hallmark of this disorder followed by axonal degeneration. The syndrome occurs with prolonged vitamin B12 deficiency, Crohn disease, Roux-­en-­Y gastric bypass or, less frequently, copper deficiency. Initial symptoms include fatigue, irritability, depression, or mental disabilities such as dementia. Neurological symptoms include (1) numbness and paresthesias of the distal extremities (then the full extremities) from dorsal column damage, (2) stiffness of the extremities leading to spastic paraplegia, (3) possible bowel and bladder dysfunction, and (4) sensory ataxia from dorsal column and spinocerebellar damage. Some symptoms may resolve with full restoration of vitamin B12 stores.   

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Dorsal root

Fasciculus gracilis

Lissauer’s zone Marginal zone

Dorsal spinocerebellar tract

Substantia gelatinosa

Lateral corticospinal tract

Nucleus proprius

Rubrospinal tract

Intermediate gray

Ventral spino cerebellar tract

Anterior (ventral) horn with lower motor neurons

Spinothalamic/spinoreticular tracts

Ventral root

Anterior Anterior Anterior Reticulospinal/ white median corticospinal vestibulospinal commissure fissure tract tracts Fasciculus gracilis

Cauda equina

Lissauer’s zone Marginal zone Dorsal spinocerebellar tract Substantia gelatinosa

Lateral corticospinal tract and rubrospinal tract

Nucleus proprius

Ventral spinocerebellar tract

Sacral parasympathetic nucleus (intermediomedial cell column)

Spinothalamic/spinoreticular tracts

Anterior (ventral) horn with lower motor neurons

Anterior Anterior Anterior white median spinal commissure fissure artery

 

10.7 SPINAL CORD HISTOLOGICAL CROSS SECTIONS (CONTINUED) Cross sections through the spinal cord at levels L4 and S2 prepared with a Weigert stain. Major gray matter and white matter zones are labeled.

Reticulospinal/ Anterior corticospinal vestibulospinal tract tracts

Pons Cerebellum Medulla

Cisterna magna

Subarachnoid space

Cervical spinal cord

Thoracic spinal cord

A. Sagittal view - Cervical spine

Caudal lumbosacral spinal cord

Lumbar cistern

Cauda equina - nerve roots in subarachnoid space

B. Sagittal view - Lumbar spine

10.8 SPINAL CORD IMAGING These two sagittal illustrations of the spinal cord are T2-­weighted magnetic resonance images that reveal the spinal cord as a dark structure and the cerebrospinal fluid (subarachnoid space) as white. A, The cervical and thoracic spinal cord. B, The lumbosacral spinal cord and the long nerve roots coursing through the subarachnoid space (lumbar cistern) as the cauda equina. Some individual nerve roots can be seen in contrast to the white cerebrospinal fluid.

  CLINICAL POINT In adults, the sacral segments of the spinal cord are located at the L1 vertebral level. Trauma or a tumor at this specific vertebral level can result in conus medullaris syndrome, which includes paralysis of the muscles of the pelvic floor (LMN damage), a flaccid bladder with overflow incontinence (loss of both parasympathetic input and sensory fibers), constipation and diminished bowel function (loss of parasympathetic control), loss of erectile function (loss of parasympathetic control in males), and “saddle” anesthesia (loss of sensory processing). Pain is sometimes experienced in the gluteal or perineal region. If passing nerve roots of the cauda equina are also damaged, additional sensory and motor impairment of the legs may be seen.   

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Spinal cord orientation Posterior columns (position sense) Lower limb Trunk Upper limb

Lateral corticospinal tract (motor)

Lower limb Trunk Upper limb

Lateral spinothalamic tract (pain and temperature); fibers decussate before ascending

Anterior spinal artery

Posterior column syndrome (uncommon) Loss of position sense below lesion Brown-Séquard syndrome (lateral cord hemisection) Ipsilateral paralysis and loss of position sense; contralateral analgesia

Anterior spinal artery syndrome Bilateral paralysis and dissociated sensory loss below lesion (analgesia but preserved position sense) Central cord syndrome Parts of 3 main tracts involved on both sides; upper limbs more affected than lower limbs

 

10.9 SPINAL CORD SYNDROMES These illustrations demonstrate a summary of normal spinal cord tract locations and the sites and consequences of incomplete spinal cord lesions, including posterior (dorsal) column syndrome, Brown-­Séquard lesion (lateral cord hemisection),

anterior spinal artery syndrome, and central cord syndrome. The clinical points for 10.3 and 10.5 provide further details of the anatomical basis for the classical consequences of some of these syndromes.

Spinal Cord

249

Section of cervical spinal cord showing cavity of syrinx surrounded by gliosis

Pain Temperature

Position Touch

Diagram demonstrating interruption of crossed pain and temperature fibers by syrinx; uncrossed light touch and proprioception fibers preserved

Bulging of spinal cord due to syrinx

Capelike distribution of pain and temperature sensation loss

Atrophy of hand muscles due to neurotrophic deficit

Axial and sagittal T2-weighted MRI showing syringomyelia and Chiari malformation, with cerebellar tonsils extending below the foramen magnum (arrow)

 

10.10 SYRINGOMYELIA Syringomyelia involves the development of a central cavity in the vicinity of the central canal of the spinal cord that expands to involve both neuronal pathways and neuronal cell groups. If congenital, syringomyelia is accompanied by Arnold-­Chiari malformation, type 1, with cerebellar tonsillar herniation and possible compression of caudal medullary or upper cervical cord structures. Pressure on the CSF from Arnold-­Chiari malformation, type 1, may contribute to the expansion of the syrinx. Syringomyelia is a rare disorder, and some cases are asymptomatic, found coincidentally in imaging studies. However, the

clinical manifestations are reflective of the anatomical organization of the spinal cord. The principal finding is dissociated sensory loss, with bilateral loss of pain and temperature sensation, but not fine, discriminative modalities, due to destruction of the anterior white commissure in the affected region of the syrinx. The syrinx may expand to involve the anterior horn (trophic changes, LMN-­ associated weakness and atrophy), the lateral funiculus (spastic weakness below the level of the lesion on the affected side due to corticospinal and rubrospinal tract damage), and further pain and temperature sensation loss due to anterolateral damage. For further anatomical and clinical discussion, see the Clinical Point for 10.4.

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Dorsal horn interneuron

From motor neuron From cutaneous receptor

(Ia) Proprioceptive fibers (afferents for monosynaptic reflex)

Axons for polysynaptic reflexes From muscle spindle

Dorsal horn interneuron

Dorsal root ganglion

Flexor reflex interneuron

From motor neuron

Ventral root

Dorsal horn interneuron

From motor neuron  motor axon

Schematic representation of motor neurons

Flexors

Flexors In cervical enlargement of spinal cord

Extensors

In lumbar enlargement of spinal cord

Extensors

  10.11 SPINAL CORD LOWER MOTOR NEURON ORGANIZATION AND CONTROL LMNs are located in the cervical, thoracic, lumbar, and sacral segments of the ventral (anterior) horn of the spinal cord. LMNs also have a medial to lateral and dorsal to ventral organization. LMNs supplying trunk musculature are found medially and ventrally; LMNs innervating more distal musculature are found dorsally and laterally. This organization also is apparent in the topography of UMN control of LMNs. UMNs

from the corticospinal system that regulate fine hand and finger movements terminate on dorsal and lateral LMNs. UMNs from reticulospinal and vestibulospinal systems that regulate basic truncal tone and posture terminate on ventral and medial LMNs. Reflex pathways regulate LMN activity through monosynaptic (muscle stretch reflex Ia afferents) or polysynaptic (flexor or cutaneous reflex afferents) pathways. Superimposed on this organization are the descending UMN control and coordination of LMNs.

Spinal Cord

A. Afferent inhibition From extensor spindle receptor (Ia fibers)

B. Stretch reflex (reciprocal inhibition)

C. Recurrent inhibition

D. Tendon organ reflex

From flexor spindle receptor (Ia fibers)

From flexor spindle (Ia fibers)

From flexor tendon organ (Ib fibers)

Axosomatic or axodendritic inhibitory synapse

Axoaxonic presynaptic inhibitory synapse

Excitatory synapse

Inhibitory synapse

Renshaw cells

Excitatory synapse To flexors

To flexors

To extensors

251

To extensors

Collaterals

To extensors

To synergistic muscles

E. Flexor withdrawal reflex

F. Renshaw cell bias

Nociceptive fibers

Ipsilateral flexion

Contralateral extension

Inhibitory synapse

Excitatory synapse

Excitatory synapse To extensors

To flexors Primary afferent axons and neurons

Excites phasic flexors

Inhibitory synapse

Renshaw cell

To extensors

To flexors

To flexors Interneurons

Inhibits tonic extensors

To extensors

Lower motor neurons (LMNs) and their motor axons

 

10.12 SPINAL SOMATIC REFLEX PATHWAYS In the muscle stretch reflex, Ia afferents excite the homonymous LMN pool directly and reciprocally inhibit the antagonist LMN pool via Ia inhibitory interneurons. The Golgi tendon organ reflex disynaptically inhibits the homonymous LMN pool and reciprocally excites the antagonist LMN pool. Flexor reflex responses excite a larger pool of LMNs through a great number of interneurons, with reciprocal inhibition of the appropriate antagonist LMNs, to bring about a protective withdrawal response from a

noxious stimulus. These reflexes can extend throughout the entire spinal cord. When an LMN fires an action potential, it excites a Renshaw cell that inhibits that same LMN, thereby ensuring a clean slate for the next set of inputs to that LMN. Renshaw cells receive input from axon collaterals of both flexor and extensor LMNs and in turn exert an inhibitory bias that focuses particularly on the inhibition of extensor LMNs and reciprocal excitation of flexor LMNs. Thus, the Renshaw cells favor flexor movements and help to inhibit extensor movements.

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Type III joint receptor (Golgi-like) in a knee ligament. These receptors are high-threshold, slowly adapting, active at far ranges of movement. Fiber stain.

Muscle and joint receptors Alpha motor neurons to extrafusal striated muscle end plates Gamma motor neurons to intrafusal striated muscle end plates Ia (A) fibers from annulospiral endings (proprioception) II (A) fibers from flower spray endings (proprioception); from paciniform corpuscles (pressure)

Type I receptor in a joint capsule. These receptors are low-threshold, slowly adapting, usually active at all ranges of movement and positions of the joint. Fiber stain.

III (A) fibers from free nerve endings and from some specialized endings (pain and some pressure) IV (unmyelinated) fibers from free nerve endings (pain) Ib (A) fibers from Golgi tendon organs (proprioception) A fibers from Golgi-type endings

A fibers from paciniform corpuscles and Ruffini terminals A and C fibers from free nerve endings

Extrafusal muscle fiber

Alpha motor neuron to extrafusal muscle fiber end plates

Intrafusal muscle fibers

Gamma motor neuron to intrafusal muscle fiber end plates

1 plate endings

II (A) fiber from flower spray endings

2 trail endings

Ia (A) fiber from annulospiral endings

Nuclear chain fiber Sheath Lymph space Nuclear bag fiber

Detail of muscle spindle

10.13 MUSCLE AND JOINT RECEPTORS AND MUSCLE SPINDLES Joints are innervated by a host of afferent receptors, including bare nerve endings, Golgi-­type endings, paciniform endings, Ruffini-­ like endings, and other encapsulated endings. Golgi tendon organs innervate tendons and respond to stretch with increased discharge, causing disynaptic inhibition of the LMNs that contract the homonymous muscles at high-­ threshold activation. Muscle spindles are complex sensory receptors within muscles; they are arranged in parallel with the extrafusal (skeletal) muscle fibers. These receptors contain small intrafusal muscle fibers that are stretched when the skeletal muscle is stretched. The Ia afferent from the muscle spindle excites the homonymous LMN pool monosynaptically and responds to both the length and the velocity (change in length with respect to time) of the extrafusal muscle fiber. These muscle reflexes assist in maintaining homeostasis during contraction and help to regulate muscle tone during movement. CLINICAL POINT Skeletal muscles are supplied by both afferent (sensory) and efferent (motor) nerves and receptors. The sensory fibers are associated mainly with specialized sensory receptors, the muscle spindles.

Efferent fibers Afferent fibers

 

Muscle spindles are small, encapsulated sensory receptors that lie in parallel with the skeletal muscle fibers (extrafusal fibers). Each spindle contains nuclear bag fibers (innervated mainly by group Ia afferents) and nuclear chain fibers (innervated mainly by group II afferents). These afferents are responsive to the tension on the muscle spindle. The group II afferents report mainly the lengths of the extrafusal fibers with which they are associated, whereas the Ia afferents report both the lengths and the velocities (dL/dt). In conjunction with the Ib afferents associated with Golgi tendon organs that report the force exerted on the tendon, Ia and group II muscle afferents provide continuous information to the CNS about the current state of the muscle and the projected changes occurring, based on the velocity response. The skeletal muscle fibers are supplied by motor axons derived from the alpha motor neurons in the ventral horn of the spinal cord. The muscle spindle’s nuclear bag and chain fibers have small contractile fibers on either end by which they are anchored into the spindle. These contractile fibers (intrafusal fibers) are innervated by gamma (γ) LMNs whose cell bodies also are found in the ventral horn of the spinal cord. Descending UMN pathways generally activate both alpha and gamma LMNs (alpha-­gamma coactivation), thereby achieving the shortening of the muscle spindle by the gamma LMNs in parallel with the shortening of the extrafusal fibers, keeping the muscle spindle in its dynamic range of sensory activity. Without such coactivation, the muscle spindle afferents would be silent in most ranges of extrafusal muscle contraction.   

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Spinal Cord

Ib fibers Ia fibers ++++ Baseline firing : +

A. Passive stretch. Both intrafusal and extrafusal muscle

Extrafusal muscle fiber Intrafusal muscle fiber

fibers stretched; spindles activated. Reflex via Ia fibers and alpha motor neurons causes secondary contraction (basis of stretch reflexes, such as knee jerk). Stretch is too weak to activate Golgi tendon organs.

Alpha motor neurons +++ Gamma motor neurons

Alpha activation from brain

Ib fibers ++

Golgi tendon organ

Ia fibers Extrafusal muscle fiber Inhibitory interneuron Alpha motor neurons ++ Intrafusal muscle fiber

Gamma motor neurons

Ib fibers ++ Ia fibers + (maintains baseline)

Golgi tendon organ

B. Active contraction. Central excitation of alpha motor neurons only causes contraction of extrafusal muscle fibers with consequent relaxation of intrafusal fibers; spindles not activated. Tension is low; does not adjust to increased resistance. Tendon organ activated, causing relaxation. This is theoretical only. Active contraction involves - coactivation. Alpha and gamma activation from brain

Extrafusal muscle fiber

Alpha motor neurons ++++ Intrafusal muscle fiber

Gamma motor neurons ++++

C. Active contraction with alpha-gamma coactivation. Intrafusal Golgi tendon organ

10.14 THE MUSCLE STRETCH REFLEX AND ITS CENTRAL CONTROL VIA GAMMA MOTOR NEURONS During passive stretch, a muscle stretch reflex excites homonymous LMNs, which results in muscle contraction to restore homeostasis. If active skeletal muscle contraction occurs without the activation of gamma LMNs (theoretical), the muscle spindle “unloads” and the tension on the intrafusal fibers is reduced, resulting in diminished firing of both Ia and II afferents. However, when LMNs contract because of activity in the brainstem’s UMNs or because of voluntary corticospinal activity, both alpha LMNs and gamma LMNs are activated together. This process, alpha-­gamma coactivation, ensures that the tension on the muscle spindle (through the intrafusal innervation by gamma fibers) adjusts immediately, that is, as the extrafusal muscle contraction occurs (through alpha fiber innervation). Although alpha and gamma LMNs can be modulated separately by specific central neuronal circuits, in normal physiological circumstances they are coactivated. If gamma LMNs are differentially activated in pathological circumstances, increased muscle tone and spasticity may ensue.

as well as extrafusal fibers contract; spindles activated, reinforcing contraction stimulus via Ia fibers in accord with resistance. Tendon organ activated, causing relaxation if load is too great.

 

CLINICAL POINT The muscle stretch reflex, a mainstay of neurological diagnosis, depends upon the activity of afferents and efferents associated with the muscle spindle and the skeletal muscle (extrafusal) fibers. When a tendon is tapped with a reflex hammer (e.g., the patellar tendon), the skeletal muscle is briefly stretched, as are the muscle spindles lying in parallel with them. The stretch of the muscle spindle puts tension on the equatorial region of the nuclear bag fibers, resulting in a burst of action potentials from the associated Ia afferents. The Ia afferents synapse directly with alpha LMNs in the spinal cord ventral horn, resulting in contraction of the homonymous muscle (quadriceps) and restoration of homeostasis. The Ia afferents also synapse on Ia inhibitory interneurons in the spinal cord, producing reciprocal inhibition of the antagonist muscles (hamstrings). The excitability of the muscle spindles can determine the robustness of the Ia afferent response to stretch. If the muscle spindle is floppy (unloaded), no Ia afferent response is forthcoming when the related tendon is tapped, and no muscle contraction occurs (areflexia or hyporeflexia); if the muscle spindle is on a hair-­trigger of heightened responsiveness, as happens when the gamma LMNs are excessively activated, then a very brisk muscle contraction occurs when the related tendon is tapped (hyperreflexia). The latter situation may occur in cases of lesions in the UMNs of the spinal cord and brain, which may produce disinhibition of the dynamic gamma LMNs accompanied by hyperreflexia of the muscle stretch reflexes and spasticity of the involved muscles.   

11

BRAINSTEM AND CEREBELLUM

Brainstem Cross-Sectional Anatomy 11.1 Brainstem Cross-Sectional Anatomy: Section 1 11.2 Brainstem Cross-­Sectional Anatomy: Section 2 11.3 Brainstem Cross-­Sectional Anatomy: Section 3 11.4 Brainstem Cross-­Sectional Anatomy: Section 4 11.5 Brainstem Cross-­Sectional Anatomy: Section 5 11.6 Brainstem Cross-­Sectional Anatomy: Section 6 11.7 Brainstem Cross-­Sectional Anatomy: Section 7 11.8 Brainstem Cross-­Sectional Anatomy: Section 8 11.9 Brainstem Cross-­Sectional Anatomy: Section 9 11.10 Brainstem Cross-­Sectional Anatomy: Section 10 11.11 Brainstem Cross-­Sectional Anatomy: Section 11 11.12 Brainstem Cross-­Sectional Anatomy: Section 12 11.13 Brainstem Cross-­Sectional Anatomy: Section 13 11.14 Brainstem Cross-­Sectional Anatomy: Section 14 11.15 Brainstem Arterial Syndromes

Cranial Nerves and Cranial Nerve Nuclei 11.16 Cranial Nerves: Schematic of Distribution of Sensory, Motor, and Autonomic Fibers 11.17 Cranial Nerves and Their Nuclei: Schematic View From Above 11.18 Cranial Nerves and Their Nuclei: Schematic Lateral View 11.19 Nerves of the Orbit 11.20 Nerves of the Orbit (Continued)

11.21 Extraocular Nerves (III, IV, and VI) and the Ciliary Ganglion: View in Relation to the Eye 11.22 Trigeminal Nerve (V) 11.23 Innervation of the Teeth 11.24 Facial Nerve (VII) 11.25 Facial Nerve Branches and the Parotid Gland 11.26 Facial Nerve Lesions and Their Manifestations 11.27 Vestibulocochlear Nerve (VIII) 11.28 Glossopharyngeal Nerve (IX) 11.29 Accessory Nerve (XI) 11.30 Vagus Nerve (X) 11.31 Hypoglossal Nerve (XII)

Reticular Formation 11.32 Reticular Formation: General Pattern of Nuclei in the Brainstem. 11.33 Reticular Formation: Nuclei and Areas in the Brainstem and Diencephalon 11.34 Major Afferent and Efferent Connections to the Reticular Formation 11.35 Sleep-­Wakefulness Control

Cerebellum 11.36 Cerebellar Organization: Lobes and Regions 11.37 Cerebellar Anatomy: Lobules 11.38 Cerebellar Anatomy: Deep Nuclei and Cerebellar Peduncles

Brainstem and Cerebellum

255



Medulla–Spinal Cord Transition—Decussation of the Pyramids Fasciculus cuneatus Fasciculus gracilis

Spinal nucleus CN V

Lateral corticospinal tract Spinal tract CN V Central canal Level of section

Dorsal spinocerebellar tract

Decussation of pyramids

Ventral spinocerebellar tract Spinothalamic/ spinoreticular tract Nucleus CN XI Pyramid Labeled image available as eFig. 11.1. Nucleus Fasciculus gracilis gracilis

Fasciculus cuneatus

Nucleus cuneatus

Spinal tract of CN V Spinal nucleus of CN V Dorsal spinocerebellar tract Lateral corticospinal tract Ventral spinocerebellar tract Spinothalamic/spinoreticular tract

Nucleus CN XI

Decussation of the pyramids

BRAINSTEM CROSS-­SECTIONAL ANATOMY 11.1 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 1 Illustrations of brainstem cross sections (Figs. 11.1–11.4) are arranged from caudal to rostral, from the spinal-­ medullary

Pyramid

junction to the rostral mesencephalon-­diencephalon junction; T1-­weighted magnetic resonance images of the brainstem and surrounding tissue are provided for each level. Corresponding histology cross sections, stained with a fiber stain, are provided of each level. CN, cranial nerve.

256

Regional Neuroscience Medulla—Level of the Dorsal Column Nuclei Fasciculus cuneatus

Dorsal spinocerebellar tract

Fasciculus gracilis Nucleus gracilis Nucleus cuneatus

Spinal tract of CN V

Tractus solitarius

Spinal nucleus of CN V

Level of section

Dorsal motor nucleus of CN X

Nucleus ambiguus Ventral spinocerebellar tract

Nucleus of CN XII Medial longitudinal fasciculus

Spinothalamic/ spinoreticular tract

Tectospinal tract

Dorsal accessory olive Medial accessory olive

Nucleus solitarius

Decussation of pyramids

Pyramid Labeled image available as eFig. 11.2. Fasciculus Nucleus Fasciculus Nucleus cuneatus cuneatus gracilis gracilis

Dorsal motor nucleus of CN X

Spinal tract of CN V

Nucleus of CN XII

Spinal nucleus of CN V

Medial longitudinal fasciculus

Dorsal spinocerebellar tract Internal arcuate fibers

Ventral spinocerebellar tract

Nucleus ambiguus Dorsal accessory olive Medial lemniscus Spinothalamic/spinoreticular tract Medial accessory olive

Pyramid

  11.2 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 2 CLINICAL POINT Several groups of lower motor neurons (LMNs) are present in the lower brainstem, including those supplying the tongue (CN XII), the pharynx and larynx (nucleus ambiguus), and the face (CN VII). Neurodegeneration of these brainstem LMNs can occur in bulbar polio, amyotrophic lateral sclerosis, and other LMN diseases. The affected muscles are atrophic and flaccid. Such a condition is called bulbar palsy (or progressive bulbar paralysis), an LMN disorder, accompanied by loss of movement, tone, and reflexes. The tongue is weak and

atrophic, and the patient cannot speak or vocalize (dysarthria or anarthria, not aphasia) and cannot swallow (dysphagia); as a consequence, the patient may aspirate in an attempt to swallow. This LMN condition must be distinguished from upper motor neuron (UMN) lesions, which, when bilateral, can also result in dysphonia, dysphagia, and weakened bulbar muscles. This UMN condition is called pseudobulbar palsy or spastic bulbar palsy. In this condition, the muscles are not atrophic, and reflexes (jaw jerk and facial reflexes) are brisk. In amyotrophic lateral sclerosis, both LMN and UMN degeneration may occur progressively during the course of the disease. Because the LMNs are the final common pathway to the muscles, the LMN state usually progresses; once the LMNs have degenerated, continuing UMN damage does not make a difference functionally.   

Brainstem and Cerebellum

Medulla—Level of the Obex External (lateral) cuneate nucleus

Nucleus cuneatus Nucleus gracilis Nucleus solitarius

Inferior cerebellar peduncle with dorsal spinocerebellar tract

Level of section

Obex Central canal Dorsal motor nucleus of CN X Nucleus of CN XII

Tractus solitarius

Internal arcuate fibers

Spinal tract of CN V Spinal nucleus of CN V

Medial longitudinal fasciculus

Spinothalamic/ spinoreticular tract

Tectospinal tract Medial lemniscus

Nucleus ambiguus

Inferior olivary nucleus

CN XII Pyramid

Medial accessory olivary nucleus

Labeled image available as eFig. 11.3.

Tractus Nucleus Nucleus Nucleus solitarius of CN XII Obex gracilis cuneatus

External (lateral) cuneate nucleus Medial longitudinal fasciculus Nucleus solitarius Dorsal spinocerebellar tract Internal arcuate fibers

Spinal tract of CN V Spinal nucleus of CN V Dorsal motor nucleus of CN X

Tectospinal tract Nucleus ambiguus

Ventral spinocerebellar tract Fibers of CN X Spinothalamic/spinoreticular tract

Medial lemniscus

Inferior olivary nucleus

Medial accessory olive Fibers of CN XII

Pyramid

 

11.3 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 3

257

258

Regional Neuroscience Medulla—Level of the Inferior Olive Nucleus cuneatus

External cuneate nucleus

Nucleus solitarius Tractus solitarius

Inferior cerebellar peduncle

Dorsal motor nucleus of CN X Choroid plexus Fourth ventricle

Spinal tract of CN V Level of section

Nucleus of CN XII

Spinal nucleus of CN V CN X Spinothalamic/ spinoreticular tract

Medial longitudinal fasciculus

Nucleus ambiguus Tectospinal tract

Inferior olivary nucleus

Medial lemniscus

Dorsal accessory olivary nucleus CN XII Labeled image available as eFig. 11.4.

Pyramid

Dorsal motor nucleus of CN X

Medial accessory olivary nucleus Nucleus Fourth of CN XII ventricle

Nucleus External (lateral) cuneatus cuneate nucleus

Tractus solitarius Nucleus solitarius Spinal tract of CN V

Inferior cerebellar peduncle with dorsal spinocerebellar tract Medial longitudinal fasciculus

Spinal nucleus of CN V Nucleus ambiguus Spinothalamic/spinoreticular tract

Tectospinal tract

Dorsal accessory olive

Fibers of CN X

Medial accessory olive

Inferior olivary nucleus Medial lemniscus Fibers of CN XII Pyramid

  11.4 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 4 CLINICAL POINT The medulla is supplied with blood by the paramedian and circumferential branches of the anterior spinal artery and the vertebral arteries. A major circumferential branch of the vertebral artery, the posterior inferior cerebellar artery (PICA), supplies a lateral wedge of medulla with blood. A brainstem stroke or an infarct in a vertebral artery or in the PICA produces a complex of symptoms called the lateral medullary syndrome (Wallenberg syndrome), which is caused by damage

to an array of nuclei and tracts. The patient can demonstrate (1) loss of pain and temperature sensation on the ipsilateral side of the face (descending nucleus and tract of V) and the contralateral side of the body (spinothalamic/spinoreticular system); (2) dysphagia and dysarthria (paralysis of ipsilateral pharyngeal and laryngeal muscles resulting from damage to the ipsilateral nucleus ambiguus); (3) ataxia of the limbs and falling to the ipsilateral side (inferior cerebellar peduncle and its afferent tracts); (4) vertigo with nausea, vomiting, and nystagmus (vestibular nuclei); and (5) ipsilateral Horner’s syndrome, with ptosis, miosis, and anhidrosis (descending axons from the hypothalamus to the T1–T2 intermediolateral cell column of the spinal cord).   

Brainstem and Cerebellum

Medulla—Level of the CN X and the Vestibular Nuclei Tractus solitarius

Nucleus solitarius

Inferior vestibular nucleus

Medial vestibular nucleus Reticular formation

Inferior cerebellar peduncle

Level of section

Dorsal motor nucleus of CN X

Hypoglossal nucleus of CN Xll

CN X

Medial longitudinal fasciculus

Spinal tract of CN V Spinal nucleus of CN V

Tectospinal tract

Spinothalamic/ spinoreticular tract

Medial lemniscus

Inferior olivary nucleus Pyramid

Labeled image available as eFig. 11.5. Dorsal motor Nucleus Medial longitudinal fasciculus nucleus of CN X of CN XII Medial vestibular nucleus Inferior vestibular nucleus Nucleus solitarius Tractus solitarius

Inferior cerebellar peduncle

Reticular formation Spinal tract of CN V Spinal nucleus of CN V Tectospinal tract

Central tegmental tract

Fibers of CN X

Spinothalamic/spinoreticular tract Medial lemniscus Inferior olivary nucleus

Pyramid

 

11.5 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 5

259

260

Regional Neuroscience Medullo-Pontine Junction—Level of the Cochlear Nuclei Dorsal cochlear nucleus

Medial vestibular nucleus

Nucleus prepositus

Reticular formation

Medial longitudinal fasciculus

Inferior cerebellar peduncle

Tectospinal tract

Ventral cochlear nucleus Level of section

Raphe nuclei (obscurus pallidus)

CN VIII CN IX Spinal tract of CN V Spinal nucleus of CN V Inferior vestibular nucleus

Inferior olivary nucleus

Spinothalamic/ spinoreticular tract

Medial lemniscus

Central tegmental tract Pontine nuclei

Middle cerebellar peduncle

Corticospinal tract

Labeled image available as eFig. 11.6. Nucleus Fourth Nucleus raphe Medial vestibular prepositus ventricle nucleus obscurus

Inferior vestibular nucleus Inferior cerebellar peduncle Dorsal cochlear nucleus

Nucleus solitarius Tractus solitarius

Spinal tract of CN V

Medial longitudinal fasciculus

Spinal nucleus of CN V

Reticular formation

Ventral cochlear nucleus

Tectospinal tract

Spinothalamic/spinoreticular tract

Fibers of CN VIII Fibers of CN IX Nucleus raphe pallidus

Medial lemniscus

Inferior olivary nucleus

Central tegmental tract

  Pyramid

11.6 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 6 CLINICAL POINT Occlusion of a paramedian branch of the basilar artery in the lower pons results in medial inferior pontine syndrome. This vascular syndrome causes (1) contralateral hemiparesis (corticospinal system) and drooping of the contralateral lower face (corticobulbar fibers); (2) loss of fine, discriminative touch, vibratory sensation, and joint

position sense on the contralateral body that is more severe in the upper extremity (medial lemniscus); (3) limb ataxia and gait ataxia (pontine nuclei and bilateral crossing connections going into the middle cerebellar peduncles); (4) paralysis of lateral gaze by the ipsilateral eye, with resultant diplopia (abducens nerve, nucleus); (5) paralysis of conjugate gaze to ipsilateral side, with preservation of convergence (parapontine reticular formation); and (6) diplopia on attempted lateral gaze to the contralateral side, called internuclear ophthalmoplegia (medial longitudinal fasciculus).   

Brainstem and Cerebellum Pons—Level of the Facial Nucleus

Lateral vestibular nucleus

Superior vestibular nucleus

Nucleus of CN VI

Superior cerebellar peduncle

Superior olivary nucleus

Dentate nucleus

Medial longitudinal fasciculus

Middle cerebellar peduncle Inferior cerebellar peduncle

Fibers of CN VII

Spinal tract of CN V

Level of section

Tectospinal tract

Spinal nucleus of CN V Nucleus of CN VII CN VIII CN VII Spinothalamic/ spinoreticular tract

Raphe nucleus (magnus)

Central tegmental tract Medial lemniscus

Trapezoid body Corticospinal tract CN VI

Pontine nuclei

Labeled image available as eFig. 11.7. Superior Lateral vestibular vestibular nucleus nucleus

Medial Tectospinal longitudinal tract fasciculus

Nucleus of CN VI

Superior cerebellar peduncle Fourth ventricle Inferior cerebellar peduncle Exiting fibers of CN VII Ascending fibers of CN VII

Spinal tract of CN V Spinal nucleus of CN V

Nucleus of CN VII

Central tegmental tract Middle cerebellar peduncle Nucleus raphe magnus

Superior olivary nucleus Spinothalamic/spinoreticular tract

Trapezoid body

Medial lemniscus

Corticospinal tract fibers Crossing fibers of middle cerebellar peduncle

Basis pontis

Pontine nuclei

  11.7 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 7

261

262

Regional Neuroscience Pons—Level of the Genu of the Facial Nerve

Superior cerebellar peduncle

Dentate nucleus

Globose and emboliform nuclei Fibers of CN VII

Superior vestibular nucleus Inferior cerebellar peduncle

Nucleus of CN VI

Middle cerebellar peduncle

Medial longitudinal fasciculus

Uvula

Lateral vestibular nucleus

Level of section

Fibers of CN VI

Spinal tract of CN V Medial vestibular nucleus

Tectospinal tract

Spinal nucleus of CN V Spinothalamic/ spinoreticular tract

Central tegmental tract

Trapezoid body

Medial lemniscus

Corticospinal tract Pontine nuclei

CN VI

Nucleus of CN VII

Labeled image available as eFig. 11.8. Medial Superior longitudinal Fourth Nucleus vestibular fasciculus ventricle of CN VI nucleus Inferior cerebellar peduncle Lateral vestibular nucleus

Superior cerebellar peduncle

Fibers of CN VI Spinal tract of CN V Spinal nucleus of CN V

Tectospinal tract

Middle cerebellar peduncle Nucleus of CN VII

Spinothalamic/spinoreticular tract Medial lemniscus Trapezoid body

Corticospinal tract fibers

Pontine nuclei

  11.8 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 8 CLINICAL POINT The pons is a common site for a hemorrhagic stroke. A pontine hemorrhage is commonly large and lethal. When not fatal, such a hemorrhage may result in the rapid progression of (1) total paralysis (quadriplegia); (2) decerebrate posturing (extensor posturing)

caused by UMN damage to the corticospinal and rubrospinal systems, thereby disinhibiting the lateral vestibular nuclei; (3) coma; (4) paralysis of ocular movements; and (5) small but reactive pupils. A pontine hemorrhage that results in coma is commonly lethal. A large infarct in the basilar artery may produce the same clinical picture. Some small, lacunar infarcts also may occur in the pons; these infarcts may produce purely motor symptoms (contralateral UMN paresis at base of pons), ataxia, or both (cerebellar peduncles, pontine nuclei).   

Brainstem and Cerebellum

263

Pons—Level of Trigeminal Motor and Main Sensory Nuclei Medial parabrachial nucleus

Lateral parabrachial nucleus

Locus coeruleus

Fourth ventricle

Superior cerebellar peduncle

Medial longitudinal fasciculus

Middle cerebellar peduncle

Level of section

Tectospinal tract

Mesencephalic nucleus of CN V

Raphe nucleus (pontis)

CN V Main (chief) sensory nucleus of CN V Motor nucleus of CN V

Central tegmental tract

Spinothalamic spinoreticular tract Crossing fibers of middle cerebellar peduncle Pontine nuclei

Medial lemniscus Corticospinal tract

Labeled image available as eFig. 11.9. Nucleus Medial raphe Locus Uvula of Fourth longitudinal pontis coeruleus cerebellum ventricle fasciculus Lateral parabrachial nucleus Medial parabrachial nucleus

Superior cerebellar peduncle

Main sensory nucleus of CN V Motor nucleus of CN V

Mesencephalic nucleus of CN V Central tegmental tract

Tectospinal tract

Spinothalamic/spinoreticular tract Medial lemniscus Middle cerebellar peduncle

Fibers of CN V Crossing fibers of middle cerebellar peduncle Corticospinal tract fibers Pontine nuclei

  11.9 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 9 CLINICAL POINT A vascular lesion of circumferential branches of the basilar artery or the anterior inferior cerebellar artery can cause lateral pontine syndrome, which is characterized by (1) contralateral loss of sensation in the body, both epicritic and protopathic (medial lemniscus and anterolateral system); (2) loss of pain and temperature sensation on the contralateral face (ventral trigeminal lemniscus, located on dorsal surface

of the medial lemniscus); (3) loss of fine, discriminative touch (main sensory nucleus of CN V) or impaired general sensation (CN V fibers) on the ipsilateral face; (4) ipsilateral paralysis of muscles of mastication (motor nucleus of CN V); (5) limb ataxia (middle and superior cerebellar peduncles); (6) paralysis of conjugate gaze to the ipsilateral side (parapontine reticular formation and its connections); and (7) other possible ipsilateral brainstem problems, depending on the extent of the vascular involvement, such as deafness or tinnitus (auditory nuclei or nerve fibers), vertigo and nystagmus (vestibular nuclei or nerve fibers), facial palsy (CN VII nucleus or nerve fibers), and Horner’s syndrome (descending hypothalamo-­spinal sympathetic connections).   

264

Regional Neuroscience

Pons-Midbrain Junction—Level of CN IV and Locus Coeruleus CN IV

Superior cerebellar peduncle

Lateral lemniscus

Locus coeruleus

Periaqueductal gray matter

Aqueduct Level of section

Spinothalamic/ spinoreticular tract

Dorsal raphe nucleus

Medial lemniscus

Medial longitudinal fasciculus

Corticospinal tract

Central superior raphe nucleus

Pontine nuclei Middle cerebellar peduncle Central tegmental tract Labeled image available as eFig. 11.10. Medial longitudinal Locus Aqueduct fasciculus coeruleus

Fibers of CN IV Lateral lemniscus Periaqueductal gray Nucleus raphe dorsalis Spinothalamic/spinoreticular tract Medial lemniscus

Superior cerebellar peduncle Central tegmental tract Nucleus centralis superior (raphe)

Corticospinal tract fibers Middle cerebellar peduncle Pontine nuclei

 

11.10 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 10

Brainstem and Cerebellum

265

Midbrain—Level of the Inferior Colliculus Inferior colliculus

Brachium of inferior colliculus

Reticular formation

Lateral lemniscus

Periaqueductal gray matter Aqueduct

Spinothalamic/ spinoreticular tract Level of section

Nucleus of CN IV Dorsal raphe nucleus

Cerebral peduncle

Medial longitudinal fasciculus

Central tegmental tract

Superior cerebellar peduncle (decussation) Interpeduncular nuclei

Medial lemniscus Substantia nigra

Pontine nuclei

Labeled image available as eFig. 11.11. Aqueduct

Brachium of inferior colliculus

Inferior colliculus Periaqueductal gray Reticular formation Nucleus of CN IV

Lateral lemniscus Spinothalamic/spinoreticular tract

Medial longitudinal fasciculus

Dorsal raphe nucleus

Central tegmental tract

Medial lemniscus Superior cerebellar peduncle Nucleus centralis superior (raphe)

Substantia nigra Cerebral peduncle Interpeduncular nuclei

  11.11 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 11 CLINICAL POINT A space-­occupying lesion in the forebrain, such as a bleed (epidural or subdural hematoma), a tumor, or increased intracranial pressure resulting from a variety of causes, can cause herniation of the fore-­ brain through the tentorium cerebelli. This transtentorial herniation displaces the thalamus and upper midbrain in a downward direction and causes a variety of changes in brain function. These changes are characterized by functions attributable to the remaining intact lower midbrain and more caudal structures, with loss of function of the upper midbrain and more rostral structures. Most conspicuous is a progressive deterioration of the state of consciousness, rapidly going from drowsiness to stupor to an unarousable state of coma;

consciousness requires an intact brainstem reticular formation and at least one functioning cerebral hemisphere. When both hemispheres are nonfunctional, coma ensues. With the loss of activity in the corticospinal system and the rubrospinal system and removal of cortical influence on the other UMN pathways, a state of decerebration occurs (called decerebrate rigidity, although it is really spasticity, not true rigidity). The neck is extended (opisthotonus), the arms and legs are extended and rotated inward, and the hands, fingers, feet, and toes are flexed. Plantar responses are extensor. Cheyne-­Stokes respiration is seen (crescendo-­decrescendo breathing), followed at a slightly later stage of damage by shallow hyperventilation. The pupils are midsized and usually unresponsive because of compression of the third nerves against the free edge of the tentorium. Caloric testing or the doll’s-­eye maneuver shows no vertical eye movements (visual tectal damage), and the eyes do not move in a conjugate fashion.   

266

Regional Neuroscience

Midbrain—Level of the Superior Colliculus Brachium of inferior colliculus

Superior colliculus Tectospinal tract Mesencephalic nucleus of CN V Periaqueductal gray matter

Spinothalamic/ spinoreticular tract Level of section

Aqueduct

Medial lemniscus

Nucleus of Edinger-Westphal Nucleus of CN III

Central tegmental tract

Medial longitudinal fasciculus Ventral tegmental decussation

Substantia nigra Red nucleus

Cerebral peduncle

CN III

Ventral tegmental area

Labeled image available as eFig. 11.12. Inferior Commissure of colliculus Aqueduct inferior colliculus

Periaqueductal gray

Nucleus of EdingerWestphal (CN III)

Brachium of inferior colliculus Spinothalamic/spinoreticular tract

Mesencephalic nucleus of CN V

Tectospinal tract

Nucleus of CN III

Medial longitudinal fasciculus

Dorsal raphe nucleus

Medial lemniscus

Decussating fibers of superior cerebellar peduncle

Central tegmental tract

Nucleus centralis superior (raphe)

Substantia nigra Cerebral peduncle

Red Ventral Ventral Exiting fibers nucleus tegmental tegmental of CN III decussation area

 

11.12 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 12

Brainstem and Cerebellum

267

Midbrain—Level of the Medial Geniculate Body Brachium of inferior colliculus

Spinothalamic/ spinoreticular tract

Medial geniculate body (nucleus)

Level of section

Superior colliculus Periaqueductal gray matter

Medial lemniscus

Aqueduct Nucleus of Edinger-Westphal

Lateral geniculate body (nucleus) Cerebral peduncle Optic tract Substantia nigra Cerebellorubrothalamic tract Central tegmental tract Red nucleus Medial longitudinal fasciculus

Labeled image available as eFig. 11.13.

Nucleus of CN III Ventral tegmental area CN III

Superior Periaqueductal colliculus gray Aqueduct

Medial geniculate nucleus Nucleus of EdingerWestphal (CN III) Central tegmental tract Medial longitudinal fasciculus Nucleus of CN III

Spinothalamic/ spinoreticular tract Lateral geniculate nucleus Medial lemniscus Optic tract Cerebellorubrothalamic tract

Substantia nigra Cerebral peduncle

Red nucleus Ventral tegmental area Exiting fibers of CN III

  11.13 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 13 CLINICAL POINT Paramedian regions of the upper midbrain receive their blood supply mainly from branches of the posterior cerebral and posterior communicating arteries. A vascular lesion at this level (Weber’s syndrome) results in damage to the exiting third nerve fibers, the medial and central portions of the cerebral peduncle, and some passing tracts. A supratentorial mass lesion also can cause lateral and downward compression of one cerebral peduncle and the third nerve against the free edge of the tentorium cerebelli, presenting a similar clinical picture. Compression of the cerebral peduncle with possible involvement of the red nucleus on the affected side produces contralateral

hemiplegia, rapidly evolving to a spastic state with a plantar extensor response. A central (lower) facial palsy occurs because of damage to corticobulbar fibers, which travel in the cerebral peduncle. An ipsilateral oculomotor palsy also occurs, with the ipsilateral eye deviated laterally and the ipsilateral pupil fixed (unresponsive to light) and dilated because of unopposed actions of the sympathetics. If the lesion involves the substantia nigra, red nucleus, pallidothalamic fibers, or dentatorubral and dentatothalamic fibers, contralateral movement problems may occur, including akinesia, intention tremor, or choreoathetoid movements. Damage to these later structures, with their accompanying contralateral problems, may occur in isolation along with third nerve damage caused by more distal vascular involvement of the paramedian branches to the upper midbrain (Benedikt’s syndrome).   

268

Regional Neuroscience

Midbrain-Diencephalon Junction—Level of the Posterior Commissure Spinothalamic/ spinoreticular Pulvinar tract

Periaqueductal gray matter

Pretectum

Posterior commissure

Medial geniculate body (nucleus)

Level of section

Medial lemniscus Lateral geniculate body (nucleus) Cerebral peduncle

Aqueduct

Nucleus of Darkschewitsch

Cerebellorubrothalamic tract Optic tract Red nucleus

Medial longitudinal fasciculus

Substantia nigra

Central tegmental tract

Lateral hypothalamic area Mammillary body Labeled image available as eFig. 11.14. Pulvinar

Brachium of superior colliculus

Posterior hypothalamic area

Central tegmental tract

Pretectum

Medial geniculate nucleus Spinothalamic/spinoreticular tract, medial lemniscus, and trigeminothalamic tracts

Posterior commissure Aqueduct Nucleus of Darkschewitsch Interstitial nucleus of Cajal

Lateral geniculate nucleus

Medial longitudinal fasciculus Red nucleus

Hypothalamus

Fibers of Cerebral optic tract peduncle

Substantia nigra

Cerebellorubrothalamic tract

 

11.14 BRAINSTEM CROSS-­SECTIONAL ANATOMY: SECTION 14

Brainstem and Cerebellum

269

MIDBRAIN Medial Midbrain Syndrome (Weber′s Syndrome)

Paramedian Midbrain Syndrome (Benedikt Syndrome) Medial lemniscus Red nucleus Oculomotor (III) nerve fibers

Oculomotor (III) nerve fibers Cerebral peduncle

Oculomotor n. (III)

Posterior cerebral artery

PONS

Lateral Pontine Syndrome (AICA Syndrome)

Medial Pontine Syndrome (Medial Basilar Infarct)

Vestibular nuclei (VIII) Spinal tract/nucleus of trigeminal n. (V) Motor nucleus of facial n. (VII)

Abducent (VI) nucleus

Ventral cochlear nucleus (VIII) Spinothalamic tract Vestibulocochlear n. (VIII) Facial n. (VII)

Medial lemniscus Abducent (VI) nerve fibers Corticospinal (pyramidal) tract Paramedian penetrating artery Short circumferential penetrating artery

Anterior inferior cerebellar artery (AICA)

Abducent n. (VI) Basilar artery

MEDULLA Lateral Medullary Syndrome (PICA Syndrome; Wallenberg Syndrome)

Medial Medullary Syndrome

Vestibular nuclei (VIII) Nucleus solitarius (X) Dorsal motor nucleus of vagus (X) Spinal tract/nucleus of trigeminal n. (V) Inferior cerebellar peduncle Vagus n. (X) Nucleus ambiguus (IX, X) Spinothalamic tract Posterior inferior cerebellar artery (PICA)

Hypoglossal nucleus

Hypoglossal (XII) nerve fibers Medial lemniscus Corticospinal (pyramidal) tract Hypoglossal n. (XII)

Vertebral artery

Anterior spinal artery

 

11.15 BRAINSTEM ARTERIAL SYNDROMES These brainstem cross sections demonstrate major regions of vascular infarcts affecting the medulla, pons, and midbrain. Thorough knowledge of the nuclei and tracts in each territory is necessary to understand the resultant symptoms. In the medulla the main syndromes are lateral medullary syndrome (see Plate

11.4 Clinical Point) and medial medullary syndrome (see Plate 4.2 Clinical Point). In the pons the main syndromes are lateral pontine syndrome (see Plate 11.9 Clinical Point) and medial pontine syndrome (see Plate 11.6). In the midbrain the main syndromes are Weber’s syndrome and Benedikt’s syndrome (see Plate 11.13 Clinical Point).

270

Regional Neuroscience III Oculomotor Motor to medial, inferior, and superior recti, inferior oblique, and levator palpebrae superioris Motor fibers IV Trochlear Sensory fibers Autonomic to ciliary muscle and pupillary constrictor muscle Superior oblique via the ciliary ganglion

V Trigeminal Sensory to face, sinuses, teeth, general sensation to anterior 2/3 of oral cavity, tongue

Motor to muscles of mastication I Olfactory

II Optic

.

th

VI Abducens Lateral rectus

ph

O

x. Ma . nd Ma

Nervus intermedius Autonomic -- submaxillary, sublingual, lacrimal glands via the pterygopalatine and submandibular ganglia Sensory taste to anterior 2/3 of tongue, soft palate

VII Facial Muscles of facial expression, stapedius

VIII Vestibulocochlear Cochlear Vestibular IX Glossopharyngeal Sensory -- taste to posterior 1/3 of tongue, general sensation to tonsil, pharynx, middle ear Motor -- stylopharyngeus, pharyngeal musculature Autonomic -- to parotid gland via otic ganglion

XII Hypoglossal Tongue muscles

Strap muscles

X Vagus Motor -- to pharynx, larynx Autonomic -- to heart, lungs, bronchi, GI tract via intramural ganglia Sensory -- heart, lungs, bronchi, trachea, larynx, pharynx, GI tract, external ear

XI Accessory

Sternocleidomastoid, trapezius (upper 2/3)

 

CRANIAL NERVES AND CRANIAL NERVE NUCLEI 11.16 CRANIAL NERVES: SCHEMATIC OF DISTRIBUTION OF SENSORY, MOTOR, AND AUTONOMIC FIBERS CNs I and II, both sensory, are tracts of the central nervous system (CNS) that are derived from the neural tube and myelinated by oligodendroglia. CNs III–XII emerge from the brainstem and supply sensory (CNs V, VII–­X), motor (CNs III—VII and IX–­XII), and autonomic (CNs III, VII, IX, X) nerve fibers to structures in the head, neck, and body (autonomic). All of the CNs that emerge from the brainstem distribute ipsilaterally to their target structures. With the exception of CN nucleus IV (trochlear) and some motor components of CN nucleus III (oculomotor), the CN nuclei are located ipsilateral to the point of emergence of the CN. The spinal accessory portion of CN XI emerges from motor neurons in the

rostral spinal cord; it ascends through the foramen magnum and then exits with CNs IX and X; thus it is considered a CN. CLINICAL POINT Multiple CNs can be affected by some pathological conditions, such as tumors and granulomas, brainstem infarcts, leptomeningeal carcinomatosis, and aneurysms. Extramedullary pathology affects mainly the sensory, motor, and autonomic components of the involved CNs; internal pathology in the brainstem also involves the long tracts. An aneurysm in the cavernous sinus may involve CNs III–VI. A large tumor in the middle cranial fossa in the retrosphenoid space may affect cranial nerves III–VI. A large tumor in the cerebellopontine angle involves CNs VII and VIII and sometimes expands to involve V and IX. Tumors and aneurysms in the jugular foramen may involve CNs IX, X, and XI. Granulomatous lesions such as sarcoids in the posterior retroparotid space may affect cranial nerves IX–­XII as well as the sympathetic nerves to the head.   

271

Brainstem and Cerebellum

Oculomotor (III) nerve Superior (cranial) colliculus

Red nucleus Edinger-Westphal nucleus Oculomotor nucleus

Termination sites for fibers in optic tract

Trochlear nucleus

Lateral geniculate body

Trochlear (IV) nerve Motor nucleus of trigeminal nerve

Mesencephalic nucleus of trigeminal nerve

Trigeminal (V) nerve and ganglion

Trigeminal (V) nerve and ganglion Principal (main) sensory nucleus of trigeminal nerve

Abducens nucleus

Facial (VII) nerve

Geniculate ganglion of facial nerve Facial nucleus Superior and inferior salivatory nuclei

Vestibulocochlear (VIII) nerve

Nucleus ambiguus

Ventral cochlear nucleus Dorsal cochlear nucleus

Glossopharyngeal (IX) nerve

Glossopharyngeal (IX) nerve

Vagus (X) nerve

Vestibular nuclei Vagus (X) nerve Efferent fibers -- Motor Afferent fibers Efferent fibers -- Autonomic

Spinal tract and spinal nucleus of trigeminal nerve

XII

Nucleus of the solitary tract

Accessory (XI) nerve Dorsal motor (autonomic) nucleus of vagus nerve (CN X) Hypoglossal nucleus

Spinal nucleus of accessory nerve

 

11.17 CRANIAL NERVES AND THEIR NUCLEI: SCHEMATIC VIEW FROM ABOVE The LMNs of the brainstem are localized in a medial column (CN motor nuclei for III [oculomotor], IV [trochlear], VI [abducens], and XII [hypoglossal]) and a lateral column (CN motor nuclei for V [trigeminal], VII [facial], IX and X [ambiguus], and XI [spinal accessory]). Preganglionic parasympathetic nuclei are found medially in the Edinger-­Westphal nucleus (CN III) and the dorsal (motor) vagal nucleus (CN X) and laterally in the superior (CN VII) and inferior (CN IX) salivatory nuclei. Secondary sensory nuclei include the main sensory and descending nuclei of CN V, the vestibular nuclei and cochlear nuclei (CN VIII), and the nucleus solitarius (CNs VII, IX, and X). The superior colliculus and the lateral geniculate body (nucleus) receive secondary sensory axonal projections from the optic tract; the inferior colliculus receives input from the cochlear nuclei and other accessory auditory nuclei. The nuclei gracilis and cuneatus, located in the medulla, receive input from dorsal root ganglion cells, which convey epicritic somatosensory modalities (fine, discriminative touch; vibratory sensation; joint position sense).

CLINICAL POINT CNs I, II, V, and VII–X have primary afferent components. CN I, the olfactory nerve, is a CNS tract and terminates directly in limbic fore-­ brain structures, unlike any other CNs. CN II, the optic nerve, also is a CNS tract; its retinal ganglion cells act as a secondary sensory nucleus, projecting to the thalamus (lateral geniculate body), superior colliculus, pretectum, suprachiasmatic nucleus of the hypothalamus, and other brainstem sites. CNs V and VII–X can be affected by peripheral nerve problems, such as demyelinating disease (Guillain-­Barré syndrome), neuropathies (diabetic), tumors, vascular infarcts, traumas, and other pathology; these nerve problems generally result in loss of the specific sensory modality carried by that nerve. Secondary sensory CN nuclei associated with the peripheral CNs (III–XII) include the trigeminal nuclei (main sensory, descending [spinal] nucleus), nucleus solitarius, cochlear nuclei (dorsal and ventral), and vestibular nuclei (medial, lateral, inferior, superior). These nuclei can be damaged by vascular infarcts, tumors, and other pathology; such pathology often involves other central nuclei and long tracts and produces syndromes that clearly indicate CNS pathology (e.g., UMN damage). Involvement of some secondary sensory cranial nerve nuclei (e.g., the descending nucleus of CN V damaged by a posterior inferior cerebellar artery infarct) results in a dissociated loss of a specific set of modalities (pain and temperature) in the innervated territory (ipsilateral face); a trigeminal nerve lesion on one side results in total anesthesia in the innervated territory.   

272

Regional Neuroscience Medial dissection

Edinger-Westphal nucleus Oculomotor nucleus Trochlear nucleus

Red nucleus

Trochlear nerve (IV)

Oculomotor nerve (III)

Mesencephalic nucleus of trigeminal nerve

Trigeminal nerve (V) and ganglion

Abducens nucleus Internal genu of facial nerve

Principal (main) sensory nucleus of the trigeminus

Facial nucleus Vestibular nuclei

Motor nucleus of trigeminal nerve

Dorsal and ventral cochlear nuclei

Facial nerve (VII)

Superior and inferior salivatory nuclei

Vestibulocochlear nerve (VIII) Abducens nerve (VI)

Solitary tract nucleus

Glossopharyngeal nerve (IX) Dorsal motor (autonomic) nucleus of the vagus (CN X) Hypoglossal nucleus

Hypoglossal nerve (XII) Vagus nerve (X)

Nucleus ambiguus

Accessory nerve (XI)

Spinal nucleus of accessory nerve

Olive Motor (efferent) structures Sensory (afferent) structures Autonomic structures

Spinal tract and spinal nucleus of trigeminal nerve

  11.18 CRANIAL NERVES AND THEIR NUCLEI: SCHEMATIC LATERAL VIEW CN III exits from the ventral and medial surface of the midbrain. CN IV is the only CN to exit from the dorsal surface of the brainstem, in the midbrain near the pons-­midbrain junction. CN V exits from the lateral surface of the mid pons. CN VI exits from the pons medially, just rostral to the medullopontine junction. CNs VII and VIII exit from the cerebellopontine angle at the junction of the medulla and pons. CNs IX and X exit from the lateral part of the medulla and are joined by CN XI, which ascends through the foramen magnum. CN XII exits medially from the preolivary sulcus. These CN sites of entry and exit are important localizing features in the brainstem that permit regional localization of lesions resulting from vascular insults, tumors, and degenerative disorders.

CLINICAL POINT The CN nuclei that contain LMNs are found in two longitudinal columns, including a medial column (CN nuclei III, IV, VI, and XII) and a lateral column (motor CN nuclei V, VII, and nucleus ambiguus). These LMN groups are found in the CNS and send axons into the peripheral nervous system to synapse on their appropriate groups of skeletal muscles using acetylcholine, and they exert important trophic influences on their innervated muscles. An LMN lesion (bulbar polio, amyotrophic lateral sclerosis, and other LMN palsies) results in total paralysis of the affected muscle; atrophy is caused by denervation, loss of tone, and loss of reflexes. Denervated muscles commonly demonstrate denervation hypersensitivity, with resultant fibrillation as seen on an electromyogram. As LMNs die (particularly conspicuous in amyotrophic lateral sclerosis), their agonal electrical responses occur as spontaneous discharges of individual motor units (an LMN and its innervated muscle fibers); each discharge produces a visible fasciculation (or twitch). With some LMN disorders such as polio, if enough neighboring LMNs survive, their axons can sprout and reinnervate previously denervated skeletal muscle fibers; this process must occur within approximately 1 year, or the atrophy becomes permanent. In UMN paralysis, in which the LMNs do not die, the affected muscle fibers are not denervated; reflexes are brisk, tone is increased with passive stretch (spasticity), and pathological reflexes (plantar extensor response) are seen.   

Brainstem and Cerebellum

Supratrochlear nerve Medial rectus muscle

Medial branch Lateral branch

of supraorbital nerve

273

Superior View

Levator palpebrae superioris muscle

Superior oblique muscle

Superior rectus muscle

Nasociliary nerve

Eyeball Lacrimal gland

Cribriform plate of ethmoid bone

Supraorbital nerve

Common annular tendon

Lacrimal nerve

Optic (II) nerve

Lateral rectus muscle Frontal nerve

Optic chiasm

Ophthalmic nerve Maxillary nerve

Pituitary stalk (infundibulum)

Meningeal branch of maxillary nerve

Oculomotor (III) nerve

Mandibular nerve

Trochlear (IV) nerve

Meningeal branch (nervus spinosus) of mandibular nerve

Abducens (VI) nerve Tentorial (meningeal) branch of ophthalmic nerve

Lesser petrosal nerve Greater petrosal nerve Tentorium cerebelli

Trigeminal ganglion

 

11.19 NERVES OF THE ORBIT CN II carries visual information from the ipsilateral retina. Axons from the temporal hemiretinas remain ipsilateral, whereas axons from the nasal hemiretinas cross the midline in the optic chiasm. All axons then enter the optic tract. CNs III (from oculomotor nuclei), IV, and VI innervate the extrinsic muscles of the eye. Sensory portions of the ophthalmic division of V supply general sensation to the cornea and eyeball and provide the afferent limb of the corneal reflex. Motor fibers of CN VII innervate the orbicularis oculi muscle, closing the eye; these fibers constitute the efferent limb of the corneal reflex.

CLINICAL POINT CN II (the optic nerve) is a CNS tract myelinated by oligodendroglia. It can be damaged by demyelinating disease (optic neuritis in multiple sclerosis), by optic nerve gliomas, by ischemic injury (central retinal artery), or by trauma (sphenoid fracture). The resultant defect is ipsilateral blindness or a scotoma (blind spot). The ipsilateral nature of the deficit rules out optic chiasm, optic tract, or central visual lesions. The retina also is CNS tissue and can undergo neurodegenerative changes. Macular degeneration involves damage to the cone-­intensive regions of the retina (macula) and leads to the inability to read and the loss of acuity. Increased intracranial pressure can result in papilledema, a condition in which pressure pushes the optic nerve head inward (toward the center of the eyeball), producing a swollen appearance on ophthalmoscopy. This process takes 24 hours to occur after onset of intracranial pressure; the presence of papilledema is used diagnostically to identify increased intracranial pressure.   

274

Regional Neuroscience A. Superior view with extraocular muscles partially cut away Supratrochlear nerve (cut)

Levator palpebrae superioris muscle (cut) Superior rectus muscle (cut)

Medial and lateral branches of supraorbital nerve (cut)

Lacrimal nerve (cut)

Infratrochlear nerve

Short ciliary nerves

Anterior ethmoidal nerve

Branch of oculomotor nerve to inferior oblique muscle

Long ciliary nerves

Ciliary ganglion

Optic (II) nerve

Motor (parasympathetic) root from oculomotor nerve

Posterior ethmoidal nerve

Sympathetic root from internal carotid plexus

Nasociliary nerve

Sensory root from nasociliary nerve

Ophthalmic nerve

Branches to medial and inferior rectus muscles

Trochlear (IV) nerve (cut)

Abducens (VI) nerve (to lateral rectus muscle)

Oculomotor (III) nerve

Inferior division of oculomotor nerve Superior division of oculomotor nerve

Abducens (VI) nerve

B. Coronal section through the cavernous sinus Optic chiasm Internal carotid artery Diaphragma sellae Oculomotor (III) nerve Trochlear (IV) nerve Pituitary gland Internal carotid artery Abducens (VI) nerve Ophthalmic nerve Cavernous sinus Maxillary nerve

11.20 NERVES OF THE ORBIT (CONTINUED) Parasympathetic preganglionic fibers from the nucleus of Edinger-­ Westphal distribute to the ciliary ganglion, which supplies the pupillary constrictor muscle and the ciliary muscle (accommodation for near vision). Preganglionic parasympathetic axons from the superior salivatory nucleus distribute to the pterygopalatine ganglion, which supplies the lacrimal glands (tear production). Sympathetic postganglionic nerve fibers from the superior cervical ganglion supply the pupillary dilator muscle and the superior tarsal muscle (damage results in mild ptosis). CNs III, IV, VI, and V (ophthalmic and maxillary divisions) traverse the cavernous sinus and are vulnerable to damage by cavernous sinus thrombosis. CLINICAL POINT The extraocular nerves can be damaged by trauma, vascular infarcts, tumors, aneurysms, pressure (compression of CN III against the free edge of the tentorium with transtentorial herniation), or other

 

pathology. Oculomotor palsy (CN III) results in paralysis or weakness of the medial rectus, superior and inferior rectus, inferior oblique, and levator palpebrae superioris muscles. The most conspicuous deficit is the inability to adduct the ipsilateral eye, a lateral strabismus (resulting from unopposed action of the lateral rectus), and diplopia. Damage to the levator palpebrae superioris muscle results in profound ptosis of the ipsilateral eye. Lesions in CN III also disrupt the outflow from the Edinger-­Westphal nucleus to the ciliary ganglion, producing a fixed (unresponsive) and dilated ipsilateral pupil. A lesion in CN IV (trochlear) results in paralysis or weakness of the superior oblique muscle. This muscle is a depressor of the eye when it is directed nasally. Thus, a patient has difficulty walking down stairs and stepping off curbs and has trouble reading while lying down. The patient tries to compensate for a lesion in CN IV by turning the head away from the side of the lesion to avoid having to use the paralyzed muscle. A lesion in CN VI (abducens) results in paralysis or weakness of the ipsilateral lateral rectus muscle, with a resultant medial strabismus and diplopia upon attempted lateral gaze.   

Brainstem and Cerebellum

275

Short ciliary nerves Edinger-Westphal nucleus Long ciliary nerve (autonomic) Oculomotor (III) nerve Optic (II) nerve Oculomotor nucleus Ciliary ganglion Sensory root of ciliary ganglion Trochlear nucleus Sympathetic root of ciliary ganglion Superior division of oculomotor nerve Abducens nucleus Frontal nerve Superior and inferior colliculi Lacrimal nerve

Superior oblique muscle Superior rectus muscle Levator palpebrae superioris muscle

Nasociliary nerve Ophthalmic nerve

Superior tarsal muscle (involuntary)

Sphincter pupillae muscle Dilator pupillae muscle Abducens (VI) nerve Ciliary muscle

Trochlear (IV) nerve

Pterygopalatine ganglion

Oculomotor (III) nerve

Inferior division of oculomotor nerve

Inferior oblique muscle

Mandibular nerve

Medial rectus muscle

Infraorbital nerve Zygomatic nerve

Internal carotid artery and plexus Maxillary nerve

Inferior rectus muscle Motor (parasympathetic) root of ciliary ganglion

Lateral rectus muscle and abducens nerve (turned back) Cavernous plexus Common annular tendon

Levator palpebrae superioris muscle Superior rectus muscle Oculomotor (III) nerve

Medial rectus muscle Inferior rectus muscle Inferior oblique muscle

{ Lateral rectus muscle { Abducens (VI) nerve

Superior oblique muscle Trochlear (IV) nerve

Motor fibers Sensory fibers Parasympathetic fibers Sympathetic fibers

 

11.21 EXTRAOCULAR NERVES (III, IV, AND VI) AND THE CILIARY GANGLION: VIEW IN RELATION TO THE EYE CN VI innervates the lateral rectus muscle; damage results in ipsilateral paralysis of lateral gaze. CN IV innervates the superior oblique muscle; damage results in inability to look in and down (most conspicuous when climbing stairs, stepping off a curb, reading in bed). CN III (oculomotor nuclei) innervates

the medial rectus, superior rectus, inferior rectus, and inferior oblique muscles (damage results in paralysis of the ipsilateral medial gaze) and also innervates the levator palpebrae superioris muscle (damage results in profound ptosis). The ciliary ganglion gives rise to postganglionic parasympathetic axons that supply the pupillary constrictor muscle and the ciliary muscle; damage results in a fixed and dilated pupil that does not constrict for the pupillary light reflex and does not accommodate to near vision.

276

Regional Neuroscience

Motor fibers Sensory fibers

Ophthalmic nerve

Proprioceptive fibers

Tentorial (meningeal) branch

Parasympathetic fibers Sympathetic fibers

Trigeminal (V) nerve and trigeminal (semilunar) ganglion

Nasociliary nerve Sensory root of ciliary ganglion Lacrimal nerve Frontal nerve Ciliary ganglion

Motor nucleus of trigeminal nerve Mesencephalic nucleus of trigeminal nerve (proprioception) Principal sensory nucleus of trigeminal nerve (discriminatory sensation)

Posterior ethmoidal nerve

Spinal tract and spinal nucleus of trigeminal nerve (pain and temperature)

Long ciliary nerve Short ciliary nerves Supratrochlear nerve Supraorbital nerve (medial and lateral branches) Anterior ethmoidal nerve Infratrochlear nerve External nasal and internal nasal (medial and lateral rami) branches of anterior ethmoidal nerve Maxillary nerve Meningeal branch Zygomaticotemporal nerve Zygomaticofacial nerve Zygomatic nerve Infraorbital nerve

Facial (VII) nerve

Ganglionic branches and pterygopalatine ganglion Superior alveolar branches (anterior, middle, posterior) of infraorbital nerve Nasal branches (posterosuperior lateral, nasopalatine and posterosuperior medial)

Chorda tympani Superficial temporal branches Articular and auricular branches

Nerve of pterygoid canal

Auriculotemporal nerve

Pharyngeal branch

Parotid branches

Palatine nerves; major (anterior), minor (middle and posterior)

Meningeal (nervus spinosus) branch Lesser petrosal nerve (from glossopharyngeal nerve)

Deep temporal nerves (anterior, middle, and posterior) to temporalis muscle

Tensor tympani nerve

Lateral pterygoid and masseteric nerves

Otic ganglion

Buccal nerve Mental nerve Tensor veli palatini and medial pterygoid nerves Inferior dental plexus (inferior dental and gingival nerves)

 

11.22 TRIGEMINAL NERVE (V)

See next page.

Inferior alveolar nerve

Lingual nerve Submandibular ganglion

Mylohyoid nerve (to mylohyoid and anterior belly of digastric muscles) Mandibular nerve

Brainstem and Cerebellum

11.22 TRIGEMINAL NERVE (V) The trigeminal nerve (CN V) carries sensory information from the face, sinuses, teeth, and anterior portion of the oral cavity. It has three subdivisions: (1) ophthalmic—sensory innervation, (2) maxillary—sensory innervation, and (3) mandibular—sensory innervation and motor innervation of the masticatory muscles and tensor tympani muscles. Each of the subdivisions has a distinct distribution and sharp boundaries. Unlike the somatosensory dermatomes, which exhibit considerable overlap with nerve fibers of adjacent roots, the trigeminal subdivisions show no overlap at all. Damage to one of the subdivisions results in total anesthesia in the territory of sensory distribution. Primary sensory axons from trigeminal (semilunar, gasserian) ganglion cells that process fine, discriminative touch (epicritic sensation) terminate in the main sensory nucleus of CN V and the rostral portion of the descending (spinal) nucleus of CN V. Axons that process pain and temperature sensation (protopathic sensation) terminate in the caudal and middle regions of the descending (spinal) nucleus of CN V. The trigeminal nerve also carries proprioceptive information from muscle spindles in muscles of mastication and extraocular muscles. Those primary sensory cell bodies are found in the mesencephalic nucleus of CN V within the CNS, the only example of primary sensory neurons residing in the CNS.

277

CLINICAL POINT Trigeminal neuralgia (tic douloureux) involves sudden, brief (lasting less than a minute), excruciating paroxysms of pain, sometimes described as stabbing or lancinating, usually in the territory of one of the divisions of the trigeminal nerve. The maxillary and mandibular divisions are more common targets than the ophthalmic division, and the disorder is more common in older individuals. These episodes of pain may recur several times a day, with paroxysms experienced for weeks on end. Often there is a trigger point, at which mild stimuli such as light touch, chewing, or even talking can provoke an attack. During an attack, no loss of sensation occurs in the distribution of the affected branch. Trigeminal neuralgia can be idiopathic or symptomatic of other disorders. In some cases, compression of the trigeminal nerve root by a small aberrant branch of the superior cerebellar artery or another nearby artery is the suspected cause; in other cases a tumor, an inflammation, or a demyelinating plaque may precipitate such attacks. If trigeminal neuralgia occurs in the accompaniment of other progressive pathology, the neurological examination reveals sensory and motor deficits associated with the involved branch of the trigeminal nerve. Idiopathic trigeminal neuralgia usually can be treated with carbamazepine or other antiseizure and membrane-­stabilizing agents, which sometimes permits the condition to regress. Surgical decompression of a compressing blood vessel may help. In other cases, the nerve root is ablated temporarily or permanently; the resultant functional deficit is often better tolerated than the excruciating paroxysms of pain.   

278

Regional Neuroscience

Enamel Dentine and dentinal tubules Crown

Interglobular spaces Odontoblast layer Interproximal spaces Dental pulp containing vessels and nerves Gingival (gum) epithelium (stratified)

Neck

Gingival groove Lamina propria of gingiva (gum) (mandibular or maxillary periosteum) Periodontium (alveolar periosteum) Papilla Cement

Root

Root (central) canals containing vessels and nerves Bone Apical foramina

Left upper permanent teeth: labiobuccal view

Left lower permanent teeth: labiobuccal view

Central Lateral Incisors

Canines (cuspids)

11.23 INNERVATION OF THE TEETH Sensory nerve fibers of the maxillary (upper teeth) and mandibular (lower teeth) subdivisions of the trigeminal nerve innervate the dental pulp of the teeth. With erosion of a lesion (decay) into

1

2 Premolars

1

2 Molars

3

 

the dental pulp or close to the dental pulp, these nerve fibers may become exquisitely sensitive to temperature changes (especially cold) or pressure (by edema or mechanical force), resulting in the sensation of severe pain.

279

Brainstem and Cerebellum

Motor fibers

Carotid plexus (on internal carotid artery)

Greater petrosal nerve

Sensory fibers Sympathetic fibers

Geniculate ganglion

Deep petrosal nerve

Parasympathetic fibers

Facial (VII) nerve

Lesser petrosal nerve

Motor root of facial nerve

Nerve of pterygoid canal

Internal acoustic meatus

Otic ganglion

Nervus intermedius (of facial nerve) Motor nucleus of facial nerve

Pterygopalatine ganglion

Superior salivatory nucleus Facial muscles

Nucleus of the solitary tract

Occipitofrontalis muscle (frontal belly) Orbicularis oculi muscle Corrugator supercilii muscle Zygomaticus major muscle Zygomaticus minor muscle

Procerus muscle Levator labii superioris muscle

es

Levator labii superioris alaeque nasi muscle

anch Temporal br

Depressor supercilii muscle

Levator anguli oris muscle Nasalis muscle

Occipital branch of posterior auricular nerve

nch

Depressor septi muscle

Occipitofrontalis muscle (occipital belly)

Zygomatic branc hes o t n 3 / g 2 ue : ant. Buccal e t s Ta branches l bra

Orbicularis oris muscle

Mentalis muscle Transversus menti muscle

Marginal mandibular branch

Platysma

Posterior auricular nerve Nerve to stapedius muscle Stylomastoid foramen

Risorius muscle Buccinator muscle

Branches to auricular muscles

Cervi ca

Depressor labii inferioris muscle

Tympanic plexus Tympanic nerve

Sublingual gland

Glossopharyngeal (IX) nerve

Submandibular gland Submandibular ganglion

Posterior belly of digastric muscle Stylohyoid muscle

Lingual nerve Chorda tympani

11.24 FACIAL NERVE (VII) The facial nerve (VII) is a mixed nerve with motor, parasympathetic, and sensory components. The motor fibers distribute to the muscles of facial expression, including the scalp, the auricle, the buccinator, the stapedius, and the stylohyoid muscles, and to the posterior belly of the digastric muscle. Damage results in ipsilateral paralysis of facial expression, including the forehead (Bell’s palsy); facial palsy caused by central corticobulbar lesions spare the upper face. Activation of the stapedius muscle dampens the ossicles in the presence of sustained loud noise; damage to CN

Caroticotympanic nerve

 

VII results in hyperacusis. Parasympathetic nerve fibers of CN VII from the superior salivatory nucleus distribute to the pterygopalatine ganglion, which innervates the lacrimal glands, and to the submandibular ganglion, which innervates the submandibular and sublingual salivary glands. Special sensory taste fibers from the anterior two-thirds of the tongue (via the chorda tympani) and the soft palate (via the greater petrosal nerve), whose primary sensory cell bodies are located in the geniculate ganglion, convey that information to the rostral portion of nucleus solitarius in the medulla.

280

Regional Neuroscience Temporal branches Parotid gland

Zygomatic branches

Posterior auricular nerve

Parotid duct

Main trunk of facial nerve emerging from stylomastoid foramen

Buccal branches

Nerve to posterior belly of digastric muscle and to stylohyoid muscle

Marginal mandibular branch

Cervical branch

Medial pterygoid muscle

Horizontal section

Ramus of mandible

Main trunk of facial nerve

Masseter muscle

Mastoid process

Parotid gland

Temporofacial division

Temporal branch

Posterior auricular nerve

Zygomatic branches

Main trunk of facial nerve Buccal branches

Nerve to posterior belly of digastric muscle and to stylohyoid muscle Cervicofacial division

Marginal mandibular branch Cervical branch

 

11.25 FACIAL NERVE BRANCHES AND THE PAROTID GLAND The facial nerve and its branches directly penetrate the parotid gland. Surgical procedures in this region of the face, particularly those performed to remove mass lesions, may damage the facial nerve, resulting in facial palsy in affected muscles. CLINICAL POINT Bell’s palsy, the most common disorder of CN VII, usually occurs acutely, over the course of a few hours to a day or so, and results in weak or paralyzed muscles on one side of the face. Some patients report previous retroauricular pain, decreased tearing, or hyperacusis for a day or two. The facial palsy involves all of the muscles on the affected side, unlike a central facial palsy resulting from a lesion in the contralateral genu of the internal capsule, which affects only the lower part of the face. In Bell’s palsy, the ipsilateral forehead does not wrinkle,

the eye cannot be closed, the face appears smooth, and the corner of the mouth droops. Viral infections (especially herpes simplex I) or inflammation may precipitate Bell’s palsy; less commonly, Lyme disease, HIV, diabetes, sarcoidosis, or another infection may be the cause. Sensory loss is not part of the disorder, although loss of taste sensation on the anterior two-thirds of the tongue, supplied by CN VII, may occur if the nerve is affected proximal to its merging with the chorda tympani. Involvement of the nerve to the stapedius muscle results in sensitivity to loud sounds (hyperacusis). Recovery can occur within a few weeks or months, particularly if only partial damage to the nerve has occurred and only some weakness has been present. With profound paralysis of facial muscles, the regenerative process may take as long as 2 years. During such a regenerative process, some regenerating nerve fibers may sprout to aberrant sites; former autonomic fibers that innervated salivary glands may be redirected to the lacrimal glands, resulting in “crocodile tears” or an abnormal gustatory-­lacrimal reflex. Some aberrant regenerating facial nerve fibers may reach the wrong muscle fibers, resulting in tics, spasms, dyskinesias, or contractures.   

281

Brainstem and Cerebellum

Facial palsy: sites of facial (VII) nerve injury Occipitofrontalis muscle

Facial (VII) nerve

Orbicularis oculi muscle

Acoustic (VIII) nerve

Lacrimal gland Corrugator supercilii muscle

Pterygopalatine Geniculate ganglion ganglion

Pons

Greater petrosal nerve

Temporal branch

2 3

Stapedius muscle

Facial nucleus 4

Tympanum

Stylomastoid foramen

Lingual nerve

Tongue

Posterior auricular nerve 5

Orbicularis oris muscle

Abducens nucleus

1

Chorda tympani Parotid gland Buccal branch

Marginal mandibular branch Cervical branch Levator anguli oris muscle Depressor anguli oris muscle

Sublingual gland Risorius muscle

Zygomatic branch Platysma muscle Submandibular ganglion Submandibular gland Buccinator muscle

Sites of lesions and their manifestations 1. Intrapontine lesions: Peripheral motor facial paralysis associated with eye movement abnormalities (ipsilateral abducens or horizontal gaze palsies) and contralateral motor paralysis. 2. Intracranial and/or internal auditory meatus: All symptoms of 3, 4, and 5, plus deafness due to involvement of eighth cranial nerve. 3. Geniculate ganglion: All symptoms of 4 and 5 with diminished lacrimation, plus pain behind ear. Herpes of tympanum and of external auditory meatus may occur. 4. Facial canal: All symptoms of 5, plus loss of taste in anterior tongue and decreased salivation on affected side due to chorda tympani involvement. Hyperacusis due to effect on nerve branch to stapedius muscle. 5. Below stylomastoid foramen (parotid gland tumor, trauma): Facial paralysis (mouth draws to opposite side) on affected side with patient unable to close eye or wrinkle forehead; food collects between teeth and cheek due to paralysis of buccinator muscle.

 

11.26 FACIAL NERVE LESIONS AND THEIR MANIFESTATIONS The hallmark of a facial nerve lesion is paralysis of the facial muscles on the ipsilateral side, including the muscles of the upper face. Depending on the site of damage, loss of taste on the anterior

two-­thirds of the tongue, decreased salivation, hyperacusis, decreased lacrimation, and pain behind the ear may occur as additional components of damage to CN VII. More proximal lesions that affect CN VII also may damage CN VIII (deafness) and other cranial nerves (eye movement and gaze palsies).

282

Regional Neuroscience

Greater petrosal nerve Spiral ganglion of cochlea

Geniculate ganglion of facial nerve

Cochlear part of vestibulocochlear nerve

Facial canal

Motor root of facial nerve and nervus intermedius

Head of malleus Tympanic cavity

Vestibulocochlear (VIII) nerve

Incus Chorda tympani

Medulla oblongata

Ampulla of superior semicircular duct Ampulla of lateral semicircular duct Utricle Ampulla of posterior semicircular duct Saccule Internal acoustic meatus

Inferior division

Medial Vestibular nuclei

Inferior Superior Lateral

Superior division

Ventral Dorsal

of vestibular part of vestibulocochlear nerve

Vestibular ganglion

Cochlear nuclei

Vestibular part of vestibulocochlear nerve

Inferior cerebellar peduncle (to cerebellum)

 

11.27 VESTIBULOCOCHLEAR NERVE (VIII) The vestibulocochlear nerve (CN VIII) arises from bipolar primary sensory neurons in the vestibular ganglion (Scarpa’s ganglion) and the spiral (cochlear) ganglion. The peripheral process of the vestibular ganglion neurons innervates hair cells in the utricle and saccule that respond to linear acceleration (gravity) and in the ampullae of the semicircular ducts that respond to angular acceleration (movement). The utricle, the saccule, and the semicircular ducts provide neural signals for coordination and equilibration of position and for movement of the head and neck. The central processes of the vestibular ganglion cells terminate in vestibular nuclei (medial, lateral, superior, and inferior) in the medulla and pons and in the cerebellum. The peripheral processes of spiral ganglion cells innervate hair cells that lie along the cochlear duct in the organ of Corti. They convey hearing information via central axonal processes into the cochlear nuclei (dorsal and ventral). A lesion in CN VIII results in ipsilateral deafness, vertigo, and loss of equilibrium.

CLINICAL POINT The vestibulocochlear nerve emerges from the ventrolateral margin of the brainstem near the junction of the medulla, pons, and cerebellum (the cerebellopontine angle). At this site, Schwann cell tumors of CN VIII, acoustic schwannomas, can arise, usually from the vestibular portion of CN VIII. Initial irritation of the vestibular division of CN VIII can result in vertigo, dizziness, nausea, and unsteadiness or spatial disorientation. These symptoms persist with nerve destruction. Initial irritation of the auditory division of CN VIII by a schwannoma may first produce tinnitus, followed by slow loss of hearing and the inability to determine the direction from which a sound is coming. As nerve destruction occurs, tinnitus diminishes and ipsilateral deafness ensues. Because of the proximity of CNs VII and VIII, acoustic schwannomas also often produce ipsilateral facial paralysis or palsy. The tumor may extend rostrally to the trigeminal nerve or caudally to the glossopharyngeal and vagus nerves and also may affect the adjacent brainstem and cerebellum. At this point, hydrocephalus and increased intracranial pressure can occur.   

Brainstem and Cerebellum Tympanic nerve Tympanic cavity and plexus Stylomastoid foramen Parasympathetic Caroticotympanic nerve fibers Greater petrosal nerve Deep petrosal nerve Lesser petrosal nerve Nerve of pterygoid canal Pterygopalatine ganglion Sensory fibers

283

Geniculate ganglion of facial nerve

Motor fibers

Inferior salivatory nucleus

Mandibular nerve

Solitary tract nucleus

Otic ganglion Auriculotemporal nerve

Spinal tract and descending (spinal) nucleus of trigeminal (V) nerve

Parotid gland

Nucleus ambiguus

Tubal branch of tympanic plexus Auditory (eustachian) tube and pharyngeal opening

Glossopharyngeal (IX) nerve Jugular foramen

Stylopharyngeus muscle and nerve Pharyngeal plexus

Communication to auricular branch of vagus nerve Superior and inferior ganglia of glossopharyngeal nerve Communication to facial nerve Superior cervical sympathetic ganglion Vagus (X) nerve Pharyngeal branch of vagus nerve

Taste and general sensation from posterior 1/3 of tongue: Taste to rostral solitary tract nucleus; general sensation to descending (spinal) nucleus of trigeminal (V) nerve

Sympathetic trunk

Carotid sinus branch of glossopharyngeal nerve Internal carotid artery Carotid body Carotid sinus

Pharyngeal, tonsillar, and lingual branches of glossopharyngeal nerve

Common carotid artery

  11.28 GLOSSOPHARYNGEAL NERVE (IX) CN IX is a mixed nerve with motor, parasympathetic, and sensory components. Motor fibers from the nucleus ambiguus supply the stylopharyngeus muscle and may assist in the innervation of pharyngeal muscles for swallowing. Preganglionic parasympathetic axons from the inferior salivatory nucleus travel with CN IX to the otic ganglion, whose neurons innervate the parotid and mucous glands. Special sensory axons from the petrosal (inferior) ganglion carry information from taste buds on the posterior onethird of the tongue (including numerous taste buds in the vallate papillae) and part of the soft palate. These axons terminate in the rostral portion of nucleus solitarius. Axons from additional primary sensory neurons in the inferior ganglion also carry general sensation from the posterior one-third of the tongue and from the pharynx, the fauces, the tonsils, the tympanic cavity, the eustachian tube, and the mastoid cells. The central axon branches terminate in the descending (spinal) nucleus of CN V. The general sensory fibers from the pharynx provide the afferent limb of the gag reflex. Additional primary sensory neurons innervate the

carotid body (chemoreception of carbon dioxide) and the carotid sinus (baroceptors) and convey their central axons to the caudal nucleus solitarius (solitary tract nucleus). Primary sensory neurons in the superior ganglion innervate a small region behind the ear and convey general sensation into the descending nucleus of CN V. CLINICAL POINT The glossopharyngeal nerve can be affected by brief, excruciating paroxysms of pain (glossopharyngeal neuralgia) similar to those experienced in trigeminal neuralgia. The pain originates in the throat (tonsillar fossa) or sometimes the jaw and radiates to the ear. Some patients experience pain in the tongue, face, or jaw. The triggering activity is usually swallowing, coughing, sneezing, or yawning. If the irritative process activates glossopharyngeal afferents associated with brainstem vasomotor responses, the patient may experience bradycardia and syncope. The treatment of glossopharyngeal neuralgia is similar to treatment of trigeminal neuralgia. Successful treatment also has occurred surgically through decompression of a tortuous aberrant vessel.   

284

Regional Neuroscience

Nucleus ambiguus

Cranial root of accessory nerve (joins vagus nerve to supply muscles of larynx — except cricothyroid — via recurrent laryngeal nerve)

Jugular foramen Superior ganglion of vagus nerve

Vagus (X) nerve

Accessory (XI) nerve

Spinal root of accessory nerve

Internal branch of accessory nerve Inferior ganglion of vagus nerve 1st spinal nerve (C1)

Foramen magnum 2nd spinal nerve (C2) External branch of accessory nerve (to sternocleidomastoid and trapezius muscles)

Sternocleidomastoid muscle 3rd spinal nerve (C3) 4th spinal nerve (C4) Trapezius muscle

Motor fibers Proprioceptive fibers

  11.29 ACCESSORY NERVE (XI) The accessory nerve (CN XI) is a motor nerve with cranial and spinal portions. The cranial portion arises from LMNs at the caudal end of the nucleus ambiguus; the axons travel through an internal branch that distributes with the pharyngeal and laryngeal branches of the vagus nerve (CN X) and with nerves to the soft palate. These axons often are considered to be part of CN X. The spinal portion arises from LMNs in the lateral part of the upper four or five segments of the cervical spinal cord. The axons then emerge as rootlets from the lateral margin of the spinal cord, ascend behind the denticulate ligaments, and coalesce as a single nerve. This nerve then ascends through the foramen magnum and joins the vagus nerve to exit through the jugular foramen. The LMNs of the spinal accessory nerve supply the sternocleidomastoid muscle and the upper two-thirds of the trapezius muscle. Damage to this division of CN XI results in weakness in head rotation and shoulder elevation.

CLINICAL POINT The cranial portion of the accessory nerve is derived from the nucleus ambiguus and has been considered to be part of the vagal complex. The spinal accessory nerve derives from LMNs of the upper segments (C1–C4) of the cervical spinal cord; it ascends through the foramen magnus and emerges with cranial nerves IX and X through the jugular foramen. Tumors, meningitis, and trauma may damage CN XI, although these lesions commonly damage nerves IX and X as well. LMN disorders, such as polio or amyotrophic lateral sclerosis or compression of the foramen magnum as in Arnold-­Chiari malformation, can damage the spinal accessory nerve on one side. This results in ipsilateral flaccid paralysis of the sternocleidomastoid muscle and the upper two-thirds of the trapezius, causing atrophy and loss of tone. The patient has great difficulty turning his or her head to the opposite side (sternocleidomastoid). The shoulder hangs downward, with caudal and lateral displacement of the scapula, and the arm cannot be raised more than 90 degrees. In circumstances in which bilateral damage occurs to the spinal accessory nucleus (as in amyotrophic lateral sclerosis), the bilateral denervation of the sternocleidomastoid leaves the patient unable to hold up his or her head.   

Brainstem and Cerebellum Vagus (X) Nerve

Glossopharyngeal (IX) nerve Meningeal branch of vagus nerve Auricular branch of vagus nerve Auditory (eustachian) tube

285

Dorsal (motor) nucleus of CN X Solitary tract nucleus Spinal tract and spinal nucleus of trigeminal nerve

Levator veli palatini muscle Salpingopharyngeus muscle

Nucleus ambiguus (voluntary motor)

Palatoglossus

Cranial root of accessory nerve Vagus (X) nerve

Palatopharyngeus Superior constrictor muscle of pharynx

Jugular foramen Superior ganglion of vagus nerve

Stylopharyngeus muscle

Inferior ganglion of vagus nerve Pharyngeal branch of vagus nerve (motor to muscles of pharynx and palate; sensory to lower pharynx)

Middle constrictor muscle of pharynx Inferior constrictor muscle of pharynx

Vagal branch to carotid sinus branch of glossopharyngeal nerve

Cricothyroid muscle Trachea Esophagus Right recurrent laryngeal nerve

Pharyngeal plexus Internal branch (sensory) External branch (motor to cricothyroid muscle) Superior laryngeal nerve Superior cervical cardiac branch of vagus nerve Inferior cervical cardiac branch of vagus nerve Thoracic cardiac branch of vagus nerve Left recurrent laryngeal nerve (motor to muscles of larynx except cricothyroid; parasympathetic, motor, and sensory to upper esophagus and trachea)

Motor fibers Afferent fibers Parasympathetic fibers

Heart Hepatic branch of anterior vagal trunk (in lesser omentum) Celiac branches (from anterior and posterior vagal trunks to celiac plexus)

Pulmonary plexus Cardiac plexus

Pyloric branch from hepatic plexus

Esophageal plexus Anterior vagal trunk Gastric branches of anterior vagal trunk

Liver

Vagal branches (parasympathetic motor, secretomotor and sensory fibers) accompany superior mesenteric artery and its branches to small intestine, cecum, appendix, and colon, often as far as left colic (splenic) flexure

Gallbladder and bile ducts Pancreas Duodenum Ascending colon Cecum Appendix

Small intestine

  11.30 VAGUS NERVE (X) The vagus nerve (CN X) is a mixed nerve with motor, parasympathetic, and sensory components. LMN axons from neurons in the nucleus ambiguus in the medulla supply muscles of the soft palate, the pharynx, and the larynx and control speaking and swallowing. A lesion in these axons results in hoarseness, dysphagia, and decreased gag reflex (efferent limb). Preganglionic parasympathetic axons from neurons in the dorsal motor (autonomic) nucleus of CN X in the medulla distribute to intramural ganglia associated with thoracic and abdominal viscera and supply autonomic innervation to the heart, the lungs, and the gastrointestinal tract to the descending colon. Special sensory axons from the nodose (inferior) ganglion, which carry information from taste buds in the posterior pharynx (found mainly in children), send central branches to terminate in the rostral nucleus solitarius. Primary sensory axons from the inferior ganglion also convey general sensation from the larynx, the pharynx, and the thoracic and

abdominal viscera and terminate mainly in the caudal nucleus solitarius. Primary sensory axons from the superior (jugular) ganglion convey general sensation from the external auditory meatus and terminate in the descending (spinal) nucleus of CN V. CLINICAL POINT The vagus nerve emerges from the lateral surface of the medulla and can be involved in both intracranial and extracranial pathology. Intracranially, this nerve can be damaged by a tumor, hematoma, vascular infarct, aneurysm, meningitis, and other disorders. Extracranially, the vagus nerve can be damaged by a tumor, aneurysm, trauma, or infectious process. Unilateral damage to the vagus nerve results in (1) drooping of the soft palate, with the intact contralateral soft palate pulled to the opposite side during phonation, accompanied by nasal speech; (2) hoarseness resulting from involvement of the nucleus ambiguus fibers that extend to the laryngeal muscles; (3) ipsilateral laryngeal anesthesia; and (4) tachycardia and arrhythmias in some instances.   

286

Regional Neuroscience

Styloglossus muscle

Meningeal branch

Hypoglossal nucleus

Intrinsic musculature of tongue Inferior longitudinal

Transverse and vertical

Hypoglossal (XII) nerve (in hypoglossal canal)

Superior longitudinal

Occipital condyle Inferior ganglion of vagus nerve Ventral rami of C1, C2, and C3 forming cervical plexus Superior cervical sympathetic trunk ganglion Superior root (descendens hypoglossi) of ansa cervicalis Genioglossus muscle

Internal carotid artery

Geniohyoid muscle

Inferior root (descendens hypoglossi) of ansa cervicalis

Hyoglossus muscle Thyrohyoid muscle

Ansa cervicalis (ansa hypoglossi)

Omohyoid muscle (superior belly) Internal jugular vein Sternothyroid muscle

Omohyoid muscle (inferior belly)

Sternohyoid muscle

Motor fibers

 

Sensory fibers

11.31 HYPOGLOSSAL NERVE (XII) The hypoglossal nerve (CN XII) is a motor nerve. LMNs in the hypoglossal nucleus of the caudal medulla exit from the ventral surface of the medulla in the preolivary sulcus (between the medullary pyramid and the inferior olive) to innervate the extrinsic muscles of the tongue (the hyoglossus, styloglossus, chondroglossus, and genioglossus muscles) and the intrinsic muscles of the tongue (the superior and inferior longitudinal, transverse, and vertical lingual muscles). Damage to this nerve leads to weakness of the ipsilateral tongue muscles; the tongue, when protruded, deviates toward the weak side because of the unopposed action of the innervated contralateral genioglossus muscle.

CLINICAL POINT The hypoglossal nerve emerges from the ventral surface of the medulla just lateral to the medullary pyramids. The emerging hypoglossal nerve fibers can be damaged intracranially by a paramedian infarct (which also damages the pyramid and medial lemniscus, producing a so-­called alternating hemiplegia) or can be damaged peripherally by a meningeal tumor, metastatic tumor, or bony overgrowth or as an unwanted consequence of a carotid endarterectomy. Hypoglossal nerve damage on one side produces flaccid paralysis of the ipsilateral tongue musculature, accompanied by atrophy. An attempt to protrude the tongue results in deviation of the tongue toward the weak side because of the unopposed actions of the intact genioglossus muscle. As damage to CN XII progresses, fasciculations can be seen on the ipsilateral tongue up to the point where total denervation occurs.   

Brainstem and Cerebellum

287

Dopaminergic cell groups Raphe nuclei 1. Obscurus, pallidus 2. Magnus 3. Pontis 4. Dorsalis, centralis superior

Cerebral aqueduct and periaqueductal gray matter 4 Paramedian reticular formation

Raphe nuclei

Lateral reticular formation and nuclei 3

Medial reticular formation

2

Respiratory nuclei

Raphe nuclei 1

Nucleus raphe pallidus midline neurons

Major noradrenergic and adrenergic cell groups

Dendrites

Nucleus raphe pallidus midline neurons with dendrites extending dorsally, ventrally, and laterally, and contributing to the formation of dendrite bundles, which help to coordinate firing of contributing neurons of this serotonergic reticular formation group. Golgi-Cox stain.

Medial longitudinal fasciculus

Nucleus raphe dorsalis neuron Nucleus raphe dorsalis neuron within the medial longitudinal fasciculus, with widespread dendrites branching into multiple regions. Golgi stain.

 

RETICULAR FORMATION 11.32 RETICULAR FORMATION: GENERAL PATTERN OF NUCLEI IN THE BRAINSTEM The reticular formation (RF), the neuronal core of the brainstem, consists of neurons with characteristic isodendritic morphology. The RF extends from the rostral spinal cord through the hypothalamus into the septal region. RF neurons are large cells with axonal arborizations that terminate at a distance from their cell bodies and dendritic tree; they are not interneurons. The major nuclei of the RF are

found in a lateral zone (predominantly sensory functions), a medial zone (predominantly motor functions), and a column of raphe nuclei (serotonergic neurons). The serotonergic neurons exert mainly modulatory influences on their targets. The catecholaminergic neurons (locus coeruleus, tegmental noradrenergic, and adrenergic groups) in several regions of the RF have widespread projections and exert mainly modulatory influences on their targets. The dopaminergic neurons of the midbrain are included in this illustration, although some experts question whether they are RF neurons.

288

Regional Neuroscience

A. Thalamus and hypothalamus

Thalamus: Intralaminar nuclei Reticular nucleus of thalamus Midline nuclei Lateral hypothalamic area through septal nuclei

Lateral RF of the midbrain

B. Midbrain

Substantia nigra

Periaqueductal gray matter Raphe nuclei (dorsal, central superior) Ventral tegmental area

Interpeduncular nucleus

C. Pons

Locus coeruleus A5 Raphe nuclei (pontis)

Parabrachial nucleus Parapontine RF (lateral gaze center) Pontine RF (pontis, caudalis, oralis)

Lateral RF

A2

D. Medulla

Lateral RF Medullary RF (gigantocellular)

Raphe nuclei (obscurus, pallidus, magnus)

Respiratory nuclei Rostral ventrolateral medulla (RVLM) A1 Lateral reticular nucleus

E. Spinal cord–medullary junction

Lamina 7 - caudal RF

 

11.33 RETICULAR FORMATION: NUCLEI AND AREAS IN THE BRAINSTEM AND DIENCEPHALON Many of the named nuclei of the RF are present in the medulla, the pons, and the midbrain. Important medial RF groups include the medullary (gigantocellular) and the pontine (caudal and rostral) RF regions, which are involved in reticulospinal regulation of spinal cord LMNs, and the parapontine RF, also known as the horizontal (lateral) gaze center. Lateral RF areas and nuclei (such as the lateral reticular nucleus) are involved in polymodal sensory

functions. RF respiratory and cardiovascular neurons are found in the medulla. Catecholaminergic neurons are found in the locus coeruleus (group A6) and tegmental groups denoted here as groups A1, A2, and A5 (norepinephrine-­containing neurons). Raphe nuclei are found in the midline and in wings of cells that extend laterally. The core of the RF continues rostrally from the lateral regions of the brainstem into the lateral hypothalamic area and extends through the hypothalamus to the septal nuclei. Several thalamic nuclei (intralaminar, midline, and reticular nucleus of the thalamus) also are classified as part of the RF.

289

Brainstem and Cerebellum

A. Major afferent connections to the reticular formation Olfactory input via median forebrain bundle

Cerebral cortex Corticoreticular

Hypothalamus Lateral hypothalamic area, other nuclei

Globus pallidus Pallidotegmental tract

Reticular formation

Limbic formation Amygdala, septal nuclei, habenula, insular cortex, bed nucleus of stria terminalis

Cerebellar deep nuclei

Spinal cord Sensory sources

Brainstem Trigeminal nucleus, vestibular nucleus, cochlear nucleus, other auditory nuclei, nucleus of the solitary tract, superior colliculus (deep layers)

B. Major efferent connections from the reticular formation Hypothalamus, septum

Cortex Motor areas Cortex

Arousal

Thalamus Intralaminar nucleus

Limbic forebrain areas Hippocampal formation, amygdaloid nucleus, nucleus accumbens, olfactory tubercle, cingulate, prefrontal, insular cortex

via mammillary peduncles

Striatum Ascending reticular activating system (ARAS) (Lateral RF Medial RF) 1 2 Reticular formation

6

Reticular formation

3 4

Spinal cord motor regions via reticulospinal tracts

Spinal cord autonomic regions T1–L2 intermediolateral cell column, S2–S4 intermediate gray

Cerebellum Brainstem autonomic centers Nucleus of the solitary tract Multiple brainstem regions for set-point modulation

Spinal cord sensory regions Dorsal horn for nociceptive modulation

1 From lateral reticular nucleus Nucleus reticularis tegmenti pontis, paramedian reticular nucleus, locus coeruleus, raphe nuclei

2 From locus coeruleus, raphe nuclei, ventral tegmental area

3 Via median forebrain bundle, dorsal longitudinal fasciculus, habenulopeduncular tract, mammillotegmental tract

4 From adrenergic, noradrenergic (tegmental and locus coeruleus), serotonergic (raphe) nuclei

5 Including ventrolateral and ventromedial tegmentum of caudal brainstem

6 Intra-reticular connections

11.34 MAJOR AFFERENT AND EFFERENT CONNECTIONS TO THE RETICULAR FORMATION A, Extensive sensory information from spinal cord somatosensory sources (particularly nociceptive information) and from virtually all brainstem sensory modalities is sent to the lateral regions of the RF. Olfactory input arrives through olfactory tract projections into forebrain regions. Many limbic and hypothalamic structures provide input into the RF, particularly for visceral and autonomic regulatory functions. The cerebral cortex, the globus pallidus, and the cerebellum also provide input into the RF medial zones involved in motor regulation. B, The ascending reticular activating system (ARAS) of the RF is responsible for consciousness and arousal.

5

 

It projects through nonspecific nuclei of the thalamus to the cerebral cortex; lesions in this area lead to coma. The RF sends extensive axonal projections to sensory, motor, and autonomic regions of the spinal cord, modulating nociceptive input, preganglionic autonomic outflow, and LMN outflow, respectively. The RF sends extensive connections to brainstem nuclei (such as nucleus tractus solitarius) and to autonomic regulatory centers and nuclei for modulation of visceral functions. Efferent RF projections to the hypothalamus, septal nuclei, and limbic forebrain areas help to modulate visceral autonomic functions, neuroendocrine outflow, and emotional responsiveness and behavior. Efferent RF projections to the cerebellum and basal ganglia participate in modulating UMN control of LMNs.

Thalamus

Laterodorsal and pedunculopontine tegmental nuclei (ACh)

Locus coeruleus (NE)

on

mati

r for

Preoptic hypothalamic areas (ventrolateral preoptic area and median preoptic area) (GABA, Gal) Interleukins; Ventral periother blood-borne aqueductal substances gray (DA)

Sensory input

cula

Suprachiasmatic nucleus

Parabrachial nucleus (DA)

Reti

Nucleus From retina basalis (ACh)

To pineal (melatonin) Area postrema Nucleus tractus solitarius

Raphe nuclei (5-HT)

Areas associated with arousal

Sensory input

Areas associated with the induction of sleep

11.35 SLEEP-­WAKEFULNESS CONTROL Sleep is a normal physiological state involving a cyclic temporary loss of consciousness; it is readily reversed by appropriate sensory stimuli. Sleep is an active process initiated by brain activity in several chemical-­specific collections of neurons of the brain: (1) the locus coeruleus of the pons (noradrenergic); (2) the raphe nuclei of the medulla and pons (serotonergic); (3) the nucleus solitarius of the medulla; (4) the cholinergic neurons of the brainstem tegmentum (laterodorsal and pedunculopontine tegmental nuclei); (5) ventral periaqueductal gray (dopaminergic); (6) parabrachial nuclei; (7) the lateral RF, particularly in the pons; (8) several regions of the hypothalamus (anterior region, posterior region, preoptic area); (9) nuclei of the preoptic area (median preoptic nucleus, MnPO; and ventrolateral preoptic nucleus, VLPO); (10) the reticular nucleus of the thalamus; and (11) nucleus basalis (cholinergic). An ascending arousal system emanates from the rostral pons and caudal midbrain (monoamines, acetylcholine, and glutamate neurons) and acts through thalamic relay nuclei and the thalamic reticular nucleus. Monoamine neurons from the upper brainstem also project directly to the cerebral cortex, along with cholinergic and histaminergic

Spinal cord

Sympathetic chain ganglia

 

neurons, and excite cortical circuits, enhancing their processing capabilities. These circuits are maximally active during wakefulness and slow their activity during non-­REM sleep. Sleep is regulated by two neuronal groups in the preoptic ares, the MnPO and VLPO. Both of these regions innervate the entire ascending arousal system, using the inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and galanin. The VLPO is active during sleep and can suppress the ascending arousal system. Circulating substances such as interleukin-­1β can act on key sites in the hypothalamus and brainstem to influence components of sleep. Illness behavior involves enhanced slow-­ wave sleep induced by interleukin-­1β and other inflammatory mediators. Sleep that does not involve rapid eye movement, or slow-wave sleep, is initiated by hypothalamic neurons and other regions and is accompanied by decreased activity in the locus coeruleus and the cholinergic tegmental neurons. During REM sleep, activity in noradrenergic locus coeruleus neurons and serotonergic raphe neurons greatly diminishes, which prevents the cerebral cortex from attending to external stimuli. Dreams probably occur because the cortex is attending to internal stimuli provided by stored memories.

Lingula

“Unfolded” schematic of cerebellum demonstrating body map areas

Vermis Paravermis Regions

Lateral hemisphere

Lobes Anterior lobe Primary fissure

Posterior lobe

Flocculonodular lobe

Flocculus

Nodule

“Unfolded” schematic of cerebellum demonstrating regions and lobes

 

CEREBELLUM 11.36 CEREBELLAR ORGANIZATION: LOBES AND REGIONS The cerebellum is organized anatomically into three major lobes: (1) anterior, (2) posterior, and (3) flocculonodular. Distinct syndromes are associated with damage to each lobe. The functional organization of the cerebellar hemisphere follows a vertical organization: (1) vermis (midline), (2) paravermis, and (3) lateral hemispheres. Each of these functional regions is associated with specific deep nuclei (fastigial, globose and emboliform, and dentate, respectively) that help to regulate the activity of reticulospinal and vestibulospinal tracts, the rubrospinal tract, and the corticospinal tract, respectively. At least three representations of the body are mapped onto the cerebellar cortex. The cerebellar cortex has multiple orderly small infoldings, or convolutions, called folia.

CLINICAL POINT The cerebellum demonstrates both a lobular organization (anterior lobe, posterior lobe, and flocculonodular lobe), commonly associated with cerebellar syndromes, and a longitudinal organization (vermis, paravermis, lateral hemispheres), commonly associated with regulatory control over specific groups of UMNs. The vascular supply to the cerebellum comes mainly from the superior, anterior inferior, and posterior inferior cerebellar arteries. The cerebellum is quite prone to intracerebellar bleeds and hematomas. The superior cerebellar artery has fine branches that can rupture in hypertensive conditions and damage the rostral cerebellum and deep nuclei such as the dentate nucleus. A cerebellar hematoma acts as a space-­occupying lesion and also may induce further edema. As a result, increased intracranial pressure can occur and the flow of cerebrospinal fluid can be disrupted, secondarily bringing about supratentorial increased intracranial pressure. The patient experiences headache, nausea and vomiting, and vertigo and then may lapse into a coma. Decerebrate posturing, blood pressure dysregulation, and respiratory failure may ensue. Without rapid drainage, such a hematoma is commonly fatal. Smaller intracerebellar bleeds result in ipsilateral symptoms that are characteristic of the affected region of cerebellum.   

292

Regional Neuroscience A. Posterior view

Habenular trigone 3rd ventricle Pulvinar Pineal gland Superior colliculus Inferior colliculus Trochlear (IV) nerve Superior medullary velum Cerebellar peduncles

Lateral Medial

Superior cerebellar peduncle

L

Superior Middle Inferior

CL

Primary fissure CUL CUL

Lateral recess CL = central lobule CUL = culmen D = declive FOL = folium L = lingula

Geniculate bodies

Dentate nucleus Tenia of fourth ventricle

FOL TUB

TON UV

PYR = pyramid TON = tonsil TUB = tuber UV = uvula

D

Obex

PYR

Cerebellar cortex Fasciculus cuneatus Fasciculus gracilis

B. Lateral view Body of fornix Choroid plexus of 3rd ventricle

Habenular commissure

Interventricular foramen (of Monro) Thalamus Anterior commissure Lamina terminalis Posterior commissure Mammillary body Optic chiasm Oculomotor (III) nerve Superior colliculus Inferior colliculus Pons Medial longitudinal fasciculus 4th ventricle Medulla (oblongata) Tonsil Median aperture (of Magendie) Pyramidal decussation Central canal of spinal cord

Pineal gland Splenium of corpus callosum Great cerebral vein (of Galen) Cerebral aqueduct (of Sylvius) Lingula Central lobule Culmen Declive Folium Tuber

Vermis

Superior medullary velum Inferior medullary velum Choroid plexus of 4th ventricle Pyramid Uvula Nodule

Vermis

  11.37 CEREBELLAR ANATOMY: LOBULES A, Posterior view. In this horizontal (axial) section through the right cerebellar hemisphere, the left hemisphere has been removed, the cerebellar peduncles cut, and the fourth ventricle opened to show the dorsal surface of the brainstem below. The cerebellar cortex is organized into 10 lobules. The cerebellar peduncles provide the large white matter regions through which afferents and efferents pass, connecting the cerebellum with the brainstem and diencephalon. B, Lateral view. The lobules of the cerebellum are shown in midsagittal section. Inputs into the cerebellar hemispheres show a similar general organization, with variation from lobule to lobule, particularly for noradrenergic inputs from the locus coeruleus. Inputs from a vast majority of nuclei projecting to the cerebellar hemispheres arrive as mossy fibers; the inferior olivary nucleus sends climbing fibers to end on Purkinje cell dendrites in the cerebellar hemispheres, and the locus coeruleus sends diffuse varicose inputs into all three layers of many regions of the cerebellar cortex. The deep nuclei provide the “coarse adjustment” upon which is superimposed the “fine adjustment” by the cerebellar cortex. The cerebellar cortex sends

its output via Purkinje cell projections, using GABA as the principal neurotransmitter, to deep nuclei, which in turn project to UMNs. CLINICAL POINT Cerebellar tumors commonly start in a specific region of the cerebellum. Cerebellar medulloblastomas are childhood malignant tumors that often begin in the flocculonodular lobe and are detected initially because of truncal ataxia and a broad-­based uncoordinated gait. However, as the tumor slowly grows, it involves additional areas of the cerebellum by means of pressure or by invading neighboring areas. Then, in addition to the truncal ataxia, additional limb ataxia, dysmetria, dysdiadochokinesia, intention tremor, hypotonia, and other characteristics of lateral cerebellar damage are seen. Because the posterior fossa is involved, and not supratentorial regions, papilledema does not occur and does not provide a clue for diagnosis; rather, the increased posterior fossa pressure results in occipital headaches with nausea, vomiting, and nystagmus. The two most common cerebellar tumors of childhood are medulloblastomas, which can spread to adjacent portions of the CNS, and astrocytomas, which commonly are not highly invasive in the cerebellum but do grow as space-­occupying masses.   

Brainstem and Cerebellum Peduncle

Superior Middle cerebellar cerebellar peduncle peduncle

Corticospinal Inferior cerebellar tract peduncle

Inferior (restiform body)

Input (efferents) Spinocerebellar Dorsal Rostral Cuneocerebellar Olive-cerebellar Reticulocerebellar Trigeminocerebellar Raphe-cerebellar

Juxtarestiform body

Vestibulospinal (primary, secondary)

Middle (brachium pontis)

Pontocerebellar

Superior (brachium conjunctivum)

Ventral spinocerebellar Trigeminocerebellar Tectocerebellar Superior colliculus Inferior colliculus Coeruleo-cerebellar

293

Output (efferents) Fastigiobulbar, Uncinate fasciculus

To vestibular and reticular nuclei

Direct cerebellovestibular (to lateral vestibular nucleus [LVN])

Dentatothalamic Dentatorubral Dentatoreticular Interpositus-rubral connections (globose, emboliform)

Globose nucleus Emboliform nucleus

Fastigial nucleus

Dentate nucleus 4th ventricle Nucleus of CN VI

Middle cerebellar peduncle Inferior cerebellar peduncle

Medial longitudinal fasciculus

Superior cerebellar peduncle

Tectospinal tract

Lateral vestibular nucleus Genu of the facial nerve

Nucleus of CN VII CN VIII

Medial lemniscus

CN VII

Corticospinal tract

Pontine nuclei

  11.38 CEREBELLAR ANATOMY: DEEP NUCLEI AND CEREBELLAR PEDUNCLES The deep cerebellar nuclei are found at the roof of the fourth ventricle in a cross-­sectional view of the pons at the level of cranial motor nuclei for CNs VI and VII. The fastigial nucleus receives input from the vermis and sends projections to reticular and vestibular nuclei, the cells of origin of the reticulospinal and vestibulospinal tracts. Some vermal and flocculonodular Purkinje cells project directly to the lateral vestibular nuclei, which some authors consider to be a fifth deep cerebellar nucleus; this nucleus also is the UMN cell group for the vestibulospinal tract. The globose and emboliform nuclei receive input from the paravermis and project to the red nucleus, the cells of origin for the rubrospinal tract. The dentate nucleus receives input from the lateral hemispheres and projects to the ventrolateral and ventral anterior nuclei of the thalamus; these thalamic nuclei project to the cells of origin of the corticospinal and corticobulbar tracts. All three cerebellar peduncles can be seen in this cross-­section. The table lists the major afferent and efferent projections through the three cerebellar peduncles and are depicted by color.

CLINICAL POINT The inferior cerebellar peduncle conveys many afferents to the cerebellum from the spinocerebellar system, reticular formation, vestibular system, and trigeminal system, and it conveys efferents from the fastigial nucleus and flocculonodular lobe to vestibulospinal and reticulospinal UMN systems. The middle cerebellar peduncle mainly conveys afferents to the cerebellum from the cortico-­ponto-­cerebellar system. The superior cerebellar peduncle conveys selective afferents to the cerebellum and carries extensive efferents from the globose, emboliform, and dentate nuclei to the red nucleus and ventrolateral thalamus for regulation of the rubrospinal and corticospinal UMN systems. An infarct in the superior cerebellar artery can damage the blood supply to the superior and middle peduncles and the deep nuclei on one side. Lesions in these structures commonly have longer lasting and more severe clinical effects than lesions that affect only the cerebellar cortex. A superior cerebellar artery infarct can result in ipsilateral limb ataxia, dysmetria, dysdiadochokinesia, intention tremor, hypotonus, and other characteristics of lateral cerebellar damage. In addition, some midbrain structures are supplied by this artery; an infarct causes added brainstem problems, such as nystagmus and eye movement problems.   

Brainstem and Cerebellum 293.e1 Medulla–Spinal Cord Transition—Decussation of the Pyramids Fasciculus cuneatus Fasciculus gracilis

Spinal nucleus CN V

Lateral corticospinal tract Spinal tract CN V Central canal Level of section Fasciculus cuneatus

Fasciculus gracilis Central canal

Dorsal spinocerebellar tract

Decussation of pyramids

Ventral spinocerebellar tract Spinothalamic/ spinoreticular tract

Decussation of pyramids Spinal tract and nucleus of V Pyramid

Nucleus CN XI Pyramid

Nucleus Fasciculus gracilis gracilis

Fasciculus cuneatus

Nucleus cuneatus

Spinal tract of CN V Spinal nucleus of CN V Dorsal spinocerebellar tract Lateral corticospinal tract Ventral spinocerebellar tract Spinothalamic/spinoreticular tract

Nucleus CN XI

Decussation of the pyramids

eFig.11.1  Labeled Brainstem Cross-­Sectional Anatomy: Section 1

Pyramid

293.e2 Regional Neuroscience Medulla—Level of the Dorsal Column Nuclei Dorsal spinocerebellar tract

Fasciculus cuneatus Fasciculus gracilis Nucleus gracilis Nucleus cuneatus

Spinal tract of CN V

Tractus solitarius

Spinal nucleus of CN V

Level of section

Dorsal motor nucleus of CN X

Nucleus ambiguus

Fasciculus gracilis

Ventral spinocerebellar tract Fasciculus cuneatus Spinal tract and nucleus of V

Central canal Nucleus CN XII

Nucleus of CN XII Medial longitudinal fasciculus

Spinothalamic/ spinoreticular tract

Tectospinal tract

Dorsal accessory olive Medial accessory olive

Spinothalamic/ spinoreticular system

Nucleus solitarius

Decussation of pyramids

Pyramid Pyramid Fasciculus Nucleus Fasciculus Nucleus cuneatus cuneatus gracilis gracilis

Spinal tract of CN V Spinal nucleus of CN V

Dorsal motor nucleus of CN X Nucleus of CN XII Medial longitudinal faciculus

Dorsal spinocerebellar tract Ventral spinocerebellar tract

Internal arcuate fibers Nucleus ambiguus Dorsal accessory olive Medial lemniscus

Pyramid

eFig.11.2  Labeled Brainstem Cross-­Sectional Anatomy: Section 2

Spinothalamic/spinoreticular tract Medial accessory olive

Brainstem and Cerebellum 293.e3

Medulla—Level of the Obex External (lateral) cuneate nucleus

Nucleus cuneatus Nucleus gracilis Nucleus solitarius

Inferior cerebellar peduncle with dorsal spinocerebellar tract

Obex Central canal Dorsal motor nucleus of CN X Nucleus of CN XII

Tractus solitarius

Level of section

Internal arcuate fibers

Spinal tract of CN V Cerebellar tonsil Inferior cerebellar peduncle Inferior olivary nucleus

Nucleus gracilis

Spinal nucleus of CN V

Medial longitudinal fasciculus

Nucleus cuneatus

Spinothalamic/ spinoreticular tract

Medial lemniscus

Nucleus ambiguus

Pyramid

Tectospinal tract Medial lemniscus Inferior olivary nucleus

CN XII Pyramid

Medial accessory olivary nucleus

Nucleus Nucleus Tractus Nucleus solitarius of CN XII Obex gracilis cuneatus

External (lateral) cuneate nucleus Medial longitudinal fasciculus Nucleus solitarius Dorsal spinocerebellar tract Internal arcuate fibers

Spinal tract of CN V Spinal nucleus of CN V Dorsal motor nucleus of CN X

Tectospinal tract Nucleus ambiguus

Ventral spinocerebellar tract Fibers of CN X Spinothalamic/spinoreticular tract

Medial lemniscus

Inferior olivary nucleus

Medial accessory olive Fibers of CN XII

Pyramid

eFig.11.3  Labeled Brainstem Cross-­Sectional Anatomy: Section 3

293.e4 Regional Neuroscience Medulla—Level of the Inferior Olive External cuneate nucleus

Nucleus cuneatus Nucleus solitarius Tractus solitarius

Inferior cerebellar peduncle

Dorsal motor nucleus of CN X Choroid plexus Fourth ventricle

Spinal tract of CN V Level of section

Nucleus of CN XII

Spinal nucleus of CN V CN X

Nucleus and tractus solitarius Inferior cerebellar peduncle CN X Inferior olivary nucleus

Fourth ventricle

Spinothalamic/ spinoreticular tract

External cuneate nucleus

Nucleus ambiguus

Medial longitudinal fasciculus Tectospinal tract

Inferior olivary Medial lemniscus nucleus Dorsal accessory olivary nucleus CN XII

Pyramid

Medial lemniscus

Pyramid

Medial accessory olivary nucleus

Dorsal motor Nucleus Fourth Nucleus External (lateral) nucleus of CN X of CN XII ventricle cuneatus cuneate nucleus

CN XII

Tractus solitarius Nucleus solitarius Spinal tract of CN V Spinal nucleus of CN V Nucleus ambiguus Spinothalamic/spinoreticular tract Dorsal accessory olive Medial accessory olive

Inferior cerebellar peduncle with dorsal spinocerebellar tract Medial longitudinal fasciculus Tectospinal tract Fibers of CN X Inferior olivary nucleus Medial lemniscus Fibers of CN XII Pyramid

eFig.11.4  Labeled Brainstem Cross-­Sectional Anatomy: Section 4

Brainstem and Cerebellum 293.e5 Medulla—Level of the CN X and the Vestibular Nuclei Tractus solitarius

Nucleus solitarius

Inferior vestibular nucleus

Medial vestibular nucleus Reticular formation

Inferior cerebellar peduncle Dorsal motor nucleus of CN X

Level of section

Hypoglossal nucleus of CN Xll

CN X Inferior cerebellar peduncle Spinothalamic/ spinoreticular system Inferior olivary nucleus

Medial longitudinal fasciculus

Fourth ventricle Spinal tract of CN V Spinal nucleus of CN V Vestibular nuclei Spinothalamic/ spinoreticular tract Medial Inferior olivary nucleus lemniscus

Tectospinal tract Medial lemniscus

Pyramid Pyramid

Dorsal motor Nucleus Medial longitudinal nucleus of CN X of CN XII fasciculus Medial vestibular nucleus Inferior vestibular nucleus Nucleus solitarius Tractus solitarius

Inferior cerebellar peduncle

Reticular formation Spinal tract of CN V Spinal nucleus of CN V Tectospinal tract

Central tegmental tract

Fibers of CN X

Spinothalamic/spinoreticular tract Medial lemniscus Inferior olivary nucleus

Pyramid

eFig.11.5  Labeled Brainstem Cross-­Sectional Anatomy: Section 5

293.e6 Regional Neuroscience Medullo-Pontine Junction—Level of the Cochlear Nuclei Dorsal cochlear nucleus

Medial vestibular nucleus

Nucleus prepositus

Reticular formation

Medial longitudinal fasciculus

Inferior cerebellar peduncle

Tectospinal tract

Ventral cochlear nucleus

Raphe nuclei (obscurus pallidus)

CN VIII

Level of section

CN IX

Dorsal cochlear nucleus Ventral cochlear nucleus CN VIII

Fourth ventricle

Spinal tract of CN V

Spinal nucleus Vestibular of CN V nuclei Inferior vestibular nucleus Inferior cerebellar Spinothalamic/ peduncle spinoreticular tract Raphe Central tegmental tract nuclei

Corticospinal system

Middle cerebellar peduncle

Inferior olivary nucleus Medial lemniscus

Pontine nuclei

Corticospinal tract

Nucleus Fourth Nucleus raphe Medial vestibular prepositus ventricle obscurus nucleus

Inferior vestibular nucleus Nucleus solitarius

Inferior cerebellar peduncle Dorsal cochlear nucleus

Tractus solitarius Medial longitudinal fasciculus Reticular formation Tectospinal tract

Spinal tract of CN V Spinal nucleus of CN V Ventral cochlear nucleus

Spinothalamic/spinoreticular tract

Fibers of CN VIII Fibers of CN IX Nucleus raphe pallidus

Medial lemniscus

Inferior olivary nucleus

Central tegmental tract

Pyramid

eFig.11.6  Labeled Brainstem Cross-­Sectional Anatomy: Section 6

Brainstem and Cerebellum 293.e7 Pons—Level of the Facial Nucleus

Lateral vestibular nucleus

Superior vestibular nucleus

Nucleus of CN VI

Superior cerebellar peduncle

Superior olivary nucleus

Dentate nucleus

Medial longitudinal fasciculus

Middle cerebellar peduncle Inferior cerebellar peduncle Spinal tract of CN V

Level of section Cerebellar uvula Nucleus CN VI CN VIII

Fibers of CN VII Tectospinal tract

Spinal nucleus of CN V

Inferior cerebellar peduncle

Nucleus of CN VII

Fourth ventricle Middle cerebellar peduncle

CN VIII CN VII Spinothalamic/ spinoreticular tract

Raphe nucleus (magnus)

Central tegmental tract Medial lemniscus

Trapezoid body

CN VII

Corticospinal tract Medial lemniscus

Nucleus CN VII

CN VI

Pontine nuclei

CN VI Corticospinal system (basis pontis)

Superior Lateral Medial vestibular vestibular Tectospinal longitudinal nucleus nucleus tract fasciculus

Nucleus of CN VI

Superior cerebellar peduncle Fourth ventricle Ascending fibers of CN VII

Inferior cerebellar peduncle Exiting fibers of CN VII

Nucleus of CN VII

Spinal tract of CN V Spinal nucleus of CN V Central tegmental tract Middle cerebellar peduncle

Superior olivary nucleus Spinothalamic/spinoreticular tract Medial lemniscus

Nucleus raphe magnus Trapezoid body

Corticospinal tract fibers

Crossing fibers of middle cerebellar peduncle

Basis pontis

eFig.11.7  Labeled Brainstem Cross-­Sectional Anatomy: Section 7

Pontine nuclei

293.e8 Regional Neuroscience Pons—Level of the Genu of the Facial Nerve

Dentate nucleus

Superior vestibular nucleus

Superior cerebellar peduncle Globose and emboliform nuclei Fibers of CN VII

Inferior cerebellar peduncle

Nucleus of CN VI

Middle cerebellar peduncle

Medial longitudinal fasciculus

Uvula

Lateral vestibular nucleus

Level of section

Fibers of CN VI

Spinal tract of CN V Cerebellar uvula Inferior cerebellar peduncle Superior cerebellar peduncle Middle cerebellar peduncle Lateral vestibular nucleus CN VII (internal fibers)

Dentate nucleus

Medial vestibular nucleus

Tectospinal tract

Spinal nucleus of CN V Fourth ventricle

Spinothalamic/ spinoreticular tract

Central tegmental tract

Trapezoid body Nucleus CN VI Spinothalamic/ spinoreticular system

Medial lemniscus

Corticospinal tract Pontine nuclei

CN VI

Nucleus of CN VII

Medial lemniscus Corticospinal system (basis pontis)

Medial Superior longitudinal Fourth Nucleus vestibular fasciculus ventricle of CN VI nucleus Inferior cerebellar peduncle Lateral vestibular nucleus

Superior cerebellar peduncle

Fibers of CN VI Spinal tract of CN V Spinal nucleus of CN V

Tectospinal tract

Middle cerebellar peduncle Nucleus of CN VII

Spinothalamic/spinoreticular tract Medial lemniscus Trapezoid body

Corticospinal tract fibers

Pontine nuclei

eFig.11.8  Labeled Brainstem Cross-­Sectional Anatomy: Section 8

Brainstem and Cerebellum 293.e9 Pons—Level of Trigeminal Motor and Main Sensory Nuclei Medial parabrachial nucleus

Lateral parabrachial nucleus

Locus coeruleus

Fourth ventricle

Superior cerebellar peduncle

Medial longitudinal fasciculus

Middle cerebellar peduncle

Level of section

Tectospinal tract

Mesencephalic nucleus of CN V

Fourth ventricle

Raphe nucleus (pontis)

CN V Medial longitudinal fasciculus

Spinothalamic/ spinoreticular system Medial lemniscus

Superior cerebellar peduncle

Main (chief) sensory nucleus of CN V

Motor nucleus of CN V Main sensory Spinothalamic nucleus CN V spinoreticular tract Middle cerebellar peduncle Motor nucleus CN V Corticospinal system (basis pontis)

Crossing fibers of middle cerebellar peduncle Pontine nuclei

Central tegmental tract Medial lemniscus Corticospinal tract

Nucleus Medial raphe Locus Uvula of Fourth longitudinal pontis coeruleus cerebellum ventricle fasciculus

Superior cerebellar peduncle Mesencephalic nucleus of CN V Central tegmental tract Spinothalamic/spinoreticular tract Medial lemniscus Middle cerebellar peduncle

Lateral parabrachial nucleus Medial parabrachial nucleus Main sensory nucleus of CN V Motor nucleus of CN V Tectospinal tract

Crossing fibers of middle cerebellar peduncle Fibers of CN V

Pontine nuclei

eFig.11.9  Labeled Brainstem Cross-­Sectional Anatomy: Section 9

Corticospinal tract fibers

293.e10Regional Neuroscience Pons-Midbrain Junction—Level of CN IV and Locus Coeruleus CN IV

Superior cerebellar peduncle

Lateral lemniscus

Locus coeruleus

Periaqueductal gray matter

Aqueduct Level of section Lateral lemniscus

Spinothalamic/ spinoreticular system Medial lemniscus

Raphe nuclei

Pontine nuclei

Spinothalamic/ spinoreticular tract

Dorsal raphe nucleus

Medial lemniscus

Fourth ventricle transition to cerebral aqueduct

Corticospinal tract

Medial longitudinal fasciculus

Middle cerebellar peduncle

Medial longitudinal fasciculus Central superior raphe nucleus

Pontine nuclei

Central tegmental tract

Corticospinal system (basis pontis)

Medial longitudinal Locus Aqueduct fasciculus coeruleus

Fibers of CN IV Lateral lemniscus Periaqueductal gray Nucleus raphe dorsalis Spinothalamic/spinoreticular tract Medial lemniscus

Superior cerebellar peduncle Central tegmental tract Nucleus centralis superior (raphe)

Corticospinal tract fibers Middle cerebellar peduncle Pontine nuclei

eFig.11.10  Labeled Brainstem Cross-­Sectional Anatomy: Section 10

Brainstem and Cerebellum293.e11 Midbrain—Level of the Inferior Colliculus Brachium of inferior colliculus

Inferior colliculus Reticular formation

Lateral lemniscus

Periaqueductal gray matter Aqueduct

Spinothalamic/ spinoreticular tract Aqueduct

Level of section

Brachium of inferior colliculus Inferior colliculus CN IV

Periaqueductal gray matter

Nucleus of CN IV Dorsal raphe nucleus

Cerebral peduncle

Medial longitudinal fasciculus

Central tegmental tract

Superior cerebellar peduncle (decussation) Interpeduncular nuclei

Medial lemniscus Substantia nigra

Substantia nigra

Pontine nuclei

Central tegmental tract Cerebral peduncle

Aqueduct

Brachium of inferior colliculus

Inferior colliculus Lateral lemniscus Spinothalamic/spinoreticular tract Dorsal raphe nucleus

Periaqueductal gray Reticular formation Nucleus of CN IV Medial longitudinal fasciculus Central tegmental tract

Medial lemniscus Superior cerebellar peduncle Substantia nigra Cerebral peduncle Interpeduncular nuclei

eFig.11.11  Labeled Brainstem Cross-­Sectional Anatomy: Section 11

Nucleus centralis superior (raphe)

293.e12Regional Neuroscience Midbrain—Level of the Superior Colliculus Brachium of inferior colliculus

Superior colliculus Tectospinal tract Mesencephalic nucleus of CN V Periaqueductal gray matter

Spinothalamic/ spinoreticular tract Level of section

Aqueduct

Medial lemniscus

Nucleus of Edinger-Westphal

Aqueduct Superior colliculus Periaqueductal gray matter Medial lemniscus/ spinothalamic/ spinoreticular system Substantia nigra

Motor nucleus CN III Red nucleus

Nucleus of CN III Central tegmental tract

Medial longitudinal fasciculus Ventral tegmental decussation

Substantia Cerebral nigra peduncle Red nucleus

Cerebral peduncle

CN III Inferior colliculus

CN III

Commissure of Aqueduct inferior colliculus

Ventral tegmental area Periaqueductal gray

Brachium of inferior colliculus Spinothalamic/spinoreticular tract Tectospinal tract

Nucleus of EdingerWestphal (CN III) Mesencephalic nucleus of CN V

Medial longitudinal fasciculus Medial lemniscus

Nucleus of CN III Dorsal raphe nucleus

Central tegmental tract

Decussating fibers of superior cerebellar peduncle

Substantia nigra

Nucleus centralis superior (raphe)

Cerebral peduncle

Ventral Exiting fibers Red Ventral nucleus tegmental tegmental of CN III decussation area

eFig.11.12  Labeled Brainstem Cross-­Sectional Anatomy: Section 12

Brainstem and Cerebellum293.e13

Midbrain—Level of the Medial Geniculate Body Spinothalamic/ spinoreticular tract

Medial geniculate body (nucleus)

Level of section

Superior colliculus Medial geniculate nucleus Lateral geniculate nucleus

Medial lemniscus

Brachium of inferior colliculus Superior colliculus Periaqueductal gray matter Aqueduct Nucleus of Edinger-Westphal

Lateral geniculate body (nucleus) Cerebral peduncle Optic tract

Substantia nigra Aqueduct transition Cerebellorubroto III ventricle thalamic tract Edinger-Westphal Central tegmental tract nucleus CN III Red nucleus Red nucleus

Cerebral peduncle

Nucleus of CN III Ventral tegmental area CN III

Medial longitudinal fasciculus Superior Periaqueductal colliculus gray Aqueduct

Spinothalamic/ spinoreticular tract Lateral geniculate nucleus Medial lemniscus Optic tract Cerebellorubrothalamic tract

Medial geniculate nucleus Nucleus of EdingerWestphal (CN III) Central tegmental tract Medial longitudinal fasciculus Nucleus of CN III Substantia nigra Cerebral peduncle

Red nucleus Ventral tegmental area Exiting fibers of CN III

eFig.11.13  Labeled Brainstem Cross-­Sectional Anatomy: Section 13

293.e14Regional Neuroscience

Midbrain-Diencephalon Junction—Level of the Posterior Commissure Superior Spinothalamic/ spinoreticular Pulvinar colliculus tract

Periaqueductal gray matter Posterior commissure

Medial geniculate body (nucleus)

Level of section

Pretectum Pulvinar Periaqueductal gray matter Cerebral peduncle

Medial lemniscus Lateral geniculate body (nucleus) Cerebral peduncle

Aqueduct

Nucleus of Darkschewitsch

Cerebellorubrothalamic tract Midbrain Optic tract transition Red nucleus to thalamus Substantia nigra III ventricle Lateral hypothalamic area

Medial longitudinal fasciculus Central tegmental tract Posterior hypothalamic area

Mammillary body

Pulvinar

Central Brachium of tegmental superior colliculus tract

Pretectum

Posterior commissure Aqueduct Nucleus of Darkschewitsch

Medial geniculate nucleus

Interstitial nucleus of Cajal

Spinothalamic/spinoreticular tract, medial lamniscus, and trigeminothalamic tracts

Medial longitudinal fasciculus Red nucleus

Lateral geniculate nucleus

Hypothalamus

Fibers of Cerebral optic tract peduncle

eFig.11.14  Labeled Brainstem Cross-­Sectional Anatomy: Section 14

Substantia nigra

Cerebellorubrothalamic tract

12

DIENCEPHALON

 12.1 Thalamic Anatomy and Interconnections With the Cerebral Cortex 12.2 Hypothalamus and Pituitary Gland 12.3 Hypothalamic Nuclei

Diencephalon

295



Thalamocortical radiations Central sulcus

Internal medullary lamina Intralaminar nuclei Other medial nuclei

Anterior nuclei

Thalamic nuclei CM LD LP MD VA VI VL VPL VPM

Centromedian Lateral dorsal Lateral posterior Medial dorsal Ventral anterior Ventral intermedial Ventral lateral Ventral posterolateral Ventral posteromedial

MD

Midline (median) nuclei Interthalamic adhesion

LD

LP

VA Pulvinar VL VI

CM VPL

From globus pallidus and substantia nigra

Medial geniculate body (MGB)

VPM

Acoustic pathway

Reticular nucleus (pulled away)

Lateral geniculate body (LGB)

From cerebellum

Optic tract Somesthetic from body (spinothalamic tract and medial lemniscus)

12.1 THALAMIC ANATOMY AND INTERCONNECTIONS WITH THE CEREBRAL CORTEX The thalamus, the gateway to the cerebral cortex, conveys extensive sensory, motor, and autonomic information from the brainstem and spinal cord to the cortex. All sensory projections to the cortex except olfaction are processed through thalamic nuclei. Thalamic nuclei are reciprocally interconnected with regions of cortex. Specific thalamic nuclei project to circumscribed regions of cortex. These nuclei include (1) sensory projection nuclei (VPL: somatosensory; VPM: trigeminal; LGB: visual; MGB: auditory; pulvinar: sensory); (2) motor-­related nuclei (VL and VI), cerebellum (VA and VL), and basal ganglia (VA, VL, CM); (3) autonomic-­and limbic-­related nuclei (anterior and LD: cingulate cortex; MD: frontal and cingulate cortex); and (4) nuclei related to association areas (pulvinar and LP: parietal cortex). Nonspecific thalamic nuclei (intralaminar nuclei, such as CM, parafascicular, and medial VA) send diffuse connections to widespread regions of the cerebral cortex and to other thalamic nuclei. The reticular nucleus of the thalamus helps to regulate the excitability

Somesthetic from head (trigeminal nerve)

of thalamic projection nuclei. Specific lesions of the thalamus can result in diminished sensory, motor, or autonomic activity related to loss of the specific modalities processed. Some thalamic lesions can lead to excruciating paroxysms of neuropathic pain, which is referred to as thalamic syndrome. CLINICAL POINT The thalamus has a complex blood supply that is derived extensively from the penetrating posterior cerebral, posterior communicating, and other nearby arteries. Thalamic nuclei are seldom individually affected by infarcts and lesions but are damaged along with nearby regions. Lesions that affect one side of the thalamus seldom produce permanent deficits unless sensory nuclei are involved. Thalamic lesions can result in changes in consciousness and alertness (intralaminar, reticular nuclei), affective behavior (medial dorsal, ventral anterior, intralaminar nuclei), memory functions (midline, medial, mammillary, and possibly anterior nuclei), motor activity (ventrolateral, ventral anterior, posterior, other nuclei), somatic sensation (ventral posterolateral and posteromedial nuclei), vision (lateral geniculate nuclei), and perceptions and hallucinations (dorsomedial, intralaminar nuclei). Medial dorsal lesions may produce a reciprocal disconnect with the prefrontal cortex and bring about a deficit in frontal functions.   

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Regional Neuroscience Septum pellucidum Thalamus Fornix Hypothalamic sulcus Anterior commissure

Principal nuclei of hypothalamus

Paraventricular Posterior Dorsomedial Supraoptic Ventromedial Arcuate (infundibular) Mammillary

Dorsal longitudinal fasciculus and other descending pathways

Mammillothalamic tract

Optic chiasm Infundibulum (pituitary stalk) Hypophysis (pituitary gland) Hypothalamic sulcus Supraopticohypophyseal tract Arcuate Hypothalamohypophyseal tract nucleus Tuberohypophyseal tract

Interventricular foramen

Thalamus

Paraventricular nucleus

Hypothalamic area

Supraoptic nucleus Optic chiasm

Mammillary body

Hypophyseal stalk Pars tuberalis

Neural Median eminence stalk Infundibular stem

Pars intermedia

Neurohypophysis Infundibular process

Adenohypophysis

Pars distalis Cleft

Posterior lobe

  12.2 HYPOTHALAMUS AND PITUITARY GLAND The hypothalamus is the major region of the central nervous system involved in neuroendocrine regulation and control of visceral functions, such as temperature regulation, food and appetite regulation, thirst and water balance, reproduction and sexual behavior, parturition and control of lactation, respiratory and cardiovascular regulation, gastrointestinal regulation, stress responses, and reparative states. The hypothalamus is located between the rostral midbrain and the lamina terminalis, ventral to the thalamus; it surrounds the third ventricle. The hypothalamus is subdivided in rostral-­to-­caudal zones (preoptic, anterior or supraoptic, tuberal, and mammillary or posterior) as well as medial-­to-­lateral zones (periventricular, medial, lateral). These zones contain some discrete nuclei and even discrete chemical-­specific subnuclei, such as the paraventricular

Connective tissue (trabecula)

Anterior lobe

nucleus (PVN); and more diffuse centers, regions, or areas (such as anterior, posterior, and lateral regions). The neuroendocrine portion of the hypothalamus consists of (1) magnocellular portions of the PVN and the supraoptic nucleus, which send axons directly to the posterior pituitary and release vasopressin and oxytocin into the general circulation; (2) releasing factor and inhibitory­factor neurons, which project axons to the hypophyseal-­portal vasculature in the contact zone of the median eminence, through which very high concentrations of these factors (hormones) induce the release of anterior pituitary hormones into the general circulation; and (3) the tuberoinfundibular system and ascending systems (monoamine and other chemically specific neurons) that modulate the release of releasing and inhibitory factors into the hypophyseal-­portal vasculature.

Diencephalon

Corpus callosum Lateral ventricle

S ep

tum

cidum pellu

Fornix

Dorsal hypothalamic area From hippocampal formation

Thalamus

Paraventricular nucleus Anterior commissure

Interthalamic adhesion

Lateral hypothalamic area Median forebrain bundle Dorsomedial nucleus Mammillothalamic tract

Lateral preoptic nucleus

Posterior area Periventricular nucleus

Anterior hypothalamic area

Nucleus intercalatus

Medial preoptic nucleus Red nucleus Olfactory tract Fornix

Optic (II) nerve Optic chiasm

Anterior lobe of pituitary

 

Ventromedial Mammillary nucleus complex Oculomotor (III) nerve

Cerebral peduncle Dorsal longitudinal fasciculus

Tuberohypophyseal tract

Descending hypothalamic connections (from median forebrain bundle [MFB])

Supraoptic nucleus

Pons

Supraopticohypophyseal tract

Reticular formation

Posterior lobe of pituitary

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12.3 HYPOTHALAMIC NUCLEI Hypothalamic nuclei and areas are associated with many visceral and neuroendocrine functions. The magnocellular neurons of the PVN and supraoptic nucleus release oxytocin and vasopressin into the posterior pituitary general circulation. PVN parvocellular neurons containing corticotrophin-­releasing hormone project to the hypophyseal portal system in the contact zone of the median eminence and induce the release of adrenocorticotropic hormone (which stimulates the release of cortisol from the adrenal cortex). Descending axons of the PVN also project to the dorsal (motor) nucleus of CN X, the nucleus solitarius, and the intermediolateral cell column preganglionic sympathetic neurons and regulate preganglionic outflow from the autonomic nervous system. The anterior and posterior areas coordinate parasympathetic and sympathetic outflow, respectively. The dorsomedial (DM) and ventromedial (VM) nuclei and the lateral hypothalamic area regulate appetite, drinking, and reproductive behavior. The preoptic area regulates cyclic neuroendocrine behavior, thermoregulation, and the sleep-­wake cycle. The suprachiasmatic nucleus receives visual inputs from the optic tract and regulates circadian rhythms. Several hypothalamic regions are involved in the regulation of sleep.

CLINICAL POINT Hypothalamic nuclei often appear as discrete nuclei and regions that may subserve discrete functions. Early studies of lesions in the hypothalamus led to this impression, resulting in a description of centers, such as the ventromedial nucleus satiety center (lesions led to hyper-­ phagia and obesity) and a lateral appetitive stimulatory center (lesions led to aphagia and cachexia). However, such lesions often damaged passing fiber tracts (e.g., passing axons of the monoaminergic systems) and connections, sometimes even those not associated with the primary functions studied. We now know that many hormones are involved in the control of appetite and food intake. When food is ingested, cholecyctokinin and glucagon-­like peptide-­1 are released by neuroendocrine cells in the intestine, and they act in the brain to suppress appetite and give the sensation of satiety. In the absence of food, these hormone levels are low, permitting appetite and food-­seeking behavior. Long-­term regulation of food intake also involves the hormone leptin, produced by fat cells. When fat stores are high, leptin is released and acts on the hypothalamus to suppress appetite. When body nutrient stores are depleted, leptin levels are lowered. Other hormones, such as ghrelins, also regulate appetite and eating behavior. Hypothalamic physiology awaits further studies to fully integrate the complex hypothalamic circuitry with the complex hormonal regulation, over which volitional and affective control from higher brain regions is further superimposed. Given the epidemic of obesity in the United States and other “fast-­food countries,” a better understanding of the physiology of eating and appetite is urgently needed.   

CLINICAL POINT The hypothalamus is a small but complex region of the central nervous system that interconnects the limbic forebrain and the brainstem. The principal functions of the hypothalamus are neuroendocrine regulation, especially through the pituitary gland, and regulation of autonomic function. Thermoregulation is one example of the latter. Several hypothalamic sites, including the anterior and posterior hypothalamic areas, regulate the set point for body temperature within relatively tight parameters. Damage to these mechanisms by head trauma, tumor, surgery, increased intracranial pressure, or vascular problems can induce a change in thermoregulation. Posterior hypothalamic damage is often accompanied by hypothermia, whereas anterior hypothalamic damage is often accompanied by hyperthermia. In addition, inflammatory mediators such as interleukin-­1β and interleukin-­6, whether derived from an infectious process (endotoxin or pyrogen) or from other sources of inflammation, can activate some of the anterior regions of the hypothalamus such as the preoptic area and can induce fever. These inflammatory mediators also can produce classic illness behavior and can powerfully activate both the hypothalamo-­ pituitary-­adrenal axis and the hypothalamo-­sympathetic axis, driving a classic stress response. Altered internal body temperature also can be affected by intracranial surgery, susceptibility to some anesthetic agents (malignant hyperthermia), and susceptibility to some neuroleptic drugs. A major role of the hypothalamus is neuroendocrine regulation of the anterior and posterior pituitary. Neurons in the supraoptic and paraventricular nuclei send axonal connections directly to the posterior pituitary to release oxytocin and vasopressin into the general circulation. Many other collections of neurons, in the hypothalamus and elsewhere, send axonal connections to the hypophyseal-­portal vascular system in the contact zone of the median eminence and release releasing factors (hormones) and inhibitory factors (hormones) that regulate the secretion of a variety of hormones from pituicytes in the anterior pituitary. These releasing factor neurons and inhibitory factor neurons receive extensive input from brainstem, hypothalamic, and limbic forebrain sources. Some of these neurons (such as the corticotrophin-­releasing factor neurons in the PVN) also receive input from chemical sources, such as interleukin-­1β, prostaglandin E2, and nitric oxide. Interleukin-­1β, both directly and indirectly, can drive the response of corticotrophin-­releasing factor, thereby activating the hypothalamo-­pituitary-­adrenal system to stimulate cortisol production and drive the hypothalamo-­sympathetic system to stimulate the release of catecholamines. Some neurotransmitters in these releasing factor neurons and inhibitory factor neurons can be influenced pharmacologically. Dopamine in the arcuate nucleus acts as a prolactin inhibitory factor. A dopamine agonist can suppress prolactin output by a prolactin-­secreting pituitary tumor (chromophobe adenoma).   

13

TELENCEPHALON

13.1 Axial (Horizontal) Sections Through the Forebrain: Level 1—Mid Pons

13.17 Coronal Sections Through the Forebrain: Level 7—Midthalamus

13.2 Axial (Horizontal) Sections Through the Forebrain: Level 2—Rostral Pons

13.18 Coronal Sections Through the Forebrain: Level 8— Geniculate Nuclei

13.3 Axial (Horizontal) Sections Through the Forebrain: Level 3—Midbrain

13.19 Coronal Sections Through the Forebrain: Level 9— Caudal Pulvinar and Superior Colliculus

13.4 Axial (Horizontal) Sections Through the Forebrain: Level 4—Rostral Midbrain and Hypothalamus

13.20 Coronal Sections Through the Forebrain: Level 10— Splenium of Corpus Callosum

13.5 Axial (Horizontal) Sections Through the Forebrain: Level 5—Anterior Commissure and Caudal Thalamus

13.21 Layers of the Cerebral Cortex

13.6 Axial (Horizontal) Sections Through the Forebrain: Level 6—Head of Caudate and Midthalamus 13.7 Axial (Horizontal) Sections Through the Forebrain: Level 7—Basal Ganglia and Internal Capsule 13.8 Axial (Horizontal) Sections Through the Forebrain: Level 8—Dorsal Caudate, Splenium, and Genu of Corpus Callosum

13.22 Cortical Neuronal Cell Types 13.23 Vertical Columns: Functional Units of the Cerebral Cortex 13.24 Efferent Connections of the Cerebral Cortex 13.25 Neuronal Origins of Efferent Connections of the Cerebral Cortex 13.26 Cortical Association Pathways

13.9 Axial (Horizontal) Sections Through the Forebrain: Level 9—Body of Corpus Callosum

13.27 Major Cortical Association Bundles

13.10 Axial (Horizontal) Sections Through the Forebrain: Level 10—Centrum Semiovale

13.29 Color Imaging of Projection Pathways From the Cerebral Cortex

13.11 Coronal Sections Through the Forebrain: Level 1—Genu of Corpus Callosum

13.30 Functional Magnetic Resonance Imaging

13.12 Coronal Sections Through the Forebrain: Level 2—Head of Caudate Nucleus/Nucleus Accumbens 13.13 Coronal Sections Through the Forebrain: Level 3— Anterior Commissure/Columns of Fornix 13.14 Coronal Sections Through the Forebrain: Level 4— Amygdala, Anterior Limb of Internal Capsule

13.28 Color Imaging of Association Pathways

13.31 Noradrenergic Pathways 13.32 Serotonergic Pathways 13.33 Dopaminergic Pathways 13.34 Central Cholinergic Pathways 13.35 Endogenous Cannabinoid Systems

13.15 Coronal Sections Through the Forebrain: Level 5— Mammillary Body

13.36 Endogenous Opioid Systems: Beta-­Endorphin, Dynorphins, and met-­Enkephalin

13.16 Coronal Sections Through the Forebrain: Level 6— Mammillothalamic Tract/Substantia Nigra, Rostral Hippocampus

13.37 The Olfactory Nerve and Nerves of the Nose

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Level 1: Mid Pons

CN V Basis pontis Uncus

Corticospinal tract fibers Basilar artery

Temporal lobe

Level of section (mid pons)

*

Superior cerebellar peduncle

Lateral cerebellar hemisphere Medial lemniscus Cerebellar vermis

13.1A AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 1—MID PONS These axial (horizontal) sections compare anatomical sections and high-­resolution magnetic resonance (MR) images. They are cut in the true horizontal (axial) plane, not in the older 25-­degree tilt. The most important anatomical relationships in these sections center on the internal capsule (IC). The head of the caudate nucleus is medial to the anterior limb of the IC and forms the lateral margin of the frontal pole of the lateral ventricle. The thalamus is medial to the posterior limb of the IC. The globus pallidus and putamen are lateral to the wedge-­shaped IC. The

Pontine tegmentum Fourth ventricle

posterior limb of the IC carries the major descending corticospinal, corticorubral, and corticoreticular fibers and the ascending sensory fibers of the somatosensory and trigeminal systems. The most posterior portions of the posterior limb also carry the auditory and visual projections to their respective cortices. The genu of the IC carries the corticobulbar fibers. The anterior limb of the IC carries cortical projections to the striatum and the pontine nuclei (pontocerebellar system). The full-­plate MR images are T1-­ weighted; the ventricles appear dark. The scout MR images that accompany the drawings are T2-­weighted MR images, in which the cerebrospinal fluid (CSF) appears white.

Telencephalon

301

Basilar artery

Temporal lobe

Pontine tegmentum

Basis pontis (with corticospinal system)

Medial longitudinal fasciculus Fourth ventricle

Middle cerebellar peduncle

Lateral cerebellar hemisphere

Superior cerebellar peduncle

 

13.1B AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 1—MID PONS (CONTINUED)

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Level 2: Rostral Pons

Basis pontis Amygdala Corticospinal tract fibers Temporal lobe

Basilar artery

Level of section (rostral pons)

*

Superior cerebellar peduncle

Medial lemniscus

Fourth ventricle Lateral cerebellar hemisphere

Pontine tegmentum

Vermis of cerebellum

 

13.2A AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 2—ROSTRAL PONS

Telencephalon

Temporal lobe Basis pontis (with corticospinal system)

Pontine tegmentum Fourth ventricle Superior cerebellar peduncle Lateral hemisphere of cerebellum Cerebellar vermis

 

13.2B AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 2—ROSTRAL PONS (CONTINUED)

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Level 3: Midbrain

Posterior cerebral arteries Substantia nigra

CN III (oculomotor)

Cerebral peduncle Amygdala

CN II (optic) Temporal lobe

Tail of caudate nucleus

Level of section (midbrain)

Hippocampal formation Inferior horn of lateral ventricle Entorhinal cortex

Cerebral aqueduct Occipital lobe

Decussation of superior cerebellar peduncle Cerebellar vermis

 

13.3A AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 3—MIDBRAIN CLINICAL POINT The temporal lobe includes the amygdaloid nuclei, the hippocampal formation and associated cortex, the transverse gyrus of Heschl, some language-­associated cortical regions (Wernicke’s area in the dominant hemisphere), Meyer’s loop of geniculocalcarine axons, the inferior horn

of the lateral ventricle, and extensive cortical areas (superior, middle, and inferior temporal gyri). The temporal lobe can be damaged by trauma, infarcts, tumors, abscesses, and other pathological conditions. Such damage can result in auditory hallucinations, delirium and psychotic behavior, sometimes a contralateral upper quadrantanopia (if Meyer’s loop is damaged), and receptive aphasia (Wernicke’s aphasia) that involves a lack of understanding of verbal information (in a lesion of the dominant hemisphere). Some very specific lesions in the temporal lobe result in an agnosia for recognition of faces (prosopagnosia).   

Telencephalon

Amygdala

Inferior horn of lateral ventricle

Orbitofrontal cortex

Temporal lobe

Hippocampal formation Cerebral peduncle

Aqueduct Superior colliculus

Cerebellar vermis Occipital lobe

  13.3B AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 3—MIDBRAIN (CONTINUED)

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Level 4: Rostral Midbrain and Hypothalamus

Substantia nigra Cerebral peduncle

Red nucleus Orbitofrontal cortex

Medial geniculate nucleus

Mammillary bodies Amygdala Anterior cerebral artery

Lateral geniculate nucleus Hippocampal formation

Level of section (rostral midbrain and hypothalamus)

Temporal lobe Tail of caudate nucleus Temporal horn of lateral ventricle

Entorhinal cortex Posterior cerebral artery

Periaqueductal gray matter Superior colliculus Occipital lobe

Cerebral aqueduct

Optic tract Cerebellar vermis

 

13.4A AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 4—ROSTRAL MIDBRAIN AND HYPOTHALAMUS

Telencephalon

307

Orbitofrontal cortex

Cerebral peduncle

Temporal lobe

Hippocampal formation

Temporal horn of lateral ventricle

Lateral geniculate nucleus

Medial geniculate nucleus

Superior colliculus

Cerebellar vermis Occipital lobe

 

13.4B AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 4—ROSTRAL MIDBRAIN AND HYPOTHALAMUS (CONTINUED)

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Regional Neuroscience Level 5: Anterior Commissure and Caudal Thalamus

Orbitofrontal cortex Putamen Claustrum

Anterior limb of internal capsule Globus pallidus (internal and external segments) Head of caudate nucleus

Insular cortex

Anterior commissure Columns of fornix

Level of section (anterior commissure and caudal thalamus)

Posterior limb of internal capsule

Thalamus Temporal lobe Choroid plexus Tail of caudate nucleus Atrium of lateral ventricle

Extreme capsule External capsule

Hippocampal formation

Third ventricle

Pulvinar Occipital lobe

Habenular commissure

 

13.5A AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 5—ANTERIOR COMMISSURE AND CAUDAL THALAMUS CLINICAL POINT The basal ganglia assist the cerebral cortex in planning and generating desired programs of activity and suppressing undesired programs of activity. The most conspicuous arena in which these functions are observed is motor activity. Basal ganglia disorders produce movement problems that are often involuntary in nature and are commonly accompanied by cognitive and affective symptoms (e.g., Huntington’s disease). The principal route of information flow from the basal ganglia is from the thalamus and cerebral cortex to the striatum (caudate

nucleus and putamen), then to the globus pallidus, then back to the thalamus and cortex, completing the loop. Disruption of this loop can produce excessive movements (e.g., choreiform and athetoid movements, tremor) or diminished movements (bradykinesia). In some instances, specific nuclei are known to be associated with such changes. A small lacunar infarct in the subthalamic nucleus results in wild, flinging (ballistic) movements in the contralateral limbs. However, a surgical lesion in the subthalamic nucleus may ameliorate some of the movement problems seen in Parkinson’s disease. The subthalamus most likely drives activity in the internal segment of the globus pallidus, which in turn can be modified by the external segment. A pathological lesion in the globus pallidus can produce rigidity and akinesia; a surgical pallidal lesion may reduce excessive movements in other basal ganglia disorders.   

Telencephalon

Orbitofrontal cortex

Anterior commissure Temporal lobe

Head of caudate nucleus

Putamen

Columns of fornix Thalamus Third ventricle Habenula Hippocampal formation

Pulvinar

Tail of caudate nucleus

Atrium of lateral ventricle

Occipital lobe

 

13.5B AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL5—ANTERIOR COMMISSURE AND CAUDAL THALAMUS (CONTINUED)

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Level 6: Head of Caudate and Midthalamus

Frontal lobe External capsule Anterior limb of internal capsule

Level of section (head of caudate and midthalamus)

Head of caudate nucleus Claustrum

Genu of corpus callosum

Extreme capsule

Genu of internal capsule

Insular cortex

Anterior horn of lateral ventricle

Posterior limb of internal capsule Transverse temporal gyrus of Heschl Auditory radiations Tail of caudate nucleus Temporal lobe

Columns of fornix

Optic radiation

Third ventricle

Temporal pole of lateral ventricle

Globus pallidus

Choroid plexus

Putamen Splenium of the corpus callosum

Fimbria of fornix Occipital lobe

Thalamus Pulvinar

  13.6A AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 6—HEAD OF CAUDATE AND MIDTHALAMUS

Telencephalon

311

Frontal cortex Genu of corpus callosum Head of caudate nucleus

Anterior limb of internal capsule

Anterior horn of lateral ventricle

Columns of fornix

Globus pallidus Genu of internal capsule

Insular cortex

Putamen

Posterior limb of internal capsule Lateral fissure

Thalamus Temporal pole of lateral ventricle Tail of caudate nucleus

Optic radiations

Splenium of corpus callosum

 

13.6B AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 6—HEAD OF CAUDATE AND MIDTHALAMUS (CONTINUED)

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Level 7: Basal Ganglia and Internal Capsule

Anterior limb of internal capsule Putamen

Rostrum of corpus callosum

Claustrum

Frontal pole of lateral ventricle

Insular cortex

External capsule Extreme capsule

Level of section (basal ganglia and internal capsule) Lateral and ventral thalamic nuclei Posterior limb of internal capsule Pulvinar Tail of caudate nucleus Temporal pole of lateral ventricle

Septum pellucidum Head of caudate nucleus Anterior thalamic nuclei

Optic radiations Choroid plexus Medial thalamic nuclei

Body of fornix

Genu of internal capsule Splenium of corpus callosum

Occipital lobe

 

13.7A AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 7—BASAL GANGLIA AND INTERNAL CAPSULE CLINICAL POINT Huntington’s disease is an autosomal dominant disorder caused by a trinucleotide repeat (CAG) on the short arm of chromosome 4. It results in a progressive, untreatable disease that includes a movement disorder (choreiform movements: brisk, jerky, forcible, arrhythmic movements), progressive cognitive impairment, and affective disorders (such as depression, psychotic behavior). This

disease progresses from a state of minor impairment (clumsiness) with minor behavioral problems (irritability and depression) to major impairment, dementia, and a decline that leads to incapacitation and ultimately to an early death. The anatomical hallmark of this disease is marked degeneration of the caudate nucleus (also the putamen). The characteristic bulge of the head of the caudate into the frontal pole of the lateral ventricle is lost. Most of the medium spiny caudate neurons that project to the globus pallidus degenerate as the result of damage from excess Ca2+ influx caused by glutamate excitotoxic damage via activation of the N-­methyl-­D-­aspartate (NMDA) receptors. The intrinsic cholinergic interneurons of the striatum also degenerate in Huntington’s disease.   

Telencephalon

Frontal cortex

Genu of corpus callosum

Head of caudate nucleus

Septum pellucidum

Putamen

313

Anterior limb of internal capsule Columns of fornix

Insular cortex

Posterior limb of internal capsule Lateral fissure

Temporal pole of lateral ventricle

Thalamus Body of fornix

Occipital lobe

Splenium of corpus callosum Optic radiations

 

13.7B AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 7—BASAL GANGLIA AND INTERNAL CAPSULE (CONTINUED)

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Level 8: Dorsal Caudate, Splenium, and Genu of Corpus Callosum

Cingulate cortex Body of lateral ventricle

Genu of corpus callosum Frontal lobe

Body of caudate nucleus

Level of section (dorsal caudate, splenium, and genu of corpus callosum)

Insular cortex Parietal lobe

Frontal pole of lateral ventricle Occipital lobe

Septum pellucidum

Splenium of corpus callosum

 

13.8A AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 8—DORSAL CAUDATE, SPLENIUM, AND GENU OF CORPUS CALLOSUM

Telencephalon

Frontal lobe

Body of caudate nucleus

Septum pellucidum

315

Cingulate cortex

Frontal pole of lateral ventricle

Body of lateral ventricle

Parietal lobe

Splenium of corpus callosum

Occipital lobe

 

13.8B AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 8—DORSAL CAUDATE, SPLENIUM, AND GENU OF CORPUS CALLOSUM (CONTINUED)

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Level 9: Body of Corpus Callosum

Anterior cingulate cortex Body of caudate nucleus

Frontal lobe Centrum semiovale

Level of section (body of corpus callosum)

Parietal lobe

Occipital lobe Visual cortex

Body of lateral ventricle Body of corpus callosum

  13.9A AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 9—BODY OF CORPUS CALLOSUM

Telencephalon

Anterior cingulate cortex

Body of caudate nucleus

Body of corpus callosum

Body of lateral ventricle

Parietal lobe

Centrum semiovale

Visual cortex

Occipital lobe

 

13.9B AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 9—BODY OF CORPUS CALLOSUM (CONTINUED)

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Level 10: Centrum Semiovale

Cingulate gyrus

Frontal lobe

Level of section (centrum semiovale)

Parietal lobe Lateral fissure

Centrum semiovale

Occipital lobe

 

13.10A AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 10—CENTRUM SEMIOVALE See Video 13.1.

Telencephalon

Frontal lobe

Parietal lobe

Cingulate gyrus

Lateral fissure Centrum semiovale

Occipital lobe

 

13.10B AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN: LEVEL 10—CENTRUM SEMIOVALE (CONTINUED)

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Level 1: Genu of Corpus Callosum

Superior frontal gyrus Middle frontal gyrus Inferior frontal gyrus

Level of section (genu of corpus callosum)

Cingulate gyrus

Genu of corpus callosum

Frontal pole of lateral ventricle

Subcallosal gyrus Lateral fissure Temporal pole

 

13.11A CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 1—GENU OF CORPUS CALLOSUM These coronal sections compare anatomical sections and high-­ resolution MR images. They show important relationships among the internal capsule, basal ganglia, and thalamus. These sections show basal forebrain structures, such as nucleus accumbens,

substantia innominata, and nucleus basalis (cholinergic forebrain nucleus), some individual thalamic nuclei, and the important temporal lobe structures (amygdaloid nuclei, hippocampal formation) and pathways (fornix, stria terminalis). The full-­page MR images are T1-­weighted; the ventricles appear dark. The scout MR images that accompany the drawings are T2-­weighted MR images in which the CSF appears white.

Telencephalon

321

Superior frontal gyrus

Middle frontal gyrus Inferior frontal gyrus

Cingulate gyrus Genu of corpus callosum Frontal pole of lateral ventricle Subcallosal gyrus

Lateral fissure Temporal pole

 

13.11B CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 1—GENU OF CORPUS CALLOSUM (CONTINUED)

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Level 2: Head of Caudate Nucleus/Nucleus Accumbens

Cingulum Paraolfactory gyrus Head of caudate nucleus

Cingulate gyrus Body of corpus callosum Septum pellucidum

Nucleus accumbens Frontal pole of lateral ventricle

Anterior limb of internal capsule Putamen

Level of section (head of caudate nucleus/ nucleus accumbens)

External capsule

Claustrum

Insular cortex Lateral fissure Temporal pole

Amygdala Optic nerve

Extreme capsule

 

13.12A CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 2—HEAD OF CAUDATE NUCLEUS/NUCLEUS ACCUMBENS CLINICAL POINT The nucleus accumbens is located at the anterior end of the striatum in the ventral part of the forebrain. It receives a variety of inputs from limbic structures, such as the amygdala, hippocampal formation, and

bed nucleus of the stria terminalis. A major dopaminergic (DA) input innervates the nucleus accumbens via the mesolimbic DA pathway, which derives from the ventral tegmental area in the ventral midbrain. The nucleus accumbens is central to motivational states and addictive behavior, driven by DA neurotransmission. The nucleus accumbens is also a principal region of brain circuitry associated with reward, such as joy, pleasure, and gratification. This nucleus has a looped circuitry through the thalamus and cortex that helps to provide motor expression of emotional responses and accompanying gestures and behaviors.   

Telencephalon

323

Cingulate gyrus Body of corpus callosum

Frontal pole of lateral ventricle

Septum pellucidum Claustrum Insular cortex Lateral fissure

Temporal lobe

Head of caudate nucleus Anterior limb of internal capsule Putamen Nucleus accumbens Optic chiasm

Amygdala

 

13.12B CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 2—HEAD OF CAUDATE NUCLEUS/ NUCLEUS ACCUMBENS (CONTINUED)

324

Regional Neuroscience

Level 3: Anterior Commissure/Columns of Fornix Cingulate gyrus Cingulum Columns of fornix Head of caudate nucleus Body of corpus callosum

Anterior limb of internal capsule

Level of section (anterior commissure/columns of fornix)

Frontal pole of lateral ventricle

Claustrum

Septum pellucidum

Insular cortex Putamen

Extreme capsule

Lateral fissure Globus pallidus

External capsule

Anterior commissure Nucleus basalis

Third ventricle

Temporal lobe Optic chiasm

Amygdala

Supraoptic recess

 

13.13A CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 3—ANTERIOR COMMISSURE/COLUMNS OF FORNIX CLINICAL POINT Most infections in the brain are caused by viruses, bacteria, fungi, and other living organisms. A review of these infections is beyond the scope of this atlas. A prominent but rare exception to the norm is an unusual and unexpected protein infection (or prion) that is readily transmissible by a nonliving molecule, a protein. A normal neural protein, prion protein (PrPc, c = cellular) functions as a copper-­binding protein and is involved in cellular adhesion and cellular communication in neurons. An aberrant form of this protein (PrPSc, Sc = scrapie) displays an altered, aberrant folding structure. This aberrant protein form can recruit normal protein PrPc to transform to the aberrant form, PrPSc, and form large, insoluble clusters of highly damaging amyloid-­like plaques. The end result, after an incubation period, is a rapid, progressive chain reaction leading to vacuolization and degeneration/ destruction of virtually all central nervous system (CNS) regions. This is referred to as a spongiform encephalopathy, and the prion disease is also known as Creutzfeldt-­Jakob disease (CJD). The clinical symptoms of prion disease are myriad and include cognitive decline, emotional alterations, behavioral and personality changes, speech and language loss, motor and myoclonic changes, severe ataxia, swallowing problems, perceptual changes, seizures, and

many others. No brain region is protected, and prominent structural damage can be found in the cerebral cortex, limbic structures, basal ganglia, thalamus, cerebellum, brainstem, and spinal cord. There are three major forms of prion disease. A genetic form (10% to 15% of cases) arises from an altered PRNP gene, which codes for the aberrant protein PrPSc. A spontaneous form, by far the largest number of cases, arises for unknown reasons (one case per million individuals). A transmissible acquired form (variant CJD) arises from consumption of meat or body tissue from infected sheep and goats (scrapie); from cows (bovine spongiform encephalopathy) who were fed contaminated feed, leading to bovine spongiform encephalopathy in cows and mad cow disease in humans who eat the contaminated beef; and from wild game (deer, elk, with chronic wasting disease) and others. A rare acquired form was found many decades ago in Papua, New Guinea, in an indigenous tribe in which eating the brain tissue from other humans was practiced; this led to the disease kuru, which is also a prion disease. These insoluble aberrant proteins also can be transmitted from individual to individual by medical procedures and the use of contaminated surgical instruments. It was found that even prolonged, vigorous autoclaving of surgical instruments or treatment with standard chemical disinfectants does not inactivate PrPSc. A special protocol is now required to ensure that prion disease can no longer be transmitted via this route. Ensurance of inactivation of the PrPSc protein occurs with incineration at 1000°C. There is no evidence for person-to-person transmission through normal human contact. At present, there is no known successful treatment for prion disease.   

Telencephalon

Frontal pole of lateral ventricle Head of caudate nucleus Anterior limb of internal capsule Putamen Globus pallidus Temporal lobe Anterior commissure Nucleus basalis

Cingulate cortex Cingulum Body of corpus callosum Septum pellucidum External capsule Insular cortex Lateral fissure Third ventricle

Amygdala

Optic tract

 

13.B CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 3—ANTERIOR COMMISSURE/ COLUMNS OF FORNIX (CONTINUED)

325

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Level 4: Amygdala, Anterior Limb of Internal Capsule

Cingulum Stria terminalis and terminal vein

Cingulate gyrus Body of corpus callosum

Body of caudate nucleus

Body of lateral ventricle

Anterior limb of internal capsule

Level of section (amygdala, anterior limb of internal capsule)

Claustrum

Putamen Insular cortex Globus pallidus external segment Temporal cortex

Amygdala

Columns of fornix

Globus pallidus internal segment

Third ventricle Hypothalamus

Optic tract

  13.14A CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 4—AMYGDALA, ANTERIOR LIMB OF INTERNAL CAPSULE CLINICAL POINT The corpus callosum is the principal interhemispheric or commissural pathway in the brain. It interconnects one hemisphere with its counterpart on the other side, with the exception of part of the temporal lobe that is interconnected by the anterior commissure. Some large lesions resulting from trauma or tumor can damage the corpus callosum, but this is usually accompanied by a large amount of additional forebrain

damage. However, specific surgical sectioning of the corpus callosum has been performed in an attempt to alleviate the spread of seizure activity from one side of the brain to the other. This “split b ­ rain” surgery causes each hemisphere to be unaware of specific activity occurring in the other hemisphere. Thus, the left brain cannot identify a visual or somatosensory stimulus presented to the right hemisphere and does not know where the left hand and arm are located if they are kept from the left hemisphere’s view. Sometimes, the left hand may act independently of the conscious intent of the left hemisphere. Some emotional information appears to transfer through brainstem regions between the two parts of the split brain, providing a limbic context that may be perceived to some extent by both hemispheres.   

Telencephalon

327

Cingulate cortex Body of corpus callosum Septum pellucidum Lateral fissure

Cingulum Body of lateral ventricle Body of caudate nucleus Genu/anterior limb of internal capsule

Insular cortex Columns of fornix Inferior horn of lateral ventricle Amygdala Hypothalamus

Putamen Temporal lobe Globus pallidus Optic tract Third ventricle

 

13.14B CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 4—AMYGDALA, ANTERIOR LIMB OF INTERNAL CAPSULE (CONTINUED)

328

Regional Neuroscience

Level 5: Mammillary Bodies

Third ventricle Rostral thalamus Hypothalamus Posterior limb of internal capsule

Cingulate gyrus Body of corpus callosum Cingulum Columns of fornix

Globus pallidus internal segment

Level of section (mammillary bodies)

Putamen

Body of lateral ventricle Body of caudate nucleus

Globus pallidus external segment

Insular cortex Lateral fissure Claustrum Inferior horn of lateral ventricle Temporal lobe

Amygdala

Extreme capsule

Optic tract Hippocampal formation Interpeduncular fossa Mammillary body

External capsule

Middle cerebral artery Basis pontis

Cerebral peduncle Corticospinal tract in basis pontis

 

13.15A CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 5—MAMMILLARY BODY

Telencephalon

329

Body of lateral ventricle Columns of fornix Cingulate cortex Cingulum Body of caudate nucleus Putamen Insular cortex

Rostral thalamus Posterior limb of internal capsule Claustrum Temporal lobe

Lateral fissure

Amygdala Inferior horn of lateral ventricle

Third ventricle Hippocampal formation Hypothalamus

Corticospinal tract in basis pontis Basis pontis

 

13.15B CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 5—MAMMILLARY BODY (CONTINUED)

330

Regional Neuroscience Level 6: Mammillothalamic Tract/Substantia Nigra, Rostral Hippocampus

Cingulate gyrus

Body of corpus callosum

Cingulum Columns of fornix

Anterior thalamus

Body of lateral ventricle

Medial dorsal thalamus Mammillothalamic tract

Third ventricle Centrum semiovale

Body of caudate nucleus Ventral lateral thalamus

External capsule

Posterior limb of internal capsule

Extreme capsule

Level of section (mammillothalamic tract/substantia nigra, rostral hippocampus) Putamen

*

Insular cortex Optic tract Temporal pole of lateral ventricle

*

Tail of caudate nucleus Temporal cortex

Globus pallidus external segment

Hippocampal formation Cerebral peduncle Substantia nigra Corticospinal tract fibers in basis pontis

Globus pallidus internal segment Basis pontis Medulla Medullary pyramids

 

13.16A CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 6— MAMMILLOTHALAMIC TRACT/ SUBSTANTIA NIGRA, ROSTRAL HIPPOCAMPUS CLINICAL POINT The posterior limb of the IC is the major afferent and efferent route through which the cerebral cortex is connected with the rest of the brain. The cerebral cortex sends descending fibers through the IC that are destined for the spinal cord, brainstem, cerebellum (via pontine nuclei), striatum and related nuclei, thalamus, and limbic structures. Of particular importance for movement are the corticospinal system and cortical connections to other upper motor neuron regions (such

as the red nucleus) arising from the motor and premotor/supplemental motor cortices, which help to control skilled movements of the contralateral limbs, and the corticobulbar tract, which supplies motor cranial nerve nuclei with descending control, all bilaterally except for the lower facial nucleus, which receives exclusively contralateral input. The corticospinal tract travels in the posterior limb of the IC, and the corticobulbar tract travels in the genu of the IC. The posterior limb of the IC also conveys the ascending somatosensory and trigeminal sensory axons from the ventral posterolateral and posteromedial thalamus, respectively, which are susceptible to vascular infarcts in the middle cerebral artery and fine penetrating lenticulostriate arteries. Such an infarct acutely produces contralateral hemiplegia and a drooping lower face, with loss of somatic sensation. With time, the hemiplegia becomes spastic, with hyperreflexia, hypertonus, and pathological reflexes (Babinski’s reflex, or plantar extensory response).   

Telencephalon

331

Cingulum Body of lateral ventricle

Cingulate cortex Body of corpus callosum

Insular cortex

Body of caudate nucleus

Lateral fissure

Columns of fornix Putamen

Thalamus

Posterior limb of internal capsule Third ventricle

Tail of caudate nucleus Inferior horn of lateral ventricle Substantia nigra Hippocampal formation Cerebral peduncle

Corticospinal tract in basis pontis Basis pontis

 

13.16B CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 6—MAMMILLOTHALAMIC TRACT/ SUBSTANTIA NIGRA, ROSTRAL HIPPOCAMPUS (CONTINUED)

332

Regional Neuroscience Level 7: Midthalamus

Body of corpus callosum Cingulate cortex

Columns of fornix

Interventricular foramen of Munro

Third ventricle Body of lateral ventricle

Cingulum Stria terminalis

Level of section (midthalamus)

Body of caudate nucleus

Medial dorsal thalamus Insular cortex Lateral thalamus Lateral geniculate nucleus Centromedian thalamus Tail of the caudate nucleus

Hippocampal formation Medial geniculate nucleus Cortex of cerebellum

Superior cerebellar peduncle

Entorhinal cortex

Pons (floor of fourth ventricle) Inferior cerebellar peduncle Medulla

 

13.17A CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 7—MIDTHALAMUS

Telencephalon

333

Cingulum Body of lateral ventricle Cingulate cortex Columns of fornix Body of corpus callosum Thalamus

Lateral geniculate nucleus

Body of caudate nucleus Stria terminalis Third ventricle

Temporal lobe

Medial geniculate nucleus Superior cerebellar peduncle

Hippocampal formation Middle cerebellar peduncle Inferior cerebellar peduncle

 

13.17B CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 7—MIDTHALAMUS (CONTINUED)

334

Regional Neuroscience Level 8: Geniculate Nuclei Cingulate gyrus Cingulum Body of caudate nucleus

Body of corpus callosum Body of fornix Third ventricle Body of lateral ventricle

Pulvinar

Level of section (geniculate nuclei) Medial geniculate nucleus Lateral geniculate nucleus Tail of caudate nucleus Inferior pole of lateral ventricle

Hippocampal formation Posterior commissure

Pretectum Cerebellar cortex

Periaqueductal gray matter

Middle cerebellar peduncle

Cerebral aqueduct

Decussation of superior cerebellar peduncle

Medulla

Pons

 

13.18A CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 8—GENICULATE NUCLEI CLINICAL POINT Several thalamic nuclei in the posterior thalamus are important for conveying visual and auditory information to the cerebral cortex. The lateral geniculate nucleus receives segregated input from the temporal hemiretina of the ipsilateral eye and from the nasal hemiretina of the contralateral eye, and it conveys this topographical information to area 17, the primary visual cortex, located on the banks of the

calcarine fissure. A lesion in the lateral geniculate nucleus results in contralateral hemianopia. The pulvinar receives visual input from the superior colliculus and also conveys visual information to the visual cortex, to areas 18 and 19 (associative visual cortex). A lesion in the pulvinar can lead to contralateral visual neglect. The medial geniculate nucleus receives input from the inferior colliculus through the bra-­ chium of the inferior colliculus. However, because the auditory system is bilaterally represented at this level, a lesion in the medial geniculate nucleus on one side does not result in contralateral deafness. There may be some diminution of hearing contralateral to the lesion, but it is not a profound deficit. Visual areas 17, 18, and 19 correspond to visual cortices I, II, and III, as illustrated in Fig. 13.26.   

Telencephalon

Body of corpus callosum Cingulate cortex

Cingulum

Body of lateral ventricle Body of caudate nucleus Pulvinar

Columns of fornix Tail of caudate nucleus Middle cerebellar peduncle Lateral cerebellar hemisphere

Inferior horn of lateral ventricle Hippocampal formation Superior cerebellar peduncle Pons Medulla Cervical spinal cord

 

13.18B CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 8—GENICULATE NUCLEI (CONTINUED)

335

336

Regional Neuroscience Level 9: Caudal Pulvinar and Superior Colliculus

Cingulate gyrus

Body of corpus callosum

Cingulum Crus of fornix Superior colliculus

Habenula

Pulvinar

Level of section (caudal pulvinar and superior colliculus)

Body of caudate nucleus

Third ventricle Body of lateral ventricle

Tail of caudate nucleus Fimbria of hippocampal formation Inferior pole of lateral ventricle Hippocampal formation

Lateral cerebellar hemisphere Entorhinal cortex Middle cerebellar peduncle

Inferior colliculus

Cerebellar vermis

Fourth ventricle

Superior cerebellar peduncle

 

13.19A CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 9—CAUDAL PULVINAR AND SUPERIOR COLLICULUS

Telencephalon

Cingulate cortex Cingulum Parietal lobe Body of corpus callosum

Body of lateral ventricle Superior colliculus

Columns of fornix at transition to body Confluence of inferior horn and body of lateral ventricle

Hippocampal formation Inferior colliculus

Pulvinar Superior cerebellar peduncle Lateral cerebellar hemisphere

Fourth ventricle

Medulla

Middle cerebellar peduncle

 

13.19B CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 9—CAUDAL PULVINAR AND SUPERIOR COLLICULUS (CONTINUED)

337

338

Regional Neuroscience Level 10: Splenium of Corpus Callosum

Cingulate gyrus Cingulum

Splenium of corpus callosum Pineal Trigone of lateral ventricle

Crus of fornix

Choroid plexus Pulvinar Inferior pole of lateral ventricle

Level of section (splenium of corpus callosum)

Tail of caudate nucleus Optic radiations Hippocampal formation Temporal lobe

Lateral cerebellar hemisphere Dentate nucleus Cerebellar vermis

Fourth ventricle

 

13.20A CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 10—SPLENIUM OF CORPUS CALLOSUM See Video 13.2.

Telencephalon

Splenium of corpus callosum Pineal Crus of fornix Choroid plexus in ventricle

Cingulate cortex Cingulum Parietal lobe

Trigone of lateral ventricle

Optic radiations Hippocampal formation Temporal lobe Deep cerebellar nuclei Fourth ventricle

Lateral cerebellar hemisphere

Cerebellar vermis

 

13.20B CORONAL SECTIONS THROUGH THE FOREBRAIN: LEVEL 10—SPLENIUM OF CORPUS CALLOSUM (CONTINUED)

339

340

Regional Neuroscience

I

II

III

IV

V

VI

Noradrenergic axon from locus coeruleus W h i t e m a t t e r

Serotonergic axon from rostral raphe nuclei Specific afferents From other parts of cortex Association fibers To other parts of cortex

Motor fibers

 

13.21 LAYERS OF THE CEREBRAL CORTEX Regions of cerebral cortex with specific functional roles, such as the somatosensory cortex and the motor cortex, demonstrate histological characteristics that reflect that function. The sensory cortex has large granule cell layers (granular cortex) for receiving extensive input, whereas the motor cortex has sparse granule cell

layers and extensive pyramidal cell layers, reflecting extensive output. Specific and nonspecific afferents terminate differentially in these structurally unique regions of the cortex. Monoamine inputs (noradrenergic and serotonergic) terminate more diffusely than do the specific inputs, reflecting the role of monoamines as modulators and enhancers of the activity of other neuronal systems.

Telencephalon

I

Key for Abbreviations a Horizontal cell b Cell of Martinotti c Chandelier cell d Aspiny granule cell e Spiny granule cell f Stellate (granule) cell g Small pyramidal cell of layers II, III h Small pyramidal association cell i Small pyramidal association and projection cells of layer V j Large pyramidal projection cell (Betz cell)

a

g

II

341

c III

Pyramidal cells h

IV

e

f

Apical dendrites

d

i V j Basolateral dendrites

b

Multiple cortical pyramidal cells with conspicuous apical dendrites and basolateral dendrites, and other cortical cells. Fiber stain.

VI

White matter

Cortical interneurons

Cortical association neurons

Efferent neuron

Black—cell bodies and dendrites Brown—axons of interneurons and association neurons Red—axon of efferent neurons Pyramidal neuron with massive dendritic branching, particularly the basolateral dendrites. Golgi stain with background cell stain.

  13.22 CORTICAL NEURONAL CELL TYPES The cerebral cortex has many anatomically unique cell types that have characteristic cell bodies, dendritic arborizations, and axonal distributions. Granule cells are local circuit neurons with small cell bodies, localized dendritic trees, and axons that distribute locally. Granule cells function as receiving neurons for thalamic and other inputs, and they modulate the excitability of other cortical neurons. Pyramidal cells possess more varied cell

bodies (some large, some small) that have large basolateral dendritic branching patterns and apical dendritic arborizations that run perpendicular to the cortical surface and arborize in upper layers. The axons of pyramidal cells, which function as projection neurons (e.g., corticospinal tract neurons), leave the cortex and may extend for as long as a meter before synapsing on target neurons. These unique anatomical characteristics give rise to the concept that neuronal structure explains neuronal function.

342

Regional Neuroscience

Vertical columns (0.5–1.0 mm wide)

I II

III Small pyramidal cell Granule cell IV

V

Large pyramidal cell

Thalamocortical afferent terminations

VI

Corticocortical afferent Cortical projection (efferent) fibers to subcortical structures Thalamocortical afferent Corticocortical efferents (some to adjacent or nearby vertical columns)

  13.23 VERTICAL COLUMNS: FUNCTIONAL UNITS OF THE CEREBRAL CORTEX Experimental studies of sensory regions of the cerebral cortex provided anatomical and physiological evidence that discrete information that comes from a specific region or that conveys specific functional characteristics is processed in a cylindrical vertical zone of neurons in the cortex that spans all six layers of the neocortex. These vertical units vary from 0.5 to 1.0 mm in diameter. The diameter corresponds to the major horizontal

expanse of a larger pyramidal cell in that unit. Both thalamic and cortical afferents arborize in the vertical column and synapse on both stellate (granule) cells and pyramidal neuron dendrites. Information from a vertical column can be sent to an adjacent or nearby column via corticocortical efferents or can be sent to distant structures by commissural fibers (cortex on the other side) or by projection fibers (subcortical structures). The minimal elements of the vertical unit are shown.

Telencephalon

343

Association Fibers Long - to distant regions of ipsilateral hemisphere Short - to nearby regions of ipsilateral hemisphere

Commissural Fibers To cortical regions of contralateral hemisphere

Projection Fibers Corticospinal tract Corticobulbar tract Corticorubrospinal system Corticoreticulospinal system Corticobulbospinal system (polysynaptic) Corticotectal fibers Corticopontine fibers (to cerebellum) Corticostriate fibers (to basal ganglia) Corticonigral and corticosubthalamic fibers Corticonuclear fibers (to secondary sensory nuclei) Corticothalamic projections Corticohypothalamic and corticoautonomic fibers Cortico-olivary fibers Corticolimbic fibers (in subcortical forebrain)

Caudate nucleus Thalamus

Putamen

Lateral fissure

Globus pallidus Third ventricle Hypothalamus Hippocampus

Lateral ventricle (lateral pole)

 

13.24 EFFERENT CONNECTIONS OF THE CEREBRAL CORTEX Neurons of the cerebral cortex send efferent connections to three major regions: (1) association fibers are sent to other cortical regions of the same hemisphere, either nearby (short association fibers) or at a distance (long association fibers); (2) commissural fibers are sent to cortical regions of the other hemisphere through the corpus callosum or the anterior commissure; and (3) projection fibers are sent to numerous subcortical structures in the telencephalon, diencephalon, brainstem, and spinal cord. The major sites of termination of these connections are listed in the diagram. CLINICAL POINT The cerebral cortex provides the highest level of regulation over motor and sensory systems, behavior, cognition, and the functional capacities of the brain that are most characteristic of human accomplishment.

The cortex does this through three types of efferent pathways: (1) association fibers; (2) commissural fibers; and (3) projection fibers. Association fibers interconnect with either nearby (short) or distant (long) regions of cortex. Damage to long association fibers can disconnect regions of cortex that normally need to communicate; this can result in altered language function, altered behavior, and other cortex-­ related problems. Damage to commissural fibers, especially the corpus callosum and anterior commissure, sometimes done deliberately to alleviate the spread of seizure activity, can result in a disconnection between the left and right hemispheres, with each hemisphere not being fully aware of what the other is doing because it does not have separate input. Damage to the projection fibers, which commonly accompanies infarcts or lesions in the internal capsule, can disrupt cortical outflow to the spinal cord, brainstem, cerebellum, thalamus and hypothalamus, basal ganglia, and limbic forebrain structures. As a consequence, major sensory deficits (especially in the opposite side for somatic sensation and vision), contralateral spastic hemiplegia with central facial involvement, hemianopia, and other motor, sensory, and behavioral deficits may occur.   

344

Regional Neuroscience

I

Small pyramidal cell

II

III Small pyramidal cell

IV

V

Large pyramidal cell

Modified pyramidal cell

VI

Subcortical projections (mainly) Some corticocortical axons

Corticocortical axons Commissural axons

Corticocortical axons

Corticothalamic axons Some corticocortical axons Some commissural axons Some projection axons to claustrum

 

13.25 NEURONAL ORIGINS OF EFFERENT CONNECTIONS OF THE CEREBRAL CORTEX Association fibers destined for cortical regions of the same hemisphere arise mainly from smaller pyramidal cells in cortical layers II and III and from modified pyramidal cells in layer VI.

Commissural fibers destined for cortical regions of the opposite hemisphere arise mainly from small pyramidal cells in cortical layer III and from some modified pyramidal cells in layer VI. Projection fibers arise from larger pyramidal cells in layer V and also from smaller pyramidal cells in layers V and VI. Only a small number of projection fibers arise from the giant Betz cells in layer V.

Motor-sensory

Ms I Ms II

Sm I Sm II

Sensory-motor

(to Ms II)

Sensory analysis

Premotor; orientation; eye and head movements

Visual III Visual II Visual I

Prefrontal; inhibitory control of behavior; higher intelligence

Language; reading; speech Auditory I

Motor control of speech

Auditory II

Motor-sensory Premotor

Sm I Sm II

Ms I Ms II

Sensory-motor

Temporocingulate and parietocingulate pathways Prefrontal; inhibitory control of behavior; higher intelligence

Visual III Visual II Visual I

Frontocingulate pathway Cingulate gyrus (emotional behavior) and cingulum

Corpus callosum Hippocampal commissure Anterior commissure

Olfactory

  13.26 CORTICAL ASSOCIATION PATHWAYS Neurons of the cerebral cortex have extensive connections with other regions of the brain (projection neurons), with the opposite hemisphere (commissural neurons), and with other regions of the ipsilateral hemisphere (association fibers). The cortical association fibers may connect a primary sensory cortex with adjacent association areas (e.g., visual cortex, somatosensory cortex) or may link multiple regions of cortex into complex association areas (e.g., polysensory analysis regions) or interlink important areas involved in language function, cognitive function, and emotional behavior and analysis. Damage to these pathways and associated cortical regions can result in loss of specific sensory and motor capabilities, aphasias (language disorders), agnosias (failures of recognition), and apraxias (performance deficits). CLINICAL POINT Long cortical association pathways link regions of cortex with each other. Some pathways link multiple sensory areas with multimodal cortical association cortex, providing the substrate for integrated interpretation of the outside world. Some association pathways connect language areas in the dominant hemisphere with each other.

Broca’s area of the frontal cortex and Wernicke’s area in the parietotemporal region are interconnected by long association fibers of the arcuate fasciculus or superior longitudinal fasciculus. When these association fibers are damaged, Broca’s area and Wernicke’s area are disconnected. The patient does not demonstrate a classic expressive or receptive aphasia but demonstrates the inability to repeat complex words or sentences. This is called conduction aphasia. Subcortical white matter plays an important role in human behavior. Many types of pathology can affect subcortical white matter, such as multi-­infarct damage or demyelination. These conditions cause a disconnection between regions of cerebral cortex or between subcortical regions and cortex. With multiple regions of white matter damage, dementia can occur, including inattention, emotional changes, and memory problems; such changes generally occur in the absence of movement disorders or aphasias. Multi-­ infarct damage to the ascending catecholamine and serotonin pathways from the brainstem can occur with destruction of the axons in the cingulum, resulting in depression and bipolar disorder, as well as attention deficits, especially with lesions involving ascending noradrenergic and reticular activating circuitry. Bilateral damage to white matter of the frontal lobe may result in euphoria and inappropriate affect, whereas damage to the long association fibers interconnecting the frontal lobes with limbic forebrain structures may result in psychotic behavior.   

346

Regional Neuroscience

Superior occipitofrontal fasciculus

Superior longitudinal fasciculus

Inferior occipitofrontal fasciculus

Uncinate fasciculus

Cingulum Superior occipitofrontal fasciculus

Superior longitudinal fasciculus

psu ca

Thalamus

Claustrum Lateral fissure

Globus pallidus

Int

Inferior occipitofrontal fasciculus

ern

al

Putamen

le

Caudate nucleus

Hypothalamus Uncinate fasciculus

  13.27 MAJOR CORTICAL ASSOCIATION BUNDLES Association fibers interconnecting cortical regions in one hemisphere with adjacent or distant regions of the same hemisphere are categorized as short association fibers (arcuate fibers) or long association fibers. The long association fibers often are recognized anatomically as specific association bundles and may have numerous fiber systems entering, exiting, and traversing them. Important named bundles include the uncinate fasciculus, the superior longitudinal fasciculus, the superior and inferior occipitofrontal fasciculi, and the cingulum. The cingulum is a bundle through which the major monoamines (dopamine, norepinephrine, serotonin) and part of the cholinergic projections travel to their widespread target sites.

CLINICAL POINT Cortical association pathways, or bundles, can become demyelinated in multiple sclerosis and other demyelinating diseases, leading to cognitive and emotional problems in addition to the sensory, motor, and autonomic involvement that is well known in such disorders. Diminished attention and vigilance can occur with demyelination of association pathways, and that may contribute to some of the memory impairment seen in recall tasks. Inappropriate expression of emotion and euphoria or emotional disinhibition (sometimes called pseudobulbar affect) can occur with damage to frontal association pathways. Both depressive and bipolar disorders occur more commonly in patients with multiple sclerosis than in controls, and there is some correlation with the presence of demyelinating lesions in the temporal lobe, although monoaminergic pathways also may be involved. Although many clinicians view some of the demyelinating plaques that form in subcortical white matter to be “silent lesions” that produce no pathology, the endpoint for evaluation usually has been classic motor and sensory symptoms, not emotional and cognitive dysfunction. Although such deficits may be more common than previously supposed, the ability of the brain to repair demyelinated lesions often can ameliorate such deficits.   

Telencephalon

347

A. Axial view

Superior longitudinal fasciculus

Occipital-temporal association fibers

Cortical projection fibers Superior longitudinal fasciculus Splenium, corpus callosum Arcuate fasciculus Genu, corpus callosum

B. Sagittal view

 

13.28 COLOR IMAGING OF ASSOCIATION PATHWAYS These diffusion tensor images show the association pathways of the forebrain in green (anterior-­posterior direction) in an axial section and in a sagittal section. The most conspicuous association

fibers in these images are the long association pathways. Commissural fibers appear red/orange (left-­right direction) and projection fibers appear blue (superior-­inferior direction).

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Regional Neuroscience

A. Sagittal view Corona radiata coalescing into the internal capsule Cingulum Fibers of superior longitudinal fasciculus Fornix

Fibers of inferior longitudinal fasciculus Internal capsule Superior cerebellar peduncle Middle cerebellar peduncle Pyramidal tract Dorsal column system

Corona radiata Corpus callosum Fibers of uncinate fasciculus Inferior longitudinal fasciculus Motor fibers in basis pontis Superior cerebellar peduncle Pyramidal tract Ascending sensory fibers from brainstem and spinal cord

B. Sagittal view

 

13.29 COLOR IMAGING OF PROJECTION PATHWAYS FROM THE CEREBRAL CORTEX These diffusion tensor images show the projection pathways of the forebrain in blue in two sagittal sections. The widespread cortical projection bundles channel into a narrow zone of the

internal capsule and then proceed to their sites of projection in the forebrain, brainstem, or spinal cord. The descending corticospinal/corticobulbar system is particularly prominent. Projection systems associated with the cerebellum also are present. In addition, green association fibers and red commissural fibers can be seen. See Videos 13.3 and 13.4.

Telencephalon

A. Coronal section showing midline motor cortex response to alternating

B. Coronal section showing contralateral convexity motor cortex response

C. Coronal section showing Broca’s area response to a language task in

D. Axial section showing occipital cortex response to a visual task of

movement of the toes.

which subjects must silently discriminate word characteristics as abstract, concrete, single, double, upper case, or lower case over a 30-second time span.

349

and ipsilateral cerebellar response to rapid alternating sequential tapping movement of the fingers bilaterally.

viewing flickering alternating bands on a screen.

  13.30 FUNCTIONAL MAGNETIC RESONANCE IMAGING Functional magnetic resonance imaging (fMRI) is a noninvasive method that uses no radioactive tracers; it takes advantage of the fact that there is a difference in magnetic states of arterial and venous blood, thus providing an intrinsic mechanism of contrast for brain activation studies. The origin of this dual state of blood is due to the fact that the magnetic state of hemoglobin (Hb) depends on its oxygenation; the oxyhemoglobin state (arterial blood) is diamagnetic, and the venous deoxyhemoglobin state (venous blood) is paramagnetic. The change in oxygen saturation of the hemoglobin produces a detectable small signal change; hence, it is called the blood oxygenation level–dependent (BOLD) effect.

During neural activity, the supposition behind BOLD-­ fMRI is that the involved neurons represent a region of relatively greater oxygenated hemoglobin compared with nonactive regions in T2*-­weighted images. However, there is a delay of several seconds between increased neural activity and increased oxygenated arterial blood flow to that region. BOLD-­fMRI compares images during specific activity to images of the same region without such activity and can be used for processes that occur rapidly, such as language function, vision, audition, movement, cognitive tasks, and emotional responsiveness. The above images are taken from a sequence of coronal and axial sections showing regions of brain that are activated during (A) movement of toes, (B) sequential finger tapping, (C) language task, and (D) visual stimulation.

350

Regional Neuroscience D Cingulum L

NA neurons in group A1 in the medulla D

C

V Sagittal micrograph of NA axons in the dorsal NA bundle D Dorsal noradrenergic bundle Ventral noradrenergic bundle Temporal lobe D

V

Noradrenergic (NA) neurons in the locus coeruleus (group A6)

Sagittal micrograph of NA axons in the ventral NA bundle

Locus coeruleus

A5, A7

R

A1, A2 Descending noradrenergic bundle

V

D = Dorsal V = Ventral L = Lateral M = Medial C = Caudal R = Rostral

Falck-Hillarp formaldehyde fluorescence histochemistry images reprinted with permission from Felten DL and Sladek JF. 1983 Monoamine distribution in primate brain V. Monoaminergic nuclei: Anatomy, pathways and local organization. Brain Research Bulletin 10:171-284.

  13.31 NORADRENERGIC PATHWAYS Noradrenergic neurons in the brainstem project to widespread areas of the CNS. The neurons are found in the locus coeruleus (group A6) and in several cell groups in the reticular formation (RF; tegmentum) of the medulla and pons (A1, A2, A5, and A7 groups). Axonal projections of the locus coeruleus branch to the cerebral cortex, hippocampus, hypothalamus, cerebellum, brainstem nuclei, and spinal cord. The locus coeruleus acts as a modulator of the excitability of other projection systems such as the glutamate system and helps to regulate attention and alertness, the sleep-­wake cycle, and appropriate responses to stressors, including pain. The RF groups are interconnected extensively with the spinal cord, brainstem, hypothalamic, and limbic regions involved in neuroendocrine control, visceral functions (temperature regulation, feeding and drinking behavior, reproductive behavior, autonomic regulation), and emotional behavior. Serotonergic neurons of the raphe system overlap with many of these noradrenergic connections and comodulate related functional activities. A sparse set of epinephrine-­containing neurons in the medullary RF are similarly interconnected. These RF noradrenergic neurons can work in concert with the locus coeruleus during challenge or in response to a stressor to coordinate alertness and appropriate neuroendocrine and autonomic responsiveness. The central noradrenergic and adrenergic neurons and their receptors are the targets of many pharmacological agents, including those that target depression, analgesia, hypertension, and many other conditions.

CLINICAL POINT The axonal projections of the brainstem noradrenergic cell groups have incredibly widespread distribution to virtually all subdivisions of the CNS. The locus coeruleus acts as a modulator of the excitability of other axonal systems and can augment both glutamate excitability and gamma aminobutyric acid (GABA) inhibition within the same neurons (Purkinje cells). In keeping with such a modulatory role, the locus coeruleus system appears to help regulate attention, alertness, and sleep-­wakefulness cycles. Similarly, the brainstem tegmental nor-­ adrenergic systems have projections to spinal cord, brainstem, hypo-­ thalamic, and limbic regions and help to regulate neuroendocrine outflow and visceral functions, such as feeding, drinking, reproductive behavior, and autonomic regulation. In the spinal cord, descending noradrenergic projections modulate the excitability of lower motor neurons in the ventral horn. Central noradrenergic forebrain projections also influence emotional behavior and are integral to the catecholamine hypothesis of affective disorders, especially depression. Depression is hypothesized to be the result of diminished functioning of central noradrenergic connections (although serotonergic dysfunction is probably involved as well). All three major classes of drugs used for treating depression (monoamine oxidase inhibitors, tricyclic antidepressants, and psychomotor stimulants) enhance noradrenergic neurotransmission. MHPG (3-­methoxy-­4-­hydroxyphenylglycol), the major metabolite of central norepinephrine, is diminished in many depressed individuals. As a phenomenon accompanying depression, the altered noradrenergic activity in the brain of depressed patients may exert a regulatory impact on the ability of the paraventricular nucleus of the hypothalamus to activate the stress axes, accounting for the increased cortisol and peripheral catecholamine secretion seen in many depressed individuals.   

351

Telencephalon

Cingulum V Serotonergic neurons in nucleus raphe obscurus and in lateral wings of cells that extend into the adjacent reticular formation D

D R

L

C

Basal ganglia

V Sagittal micrograph of 5HT axons in the ascending serotonergic pathway

Thalamus

Ascending serotonergic pathway Serotonergic neurons in nucleus raphe pontis D

Temporal lobe Raphe dorsalis Centralis superior Raphe pontis Raphe magnus

L

Raphe pallidus and obscurus Descending serotonergic pathway Serotonergic (5HT) neurons in nucleus raphe dorsalis

V D = Dorsal V = Ventral L = Lateral M = Medial C = Caudal R = Rostral

Falck-Hillarp formaldehyde fluorescence histochemistry images reprinted with permission from Felten DL and Sladek JF. 1983 Monoamine distribution in primate brain V. Monoaminergic nuclei: Anatomy, pathways and local organization. Brain Research Bulletin 10:171-284.

13.32 SEROTONERGIC PATHWAYS Serotonergic neurons (5-­hydroxytryptamine; 5-­HT), found in the raphe nuclei of the brainstem and adjacent wings of cells in the RF, have widespread projections that innervate every major subdivision in the CNS. The rostral serotonergic neurons in nucleus raphe dorsalis and centralis superior project rostrally to innervate the cerebral cortex, many limbic forebrain structures (hippocampus, amygdala), the basal ganglia, many hypothalamic nuclei and areas, and some thalamic regions. The caudal serotonergic neurons in the nuclei raphe magnus, pontis, pallidus, and obscurus project more caudally to innervate many brainstem regions, the cerebellum, and the spinal cord. Of particular importance are the projections of the nucleus raphe magnus to the dorsal horn of the spinal cord, at which site opiate analgesia and pain processing are markedly influenced. The ascending serotonergic systems are involved in the regulation of emotional behavior and wide-­ranging hypothalamic functions (neuroendocrine, visceral/ autonomic), similar to their noradrenergic counterparts. Serotonergic neurons are involved in sleep-­wakefulness cycles and, like locus coeruleus noradrenergic neurons, stop firing during rapid eye movement (REM) sleep. Serotonergic projections to the cerebral cortex modulate the processing of afferent inputs (e.g., from the visual cortex). The descending serotonergic neurons enhance the effects of analgesia and are essential for opiate analgesia. They also modulate preganglionic autonomic neuronal excitability and enhance the excitability of lower motor neurons.

 

Many pharmacological agents target serotonergic neurons and their receptors, including drugs for treating depression, other cognitive and emotional behavioral states, headaches, pain, some movement disorders, and other conditions. CLINICAL POINT Serotonergic neurons of the raphe nuclei and adjacent reticular formation have incredibly widespread projections to virtually all subdivisions of the CNS, similar to the brainstem noradrenergic neurons. Serotonergic systems can modulate the excitability of other neural systems and are involved in the regulation of emotional behavior, neuroendocrine secretion and circadian rhythms, and widespread visceral functions (e.g., food intake, pain sensitivity, sexual behavior, and sleep-­wake cycles). During REM sleep, some raphe neurons cease their electrical firing. Many early physiological studies of the serotonergic and noradrenergic systems revealed that both systems help to regulate many of the same functions. Serotonin systems have been implicated in some patients with depression. Early consideration of tricyclic antidepressants focused on their ability to block reuptake of norepinephrine, but some of the most efficacious tricyclic compounds also blocked the reuptake of serotonin. The discovery of serotonin-­specific reuptake inhibitors such as fluoxetine led to their use for depression; they are therapeutically successful in a subset of individuals with major (unipolar) depression. It is not surprising that some side effects of their enhancing effects on central serotonin activity include diminished libido and eating disorders involving significant weight gain.   

352

Regional Neuroscience D

R

D

DA neurons in the midline region of the ventral tegmental area (group A10)

Cingulum

C Striatum

Dopaminergic (DA) axons in the nigrostriatal pathway in longitudinal section D Nucleus accumbens Mesolimbic and mesocortical pathways Nigrostriatal pathway M L

D

Hypothalamus

Tuberoinfundibular pathway Ventral tegmental area Entorhinal cortex L Substantia nigra pars compacta Locus coeruleus DA neurons in substantia nigra V V pars compacta (group A9) DA neurons in the lateral region of the ventral tegmental area (group A10) among exiting bundles of oculomotor nerve (III) fibers D = Dorsal V = Ventral L = Lateral M = Medial C = Caudal R = Rostral

Falck-Hillarp formaldehyde fluorescence histochemistry images reprinted with permission from Felten DL and Sladek JF. 1983 Monoamine distribution in primate brain V. Monoaminergic nuclei: Anatomy, pathways and local organization. Brain Research Bulletin 10:171-284.

  13.33 DOPAMINERGIC PATHWAYS DA neurons are found in the midbrain and hypothalamus. In the midbrain, neurons in the substantia nigra pars compacta (A9) project axons (along the nigrostriatal pathway) mainly to the striatum (caudate nucleus and putamen) and to the globus pallidus and subthalamus. This nigrostriatal projection is involved in basal ganglia circuitry that aids in the planning and execution of cortical activities, the most conspicuous of which involve the motor system. Damage to the nigrostriatal system results in Parkinson’s disease, a disease characterized by resting tremor, muscular rigidity, bradykinesia (difficulty initiating movements or stopping them once they are initiated), and postural deficits. The antiparkinsonian drugs such as levodopa target this system and its receptors. Dopamine neurons in the ventral tegmental area and mesencephalic RF (A10) send mesolimbic projections to the nucleus accumbens, the amygdala, and the hippocampus, and they send mesocortical projections to the frontal cortex and some cortical association areas. The mesolimbic pathway to the nucleus accumbens is involved in motivation, reward, biological drives, and addictive behaviors, particularly substance abuse. The DA projections to limbic structures can induce stereotyped, repetitive behaviors and activities. The mesocortical projections influence cognitive functions in the planning and carrying out of frontal cortical activities and in attention mechanisms. The mesolimbic and mesocortical DA systems and their receptors are the targets of neuroleptic and antipsychotic agents that influence behaviors in schizophrenia, obsessive-­compulsive disorder, attention deficit–hyperactivity disorder, Tourette’s syndrome, and other

behavioral states. Dopamine neurons in the hypothalamus form the tuberoinfundibular dopamine pathway, which projects from the arcuate nucleus to the contact zone of the median eminence, where dopamine acts as prolactin inhibitory factor. Intrahypo-­ thalamic dopamine neurons also influence other neuroendocrine and visceral/autonomic hypothalamic functions. CLINICAL POINT Several discrete DA systems are found in the brain. The midbrain nigrostriatal DA system projects from the substantia nigra pars compacta to the striatum; these neurons degenerate in Parkinson’s disease. The tuberoinfundibular and intrahypothalamic DA systems are involved in neuroendocrine regulation. A midbrain mesolimbic and mesocortical system sends widespread projections to the forebrain. The mesolimbic pathway to the nucleus accumbens regulates motivation, reward, biological drives, and addictive behaviors, playing an important role in substance abuse. Activation of this circuit can induce stereotyped, repetitive behaviors and activities. The mesolim-­ bic and mesocortical DA systems are involved in many psychiatric disorders, including schizophrenia, obsessive-­compulsive disorders, attention deficit–hyperactivity disorder, Tourette’s syndrome, and other behavioral states. The use of neuroleptic and antipsychotic medications, which are D2 receptor antagonists, to treat schizophrenia led to the hypothesis that schizophrenia is related to the regulation of dopamine. The current hypothesis is that this disease may involve excessive activity in the mesolimbic DA system and a relative decrease in activity in the mesocortical DA system in the frontal lobes. Use of neuroleptic agents must be monitored carefully because chronic D2 receptor antagonism may lead to tardive dyskinesia, or permanent drug-­induced movements.   

Telencephalon

Fornix

Medial septal nucleus

Ascending cholinergic pathway

353

Nucleus basalis (of Meynert) Hippocampus Brainstem tegmental cholinergic group Descending cholinergic pathway

 

13.34 CENTRAL CHOLINERGIC PATHWAYS Central cholinergic neurons are found mainly in the nucleus basalis (of Meynert) and in septal nuclei. Nucleus basalis neurons project cholinergic axons to the cerebral cortex, and the septal cholinergic neurons project to the hippocampal formation. These cholinergic projections are involved in cortical activation and memory function, particularly consolidation of short-­term memory. They often appear to be damaged in patients with Alzheimer’s disease (AD). Drugs that enhance cholinergic function are used for improvement of memory. Other cholinergic neurons found in the brainstem tegmentum project to structures in the thalamus, brainstem, and cerebellum. The projections to the thalamus modulate arousal and the sleep-­wake cycle and appear to be important in the initiation of REM sleep. Cholinergic interneurons are present in the striatum and may participate in basal ganglia control of tone, posture, and initiation of movement or selection of wanted patterns of activity. In some cases, pharmacological agents are targeted at reducing cholinergic activity in the basal ganglia in Parkinson’s disease, as a complementary approach to enhancing DA activity. Acetylcholine also is used as the principal neurotransmitter in all preganglionic autonomic neurons and lower motor neurons in the spinal cord and brainstem.

CLINICAL POINT Central cholinergic neurons are found in the basal forebrain (nucleus basalis of Meynert and nucleus of the diagonal band) and medial septum. The nucleus basalis cholinergic neurons are found in the substantia innominata and also along the ventral extent of the forebrain. The nucleus basalis and the nucleus of the diagonal band cholinergic neurons provide the major cholinergic input to the cerebral cortex. Cholinergic neurons of the medial septum send axons through the fornix to innervate the hippocampal formation. In patients with AD, a loss of cholinergic neurons (positive for choline acetyltransferase, the rate-­limiting enzyme for acetylcholine synthesis) is most closely correlated with cognitive impairment. AD patients also show a loss of muscarinic and nicotinic cholinergic receptors and high-­affinity choline uptake. Pharmacological agents such as the cholinesterase inhibitor tetrahydroaminoacridine (tacrine) have targeted cholinergic neurons in AD, and some data show a slowing in short-term memory dysfunction. Because choline is recycled for resynthesis of acetylcholine, some studies have used choline or lecithin in an attempt to boost precursor availability for added synthesis of acetylcholine; this approach has not met with great success. It may reflect the fact that AD alters many other neurotransmitter systems in the CNS in addition to the cholinergics, such as substance P, CRF, somatostatin, norepinephrine, and neuropeptide Y.   

354

Regional Neuroscience

Endogenous Cannabinoids: CB1 receptors

Prefrontal neocortex

Basal Ganglia

Coronal section

Parietal neocortex Sagittal section

Caudate nucleus Putamen Globus pallidus Nucleus accumbens Hypothalamus Hypothalamus Hippocampus

Cerebellum

Presynaptic neuron

Caudal brainstem areas

NT

CB1

NTR

CB

Dorsal horn Amygdala

Hippocampus

Postsynaptic neuron Neurotransmitters (NT) from presynaptic neurons activate postsynaptic neurotransmitter receptors (NTR). This triggers release of endogenous cannabinoids, which bind to cannabinoid receptor CB1 on presynaptic neurons, inhibiting further neurotransmitter release.

13.35 ENDOGENOUS CANNABINOID SYSTEMS Endogenous cannabinoids (endocannabinoids, ECs) are arachidonic acid derivatives synthesized from membrane-­associated lipids. Two principal ECs, anandamine (N-­arachidonoylethanolamine) and 2DG (2-­arachidonoylglycerol), are released from neurons as “reverse neurotransmitters” and activate cannabinoid receptors. They are taken up into neurons and astrocytes and catabolized by an enzyme (fatty acid hydrolase); an attempt to block this enzyme with an experimental pharmaceutical agent led to toxic consequences, including death. These ECs are the endogenous ligands for cannabinoid receptors (CB1: found mainly on neurons, axons, and nerve terminals; CB2: in periphery on macrophages and lymphocytes, with a role in inflammation). CB receptors are G1/G0 proteins and can initiate signaling events. CB1 receptors in the CNS are found in high concentrations in the neocortex, limbic forebrain structures (amygdala, hippocampus),

Spinal cord

 

basal ganglia, nucleus accumbens, hypothalamic areas, cerebellum, brainstem nuclei, and spinal cord (especially on primary afferents). At synapses, ECs act as reverse or retrograde signal molecules. Membrane activation postsynaptically produces ECs (from precursors in the neuron), which are released to act on CB1 receptors on the presynaptic terminals, which mainly results in inhibition of other neurotransmitters (both excitatory and inhibitory transmitters). Exogenous cannabinoid administration also can activate CB1 receptors in the brain. ECs are implicated in cognitive activities and judgment, learning and memory of new information, emotional responsiveness (panic, paranoia, euphoria), reaction time, coordination, antinausea effects, increased appetite, pain sensitivity, and many other physiological activities. ECs also may play a neuroprotective role in traumatic brain injury and in neuronal repair in neurodegenerative diseases.

Telencephalon

355

Endogenous Opioids: Beta Endorphin Thalamus

Periaqueductal gray Nucleus raphe dorsalis Locus coeruleus Parabrachial nucleus

Septal nuclei Paraventricular nucleus Preoptic area Amygdala

Arcuate nucleus Nucleus raphe magnus Reticular formation Nucleus solitarius Endogenous Opioids: Dynorphins

To spinal cord (dorsal horn) Coronal section

Bed nucleus of stria terminalis Sagittal section

Caudate nucleus

Putamen

Hypothalamus Nucleus accumbens

Dentate gyrus Entorhinal cortex Dorsal horn

Central nucleus of amygdala

Hippocampus

Entorhinal cortex Dyn Spinal cord

Hippocampus Dentate Parahippocampal gyrus gyrus

KOR Inhibitory interneurons release dynorphins (Dyn), which bind to kappa opioid receptors (KOR) on target neurons

 

13.36A ENDOGENOUS OPIOID SYSTEMS: BETA-­ENDORPHIN, DYNORPHINS, AND MET-­ENKEPHALIN

356

Regional Neuroscience

Endogenous Opioids: met-Enkephalin

Cerebral cortex Coronal section

Sagittal section

Basal Ganglia Caudate nucleus

Bed nucleus of stria terminalis

Putamen Thalamus

Thalamus Globus pallidus Nucleus accumbens

Hypothalamus Dentate gyrus

Hypothalamus Periaqueductal gray Anterior and posterior pituitary

Nucleus raphe magnus Caudal spinal trigeminal nucleus

Met

Dorsal horn

DOR met-Enkephalin (Met) binds to delta opioid receptors (DOR) on sensory neurons, producing analgesia

Amygdala Dentate gyrus

Spinal cord

 

13.36B ENDOGENOUS OPIOID SYSTEMS: BETA-­ ENDORPHIN, DYNORPHINS, AND MET-­ ENKEPHALIN (CONTINUED) Beta-­endorphin neurons. Beta-­endorphin neurons are found mainly in the arcuate nucleus in the hypothalamus (sometimes referred to as the peri-arcuate region) and, to a lesser extent, in the nucleus of the solitary tract (nucleus solitarius). Beta-­endorphin neurons in the arcuate nucleus project axons to limbic structures, numerous hypothalamic regions, some thalamic sites, and numerous brainstem nuclei. Beta-­endorphin neurons in nucleus solitarius project axons to the spinal cord. In the hypothalamus, beta-­endorphin neurons innervate corticotropin-releasing hormone (CRH) neurons and inhibit CRH release. Beta-­endorphin also inhibits activity of the stress axes. Beta-­endorphin plays an important physiological role in analgesia, regulation and release of pituitary hormones, amelioration of anxiety, appetitive behavior, temperature regulation, and other visceral functions. Beta-­ endorphin binds to mu, kappa, and delta opioid receptors. Dynorphin neurons. Dynorphins are found in neurons in the hippocampus (dentate gyrus mossy fibers), entorhinal cortex, other limbic structures (central amygdaloid nucleus, bed nucleus of the stria terminalis), basal forebrain (nucleus accumbens), striatum (caudate nucleus, putamen), brainstem nuclei, and

the spinal cord. Dynorphins act mainly on kappa opioid receptors and generally inhibit excitatory neurons. Dynorphins play a functional role in pain responses, stress responses, appetitive behaviors, temperature regulation, learning and memory, and emotional control. Dynorphins also are involved in neurological disorders, including seizure disorders, addictive behaviors, and psychiatric disorders (depression, schizophrenia). met-­Enkephalin neurons. met-­Enkephalin is found in small, local circuit neurons in widespread CNS sites, including the cerebral cortex, basal ganglia (medium spiny neurons), limbic sites (amygdala, hippocampal granule cells in the dentate gyrus, bed nucleus of the stria terminalis), basal forebrain (nucleus accumbens), thalamic and hypothalamic regions, many brainstem nuclei, and the spinal cord. met-­Enkephalin cells also are found in the adrenal medulla and the anterior and posterior pituitary. met-­Enkephalin acts mainly on delta opioid receptors and, to a lesser extent, on mu receptors. met-­Enkephalin integrates sensory information related to pain perception and emotional responsiveness. met-­Enkephalin also helps to modulate memory responses, some visceral hypothalamic responses (food and water regulation), and dopamine release in the mesolimbic and mesocortical pathways from neurons in the ventral tegmental area.

357

Telencephalon A. Lateral wall Anterior ethmoidal nerve

Olfactory bulb Olfactory nerves Cribriform plate of ethmoid bone

Internal nasal branch (lateral ramus) External nasal branch

Olfactory tract Lateral posterior superior nasal branches Maxillary nerve Pterygopalatine ganglion and branches Nerve of pterygoid canal Greater petrosal nerve Deep petrosal nerve Pharyngeal branch Nasopalatine nerve (passing to septum) Posterior inferior nasal branch Lesser (minor) palatine nerves Greater (major) palatine nerve and branches

B. Nasal septum

Cribriform plate of ethmoid bone

Olfactory bulb Olfactory nerves Olfactory tract

Internal nasal branch (medial ramus) of anterior ethmoidal nerve

Nasopalatine nerve

Incisive canal

  13.37 THE OLFACTORY NERVE AND NERVES OF THE NOSE The olfactory nerves and their projections into the CNS are important components of forebrain function. Bipolar cells in the olfactory epithelium are the primary sensory neurons. The peripheral axon, a chemosensory transducer, and its branches respond to the unique chemical stimuli of airborne molecules entering the nose. The central axons of the bipolar neurons aggregate into groups of approximately 20 slender olfactory nerves that traverse the cribriform plate and end in glomeruli of the ipsilateral olfactory bulb. These nerves are vulnerable to tearing, which results in anosmia. Unlike neurons in other sensory systems, these bipolar neurons can proliferate and regenerate. After processing information in the olfactory bulb, mitral neurons and tufted neurons project via the olfactory tract directly and indirectly to limbic forebrain structures, including septal nuclei and amygdaloid nuclei. These projections bypass the thalamus, have immediate access to limbic forebrain structures, and directly influence the hypothalamus and its regulation of neuroendocrine and visceral/autonomic function. The olfactory system is essential for survival in many species and is involved in territorial recognition and defense, food and water acquisition, social behavior,

reproductive behavior, signaling of danger, stress responses, and other visceral functions. CLINICAL POINT The olfactory nerves possess receptors that can detect a wide range of unique odorants. This information is conveyed through the olfactory bulb to central forebrain sites, particularly those in the limbic fore-­ brain, bypassing the thalamus, usually a processing zone for sensory projections to the forebrain. Olfaction is particularly important in recognizing the taste of food. What many people interpret as taste actually has a major olfactory component. Even very strong-­tasting substances cannot be readily discerned by most people when the olfactory system is blocked, perhaps explaining the reduced gustatory experience of a good meal when someone has a cold. Clearly, both taste and smell must work together for full appreciation of food. Several regions of the brain have been identified as important sites for the interpretation of smell, including the orbitofrontal cortex and its major interconnected thalamic nucleus (medial dorsal) as well as the anterior temporal lobe. Ablation of the anterior temporal lobe, particularly on the dominant side, leads to olfactory agnosias. The involvement of the temporal lobe in the interpretation and processing of olfaction is further emphasized by olfactory auras of highly aversive or foul smells during temporal lobe seizures. Stimulation of specific olfactory receptors with odorant molecules can influence visceral responses such as appetite, relaxation, alertness, motion sickness, nausea, insomnia, headache pain, and others.   

Section III SYSTEMIC

NEUROSCIENCE

14.  Sensory Systems Somatosensory Systems Trigeminal Sensory System Sensory System for Taste Auditory System Vestibular System Visual System 15.  Motor Systems Lower Motor Neurons Upper Motor Neurons Cerebellum Basal Ganglia 16.  Autonomic-Hypothalamic-Limbic Systems Autonomic Nervous System Hypothalamus and Pituitary Limbic System Olfactory System

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14

SENSORY SYSTEMS



Somatosensory Systems

14.18 VIII Nerve Innervation of Hair Cells of the Organ of Corti

  14.1 Somatosensory Afferents to the Spinal Cord

14.19 Cochlear Receptors

  14.2 Spinal Somatic Reflex Actions and Pathways

14.20 Afferent Auditory Pathways

  14.3 Somatosensory System: Spinocerebellar Pathways

14.21 Afferent Auditory Pathways (Continued)

  14.4 Somatosensory System: The Dorsal Column System and Epicritic Modalities

14.22 Centrifugal (Efferent) Auditory Pathways

  14.5 Somatosensory System: Neuronal Organization of Dorsal Column and Thalamic Nuclei   14.6 Somatosensory System: The Spinothalamic and Spinoreticular Systems and Protopathic Modalities   14.7 Spinothalamic and Spinoreticular Nociceptive Processing in the Spinal Cord   14.8 Mechanisms of Neuropathic Pain and Sympathetically Maintained Pain   14.9 Descending Control of Ascending Somatosensory Systems

Trigeminal Sensory System



Vestibular System

14.23 Vestibular Receptors 14.24 Vestibular Pathways 14.25 Nystagmus

Visual System

14.26 Anatomy of the Eye 14.27 Anterior and Posterior Chambers of the Eye 14.28 The Retina: Retinal Layers 14.29 The Retina: Photoreceptors

14.10 Trigeminal Sensory and Associated Sensory Systems

14.30 The Retina: Optic Nerve

14.11 Trigeminal System Peripheral and Central Connections

14.31 Arteries and Veins of the Eye

14.12 Pain-­Sensitive Structures of the Head and Pain Referral

14.32 Anatomy and Relationships of the Optic Chiasm

14.13 Mechanisms of Migraine Headaches

14.33 Damage Affecting the Optic Chiasm



Sensory System for Taste

14.34 Visual Pathways: Retinal Projections to the Thalamus, Hypothalamus, and Brainstem

14.14 Anatomy of Taste Buds and Their Receptors

14.35 Pupillary Light Reflex

14.15 Taste Pathways

14.36 Visual Pathway: The Retino-­Geniculo-­Calcarine Pathway



Auditory System

14.16 Peripheral Pathways for Sound Reception 14.17 Bony and Membranous Labyrinths

14.37 Visual Pathways in the Parietal and Temporal Lobes 14.38 Visual System Lesions

361

362

Systemic Neuroscience

 Proprioception

Conscious Unconscious la afferents

Touch and pressure Pain (nociception) and temperature I II III IV V VI VII Anterior white commissure

Dorsal spinocerebellar tract

Spinothalamic and spinoreticular tracts Lower motor neurons To skeletal muscle

SOMATOSENSORY SYSTEMS 14.1 SOMATOSENSORY AFFERENTS TO THE SPINAL CORD Unmyelinated (UNM) and small myelinated (M) axons that convey nociception and temperature sensation terminate in laminae I and V (origin of the spinothalamic tract). Other UNM axons terminate in the dorsal horn, from which neurons for polysynaptic reflexes and for the spinoreticular system originate. M axons for touch and pressure terminate in the dorsal horn, from which additional reflex connections, spinothalamic projections, and supplementary epicritic projections to the dorsal column (DC) nuclei originate. M axons also project directly into fasciculi gracilis and cuneatus, destined for nuclei gracilis and cuneatus; these lemniscal pathways process epicritic information for conscious interpretation. M proprioceptive axons (Ia afferents) terminate directly on lower motor neurons (LMNs) and on the Ia interneuronal pool. Additional M axons terminate in the dorsal horn on neurons of origin for the spinocerebellar tracts.

CLINICAL POINT Primary afferents include both epicritic afferents (mainly larger diameter M axons that convey fine, discriminative touch; vibratory sensation; and joint position sense) and protopathic afferents (mainly small M or UNM axons that convey mainly nociceptive information and temperature sensation). These axons can be affected differentially in neuropathies. Some peripheral neuropathies can affect all modalities, leading to a total loss of sensation; other peripheral neuropathies affect selected populations of axons and their related modalities. Selective loss of protopathic modalities may occur in leprosy, in amyloid neuropathy, and in some cases of diabetic neuropathy, leading to insensitivity to pain and temperature. Selective loss of epicritic sensation may occur in some distal symmetrical polyneuropathies, neuropathy with vitamin B12 deficiency, Guillain-­Barré syndrome, and others, accompanied by paresthesias (numbness and tingling,

“pins and needles,” abnormal sensations), dysesthesias (disagreeable or abnormal sensations in the absence of stimulation), hyperesthesia (increased sensation with stimulation), or hypesthesia (diminished sensation with stimulation). Some neuropathic conditions also are accompanied by allodynia (pain evoked by normally nonpainful stimuli) and burning, stabbing, radiating pain. Peripheral neuropathies that affect larger diameter M axons often can also affect the motor axons, leading to weakness and hyporeflexia or areflexia. Some small fiber neuropathies, especially diabetic neuropathies, may affect small autonomic axons to bowel, bladder, reproductive organs, and peripheral blood vessels, leading to orthostatic hypotension, bladder dysfunction, chronic gastrointestinal problems, or erectile dysfunction.   

CLINICAL POINT The monosynaptic reflex (the muscle stretch reflex) is tested in a clinical neurological examination. Specific muscle tendons are tapped, with the expected result of contraction of the homonymous muscle (e.g., tapping of the patellar tendon resulting in contraction of the ipsilateral quadriceps muscle). The muscle stretch reflexes routinely tested in a neurological examination include the biceps reflex, triceps reflex, brachioradialis reflex, patellar (knee-­jerk) reflex, and ankle-­jerk reflex on both sides. The reflexes are graded on a numerical scale ranging from hyporeflexic to normoreflexic to hyperreflexic; normal physiological reflexes may vary in responsiveness, so the result of reflex testing must be considered in conjunction with other clinical signs and symptoms. For example, hyperreflexia in a pathological state such as stroke or spinal cord injury may be accompanied by hypertonia of the affected muscle, spasticity, abnormal reflexes (extensor plantar response), and repetitive alternating hyperreflexic responses (clonus). In contrast, hyporeflexia or areflexia accompanying peripheral neuropathy may be accompanied by muscle weakness and flaccidity and diminished sensation of epicritic modalities, protopathic modalities, or both. More formal testing of reflexic responses can be done with electromyography and conduction velocity studies.   

363

Sensory Systems

A. Presynaptic B. Muscle stretch reflex inhibition

(reciprocal inhibition)

From extensor spindle receptor (Ia fibers)

C. Recurrent inhibition

D. Golgi tendon organ reflex

From flexor spindle receptor (Ia fibers)

From flexor tendon organ (Ib fibers)

Axosomatic or axodendritic inhibitory synapse

From flexor spindle (Ia fibers) Axoaxonic presynaptic inhibitory synapse

Excitatory synapse

Inhibitory synapse Renshaw cells

Excitatory synapse To flexors

To flexors To extensors

To extensors

E. Flexor withdrawal reflex

Collaterals To synergistic muscles

To extensors

F. Renshaw cell bias

Nociceptive fibers

Ipsilateral flexion

Contralateral extension

Inhibitory synapse

Inhibitory synapse

Excitatory synapse

Excitatory synapse

To extensors To flexors

Excites phasic flexors Renshaw cell To flexors

To flexors To extensors

14.2 SPINAL SOMATIC REFLEX ACTIONS AND PATHWAYS A, Presynaptic inhibition. Some interneurons synapse on the terminal arborizations of other axons, as in the case of some afferent pools associated with muscle stretch reflexes. These axoaxonic contacts permit the modulation of neurotransmitter release from the second (target) axon terminal by depolarization of the terminal membrane, altering the influx of Ca++. B, Muscle stretch reflex. In the muscle stretch reflex, Ia afferents excite the homonymous LMN pool directly and inhibit the antagonist LMN pool reciprocally via Ia inhibitory interneurons. C, Recurrent inhibition. Some interneurons receive recurrent collaterals from axons (e.g., LMN axons) and project back onto the dendrites or cell body of origin of that axon, usually inhibiting that neuron. This process can help to regulate the excitability and timing of excitation of the target neurons. Collaterals of LMN axons excite Renshaw cells (large interneurons), which inhibit the LMN of origin as well as LMNs projecting to synergistic muscles. Renshaw inhibition permits wiping the slate clean, after original excitation, of pools of LMNs, requiring additional incoming stimulation in order to excite these LMNs again. D, Golgi tendon organ reflex. Ib axons from Golgi tendon organs in muscle tendons terminate on pools of interneurons that inhibit LMNs to the homonymous muscle disynaptically and excite LMNs to the antagonist muscle

Inhibits tonic extensors

To extensors

 

reciprocally. The action of this reflex as a protective mechanism to prevent damage to a muscle during generation of maximal tension on the tendon is seen in attempted passive stretch of a spastic muscle; the resultant inhibition of the homonymous LMN pool is called a clasp-­knife reflex. E, Flexor withdrawal reflex. A flexor reflex (also called a withdrawal reflex or a nociceptive reflex) occurs when afferents derived from a noxious stimulus terminate on pools of interneurons that excite appropriate pools of LMNs (often flexor LMNs) to bring about a protective withdrawal from the source of the noxious stimulus. These interneurons also inhibit the antagonist LMNs through reciprocal inhibition. Flexor reflexes can extend throughout the spinal cord, as happens when one touches a hot stove with a finger; the result is the removal of the entire arm, or even the entire body, away from the source of heat. These flexor reflexes may involve both sides of spinal cord. F, Renshaw cell bias. Some reflex responses such as Renshaw reflexes (see part C) may result in the distribution of influence (bias) in a manner that favors a particular type of action. Renshaw cells receive inputs from axon collaterals of both flexor and extensor LMNs, but their projections are directed mainly toward the inhibition of tonic extensor LMNs (and through reciprocal inhibition with the excitation of phasic flexor LMNs). Thus, the Renshaw cell response favors flexor movements and helps to inhibit extensor movements.

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Systemic Neuroscience

Cerebellum

Superior cerebellar peduncle

Pons

Cerebellum

Cuneocerebellar tract Inferior cerebellar peduncle Lateral (accessory) cuneate nucleus

Medulla

Rostral spinocerebellar tract (RSCT)

Upper Body (above T6) Ia (to cuneocerebellar tract) Ib (to RSCT) Dorsal spinocerebellar tract (DSCT)

Ventral spinocerebellar tract (VSCT)

Lower Body (below T6) Ia (to DSCT) Ib (to VSCT) Anterior white commissure

14.3 SOMATOSENSORY SYSTEM: SPINOCEREBELLAR PATHWAYS Proprioceptive primary somatosensory axons from joints, tendons, and ligaments (represented in this figure by Ib afferents from Golgi tendon organs) terminate on neurons of origin (border cells, dorsal horn) of the ventral spinocerebellar tract (VSCT) and the rostral spinocerebellar tract (RSCT) from the lower and upper body, respectively (level T6 is the cut-­off point). Proprioceptive primary somatosensory axons from muscle spindles (represented in this figure by Ia afferents) terminate on neurons of origin (Clarke’s nucleus, lateral [external] cuneate nucleus of the medulla) of the dorsal spinocerebellar tract (DSCT) and the cuneocerebellar tract from the lower and upper body, respectively (level T6 is the cut-­off point). The DSCT, RSCT, and cuneocerebellar tracts remain ipsilateral. The VSCT crosses twice, once in the anterior white commissure of the spinal cord and again in the cerebellum.

 

CLINICAL POINT The dorsal and ventral spinocerebellar pathways travel in a conspicuous site at the lateral edge of the lateral funiculus throughout most of its length; these pathways are vulnerable to lesions that impinge on this zone of the spinal cord. They include tumors, radiculopathies with accompanying myelopathies, combined-­system degeneration, demyelinating diseases, vascular infarcts in the anterior circulation of the cord, Brown-­Séquard lesions, and other pathologies. Such a lesion, if superficial in the lateral funiculus, results in ipsilateral ataxia, dysmetria, clumsiness, and mild hypotonia, with impaired ability to perform heel-­to-­shin testing and tandem walking. However, lesions of the lateral funiculus often also involve the descending upper motor axons of the lateral corticospinal tract and the rubrospinal tract. Lesions that involve these tracts cause ipsilateral spastic hemiparesis or monoparesis below the level of the lesion, depending on the level of the lesion. The resulting spastic weakness, hyperreflexia, and hypertonus predominate in the clinical picture, thus masking the spinocerebellar symptomatology. Thus, an initial picture of spinocerebellar damage may give way to a progressive picture of spastic paresis on the same side.   

365

Sensory Systems

Cerebrum

Cerebral cortex: postcentral gyrus Posterior limb of internal capsule

Intralaminar nucleus

Ventral posterolateral (VPL) nucleus of thalamus

Midbrain Medial lemniscus

Pons

Medial lemniscus

Gracile nucleus Cuneate nucleus

Lower medulla Internal arcuate fibers (decussation of the medial lemniscus) Fasciculus gracilis Fasciculus cuneatus

Lateral cervical nucleus (C1-C2 only)

Cervical spinal cord

Spinocervical tract

Proprioception, position Touch, pressure, vibration

Lumbar spinal cord Proprioception, position Touch, pressure, vibration

14.4 SOMATOSENSORY SYSTEM: THE DORSAL COLUMN SYSTEM AND EPICRITIC MODALITIES Primary somatosensory myelinated axons conveying fine, discriminative touch, pressure, vibratory sensation, and consciousness of joint position project directly into the DC system (fasciculus gracilis for lower body, below T6, and fasciculus cuneatus for upper body, T6 and above), where they are topographically organized. They terminate in nuclei gracilis and cuneatus, respectively, from which the medial lemniscus originates. This tract crosses (decussates) in the medulla, rostral to the decussation of the pyramids, and projects to the ventroposterolateral (VPL) nucleus of the thalamus. Axons of neurons in the VPL nucleus terminate in the primary sensory cortex topographically. The entire DC/medial

 

lemniscal system is topographically organized; the lower body is represented medially in the primary somatosensory cortex, and the upper body (and face from trigeminal projections) is represented laterally. This representation is sometimes drawn proportionally (the resultant figure is called a homunculus); information from the fingers and hands has far greater representation in the cerebral cortex than information from the back. The spinocervical system is a small supplement to the DC system. Primary afferent projections terminate in the medial part of the dorsal horn; these neurons project to the lateral cervical nucleus (in C1 and C2 only). This nucleus contributes additional crossed axons with polysynaptic mechanoreceptive information. The supplemental epicritic information contributing to the dorsal column/medial lemniscal system ascends in the dorsal portion of the lateral funiculus.

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Systemic Neuroscience

Cerebral cortex Sensory cortex

Thalamus

Thalamus

Medial lemniscus Crossing Dorsal column Gracile nucleus nuclei Cuneate nucleus

Dorsal column nuclei

Lower medulla

Dorsal root ganglion Dorsal root ganglia Spinal cord

From T6 and above Dorsal root ganglion From T7 and below

Principal neurons (blue)

14.5 SOMATOSENSORY SYSTEM: NEURONAL ORGANIZATION OF DORSAL COLUMN AND THALAMIC NUCLEI The classic organization of the epicritic somatosensory system is illustrated on the left part of the plate. The more complex interactions in the dorsal column and thalamic nuclei are illustrated on the right. The dorsal column nuclei (gracilis and cuneatus) project to the thalamus (ventral posterolateral nucleus, VPL) but also to the posterior thalamus, inferior colliculus, pontine nuclei, cerebellum, several brainstem nuclei, and spinal cord. Collaterals from the principal neurons can inhibit adjacent dorsal column neurons, sharpening the somatosensory message. The dorsal column nuclei (DCN) contain inhibitory intrinsic neurons, using glycine and GABA as neurotransmitters. The cerebral cortex sends corticonuclear fibers to the DCN and can disinhibit transmission through these neurons. The cortex also can select the frequency and intensity of inputs to these neurons. Corticonuclear axons end on small and medium dendrites of DCN principal neurons and also end on the interneurons. The DCN interneurons themselves postsynaptically inhibit the DCN principal neurons. Slow-­conducting corticonuclear fibers tonically inhibit the DCN principal neurons as well as some inhibitory interneurons.

Dorsal column interneurons (purple) Interneurons of thalamus (green)

Cortical neurons (orange)

 

Fast-­conducting corticonuclear fibers can activate principal neurons during movement, particularly during limb manipulation and exploratory activities, overriding underlying inhibition. Interneurons also are present in the thalamic VPL nucleus. The interneurons are fewer in number than the principal neurons in both the DCN and VPL. In VPL, the inhibitory interneurons form dendrodendritic connections with principal neurons and inhibit flow of information to the sensory cortex. Input to principal neurons in VPL from axons of the medial lemniscus produces a brief depolarization for flow of information to the sensory cortex, followed by hyperpolarization from the interneurons and a cessation of information flow to the sensory cortex. The sensory cortex controls principal neurons in VPL through connections with distal dendrites, not with inputs to the synaptic glomeruli formed by medial lemniscus axon connectivity to VPL principal neurons. Thus, the interneurons fine-­ tune somatic sensation and responses to it through a small, but powerful, set of inhibitory interneurons in the DCN and nucleus VPL of the thalamus.

367

Sensory Systems

Cerebrum

Cerebral cortex: postcentral gyrus Posterior limb of internal capsule

Nonspecific thalamic nuclei (centromedian)

Ventral posterolateral (VPL) nucleus of thalamus

Hypothalamus

Midbrain

Deep layers of superior colliculus and periaqueductal gray

Parabrachial nuclei

Pons

Lower medulla

Lateral reticular formation

Spinothalamic/spinoreticular system (from all spinal levels)

Cervical spinal cord Anterior white commissure

Pain, temperature Pain

Lumbar spinal cord Anterior white commissure

14.6 SOMATOSENSORY SYSTEM: THE SPINOTHALAMIC AND SPINORETICULAR SYSTEMS AND PROTOPATHIC MODALITIES

See next page. 

Pain, temperature Pain

 

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Systemic Neuroscience

14.6 SOMATOSENSORY SYSTEM: THE SPINOTHALAMIC AND SPINORETICULAR SYSTEMS AND PROTOPATHIC MODALITIES (CONTINUED) Primary somatosensory unmyelinated (C) fibers and small myelinated (A delta) fibers that convey nociceptive information (fast, localizing pain), temperature sensation, and light, moving touch terminate on neurons in laminae I and V. These dorsal horn neurons send crossed axons into the spinothalamic tract, projecting to neurons in the VPL nucleus of the thalamus (red). This pool of neurons in the VPL nucleus is different from the pool receiving input from nuclei gracilis and cuneatus from the DC system. These thalamic neurons in the VPL nucleus project to the second somatosensory cortex (SII) as well as to the primary sensory cortex. Primary sensory C fibers also terminate in the dorsal horn and contribute to a large, cascading network for bilateral projections into the spinoreticular tract (blue). This system ends mainly in the reticular formation, from which polysynaptic projections lead to nonspecific medial dorsal and anterior thalamic nuclei. Some spinoreticular fibers also terminate in the deeper layers of the superior colliculus (spinotectal pathway), in the parabrachial nuclei of the pons, and in the periaqueductal gray. Cortical regions such as the cingulate, insular, and prefrontal regions then process and interpret nociceptive information related to slow, agonizing, excruciating pain. In addition, axonal projections from neurons in the dorsal horn of the spinal cord, descending nucleus of V, and parabrachial nuclei of the pons terminate directly in the hypothalamus. These nociceptive axons to the hypothalamus help to coordinate visceral responses (e.g., fight-­or-­flight, autonomic reactions to pain such as blood pressure and cardiovascular responses, stress hormone secretion of cortisol and epinephrine, and emotional responses). Direct somatosensory inputs also help to mediate sexual responses and oxytocin release for milk letdown from suckling. CLINICAL POINT The spinothalamic tract conveys lemniscal information from primary afferents for nociception and temperature sensation to secondary sensory neurons in laminae I and V of the dorsal horn of the spinal cord. These dorsal horn neurons then project contralateral spinothalamic tract axons to the VPL nucleus of the thalamus, which in turn sends some information about “fast pain” (not outlasting the duration of the stimulus) to sensory cortices I and II in the parietal lobe. This is the principal protopathic system tested in the neurological examination, using light pin prick and touching the body with test tubes containing

water of various temperatures. This spinothalamic tract system does not convey chronic, agonizing, deep pain that characterizes many chronic diseases; such chronic “slow” pain is conveyed through a vast polysynaptic network through the dorsal horn of the spinal cord and then the lateral reticular formation of the brain. This spinoreticular processed information eventually reaches the nonspecific thalamic nuclei (such as the centromedian) and is conveyed to limbic structures for more subjective, interpretative aspects of pain and to the hypothalamus for appropriate visceral autonomic and hormonal responses to pain. This latter spinoreticular network can be influenced by a host of other inputs, including the cortex, the limbic system, the descending forebrain and diencephalic systems, and collaterals of the DC system. Collaterals of the DC system can gate nociceptive processing through the dorsal horn by activating neurons that dampen transmission of information through the cascading dorsal horn network. This process is evoked in a simple fashion by light rubbing on or adjacent to an injured part of the body. In a more chronic fashion, DC stimulation (by a transcutaneous electrical nerve stimulation [TENS] unit) can electrically activate large-­diameter axons that then gate the painful stimuli bombarding the dorsal horn nociceptive axons.   

CLINICAL POINT The DC system consists of fasciculus gracilis (lower half of the body, with T6 cutoff) and fasciculus cuneatus (upper half of the body). These pathways consist of primary sensory axons conveying fine, discriminative touch sensation, vibratory sensation, and joint position sense (the epicritic sensations) toward the first synapse in the secondary sensory nuclei gracilis and cuneatus in the caudal medulla. These epicritic sensations are called primary DC modalities, the basic information coded mainly by large-­diameter myelinated axons. Additional DC modalities are sometimes tested if the primary modalities are intact, including two-­point discrimination, stereognosis (knowing what an object is just by touch), and graphesthesia (interpreting a number drawn into the palm of the hand). These are considered cortical modalities of the DC system; they require that the primary DC modalities be intact and also require the ability of the sensory cortices to interpret the information conveyed and to draw conclusions about that information. If the primary modalities are impaired, there is no reason to attempt to test the cortical modalities that depend on unimpaired primary modalities. Pure lesions of the DC system do not entirely eliminate the primary epicritic modalities; they just remove some interpretive capabilities. Such a patient may realize that a vibratory stimulus is being applied to the upper extremity but may be unable to distinguish vibratory stimuli of different frequencies. The dorsal portion of the lateral funiculus carries additional epicritic information to the DC nuclei from the spinal cord dorsal horn. A lesion of both the DC and the dorsal portion of the lateral funiculus results in total loss of epicritic sensation on the affected side.   

369

Sensory Systems

Gating Mechanism

Spinal Mechanisms of Nociceptive Processing Dorsal column afferent

C and A delta C and A delta C

Nociceptive afferent I II III IV V VI VII

Spinothalamic/ spinoreticular tract

Recruitment by Convergence

 

14.7 SPINOTHALAMIC AND SPINORETICULAR NOCICEPTIVE PROCESSING IN THE SPINAL CORD Primary afferents (C and A delta fibers) conveying fast, localized pain and temperature sensation terminate in laminae I and V of the dorsal horn of the spinal cord, from which the crossed spinothalamic axons originate. Unmyelinated primary afferents (C fibers) also terminate on neurons in the dorsal horn, from which a cascading system involving recruitment, convergence, and polysynaptic interconnections originates. This system (shown in red) contributes to the spinoreticular tract (mainly crossed, but some

are uncrossed), which projects into the RF and continues polysynaptically to nonspecific medial dorsal and anterior thalamic nuclei. This system contributes to perception of excruciating pain and its emotional connotation via cortical regions such as the cingulate, insular, and prefrontal cortices. The gating mechanism, shown in blue on the left, allows primary DC axon collaterals to dampen pain processing in the dorsal horn via inhibitory interneuronal connections that inhibit the flow of information through the cascading dorsal horn system that contributes to the spinoreticular pathway.

370

Systemic Neuroscience

Central serotonin and

Mechanisms of Neuropathic Pain

central norepinephrine 1. Sprouting of sympathetic postganglionic nerve fibers on 1° afferent endings and 1° sensory cell bodies pathways 2. Lowered threshold for firing of C fibers (hyperesthesia) and A delta fibers (allodynia) 3. Proliferation of alpha ()-adrenergic receptors on 1° sensory afferent endings and 1° sensory cell bodies 7 4. Possible ephaptic afferent activation 5. Permanent hyperactivation of wide dynamic range neurons 6. Glutamate excitotoxic cell death of inhibitory neurons (glutamate storms) 7. Inadequacy of central descending serotonin, norepinephrine, opioid 8 10 9 peptide pathways to control nociception 8. Immobilization by pain decreases gating of nociceptive input, limiting 5 physical therapy to initiate gating 9. Sprouting of C fibers in spinal cord 10. Extension of interneuron dendrites into Enkephalin additional spinal cord laminae 3 Dorsal root ganglion

neuron

  

6

1

4

CRUSH Ventral root A

2

3  C    1

Preganglionic sympathetic fiber Postganglionic sympathetic fiber Sympathetic chain ganglion

14.8 MECHANISMS OF NEUROPATHIC PAIN AND SYMPATHETICALLY MAINTAINED PAIN The cascading dorsal horn system receives primary afferent C fibers of nociceptive origin and projects into the spinoreticular system for the conscious interpretation of excruciating pain and neuropathic pain, shown in this illustration. Connections from the sympathetic nervous system can innervate terminals and cell bodies of primary nociceptive neurons directly. In neuropathic pain syndromes such as complex regional pain syndrome (CRPS), formerly called reflex sympathetic dystrophy (RSD), sympathetic postganglionic neurons may activate receptors on greatly sensitized primary afferent nerve terminals and cell bodies, either directly (via synapses) or indirectly (through secretion of norepinephrine into the blood); such activation may exacerbate the perception of the neuropathic pain. Multiple mechanisms are thought to contribute to sensitization of pain-­related neurons and presence of chronic, agonizing neuropathic pain in CRPS and related syndromes. These mechanisms are noted in this illustration as numbered sites. Descending central noradrenergic and serotonergic projections are thought to play an important modulatory role in the processing of neuropathic and nonneuropathic pain.

 

CLINICAL POINT In some cases of nerve damage or compression, particularly that associated with a sprain, a crush injury, a direct injection into a nerve, or even relatively minor trauma, a pathological reaction of primary afferents can result in a chronic neuropathic pain syndrome called reflex sympathetic dystrophy, more recently renamed CRPS. It is related to the type of chronic, agonizing central pain experienced in phantom limb syndrome. CRPS affects the hand, arm, and shoulder to a greater extent than the lower extremity. Intense burning or stabbing pain is felt, with allodynia and hyperesthesia (extreme sensitivity to touch and painful stimuli, respectively). When this phenomenon affects one nerve (perhaps following a bullet wound) it is sometimes called causalgia. The primary afferents involved in CRPS appear to proliferate alpha-­adrenergic receptors on their sensory receptor endings and on the dorsal root ganglion cell body and often show extraordinary sensitivity to catecholamines, which provoke a lower threshold for response to nociceptive stimuli. In syndromes such as CRPS, permanent destruction of dorsal horn inhibitory interneurons (by glutamate excitotoxicity) and permanently altered thresholds for wide dynamic range spinoreticular neurons also have been observed. Sympathetic-related characteristics may be noted in CRPS, such as changes in skin appearance due to vascular flow changes (vasomotor), atrophic skin and nails (trophic changes), altered sweating and skin temperature (sudomotor), and altered bone density on a triphasic bone scan. Treatment must occur quickly after detection and must employ simultaneous vigorous therapeutic approaches. Treatment choices normally include analgesics, tricyclic or other antidepressants to alter pain threshold in the spinal cord, membrane-­stabilizing agents (e.g., Neurontin), physical therapy, and nerve stimulation of large-diameter myelinated “gating” axons.   

Sensory Systems From cerebral cortex and limbic forebrain

From hypothalamus (includes betaendorphin axonal projections)

371

Stimuli from higher From centers (psychosensory logical, placebo cortex effect, etc.) Enkephalin-containing neuron Periaqueductal gray matter

Midbrain

Locus coeruleus Afferent pain fibers in trigeminal nerve Spinal trigeminal tract and nucleus

Lateral reticular formation

Medulla

Enkephalin-containing neuron

Medullary reticular formation

Brainstem tegmental noradrenergic cell groups

Raphe nuclei

Descending norepinephrine pathway

Corticonuclear fibers

Descending serotonin pathway

Spinoreticular pathway Decussation of the pyramids

Posterolateral funiculus Enkephalin-containing neuron in substantia gelatinosa Afferent pain neuron of dorsal root ganglion

II III IV V VI

CLINICAL POINT Several regions of the central nervous system (CNS) send projections, direct and indirect, to regulate nociceptive processing through the

Anterolateral funiculus

Spinal cord

 

Spinoreticular neuron

14.9 DESCENDING CONTROL OF ASCENDING SOMATOSENSORY SYSTEMS The processing of nociceptive information in the dorsal horn of the spinal cord can be modulated by descending connections from the cerebral cortex, limbic forebrain structures, hypothalamus (paraventricular nucleus), periarcuate beta-­endorphin neurons, periaqueductal gray, RF of the brainstem, central noradrenergic neurons (of locus coeruleus and other brainstem tegmental groups), and serotonergic (5HT) neurons (nucleus raphe magnus). The central descending noradrenergic and 5HT pathways, modulated by the periaqueductal gray and other higher centers, are particularly important for endogenous and exogenous (i.e., opioid) modulation of pain.

I

dorsal horn of the spinal cord for the body and the descending nucleus of V for the face. These areas include regions of cerebral cortex, limbic forebrain areas, hypothalamic regions including endorphin nuclei, and sensory cortical centrifugal connections. Some of these projections use endogenous opiates. Enkephalin and dynorphin interneurons are found in pain-­processing regions, particularly in the dorsal horn of the spinal cord and the descending nucleus of V, and in many hypothalamic and limbic sites that may be involved in the subjective interpretation of pain. The beta-­endorphin neurons of the periarcuate region (sometimes called just the arcuate nucleus) of the hypothalamus send connections to the periaqueductal gray, locus coeruleus and brainstem noradrenergic nuclei, raphe nuclei, and many limbic regions. The periaqueductal gray is particularly important for opioid activation of the nucleus raphe magnus and other descending monoamine pathways that activate enkephalins and assist in opiate analgesia. The periaqueductal gray–raphe connection is essential for full functionality of opioid analgesia. Systemic administration of synthetic opiates activates neurons of the periarcuate region of the hypothalamus and periaqueductal gray, resulting in analgesia.   

372

Systemic Neuroscience

Cerebral cortex: postcentral gyrus Centromedian nucleus (intralaminar)

Internal capsule

Ventral posteromedial (VPM) nucleus of thalamus

Midbrain Dorsal trigeminal lemniscus (dorsal trigeminothalamic tract) Ventral trigeminal lemniscus (ventral trigeminothalamic tract) Pontine reticular formation

Pons

Trigeminal mesencephalic nucleus Trigeminal motor nucleus Principal (main, chief) sensory trigeminal nucleus Touch, pressure Pain, temperature Proprioception - from muscle spindles Trigeminal (semilunar) ganglion Ophthalmic nerve Maxillary nerve Sensory root and motor root of mandibular nerve

Medullary reticular formation: Lateral reticular formation Medial reticular formation Ventral trigeminal lemniscus Spinal (descending) trigeminal tract

Facial (VII) nerve

Spinal (descending) trigeminal nucleus Dorsolateral fasciculus (of Lissauer)

Glossopharyngeal (IX) nerve

Cervical spinal cord Vagus (X) nerve Substantia gelatinosa (lamina II)

TRIGEMINAL SENSORY SYSTEM 14.10 TRIGEMINAL SENSORY AND ASSOCIATED SENSORY SYSTEMS Axons of primary sensory trigeminal neurons enter the brainstem, travel in the descending (spinal) tract of V, and terminate in the descending (spinal) nucleus of V. Axons of the trigeminal ganglion (V) supply the face, anterior oral cavity, and teeth and gums; axons of the geniculate ganglion (VII) and jugular ganglion (X) supply a small zone of the external ear. Axons of the petrosal ganglion (IX) supply general sensation to the posterior oral cavity and pharynx. Axons of the descending nucleus of V project into the ventral trigeminal lemniscus (ventral trigeminothalamic tract; mainly crossed axons) and terminate in the ventral posteromedial (VPM) nucleus of the thalamus. The VPM nucleus projects to the lateral primary sensory cortex and to intralaminar thalamic nuclei, which are associated with nociceptive processing. The caudal descending nucleus also sends contralateral

 

projections to the RF for processing of excruciating pain (similar to the spinoreticular system). Primary sensory axons carrying fine, discriminative modalities from V (similar to the DC system) terminate in the rostral portion of the descending nucleus of V and in the main (chief) sensory nucleus of V, which contribute to the ventral trigeminothalamic tract. A portion of the main sensory nucleus also projects ipsilaterally to the VPM nucleus via the dorsal trigeminothalamic tract. Although most of the trigeminal system is represented on the lateral portion of the contralateral primary sensory cortex (postcentral gyrus), part of the epicritic trigeminal projections as well as taste are represented in the ipsilateral sensory cortex. The mesencephalic nucleus of V is the only primary sensory nucleus found inside the CNS; these neurons supply muscle spindles for masticatory and extraocular muscles and mediate associated muscle spindle reflexes. See page 433 for a Clinical Point.

373

Sensory Systems

Thalamus

Mesencephalic nucleus of V

Postcentral gyrus Precentral gyrus

Principal sensory nucleus of V

Ophthalmic Maxillary Mandibular

Divisions of trigeminal nerve V

From cheek From upper teeth, jaw, gum, palate

Motor nucleus of V

To temporalis, masseter, pterygoids

Nucleus of VII Nucleus of tractus solitarius VII

C1

Nucleus of XII

IX

C2 X

Spinal tract and nucleus of V To muscles of tongue Somatic efferents Afferents and CNS connections Thalamocortical path Proprioception

XII

To infrahyoid muscles (fix hyoid bone) From tongue (posterior part)

14.11 TRIGEMINAL SYSTEM PERIPHERAL AND CENTRAL CONNECTIONS This illustration is a summary of trigeminal-related pathways and connections, including cortical and reflex connections.

From tongue (anterior part) (lingual nerve) To buccinator and orbicularis oris To mylohyoid and digastric (anterior belly) From lower teeth, jaw, gum (inferior alveolar nerve)

 

374

Systemic Neuroscience

Pain sensation

Dural sinus Middle meningeal artery Temporal artery

Proximal cerebral arteries Anterior head

Tentorium cerebelli Internal and external carotid arteries

Ophthalmic (V1) nerve Central pain pathway

Afferent nerves from intracranial and extracranial structures of anterior 2/3 of head and somatic pain afferent nerves from forehead and scalp are carried by ophthalmic nerve. These neurons refer pain from intracranial structures to forehead, scalp, or retrobulbar sites.

Spinal nucleus of trigeminal (V) nerve

Spinal ganglia C1–3

Dura of posterior fossa

Vertebrobasilar arteries

Posterior head Afferent nerves from occipital region, ear, and neck and from dura of posterior fossa and vertebrobasilar arteries are carried by dorsal roots of C1–3 spinal ganglia, accounting for pain referral to these sites

  14.12 PAIN-­SENSITIVE STRUCTURES OF THE HEAD AND PAIN REFERRAL Pain-­sensitive structures of the head include dural structures (e.g., sinuses, tentorium cerebelli), arteries, and muscles. Primary

headaches can arise as migraine headaches, tension headaches, and neuralgias. Secondary headaches can arise from tumors, abscesses, hematomas, bleeding (e.g., ruptured berry aneurysm), and meningitis or meningeal irritation.

375

Sensory Systems

Central mechanisms Pain perception

Peripheral mechanisms Migraine may be initiated by afferent stimulation from central centers in cortex, thalamus, and hypothalamus or by peripheral afferent stimulation via trigeminal nerve or cervical roots C1–3

Periaqueductal gray matter Nucleus raphe dorsalis Locus coeruleus

Local defect in endogenous pain control system prevents inhibition of pain stimulation (disinhibition) in spinal nucleus of trigeminal nerve

V1 V2 Central pain pathway

Nucleus raphe magnus Second order neuron

Trigeminal nerve pain pathway

Unopposed pain stimulation in spinal nucleus of trigeminal nerve

Peripheral inflow

Trigeminal V3 (V) n. Trigeminal vascular reflex Afferent stimulation of pain centers in spinal nucleus of trigeminal nerve increased and perpetuated by cycle of parasympathetic dilation of internal and Facial external carotid arteries mediated via facial nerve, (VII) n. resulting in stimulation of pain centers by trigeminal nerve afferents Parasympathetic (vasodilation) outflow Impaired inhibition in endogenous pain control system Pain stimulation in spinal nucleus of trigeminal nerve via afferent input from higher sources and via cervical roots C1–3

C1–3 pain pathway Adapted from Lance

14.13 MECHANISMS OF MIGRAINE HEADACHES A common migraine headache is a headache lasting from 4 to 72 hours, accompanied by nausea, vomiting, and aversion to light (photophobia) and/or sound (phonophobia). The headache is usually unilateral, severe, throbbing or pulsatile, and intensified by physical activity. A classical migraine headache, occurring in 15% of migraine patients, is foreshadowed by an aura, consisting of neurological symptoms such as visual field deficits, scotomas, light flashes, or sensory/motor symptoms. The aura generally lasts less than 1 hour, usually followed by the

 

headache. Prodromes such as emotional or mood disturbances, fatigue, drowsiness, and other general symptoms often occur. Migraine headaches are three times more common in women than in men. The mechanisms of migraine headache include dilation of meningeal blood vessels, release of vasoactive neuropeptides, neurogenic inflammation, activation of trigeminal pain pathways, and inhibition of endogenous pain-­dampening central mechanisms. Chronic migraines are migraine headaches that persist for at least 15 days a month.

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Systemic Neuroscience

Root

Epiglottis Median glossoepiglottic fold Lateral glossoepiglottic fold Vallecula Palatopharyngeal arch and muscle (cut) Palatine tonsil (cut) Lingual tonsil (lingual nodules) Palatoglossal arch and muscle (cut) Foramen cecum Terminal sulcus Vallate papillae Foliate papillae Filiform papillae

Body

Fungiform papilla Midline groove (median sulcus) Dorsum Filiform papillae of tongue

Lingual tonsil

Apex Fungiform papilla

Keratinized tip of papilla

Section through vallate papilla

Duct of gland Crypt Intrinsic muscle Lymph follicles Mucous glands Vallate papilla Stereogram: area indicated above Taste buds Furrow Lingual glands (serous glands of von Ebner) Taste bud Taste buds

Epithelium Basement membrane

Duct of gustatory (Ebner's) gland Microvilli Taste pore

Nerve plexus Nerve fibers emerging from taste buds

Taste cells

 

SENSORY SYSTEM FOR TASTE 14.14 ANATOMY OF TASTE BUDS AND THEIR RECEPTORS Taste buds are chemosensory transducers that consist of bundles of columnar cells that lie within the epithelium. They translate individual molecular configurations or combinations of molecules for salty, sweet, sour, bitter, and umami (glutamate)

sensations into action potentials of both large and small primary sensory axons. The taste buds are found on the anterior and posterior regions of the tongue and, less frequently, on the palate and epiglottis, mainly in children. Nerve fibers for taste show complex responses of electrical activity across populations of many nerve fibers. The integrative interpretation of taste takes place in the CNS.

Sensory Systems

377

Ventral posteromedial (VPM) nucleus of thalamus Sensory cortex (just below face area) Lateral hypothalamic area Amygdala Pontine taste area (parabrachial nucleus) Trigeminal (V) nerve Trigeminal (semilunar) ganglion

Mesencephalic nucleus Motor nucleus of trigeminal nerve

Ophthalmic nerve Maxillary nerve Mandibular nerve

Pons Pterygopalatine ganglion Greater petrosal nerve Geniculate ganglion

Otic ganglion

Facial (VII) nerve Nervus intermedius Rostral part of nucleus of solitary tract

Chorda tympani

Glossopharyngeal (IX) nerve

Nerve of pterygoid canal Lingual nerve

Fungiform papillae Foliate papillae

Lower part of medulla oblongata

Vallate papillae Epiglottis

Petrosal (inferior) ganglion of glossopharyngeal nerve

Larynx

Nodose (inferior) ganglion of vagus nerve Vagus (X) nerve

14.15 TASTE PATHWAYS Primary sensory axons of neurons of the geniculate ganglion (VII), petrosal ganglion (IX), and nodose (inferior) ganglion (X), supply taste buds on the anterior two thirds of the tongue, the posterior one third of the tongue, and the epiglottis and palate, respectively. These axons terminate in the rostral part of nucleus solitarius (nucleus of the solitary tract), which sends ipsilateral projections mainly to the parabrachial nucleus in the pons (and a few projections to nucleus VPM of the thalamus). The para­ brachial nucleus projects fibers to nucleus VPM of the thalamus, to the hypothalamus (lateral hypothalamic area, paraventricular nucleus), and to amygdaloid nuclei. These nonthalamic projections are associated with the emotional, motivational, and behavioral aspects of taste and food intake. CLINICAL POINT Taste pathways arise from primary receptors, the taste buds, which are associated with cranial nerves VII (anterior two thirds), IX (posterior

Superior laryngeal nerve

 

one third), and X (epiglottis). The taste buds detect sweet, salty, bitter, sour, and umami (glutamate); each taste bud appears to be associated mainly with one such modality. Combined taste receptor activation can code for a tremendous array of subtle tastes and flavors. Olfaction plays a major role in the discrimination of what an individual perceives to be taste. The primary taste afferents terminate in the rostral nucleus solitarius, which projects mainly to a pontine parabrachial nucleus and then to the parvicellular part of the VPM nucleus of the thalamus, several hypothalamic sites, and the amygdaloid complex. Some cortical areas, such as the anterior portion of the insular cortex and a lateral zone of the posterior orbitofrontal cortex, are involved in subjective aspects of taste and the gustatory experience. These pathways are mainly ipsilateral. Chemical influences can also have a profound effect on taste. Smoking may blunt taste. Many illnesses, including severe nasal congestion, liver dysfunction, autonomic problems, postradiation responses, some vitamin deficiencies, and some medications, may distort or alter the tastes of foods or may leave a lingering, unpleasant, distinctive taste. Many chemotherapeutic agents also profoundly alter taste sensation, perhaps accounting in part for loss of appetite in such individuals. The sequelae of COVID-19 viral infection may include temporary or long-term loss of taste and smell.   

378

Systemic Neuroscience

Frontal section Base of stapes in oval (vestibular) window Tegmen tympani

Facial nerve (VII) (cut) Vestibule Semicircular ducts, ampullae, utricle, and saccule

Prominence of lateral semicircular canal

Facial nerve (VII) (cut)

Malleus (head) Internal acoustic meatus Epitympanic recess

Vestibulocochlear nerve (VIII)

Auricle Cochlear nerve Incus Vestibular nerve Limbs of stapes External acoustic meatus Tympanic membrane Helicotrema

Tympanic cavity

Nasopharynx

Promontory Scala vestibuli Cochlear duct containing spiral organ (Corti)

Round (cochlear) window Pharyngotympanic (auditory) tube

AUDITORY SYSTEM 14.16 PERIPHERAL PATHWAYS FOR SOUND RECEPTION The sound transduction process involves complex mechanical transduction of sound waves through the external ear and the external acoustic meatus and across the tympanic membrane; there it is leveraged as a mechanical force by the bones of the middle ear (ossicles) via the oval window to produce a fluid wave in the cochlear duct. This fluid wave causes differential movement of the basilar membrane, stimulating hairs on the apical portion of hair cells to release neurotransmitters that stimulate primary sensory axons of neurons of the cochlear (spiral) ganglion. The basilar membrane in the cochlea shows maximal displacement spatially according to the frequency of impinging tones, with low frequencies maximally stimulating the apex (helicotrema) and high frequencies maximally stimulating the base. The eustachian (pharyngotympanic) tube permits pressure equilibrium between the middle ear and the outside world.

Scala tympani

Cochlea

 

CLINICAL POINT Hearing loss may be partial or total and can involve virtually any range of detectable frequencies. The most devastating for human communication is a loss in the frequencies of speech (300 to 3000 Hz) of 40 or more decibels. In general, hearing loss can be subdivided into two categories: sensorineural and conductive. Sensorineural hearing loss involves damage to the hair cells, the auditory nerve, or central auditory pathways. Because of the neural damage, both air conduction and bone conduction are diminished. Conductive hearing loss involves damage to the outer or middle ear. Air conduction is impaired because the sound is not properly transduced into the inner ear, but bone conduction is normal. These two types of hearing loss can be tested for at the bedside by using a tuning fork of 512 Hz. The Weber test involves placing the vibrating tuning fork on the center of the forehead. Normally, the patient hears the fork equally in both ears. With sensorineural loss, the sound is heard best in the unaffected ear; with conductive loss, the sound is heard best in the affected ear. The Rinne test involves holding the vibrating tuning fork against the mastoid bone. When the fork is no longer heard, it is immediately placed just outside the external auditory meatus. Normally, air conduction is more effective than bone conduction, and the fork will again be heard when moved adjacent to the external auditory meatus (air conducting sound better than bone). If conductive hearing loss is present, once bone conduction is no longer heard, air conduction also will not be heard (bone conducting sound better than air). If sensorineural hearing loss is present, air conduction may be greater than bone conduction, although both may be diminished.   

379

Sensory Systems

Bony and membranous labyrinths Ampullae Anterior semicircular canal and duct Dura mater

Posterior semicircular canal and duct

Endolymphatic sac Endolymphatic duct in vestibular aqueduct

Common body and membranous limbs

Utricle

Lateral semicircular canal and duct

Saccule Helicotrema of cochlea

Otic capsule Stapes in oval (vestibular) window

Ductus reuniens Scala vestibuli

Incus

Cochlear duct

Malleus

Scala tympani

Tympanic cavity External acoustic meatus Umbo Tympanic membrane Round (cochlear) window (closed by secondary tympanic membrane)

14.17 BONY AND MEMBRANOUS LABYRINTHS The relationship between the cochlea and the vestibular apparatus (utricle, saccule, semicircular canals, and ducts) and the bony labyrinth that surrounds them is illustrated. The ossicles (malleus, incus, stapes) leverage the movement of the tympanic membrane to produce movement of the oval window. Movement of the oval window causes a fluid wave to move through the scala vestibuli and the scala tympani of the cochlea and ricochet onto the round window, causing differential movement of the basilar membrane and stimulation of selected responsive hair cells. The three semicircular canals are located at 90-­degree angles to each other, representing tilted x, y, and z axes. A mismatch of vestibular inputs from the two sides is interpreted as turning, resulting in vertigo, an internal or external sensation of spinning, usually accompanied by nausea and dizziness. Vertigo can arise from CN VIII (neuritis, acoustic Schwannoma), cerebellum (tumor, hemorrhage, infarct), brainstem (infarct, demyelination), or temporal lobe (tumor, abscess).

Cochlear aqueduct Vestibule

Otic capsule

Pharyngotympanic (auditory) tube

 

CLINICAL POINT The semicircular canals (ducts) contain the ampullae that have hair cells that respond to angular acceleration. The utricle contains the otolith organ in the macula that responds to linear acceleration and detects gravitation. The saccule responds best to low-­frequency vibratory stimuli. The cochlea contains the hair cells that respond to fluid movements in the scalae vestibuli and tympani, brought about by the leveraging of the ossicles against the oval window; this movement affects hair cells in the cochlear duct. The activity of the utricle can sometimes become distorted when debris moves away from the hairs and induces activation of the hair cells in the ampulla of the posterior semicircular canal. This produces vertigo and nystagmus that are associated with a specific position of the head (benign postural or positional vertigo). This disorder is the most common cause of vertigo seen in neurological practice. These attacks commonly occur when the patient is lying down, moving to a particular position, or tilting the head back; they may recur either briefly or for a longer period of days or weeks. Attacks can be induced by an examiner through the Hallpike maneuver (tilting the patient’s head back and then 30 degrees to the side), resulting in a brief attack of vertigo and nystagmus. No pharmacological treatment is available. Attempts to reposition the debris by deliberate Hallpike-­like head movements have met with some success.   

380

Systemic Neuroscience

Section through turn of cochlea Scala vestibuli (perilymph weakly +)

Osseous spiral lamina

Vestibular (Reissner's) membrane Cochlear duct (endolymph + 80 mV)

Nerve fibers

Spiral ligament Modiolus of cochlea Tectorial membrane Spiral ganglion Spiral organ (Corti) Scala tympani (perilymph 0 mV)

Basilar membrane

Cochlear nerve

Osseous cochlea

Outer hair cells

Pillar (rod) cells Inner hair cell

14.18 VIII NERVE INNERVATION OF HAIR CELLS OF THE ORGAN OF CORTI Primary sensory axons of the spiral (cochlear) ganglion innervate inner and outer hair cells of the organ of Corti, located on the basilar membrane. The axons are activated by release of neurotransmitters from the hair cells, which occurs when the hairs on the apical surface are moved by shearing forces resulting from movement of the basilar membrane (fluid wave through the scalae vestibuli and tympani) in relation to the more rigidly fixed tectorial membrane. This represents the complex transduction process of the conversion of external sound waves to action potentials in spiral ganglion axons. The ionic potentials (in millivolts) are indicated for the scala tympani and vestibuli (perilymph) and the cochlear duct (endolymph). These potential differences contribute to the excitability of the hair cells.

 

CLINICAL POINT Hair cells in the organ of Corti respond to fluid movements in the scalae vestibuli and tympani that induce shearing motion of the tectorial membrane relative to the basilar membrane. Each region of the spiraled cochlea contains hair cells that respond optimally to movement of the basilar membrane; low frequencies stimulate hair cell movement in the apex (helicotrema) and high frequencies stimulate hair cell movement in the basilar coils of the cochlea. The hair cells can be damaged by many pathological processes, such as viral infections (e.g., mumps), drugs (e.g., quinine), antibiotics, exposure to sustained loud noise, and age-­related deterioration caused by free radical damage. Exposure to loud noises above 85 decibels can selectively damage hair cells, especially those in the basilar coils of the cochlea that transduce high-­frequency sounds. High-­pitched machinery noise (jet engines), gunfire without ear protection, exposure to loud music at concerts or by earphones, and loud ambient noise in construction or industrial sites can induce temporary damage that can become permanent with repeated exposure. Environmental protection regulations now require ear protection in personnel working at such sites.   

Sensory Systems

1. Sound waves impinge on ear drum, causing it to vibrate.

4. Sound waves transmitted up scala vestibuli in medium of its contained perilymph.

5. Short waves (high frequency, high pitch) act at base of cochlea.

Long waves (low frequency, low pitch) act at apex of cochlea.

381

Distort Reissner’s membrane and basilar membrane of cochlear duct and its contained organ of Corti, thus stimulating hair cells that are in contact with the tectorial membrane. Impulses then pass up cochlear nerve.

3. Stapes moves in and out of oval window. 2. Ossicles vibrate as a unit.

8. Impact of wave on membrane of round window causes it to move in and out at round window in opposite phase to oval window.

7. Waves descend scala tympani in medium of its contained perilymph.

14.19 COCHLEAR RECEPTORS Fluid movement through scala vestibuli, around the helicotrema, and back through the scala tympani differentially moves the basilar membrane on which the organ of Corti and its hair cells reside. Movement of hairs on the apical portion of the hair cells by shearing forces of the tectorial membrane results in their

6. Wave transmitted across cochlear duct in medium of endolymph, from scala vestibuli to scala tympani. (Note: waves may also travel around helicotrema at apex of cochlea.)  

depolarization and the release of neurotransmitters. This release stimulates action potentials in the primary afferent axons of spiral ganglion cells. Efferent axons from the olivocochlear bundle, controlled by descending central auditory pathways, can modulate the excitability of hair cells and the sensory transduction process.

382

Systemic Neuroscience

Acoustic area of temporal lobe cortex

Medial geniculate body

Brachium of inferior colliculus Inferior colliculus Midbrain Correspondence between cochlea and acoustic area of cortex: Low tones Middle tones High tones

Lateral lemnisci Nuclei of lateral lemnisci

Medulla oblongata

Superior olivary complex Dorsal cochlear nucleus Inferior cerebellar peduncle Ventral cochlear nucleus Cochlear division of vestibulocochlear nerve

Intermediate acoustic stria

Dorsal acoustic Reticular stria formation Trapezoid body (ventral acoustic stria)

14.20 AFFERENT AUDITORY PATHWAYS Central axon projections of the spiral ganglion neurons terminate in dorsal and ventral cochlear nuclei in several tonotopic maps (receptor origination shown in the cochlea in colors). These cochlear nuclei project into the lateral lemniscus via acoustic striae; many of these projections remain ipsilateral. The lateral lemniscus terminates in the nucleus of the inferior colliculus, which in turn projects via the brachium of the inferior colliculus to the medial geniculate body (nucleus) of the thalamus. The thalamus sends tonotopical projections to the primary auditory cortex

Inner

Outer

Spiral ganglion Hair cells

 

on the transverse gyrus of Heschl. Several accessory auditory brainstem nuclei (the superior olivary nucleus for lateral sound localization, the nuclei of the trapezoid body [not shown], and the lateral lemniscus) send both crossed and uncrossed projections through the lateral lemniscus. Sound is represented throughout the afferent auditory pathways bilaterally; thus a unilateral lesion in the lateral lemniscus, auditory thalamus, auditory radiations, or auditory cortex does not produce contralateral deafness. With such a lesion, there is a diminution in hearing and auditory neglect contralateral to the lesion with bilateral simultaneous stimulation.

Sensory Systems

Large acoustic Schwannoma intruding in the cerebellopontine angle, causing damage to both the vestibular and cochlear portions of CN VIII, CN VII, other cranial nerves (V, IX, X), and brainstem structures

383

V VII VIII IX X

MRI of vestibular schwannoma at the cerebellopontine angle; axial (left) and coronal (right)

 

14.21 AFFERENT AUDITORY PATHWAYS (CONTINUED)

CLINICAL POINT The cochlear nerve contains axons that innervate the hair cells of the organ of Corti in the spirals of the cochlea. Primary cochlear axons enter the lateral portion of the caudal pons, terminating in the dorsal and ventral cochlear nuclei with several tonotopically representative maps of the auditory frequency world. The auditory nerve can be damaged by infections, tumors (e.g., acoustic Schwannoma), and traumas, particularly those associated with the petrous portion of the temporal bone; both the auditory portion and vestibular portion of CN VII are affected clinically. Irritation of auditory nerve fibers can produce tinnitus, a sense of ringing in the ears (or buzzing, humming, clicking, or other sounds). When the nerve is actually destroyed, the

tinnitus stops and hearing loss ensues. Auditory nerve damage has symptoms that are present on the ipsilateral side with respect to the damage. In the brainstem, the acoustic striae project axons to a host of nuclei in bilateral fashion, including the superior olivary nuclei, the nuclei of the trapezoid body, the nuclei of the lateral lemnisci, and the inferior colliculi. The inferior colliculi, a mandatory synaptic processing site for central auditory processing, receive information from both ears. These projections proceed to the medial geniculate nucleus and then via the auditory radiations to the auditory cortex (transverse gyrus of Heschl). Damage in the interior of the brainstem or, more likely, in the temporal lobe, generally caused by a vascular infarct, tumor or abscess, or trauma, may result in diminished hearing and auditory neglect from contralateral stimuli but not unilateral deafness. Schwannomas frequently arise from the vestibular division of CN VIII and involve both the vestibular and auditory divisions of this cranial nerve.   

384

Systemic Neuroscience

Excitatory endings Inhibitory endings Intermediate endings Temporal cortex

Fibers may be excitatory or inhibitory

Inferior colliculus Tensor tympani muscle

Stapedius muscle Incus Malleus

Medial geniculate body Brachium of inferior colliculus Inferior colliculus Tympanic membrane

Nuclei of lateral lemnisci

Stapes Lateral lemniscus

Middle ear

Trigeminal nerve fibers Motor nucleus of trigeminal nerve Facial nerve fibers Dorsal cochlear nucleus Ventral cochlear nucleus Efferent olivocochlear fibers (inhibit hair cells and afferent nerve terminals via cochlear division of vestibulocochlear nerve)

Facial nucleus Reticular formation Trapezoid body Superior olivary complex

14.22 CENTRIFUGAL (EFFERENT) AUDITORY PATHWAYS Descending pathways travel from the auditory cortex, the medial geniculate body of the thalamus, the inferior colliculus, and accessory auditory nuclei of the brainstem to terminate in caudal structures in the pathway, such as the cochlear nuclei and the superior olivary nucleus. These centrifugal connections permit

Hair cells Efferent nerve fibers Afferent nerve fibers

 

descending control of incoming auditory information. The olivocochlear bundle, from the superior olivary nuclei, projects back to the hair cells in the organ of Corti and modulates the transduction process between the hair cells and the primary afferent axons. The motor nuclei of V and VII send LMN axonal projections to the tensor tympani and stapedius muscles, respectively, for reflex dampening of the ossicles in the presence of sustained loud noise.

385

Sensory Systems

B. Position within base of skull

A. Membranous labyrinth

Vestibular ganglion Vestibular and cochlear divisions of vestibulocochlear nerve

Utricle

Superior semicircular canal

30˚

Horizontal semicircular canal

60˚ Plane of saccule Plane of superior canal

Cristae within ampullae

Posterior semicircular canal

E. Structure and innervation of hair cells

Gelatinous cupula Hair tufts

Kinocilium

Hair cells Nerve fibers Basement membrane

Stereocilia Cuticle Hair cell (type I)

D. Section of macula Otoconia Gelatinous otolithic membrane Hair tuft Hair cell Supporting cells Basement membrane Nerve fibers

Superior Horizontal

90˚ Plane of posterior canal

C. Section of crista Opposite wall of ampulla

Posterior

Saccule

Cochlear duct (scala media) Macula

Canals: Superior

Plane of horizontal canal and utricle

Posterior

Excitation Inhibition Basal body Cuticle

Kinocilium Stereocilia Basal body Hair cell (type II)

Supporting cells

Supporting cells

Afferent nerve calyx

Efferent nerve ending

Efferent nerve ending

Afferent nerve calyx

Basement membrane Myelin sheath

VESTIBULAR SYSTEM 14.23 VESTIBULAR RECEPTORS The vestibular receptors include hair cells in the maculae of the utricle (linear acceleration or gravity) and saccule (low frequency vibration) and in the cristae ampullaris of the orthogonally oriented semicircular canals (angular acceleration or movement of the head). Hair tufts from the cristae ampullaris and the maculae are embedded in a gelatinous substance, which is moved when

Myelin sheath

 

gravity (utricle) exerts force on the calcium carbonate crystals (otoliths) resting on top of the hairs or when fluid movement occurs in a semicircular canal (head movement). Bending of the kinocilium in the hair tufts depolarizes the hair cell, causing the release of neurotransmitters that stimulate action potentials in primary sensory axons of the vestibular (Scarpa’s) ganglion. Additional efferent projections from the CNS modulate this transduction process, similar to centrifugal regulation of auditory transduction.

386

Systemic Neuroscience Vestibulospinal Tracts

Superior Medial Vestibular nuclei Lateral Inferior Rostral Upper limb Trunk Ventral Dorsal To cerebellum Lower limb Caudal Somatotopical pattern in lateral vestibular nucleus

Excitatory endings Inhibitory endings Ascending fibers in medial longitudinal fasciculi Ascending tract of Deiters

Vestibular ganglion and nerve Motor neuron (controlling neck muscles) Medial vestibulospinal fibers in medial longitudinal fasciculi

Lateral vestibulospinal tract

Excitatory endings to back muscles

Excitatory interneuron Inhibitory interneuron

Fibers from cristae (rotational stimuli)

Fibers from maculae (gravitational stimuli)

To flexor muscles To extensor muscles

Lower part of cervical spinal cord

Inhibitory ending

To axial muscles Inhibitory ending Lumbar part of spinal cord

To axial muscles Excitatory ending Lateral vestibulospinal tract

Inhibitory interneuron Excitatory synapse To flexor muscles To extensor muscles

  14.24 VESTIBULAR PATHWAYS Primary afferent vestibular axons from the vestibular ganglion terminate in the four vestibular nuclei (superior, inferior, medial, and lateral) and directly in the cerebellum (deep nuclei and cortex). Descending axons are sent via the medial vestibulospinal tract (from the medial nucleus) to spinal cord LMNs that regulate head and neck movements. Descending axons are sent via the lateral vestibulospinal tract (from the lateral nucleus) to all levels of spinal cord LMNs to activate extensor movements. Multiple vestibular nuclei project to the cerebellum to modulate and coordinate muscle activity for basic tone and posture and to extraocular LMNs via the medial longitudinal fasciculus to coordinate eye movements with head and neck movements. Some ascending axons from the vestibular nuclei may reach the thalamus (near the VPM and posterior nuclei), with thalamic projections to the lateral postcentral gyrus (area 2, motion perception and spatial orientation) and to the insular cortex and temporoparietal cortex.

CLINICAL POINT The vestibular nerve consists of axons that supply the hair cells of the cristae in the ampullae of the semicircular canals, as well as the maculae of the utricle and saccule. These primary vestibular axons terminate in the four vestibular nuclei and directly in the vestibular cerebellum (part of the vermis and flocculonodular lobe). The vestibular nuclei send axonal projections to the LMNs of the spinal cord (via vestibulospinal tracts), the cerebellum, the extraocular nuclei (via the medial longitudinal fasciculus), and the RF. The peripheral vestibular and auditory apparatus can be damaged by increased endolymphatic pressure that gradually destroys hair cells in both the vestibular and auditory peripheral systems. This condition, called Meniere’s disease, is characterized by abrupt attacks of severe vertigo that can last for as long as several hours. The attacks are incapacitating and immobilizing and produce nausea and vomiting. The vestibular symptoms are accompanied by auditory symptoms, including tinnitus and progressive sensorineural deafness. Most cases are unilateral, but bilateral disease does occur. After many episodes, some remission is occasionally seen, but the disease can progress to the point where the hearing loss and vestibular damage are almost total.   

Sensory Systems

Slow phase

Rapid phase (saccadic movement)

Direction of maintained head acceleration

Direction of maintained head acceleration Horizontal semicircular canal depressed

Horizontal semicircular canal excited

Medial rectus motor neurons excited Ascending tract of Deiters

Medial rectus motor neurons depressed Abducens internuclear neuron Inhibitory interneurons

Medial and lateral vestibular nuclei excited Abducens nucleus depressed Oculomotor (III) nerve Lateral rectus muscle

Abducens nucleus excited

Parapontine reticular formation (PPRF) Medial rectus muscles

Abducens (VI) nerve

Lateral rectus muscle

Eyes move in direction opposite from head; tend to preserve visual fixation; rate determined by degree of horizontal canal excitation.

Horizontal semicircular canal depressed

Horizontal semicircular canal input continues but is opposed by inhibition from saccadic center

Medial rectus motor neurons excited

Medial rectus motor neurons depressed

Abducens nucleus depressed

Vestibular nuclei depressed by saccadic center

Inhibitory burst interneuron

Abducens nucleus excited by saccadic center Abducens (VI) nerve Lateral rectus muscle

387

Excitatory burst interneuron Saccadic center (parapontine reticular formation [PPRF]) Medial rectus muscles

Oculomotor (III) nerve Lateral rectus muscle

Eyes snap back in same direction as head.

 

14.25 NYSTAGMUS Nystagmus is repetitive, alternating back-­and-­forth movements of the eye, requiring central coordination of extraocular LMNs and eye movements. Optokinetic nystagmus is a normal process of visually activated movement of the eyes via tracking mechanisms, with the eyes returning to a forward position by means of visual association cortex projections through the superior colliculus to extraocular LMNs. Vestibular nystagmus results from asymmetrical input from

receptors in the semicircular canals or from damage to vestibular nuclei or the vestibular cerebellum and is mediated by vestibular projections via the medial longitudinal fasciculus to extraocular nuclei (LMNs); the asymmetrical input provokes the slow phase (or drift) of vestibular nystagmus, eliciting eye movements as if the head were turning. The fast phase (saccadic movement) is the return of the eyes to a forward position, which is provoked when the slow phase moves the eyes to a maximal position.

388

Systemic Neuroscience

Horizontal section Scleral venous sinus (Schlemm’s canal)

Iris

Lens

Scleral spur Zonular fibers (suspensory ligament of lens) Ciliary body and ciliary muscle

Capsule of lens Cornea Anterior chamber Posterior chamber Iridocorneal angle Ciliary processes Bulbar conjunctiva

Ciliary part of retina

Ora serrata

Tendon of lateral rectus muscle Tendon of medial rectus muscle

Vitreous body Optic (visual) part of retina

Hyaloid canal

Choroid Perichoroidal space

Lamina cribrosa of sclera

Sclera Optic nerve (II)

Fascial sheath of eyeball (Tenon’s capsule)

Central retinal artery and vein

Episcleral space Fovea centralis in macula Outer sheath of optic nerve Subarachnoid space

 

VISUAL SYSTEM 14.26 ANATOMY OF THE EYE The eye consists of three major layers, or tunics. The outer fibrous layer, the fibrous tunic, consists of the protective cornea (transparent) and the sclera (opaque). The middle layer, the vascular tunic (uveal tract), consists of the choroid, the ciliary body, and the iris. The transparent biconvex lens, with its surrounding capsule of zonular fibers, is suspended from the ciliary process of the ciliary body. The inner layer, or tunic, consists of the neuroretina, the nonpigment epithelium of the ciliary body, and the pigment epithelium of the posterior iris. The retina contains the photoreceptors for transduction of photon energy from light into neuronal activity. Aqueous humor is secreted from blood vessels of the iris into the posterior chamber and flows through the aperture of the pupil into the anterior chamber, where it is absorbed into the trabecular meshwork into Schlemm’s canal at the iridocorneal angle. Blockage of this absorption of aqueous humor results in glaucoma. The vitreous humor fills the interior of the eyeball.

CLINICAL POINT When light impinges on the eye, it is refracted to focus on the photo-­ receptors of the retina to permit interpretation of the outside visual world. A vast proportion (close to 90%) of the refraction of light is accomplished by the cornea. A smaller percentage (approximately 10%) of the refraction is accomplished by the lens; however, this smaller percentage can be regulated neurologically, via CN III and its influence on accommodation to near vision. If the cornea is opacified (e.g., following abrasion that results in vascularization) it may impede the light pathway and cause a distortion of vision. Accommodation to near vision occurs when one tries to look at an object that is close rather than distant and usually involves simultaneous convergence, constriction (pupil), and accommodation. Accommodation involves a portion of the nucleus of Edinger-­Westphal, which acts through CN III axonal projections to the ciliary ganglion. This portion provides postganglionic parasympathetic cholinergic innervation to the ciliary muscle. When this parasympathetic system is activated, the ciliary muscle lifts up and in, releasing tension on the zonular fibers that suspend the lens, permitting the lens to bunch up (fatten) and refract light. Accommodation commonly diminishes with age (presbyopia). A CN III palsy damages both pupillary constriction (resulting in a fixed, dilated pupil) and accommodation to near vision. Accommodation also can be damaged by trauma, diabetes, viral infections, and other pathology. If accommodation is impaired, corrective lenses are needed to allow proper focusing of light on the retina.   

Sensory Systems Schwalbe's line Trabecular meshwork and spaces of iridocorneal angle (Fontana) Scleral venous sinus (Schlemm's canal) Scleral spur Iridocorneal angle

389

Posterior limiting lamina (Descemet's membrane) Endothelium of anterior chamber Cornea

Pectinate ligament Major arterial circle of iris Anterior ciliary vein

Anterior chamber

Bulbar conjunctiva Sclera

Folds of iris Minor arterial circle of iris Lens

Posterior chamber

Ciliary process Ciliary part of retina

Meridional Circular fibers fibers Ciliary muscle

Dilator Zonular fibers muscle (suspensory of pupil ligament of lens) Pigment epithelium (iridial part of retina)

Nucleus of lens

Capsule of lens Ciliary body Sphincter muscle of pupil Perichoroidal space Note: For clarity, only a single plane of zonular fibers is shown; actually, fibers surround entire circumference of the lens. Optic part of retina

Zonular fibers fanning out and blending into lens capsule

Ora serrata

Iris

Orbiculus ciliaris of ciliary body covered by ciliary part of retina

Lens Zonular fibers

Ciliary processes The lens and supporting structures

14.27 ANTERIOR AND POSTERIOR CHAMBERS OF THE EYE The ciliary muscle and the pupillary constrictor muscle are supplied by parasympathetic postganglionic myelinated nerve fibers from the ciliary ganglion (innervated by preganglionics in the nucleus of Edinger-­Westphal in CN III). Contraction of the ciliary muscle reduces the tension on zonular fibers and causes the lens to curve or bunch, which induces accommodation for near vision. The pupillary constrictor muscle also is supplied by parasympathetic postganglionic fibers from the ciliary ganglion. In the pupillary light reflex, light shone into one eye stimulates photoreceptors and related neurons in the retina; retinal ganglion cells send neural projections via the optic (II) nerve (afferent limb), which terminate in the pretectum. Neurons of the pretectum project bilaterally (crossed axons through the posterior commissure) to the Edinger-Westphal nucleus. This nucleus projects to the ciliary ganglion via CN III (efferent limb), which causes both direct (ipsilateral) and consensual (contralateral) pupillary constriction. The pupillary dilator muscle is supplied by noradrenergic sympathetic postganglionic unmyelinated nerve fibers from the superior cervical ganglion (innervated by preganglionics in T1 and T2). Schlemm’s canals are conspicuous at the iridocorneal angle.

 

The lens is surrounded by a capsule anchored and suspended by an array of zonular fibers fanning out in circular fashion to attach to the ciliary processes of the ciliary body. Some interior zonular fibers extend along the ciliary body to the junction at the ora serrata. CLINICAL POINT Aqueous humor is secreted from the vasculature of the ciliary apparatus into the posterior chamber. It circulates through the pupillary aperture into the anterior chamber. From the anterior chamber, the aqueous humor is resorbed into the scleral venous sinuses, called the canals of Schlemm. If the canals of Schlemm are blocked, preventing absorption of aqueous humor, increased ocular pressure occurs; this results in pressure on the optic nerve head, cupped discs, atrophy, and defective vision of increasing severity, including total blindness. Glaucoma, the most common cause of optic nerve damage, occurs in more than 1% of the population over 40 years of age. This condition can be detected through ophthalmoscopy and tonometry. The principal type of glaucoma is called wide-­angle glaucoma, which involves gradual sclerosis of the canals of Schlemm. A far less common type of glaucoma is narrowangle (acute or closed-­angle) glaucoma, a medical emergency in which bunching of the dilator muscle or narrowing of the iridocorneal angle blocks resorption of aqueous humor. The eye is red, swollen, and painful, sometimes causing a headache. It can be precipitated by pupillary dilation during an ophthalmological examination and must be reversed by means of pharmacological pupillary constriction.   

390

Systemic Neuroscience Retinal Layers

Section through retina

Nerve fiber layer

Cells Inner limiting membrane Axons at surface of retina passing via optic nerve, chiasm, and tract to lateral geniculate body

Ganglion cell layer

Inner plexiform layer Ganglion cell Müller cell (supporting glial cell)

Inner nuclear layer

Bipolar cell Amacrine cell Outer plexiform layer

Horizontal cell Rod Cone

Outer nuclear layer

Pigment cells of choroid Photoreceptor layer

Pigment epithelium

  14.28 THE RETINA: RETINAL LAYERS The retina is a tissue paper–thin piece of CNS tissue that contains the photoreceptors; it is attached to the vascular tunic at the ora serrata. The layers of the retina in the interior of the eyeball are oriented from outer to inner. The pigment epithelium is at the outer margin, followed by the outer nuclear layer (photoreceptors), the inner nuclear layer (bipolar neurons, amacrine and horizontal cells), and the ganglion cell layer. The outer and inner plexiform layers are the zones of synaptic connectivity. The ganglion cell axons form an inner nerve fiber layer projecting centrally toward the optic nerve head, into which they collect as the optic nerve, CN II. The outer segments of the photoreceptors, the rods and cones, are embedded in a pigment epithelium in the outer part of the interior eyeball to prevent backscatter of light. The rods and cones connect synaptically with bipolar cells in the outer plexiform layer; these bipolar neurons connect with the ganglion cells of the retina in the inner plexiform layer. The retinal ganglion cells are the equivalent of secondary sensory nuclei for other sensory modalities. Horizontal and amacrine cells provide horizontal interconnections in the retina, mainly at the outer plexiform layer and the inner plexiform layer, respectively. These cells modulate the central flow of information from the photoreceptors to the bipolar neurons to the retinal ganglion cells. The central point for visual focusing is the fovea centralis (0.4 mm in diameter) in the macula (3 mm in diameter), which is found temporally and slightly below the geometric midpoint. The fovea consists purely of cones for color vision (photopic); these cone

projections to ganglion cells involve very little convergence. In the fovea, there is close to a one-­to-­one-­to-­one relationship among the cones, bipolar neurons, and ganglion cells. The peripheral retinal photoreceptors are mainly rods, for night vision (scotopic); there is huge convergence of rods onto bipolar neurons, which in turn converge onto single ganglion cells. Thus, acuity is best achieved in the fovea, the region for color vision.

CLINICAL POINT Cones permit color vision and are concentrated in the macula of the retina, the point of focus for high-­acuity vision. The center of the macula, the fovea centralis, consists entirely of cones. These cones are connected with bipolar retinal cells, which in turn contact retinal ganglion cells, resulting in conveyance of visual information via the optic nerve into other CNS structures (superior colliculus, pretectum, hypothalamus, lateral geniculate nucleus). The macular pathway is essential for photopic (color, high-­acuity) vision. The peripheral retina contains rods as the main photoreceptors; rods massively converge onto bipolar neurons. This peripheral retinal pathway is active in scotopic (night) vision. The macula can undergo a gradual process of depigmentation and degeneration in elderly individuals, leading to the loss of central vision and reading capability. Although there is no immediate cure for macular degeneration, carotenoid supplements of lutein and zeaxanthin appear to replenish the macula with these important depleted carotenoids, slowing the degenerative process. Although macular degeneration is mainly a disease of the elderly, some young individuals with inherited storage diseases (Tay-­Sachs) or infectious processes may experience macular degeneration.   

391

Sensory Systems

Rod photoreceptor

Synaptic ending depolarized

Rod in dark

Cone photoreceptor

Synaptic ending fully polarized

Horizontal cell Bipolar cell

Rod in light Photons of light

Rhodopsin

all-cis retinol

Nucleus Inner segment

Nucleus

all-trans retinol Intracellular transduction via phosphodiesterase Current flow Na+ permeability increased through cGMP-gated Na+ channels

Outer plexiform layer

+ Opsin all-cis retinol Vitamin A

hydrolysis of intracellular cGMP decreased Na+ permeability

Inner segment

Mitochondria Ca++

ion flow modulates light adaptation Outer segment

Cilium Ca++ Photopigments cone opsins (blue, green, red plus all-cis retinol)

Plasma membrane

Outer segment

Pigment epithelium

 

14.29 THE RETINA: PHOTORECEPTORS Rods use the photopigment rhodopsin to achieve transduction of photons of energy from light into neurotransmitter release that can activate electrical activity in bipolar neurons. Rod light transduction involves conversion of all-­cis-­retinol (from rhodopsin) to an all-­trans form, provoking calcium influx and a decrease in

sodium conductance with hyperpolarization. This process is outlined in detail in the first two parts of the figure, a rod in the dark and a rod in light. When a rod is activated by light, it hyperpolarizes rather than depolarizes. A cone uses opsin photopigments for blue, green, and red, as well as all-­cis retinal; these cone pigments permit color vision.

392

Systemic Neuroscience

A. Topography of retinal nerve fibers Macular nerve fibers course directly to optic disc. Arcuate nerve fibers from temporal periphery of retina must arc around macular bundle.

Optic disc (blind spot)

Temporal retina Median horizontal raphe. Inferior and superior arcuate fibers meet but do not cross.

Nasal retina Nerve fibers of nasal retina course directly to optic disc.

Macula (fixation point)

B. Anatomy of optic nerve Retinal nerve fibers Retina

Optic nerve layers Nerve fiber layer

Choroid Sclera Central retinal vessels

Prelaminar layer Laminar layer

Vascular circle of Zinn-Haller Short posterior ciliary artery Lamina cribrosa

Retrolaminar layer

Nerve fiber bundles Pial layer Arachnoid layer Dura mater

 

14.30 THE RETINA: OPTIC NERVE A, The retina is topographically organized; a representation of the visual world (referred to as a visual field) is mapped onto the retina of each eye. Because the eye acts like a camera, the visual world is inverted as it projects onto the retina. The temporal (lateral) visual field falls on the nasal hemiretina, and the nasal (medial) visual field falls on the temporal hemiretina. The upper visual field falls on the lower hemiretina, and the lower visual field falls on the upper hemiretina. When viewing the retina directly using ophthalmoscopy, the macula is located temporally and slightly inferior to the geometric midpoint of the retina. The optic disc (zone of optic nerve fibers, sometimes called the blind spot) is located nasally and slightly above (superior to) the geometric midpoint. The precise retinotopic organization is maintained throughout the projections of the main visual pathway (the

retino-­geniculo-­calcarine pathway). B, The optic nerve (CN II) is a CNS tract that consists of myelinated axons of the ganglion cells of the retina. These axons collect across the innermost layer of the neuroretina and form the optic nerve, which exits from the eyeball nasally, slightly above the horizontal midline. These optic nerve fibers are myelinated by oligodendroglia. The optic nerve is surrounded by meninges, as part of the CNS. A subarachnoid space containing cerebrospinal fluid is present between the arachnoid and pial layers of the meninges. Elevated intracranial pressure can exert pressure on the optic nerve head (where the ganglion cell axons first form the optic nerve), forcing it inward; this phenomenon is called papilledema and is evidence of increased intracranial pressure; approximately 24 hours are required for increased intracranial pressure to cause papilledema. Major retinal vessels from the central retinal artery and vein travel in the optic nerve.

Sensory Systems

Cornea Anterior chamber Scleral venous sinus (Schlemm's canal)

393

Minor arterial circle of iris Major arterial circle of iris Blood vessels of ciliary body Bulbar conjunctiva and conjunctival vessels Anterior ciliary artery and vein Iris

Iridocorneal angle

Lens

Ciliary body Ora serrata

Posterior chamber

Muscular artery and vein

Zonular fibers

Extrinsic eye muscle

Retina Vitreous chamber

Choroid

Long posterior ciliary artery

Sclera Vorticose vein Episcleral artery and vein Retinal artery and vein Long posterior ciliary artery Short posterior ciliary arteries Superior macular arteriole and venule

Central retinal artery and vein Optic nerve (II)

Superior nasal retinal arteriole and venule Superior temporal retinal arteriole and venule

Optic disc

Macula and fovea centralis

Inferior nasal retinal arteriole and venule

Inferior temporal retinal arteriole and venule Inferior macular arteriole and venule

Right retinal vessels: ophthalmoscopic view

 

14.31 ARTERIES AND VEINS OF THE EYE The central retinal artery and its branches supply blood to the retina. This arterial system, derived from the ophthalmic artery (the first branch off the internal carotid artery), is commonly the first site where ischemic or embolic events (transient ischemic attacks) herald the presence of serious vascular disease and high risk for a future stroke. Ciliary arteries supply the middle vascular tunic, which also contributes partial blood supply to the retina; this component of blood supply can be disrupted by a detached retina. Blood vessels enter and exit the retina at the optic disc (nerve head), located nasally and slightly superiorly from the geometric midpoint of the eyeball. The macula is located temporally and slightly inferiorly from this midpoint.

CLINICAL POINT The central retinal artery is a common site of emboli in impending cerebrovascular disease; such emboli are forerunners of stroke and indications of carotid atherosclerosis or occlusion. An embolus in the central retinal artery may produce temporary (fleeting) blindness in the affected eye, called amaurosis fugax, which lasts for several minutes but less than an hour; such an episode is called a transient ischemic attack. An infarct in the central retinal artery produces characteristic ophthalmologic findings, such as loss of opalescence in the fovea (a so-­called cherry-­red spot). If the central retinal vein is occluded, a hemorrhage is seen, and the resultant visual loss may be significant. In addition to hemorrhages, edema and exudates may be present, indicative of hypertension or diabetic problems. If the retina becomes detached, it may be separated from part of its blood supply from the ciliary arteries in the middle vascular tunic, which also results in loss of vision.   

394

Systemic Neuroscience

Superior Temporal Nasal Retinal fibers

(Optic nerve) Prechiasmatic

Inferior Nasal Temporal

Chiasm Postchiasmatic

Left eye

Optic tract Optic radiations

Optic nerve

Occipital cortex Key Uncrossed (temporal) fibers

Right eye Inferior nasal fibers decussate in anterior chiasm and then project into optic tract as anterior fibers Inferior nasal fibers Chiasm

Crossed (nasal) fibers

Optic tract

Optic pathway (superior view)

Superior nasal fibers

Superior view

 

14.32 ANATOMY AND RELATIONSHIPS OF THE OPTIC CHIASM Axons from ganglion cells in the temporal hemiretinas (carrying information from the nasal visual fields) travel into the optic nerve and remain ipsilateral in the optic chiasm; they synapse in the ipsilateral lateral geniculate body or nucleus. Axons from ganglion cells in the nasal hemiretinas (carrying information from the temporal visual fields) travel into the optic nerve and cross the midline in the optic chiasm; they synapse in the contralateral lateral geniculate body. Therefore, crossing axons in the optic

chiasm carry information from the temporal visual fields, which are derived from retinal ganglion cells in the nasal hemiretinas. These crossing axons are susceptible to disruption by a pituitary adenoma; such a lesion can produce a bitemporal hemianopia, starting first as an upper visual quadrant defect and progressing to full hemianopia. The optic tract contains axons from the ipsilateral temporal hemiretina and the contralateral nasal hemiretina, representing the contralateral visual field; disruption of the optic tract results in contralateral hemianopia.

Sensory Systems

Bitemporal hemianopsia

Optic nerves Pituitary tumor compressing or invading optic chiasm

MRI showing pituitary macroadenoma with suprasellar and right cavernous sinus extension. Optic chiasm is raised slightly, but visual fields are normal.

Crossed pathways from nasal part of retina interrupted at optic chiasm

MRI showing pituitary macroadenoma with suprasellar and bilateral cavernous sinus extension. The optic chiasm is compressed, causing bitemporal superior quadrant vision loss.

Optic tract

MRI showing pituitary macroadenoma with suprasellar, bilateral cavernous, and sphenoid extensions. The optic chiasm is markedly compressed, causing complete bitemporal hemianopsia.

Reprinted with permission from Young WF. The Netter Collection of Medical Illustrations, Volume 2 – Endocrine System. Elsevier, Philadelphia, 2011.

 

14.33 DAMAGE AFFECTING THE OPTIC CHIASM Tumors, aneurysms, and infarcts can produce damage to the optic chiasm. This illustration demonstrates increasing severity (as noted by MRIs) of pituitary adenomas impinging on the optic chiasm.

395

396

Systemic Neuroscience To visual cortex From visual cortex

Optic radiation

Pulvinar

Optic tract

Pretectum

Suprachiasmatic nucleus

Brachium of superior colliculus

Optic chiasm Optic (II) nerve

Superior colliculus Accessory optic tract

Lateral geniculate body (dorsal and ventral lateral geniculate nuclei) Nucleus of transpeduncular tract

Brachium of inferior colliculus Inferior colliculus

Cerebral peduncle Transpeduncular tract

Nucleus of accessory optic tract

Nucleus reticularis tegmenti pontis Pons To thalamus Superior Mesencephalic colliculus reticular formation

Superior cerebellar peduncle Middle cerebellar peduncle

Oculomotor nucleus

Inferior cerebellar peduncle

Medial pontine reticular formation

Inferior olive

Pons Reticular formation Medulla Tectospinal tract

’  14.34 VISUAL PATHWAYS: RETINAL PROJECTIONS TO THE THALAMUS, HYPOTHALAMUS, AND BRAINSTEM Retinal projections travel through the optic nerve, chiasm, and tract and terminate in several regions, including the lateral geniculate body or nucleus, the upper layers of the superior colliculus, the pretectum, the hypothalamus (suprachiasmatic nucleus), and the nucleus of the accessory optic tract. The lateral geniculate body mediates conscious visual interpretation of visual input via the retino-­geniculo-­calcarine (area 17) pathway. The superior colliculus provides a second visual pathway through projections to the pulvinar, which in turn projects to the associative visual cortex (areas 18 and 19), providing localizing information for coordinating movement of the eyes to novel or moving visual stimuli. Neurons in deeper layers of the superior colliculus also provide descending contralateral connections (tectospinal tract) to cervical LMNs to mediate reflex visual effects on head and neck movements; collaterals of this descending system terminate in the brainstem reticular formation. The superior colliculus receives input from the visual cortex. The pretectum mediates the pupillary light reflex. The suprachiasmatic nucleus of the hypothalamus

integrates light flux and regulates circadian rhythms and diurnal cycles. The nucleus of the inferior accessory optic tract may help to mediate brainstem responses for visual tracking and may interconnect with sympathetic preganglionic neurons in T1 and T2 (regulating the superior cervical ganglion). CLINICAL POINT Ganglion cells of the retina (the neural equivalents of the secondary sensory nuclei in other sensory systems, such as the nuclei gracilis and cuneatus) send projections through the optic nerve, chiasm, and tract to terminate in the superior colliculus, the lateral geniculate nucleus of the thalamus, the pretectum, the suprachiasmatic nucleus of the hypothalamus, and some brainstem sites. However, they all require the projection of axons through the optic nerve, chiasm, and tract. If the optic nerve is damaged (by multiple sclerosis, glaucoma, inflammatory disorder, trauma, vascular pathology), there is visual loss in a selected area (scotoma) or in the entire ipsilateral eye (monocular blindness). If the optic chiasm is damaged, usually by a pituitary tumor, the growth of the tumor impinges on the crossing fibers in a manner that disrupts the outer visual fields (bitemporal hemianopia), usually from the upper to the lower fields (much like pulling down the shades). If the optic tract is damaged, axons from the ipsilateral temporal hemiretina and the contralateral nasal hemiretina are disrupted, producing a contralateral visual field deficit (homonymous contralateral hemianopia).   

Sensory Systems

397

Light

Optic nerves

Short ciliary nerves Ciliary ganglion

Optic chiasm

CN III

Optic tract Red nucleus

EdingerWestphal nucleus

Pretectal nucleus Superior colliculus

14.35 PUPILLARY LIGHT REFLEX The pupillary light reflex requires CN II, CN III, and central brainstem connections. Light shined in one eye stimulates retinal photoreceptors, and subsequently retinal ganglion cells, whose axons travel through the optic nerve, chiasm, and tract to terminate in the pretectum (pretectal nucleus). The pretectal neurons project to a portion of the nucleus of Edinger-­Westphal on both sides. This preganglionic parasympathetic nucleus projects to ciliary ganglion neurons, which in turn send postganglionic cholinergic axons to innervate the pupillary constrictor muscle.

 

Thus, light shined in one eye normally results in the constriction of both pupils (ipsilateral pupillary constriction—direct response; contralateral pupillary constriction—consensual response). Lesions of CN II produce an unresponsive pupillary light reflex on both sides (afferent pupillary defect) from light shined in the eye on the side of the CN II lesion. With light shined in the unaffected eye, both pupils constrict. Lesions of CN III result in unresponsive ipsilateral pupillary constriction on the affected side (the pupil is “fixed and dilated”) when light is shined in either eye (efferent pupillary defect).

398

Systemic Neuroscience

Central darker circle represents macular zone Overlapping visual fields

Lightest shades represent monocular fields Each quadrant a different color

Projection on left retina

Projection on right retina Optic (II) nerves Optic chiasm

Ipsilateral 6 5 4 3 2 1

Projection on left dorsal lateral geniculate nucleus Meyer's loop

Meyer's loop

Optic tracts Lateral geniculate bodies

Contralateral

Projection on right dorsal lateral geniculate nucleus

Ipsilateral 6 5 4 3 2 1

Contralateral

Projection on left occipital lobe

Projection on right occipital lobe

Calcarine fissure

  14.36 VISUAL PATHWAY: THE RETINO-­ GENICULO-­CALCARINE PATHWAY The retino-­geniculo-­calcarine pathway conveys information about fine-­grained conscious visual analysis of the outside world. It is organized topographically (retinotopic) throughout its course to the calcarine (visual) cortex in the occipital lobe. The nasal hemiretinal ganglion cell axons cross the midline in the optic chiasm, whereas the temporal hemiretinal ganglion cell axons remain ipsilateral. Thus, each optic tract conveys information from the contralateral visual world (or visual field); damage to the optic tract produces contralateral hemianopia. The optic tract terminates in the lateral geniculate body or nucleus and is organized in six layers, as shown. However, binocular convergence does not take place here; ganglion cell axons from the ipsilateral temporal hemiretina terminate in layers 2, 3, and 5, and ganglion cell axons from the contralateral nasal hemiretina terminate in layers 1, 4, and 6. The optic radiations project to the calcarine (striate) cortex (area 17,

the primary visual cortex). A portion of the optic radiations loops through the temporal lobe (Meyer’s loop) and can be damaged by a tumor or mass, resulting in contralateral upper quadrantanopia. Bilateral convergence from right and left retinas first takes place in the primary visual cortex, area 17. The retinotopic organization of this pathway is shown in color in this illustration. CLINICAL POINT Meyer’s loop consists of axons of the lateral geniculate nucleus that loop downward through the temporal lobe before extending posteriorly to synapse on cortical neurons in layer 4 of the lower bank of the ipsilateral calcarine fissure (area 17, primary visual cortex). The temporal lobe is a site at which tumor or abscess formation is far more likely than it is in the parietal or occipital lobes. If such a mass lesion damages fibers of Meyer’s loop, the individual loses vision in the upper quadrant of the contralateral visual field (upper contralateral quadrantanopia), reflecting the persistent “retinotopic” organization of the entire retino-­ geniculo-­calcarine pathway that is depicted in this illustration. This visual deficit is sometimes referred to as a “pie in the sky” deficit.   

Sensory Systems

Parietal lobe

399

Spatial visual pathway: positional relationships among objects in visual scene, analysis of motion

Frontal lobe Middle temporal area: direction selective and motion responsive

Occipital lobe MT V3 V2 V4

V3

V1

V2

V4: shape and color perception Temporal lobe

Object recognition pathway: high resolution and form

 

14.37 VISUAL PATHWAYS IN THE PARIETAL AND TEMPORAL LOBES Neurons in the primary visual cortex (V1, area 17) send axons to association visual cortices (V2 and V3, areas 18 and 19). V2 and V3 also receive input from the superior colliculus via the pulvinar. V1, V2, and V3 project to the middle temporal (MT) area and V4. Middle temporal neurons are direction selective and motion responsive and further project into the parietal lobe for spatial visual processing. The parietal neurons provide analysis of motion and positional relationships among objects in the visual field. V4 neurons are involved in shape and color perception. Neurons in V4 project into the temporal lobe, in which further neuronal processing provides high-­resolution object recognition, including faces, animate and inanimate objects, and the classification and orientation of objects. Small infarcts in the temporal lobe may produce specific agnosias, or the inability to recognize specific types of objects, such as faces or animate objects.

CLINICAL POINT The retino-­geniculo-­calcarine pathway projects to area 17, the primary visual cortex; subsequent axonal projections are sent to areas 18 and 19. In these visual association cortices, feature extraction from simple to complex to hypercomplex cells occurs, giving form to new visual information. A parietal cortical pathway further processes information related to the direction and motion of objects—a spatial visual pathway. A temporal cortical pathway conveys further information about the shape, color, and form of objects. Some discrete lesions in these parietal and temporal cortical pathways can produce distinctive visual deficits. Visual agnosias occur when an individual cannot recognize objects that are viewed but has full visual acuity. This can happen with lesions in the occipito-­temporal visual pathway. Visual agnosias are particularly common with lesions in the dominant mesial portion of the occipital cortex; they accompany a right homonymous hemianopia. Cortical color agnosias (cortical color blindness) also can occur with lesions in the occipito-­temporal visual pathway, through V4. Some specific lesions of the occipito-­temporal pathway, especially when bilateral, can result in prosopagnosia, or the inability to recognize faces. Some lacunar infarcts in this pathway also may result in the inability to distinguish between animate and inanimate objects. Lesions in the occipito-­parietal visual pathway, particularly in the nondominant hemisphere, can cause visual-­spatial disorientation, appearing clinically as impaired ability to see.   

400

Systemic Neuroscience

Visual fields Visual system lesions Ipsilateral optic nerve lesion

Overlapping visual fields

Chiasm lesion (bitemporal hemianopia)

Optic (II) nerves Optic chiasm

Meyer’s loop

Optic tracts

Optic tract lesion (left homonymous hemianopia)

Meyer’s loop

Lateral geniculate bodies

Meyer’s loop (partial) (superior quadrantanopia)

Optic radiations (partial) (inferior quadrantanopia)

Optic radiations (complete) (left homonymous hemianopia)

Localization 1. Unilateral vision loss: lesion of optic nerve 2. Congruous visual field loss of both eyes: posterior to optic chiasm 3. Incongruous visual field loss of both eyes: lesion at or near optic chiasm

14.38 VISUAL SYSTEM LESIONS Lesions of the optic nerve, optic chiasm, optic tract, Meyer’s loop in the temporal lobe, optic radiations, and visual cortex produce specific visual field deficits, as shown in this figure.

Occipital lobe lesion sparing occipital pole (macular sparing homonymous hemianopia)

 

15 

MOTOR SYSTEMS

Lower Motor Neurons

Cerebellum

15.1 Alpha and Gamma Lower Motor Neurons

15.17 Functional Subdivisions of the Cerebellum

15.2 Distribution of Lower Motor Neurons in the Spinal Cord

15.18 Cerebellar Neuronal Circuitry

15.3 Distribution of Lower Motor Neurons in the Brainstem

15.19 Circuit Diagrams of Afferent Connections in the Cerebellum



15.20 Afferent Pathways to the Cerebellum

Upper Motor Neurons

15.4 Cortical Efferent Pathways

15.21 Cerebellar Efferent Pathways

15.5 Color Imaging of Cortical Efferent Pathways

15.22 Cerebellovestibular and Vestibulocerebellar Pathways

15.6 Corticobulbar Tract 15.7 Corticospinal Tract

15.23 Schematic Diagrams of Efferent Pathways From the Cerebellum to Upper Motor Neuron Systems

15.8 Corticospinal Tract Terminations in the Spinal Cord



15.9 Rubrospinal Tract

15.24 Connections of the Basal Ganglia

15.10 Vestibulospinal Tracts

15.25 Simplified Schematic of Basal Ganglia Circuitry and Neurochemistry

15.11 Reticulospinal and Corticoreticular Pathways 15.12 Tectospinal Tract and Interstitiospinal Tract 15.13 Spinal Cord Terminations of Major Descending Upper Motor Neuron Tracts 15.14 Central Control of Eye Movements 15.15 Central Control of Respiration

Basal Ganglia

15.26 Surgical Approaches to Movement Disorders 15.27 Neurotransmitter Involvement in Parkinson’s Disease and Huntington’s Disease 15.28 Parallel Loops of Circuitry Through the Basal Ganglia 15.29 Connections of Nucleus Accumbens

15.16 Neural Circuitry of Swallowing

401

402

Systemic Neuroscience



Ia afferent synapse on -LMN LMN

-LMN

Neuromuscular junctions on extrafusal skeletal muscle fibers Trail and plate endings on contractile elements (intrafusal fibers) of muscle spindles

Skeletal muscle fibers (extrafusal)

Ia afferent nerve fibers

Nuclear bag fiber Nuclear chain fiber

Muscle spindle

LOWER MOTOR NEURONS 15.1 ALPHA AND GAMMA LOWER MOTOR NEURONS All lower motor neuron (LMN) groups except the facial nerve nucleus that supplies the muscles of facial expression consist of both alpha LMNs that supply the skeletal muscle fibers (extrafusal fibers) and gamma LMNs that supply the small contractile elements in the muscle spindles (intrafusal fibers). The muscles of facial expression do not have muscle spindles and are not supplied by gamma LMNs. The alpha LMNs regulate contraction of the skeletal muscles to produce movement. The gamma LMNs regulate the sensitivity of the muscle spindles for group Ia and group II afferent modulation of alpha LMN excitability. CLINICAL POINT An alpha LMN supplies a motor axon to a variable number of skeletal muscle fibers (extrafusal fibers), ranging from just a few (e.g., extraocular muscles) to several thousand (large muscles such as the quadriceps). The LMN and its innervated skeletal muscle fibers are called a motor unit. Supporting cells (such as Schwann cells) and myocytes produce trophic factors to maintain the nerve-­muscle association; when nerve injury occurs, growth factors help to attract motor axonal regrowth to reestablish the prior nerve-­muscle association. When motor axons degenerate, the neuromuscular junctions (NMJs) disappear, and the nicotinic cholinergic receptors spread

across the membrane of the denervated skeletal muscle fibers. This results in denervation hypersensitivity to nicotinic cholinergic stimulation, noted as random individual muscle fiber twitches (fibrillation), best observed by electromyography. If motor nerves are attracted back to the muscle fibers and NMJs are restored, the nicotinic cholinergic receptors are again restricted to the secondary folds of the NMJ. If the motor axon that was lost cannot regrow, neighboring motor axons of other motor units that supply adjacent skeletal muscle fibers may send sprouts to the denervated muscle fibers and incorporate them into the motor unit; the consequence is a larger motor unit and a greater demand on the LMN cell body that now supplies a greater than normal number of skeletal muscle fibers. This mechanism may account for recovery of physiological function in some LMN diseases such as polio. If the alpha-­LMN cell body itself is damaged or is in the process of dying (e.g., in amyotrophic lateral sclerosis), the axon may produce aberrant action potentials (agonal bursts of electrical activity) that result in muscle fiber contraction throughout the motor unit, called a fasciculation, which is visually observable. A denervated muscle fiber must be reinnervated within 1 year or so if it is to restore relatively normal function; a longer period leads to permanent changes that preclude proper reinnervation. Many experimental approaches are seeking to restore innervation or attract a more robust nerve supply to denervated muscle fibers by applying or inducing gene expression of growth factors and trophic factors. Denervated skeletal muscle fibers are flaccidly paralyzed, lack muscle tone, cannot be induced to contract with muscle stretch reflexes, and undergo atrophy; these are classic characteristics of LMN syndrome.   

Motor Systems

403

A. Cytoarchitecture of the spinal cord gray matter Nuclear cell columns

Laminae of Rexed

Nucleus posterior marginalis (marginal zone) Substantia gelatinosa (lamina II) Nucleus proprius of posterior horn Nucleus dorsalis; Clarke‘s column (T1– L3) Lateral basal nucleus

II

Spinal reticular zone

III

Intermediolateral cell column; sympathetic preganglionic neurons (T1–L2)

IV V

Intermediomedial cell column; parasympathetic preganglionic neurons (S2–4)

VI X VII IX

VIII Motor neurons to limb muscles (cervical and lumbar enlargements of cord)

I

Flexors

IX

Extensors

IX

Distal part of limb Proximal part of limb

Motor neurons to trunk and neck muscles (C1–3 and T2–12)

B. Representation of motor neurons

Flexors In cervical enlargement of spinal cord

Extensors

Flexors In lumbar enlargement of spinal cord

Extensors

 

15.2 DISTRIBUTION OF LOWER MOTOR NEURONS IN THE SPINAL CORD LMNs are found as clusters of neurons in the anterior (ventral) horn of the spinal cord, represented as lamina IX of Rexed. Distinct clusters of LMNs supply distinct skeletal muscles with motor innervation. These LMN groups are organized

topographically; LMNs distributing to trunk and neck muscles are found medially, and LMNs distributing to muscles of distal extremities are found laterally. Within spinal cord segments, LMNs distributing to flexor muscle groups are found dorsally, and LMNs distributing to extensor muscle groups are found ventrally.

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Systemic Neuroscience

Oculomotor (III) nerve

Red nucleus

Oculomotor nucleus Trochlear nucleus Trochlear (IV) nerve Trigeminal (V) nerve and ganglion

Trigeminal (V) nerve and ganglion Motor nucleus of trigeminal nerve Abducens nucleus

Facial (VII) nerve

Facial (VII) nerve Facial nucleus Nucleus ambiguus

Glossopharyngeal (IX) nerve

Glossopharyngeal (IX) nerve

Vagus (X) nerve

Vagus (X) nerve

Accessory (XI) nerve Hypoglossal (XII) nucleus

Spinal nucleus of accessory nerve Spinal cord ventral horn (at all spinal levels)

 

15.3 DISTRIBUTION OF LOWER MOTOR NEURONS IN THE BRAINSTEM LMNs are found in medial and lateral columns in a longitudinal view of the brainstem. The medial column (LMNs of the oculomotor nucleus, trochlear nucleus, abducens nucleus, and hypoglossal nucleus) derives from the general somatic efferent system,

and the lateral column (LMNs of motor nucleus V, facial nucleus, nucleus ambiguus, and spinal accessory nucleus) derives from the special visceral efferent system. LMNs in the spinal cord are found in a longitudinal column coursing through the anterior horn at all levels.

Motor Systems Cerebral Cortex: Efferent Pathways 8

6

405

4 31 2

19

From frontal cortex to thalamus, basal ganglia, pontine nuclei, and reticular formation

18

41 42

17

Corticobulbar, corticorubral, corticonuclear, and corticospinal pathways

From parietal cortex to thalamus, pontine nuclei and reticular formation Thalamus

Caudate nucleus

Posterior limb of internal capsule

Anterior limb of internal capsule From occipital eye fields to superior colliculus

Globus pallidus

Lentiform nucleus

From auditory cortex to inferior colliculus

Putamen

Superior colliculi

From frontal eye fields to interstitial nucleus of Cajal

Interstitial nucleus of Cajal Inferior colliculus

Cerebral peduncle Red nucleus

Trigeminal sensory nucleus Corticospinal axons

Trigeminal motor nucleus

Corticonuclear axons

Reticular formation

Pons

Pontine nuclei

For pontocerebellar connections

Solitary tract nucleus

Facial nerve nucleus of opposite side for lower face

Nucleus ambiguus Dorsal motor nucleus of vagus and glossopharyngeal nerves Hypoglossal nucleus

Middle part of medulla oblongata

Reticular formation

Pyramids

Cuneate nucleus Gracile nucleus

Lower part of medulla oblongata

Reticular formation

Decussation of pyramids

Lateral (crossed) corticospinal tract

Anterior (direct) corticospinal tract Spinal cord

Posterior (dorsal) horn Anterior white commissure AWC

Anterior (ventral) horns

 

UPPER MOTOR NEURONS 15.4 CORTICAL EFFERENT PATHWAYS Cortical neurons in the motor cortex (area 4) and the supplemental and premotor cortices (area 6) send axons to the basal ganglia (caudate nucleus and putamen), the thalamus (ventral anterior [VA] and ventral lateral [VL] nuclei), the red nucleus, the pontine nuclei, the cranial nerve (CN) motor nuclei on both sides, and the spinal cord ventral horn, mainly on the contralateral side. These axons form the corticospinal tract, corticobulbar tract, corticostriatal projections, corticopontine projections, corticothalamic projections, and cortical connections to the upper motor neurons (UMNs) of the brainstem (reticular formation

[RF] motor areas, red nucleus, superior colliculus). Neurons of the sensory cortex (areas 3, 1, 2) send axons mainly to secondary sensory nuclei (corticonuclear fibers) to regulate incoming lemniscal sensory projections destined for conscious interpretation. Neurons in the frontal eye fields (area 8) project to the superior colliculus, the horizontal and vertical gaze centers of the brainstem, and the interstitial nucleus of Cajal to coordinate voluntary eye movements and associated head movements. Other regions of sensory cortex project axons to thalamic and brainstem structures that regulate incoming lemniscal sensory information. Some cortical efferent fibers project to limbic forebrain regions, such as the amygdaloid nuclei, hippocampal formation, and septal nuclei.

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Systemic Neuroscience

Lateral/oblique view

Cortical efferent fibers

Cortical efferent fibers

Midline fibers, corpus callosum

Superior cerebellar peduncle

Pyramids

 

15.5 COLOR IMAGING OF CORTICAL EFFERENT PATHWAYS This diffusion tensor image shows the cortical efferent pathways in a lateral oblique section. These pathways, shown in blue, channel from widespread areas of the cerebral cortex to structures

in the forebrain, the thalamus, the brainstem, the cerebellum (indirectly, through the pontine nuclei), and the spinal cord. Additional cortical association pathways are depicted in green (running in anterior-­posterior direction) and commissural pathways are shown in red (running in left-­right direction).

Motor Systems

Area 6

407

Area 4

Hip Trunk

Arm Hand e Fac

Primary motor cortex (Area 4) Neck Brow Eyelid

Lateral aspect of cerebral cortex to show topographic projection of motor centers on precentral gyrus and premotor and supplemental motor cortex

Nares Lips Tongue

Posterior limb

Larynx

Internal capsule Anterior limb

III III

IV

Midbrain

III (ipsilateral and contralateral) IV (ipsilateral and contralateral)

IV

VI

Pons

VI

V

VI

V

VII upper VII lower

VI (ipsilateral and contralateral) V

Upper

VII to upper face (ipsilateral and contralateral)

Lower

VII to lower face (contralateral only) VII

Medulla

XII

V (ipsilateral and contralateral)

Nucleus ambiguus (IX, X, XI)

VII

XII XII

IX, X, XI

XII (ipsilateral and contralateral)

IX, X, XI

IX, X, and XI (ipsilateral and contralateral)

 

15.6 CORTICOBULBAR TRACT The corticobulbar tract (CBT) arises mainly from the lateral portion of the primary motor cortex (area 4). CBT axons project through the genu of the internal capsule into the cerebral peduncle, the basis pontis, and the medullary pyramids on the ipsilateral side. The axons distribute to CN motor nuclei on the ipsilateral and contralateral sides except for the portion of the facial nerve nucleus (CN VII) that supplies the muscles of facial expression

for the lower face, which receives exclusively contralateral projections. The CBT projections to the hypoglossal nucleus are mainly contralateral; CBT projections to the spinal accessory nucleus are mainly ipsilateral. CBT lesions result mainly in contralateral drooping of the lower face that is paretic to attempted movements from voluntary commands (central facial palsy), in contrast to Bell’s palsy (CN VII palsy), in which the entire ipsilateral face is paralyzed.

408

Systemic Neuroscience

Knee

Primary motor cortex (Area 4)

Ankle

Area 4

Hip Trunk

Trun

Hip

k Sh ou lde r Elb ow

Area 6

Arm

t

W

ris

Hand

ers

g Fin

e

Fac

mb

Thu Toes

Lateral aspect of cerebral cortex showing topographic localization of motor centers on precentral gyrus and premotor and supplemental motor cortex

Posterior limb

Internal capsule

Posterior

Anterior limb

Visual and auditory Temporopontine Horizontal section through internal capsule showing location of principal pathways

Midbrain

Sensory Corticospinal Corticobulbar Frontopontine Frontothalamic

Pons Anterior

Ventral aspect of brainstem showing decussation of pyramids

Medulla

Decussation of pyramids (approximately 80% of CST fibers)

Spinal cord

Lateral (crossed) corticospinal tract Anterior (direct) corticospinal tract

 

15.7 CORTICOSPINAL TRACT

See next page. 

Decussation

Motor Systems

15.7 CORTICOSPINAL TRACT (CONTINUED) The motor portion of the corticospinal tract (CST) originates from neurons of many sizes, mainly from the primary motor cortex (area 4) and the supplemental and premotor cortices (area 6). The primary sensory cortex (areas 3, 1, 2) contributes axons into the CST, but these axons terminate mainly in secondary sensory nuclei to regulate the processing of incoming lemniscal sensory information. The CST travels through the posterior limb of the internal capsule, the middle region of the cerebral peduncle, numerous fascicles of axons in the basis pontis, and the medullary pyramid on the ipsilateral side. Most of the CST axons (approximately 80% but variable from individual to individual) cross the midline in the decussation of the pyramids at the medullary–­ spinal cord junction. These crossed fibers descend in the lateral CST in the lateral funiculus of the spinal cord and synapse on alpha and gamma LMNs, both directly and indirectly through interneurons. CST axons that do not decussate continue as the anterior CST in the anterior funiculus of the spinal cord and then decussate at the appropriate level through the anterior white commissure to terminate directly and indirectly on alpha and gamma LMNs contralateral to the cortical cells of origin. Only a very small portion of the motor connections of the corticospinal tract terminate on LMNs on the ipsilateral side of the spinal cord. CLINICAL POINT The motor portion of the CST arises mainly from neurons in the primary motor cortex (area 4) and the supplemental and premotor cortices (area 6). The primary sensory cortex and superior parietal lobule contribute corticospinal axons (corticonuclear fibers) to secondary sensory nuclei in the lower brainstem and spinal cord. Approximately 80% of the CST axons cross in the decussation of the pyramids and terminate directly and indirectly with alpha and gamma LMNs that control movements of the distal extremities, especially the hands and fingers. At least 10% of the CST terminates monosynaptically on alpha LMNs, especially those associated with hand and finger musculature. A lesion in the internal capsule damages the CST, corticorubral fibers, and corticoreticular fibers, resulting in contralateral hemiplegia. Initially, the hemiplegia is flaccid, with loss of tone and reflexes. Within days to a week or so, the hemiplegia becomes spastic, with hyperreflexia and hypertonus. The affected musculature shows initial resistance to attempted passive movement, followed by a dissipation or “melting” of tone (the clasp-­knife reflex), perhaps because of high threshold Ib Golgi tendon organ inhibitory influences on the

409

homonymous LMNs. The initial suspected mechanism of classical UMN syndrome was disinhibition of dynamic gamma LMNs, which drives initial resistance to passive stretch, mediated via subsequent Ia afferent influences over alpha LMNs; this mechanism was reinforced by observations that dorsal root sectioning diminished spasticity in UMN syndromes. Further studies have revealed additional potential mechanisms, including diminished reciprocal inhibition, recurrent Renshaw inhibition, and presynaptic inhibition on Ia afferents, all suggestive of major changes in interneurons of the spinal cord following a classic UMN lesion. In UMN syndrome, the plantar reflexes are extensor (reverting to a developmentally early stage in the absence of the CST), and abdominal reflexes are absent on the affected side. Clonus (repetitive alternating flexor and extensor muscle stretch reflexes) also may occur and is possibly attributable to interneuronal changes such as diminished Renshaw inhibition.   

CLINICAL POINT The CBT arises mainly from the lateral portion of the primary motor cortex; it descends through the genu of the internal capsule and the cerebral peduncle (medial to the corticospinal tract fibers) ipsilaterally, and it distributes bilaterally to the motor CN nuclei (CNN) of the brainstem, except to the facial nucleus for the lower face, which receives almost exclusively contralateral projections. The cortico-­ bulbar axons terminate mainly on interneurons that regulate LMN output. Originally, corticobulbar was a term reserved for cortical projections to LMNs of the medulla (bulb), but it now has been expanded to include CNN for V, VII, nucleus ambiguus, XII, and the spinal accessory (XI) nucleus. A lesion in the genu of the internal capsule (embolic or thrombotic stroke or hemorrhage of the middle cerebral artery or its branches) or the cerebral peduncle (Weber’s syndrome, compression of the peduncle against the free edge of the tentorium cerebelli with transtentorial herniation) results mainly in a drooping lower face (central facial palsy) on the contralateral side. The intact hemisphere can control voluntary movement of the LMNs in the CNN for all other brainstem motor nuclei on both sides. In some individuals, a predominance of contralateral fibers to LMNs for the soft palate or the tongue is noted, resulting in a temporary contralateral palsy, or a predominance of ipsilateral fibers to LMNs of XI may be noted, resulting in an ipsilateral palsy of the sternocleidomastoid and upper trapezius muscles. This central paresis occurs without atrophy. Bilateral corticobulbar lesions result in profound paralysis of voluntary movement in all muscles supplied by CNN, with preservation of muscle bulk, reflex responses, and some emotional responses using those LMNs. The LMNs in CNN III, IV, and VI receive cortical input from the frontal eye fields (area 8) and parietal eye fields of both sides.   

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Systemic Neuroscience

Lateral corticospinal tract

Minor component of anterior corticospinal tract (ipsilateral)

Lateral muscles

Medial muscles

Anterior white commissure

Anterior corticospinal tract

 

15.8 CORTICOSPINAL TRACT TERMINATIONS IN THE SPINAL CORD Crossed axons in the lateral CST, intermixed with axons of the rubrospinal tract, travel in the lateral funiculus. These CST axons terminate directly and indirectly mainly on LMNs associated with distal musculature, especially for skilled hand and finger movements. The uncrossed anterior CST axons decussate predominantly in the anterior white commissure and terminate directly and indirectly mainly on LMNs that supply medial musculature. A small number of anterior CST axons terminate ipsilateral to the cortical cells of origin. An isolated lesion in the CST in the medullary pyramids results in weakness of contralateral fine, dexterous hand and finger movements. All other lesions involving the CST at other levels (internal capsule, cerebral peduncle, pons), where these descending fibers are intermixed with other descending motor systems, produce contralateral spastic hemiplegia with hypertonus, hyperreflexia, and plantar extensor responses as long-­term consequences. Lesions in the lateral CST produce similar symptoms ipsilateral to the damaged lateral funiculus below the level of the lesion.

CLINICAL POINT Cerebral palsy is a general term referring to a group of motor impairment syndromes from congenital or developmental lesions. Approximately two-­thirds of these lesions occur prenatally, and 10% occur perinatally. Some cases appear as delays in developmental milestones. The motor deficits may include monoplegia, diplegia, hemiplegia, or quadriplegia. The most common appearance (75%) is lower extremity diplegia with scissoring gait (adductor spasms), sometimes accompanied by hip, knee, or elbow flexion. Hemiplegic cerebral palsy mainly affects the upper extremity, accompanied by a persistent grasp reflex. Motor characteristics often are spastic but may be hypotonic or atonic, or dyskinetic. Quadriplegic cerebral palsy is often accompanied by cortical defects, mental impairment, seizures, visual defects, and oculomotor defects.   

Motor Systems

411

Primary motor cortex (area 4) Small pyramidal cells Giant pyramidal cells

Fibers from globose and emboliform nuclei some from dentate deep nuclei via superior cerebellar peduncle

Red nuclei Ventral tegmental decussation Crossed rubrospinal and rubromedullary fibers

Helps to hold flexor actions of RST on upper extremities in check Helps to drive flexor actions of RST for lower extremities Midbrain To pyramid

Facial nerve nucleus

Lateral reticular nucleus

Uncrossed rubromedullary (rubrobulbar) fibers Medulla oblongata Medullary reticular formation

Rubrospinal tract

Inferior olivary nucleus

Inhibitory interneuron

Cervical part of spinal cord

Excitatory interneuron

Lateral (crossed) corticospinal tract Rubrospinal tract Posterior (dorsal) horn interneurons controlling afferent input to spinal cord

To extensor muscles

Lumbar part of spinal cord To flexor muscles

Inhibitory interneuron Excitatory interneuron

  15.9 RUBROSPINAL TRACT The cortico-­rubro-­spinal system is an indirect corticospinal system that regulates spinal cord LMNs. The red nucleus in the midbrain receives topographically organized ipsilateral connections from the primary motor cortex (area 4). Axons of the rubrospinal tract (RST) decussate in the ventral tegmental decussation and descend in the lateral brainstem and the lateral funiculus of the spinal cord, where they are intermixed extensively with axons of the lateral CST. The RST terminates directly and indirectly on alpha and gamma LMNs in the spinal cord, particularly those associated with flexor movements of the extremities. The RST

helps to drive flexor movements of the upper extremity and helps to hold in check flexor movements of the lower extremity. RST lesions usually occur in conjunction with the CST in the spinal cord; corticorubral lesions also occur in conjunction with the CST in the internal capsule and cerebral peduncle. These lesions result in contralateral spastic hemiplegia as long-­term consequences. Brainstem lesions caudal to the red nucleus result in decerebration (extensor spasticity), reflecting the removal of the flexor drive of the rubrospinal tract to LMNs supplying the upper limbs. See page 433 for a Clinical Point.

412

Systemic Neuroscience Superior Medial Vestibular nuclei Lateral Upper limb Inferior

Excitatory endings Inhibitory endings

Rostral Trunk Dorsal

Ventral To cerebellum

Lower limb Caudal

Motor neuron (controlling neck muscles) Medial vestibulospinal fibers in medial longitudinal fasciculi Excitatory endings to LMNs supplying back muscles Cervical part of the spinal cord Lower part of cervical spinal cord

Lumbar part of spinal cord

Vestibular ganglion and nerve

Somatotopical pattern in lateral vestibular nucleus

Lateral vestibulospinal tract Inhibitory interneuron Excitatory interneuron To flexor muscles To extensor muscles Inhibitory ending To axial muscles Excitatory ending Lateral vestibulospinal tract

Fibers from cristae (rotational stimuli)

Inhibitory interneuron Excitatory synapse To flexor muscles To extensor muscles

Fibers from maculae (gravitational stimuli)

  15.10 VESTIBULOSPINAL TRACTS The lateral vestibulospinal tract arises from the lateral vestibular nucleus and terminates directly and mainly indirectly on ipsilateral alpha and gamma LMNs associated with extensor musculature, especially proximal musculature. If this powerful antigravity extensor system were not kept in check by descending connections from the red nucleus and by connections from the cerebellum, it would produce a constant state of extensor hypertonus. Removal of these influences can occur with lesions caudal to the red nucleus, producing decerebration with powerful extensor posturing. The medial vestibulospinal tract arises from the medial vestibular nucleus and provides inhibition of alpha and gamma ­LMNs controlling neck and axial musculature. The medial vestibulospinal tract terminates mainly on interneurons in the cervical spinal cord ventral horn. These two vestibulospinal tracts stabilize and coordinate the position of the head, neck, and body and provide important reflex and brainstem control over tone and posture. The vestibulospinal tracts work with the reticulospinal tract to control tone and posture.

CLINICAL POINT Primary vestibular input from both the maculae of the utricle and the cristae of the ampullae of the semicircular canals terminates in the vestibular nuclei of the medulla and pons, including the cells of origin of the vestibular UMN tracts, the lateral and medial vestibular nuclei. This allows influences from the direction of the gravitational field (linear acceleration) and head movement (angular acceleration) to affect the firing of neurons in the vestibular nuclei. The lateral vestibular nuclei give rise to a powerful vestibulospinal antigravity system that terminates mainly indirectly on alpha and gamma ­LMNs in the medial part of the ventral horn, which is associated with proximal extensor musculature. This system, if left unchecked and uninhibited, would drive the neck and body into marked extensor posturing, called decerebration (or decerebrate rigidity). The lateral vestibulospinal system is inhibited mainly by the red nucleus and the anterior cerebellum. In decerebrate posturing, sectioning of the dorsal roots (dorsal rhizotomy) abolishes the extraordinary “rigidity” (it is actually spasticity, not true rigidity), suggesting that decerebration results from the unregulated activity of the reticulospinal and lateral vestibulospinal tract driving the gamma LMNs. This is consistent with the earlier hypothesis of the mechanism of spasticity, although additional spinal interneuronal inhibition is also most likely involved in decerebrate posturing. The medial vestibulospinal tract exerts inhibitory influences on LMNs that innervate neck muscles, permitting unconscious adjustments to move the head in response to vestibular stimuli. Thus, the vestibulospinal tracts help to promote body and head movements to maintain appropriate posture with vestibular activation, particularly during movement; these systems also coordinate with projections via the medial longitudinal fasciculus that synchronize eye movements.   

Motor Systems

Thickness of blue line indicates density of cortical projection Excitatory endings

Parietal

6

4

3,1,2

Frontal Orbitofrontal Occipital

Inhibitory endings

Medial pontine reticular formation Pons Receives input from multiple sensory systems via lateral reticular formation

413

Temporal

Trigeminal motor nucleus

Receive excitatory inputs from pontine, inhibitory fibers from medullary reticular formation

Medial medullary reticular formation Medulla oblongata Facial nerve nucleus Lateral reticulospinal tract (partially crossed); excites and inhibits axial (neck and back) motor neurons and modulates afferent input to spinal cord

Exerts strong drive over medullary reticulospinal tract Medial (anterior) reticulospinal tract; produces direct and indirect excitation of motor neurons Cervical part of spinal cord Posterior (dorsal) horn interneurons regulating sensory input to spinal cord

Motor neurons (alpha and gamma)

Excitatory interneuron Inhibitory interneuron Lumbar part of spinal cord

  15.11 RETICULOSPINAL AND CORTICORETICULAR PATHWAYS The pontine reticulospinal tract (RetST) arises from neurons of the medial pontine RF (nuclei pontis caudalis and oralis). Axons descend as the pontine (medial) RetST, mainly ipsilaterally, and terminate directly and indirectly on alpha and gamma LMNs at all levels. This tract has a distinct extensor bias for axial musculature and reinforces the action of the lateral vestibulospinal tract. Although some cortical axons terminate in the nuclei of origin of the pontine RetST, the cortex provides minimal influence on the activity of this tract; the pontine RetST

is driven primarily by polysensory input from trigeminal and somatosensory sources. The medullary RetST originates from the medial RF (nucleus gigantocellularis) and is heavily driven by cortical input, especially from the motor cortex and supplemental and premotor cortices. Axons of the medullary (lateral) RetST terminate bilaterally, directly and indirectly, on alpha and gamma LMNs at all levels. The medullary RetST exerts a flexor bias, reinforcing the CST and RST. The reticulospinal tracts are important regulators of basic tone and posture. They are not organized somatotopically. See page 433 for a Clinical Point.

414

Systemic Neuroscience Superior colliculus Interstitial nucleus of Cajal Dorsal tegmental decussation

Midbrain

Medial longitudinal fasciculus

Pons

Upper cervical spinal cord To neck musculature

To axial muscles of the trunk for rotational movement

Thoracic spinal cord

To axial muscles of the trunk for rotational movement

  15.12 TECTOSPINAL TRACT AND INTERSTITIOSPINAL TRACT The tectospinal tract arises from neurons in deep layers of the superior colliculus, decussates in the dorsal tegmental decussation, descends contralaterally near the midline, and terminates directly and indirectly on alpha and gamma LMNs in the cervical spinal cord associated with head and neck movements. This pathway mediates reflex and visual tracking influences for positioning the head with regard to visual input. The interstitiospinal tract arises from the interstitial nucleus of Cajal, a region of the midbrain that helps to coordinate eye movements and gaze centers. The interstitiospinal tract descends ipsilaterally in the medial longitudinal fasciculus and terminates directly and indirectly on

alpha and gamma LMNs associated with the axial musculature of the trunk that is involved in rotational movement of the body around its central axis. CLINICAL POINT The superior colliculus, neurons of origin of the tectospinal tract, is responsive to input from the retina, the visual cortex, and the frontal eye fields. Of particular note is the role of tectospinal and tectobulbar projections (especially to the reticular formation) that help to coordinate movements of both the head and the eyes. Part of the tectospinal pathway may receive indirect input from the inferior colliculus and help to mediate head movements in response to loud or conspicuous sounds.   

Motor Systems

A. Corticospinal tracts

Right side of cord

VII IX

X

II

IV V VI VII

X

X IX

VIII IX

IX M

IXM

Right side of cord

I

II

II IV V

Lateral (crossed) corticospinal tract

B. Rubrospinal tracts Left side of cord

I

415

Anterior (direct) corticospinal tract

IV V VII VIII IXM

IX

Left side of cord

I

VIII

IX

IX

Right rubrospinal tract Fibers from left motor cortex

Fibers from left red nucleus

Fibers from left sensory cortex

C. Reticulospinal tracts

I

Lateral reticulospinal tract

D. Vestibulospinal tracts

I II

II IV V VI

VII

VII

IV V VI

IX

IX M

X

IX

VIII

IX

II

IXM

IX

Medial reticulospinal tract

Medial vestibulospinal fibers

I

IV V VII VII

IX VIII IX IX M

Lateral vestibulospinal tract

Fibers from left pontine reticular formation

Fibers from left lateral (Deiters) nucleus

Fibers from left medullary reticular formation

Fibers from left medial and inferior nuclei (only to cervical and thoracic levels)

 

15.13 SPINAL CORD TERMINATIONS OF MAJOR DESCENDING UPPER MOTOR NEURON TRACTS The lateral corticospinal tract and the rubrospinal tract terminations are directed mainly toward LMNs associated with distal

limb musculature. The anterior CST, the reticulospinal tracts, and the vestibulospinal tracts are directed mainly toward LMNs associated with more proximal and axial musculature.

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Systemic Neuroscience

Excitatory endings Inhibitory endings

Frontal eye fields (Brodmann’s area 8) Occipital eye fields (Brodmann’s areas 17, 18, 19)

Interstitial nucleus of Cajal

Superior colliculus Oculomotor nucleus Abducens internuclear neuron projection

Medial longitudinal fasciculus

Superior oblique muscle

Oculomotor (III) nerve

Superior rectus muscle

Trochlear (IV) nerve Medial rectus muscle Trochlear nucleus

Lateral rectus muscle

Corticoreticular fibers

Medial longitudinal fasciculi Medial longitudinal fasciculi Abducens nucleus

Ascending tract of Dieters Superior Medial Lateral Inferior

Vestibular nuclei

Inferior oblique muscle

Inferior rectus muscle

Vestibular nerve Abducens (VI) nerve Parapontine reticular formation (lateral gaze center)

  15.14 CENTRAL CONTROL OF EYE MOVEMENTS Central control of eye movements is achieved through the coordination of extraocular motor nuclei for CNs III (oculomotor), IV (trochlear), and VI (abducens). This is achieved by the parapontine reticular formation (horizontal gaze center); it receives input from the vestibular nuclei, the deep layers of the superior colliculus (input from V1, V2, and V3), the cerebral cortex (frontal eye fields), and the interstitial nucleus of Cajal (which receives input from the vestibular nuclei and the frontal eye fields). The

parapontine reticular formation supplies the ipsilateral VI nucleus for movement of the lateral rectus muscle and the contralateral III nucleus (via interneurons in VI nucleus) for movement of the medial rectus muscle, thus coordinating horizontal eye movements. The interstitial nucleus of Cajal helps to coordinate vertical and oblique eye movements. Secondary sensory vestibular projections also terminate in the extraocular motor CNN. Axons interconnecting the extraocular motor CNN travel through the medial longitudinal fasciculus. See page 433 for a Clinical Point.

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Motor Systems Descending control from higher centers Superior cerebellar peduncle

Cerebral cortex

Amygdala

Medial parabrachial nucleus

Regulates pacemaker function

Pacemaker Ventral Dorsal respiratory respiratory nucleus nucleus

Dorsal motor nucleus of CN X Pons

Dorsal respiratory nucleus (ventrolateral nucleus solitarius)

Nucleus of CN XII

Mutual inhibition

CN X

Central chemoreceptor zone

Dorsal respiratory nucleus (ventrolateral nucleus solitarius)

Central chemoreceptor zone (Pco2) near foramen of Luschka Nucleus ambiguus

Ventral respiratory nucleus Aortic body

CN IX

Ventral respiratory nucleus (retroambiguus nucleus) Carotid body Lower motor neurons of phrenic nucleus

Polysynaptic connections

To lower motor neurons for expiratory muscles To lower motor neurons for inspiratory muscles

Spinal cord (C3, C4, C5) Lower motor neurons for intercostal and accessory muscles of respiration

Spinal cord (T6–12)

15.15 CENTRAL CONTROL OF RESPIRATION Inspiration and expiration are regulated by nuclei of the RF. The dorsal respiratory nucleus (lateral nucleus solitarius) sends crossed axons to terminate on cervical spinal cord LMNs of the phrenic nucleus and on thoracic spinal cord LMNs that supply intercostal muscles and accessory musculature associated with inspiration. The ventral respiratory nucleus (nucleus retroambiguus) sends crossed axons to terminate on thoracic spinal cord LMNs that supply accessory musculature associated with expiration. The dorsal respiratory nucleus receives input from the carotid body (via CN IX), from the aortic body chemosensors (via CN X), and from central chemoreceptive zones of the lateral medulla. The dorsal respiratory nucleus and ventral respiratory nucleus mutually inhibit each other. The medial parabrachial nucleus acts as a respiratory pacemaker to regulate the dorsal respiratory nucleus and the ventral respiratory nucleus. The medial parabrachial nucleus receives input from higher centers, such as the amygdala and the cerebral cortex.

 

CLINICAL POINT The dorsal respiratory nucleus (lateral nucleus solitarius) sends axonal projections to the contralateral cervical LMNs of the phrenic nucleus and thoracic LMNs of accessory respiratory muscles, regulating inspiration. The ventral respiratory nucleus (nucleus retroambiguus) sends axonal projections to contralateral thoracic LMNs that supply accessory musculature associated with expiration. The medial parabrachial nucleus functions as a pacemaker and receives input from higher levels of the central nervous system. Progressive damage to the forebrain and brainstem elicits relatively predictable changes in respiration. Progressive damage through the telencephalon and diencephalon elicits Cheyne-­Stokes respiration (crescendo-­decrescendo breathing; periods of hyperpnea alternating with brief periods of apnea). The hyperpnea phase is provoked by Pco2 from the apneic phase and results in the lowering of Pco2, again provoking apnea. If damage extends through the mesencephalon and upper pons, respiration becomes shallow, with hyperventilation, but the patient still is relatively hypoxic. If damage extends through the lower pons, respiration involves long inspiratory pauses prior to expiration, called apneustic breathing. Damage extending further into the medulla produces ataxic breathing with irregular patterns, including inspiratory gasps and periods of apnea. This pattern of breathing foreshadows total respiratory failure and death as the basic brainstem centers fail.   

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Systemic Neuroscience

Peripheral Mechanisms V to tensor veli palatini muscle X (XI) to levator veli palatini muscle

Pharyngeal plexus V from from soft palate V from tongue (lingual nerve) V to myohyoid & ant. belly of digastric IX from soft palate, fauces, pharynx IX to stylopharyngeus pharynx, larynx, upper esophagus X from from lower esophagus & GI tract

Mylohyoid nerve

to muscles of pharynx, larynx, upper esophagus to muscles of lower esophagus & GI tract XII to muscles of tongue & geniohyoid

X

Ansa hypoglossi to infrahyoid muscles Sympathetic efferents

Recurrent laryngeal nerve

Afferents Sympathetic efferents Afferents

Soft palate (slight) Pharyngeal wall Anterior pillar Tonsil Posterior pillar Posterior part of tongue

Sympathetic efferents Thoracic greater splanchnic nerve Afferents

Areas from which deglutition reflex may be excited (stippled) Celiac ganglion  

15.16 NEURAL CIRCUITRY OF SWALLOWING Consumption of food and water requires the complex process of swallowing, which involves the coordinated activity of CNs V, VII, IX, X, and XII. Swallowing involves motor and sensory activities of the oral cavity, pharynx, larynx, and esophagus. Protection of the airway from aspiration is a vital component of this process. Initial processing in the oral cavity requires chewing and mandible movement (CN V), closure of the oral cavity (CN VII), tongue movement (CN XII), soft palate movement (CN IX), and salivation (CNs VII and IX). Taste is perceived by CNs VII

 

(anterior two-­thirds of the tongue) and IX (posterior one-­third of the tongue), coordinated with CN I (olfaction) for perception of the food. Propulsion of the food into the oropharynx requires timing and movement, as well as prevention of nasal regurgitation, from coordinated activities of CNs V, VII, IX, and X. A swallowing reflex allows the food to move into the pharynx. Food passes through the pharynx into the esophagus through coordinated action of CNs X (pharyngeal contraction) and XII (tongue movement) at the same time that the larynx is closed off by laryngeal muscles (CN X). If this protective process is not fully functional, a cough or choking reaction occurs (afferent

Motor Systems

419

Central Mechanisms Thalamus

Hypothalamus

V Principal sensory nucleus of V IX

X

Motor nucleus of V

VII

Deglutition center Nucleus of XII Dorsal nucleus of X (motor and sensory) Nucleus of solitary tract Nucleus ambiguus

XI XII Stellate ganglion T4

Thoracic sympathetic Dorsal root ganglionic chain ganglion T5 Key Sympathetic efferents Parasympathetic efferents Somatic efferents Afferents (and CNS connections) Indefinite paths

T6 T7 T8 aa

component of CNs IX and X). CNs IX and X are the sensory components of swallowing, projecting to a medullary swallowing center in nucleus solitarius. Nucleus solitarius then connects with nucleus ambiguous to initiate the major motor activation needed for swallowing. As the food passes by the closed pharynx, the cricopharyngeal muscle (CN X) controls passage through the cricopharyngeal sphincter at the proximal end of the esophagus, into the esophagus. The dorsal motor (visceral) nucleus of the vagus innervates the involuntary muscles of the esophagus and more distal portions of the gastrointestinal tract through part of the colon.

CLINICAL POINT A swallowing disorder, dysphagia, may occur with a wide range of clinical disorders. Peripheral (cranial) nerve damage may occur with Guillain-­Barré syndrome, mass lesions impinging on cranial nerves of the medulla, pharyngeal or myotonic dystrophies, myasthenia gravis, or other pathological processes impinging on the many cranial nerves involved in swallowing. Central lesions also may be accompanied by dysphagia, including forebrain or brainstem infarcts, movement disorders (Parkinson’s disease), demyelinating disorders (multiple sclerosis), motor neuron disorders (amyotrophic lateral sclerosis, motor involvement in syringobulbia), or tumors.   

420

Systemic Neuroscience

Lingula

Vermis

Paravermis Lateral hemisphere

Anterior lobe

Primary fissure “Unfolded” schematic of cerebellum demonstrating body map areas

Posterior lobe

Flocculonodular lobe

Flocculus

Nodule

“Unfolded” schematic of cerebellum demonstrating regions and lobes

Schema of theoretical “unfolding” of cerebellar surface in derivation of above diagram

 

CEREBELLUM 15.17 FUNCTIONAL SUBDIVISIONS OF THE CEREBELLUM The cerebellum is classically subdivided into anterior, middle (posterior), and flocculonodular (FN) lobes, each associated with ipsilateral syndromes, such as stiff-­legged gait (anterior lobe) and loss of coordination with dysmetria, action tremor, hypotonus, ataxia, and decomposition of movement (middle lobe) and truncal ataxia (FN lobe). The cerebellum also is classified according to

a longitudinal scheme that is based on cerebellar cortical regions that project to deep cerebellar nuclei, which in turn project to and coordinate the activity of specific UMN cell groups. This scheme includes the vermis and FN lobe (projecting to the fastigial nucleus and the lateral vestibular nucleus), the paravermis (projecting to the globose and emboliform nuclei), and the lateral hemispheres (projecting to the dentate nucleus). Each cerebellar subdivision is interlinked with circuitry related to specific UMN systems.

Motor Systems

421

Cerebellar Cortex Excitatory endings

Golgi (inner stellate) cell (inhibitory)

Inhibitory endings

Granule cells (excitatory) Parallel fibers (axons of granule cells)

Molecular layer

Parallel fibers (cut) Purkinje cells (inhibitory)

Purkinje cell layer

Dendrites of Purkinje cell Outer stellate cell (inhibitory) Granular layer

Basket cell (inhibitory)

White matter

Purkinje cell axon Climbing fiber (excitatory) Glomeruli Mossy fibers (excitatory) Varicose axon of locus coeruleus (noradrenergic) Purkinje cell axon Climbing fiber (excitatory) To deep cerebellar nuclei

 

15.18 CEREBELLAR NEURONAL CIRCUITRY The cerebellum is organized into four parts: an outer three-layer cortex, white matter, deep cerebellar nuclei, and cerebellar peduncles that connect with the spinal cord, brainstem, and thalamus. In the cortex, the Purkinje cells (the major output neurons) have their dendritic trees in the molecular layer (arranged in parallel “plates” adjacent to each other), their cell bodies in the Purkinje cell layer, and their axons in the granular layer and deeper white matter. Inputs into the cerebellar cortex arrive as climbing fibers (from inferior olivary nuclei), mossy fibers (all other inputs except monoaminergic), or fine, highly branched, varicose arborizations (noradrenergic and other monoaminergic inputs). The mossy fibers synapse on granule cells, whose axons form an array of parallel fibers that extend through the dendritic trees of several hundred Purkinje cells. Additional interneurons modulate interconnections in the molecular layer (outer stellate cells), at the Purkinje cell body (basket cells), and at granule cell–­molecular layer associations (Golgi cells). Noradrenergic axons of locus coeruleus neurons terminate in all three layers and modulate the excitability of other cerebellar connectivities.

CLINICAL POINT The cerebellum is a target for significant adverse effects of several types of drugs, sometimes in therapeutic dose ranges and sometimes in toxic dose ranges. Many pharmacologic agents can exert both direct effects on the cerebellum and more global neurological effects, including ischemia or hypoxia. Cerebellar damage is usually manifested first as impairment of gait, followed later by limb ataxia. These cerebellar side effects often resolve after discontinuation of the medication, but some deficits may remain. Some antiseizure agents, including phenytoin, carbamazepine, and barbiturates, can lead to cerebellar symptoms; after prolonged treatment, particularly with phenytoin, some permanent deficits such as degeneration of Purkinje cells may occur. Valproate may provoke an intention tremor. Some cancer chemotherapeutic agents also can cause adverse cerebellar effects, occasionally permanently. Treatment of psychiatric disorders by multiple pharmacologic agents, particularly neuroleptics, also can produce adverse cerebellar effects. Toxic damage resulting from exposure to dangerous environmental agents also may damage the cerebellum. Exposure to organophosphate agents and organic solvents may induce cerebellar symptomatology. Exposure to heavy metals, including methylmercury, lead, and thallium, can induce gait disturbance and ataxia.   

422

Systemic Neuroscience

A. General Scheme

B. Deep Nuclei Relationship with Afferents Cerebellar cortex

Deep nuclei Purkinje cell Upper motor neurons

Granule cell

Lower motor neurons

Afferents

Deep nucleus

Skeletal muscle

Mossy fiber

C. Circuitry of Cerebellar Neurons - Mossy Fibers

Climbing fiber

D. Circuitry of Cerebellar Neurons - Climbing Fibers

Outer stellate cell

Basket cell

Purkinje cell

Purkinje cell Basket cell Granule cell

Golgi cell

Granule cell

Deep nucleus

Mossy fiber

Deep nucleus

Golgi cell

Climbing fiber

 

15.19 CIRCUIT DIAGRAMS OF AFFERENT CONNECTIONS IN THE CEREBELLUM Afferents to the cerebellum include mossy fibers, climbing fibers, and locus coeruleus noradrenergic fibers. The mossy fibers synapse in deep nuclei and on granule cells. The climbing fibers intertwine around a Purkinje cell dendritic tree. The noradrenergic locus coeruleus axons terminate on all cell types in the cerebellar

cortex. The loops and circuits in parts C and D of the figure show interneuronal modulation of afferent connections and Purkinje cell outflow. The entire circuitry of the cerebellar cortex provides fine-­tuning of the original processing in the deep cerebellar nuclei. The entire Purkinje cell output to the deep nuclei is mediated by inhibition, using gamma-­aminobutyric acid (GABA) as the neurotransmitter.

Cortical input

Superior cerebellar peduncle Middle cerebellar peduncle

Red NUC

Nucleus reticularis tegmenti pontis

To contralateral cerebellar cortex

Trig NUC

Leg

Pontine nuclei (contralateral)

Arm

Fa

ce

Spinal input

Primary fissure

Inferior olive Upper part of medulla oblongata Spinal input

To nodule and flocculus Vestibular nuclei

Vestibular nerve and ganglion

Inferior cerebellar peduncle

Lower part of medulla oblongata Cortical input

Reticulocerebellar tract Cuneocerebellar tract Gracile nucleus

Lateral reticular nucleus

Main cuneate nucleus (relay for cutaneous information)

Spinal input Cervical part of spinal cord

External cuneate nucleus (relay for proprioceptive information)

Motor interneuron Rostral spinocerebellar tract

From skin (touch and pressure)

Spinal border cells

From muscle (spindles and Golgi tendon organs)

Motor interneuron

From skin and deep tissues (pain and Golgi tendon organs)

Lumbar part of spinal cord

From skin (touch and pressure) and from muscle (spindles and Golgi tendon organs)

Clarke’s column Ventral spinocerebellar tract

Dorsal spinocerebellar tract

  15.20 AFFERENT PATHWAYS TO THE CEREBELLUM Afferents to the cerebellum terminate in both the deep nuclei and the cerebellar cortex in topographically organized zones. The body is represented in the cerebellar cortex in at least three separate regions. Afferents traveling through the inferior cerebellar peduncle include spinocerebellar pathways (dorsal and rostral spinocerebellar tracts, cuneocerebellar tract), the inferior olivary input, RF input from the lateral reticular nucleus and other regions, vestibular input from the vestibular ganglion and vestibular nuclei, and some trigeminal input. The middle cerebellar peduncle conveys mainly pontocerebellar axons carrying crossed corticopontocerebellar inputs. Afferents traveling through the superior cerebellar peduncle include the ventral spinocerebellar tract, visual and auditory tectocerebellar input, some trigeminal input, and noradrenergic locus coeruleus input. The dorsal spinocerebellar tract and cuneocerebellar tract derive mainly from muscle spindle afferent information, whereas the ventral and rostral spinocerebellar tracts derive mainly from Golgi tendon and other receptor organ afferent information.

CLINICAL POINT Several forms of progressive neuronal degeneration involve cerebellar neurons and connections, including Friedreich’s ataxia and olivopontocerebellar atrophy. Friedreich’s ataxia is an autosomal recessive disorder that begins in late childhood and progresses over several decades. The disorder commonly starts with ataxia and gait dysfunction, dysmetria and decomposition of movement, and dysarthria. Spastic motor involvement and sensory losses also may occur. Neuropathological examination reveals degeneration of primary afferents and of axons in the spinal cord white matter, especially the dorsal and lateral funiculi, including the spinocerebellar tracts. Some axonal damage also may occur in both the peripheral nervous system and the central nervous system, but the cerebellum itself is usually not a focus of direct neuronal degeneration. Olivopontocerebellar atrophy is a progressive, mainly autosomal dominant, neurodegenerative disorder that affects adults in midlife. This disorder commonly begins with gait abnormalities and progresses to full-­blown cerebellar dysfunction with limb ataxia and dysarthria. Additional symptoms, such as chorea, dystonia, and rigidity, suggest some degenerative involvement of the basal ganglia as well. Neuropathological examination usually reveals neurodegeneration of the cerebellar cortex, the inferior olivary nuclei, and the pontine nuclei. As a consequence, the inferior and middle cerebellar peduncles are diminished. Additional degenerative changes in the cerebral cortex and descending UMN pathways and in the basal ganglia also are commonly present.   

424

Systemic Neuroscience

Excitatory endings

Motor and premotor cerebral cortex

Inhibitory endings of Purkinje cells

Internal capsule

Cerebral peduncle

Ventral anterior and ventral lateral nuclei of thalamus

Decussation of superior cerebellar peduncles

Mesencephalic reticular formation Red nucleus

Descending fibers from superior cerebellar peduncles

Fastigial nucleus Hook bundle of Russell

Globose nuclei Emboliform nucleus Dentate nucleus Cerebellar cortex

Section A–B viewed from below

Section B–C viewed from above Vestibular nuclei Inferior cerebellar peduncle A Planes of section: red arrows indicate direction C of view

Inferior olive Lateral reticular nucleus Medulla oblongata Pontomedullary reticular formation

B

  15.21 CEREBELLAR EFFERENT PATHWAYS Efferents from the cerebellum derive from the deep nuclei. Projections from the fastigial nucleus exit mainly through the inferior cerebellar peduncle and terminate mainly ipsilaterally in the lateral vestibular nucleus and in other vestibular nuclei as well as in pontine and medullary reticular nuclei that give rise to the reticulospinal tracts; there, they primarily modulate the activity of the vestibulospinal and reticulospinal UMN pathways. Axons from neurons of the globose and emboliform nuclei project mainly contralaterally through the decussation of the superior cerebellar peduncle to the red nucleus, with a smaller contribution to the VL nucleus of the thalamus; primarily, they modulate activity of the RST. Axons from neurons in the dentate nucleus project mainly contralaterally through the decussation of the superior cerebellar peduncle to the VL and to a lesser extent to the VA nuclei of the thalamus; mainly, they modulate the activity of the corticospinal tract. A small projection from the dentate nucleus also distributes to the contralateral red nucleus and to brainstem reticular motor nuclei.

CLINICAL POINT Paraneoplastic syndrome is a relatively uncommon progressive ­disorder that causes damage to the cerebellum and other neural structures as a secondary effect of cancer. Sometimes the onset of cerebellar symptomatology may precede the detection of the cancer. One major hypothesis about the cause of this disorder is the presence of an ­autoimmune reaction in which antibodies generated by the immune system against some epitope associated with the cancer cross-­react with neural targets. The Purkinje cells appear to be a major target of these immunoglobulin G antibodies. The syndrome often is triggered or exacerbated by chemotherapy or radiation therapy. The entire cerebellum may be targeted, and symptoms may include gait disturbance, ataxia of the limbs with accompanying cerebellar symptoms, dysarthria, and oculomotor coordination problems. Other possible targets of paraneoplastic syndrome include the cerebral cortex and its UMN projections as well as peripheral nerves.   

Motor Systems

Cerebellovestibular pathways

425

Vestibulocerebellar pathways Fastigial nucleus

Excitatory endings Inhibitory endings

Globose nuclei

Vermis

Emboliform nucleus Dentate nucleus Hook bundle of Russell

Flocculus Mossy fibers

Superior Vestibular nuclei

Granule cell

Lateral

Purkinje cell

Medial Inferior Vestibular ganglion

Vestibular nerve

Nodule

Fibers from cristae

Fibers from maculae

 

15.22 CEREBELLOVESTIBULAR AND VESTIBULOCEREBELLAR PATHWAYS Primary sensory vestibular inputs terminate in the four vestibular nuclei and in the fastigial nucleus and the cerebellar cortex of the vermis and FN lobe. The vestibular nuclei also project to the cerebellar cortex of the vermis and FN lobe. Purkinje cells in the vermis and FN lobe, in turn, project back to the vestibular nuclei and the fastigial nucleus. The fastigial nucleus projects to the vestibular nuclei and to the pontine and medullary medial reticular formation. Thus, primary and secondary vestibular neurons project to the fastigial nucleus and cerebellar cortex, and both the cerebellar cortex and deep nuclei project back to the vestibular nuclei. This extensive reciprocal vestibulocerebellar circuitry regulates basic spatial position and body tone and posture. CLINICAL POINT Alcohol consumption may result in acute or chronic dysfunction of the cerebellum and its pathways. Acutely, alcohol intoxication can cause global cerebellar dysfunction, including staggering gait, limb ataxia, dysmetria, dysdiadochokinesia, dysarthria, and oculomotor

dysfunction. Cerebellar testing for alcohol intoxication in the field involves tandem walking, finger-­to-­nose testing, speech patterns and coordination, and gait testing. These more global effects of alcohol on the cerebellum generally subside with catabolism of the alcohol. Chronic alcoholism results in more permanent damage to the cerebellum, with a particular initial predilection for the anterior lobe of the cerebellum and the vermis (paleocerebellum). The patient may show a staggering, broad-­based gait with a stiff-­legged movement. The mechanism of this unusual appearance of cerebellar damage (in contrast to the hypotonic, ataxic gait that occurs with global cerebellar damage, particularly in the lateral hemispheres) appears to be removal of the anterior cerebellar influence, via cerebellovestibular connections, on the lateral vestibular nucleus, disinhibiting this extensor-dominant system. This anterior cerebellar syndrome may diminish if the patient stops drinking. With further alcohol exposure, the entire cerebellum may become damaged, leading to the classic appearance of global cerebellar dysfunction, including gait disturbance, hypotonia, limb ataxia, dysarthria, and uncoordinated extraocular involvement. In addition to direct toxicity from alcohol, neural damage may occur because of vitamin deficiencies, liver dysfunction, and other metabolic aspects of alcoholism. Other parts of the brain, including the cerebral cortex, also can be significantly damaged in chronic alcoholism.   

426

Systemic Neuroscience

Cerebral cortex

Thalamus Lateral hemisphere Cerebellar cortex

Dentate nucleus

Paravermis

Globose and emboliform nuclei

Red nucleus

Pontine nucleus

Corticorubral connection Skeletal muscles

Lower motor neurons

Corticospinal connection

Cerebellar cortex Flocculus Vestibular nuclei Vermis Cerebellar cortex

Fastigial nucleus

Nodule

Reticular nuclei

To flocculonodular lobe Spinocerebellar tracts

Vestibular afferents and secondary sensory projections

Lower motor neurons

Skeletal muscles

 

15.23 SCHEMATIC DIAGRAMS OF EFFERENT PATHWAYS FROM THE CEREBELLUM TO UPPER MOTOR NEURON SYSTEMS The lateral cerebellar hemisphere connects through the dentate nucleus with nuclei VA and VL of the thalamus; the major thalamic inputs to the cells of origin of the CST in the motor cortex and with the supplemental and premotor cortices. The paravermal cerebellar cortex connects through the globose and emboliform nuclei with the red nucleus, cells of origin for the RST. The cerebellar connections to the cells of origin for the CST and RST

are mainly crossed, and these UMN systems cross again before terminating on LMNs. Thus, the cerebellum is associated with the ipsilateral LMNs through two crossings. The vermis and FN lobe connect with the fastigial nucleus and lateral vestibular nuclei. The fastigial nucleus projects mainly ipsilaterally to cells of origin of the vestibulospinal and reticulospinal tracts, exerting mainly an ipsilateral influence on spinal cord LMNs through these UMN systems. The lateral vestibular nucleus is the source of the lateral vestibular tract, which exerts a marked extensor influence on ipsilateral LMNs of the spinal cord.

Motor Systems

Frontal

Internal capsule

Ar

ea

6

427

Precentral cerebral cortex

Ar

ea

4

, 7, 2

3 Area

Head Caudate nucleus Body Tail

Postcentral cerebral cortex Claustrum

Temporal cortex

Thalamus

Putamen External segment Globus Internal segment pallidus

Ventral anterior nucleus Ventral lateral nucleus Centromedian nucleus

Fasciculus lenticularis

Subthalamus

Ansa lenticularis

Hypothalamus Substantia nigra

Pars compacta Pars reticularis

Corticorubral, corticobulbar, and corticospinal fibers Raphe nuclei from upper pons and midbrain (shown separately) Projections from cortex and basal ganglia

Projections back to cortex and basal ganglia Dopaminergic projection of substantia nigra

Lentiform nucleus

Cortical projection Corticostriatal projection

Thalamic and subthalamic projections

Striatal projection Pallidal projection

 

BASAL GANGLIA 15.24 CONNECTIONS OF THE BASAL GANGLIA The basal ganglia consist of the striatum (caudate nucleus and putamen) and the globus pallidus. The substantia nigra (SN) and the subthalamic nucleus (STN), which are reciprocally connected with the basal ganglia, are often included as part of the basal ganglia. Inputs into the basal ganglia from the cerebral cortex, the thalamus (intralaminar nuclei), the SN pars compacta (dopaminergic input), and rostral raphe nuclei (serotonergic input) are directed mainly toward the striatum. Inputs from the STN are directed mainly toward the globus pallidus. The striatum projects to the globus pallidus. The internal segment of the globus pallidus projects to the thalamus (VA, VL, and centromedian nuclei), and the external segment projects to the STN. The VA and VL thalamic nuclei provide input into the cells of origin of the corticospinal tract. Damage to basal ganglia components often results in movement disorders. Damage to the dopamine neurons in SN pars compacta results in Parkinson’s disease (characterized by resting tremor, muscular rigidity, bradykinesia, and postural instability).

CLINICAL POINT Disorders of the basal ganglia are frequently referred to as movement disorders and were previously called involuntary movement disorders. Despite the conspicuous presence of motor-­related symptoms, the basal ganglia also are involved in cognitive and affective processing, particularly in assisting the cerebral cortex to select wanted subroutines of activity and to suppress unwanted patterns. The basal ganglia assist in providing a connection between motivation and emotional context on one hand and movement on the other. Observations of discrete infarcts of parts of the basal ganglia have revealed such abnormalities as abnormal positioning of parts of the body with the presence of increased tone (dystonia) and other movements such as athetosis (slow, writhing movements) or chorea (brisk, dance-like movements). With caudate nucleus damage, more cognitive and affective symptoms may occur, such as apathy and loss of initiative, slowed thinking, and blunted emotional reactivity (abulia), possibly related to the interconnections between the caudate nucleus and the prefrontal cortex. In the classic movement disorders, as in progressive neurodegenerative diseases, there is a mixture of symptoms showing loss of action, such as bradykinesia (difficulty in initiating movements or diminished movements such as blinking), and symptoms showing an excess of action, such as rigidity, athetosis, chorea, or dystonia. As an example of excess movement, Tourette’s syndrome involves tics and involuntary vocalizations, sometimes accompanied by echolalia, grunts and vocal spasms, explosive cursing, and hyperactive behavior, often starting in childhood. Treatment strategies have included use of D2 dopamine antagonists such as haloperidol.   

428

Systemic Neuroscience

Glutamatergic GABA Acetylcholine Dopamine

Cerebral cortex Caudate nucleus Putamen

Centromedian parafascicular complex

Globus pallidus (external segment) Globus pallidus (internal segment)

This illustration schematically demonstrates the major circuitry of the basal ganglia and the principal neurotransmitters used by neurons in these pathways.

Subthalamic nucleus Substantia nigra (pars compacta) Substantia nigra (pars reticularis) Pedunculopontine nucleus Pons

A. Substantia nigra pars

B. Substantia nigra pars

C. Dopaminergic nerve terminals

D. Dopaminergic nerve

compacta dopaminergic neurons in young adulthood. GA fluorescence histochemistry.

in the caudate nucleus in young adulthood. GA fluorescence histochemistry.

compacta dopaminergic neurons in old age, demonstrating diminished numbers of neurons and the presence of yellow-staining lipofuscin (aging pigment). GA fluorescence histochemistry.

terminals in the caudate nucleus in old age, demonstrating diminished density and number of dopaminergic terminals, and the presence of yellow-staining lipofuscin pigment. GA fluorescence histochemistry.

 

15.25 SIMPLIFIED SCHEMATIC OF BASAL GANGLIA CIRCUITRY AND NEUROCHEMISTRY CLINICAL POINT In Parkinson’s disease, the pars compacta of the substantia nigra shows loss of pigmented (melanin-­containing) neurons that use dopamine as their major neurotransmitter. Both the substantia nigra and the target of the axonal projections, the caudate nucleus and putamen, are severely depleted of their dopamine content. By the time symptoms of Parkinson’s disease are clinically evident, at least 50% (and sometimes as much as 80%) of the dopamine neurons in the pars compacta of the substantia nigra have degenerated. Neurons in the substantia nigra sometimes demonstrate Lewy inclusion bodies or neurofibrillary tangles, further evidence of the degenerative process in Parkinson’s disease. The neuropathology of Parkinson’s disease sometimes also includes the degeneration of

dopamine neurons in the ventral tegmental area of the midbrain, of serotonergic neurons in the raphe nuclei, of cholinergic neurons in nucleus basalis, and of other pigmented neurons in regions such as the dorsal (motor) nucleus of CN X. Although the dopamine deficit in the substantia nigra is the most conspicuous pathological hallmark of Parkinson’s disease, these other degenerative processes may contribute to some of the symptoms. The major manifestations of Parkinson disease include both negative and positive (excessive) symptomatology, including (1) resting tremor (approximately 2 cps), which dissipates with movement (i.e., not a movement tremor); (2) muscle rigidity (lead pipe rigidity), in which limb musculature shows resistance to passive movement through all ranges of movement, both flexion and extension (NOT similar to spasticity); (3) bradykinesia (difficulty initiating movement or halting movement once it is initiated); and (4) postural instability. Also, sometimes present are head tremor (titubation), rigid facies (fixed, austere-­appearing facial expression), and depression.

Motor Systems

Stereotactic needle guide Stereotactic frame attached to patient's head creates space with X, Y, and Z coordinates. Any location within that space can be targeted by probes using these coordinates. Specific Caudate localization is selected by stereotactic targeting software nucleus using common neuroanatomic sites as reference points.

429

Thalamus Globus pallidus

Sites within globus pallidus, thalamus and STN used in control of movement disorders Stereotactic frame Thalamotomy/DBS site Ventralis intermedius nucleus (VIM) preferred site for tremor-controlling lesions

Patient usually awake Stereotactic placement of lesions or electrodes

Pallidotomy/DBS site Posteroventrolateral region (PVL) of pars interna of globus pallidus (GPi) preferred site to treat rigidity, tremor, bradykinesia, and dyskinesias. Subthalamic nucleus—DBS site Preferred site to treat Parkinson′s disease Deep brain stimulation (DBS) High-frequency stimulation (DBS) of VIM region of thalamus is Subthalamic DBS site (STN) predominant treatment of medically refractory tremor. Pallidotomy/DBS site (PVL) Globus pallidus and STN sites provide relief for Parkinson′s disease and dystonia. DBS electrodes are implanted and connected to subclavicular battery pack.

Thalamotomy/DBS site (VIM)

Care must be taken to avoid damage to optic tract and internal capsule DBS electrodes in position in VIM nucleus of each thalamus

Subclavicular battery pack

 

15.26 SURGICAL APPROACHES TO MOVEMENT DISORDERS Surgical approaches to ameliorating Parkinson’s disease and other movement disorders are based on deliberate disruption or ­ stimulation of specific anatomical components of the complex basal ganglia circuitry involved in the disorder. Initially, stereotaxic lesions were performed in the thalamus (nucleus ventralis intermedius) for tremors; in the internal segment of the globus pallidus (posterior ventrolateral portion) for rigidity, tremors, bradykinesia, and dyskinesias; and in the subthalamus for treating Parkinson’s disease. Lesion approaches have been replaced with deep brain stimulation (DBS) with implantable electrodes. Targets for DBS include the internal segment of the globus pallidus, the subthalamic nucleus, and the ventral intermedius nucleus of the thalamus. DBS appears to be more effective in patients with a good response to levodopa-­carbidopa. DBS is utilized for patients with PD who show motor fluctuations and drug-­involved dyskinesias. Symptom relief is seen contralateral to the side of DBS.

CLINICAL POINT The mainstay of pharmacological treatment of Parkinson’s disease is levodopa-­carbidopa (Sinemet). Levodopa does not readily cross the blood-­brain barrier but is assisted by blocking aromatic L-­amino acid decarboxylase (ALAAD) with carbidopa. This approach constitutes replacement therapy with L-­dopa to enhance dopamine presence in the nigrostriatal neurons and nerve terminals. Dopamine agonists also have been used, but the side effects have limited their effective use. Brain cell transplantation with fetal dopaminergic neurons into the striatum, initially described as dopaminergic neuronal replacement, also has been attempted, but problems with rejection of the transplant, marginal efficacy, and lack of understanding of the mechanism of the treatment have not led to widespread use. The transplants may have temporarily stimulated growth factor production or release in the striatum or contributed to sprouting of remaining dopamine axons in the striatum. Other pharmacologic approaches have attempted to alter the activity of neurotransmitters other than dopamine, such as acetylcholine, to compensate for the loss of dopamine. These many attempted treatments do not appear to halt the pathological process of the disease, but some may provide partial relief of symptoms.   

430

Systemic Neuroscience A. Parkinson’s disease (PD) - anatomy with biochemical pathways

Medullary lamina

Thalamus: anterior (A) lateral (L), and medial (M) nuclei

Caudate nucleus Corpus striatum Putamen Globus pallidus

Fasciculus thalamicus Zona incerta A L

Fasciculus lenticularis

M

Ansa lenticularis Subthalamic nucleus

Hypothalamus

Basis pedunculi Red nucleus

Striofugal System (Striothalamic and striatonigral projections)

Substantia nigra

Cholinergic -Aminobutyric acid (GABA) Striopetal System Dopaminergic (Nigrostriatal projection) Unknown

Subcortical Dementias Parkinson’s disease Dementia

Dopamine projections to corpus striatum from substantia nigra

Lewy body

Masklike facies Rigidity and flexed posturing Tremor Loss of dopamine projections to frontal cortex from ventral tegmentum may result in dementia

Dopamine Normal NE

B. Huntington’s chorea

Short shuffling gait

Ventriculomegaly Atrophy of caudate nucleus



GABA 

Ach 

Substantia nigra shows marked loss of neurons and pigment. Residual Dopamine neurons may exhibit Lewy bodies Parkinson’s disease Huntington′s disease Dementia

Bilateral distal and proximal choreiform movements of the limbs and also the face

Motor neuron Loss of inhibitory GABA neurons contributes to Huntington’s chorea

Atrophy of caudate nucleus and striatum and cortical atrophy of frontal cortex

Chromosome 4

  15.27 NEUROTRANSMITTER INVOLVEMENT IN PARKINSON’S DISEASE AND HUNTINGTON’S DISEASE

Locus for Huntington’s chorea on chromosome 4. Autosomal dominant inheritance

Motor Systems

A. Motor loop

B. Limbic loop

Cortex Primary motor cortex Premotor/supplemental cortex Primary sensory cortex

STN Striatum Putamen

SN

GP

PC

External segment

C. Cognitive loop

STN Striatum Ventral striatum Nucleus accumbens

GPI, Midbrain Internal segment SN - PR

STN

Thalamus VA - magno MD - paralamellar

Striatum Caudate nucleus – body GPI, Midbrain

GP

GPI, Midbrain

PC

Cortex

Frontal eye fields Posterior parietal cortex Dorsolateral prefrontal cortex

VA - parvo, magno MD - parvo, magno

SN

Ventral pallidum Ventral tegmental area

PC

D. Oculomotor loop

Caudate nucleus – head Dorsolateral Ventromedial

External segment

SN

External segment

Thalamus

GP

GPI, Midbrain

GP

Dorsolateral prefrontal cortex Lateral orbitofrontal cortex

Striatum

Thalamus MD (parvo)

VL VA CM

Cortex

STN

Cortex

Anterior cingulate cortex Temporal cortex Entorhinal cortex and hippocampus Inferior prefrontal cortex

Thalamus

431

External segment

Internal segment (lateral and medial) SN - PR

SN PC

Internal segment (central zone) SN - PR (ventrolateral) Midbrain

Horizontal and vertical gaze centers CM = Centromedian nucleus GPI = Globus pallidus internal segment magno = Magnocellular MD = Medial dorsal nucleus

parvo = Parvocellular PC = Pars compacta PR = Pars reticulata SN = Substantia nigra

Superior colliculus

STN = Subthalamic nucleus VA = Ventral anterior nucleus VL = Ventrolateral nucleus

 

15.28 PARALLEL LOOPS OF CIRCUITRY THROUGH THE BASAL GANGLIA The corticostriatal, striatopallidal, and pallidothalamic connections form parallel loops for motor, limbic, cognitive, and oculomotor circuitry. The motor circuitry is processed through the putamen, the limbic circuitry through the ventral pallidum and nucleus accumbens, the cognitive circuitry through the head of the caudate nucleus, and the oculomotor circuitry through the body of the caudate nucleus. Connections through

the globus pallidus and the pars reticulata of the substantia nigra or v­ entral tegmental area then project to appropriate regions of the thalamus to link back to the cortical neurons of origin for the initial corticostriatal projections. These parallel loops through the basal ganglia and the cortex serve to modulate ­specific subroutines of cortical activity distinct to the appropriate function. The pars compacta of the substantia nigra may act as the principal interconnections among these parallel loops.

432

Systemic Neuroscience

Hippocampal formation

Precommissural fornix Amygdaloid nuclei

Bed nucleus of the stria terminalis

Ventral amygdalofugal pathway

Globus pallidus (for limbic loop)

Dopamine median forebrain bundle

Nucleus accumbens

Ventral tegmental area (midbrain)

Brainstem (substantia nigra)

Hypothalamus (lateral hypothalamic area)

 

15.29 CONNECTIONS OF NUCLEUS ACCUMBENS Nucleus accumbens is located at the anterior end of the striatum in the interior of the ventral and rostral forebrain (see Fig. 13.12). Inputs are derived from limbic structures (amygdala, hippocampal formation, bed nucleus of the stria terminalis) and from the ventral tegmental area of the midbrain via a rich dopaminergic projection. Nucleus accumbens is central to motivational states and addictive behaviors. It also appears to be a principal region in brain reward circuits associated with joy, pleasure, and gratification. The involvement of nucleus accumbens with a specific limbic basal ganglia loop (via globus pallidus) helps to provide motor expression of emotional responses and accompanying gestures and behaviors.

CLINICAL POINT The extended amygdala refers to forebrain circuitry involved in processing risk-­or-­reward perception. This circuitry includes the bed nucleus of the stria terminalis and nucleus accumbens. These fore-­ brain structures have interconnections with the corticomedial and central nuclei of the amygdala (see Plate 16.36 for a summary of amygdaloid circuitry). The bed nucleus of the stria terminalis is involved in processing uncertainty and uncertain threats or risks, in contrast to amygdaloid processing of more specific threats or risks. Nucleus accumbens is involved in processing control of behavioral actions in the face of uncertain threats or risks and, in concert with the amygdala and frontal cortex, is involved with active avoidance behavior (see the work of Joseph LeDoux and colleagues). When the amygdala and the extended amygdala are activated by potential threats, a quick unconscious response from thalamic input (not the fine-­grain analytical lemniscal thalamic components) prepares the brainstem circuitry for needed action. If the amygdaloid-­ related processing is sent to the prefrontal cortex (medial and lateral) and the parietal cortex, then conscious awareness of the threat and appropriate decision making regarding that threat are activated. More specific threats are processed through the amygdala and specific thalamic projections through sensory cortices to the prefrontal cortex.   

Motor Systems CLINICAL POINT The ventromedial prefrontal cortex (vmPFC) regulates dopamine release in the nucleus accumbens and mediates the response of the amygdala to perceived challenges. The vmPFC inhibits the release of mesolimbic dopamine in the nucleus accumbens, but not of mesocortical dopamine in the prefrontal cortex, during amygdaloid activation. Thus, medial prefrontal cortex mediates the behavioral impact of amygdaloid reactivity through mesolimbic dopamine in the nucleus accumbens. In turn, the mesolimbic dopamine projections modulate amygdaloid emotional responsiveness, and the mesocortical dopamine projections modulate prefrontal cortical decision making and executive functions.   

CLINICAL POINT See Fig. 14.10. The varicella-­zoster virus of childhood chickenpox can reside as a latent virus in dorsal root ganglia, the trigeminal sensory ganglia, and other sensory ganglia. During immunosuppression (medication, cancers, chronic stressors), the reactivation of this virus can cause painful eruptions in the distribution of a sensory nerve root or a division of the trigeminal nerve; this condition is commonly known as shingles or herpes zoster (postherpetic) neuralgia. The most common sites are the thoracic nerve roots or the ophthalmic division (Vj) of the trigeminal nerve. The skin erupts with vesicles and a sharp, radiating or burning pain is felt in the region of the eruptions. Sometimes the painful sensations (dysesthesias) occur several days before the eruptions appear. A particular risk related to the ophthalmic division of CN V is corneal ulcerations and subsequent opacities. The nerve, the ganglion, and sometimes the surrounding tissues show inflammatory reactivity. Usually, with combined antiviral therapy and analgesics, the eruptions can subside within a week or so. However, the postherpetic neuralgia, with burning pain, can last for weeks to months and may require the same type of treatment that other neuropathic pain syndromes (reflex sympathetic dystrophy or complex regional pain syndrome) require, including analgesics, tricyclic anti-­ depressants to alter the pain threshold, membrane-­stabilizing agents, anti-­inflammatory medication, and other approaches.   

CLINICAL POINT See Fig. 15.9. The rubrospinal tract, arising from magnocellular neurons of the red nucleus, is part of a cortico-­rubro-­spinal system that may represent an indirect corticospinal pathway. Rubrospinal tract connections are contralateral and have mainly indirect effects (through interneurons) on both alpha and gamma LMNs. Some authors believe that the rubrospinal tract has a minor role in humans, although observations of decorticate and decerebrate posturing suggest otherwise. In conditions of UMN pathology, the cortico-rubro-­spinal system is usually damaged in conjunction with the corticospinal tract (posterior limb of the internal capsule, lateral funiculus of the spinal cord), resulting in a clinical picture of UMN syndrome. Bilateral damage to the forebrain and diencephalon, leaving only the rubrospinal tract, reticulospinal tracts, and vestibulospinal tracts intact, results in a classic UMN appearance bilaterally, with upper limbs in a flexed position and lower limbs in an extended posture (called decorticate posturing). If the lesion extends caudally just below the red nucleus, further removing rubrospinal tract influences, the lateral vestibulospinal tracts are markedly disinhibited, resulting in decerebrate posturing with all four limbs extended. These observations suggest that the rubrospinal system particularly drives flexor activity in the upper extremities and has a lesser role in the lower extremities.   

433

CLINICAL POINT See Fig. 15.11. The reticulospinal tracts originate from isodendritic neurons in the medial portion of the pontine and medullary RF. The pontine RF gives rise to the pontine (medial) reticulospinal tract, which influences mainly proximal musculature. The medullary RF gives rise to the medullary (lateral) reticulospinal tract, which lies more laterally in the spinal cord and influences muscles of the extremities. The reticulospinal tracts help to regulate basic tone and postural responses, sometimes coordinating musculature supplied by LMNs at multiple spinal cord levels. These tracts also may help to direct stereotyped movements such as those involved in extending a limb toward an object. The reticulospinal tracts can selectively influence both alpha and gamma LMNs, thus providing a mechanism for activation of static or dynamic gamma LMNs in conditions of damage to other descending systems, such as the corticospinal and cortico-­ rubro-spinal systems.   

CLINICAL POINT See Fig 15.14. Vestibular nuclei receive input from the hair cells in the ampullae of the semicircular canals and are connected with extraocular CN motor nuclei, thereby permitting vestibular reflex control of eye movements. This circuitry establishes the connections of the vestibulo-­ocular reflex. When the head is rotated in one direction, the lateral semicircular canal initiates a vestibulo-­ocular reflex that moves the eyes in the opposite direction, thereby maintaining the position of the eyes. Stimulation of the hair cells on one side of the vestibular apparatus with cold water in the external auditory meatus (the caloric response) provides the brainstem on that side with the neural signaling of apparent movement and elicits eye movements that would be appropriate to an actual movement, were one occurring. This elicited movement is called caloric nystagmus; it evokes a sense of apparent movement, a tendency to fall to one side, and past-­pointing. With caloric nystagmus, there is a slow phase and a compensatory fast phase. Cold water results in the fast phase directed to the opposite side, and warm water results in the fast phase directed to the same side. A lesion or irritative stimulation of the vestibular nerve on one side also gives the neural perception of movement, eliciting pathological nystagmus. If a person rotates in one direction to a greater extent than a simple vestibulo-­ocular reflex can easily correct through compensatory eye movements, the eyes will be directed sufficiently far to one side that a quick movement (saccade) will be necessary to refocus them straight ahead. This is called rotational nystagmus, with the slow phase opposite from the direction of movement and the saccade (fast phase) in the direction of the movement; the saccade is neurally directed from the occipital lobe visual cortices. After the rotation stops, the individual will feel as if she or he is still rotating but in the opposite direction (postrotational nystagmus), with the saccade in the direction opposite from the original movement and past-­pointing in the direction of apparent movement. If an individual is stationary and stimuli move past the visual field (telephone poles and a person in a moving car), tracking reflexes move the eyes and a cortically evoked saccade corrects the eye position with a quick movement of the eyes. This normal physiologic process is called optokinetic nystagmus.   

16

AUTONOMIC-­ HYPOTHALAMIC-­LIMBIC SYSTEMS



Autonomic Nervous System

16.1 General Organization of the Autonomic Nervous System

Hypothalamus and Pituitary

16.23 Long-­Term Regulation of Blood Pressure 16.24 Neural Control of Appetite and Hunger 16.25 Signaling Systems Involved in Regulation of Food Intake, Body Weight, and Metabolism

16.2 General Anatomy of the Hypothalamus

16.26 Hypothalamic Regulation of Sleep and Waking States

16.3 Sections Through the Hypothalamus: Preoptic and Supraoptic Zones

16.27 Neural and Neuroendocrine Roles in the Fight-­or-­Flight Response

16.4 Sections Through the Hypothalamus: Tuberal Zone

16.28 Neuroimmunomodulation

16.5 Sections Through the Hypothalamus: Mammillary Zone 16.6 Schematic Reconstruction of the Hypothalamus 16.7 Forebrain Regions Associated With the Hypothalamus 16.8 Afferent and Efferent Pathways Associated With the Hypothalamus



Limbic System

16.29 Anatomy of the Limbic Forebrain 16.30 Hippocampal Formation: General Anatomy 16.31 Neuronal Connections in the Hippocampal Formation

16.9 Schematic Diagram of Major Hypothalamic Afferent Pathways

16.32 Major Afferent and Efferent Connections of the Hippocampal Formation

16.10 Schematic Diagram of Major Hypothalamic Efferent Pathways

16.33 Afferent and Efferent Connections of the Entorhinal Cortex

16.11 Summary of General Hypothalamic Connections 16.12 Paraventricular Nucleus of the Hypothalamus: Regulation of Pituitary Neurohormonal Outflow, Autonomic Preganglionic Outflow, and Limbic Activity 16.13 Mechanisms of Cytokine Influences on the Hypothalamus and Other Brain Regions and on Behavior 16.14 Circumventricular Organs 16.15 Circumventricular Organs: Functional Considerations 16.16 The Hypophyseal Portal Vasculature 16.17 Regulation of Anterior Pituitary Hormone Secretion 16.18 Posterior Pituitary (Neurohypophyseal) Hormones: Oxytocin and Vasopressin 16.19 Vasopressin (Antidiuretic Hormone) Regulation of Water Balance and Fluid Osmolality 16.20 The Hypothalamus and Thermoregulation 16.21 Hypothalamic Regulation of Cardiac Function 16.22 Short-­Term Regulation of Blood Pressure

16.34 Major Afferent Connections of the Amygdala 16.35 Major Efferent Connections of the Amygdala 16.36 Summary of Major Afferents, Efferents, and Interconnections of the Amygdala 16.37 Major Afferent and Efferent Connections of the Septal Nuclei 16.38 Bed Nucleus of the Stria Terminalis 16.39 Major Connections of the Cingulate Cortex 16.40 Insular Cortex 16.41 Prefrontal Cortex 16.42 Key Forebrain Regions Associated With Limbic and Cortical Reactivity and Their Functional Roles

Olfactory System

16.43 Olfactory Receptors 16.44 Olfactory Pathways

Autonomic-Hypothalamic-Limbic Systems

 Inputs to autonomic preganglionic neurons of sympathetic and parasympathetic nervous systems: Limbic forebrain structures Some cortical regions Hypothalamic regions Brainstem centers and nuclei Sensory inputs

Inputs to autonomic preganglionic neurons Preganglionic sympathetic Postganglionic sympathetic Preganglionic parasympathetic

Nucleus of Edinger-Westphal

Postganglionic parasympathetic

Pupillary constrictor muscle Ciliary muscle

Ciliary ganglion

Lacrimal glands Glands of nasal mucosa Submandibular gland Sublingual gland

Pterygopalatine ganglion

Oculomotor (III) nerve

Submandibular ganglion

Facial (VII) nerve

Salivary glands

Otic ganglion

Vagus (X) nerve

Lateral horn (intermediolateral cell column)

Intramural ganglia

To vascular smooth muscle in skin and muscles, arrector pili muscles, sweat glands in limbs

Spinal nerve White ramus communicans

Secretion of epinephrine and norepinephrine into blood

Inferior salivatory nucleus

Glossopharyngeal (IX) nerve

Parotid gland Smooth muscle, cardiac muscle, secretory glands in heart, lung viscera, GI tract to descending colon

Superior salivatory nucleus

Adrenal medulla

Gray ramus communicans

Ventral root

Dorsal motor (autonomic) nucleus of X

Thoracic spinal cord (T1-L2)

Splanchnic nerve Sympathetic chain ganglia Intermediate gray

To cardiac muscle, smooth muscle, secretory glands, metabolic cells (liver, fat), cells of immune system

Ventral root

Collateral ganglia

Sacral spinal cord (S2-S4)

Smooth muscle, secretory glands in lower GI tract, pelvic viscera Intramural ganglia

AUTONOMIC NERVOUS SYSTEM 16.1 GENERAL ORGANIZATION OF THE AUTONOMIC NERVOUS SYSTEM See next page. 

Pelvic nerves

435

436

Systemic Neuroscience

16.1 GENERAL ORGANIZATION OF THE AUTONOMIC NERVOUS SYSTEM (CONTINUED) The autonomic nervous system is a two-­neuron chain connecting preganglionic neurons through ganglia to visceral target tissues (cardiac muscle, smooth muscle, secretory glands, metabolic cells, cells of the immune system). The sympathetic division (sympathetic nervous system; SNS) is a thoracolumbar (T1-­L2) system arising from the intermediolateral cell column of the lateral horn of the spinal cord, acting through chain ganglia and collateral ganglia; it is a system designed for enhancing activities and for fight-­or-­flight reactions in an emergency. The parasympathetic division (parasympathetic nervous system) is a craniosacral system arising from brainstem nuclei associated with cranial nerves (CNs) III, VII, IX, and X and from the intermediate gray in the S2–S4 spinal cord. Connections from CNs III, VII, and IX act through cranial nerve ganglia; connections from the vagal system and sacral system act through intramural ganglia in or near the target tissue. The parasympathetic nervous system is a homeostatic reparative system. Central connections from the limbic forebrain, hypothalamus, and brainstem regulating the sympathetic and parasympathetic nervous systems’ outflow to the body act mainly through connections to vagal and sympathetic preganglionic neurons.

CLINICAL POINT Preganglionic parasympathetic neurons in the brainstem and sacral spinal cord, as well as preganglionic sympathetic neurons in the thoracolumbar spinal cord, send projections to ganglion cells and use acetylcholine as the principal neurotransmitter. The ganglion cells possess mainly nicotinic cholinergic receptors for transducing fast neurotransmission responses. Postganglionic sympathetic neurons use mainly norepinephrine as their neurotransmitter, whereas post-­ ganglionic parasympathetic neurons use acetylcholine. Target tissue possesses alpha and beta adrenoceptor subclasses and cholinergic muscarinic receptor subclasses (M1–M3). In the heart, beta1 receptors increase the force and rate of contraction, increase cardiac output, and dilate coronary arteries, whereas M2 receptors decrease the force and rate of contraction and cardiac output. In vascular smooth muscle and smooth muscles of the pupil, ureters, and bladder, alpha1 receptors cause contraction. In blood vessels, alpha2 receptors also cause constriction. In smooth muscle of the tracheobronchial system, uterus, and gastrointestinal tract vasculature, beta2 receptors cause relaxation. Alpha1 receptors cause relaxation of gastrointestinal smooth muscles, and M1 receptors cause slow contraction. M3 receptors cause contraction of most parasympathetic smooth muscle target structures. In salivary glands, alpha1 receptors cause secretion and beta2 receptors cause mucus secretion. In adipose tissue, alpha1 receptors cause glycogenolysis, beta1 receptors cause lipolysis, and alpha2 receptors inhibit lipolysis. In sweat glands, alpha1 receptors cause secretion. In the kidney, alpha1 receptors enhance reabsorption of Na+, and beta1 receptors provoke renin release. In liver and skeletal muscles, beta2 receptors cause glycogenolysis. In the pancreas, beta2 receptors stimulate insulin release, and alpha2 receptors inhibit insulin release. On immunocytes, beta-­adrenergic receptors decrease natural killer (NK) cell activity and decrease the secretion of Th1 cytokines (interferon-­gamma, interleukin 2) by Th1 lymphocytes. The balance of adrenergic and cholinergic neurotransmission determines the relative degree of activation of target tissues, and differential affinity of ligands for the various receptor subclasses helps to determine the final integrative physiological response.   

Autonomic-Hypothalamic-Limbic Systems

437

17 19 16 15

14 13

6 7

2 1 3

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Preoptic nuclei Paraventricular nucleus Anterior hypothalamic area Supraoptic nucleus Lateral hypothalamic area Dorsal hypothalamic area Dorsomedial nucleus Ventromedial nucleus Posterior hypothalamic area Mammillary body (nuclei) Optic chiasm Lamina terminalis Anterior commissure Hypothalamic sulcus Interthalamic adhesion Fornix Septum pellucidum Midbrain Thalamus Tuber cinereum Optic nerve Infundibulum Anterior lobe of pituitary Posterior lobe of pituitary

9 18

8

5

4

12

10

20 20

11

22

21

24

23

1

2

3

4

5 6

Planes of frontal sections

 

HYPOTHALAMUS AND PITUITARY 16.2 GENERAL ANATOMY OF THE HYPOTHALAMUS The hypothalamus is a collection of nuclei and fiber tracts in the ventral diencephalon that regulates visceral autonomic functions and neuroendocrine functions, particularly from the anterior and posterior pituitary. Many nuclei are found between the posterior boundary (mammillary bodies) and the anterior boundary (lamina terminalis, anterior commissure) of the hypothalamus;

these nuclei are subdivided into four general hypothalamic zones, from rostral to caudal: (1) preoptic, (2) anterior or supraoptic, (3) tuberal, and (4) mammillary or posterior. From the medial boundary at the III ventricle to the lateral boundary, the nuclei are subdivided into three general zones or areas: (1) periventricular, (2) medial, and (3) lateral. The pituitary gland is attached at the base of the hypothalamus by the infundibulum (pituitary stalk), which possesses an important zone of neuroendocrine transduction, the median eminence.

438

Systemic Neuroscience

Plane 1

Plane 2

Corpus callosum

Interventricular foramen (of Monro) 3rd ventricle Column of fornix Periventricular nucleus Ansa lenticularis Paraventricular nucleus Inferior thalamic peduncle Lateral hypothalamic area

Septum pellucidum Anterior horn of lateral ventricle Head of caudate nucleus Septal area Column of fornix Anterior limb of internal capsule Putamen Globus pallidus 3rd ventricle Anterior commissure Hippocampal formation Optic Medial Lateral Substantia chiasm preoptic preoptic innominata area area

Supraoptic nucleus

Optic chiasm

Optic tract

Anterior hypothalamic area Suprachiasmatic nucleus

 

16.3 SECTIONS THROUGH THE HYPOTHALAMUS: PREOPTIC AND SUPRAOPTIC ZONES The major nuclei in the preoptic zone (Plane 1) include the medial and lateral preoptic areas. The organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ (with no blood-­brain barrier), is present in this hypothalamic area. The major nuclei in the supraoptic (anterior) zone (Plane 2) include the supraoptic (SON) and paraventricular (PVN) nuclei, the suprachiasmatic nucleus, the anterior hypothalamic area, and the lateral hypothalamic area (LHA). Some nuclei such as the PVN have many subregions (such as the magnocellular and parvocellular regions) that contain many collections of chemically specific neurons (20 or more) that have discrete projections and functions. These groups are sometimes intermingled within one subregion of the nucleus. CLINICAL POINT The hypothalamus and brainstem structures are involved in regulating the sleep-­wake cycle. Ablative lesions of the preoptic area result in insomnia. Some preoptic neurons appear to be maximally activated during sleep and may inhibit neurons in the posterior hypothalamus (such as tuberomammillary neurons) that contribute to wakefulness. The LHA also contains neurons involved in wakefulness through the secretion of an activating neuropeptide, hypocretin. Neurons of the LHA activate the tuberomammillary neurons as well as the locus coeruleus in the pons, a noradrenergic cell group with widespread projections to all regions of the central nervous system (CNS) and a major role in arousal and wakefulness. Early epidemics of encephalitis lethargica (sleeping sickness) demonstrated damage to the midbrain and posterior regions of the hypothalamus. This scheme is consistent with a role for the posterior hypothalamus in sympathetic activation and arousal and with a role for the anterior and preoptic hypothalamus in parasympathetic activation and quiet, reparative, homeostatic functions. Narcolepsy is a condition

of episodic periods of overwhelming daytime drowsiness and then an abrupt episode of sleep, even in the middle of an activity. The person then awakens and feels alert. Nighttime sleep may be disturbed, but this is not the cause of daytime sleep episodes; patients with narcolepsy go into rapid eye movement sleep in a matter of minutes rather than hours. Many stimuli (e.g., intense emotion, excitation, laughter) may precipitate an episode of cataplexy in which the knees give out, the person falls, and an abrupt sleep episode follows. Sleep apnea is a major sleep disorder, often associated with obesity, in which patients have prolonged periods of apnea, followed by gasping and including disturbed sleep and loud snoring. It is a major risk factor for heart disease. The suprachiasmatic nucleus (SCN) sits just above the optic chiasm and contains the major neurons of the CNS that act as a “pacemaker” system for the control of diurnal, or circadian, rhythms. The intrinsic pacemaker has a cycle that is a bit longer than 24 hours (studied in humans who lived in caves with no external light cues); however, input from the retina to the suprachiasmatic nucleus entrains the diurnal rhythms to a 24-­hour period. These diurnal rhythms drive many hormone and metabolic levels (e.g., cortisol is low in the late evening and high in the morning before rising; melatonin is highest in late evening) and physiological functions (blood pressure and core body temperature are lowest in early morning and highest in late afternoon). Superimposed on these diurnal rhythms are broader factors, such as effects of the sleep-­wake cycle, life stress, levels of activity, and other environmental factors. Sleep has a particularly important influence on cortisol rhythms. Disrupted or poor sleep habits can ablate the diurnal cortisol rhythm, leading to a propensity for fat to be deposited in a central abdominal location because of the effects of high cortisol levels. This can contribute to the likelihood of metabolic syndrome, with its elevated inflammatory mediators (C-­reactive protein and interleukin [IL]-­6) and increased risk for cardiovascular disease, stroke, type II diabetes, and many cancers. The SCN is influenced by a host of limbic and other forebrain influences superimposed on diurnal rhythms. The SCN, in turn, has axonal projections to other regions of the hypothalamus, the locus coeruleus, and limbic sites through which the diurnal regulatory control of these hormones and physiological functions is achieved.   

Autonomic-Hypothalamic-Limbic Systems

Plane 3 Corpus callosum

Septum pellucidum

Plane 4 Anterior horn of lateral ventricle Body of caudate nucleus Body of fornix

3rd ventricle

Thalamus

Mammillothalamic tract Interthalamic adhesion Posterior limb of internal capsule Zona incerta and fields of Forel Putamen Fasciculus lenticularis Dorsal hypothalamic area Periventricular nucleus Dorsomedial nucleus Aberrant pallidofugal fibers Lateral hypothalamic area

Thalamus Mammillothalamic tract 3rd ventricle Posterior limb of internal capsule Putamen Globus pallidus Dorsal hypothalamic area

Periventricular arcuate nucleus Infundibulum Suprachiasmatic nucleus

Optic tract

439

Supraoptic nucleus

Paraventricular nucleus Ansa lenticularis Column of fornix Periventricular nucleus Lateral hypothalamic area

Periventricular arcuate nucleus

Tuberal nuclei

Supraoptic nucleus

Optic tract

Ventromedial nucleus

Anterior hypothalamic area

 

16.4 SECTIONS THROUGH THE HYPOTHALAMUS: TUBERAL ZONE The major nuclei in the tuberal zone (Planes 3 and 4) include the dorsomedial nucleus, the ventromedial nucleus, the periventricular area or nucleus, the arcuate nucleus, the periarcuate area (beta-­endorphin cells), the tuberal nuclei, the dorsal hypothalamic area, and the LHA. Some nuclei from the supraoptic zone (PVN, SON, LHA) extend caudally into this zone. The median eminence extends from this region, and axons from releasing-­ factor and inhibitory-­factor neurons that control the release of anterior pituitary hormone funnel down to the contact zone, where they release these factors (hormones) into the hypophyseal portal system, which bathes the cells of the anterior pituitary. CLINICAL POINT The secretion of hormones by the anterior pituitary gland is regulated by releasing factors (hormones) and inhibitory factors (hormones) that are produced by neurons of the hypothalamus and adjacent sites and are secreted by their axons into the hypophyseal portal vasculature for delivery in extraordinarily high concentrations to cells of the anterior pituitary. A well-­ known releasing factor is corticotropin–releasing hormone or factor (CRH or CRF), produced by parvocellular neurons of the paraventricular nucleus, which regulates subsequent secretion of adrenocorticotropic hormone (ACTH) and cortisol. Another important releasing hormone, growth hormone-­releasing hormone, is produced by neurons in the arcuate nucleus and delivered by their axons to the hypophyseal portal system. Somatostatin is a growth hormone-­ inhibitory hormone and is produced by other neurons in the arcuate nucleus as well as elsewhere. These hormones are regulated by neural connections, hormonal influences, and metabolic factors. Growth hormone (GH) is released in pulsatile bursts during stage 3 and stage 4 sleep, accounting for 70% of GH release. GH release also is stimulated by exercise, acute stressors, hypoglycemia, and intake of protein, and is suppressed by intake of glucose and many fatty acids.

Children who experience emotional deprivation secrete low levels of GH and may fail to grow. Recent studies have shown that mirthful laughter associated with viewing humorous videos markedly stimulates GH secretion and diminishes cortisol and epinephrine secretion. Even more remarkable, when subjects anticipate viewing something humorous, the anticipation itself provokes GH secretion that is as great as or greater than the GH secretion seen in stage 3 and stage 4 sleep. Sex steroid hormones influence brain development. In a male fetus, the developing testes provide androgens (converted in the brain to estradiol) that influence CNS development in a male pattern during critical developmental periods. All developing fetuses are exposed to maternal estrogen as well as some placental hormones, but the estrogen is bound by alpha-­fetoprotein, which protects the female fetus from masculinization by the CNS. One important consequence of fetal exposure to sex steroids is the subsequent hypothalamic control of follicle-­stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. In females, these hormones are released in a cyclic fashion. In males, FSH and LH are released in steady amounts, a phenomenon dependent upon CNS exposure to estradiol via androgens during fetal development. In the CNS, FSH and LH secretion is controlled by gonadotropin-­releasing hormone (GnRH), formerly called luteinizing hormone-­ releasing hormone. GnRH neurons in the preoptic area project to the contact zone of the median eminence, ending on the hypophyseal-­portal vessels. The GnRH neurons are responsive to estrogen in the female brain but not in the male brain, perhaps accounting for the cyclic secretion of FSH and LH in females. The ventromedial (VM) nucleus of the hypothalamus appears to control some aspects of sexual behavior; VM neurons respond to progesterone via receptors in the female brain but not in the male brain. The male brain responds behaviorally to circulating androgens but not to estrogen. Anatomically, preoptic and VM neurons show male-­female differences in morphological and synaptic features. A specialized portion of the preoptic area, the sexually dimorphic nucleus, is considerably larger in the male brain than in the female brain, apparently triggered by developmental hormonal exposure.   

440

Systemic Neuroscience

Plane 5

Medial and lateral parts of medial mammillary nucleus

Corpus callosum Body of caudate nucleus Anterior horn of lateral ventricle Body of fornix 3rd ventricle Thalamus Posterior limb of internal capsule Field H1 of Forel Field H2 of Forel Mammillothalamic tract Putamen Globus pallidus Posterior hypothalamic area Subthalamic nucleus Capsulopeduncular transition zone Lateral hypothalamic area Optic tract Column of fornix Nucleus intercalatus Principal mammillary fasciculus Lateral mammillary nucleus

Plane 6 Thalamus 3rd ventricle Field H1 of Forel Field H2 of Forel Putamen Globus pallidus Mammillothalamic tract Posterior hypothalamic area Subthalamic nucleus Inferior horn of lateral ventricle Lateral hypothalamic area Hippocampal formation

Medial mammillary nucleus

Mammillary peduncle Supramammillary decussation

  16.5 SECTIONS THROUGH THE HYPOTHALAMUS: MAMMILLARY ZONE The major nuclei in the mammillary zone (Planes 5 and 6) include the medial and lateral mammillary nuclei, the posterior hypothalamic area, and the LHA. The LHA extends throughout most of the length of the hypothalamus and shows neuronal characteristics seen in the brainstem reticular formation. CLINICAL POINT In the 1930s, James Papez proposed a brain circuit that was viewed as a substrate for control of emotional behavior and later as a substrate for memory, especially for consolidation of immediate and short-­term memory into long-­term memory. This Papez circuit includes hippocampal formation (especially the subiculum) via the fornix to the mammillary nuclei (especially medial nuclei); via the mammillothalamic tract to the anterior thalamic nuclei; via the internal capsule to the anterior cingulate cortex; and via polysynaptic connections in the cingulum to the entorhinal cortex, subiculum, and hippocampus. This

circuit is proposed as a site of major damage in Wernicke-­Korsakoff syndrome, a disorder that is commonly seen in chronic alcoholic patients with a vitamin B1 (thiamine) deficiency. This syndrome includes Wernicke’s encephalopathy and the memory dysfunction of Korsakoff ’s syndrome. Wernicke’s encephalopathy involves a confused and psychotic state involving confabulation (made-­up stories derived from a host of confused past memories or experiences), cerebellar ataxia, extraocular and gaze palsies, and nystagmus. Korsakoff amnestic syndrome involves the inability to consolidate immediate and short-­term memory into long-­term traces (anterograde amnesia) as well as long-­term memory loss concerning events that have occurred since the onset of the disease. Degeneration has been described in the mammillary bodies, fornix, hippocampal formation, and anterior and medial dorsal thalamus. However, the extent to which the mammillary nuclei themselves play a role in consolidation of memory traces remains to be shown. Thiamine administration may help to reverse some of the symptoms, but the amnesias may persist. Administration of glucose (carbohydrate loading) without thiamine may cause death as the result of nutritional cardiomyopathy.   

Autonomic-Hypothalamic-Limbic Systems

441

Corpus callosum

Septum pellucidum

Fornix

Lateral ventricle

From hippocampal formation

Thalamus Paraventricular nucleus

Interthalamic adhesion

Anterior commissure Dorsal hypothalamic area

Lateral hypothalamic area

Mammillothalamic tract

Median forebrain bundle

Posterior area Dorsomedial nucleus

Lateral preoptic nucleus

Periventricular nucleus

Anterior hypothalamic area

Nucleus intercalatus Red nucleus

Medial preoptic nucleus

Cerebral peduncle Fornix

Olfactory tract Optic (II) nerve Optic chiasm

Mammillary complex

Ventromedial nucleus

Tuberohypophyseal tract Oculomotor (III) nerve Supraoptic nucleus Supraopticohypophyseal tract Posterior lobe of pituitary

Dorsal longitudinal fasciculus Descending hypothalamic connections (from MFB) Pons Reticular formation

Anterior lobe of pituitary

 

16.6 SCHEMATIC RECONSTRUCTION OF THE HYPOTHALAMUS A schematic three-­dimensional reconstruction of the hypothalamus in sagittal section shows the nuclei, areas, and zones that occupy this small, compact region of the diencephalon. Many pathways are represented in this schematic reconstruction, including the fornix, the

mammillothalamic tract, the median forebrain bundle (MFB), the supraopticohypophyseal tract, the tuberohypophyseal (tuberoinfundibular) tract, and brainstem connections with the hypothalamus via the dorsal longitudinal fasciculus, the descending median forebrain bundle, the mammillotegmental tract, and descending connections from the PVN to preganglionic autonomic nuclei.

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Motor area

Cingulate gyrus Fornix

Somatosensory area

Thalamus Prefrontal area

Corpus callosum Visual area

Olfactory bulb Hypothalamus Orbitofrontall cortex Amygdala Hippocampal formation Parahippocampal gyrus

  16.7 FOREBRAIN REGIONS ASSOCIATED WITH THE HYPOTHALAMUS Numerous forebrain regions are intimately connected with the hypothalamus, some through direct fiber projections and others through indirect connections. These important regions of the cerebral cortex include the prefrontal cortex, orbitofrontal cortex, cingulate cortex, insular cortex, parahippocampal cortex, and periamygdaloid cortex. The important subcortical regions of the limbic forebrain include the hippocampal formation (a three-­layer archicortex), amygdaloid nuclei, and septal nuclei. Important thalamic connections include the medial dorsal and anterior nuclei. Important olfactory connections include the olfactory tract, nuclei, and cortex. CLINICAL POINT The placebo effect is a positive change in a patient’s symptoms or subjective experience, or in a patient’s physiological state, including pain modulation, altered cardiovascular function, and immune reactivity (both innate and acquired), based on the patient’s expectations, interactions with health care personnel and treatments, or administration of medication (e.g., a pill) that normally has little direct pharmacological effects. Negative effects from such expectations or interactions are called a nocebo effect. The placebo effect has been described as “not real, ” “not a medicine,” “based on belief,” and having “no effect on disease processes or illnesses.” However, in pharmaceutical testing of highly reactive medications, it is often observed that the placebo is almost as effective as the pharmacological medication for altering clinical outcomes. Placebo effects, often involving conditioned responses, do indeed alter physiological processes, sometimes profoundly, with effects on disease

outcome, as happens with conditioned immune responses in which a “placebo” alters lethal outcomes in experimental models of immune-­ related diseases (see the work of Robert Ader and Nicholas Cohen). Placebo effects occur through known pathways and circuitry of the brain, including prefrontal cortex, anterior insular cortex, rostral anterior cingulate cortex, some amygdaloid nuclei, and in the brainstem, the periaqueductal gray. These structures act through influences on autonomic and neuroendocrine outflow, as well as by initiating appropriate behavioral responses. Disruption of these forebrain circuits can prevent the physiological effects of the placebo. Neurotransmitter systems such as endorphins, cannabinoids, dopamine and other catecholamines, and cortisol are involved in mediating placebo effects, and their pharmacological alterations (e.g., naloxone blockade of opioid receptors in placebo administration for pain) can prevent the physiological and behavioral alterations seen in the placebo effect. Use of placebo effects and acknowledgment of conditioned responses have an important role in clinical medicine and disease treatment. It is likely that many complementary medicine approaches utilize, in part, placebo effects with their appropriate forebrain circuitry and neurotransmitter systems. This is consistent with the “relaxation response” described and documented by Herb Benson and colleagues, and the use of guided imagery, meditation, qi gong, and other parasympathetic-­inducing practices. See references for thoughtful discussions of placebo effect: Colloca L, Barsky AJ: Placebo and nocebo effects. N Engl J Med 382:555–562, 2020. Finnias DG, Kaptchuk TJ, Miller FG, Bennetti F: Biological, clinical, and ethical advances of placebo effect. Lancet 375:686-­695, 2010. Kaptchuk TJ, Miller FG: Placebo effects in medicine. N Engl J Med 373:8-­9, 2015.   

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Fasciculus retroflexus (habenulopeduncular tract) Stria medullaris thalami Cingulate gyrus Habenula Corpus callosum

Medial dorsal and Anterior nuclei of thalamus Septal nuclei From septal, subcallosal, preoptic, and frontotemporal areas

Prefrontal cortex

Hypothalamic nuclei Olfactory tract Olfactory bulb Stria terminalis

Orbitofrontal cortex projections Hippocampal formation Hypophysis Ventral amygdalofugal pathway

Reticular formation

Amygdala Interpeduncular nucleus Mammillotegmental tract Dorsal longitudinal fasciculus Median forebrain bundle (descending) Medullary cardiovascular centers Vagus (X) nerve Arrows represent afferent and efferent pathways.

 

16.8 AFFERENT AND EFFERENT PATHWAYS ASSOCIATED WITH THE HYPOTHALAMUS Hypothalamic connections are numerous and complex. Some regions of the cerebral cortex (prefrontal, orbitofrontal) and thalamus (anterior) send axonal projections directly to the hypothalamus. Diverse afferent pathways arise from the hippocampal formation and the subiculum (fornix), amygdaloid nuclei (stria terminalis, ventral amygdalofugal pathway), and habenula (fasciculus retroflexus). The retina sends direct retinohypothalamic fibers to the suprachiasmatic nucleus of the hypothalamus. Numerous brainstem projections, some compact and some diffuse, ascend to the hypothalamus by multiple pathways (not shown here). Efferent connections from the hypothalamus include those to the median eminence (from multiple nuclei), the posterior pituitary (supraopticohypophyseal tract), the septal nuclei and the anterior perforated substance (median forebrain bundle), the thalamus (mammillothalamic tract), and many brainstem and spinal cord sites (dorsal longitudinal fasciculus, median forebrain bundle, mammillotegmental tract, direct connections from PVN to preganglionic neurons, and others). The habenula receives afferents from the septal nuclei, lateral preoptic hypothalamic region, and anterior thalamic nucleus via the stria medullaris thalami, and sends projections to the preoptic area and septal nuclei.

CLINICAL POINT The hypothalamus receives inputs from the hippocampal formation and subiculum, amygdaloid nuclei, habenula, retina, some cortical areas, and many brainstem regions; a good number of these inputs are limbic forebrain and brainstem connections. The role of the hypothalamus is to regulate the visceral milieu and neuroendocrine secretion, particularly via the anterior and posterior pituitary. The efferents of the hypothalamus reflect this role and are directed to the posterior pituitary and contact zone of the median eminence (for control of anterior pituitary hormonal secretion), some limbic forebrain structures, and widespread areas of the brainstem and spinal cord that are involved in autonomic and visceral regulation. These connections help to coordinate appropriate behavioral responses to external and internal inputs and perceived challenges in the environment. The posterior and lateral hypothalamic regions are particularly involved in sympathetic drive and activational responses, such as the acquisition of food and water, the increase of core body temperature, sympathetic arousal, activities involved in aggressive interactions with the environment, and wakefulness states. Many of these activities are coordinated through connections in the median forebrain bundle. In contrast, the anterior and medial hypothalamic regions are particularly involved in parasympathetic functions, such as satiation, decreased core body temperature, quiet and reparative homeostatis-­related activities, and sleep. Many of these activities are coordinated through connections in the dorsal longitudinal fasciculus and other descending pathways.   

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Brainstem and Blood-Borne Inputs

Diencephalon and Telencephalon Inputs

Blood-borne information

Retina

Dorsal, ventral, tegmental nuclei

Assoc. RF polysensory information

(to SCN)

DLF

Retinohypothalamic pathway

Thalamus (to LHA, lateral preoptic area)

Mammillary peduncle

Periaqueductal gray

(glucose, Na+, cytokines, hormones, others)

MD midline nuclei

(to lateral mammillary nucleus) (to medial areas)

Cerebral cortex

Hypothalamus

MFB (to PVN)

MFB Brainstem RF

(to LHA)

NTS

(to PVN, LHA)

(to LHA, lateral preoptic area, others)

Anterior cingulate cortex Posterior orbitofrontal cortex Olfactory bulb, related regions Amygdala

Parabrachial nuclei

(to PVN)

(to medial preoptic area, AHA, SON) (via MFB, ST, VAFP)

Locus coeruleus Lateral tegmental CA nuclei (A1, A2, A5, A7)

(to preoptic, medial areas)

Dorsal and ventral NA bundles (via MFB, DLF)

Ventral amygdalofugal pathway

Subiculum (to medial mammillary nucleus) (to all 3 zones)

AHA = Anterior hypothalamic area CA = Catecholamine DLF = Dorsal longitudinal fasciculus 5HT = 5-Hydroxytryptamine, serotonin LHA = Lateral hypothalamic area

Olfactory-related projection

(to widespread areas)

Dorsal raphe nucleus Nucleus centralis superior 5HT

Stria terminalis

Postcommissural fornix Precommissural fornix Septum

(to widespread areas) MD = Medial dorsal nucleus of thalamus MFB = Median forebrain bundle NA = Noradrenergic NTS = Nucleus tractus solitarius PVN = Paraventricular nucleus

Hippocampal RF = Reticular formation pyramidal cells SCN = Suprachiasmatic nucleus SON = Supraoptic nucleus ST = Stria terminalis VAFP = Ventral amygdalofugal pathway

 

16.9 SCHEMATIC DIAGRAM OF MAJOR HYPOTHALAMIC AFFERENT PATHWAYS The hypothalamus receives extensive input from many regions of the CNS. Descending inputs arrive from limbic forebrain structures (hippocampal formation, subiculum, amygdaloid nuclei), the cerebral cortex (anterior cingulate, orbitofrontal, prefrontal), and the thalamus (medial dorsal). Ascending inputs arrive from extensive areas of the autonomic brainstem (tegmental

nuclei, periaqueductal gray, parabrachial nuclei, nucleus tractus solitarius, locus coeruleus and tegmental catecholamine nuclei, raphe serotonergic nuclei) and from the brainstem reticular formation. The retina sends input directly to the suprachiasmatic nucleus, a nucleus of the hypothalamus that modulates diurnal rhythms. Blood-­borne substances (cytokines, hormones, glucose, Na+, others) influence the hypothalamus via numerous routes and mechanisms.

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Diencephalon, Telencephalon, and Pituitary Efferent Pathways

Brainstem Efferent Pathways M Teg T

Posterior pituitary Dorsal and ventral tegmental nucleus Lateral midbrain reticular formation

(from magnocellular PVN, SON)

Pontine and medullary reticular formation

Nauta’s limbic midbrain (tegmental nucleus) CA and 5HT nuclei Preganglionic SNS neuron (polysynaptic)

(from arcuate, periventricular nuclei)

MFB

(from LHA)

Hypothalamus

Brainstem reticular formation

Interpeduncular nucleus

Median eminence

DLF

ß–endorphin pathway

(from medial periventricular area)

Tuberohypophyseal tract

MFB

Septal nuclei Anterior perforated substance Anterior thalamic nucleus

(from medial mammillary nuclei)

Fasc. Retroflexus

(from periventricular nucleus)

Mammillothalamic tract

Medial dorsal thalamic nucleus Orbitofrontal cortex Temporal association cortex

(from septal nuclei, preoptic area) (from periarcuate area) (from parvocellular PVN)

Periaqueductal gray Brainstem CA, 5HT nuclei Parabrachial nuclei Locus coeruleus NTS and DMN of X (preganglionic PSNS neurons) ILC of T1 - L2 spinal cord (preganglionic SNS neurons)

Anterior pituitary

(from RF and IF neurons)

Preganglionic PSNS neurons

Ventral preaqueductal gray Dorsal tegmental nucleus

Supraopticohypophyseal tract

MFB

(from parvocellular PVN and some scattered areas, lateral and dorsal)

CA = Catecholamine DLF = Dorsal longitudinal fasciculus DMN of X = Dorsal motor (autonomic) nucleus of X Fasc. Retroflexus = Fasciculus retroflexus (habenulopeduncular tract) 5HT = 5-Hydroxytryptamine, serotonin

(from periarcuate area)

Amygdala

ß–endorphin pathway Thalamus Nucleus accumbens Bed nucleus of ST Amygdala

IF = Inhibitory factor ILC = Intermediolateral cell column LHA = Lateral hypothalamic area MFB = Median forebrain bundle M Teg T = Mammillotegmental tract NTS = Nucleus tractus solitarius

PSNS = Parasympathetic nervous system PVN = Paraventricular nucleus RF = Releasing factor SNS = Sympathetic nervous system SON = Supraoptic nucleus ST = Stria terminalis

 

16.10 SCHEMATIC DIAGRAM OF MAJOR HYPOTHALAMIC EFFERENT PATHWAYS The hypothalamus gives rise to extensive efferent projections to many regions of the CNS. Ascending efferents are sent to limbic forebrain structures (amygdaloid nuclei, septal nuclei, the anterior perforated substance), the cerebral cortex (orbito frontal cortex and temporal association cortex), and the thalamus (medial dorsal, anterior). Extensive projections are sent to the median eminence (releasing and inhibitory factors for control of anterior pituitary hormones, dopamine projections from the arcuate

nucleus and periventricular nucleus) and to the posterior pituitary. Additional efferent projections are sent directly and indirectly to the preganglionic neurons of the sympathetic and the parasympathetic nervous systems (median forebrain bundle, dorsal longitudinal fasciculus, mammillotegmental tract, and direct projections from the paraventricular nucleus), to widespread autonomic and visceral nuclei (noradrenergic neurons, serotonergic neurons, parabrachial nuclei, nucleus tractus solitarius, periaqueductal gray, tegmental nuclei, interpeduncular nucleus), and to the brainstem reticular formation.

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MFB

Cortex

Papez circuit

Limbic forebrain structures

FX

Lateral hypothalamus MFB

ST, VAFP

MD Thalamus Anterior thalamus

Medial hypothalamus

Midbrain tegmentum Brainstem autonomic structures

DLF, MTT

Brainstem autonomic structures

Hypophyseal portal system Anterior pituitary Posterior pituitary

Periventricular hypothalamus

Spinal cord SNS preganglionics

Supraopticohypophyseal tract

DLF = Dorsal longitudinal fasciculus FX = Fornix MD = Medial dorsal nucleus of thalamus MFB = Median forebrain bundle

MTT = Mammillothalamic tract SNS = Sympathetic nervous system ST = Stria terminalis VAFP = Ventral amygdalofugal pathway

 

16.11 SUMMARY OF GENERAL HYPOTHALAMIC CONNECTIONS The lateral, medial, and periventricular zones of the hypothalamus have specific connections with the cerebral cortex, limbic forebrain structures, thalamus, and widespread areas of the brainstem. Extensive efferent projections of the hypothalamus

are directed toward regulation of preganglionic sympathetic and parasympathetic neurons and toward release and regulation of hormones of the anterior and posterior pituitary. The anterior pituitary hormones regulate hormonal secretion and functional activities of many target structures throughout the body.

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To amygdala PVN

Locus coeruleus Parabrachial nuclei

Hypothalamus

Hypophyseal portal system in the median eminence

Anterior pituitary

Posterior pituitary

Nucleus tractus solitarius

To intramural ganglia

Vagus (X) nerve

Dorsal motor (autonomic) nucleus of X complex

Intermediolateral cell column in lateral horn To sympathetic chain ganglia, collateral ganglia, adrenal medulla

Thoracic spinal cord (T1-L2)

  16.12 PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS: REGULATION OF PITUITARY NEUROHORMONAL OUTFLOW, AUTONOMIC PREGANGLIONIC OUTFLOW, AND LIMBIC ACTIVITY The PVN has many projections that help to coordinate pituitary neurohormonal outflow, autonomic preganglionic outflow, and limbic activity. Magnocellular neurons send axons to the posterior pituitary, releasing oxytocin and vasopressin into the general circulation. Corticotropin-­releasing factor (CRF) neurons and some vasopressin neurons send axons to the median eminence; these axons release their hormones into the hypophyseal portal system, influencing the release of ACTH. PVN parvocellular neurons send direct descending projections to preganglionic neurons for the parasympathetics (dorsal motor nucleus of CN X) and sympathetics (intermediolateral cell column in the T1–L2 lateral horn of the spinal cord) and to the nucleus tractus solitarius. PVN parvocellular neurons also send axons to several important limbic-­related structures, such as the amygdaloid nuclei, parabrachial nuclei, and locus coeruleus.

CLINICAL POINT The PVN of the hypothalamus is a small region along the upper borders of the third ventricle in the dorsal hypothalamus. It contains a remarkable array of chemically specific neural populations. The magnocellular neurons produce oxytocin and vasopressin along with neurophysins and project to the median eminence. Some parvocellular neurons synthesize corticotropin-­releasing hormone and send axons to the contact zone of the median eminence, where corticotropin-­releasing hormone is released into the hypophyseal portal vessels. Parvocellular neurons also send descending projections to the brainstem (particularly the nucleus solitarius) and the intermediolateral cell column of the thoracolumbar spinal cord, where activation of the SNS can occur. The PVN therefore can coordinate the activation of both the neuroendocrine components (hypothalamic-­pituitary-­adrenal axis and cortisol secretion) and the autonomic components (sympathetic activation, diminished parasympathetic activity) of a stress response or activational response. The PVN receives inputs from many limbic regions and from brainstem sites (parabrachial nuclei, brainstem noradrenergic nuclei, nucleus tractus solitarius) that provide visceral information to the PVN. In addition, the PVN receives a variety of inputs that help it to monitor inflammatory mediators (IL-­1β, IL-­6, tumor necrosis factor [TNF]-­α, prostaglandin E2 [PGE2]), and other small molecules (nitric oxide) that reflect the outside chemical milieu. This information is received through the hypothalamus and circumventricular organs, and some of it through the vagus nerve afferents and nucleus tractus solitarius. Thus, PVN is a key regulatory site for behavioral responses that require autonomic reactivity.   

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Behaviors Influenced by Cytokines: Illness behavior Affective behavior Cognitive behavior Autonomic and neuroendocrine regulation Cerebral vasculature with blood-brain barrier (BBB) Interleukin-1 (IL-1) Other cytokines acting on brain: IL-6 (interleukin-6) TNF- (tumor necrosis factor-) IL-2 (interleukin-2) 1 Cytokines transported directly across the BBB Cytokines and prostaglandin E2 (PGE2) crossing 2 into cerebrospinal fluid at OVLT or acting on cells that release PGE2 or neurons that project to visceral-autonomic structures

1

2 3

Organum vasculosum of the lamina terminalis (OVLT) Vasculature to hypothalamus

Cytokine-stimulated release of small molecules 3 (such as nitric oxide and PGE2) that directly cross into the brain and act as mediators Cytokine and PGE2 stimulation of vagal afferents (through paraneurons) that modulate activity 4 in nucleus tractus solitarius, influencing the multiple activities of the paraventricular nucleus and many other sites Cytokine and PGE2 activation of other afferents 5 that modulate dorsal horn sensory processing to many sites Cytokine modulation of norepinephrine release 6 from sympathetic nerve terminals

8

Sensory ganglion of X

Nucleus tractus solitarius

Vagal afferents in viscera 4

Vagal efferents to intramural ganglia

Dorsal root ganglion

Paraganglion cells associated with Somatic Peripheral nerve vagal afferents afferents 5

Cytokine modulation of neurotransmitter intracellular 7 signaling in target cells

Sympathetic ganglion

Dorsal motor (autonomic) nucleus of X

Dorsal horn Spinal cord

6 Target

8 Cytokine modulation of pituitary hormone release

7

 

16.13 MECHANISMS OF CYTOKINE INFLUENCES ON THE HYPOTHALAMUS AND OTHER BRAIN REGIONS AND ON BEHAVIOR Cytokines, including IL-­1β, IL-­6, TNF-­α, and IL-­2, can influence central neuronal activity and behavior. This figure illustrates IL-­ 1β access to the brain: (1) directly crossing the blood-­brain barrier into the brain (especially in cortical regions); (2) acting on circumventricular organs (the OVLT) to release small mediators such as PGE2; (3) acting on vascular endothelial cells to release nitric oxide, which acts in the CNS; (4) activating vagal afferents that project into the nucleus tractus solitarius via paraganglion cells; and (5) activating other afferent nerve fibers. IL-­1β can evoke illness behavior (fever, induction of slow-­wave sleep, decreased appetite, lethargy, classical illness symptoms), can influence autonomic and neuroendocrine regulation, and can influence both affective and cognitive functions and behavior.

CLINICAL POINT There is a widespread influence of cytokines, especially inflammatory cytokines (IL-­1β, IL-­6, TNF-­α), as well as prostaglandin E2 (PGE2), on the nervous system. A key target of these influences is the PVN of the hypothalamus. Inflammatory cytokines can provoke a robust activation of cortisol secretion (through the hypothalamopituitary-­adrenal axis) and SNS activation (via descending projections of the PVN). The consequences of prolonged stress activation include increased risk for many chronic diseases, such as cardiovascular disease and stroke, metabolic syndrome, type II diabetes, and many cancers. The cytokines can influence the PVN and other central neurons through several mechanisms, including some direct transport into the forebrain, actions on neurons of the OVLT that release PGE2 and signal the PVN, release of nitric oxide and PGE2 from vascular endothelial cells, and activation of vagal afferents and other afferents that send neural signals to the PVN. Inflammatory cytokines also can stimulate the release of some hormones from pituitary cells, can alter neurotransmitter release in both the CNS and the autonomic nervous system (especially sympathetic norepinephrine), and can interact with neurotransmitter effects on target cells of autonomic innervation. Other cytokines such as IL-­2 also appear to have central effects; the infusion of IL-­2 in immunotherapy for some cancers was curtailed because of adverse effects of IL-­2 on the brain, including depression and suicidal behavior.   

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Subfornical organ

Subcommisural organ Pineal gland

Organum vasculosum of the lamina terminalis (OVLT)

Median eminence Posterior pituitary (neurohypophysis)

Area postrema

 

16.14 CIRCUMVENTRICULAR ORGANS Circumventricular organs are “windows on the brain” that are devoid of the usual tight junction endothelial appositions and instead have fenestrated vasculature. Thus, the circumventricular organs have no blood-­brain barrier. Some of these organs (the OVLT, the subfornical organ, and the area postrema) have associated neurons that project to the hypothalamic and other visceral structures. They also have cells that can release small molecules such as PGE2 into the cerebrospinal fluid, thus affecting target structures at a distance. The neurohypophysis is a site of axonal release (from PVN and SON magnocellular neurons) of oxytocin and arginine vasopressin into the general circulation. The median eminence is a zone of neuroendocrine transduction for the secretion of releasing factors and inhibitory factors into the hypophyseal portal vasculature; these factors influence the release of anterior pituitary hormones. The pineal gland synthesizes and releases the hormone melatonin.

CLINICAL POINT The CNS is protected from damage caused by many potentially harmful substances in the periphery by the blood-­brain barrier. The CNS capillary endothelial cells contain tight junctions as well as specific transport mechanisms for the uptake of certain important substances (such as amino acids needed for neurotransmitter synthesis, glucose). Brain capillaries also can actively pump some substances out of the brain. Some regions of the brain contain fenestrated capillaries, and this permits the sampling of circulating substances. These are the circumventricular organs. The area postrema contains neurons that project to the nucleus tractus solitarius and activate the vomiting reflex. The subfornical organ contains neurons that respond to salt content in the blood and elicit protective neuroendocrine responses. The OVLT contains neurons that help to regulate blood pressure through an angiotensin II mechanism; these neurons also regulate PGE2 availability to the PVN and other central areas to influence activation of the hypothalamo-­pituitary-­adrenal axis and the SNS. The OVLT and subfornical organ also respond to pyrogens and help to regulate hypothalamic responses for control of body temperature. At the median eminence, circulating hormones and other substances can interact with the projecting axonal terminals that secrete releasing hormones and inhibitory hormones at the contact zone for regulation of anterior pituitary hormonal secretion. The posterior pituitary and the pineal gland also have fenestrated capillaries, enabling their secretion of hormones directly into the systemic circulation.   

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Circumventricular Organs: Functional Considerations Structure

Location and Functional Roles

Organum • Location: anteroventral region of the third ventricle vasculosum of • Contains osmoreceptors, responds to osmotic factors; helps to regulate vasopressin secretion from magnocellular the lamina paraventricular nucleus (PVN) and supraoptic nucleus (SON) neurons. Projects to median preoptic nucleus to help terminalis (OVLT) control thirst • Angiotensin II stimulates OVLT (and subfornical organ), elevating blood pressure (BP) • Produces IL-1β during fever; helps provoke illness behavior • Responds to Na+ and increases lumbar sympathetic and adrenal catecholamine reactivity, elevating BP Subfornical organ

• Location: just below the fornix at rostral end of the third ventricle • Senses Na+ concentration and dehydration; controls water intake • Excited by angiotensin II and cholecystokinin; influences water intake and BP, triggers drinking behavior • Angiotensin II may help to drive chronic hypertension • Responds to glucose during hyperglycemia • Responds to ghrelin to increase food intake, responds to satiety signal molecules amylin and leptin, providing a dual feeding response

Subcommissural organ (SCO)

• Location: dorsal caudal region of third ventricle, near the aqueduct • Ependymal cells produce transthyretin, which helps to move cerebrospinal fluid (CSF), transport thyroid hormone in the blood • Secretes transthyretin and other glycoproteins, and basic fibroblast growth factor into adult and fetal CSF; may regulate neuronal stem cell production, neuronal differentiation, and axonal growth and extension • Secretes basic fibroblast growth factor: a mitogenic factor and brain repair molecule • Secretes SCO-spondin: helps commissural axonal connectivity • May be involved in water balance • Receives extensive inputs from dopamine, norepinephrine, neuropeptides, CSF factors

Area postrema

• Location: at the inferior and posterior limit of fourth ventricle, near obex • Detects toxins in the blood, triggers nausea and vomiting; integrates humoral and neural signaling; a lesion prevents detection of poisons and vomiting response, impairs taste aversion • Integrates visceral information from vagal and sympathetic afferent inputs; area postrema connects with nucleus solitarius, triggers nausea and vomiting • Integrates cardiovascular, feeding, and metabolic responses, osmoregulation and electrolyte balance, and BP control • Responds to opiates to trigger nausea and vomiting • Transports many substances into and out of the CSF (as do tanycytes)

Pineal

• Location: in epithalamus, near the center of the brain • Pinealocytes synthesize melatonin (stimulated in dark, inhibited in light) • Melatonin synthesized from serotonin, through a rate-limiting enzyme (serotonin N-acetyl transferase), regulated by sympathetic norepinephrine input from superior cervical ganglion; pathway for control is retina to suprachiasmatic nucleus to PVN of the hypothalamus to preganglionic neurons in T1–T2 lateral horn or directly to pineal • Modulates sleep patterns in circadian rhythms and seasonal rhythms • Modulates follicle-stimulating hormone and luteinizing hormone as an “antigonadotropin” response • Exogenous melatonin may help to entrain new sleep patterns in jet lag • Brainstem parasympathetics and PVN and other hypothalamic nuclei may directly innervate the pineal, in addition to sympathetics

Median eminence

• Location: upper part of the infundibular stem (stalk); lacks neurons • Provides a contact zone of capillary loops onto which nerve terminals of the tuberoinfundibular tract secrete hypophysiotropic hormones (releasing and inhibitory factors for anterior pituitary hormones) into the hypophysealportal closed vascular system • Hypophysiotropic hormones: CRF, gonadotropin-releasing hormone, thyrotropin-releasing hormone, growth hormone–releasing hormone, dopamine (prolactin inhibitory factor), vasopressin, and many other neuromodulators

Neurohypophysis • Location: posterior region of the pituitary gland, beneath hypothalamus (posterior • A site where oxytocin and vasopressin are secreted by axon terminals from neurons of PVN and SON into the pituitary) systemic circulation

 

16.15 CIRCUMVENTRICULAR ORGANS: FUNCTIONAL CONSIDERATIONS

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Blood Supply of Hypothalamus and Pituitary Gland

Hypothalamic vessels

Section through paraventricular nucleus (vessels injected )

Primary plexus of hypophyseal portal system Anterior branch

Long hypophyseal portal veins

Posterior branch

Short hypophyseal portal veins

Superior hypophyseal artery

Artery of trabecula Capillary plexus of infundibular process

Trabecula Efferent vein to cavernous sinus

Posterior lobe

Anterior lobe Similar section through supraoptic nucleus Secondary plexus of hypophyseal portal system Stalk Anterior lobe Posterior lobe

Efferent vein to cavernous sinus Lateral branch and Medial branch of Inferior hypophyseal artery

Efferent vein to cavernous sinus Cavernous sinus Internal carotid artery Posterior communicating artery Superior hypophyseal artery Portal veins Lateral hypophyseal veins Inferior hypophyseal artery Posterior lobe veins

Inferior aspect

 

16.16 THE HYPOPHYSEAL PORTAL VASCULATURE The hypophyseal portal vascular system derives from arterioles coming into the median eminence at the base of the hypothalamus. The primary capillary plexus is a site where releasing and inhibitory factors that influence the secretion of anterior pituitary hormones are

released from axons (neurocrine secretion) whose neurons reside in the hypothalamus and other CNS sites. These releasing and inhibitory factors then travel through venules into the secondary capillary plexus in very high concentrations and act directly on anterior pituitary cells that synthesize and secrete the hormones of the anterior pituitary.

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Emotional and exteroceptive influences via afferent nerves to hypothalamus

Paraventricular nucleus Neurons for releasing, and inhibitory factors for growth hormone, FSH, LH, TSH (representative)

CRF (CRH) neuron VP, OXY

Supraoptic nucleus

Blood-borne molecular influences on CRF neurons

Hypothalamic artery

Neurosecretion of releasing factors and inhibitory factors from hypothalamus into primary plexus of hypophyseal portal circulation Hypophyseal portal veins carry neurosecretions to anterior lobe

Superior hypophyseal artery

Specific secretory cells of anterior lobe (adenohypophysis) influenced by neurosecretions from hypothalamus

Blood levels—regulatory influence

Posterior lobe (neurohypophysis)

Skin (melanocytes)

MSH

GH

IGF-1

TSH

ACTH

LH

FSH

Prolactin

Fat tissue Thyroid gland

Thyroid hormones

Testis

Ovary

Adrenal cortex

Cortical hormones

Bone, muscle, organs (growth)

Testosterone and inhibin

Estrogen, progesterone, and inhibin

  16.17 REGULATION OF ANTERIOR PITUITARY HORMONE SECRETION

See next page.

Breast (milk production)

Muscle

Autonomic-Hypothalamic-Limbic Systems

16.17 REGULATION OF ANTERIOR PITUITARY HORMONE SECRETION Neurons that synthesize releasing and inhibitory factors for control of anterior pituitary hormones send axons that terminate on the primary plexus of the hypophyseal portal system (the zone of neuroendocrine transduction) and release these factors into the hypophyseal portal blood. These factors then flow into the secondary hypophyseal portal plexus and regulate the release of anterior pituitary hormones. The major anterior pituitary hormones are thyroid-­stimulating hormone (TSH), adrenal corticotropic hormone (ACTH), follicle-­stimulating hormone (FSH), luteinizing hormone (LH), prolactin (LTH), growth hormone (GH), and melanocyte-­stimulating hormone (MSH). These anterior pituitary hormones act on peripheral target organs to effect release of target organ hormones or to influence metabolic and functional activities. For example, CRF neurons release CRF (CRH, corticotropin-­releasing hormone) into the hypophyseal portal blood, regulating the release of ACTH, which in turn regulates the release of cortisol from the adrenal cortex. Magnocellular neurons of the PVN and SON send axons directly to the posterior pituitary and release oxytocin and arginine vasopressin directly into the systemic circulation. CLINICAL POINT The term hypopituitarism refers to the deficiency or absence of one or more anterior pituitary hormones. The process of pituitary dysfunction can be very slow in onset because of the great reserve; more than 75% of the anterior pituitary must be destroyed before symptoms become evident. Pituitary damage may result from tumors, ischemia and infarction, infiltrative lesions (e.g., sarcoidosis), head injury, immunological damage during pregnancy, or other causes. With some tumors such as pituitary adenomas initial symptoms may occur because of disruption of releasing hormones, such as gonadotropin-releasing hormone (GnRH), leading to elevated secretion of prolactin, FSH, LH, and ACTH and cortisol, producing gonadal dysfunction. With progressive pituitary insufficiency, the first hormones to markedly fall generally are growth hormone (GH), which is highly conspicuous in children whose growth is impaired, and gonadotropins, causing amenorrhea in women and impotence or sexual dysfunction in men. At a later stage, impairment of TSH, ACTH, prolactin, and other hormones occurs; hormonal replacement therapy

453

is necessary. Diabetes insipidus caused by posterior pituitary damage also may accompany pituitary insufficiency. Many pituitary tumors secrete anterior pituitary hormones, leading to symptoms of pituitary hypersecretion. Prolactinomas (adenomas) result in excess prolactin secretion, gonadal dysfunction, and galactorrhea. GH-­secreting adenomas result in gigantism if they are present before the epiphyseal plates of the long bones are closed and in acromegaly in adults, with soft tissue enlargement, enlarged hands and feet, and coarse facial features. ACTH-­secreting adenomas lead to Cushing’s disease. Pituitary tumors commonly impinge on the optic chiasm and produce bitemporal visual field defects (bitemporal hemianopia), usually starting in the upper outer fields.   

CLINICAL POINT The hypothalamus and anterior pituitary gland are subject to extensive hormonal feedback. In the hypothalamo-­pituitary-­adrenal (HPA) axis, cortisol acts via a negative long feedback loop to inhibit the secretion of both ACTH and CRH (CRF). ACTH acts via a short feedback loop to inhibit the secretion of CRH. Exogenous administration of corticosteroids also results in feedback inhibition of ACTH and CRH. High cortisol levels can result in hypertension, muscle weakness, mood alterations, polydipsia and polyuria, weight gain, moon-­like facies, and other symptoms. The regulation of thyroid hormone secretion involves hypothalamic thyrotropin-­releasing hormone (TRH) stimulating the release of TSH from the anterior pituitary, which acts on the thyroid gland to stimulate the release of the thyroid hormones triiodothyronine (T3) and thyroxine (T4). T3 and T4 feed back on the anterior pituitary and hypothalamus to inhibit the secretion of TRH and TSH. Administration of exogenous thyroid hormone produces the same negative feedback loop. Thyroid-­binding globulin (TBG) is a human protein that helps to transport T3 and T4 into the blood. Thus, thyroid hormones in the blood can be free T3 and T4 as well as bound T3 and T4. Sex steroids are regulated through the hypothalamus and the anterior pituitary. Hypothalamic GnRH stimulates the release of LH and FSH from the anterior pituitary, which act on the testes in males to produce testosterone and on the ovaries in females to produce estradiol and progesterone, which regulate menstruation and the reproductive cycle. Long-­term exogenous testosterone in males may exert initial desirable effects on muscle mass, libido, and other characteristics but also may act in a negative manner to diminish spermatogenesis, shrink the testes, increase the risk of clotting, and increase the risk of strokes and heart attacks.   

454

Systemic Neuroscience Neurosecretory endings (posterior pituitary)

Forebrain pathways

Pituicyte processes Axon

Axon

Magnocellular neuron Brainstem pathways

Magnocellular neuron of the supraoptic nucleus demonstrating extensive horizontal and vertical dendritic arborizations. Golgi-Cox stain.

Fibroblast Neurosecretory Endothelium vesicles Collagen space Mast cell Paraventricular Basement nucleus (PVN) membrane Supraoptic Origin of vasopressin nucleus (SON) Cell of supraoptic nucleus Capillary

Arterial supply to hypothalamus

Blood-borne signals reaching SON and PVN

Neurohypophyseal tract Herring bodies Anterior lobe

Posterior lobe (neurohypophysis) Site of vasopressin absorption Venous drainage of posterior lobe

Axonal transport of secretory product

Fenestrated capillary

Posterior lobe

Inferior hypophyseal artery

  16.18 POSTERIOR PITUITARY (NEUROHYPOPHYSEAL) HORMONES: OXYTOCIN AND VASOPRESSIN Magnocellular neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) send axons directly through the infundibular region and the pituitary stalk to terminate on the vasculature in the posterior pituitary. Neurons from both nuclei synthesize and release oxytocin and arginine vasopressin into the systemic vasculature. Brainstem and forebrain pathways terminate on the magnocellular neurons and regulate their secretion of oxytocin and vasopressin. These magnocellular neurons possess extensive protein synthesis capacity and transport the vesicles in which their hormones are packaged to the axon terminals with very fast axoplasmic transport. The hormones are released from the terminals and diffuse through the fenestrated capillaries directly into the systemic vasculature (see inset of neurosecretory efferent endings from magnocellular neurons in PVN and SON). CLINICAL POINT The SON and magnocellular neurons of the PVN of the hypothalamus synthesize and secrete both oxytocin and arginine vasopressin (antidiuretic hormone, or ADH), along with their neurophysin

carrier proteins. A majority of vasopressin comes from the SON, and a majority of oxytocin comes from magnocellular PVN. These neuronal groups send axons (the supraopticohypophyseal tract) into the posterior pituitary, where they terminate on fenestrated capillaries and secrete their hormones directly into the systemic circulation. These neurons are called neuroendocrine transducer cells. Oxytocin cells respond to estrogen and to afferent signals caused by suckling, and they stimulate milk let-­down (milk ejection reflex) and uterine contraction in pregnancy. Vasopressin neurons respond to changes in blood osmolarity, secreting vasopressin in the presence of high osmolarity. This causes the collecting tubules in the kidney to increase water resorption and prevent diuresis. If the supraopticohypophyseal tract or associated neurons (seen in congenital disorders) are damaged, as happens with pituitary stalk sectioning, diabetes insipidus results. Diabetes insipidus involves the loss of vasopressin secretion and the production of huge amounts (10+ liters per day) of dilute urine, provoking marked polydipsia. Vasopressin replacement therapy is necessary. Alcohol consumption, some antiseizure drugs (phenytoin), and anticholinergic agents may also inhibit vasopressin secretion. Excessive vasopressin secretion (called inappropriate secretion of ADH, or SIADH) may occur because of partial damage to the hypothalamus, a vasopressin-­secreting tumor in the periphery (e.g., lung carcinoma), or as the result of treatment by chemotherapeutic and other pharmacological agents. SIADH results in hypo-­osmolar serum, hyponatremia, and high urine osmolarity.   

Autonomic-Hypothalamic-Limbic Systems

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Mechanism of Antidiuretic Hormone in Regulating Urine Volume and Concentration ADH is produced in supraoptic and paraventricular nuclei of the hypothalamus and descends along nerve fibers to the neurohypophysis, where it is stored for subsequent release.

Blood osmolality and volume are modified by fluid intake (oral or parenteral); water and electrolyte exchange with tissues, normal or pathological (edema); loss via gut (vomiting, diarrhea); loss into body cavities (ascites, effusion); or loss externally (hemorrhage, sweat).

ADH release is increased by high blood osmolality affecting hypothalamic osmoreceptors and by low blood volume affecting thoracic and carotid volume receptors; low osmolality and high blood volume inhibit ADH release.

H 2O

H2O

In the presence of ADH, blood flow to the renal medulla is diminished, thus augmenting hypertonicity of the medullary interstitium by minimizing depletion of solutes via the bloodstream.

H2O

ADH causes walls of collecting ducts to become more permeable to water and thus permits osmolar equilibration and absorption of water into the hypertonic interstitium; a small volume of highly concentrated urine is excreted.

H2O Max Plasma (ADH)

Plasma (ADH)

Max

H2O

0 310 270 290 Plasma osmolality (mOsm/kg H2O)

0 302010 0 10 20 % Change in blood volume or pressure

 

16.19 VASOPRESSIN (ANTIDIURETIC HORMONE) REGULATION OF WATER BALANCE AND FLUID OSMOLALITY Vasopressin regulates the volume of water secreted by the kidneys. Its secretion is regulated by the osmolality of body fluids and by blood volume and pressure. Changes in body fluid osmolality of a small percentage are sufficient to significantly alter vasopressin secretion.

Decreases in blood volume and pressure of 10% to 15% or more are needed to affect vasopressin secretion. The blood volume and pressure sensors are found in the large pulmonary vessels, the carotid sinus, and the aortic arch. These baroreceptors respond to the stretching of the vessel wall, which is dependent on blood volume and pressure. The figure shows the mechanisms of action of vasopressin on the kidney, with resultant effects on urine volume and concentration.

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Systemic Neuroscience

Afferent inputs from limbic forebrain structures

Thermoreception and regulation of heat loss

Conservation and production of heat

Inflammatory cytokines, pyrogens Neurohumeral mechanism for increasing thyrotropic activity of anterior lobe to elevate metabolism Pituitary gland Thyrotropic hormone

Shivering

Respiratory centers

Increased thyroid activity

Cardiovascular regulation centers Accelerated respiration, panting

37°C (98.6°F)

Cutaneous blood vessel constriction (dilation)

Acetylcholine

Sympathetic trunk ganglion

Perspiration

 

16.20 THE HYPOTHALAMUS AND THERMOREGULATION The preoptic area of the hypothalamus contains heat-­sensitive neurons, and the posterior hypothalamic area contains coldsensitive neurons. The preoptic area and the anterior hypothalamic area initiate neuronal responses for heat dissipation (parasympathetic); the posterior hypothalamic area initiates neuronal responses for heat generation (sympathetic). Neuronal pathways arising from the brainstem and limbic forebrain areas can

modulate the activity of these thermoregulatory systems. The preoptic area is responsive to pyrogens and the inflammatory cytokine IL-­1β; this area can generate an increased set point for temperature regulation, thus initiating a disease-­associated fever. Extensive hypothalamic connections with the brainstem and spinal cord are used to initiate appropriate heat-­dissipation or heat-­ generation responses. Appropriate behavioral responses also are initiated to optimize thermoregulation (e.g., going to a warmer or cooler location).

Autonomic-Hypothalamic-Limbic Systems

Paraventricular nucleus and lateral hypothalamus

457

Emotional stress or anticipation of exercise may stimulate sympathetic nerves via hypothalamus Medial prefrontal cortex Amygdala Afferent nerve fibers from baroreceptors in carotid sinuses via glossopharyngeal nerves (IX) and in aorta via vagus nerves (X) form afferent limbs of reflex arcs to vagus and sympathetic efferents IX

Nucleus of solitary tract Dorsal motor (autonomic) nucleus of X Ventral medullary cardiovascular centers Descending tract to spinal intermediolateral cell column

Carotid sinuses

X Vagus efferent cardiac fibers go chiefly to SA node and AV node: stimulation causes release of acetylcholine at nerve endings, slowing heart rate and conduction; vagal inhibition causes acceleration of heart rate and conduction Sympathetic efferent-fiber stimulation accelerates heart rate, increases force of contraction, and dilates coronary arteries by releasing norepinephrine at nerve endings, stimulating  receptors. Sympathetic trunk Sympathetic vasoconstriction Increased pH heightens catecholamine and lowers acetylcholine actions. pH

Output of catecholamines from adrenal medulla promoted by sympathetic stimulation

Circulating catecholamines have same action on arteries as sympathetic efferent nerves

 

16.21 HYPOTHALAMIC REGULATION OF CARDIAC FUNCTION Regulation of cardiovascular (CV) function by the brain involves several domains of neuronal control. In the forebrain, medial prefrontal cortex, limbic cortical areas, and amygdaloid nuclei mediate emotional and behavioral responses and influence cardiovascular function. These forebrain areas act through projections to the hypothalamus (lateral hypothalamic area, paraventricular nucleus, preoptic and anterior hypothalamic areas for parasympathetic control, and the posterior hypothalamic area for sympathetic control). These hypothalamic regulatory regions send projections to many brainstem sites, including the parabrachial nuclei, ventral medullary cardiovascular centers, nucleus solitarius, the dorsal

motor (autonomic) nucleus or X, and the intermediolateral cell column of the thoracic spinal cord lateral horn. The parabrachial nuclei also respond to visceral afferent input and nociceptive input to regulate CV responses to pain, respiratory challenges, and gastrointestinal activity. The ventromedial CV medullary area generates CV responses needed for thermogenesis, and the ventrolateral CV medullary area helps to maintain blood pressure and CV responses during an upright posture and is responsive to baroreceptor reflexes. The nucleus solitarius is a major integrative center for descending (limbic and hypothalamic), local brainstem, and ascending regulation of autonomic preganglionic responses (dorsal motor [autonomic] nucleus of X for parasympathetic, intermediolateral cell column for sympathetic).

Systemic Neuroscience

Cervical

SYMPATHETIC Brainstem

Brainstem

PARASYMPATHETIC

Ganglion Vagus nerves

ACh ACh SA NE

Cervical

458

Ganglion

ACh AV NE

ACh

Adrenal medulla 80 % E

Thoracic

Thoracic

NE

ACh

20 % NE

ACh

Sacral

ACh

Spinal cord

Some vascular beds

ACh

Lumbar

NE

Change in posture (sitting to standing) Venous return

Sympathetic efferent nerve activity (% baseline)

Lumbar

Small arteries and arterioles

200

100

Stroke volume

Parasympathetic efferent output SA node

Heart rate

CNS (medulla)

Cardiac output

0

MAP Firing rate of baroreceptor afferent fibers

MAP

0 100 MAP (mm Hg)

200

Sympathetic efferent output Arterioles

Veins

Ventricle

Venous return

Contractility

Peripheral resistance Cardiac output

Stroke volume

 

16.22 SHORT-­TERM REGULATION OF BLOOD PRESSURE Both the sympathetic and parasympathetic divisions of the autonomic nervous system are involved in maintaining blood pressure on a second-­by-­second basis. Numerous descending pathways from the brainstem (including the nucleus tractus solitarius, tegmental catecholamine nuclei, locus coeruleus, raphe nuclei, rostral ventrolateral medulla and other medullary reticular regions, parabrachial nuclei, angiotensin II–containing neurons, and many other sites) and the hypothalamus

regulate the outflow of autonomic preganglionic neurons associated with short-­term blood pressure regulation. The hypothalamus and the nucleus tractus solitarius are key sites integrating limbic forebrain and cortical influences over these brainstem regions that regulate blood pressure. The brainstem sites have extensive interconnections with each other. The example of blood pressure regulation in this figure is based on change in posture. ACh, acetylcholine; AV, atrioventricular node; E, epinephrine; MAP, mean arterial pressure; NE, norepinephrine; SA, sinoatrial node.

Autonomic-Hypothalamic-Limbic Systems

Response to Decreased Blood Volume and Pressure

Response to Increased Blood Volume and Pressure

Thirst

Sympathetic nerve activity

459

Sympathetic nerve activity

ADH Brain

ADH Brain

CN IX, X

CN IX, X

Angiotensin II

Heart and lungs

Heart and lungs ANP

Liver

Adrenals

Angiotensinogen

Adrenals

Angiotensin I

Aldosterone Renin and angiotensin II

Renin (decreases NaCl excretion) Aldosterone (stimulates renin secretion and decreases NaCl excretion)

Kidneys

(decreases water excretion)

Kidneys

NaCl and H2O excretion

Blood volume and pressure

NaCl and H2O excretion

(increased H2O intake)

Blood volume and pressure

 

16.23 LONG-­TERM REGULATION OF BLOOD PRESSURE When blood volume and blood pressure change, the kidneys respond by either retaining NaCl and water or excreting NaCl and water in order to restore blood volume to its normal homeostatic state. With increased sympathetic activation,

norepinephrine and epinephrine secretion from sympathetic nerve terminals and the adrenal medulla increase in the circulation and act on the kidneys to reduce NaCl excretion. ADH, antidiuretic hormone [also called vasopressin]; ANP, atrial natriuretic peptide.

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Systemic Neuroscience

Smell Ventromedial hypothalamic area of food (inhibitory: “satiety center”) Lateral hypothalamic area (facilitative: “appetite center”)

Thalamus Sight of food Calcarine fissure

I Touch (sucking reflex)

II

Geniculate bodies (schematic)

Memory and/or fantasy

V Taste of food

Dorsal nucleus of vagus

VII

Chorda tympani

VIII Nucleus of solitary tract IX X

Hearing (sounds of food preparation, call to dinner, Decreased levels bell, etc.) of CCK, GLP-1, and leptin

Vagus nerve Thoracic sympathetic ganglionic chain

Dorsal root ganglion

T6

Depletion of body nutrient stores

Myenteric and submucous plexuses

T7 T8

Mode of inducing hunger contractions unknown KEY Sympathetic efferents Parasympathetic efferents Afferents (and CNS connections) Indefinite paths

Thoracic splanchnic nerves

T9

T10

Hunger contractions in stomach

Celiac ganglion

 

16.24 NEURAL CONTROL OF APPETITE AND HUNGER The sensations of hunger and satiety are complex and include multiple neural pathways and circulating hormones. This figure depicts pathways involved in the sensation of hunger. Although our understanding is incomplete, the hypothalamus is known to play a critical role in controlling appetite and food intake. When food is ingested, cholecystokinin (CCK) and glucagon-­like peptide (GLP-­1) are released from neuroendocrine cells in the intestine. These hormones suppress appetite and give the sensation of

satiety. In the absence of food, the levels of these hormones are low. Long-­term regulation of food intake involves the hormone leptin, which is produced by fat cells. When fat stores are high, leptin is released and appears to act on the hypothalamus to suppress appetite. When body nutrient stores are depleted, leptin levels are low. Other hormones such as ghrelins also are involved with control of hunger and satiety. Both the cerebral cortex and limbic forebrain structures have regulatory connections with this hypothalamic circuitry, permitting cognitive and emotional factors to influence appetite and eating behavior.

Autonomic-Hypothalamic-Limbic Systems

461

Arcuate nucleus Brain

Third ventricle Second order neuron

POMC NPY AgRP

Hunger signal Ghrelin

GABA

Nutrientrelated signals

Adiposity signals Insulin

Food intake

Energy expenditure Energy balance

Leptin Liver Adipose mass

Stomach

Pancreas

Glucose production Plasma glucose

 

16.25 SIGNALING SYSTEMS INVOLVED IN REGULATION OF FOOD INTAKE, BODY WEIGHT, AND METABOLISM The hypothalamus regulates food intake, body weight, and metabolism. The hormone ghrelin is produced by the gastric mucosa of the stomach when it is empty and stimulates cells in the arcuate nucleus of the hypothalamus to bring about increased food intake. The hormone leptin is made by white adipose tissue during robust metabolic activity and also acts on cells in the arcuate nucleus. High levels of ghrelin and low levels of leptin stimulate food intake, but high levels of leptin do not suppress eating activity. Ghrelin and leptin have access to the arcuate nucleus neurons through the hypophyseal portal vessels, which are devoid of a blood-­brain barrier. These hormones act on cells of the arcuate nucleus that use neuropeptide Y (NPY) and agouti-­related

protein (AgRP) as neurotransmitters. These arcuate neurons act through connections in the hypothalamus with the paraventricular nucleus, ventromedial nucleus, dorsomedial nucleus, and lateral hypothalamic area, and with descending connections with the parabrachial nuclei, and can activate feeding behavior. Other neurons in the arcuate nucleus, using proopiomelanocortin (POMC) derivatives such as alphamelanocyte-stimulating hormone and beta-­endorphin, have connections with these same hypothalamic and brainstem targets and can suppress feeding behavior. Circadian-­related circuits from the suprachiasmatic nucleus project to these same hypothalamic nuclei, superimposing circadian influences on feeding behavior. Superimposed on this circuitry are limbic and cortical connections, including olfactory projections, which can provide emotional, behavioral, or volitional components to the control of food intake and appetite.

462

Systemic Neuroscience Ascending arousal pathways

Thalamus LHA (ORX, vPAG glutamate) (DA) BF (ACh, GABA)

LDT (ACh) TMN (His)

Cholinergic pathway to open up thalamocortical transmission

PPT (ACh)

Cerebellum

PB/PC (Glutamate)

Raphe (5-HT) LC (NE)

Monoaminergic and glutamatergic pathways to activate cerebral cortex

Pons

VLPO and MnPO axons innervate the entire ascending arousal system

Thalamus VLPO/MnPO (GABA, Gal)

LHA (ORX, glutamate) vPAG (DA) LDT (ACh)

TMN (His)

VLPO/MnPO axons

PPT (ACh)

Cerebellum

PB/PC (Glutamate)

Raphe (5-HT) LC (NE)

Pons

  16.26 HYPOTHALAMIC REGULATION OF SLEEP AND WAKING STATES The state of alertness or wakefulness is dependent on neuronal systems that originate from the rostral pons and caudal midbrain and include cholinergic neurons (pedunculopontine tegmental nucleus [PPT] and the laterodorsal tegmental nucleus [LDT]), noradrenergic neurons (locus coeruleus), serotonergic neurons (dorsal raphe nucleus, central superior nucleus), dopamine neurons (ventral periaqueductal gray), histaminergic neurons (tuberomammillary nucleus), and glutaminergic neurons (parabrachial nucleus, pre-­coeruleus nucleus). Projections from this collection of chemically specific neurons funnel into the lateral hypothalamic area and are joined by axons originating from this area (orexin neurons and glutaminergic neurons). This array of axons then is joined in the basal forebrain by cholinergic and

γ-­aminobutyric acid (GABA)-­ergic neurons to collectively activate cortical neurons for processing information. The more caudal cholinergic projections inhibit the sheet-­like reticular nucleus of the thalamus, which helps to activate the thalamic relay nuclei projecting to the cortex. During sleep, the activity of these multiple pathways diminishes. During REM sleep, some cholinergic and glutaminergic neurons demonstrate rapid firing, while the monoaminergic neurons cease firing. Sleep is regulated by hypothalamic neurons in the median preoptic (MnPO) nucleus and ventrolateral preoptic (VLPO) nucleus, whose neurons begin firing at the onset of sleep. VLPO communicates with the ascending systems above, using GABA and galanin to diminish arousal.

Autonomic-Hypothalamic-Limbic Systems

463

Neural, Neuroendocrine and Systemic Components of Rage Reaction Rage pattern released and directed by cortex and limbic forebrain Fornix (from hippocampal formation) Mammillothalamic tract Hypothalamus (blue: parasympathetic; red: sympathetic)

Corticohypothalamic pathways

Dorsal longitudinal fasciculus; median forebrain bundle, and other descending pathways

Orbitofrontal cortex Median forebrain bundle

Thyrotropin (elevates metabolism)

Olfactory bulb III to pupils (constriction) VII to sublingual and submaxillary glands (secretion) IX to parotid gland (secretion)

X to heart and GI tract (depresses heart rate and intestinal motility) To heart Adrenocorticotropin (releases (elevates rate) cortisol, provokes stress reaction)

To Splenic contraction adrenal To vessels of skin medulla (leukocytes and Spinal nerve (effecting rise platelets pressed (contraction) and muscles (dilation) in blood sugar out) and visceral vasoconstriction) To GI tract and vessels (depression Prevertebral ganglion of motility; vasoconstriction)

Pelvic nerve (sacral parasympathetic outflow)

Thoracic part of spinal cord

Sympathetic trunk ganglia

Sacral part of spinal cord

To lower bowel and bladder (evacuation)

 

16.27 NEURAL AND NEUROENDOCRINE ROLES IN THE FIGHT-­OR-­FLIGHT RESPONSE The classic sympathetic fight-­or-­flight response, shown here as a rage response, involves the secretion of neuroendocrine “stress hormones,” including cortisol from the hypothalamopituitary-­adrenal (HPA) axis and norepinephrine and epinephrine from sympathetic nerve terminals and the adrenal medulla. Sympathetic connections with the viscera initiate physiological changes to support the integrated fight-­or-­f light response. These changes include diversion of blood from the

viscera and skin to the muscles, increased heart rate and cardiac output and contractility, bronchodilation, pupillary dilation, decreased gastrointestinal activation, decreased renal activity, glycogenolysis from the liver with increased blood glucose for fuel, and many other actions. Inputs from limbic forebrain regions, the cerebral cortex, and the brainstem regulate the complex hypothalamic control of neuroendocrine and autonomic outflow and are key in initiating the classic fight-­ or-­f light response. In this response, the brainstem parasympathetic neurons are inhibited.

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Systemic Neuroscience

Nerve terminals

Limbic forebrain areas (cingulate cortex, amygdala)

Nerve fibers Cerebral cortex PVN Extensive tyrosine hydroxylase (TH)-positive noradrenergic nerve fibers and terminals in parenchymal regions of the medullary cords and paracortex of a mesenteric lymph node. Immunohistochemical stain for TH.

Median eminence

Cytokine and inflammatory mediator feedback to the brain and pituitary Vascular delivery of neuroendocrine hormones to lymphoid organs and other peripheral structures Thymus Bone marrow

ACTH, GH, prolactin, MSH, -end, TSH, LH, FSH Releasing and inhibiting factors Norepinephrine, epinephrine

ACTH

Preganglionic vagal efferents

Cortisol

Vagus (X) nerve

Brainstem nuclei (autonomic)

Nucleus tractus solitarius Dorsal motor (autonomic) nucleus of X

Pulmonary MALT

Spleen Lymph nodes Gut-associated lymphoid tissue (GALT)

Preganglionic sympathetic axon

Adrenal medulla Adrenal cortex

Collateral sympathetic ganglion

Sympathetic chain

Skin lymphoid tissue

NA postganglionic sympathetic innervation of parenchymal regions of the thymus. GA fluorescence histochemistry.

 

16.28 NEUROIMMUNOMODULATION Connections from the cerebral cortex, limbic forebrain, hypothalamus, and brainstem can exert extensive modulation of autonomic preganglionic outflow and neuroendocrine outflow. Hormones and neurotransmitters from this outflow target lymphoid organs and cells of the immune system. This circuitry provides the substrate for behavior, emotional responsiveness, chronic stressors, and positive complementary and behavioral interventions to influence immune responses. Sympathetic postganglionic noradrenergic fibers directly innervate virtually all organs of the immune system, including (1) primary lymphoid organs (bone marrow, thymus), (2) secondary lymphoid organs (spleen, lymph nodes), (3) mucosa-­associated lymphoid organs (gut and lung), and (4) skin-­ associated lymphoid cells. Vagal postganglionic nerve fibers innervate pulmonary-­and gut-­associated lymphoid tissue. Pituitary hormones in the circulation (e.g., CRF, ACTH, prolactin, GH, endorphins) and their target organ hormones (cortisol, thyroid hormone) modulate immune reactivity in all lymphoid organs. Cortisol, norepinephrine, and epinephrine are particularly important in mediating chronic stress responses related to immune reactivity. Circulating and local cytokines and inflammatory mediators act on the brain and pituitary to provide feedback information from lymphoid organs (immune-­neural signaling) and can modulate CNS neurotransmitter turnover, inflammatory responses, and illness behavior. The gene expression of hormones from secretory cells, cytokines from cells of the immune system, and neurotransmitters from neurons innervating lymphoid organs can be regulated by the presence of multiple signal molecules in the local environment. Some mediators are

produced by neurons, paracrine cells, and cells of the immune system and modulate all of these systems. GALT, gut-­associated lymphoid tissue; MALT, mucosa-­associated lymphoid tissue. CLINICAL POINT The PVN of the hypothalamus is a key regulatory site for neural modulation of immune responses; it acts through both hormonal secretion and autonomic regulation. The principal neural outflow systems that act on peripheral immunocytes are the HPA axis and the SNS connections to organs of the immune system and secretion into the general circulation. Activation of the HPA and the SNS can block some immune defenses, leading to greater susceptibility to viral infections (10-fold in experimental models of murine influenza). Other anterior pituitary hormones also exert immunomodulatory effects. Chronic stressors can influence neural-­immune outflow via cortical and limbic connections to the hypothalamus (especially the PVN); chronic stressors exert both HPA and SNS effects that produce diminished cell-­mediated immunity and natural killer cell activity. Both immune-­inhibiting and immune-­ enhancing responses can be classically conditioned, a process that requires forebrain involvement and subsequent neural and hormonal outflow (but not cortisol; conditioned immunosuppression occurs in adrenalectomized animals). Both circulating cytokines and endogenous brain cytokines, including IL-­1β, IL-­6, and TNF-­α, can act on the PVN and other CNS sites involved in neuroendocrine and SNS outflow to immune targets, markedly activating cortisol production and catecholamine secretion. In adults, the regulation of secretion of dangerous inflammatory mediators as well as behavioral and lifestyle influences on the HPA axis and SNS may be important components of maintaining robust antiviral and antitumor immunity (anti-metastatic spread) and may aid in protection from many chronic diseases. These mediators are key components targeted in integrative medical treatment, directed toward enhancing PSNS activity and diminishing SNS activity.   

Autonomic-Hypothalamic-Limbic Systems

Anterior nucleus of thalamus Interventricular foramen

465

Interthalamic adhesion Fornix Stria terminalis

Anterior commissure

Stria medullaris Habenula

Cingulate gyrus Indusium griseum Corpus callosum Septum pellucidum Precommissural fornix Septal nuclei Subcallosal area Paraterminal gyrus Hypothalamus

Lamina terminalis Olfactory

bulb tract medial stria lateral stria

Anterior perforated substance Optic chiasm Calcarine sulcus (fissure)

Postcommissural fornix Mammillary body and mammillothalamic tract

Gyrus fasciolaris Dentate gyrus

Medial forebrain bundle

Fimbria of hippocampus Hippocampus

Amygdaloid body (nuclei) Interpeduncular nucleus Uncus Fasciculus retroflexus

Parahippocampal gyrus Descending connections to reticular and tegmental nuclei of brainstem (dorsal longitudinal fasciculus)

 

LIMBIC SYSTEM 16.29 ANATOMY OF THE LIMBIC FOREBRAIN Structures of the limbic forebrain are found in a ring (limbus) that encircles the diencephalon. Two major temporal lobe structures, the hippocampal formation with its fornix and the amygdala with its stria terminalis, send C-­shaped axonal projections through the forebrain, around the diencephalon, and into the hypothalamus and septal region. The amygdala also has a more direct pathway (the ventral amygdalofugal pathway) into the hypothalamus. The

septal nuclei sit just rostral to the hypothalamus and send axons to the habenular nuclei via the stria medullaris thalami. The cingulate, prefrontal, orbito-frontal, entorhinal, and periamygdaloid areas of the cortex interconnect with subcortical and hippocampal components of the limbic forebrain and are often considered part of the limbic system. The limbic system is thought to be a major substrate for regulation of emotional responsiveness and behavior, for individualized reactivity to sensory stimuli and internal stimuli, and for integrated memory tasks.

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Systemic Neuroscience

Lateral ventricle

Corpus callosum

Body of caudate nucleus CA1

Fornix

A

CA3

Thalamus Basal ganglia Temporal horn of the lateral ventricle

Choroid plexus

Optic tract Third ventricle

Fimbria Dentate gyrus

CA2

B CA3 CA2 CA1

Mammillary nuclei

CA4

Pyramidal cell layer of subiculum

C

Pyramidal cell layer of entorhinal cortex CA regions of hippocampal formation (pyramidal cells)

Dentate gyrus

Hippocampal pyramidal neurons in CA1 (A), CA2 and CA3 (B) and CA4 (C) sectors of the hippocampus, and granule cells in the dentate gyrus (C). Cell stain.

 

16.30 HIPPOCAMPAL FORMATION: GENERAL ANATOMY The hippocampal formation consists of the dentate gyrus, the hippocampus proper (cornu ammonis [CA] regions), and the subiculum. These structures are intimately interconnected with the adjacent entorhinal cortex. The hippocampus is a seahorse-­ shaped structure found in the medial portion of the anterior temporal lobe. It bulges laterally into the temporal horn of the lateral ventricle. The hippocampus is divided into several zones of pyramidal cells, called CA regions (CA1–CA4). The dentate gyrus and hippocampus are three-­layered cortical regions. Granule cells populate the dentate gyrus, and pyramidal cells are the main neurons in the CA regions of the hippocampus. The hippocampal formation has extensive interconnections with cortical association areas and with limbic forebrain structures, such as the septal nuclei and the cingulate gyrus. The hippocampal formation is involved with consolidation of short-­term memory into long-­term traces, in conjunction with extensive regions of neocortex.

CLINICAL POINT Pyramidal cells in the CA1 region of the hippocampus are particularly vulnerable to apoptosis resulting from ischemia. Following a heart attack with delayed resuscitation, an episode of cerebral ischemia, or multi-­infarct problems, or after increasingly poor blood flow in the anterior circulation to the brain, destruction of CA1 neurons (Sommer’s sector) can result in loss of short-­term memory and in spatial disorientation. CA3 pyramidal neurons are particularly vulnerable to high or persistently elevated levels of cortisol (or synthetic glucocorticoids), resulting in similar functional deficits. The combination of cerebral ischemia and high cortisol is particularly damaging to the hippocampus. This combination of relative ischemia and high circulating glucocorticoids may occur in older individuals with atherosclerosis and compromised cerebral blood flow (but still free of symptoms) who experience a highly stressful experience (e.g., hospitalization or institutionalization) in which they are exposed to nosocomial organisms and generate cytokine responses, further exacerbating cortisol secretion. This situation may help to precipitate hippocampal damage that leads to consolidation problems relating to immediate and short-­term memory and confusion and produces disorientation, conditions frequently encountered in hospitalized or institutionalized elderly patients.   

Autonomic-Hypothalamic-Limbic Systems

467

CA2 Choroid plexus

Alveus

Temporal horn of lateral ventricle

Fimbria CA3 Mossy fiber

Schaffer collaterals

Dentate gyrus CA1 Inputs to subiculum from cingulate cortex, amygdala Subiculum

Inputs to entorhinal cortex (cingulate cortex, sensory association cortices, basolateral amygdala, insular cortex, olfactory bulb, and prefrontal cortex)

Perforant pathway from entorhinal cortex to dentate gyrus, CA1 and CA3, and the subiculum

Entorhinal cortex

 

16.31 NEURONAL CONNECTIONS IN THE HIPPOCAMPAL FORMATION The hippocampal formation has an internal circuitry that is interconnected with the entorhinal cortex. Pyramidal neurons of the entorhinal cortex send axons to granule cell dendrites in the dentate gyrus. These granule cell axons (mossy fibers) synapse on pyramidal cell dendrites in CA3. Pyramidal cells in CA3 project to pyramidal cell dendrites in CA1 (Schaffer collaterals) and CA2. CA1 pyramidal axons project to pyramidal neurons in the subiculum. The subiculum sends axonal projections back to the pyramidal neurons of the entorhinal cortex. This information flow represents an internal circuit. Superimposed on this circuitry is a host of interconnections with association regions of the neocortex and other limbic forebrain structures. Neurons of the subiculum and pyramidal neurons of CA1 and CA3 send axons into the fornix as efferent projections to target structures. The subiculum also sends axons to the amygdala and association areas of the temporal lobe. CA4 is the hilar region, or hilus of the dentate gyrus. The cells are mossy cells, not pyramidal cells, and receive mossy fiber input from the granule cells in other sectors of the CA regions.

CLINICAL POINT Many temporal lobe structures are associated with the flow of information through the hippocampal formation, including the hippocampus, subiculum, entorhinal cortex, and associated cortical areas of the temporal lobe. Many of these cortical regions are particularly susceptible to neuronal degeneration in Alzheimer’s disease (AD), a neurodegenerative disease that damages and destroys neurons in the cerebral cortex and higher centers of the brain and is accompanied by marked cognitive deficits. Disruption of hippocampal circuitry leads to the inability to consolidate immediate and short-­term memory into long-­term traces. Temporal lobe damage and disruption of connections with the basal forebrain, cingulate cortex, frontal cortex, and other forebrain structures also affected by AD contribute to the marked cognitive decline in patients with AD. In AD, the brain shows extensive neuronal loss, impaired functioning of synaptic connections, and damage to important neurotransmitter systems that participate in functions such as memory. AD is characterized by the accumulation of altered and aberrant proteins inside neurons, called neurofibrillary tangles, and outside of neurons, called senile plaques. However, severe cognitive decline may occur in the absence of neurofibrillary tangles and senile plaques, and the presence of these proteins in the brain is not always predictive of cognitive dysfunction. Proposed causes of AD include the accumulation of amyloid-β protein and its precursor protein (in plaques) and/or excessive phosphorylation of an important protein (tau; in tangles) that helps to give neurons their structural integrity. A form of apolipoprotein E (epsilon 4) is linked with excessive production of free radicals that may kill neurons. Inflammatory molecules (e.g., IL-­1β) also may cause neuronal damage. At present, there is no common agreement on a specific sequence of events or cascade of pathology in AD.   

468

Systemic Neuroscience Cingulate cortex

Afferent connections Efferent connections

Fornix

Postcommissural fornix Precommissural fornix

Mammillothalamic tract

Corpus callosum

Mammillotegmental tract Calcarine fissure

Association areas of frontal lobe

Thalamus

Septal nuclei

Inputs to hippocampus and dentate gyrus: Raphe nuclei (5HT) Locus coeruleus (NE)

Hypothalamus

Fimbria Nucleus accumbens (ventral striatum) Mammillary body

Amygdala

Efferents of subiculum to amygdala, association areas of temporal lobe

Entorhinal cortex Dentate gyrus

Subiculum

CA regions of hippocampus

Perforant pathway

Inputs to entorhinal cortex: Sensory association cortices Polysensory association cortex Prefrontal cortex Insular cortex Amygdala Olfactory bulb Inputs to subiculum: Amygdala

 

16.32 MAJOR AFFERENT AND EFFERENT CONNECTIONS OF THE HIPPOCAMPAL FORMATION Pyramidal neurons in the subiculum and hippocampal regions CA1 and CA3 give rise to the efferent fornix. The subiculum projects axons to hypothalamic nuclei (especially mammillary nuclei) and thalamic nuclei via the postcommissural fornix. CA1 and CA3 of the hippocampus send axons to the septal nuclei, the nucleus accumbens, the preoptic and anterior hypothalamic regions, the cingulate cortex, and association areas of the frontal lobe. Afferent cholinergic axons from septal nuclei traverse the fornix to supply the dentate gyrus and hippocampal CA regions. Massive inputs arrive in the hippocampal formation from sensory association cortices, polysensory association cortices, the prefrontal cortex, the insular cortex, the amygdaloid nuclei, and the olfactory bulb via projections to the entorhinal cortex. The entorhinal cortex is fully integrated into the internal circuitry of the hippocampal formation. The subiculum is connected reciprocally with the amygdala and also sends axons to cortical association areas of the temporal lobe. 5HT, 5-­hydroxytryptamine [serotonin]; NE, norepinephrine.

CLINICAL POINT Explicit memory is acquisition of information about objects, stimuli, and information that is consciously noted and recallable, and it includes information about personal events, factual knowledge, and information about which cognitive assessment takes place. Explicit memory involves structures in the medial temporal lobe, including the hippocampal formation. Implicit memory is the process of learning how to perform tasks or acquire skills that are not recallable by conscious processes; this form of memory depends upon other brain circuitry and is not lost in classic cases of hippocampal lesions. Explicit memory recall depends upon reassembly of information stored in the brain and involves reconstruction that depends upon sensory perceptions. It is not a video record of the precise external events and can be markedly different from reality, which raises serious questions about the accuracy of “recovered memory” of past events. Explicit memory requires the formation of new synaptic connections and gene expression for new sets of neuronal proteins. The consolidation of immediate and short-­term explicit memory into long-­term traces involves a process of long-­term potentiation, which involves a burst of activity in a specific temporal pattern from an incoming axon that enhances the likelihood that the target neuron will be activated by this same input and other incoming inputs, providing an increased response to the same magnitude of excitation. Thus, a brief, sustained pattern of input makes it more likely that future synaptic activity will occur. Long-­term potentiation occurs in dentate granule cells, CA1 neurons, and CA3 neurons. In the former two neurons, it requires N-­methyl-­D-­aspartate receptor activation, depolarization, Ca++ influx, and communication between pre- and postsynaptic elements. In CA3 neurons, long-­term potentiation depends on presynaptic Ca++ influx and subsequent cyclic adenosine monophosphate–dependent protein kinase production.   

469

Autonomic-Hypothalamic-Limbic Systems Afferent and efferent cortical connections of entorhinal cortex Direct connections

Orbitofrontal cortex

Indirect connections

Perirhinal cortex

Olfactory bulb Insula Superior temporal gyrus Entorhinal cortex

Area 9 Area 23 Areas 11–13 Area 46 Area 8 Area 22 Area 21 Area 20 Area 7 Area 19

Cingulate gyrus

Entorhinal cortex Entorhinal cortex is a major source of projections to hippocampus (major processing center for recent memory). Polysensory association cortices project directly to entorhinal cortex or indirectly via perirhinal cortex or parahippocampal gyrus. Association cortices receive reciprocal projections from entorhinal cortex. Area numbers refer to Brodmann classifications.

Possible processing circuit for recent memory Primary sensory cortices Primary somatosensory cortex

Unisensory association cortices

Polysensory association cortices

Primary visual cortex Primary auditory cortex

Corticocortical projections

Neuronal loss or dysfunction in entorhinal hippocampal circuit, as in Alzheimer′s disease, may disconnect this memory processing area from input of new sensory information and from retrieval of memory stored in neocortex. Loss of corticocortical projections interferes with memory processing and may contribute to memory deficits in Alzheimer′s disease.

Specific sensory input successively processed through primary sensory, unisensory, and polysensory association cortices. These cortices project directly or indirectly to entorhinal cortex, which projects to hippocampus. All sensory information indexed in hippocampus and projected back to entorhinal cortex, from which it is diffusely projected to neocortex for storage as memory.

CA1 CA3 Dentate gyrus Subiculum Perforant pathway

Entorhinalhippocampal circuit

Olfactory bulb Amygdala (Primary olfactory cortex may project directly to entorhinal cortex) Entorhinal cortex

16.33 AFFERENT AND EFFERENT CONNECTIONS OF THE ENTORHINAL CORTEX The entorhinal cortex is located in the medial temporal lobe and is integrated into the hippocampal formation circuitry related to memory formation and consolidation and declarative and spatial memory. Afferents project to the entorhinal cortex from both cortical and subcortical sources. Cortical inputs include the association cortex (from all sensory modalities), perirhinal cortex, parahippocampal cortex, orbitofrontal and prefrontal cortex, cingulate cortex, and the hippocampus (to layers V and VI). Subcortical inputs derive from the septal region (especially the cholinergic medial septal nucleus via the fornix), basal forebrain (substantia

 

innominate, nucleus of the diagonal band, the olfactory bulb), amygdala (basolateral nuclei), claustrum, thalamus (mainly midline nuclei), and brainstem monoaminergic nuclei (dopaminergic ventral tegmental area, noradrenergic locus coeruleus, and serotonergic rostral raphe nuclei). Efferent projections are directed to components of hippocampal circuitry, polysensory association cortex, and subcortical regions. For hippocampal circuitry, neurons in layer II project to the dentate gyrus and the CA3 region, and neurons in layer III project to the CA1 region and the subiculum. Efferents to subcortical regions project to the claustrum, nucleus accumbens, and thalamus (medial dorsal nucleus, lateral dorsal nucleus, medial pulvinar).

470

Systemic Neuroscience Thalamus Bed nucleus of the stria terminalis

Cingulate cortex

Intralaminar Medial dorsal nuclei nucleus

Anterior commissure

Brainstem inputs: Parabrachial nuclei Periaqueductal gray Stria terminalis Ventral tegmental area (DA) Raphe nuclei (5HT) Locus coeruleus (NE) Nucleus tractus solitarius

Corpus callosum

Septal nuclei Prefrontal cortex

Hypothalamus

Olfactory bulb Hypothalamic inputs: Lateral hypothalamic area Ventromedial nucleus Corticomedial nuclei of the amygdala Subiculum (hippocampal formation)

Basolateral nuclei of the amygdala

Sensory association inputs: Temporal lobe sensory association cortex Entorhinal cortex Insular cortex Medial frontal lobe

  16.34 MAJOR AFFERENT CONNECTIONS OF THE AMYGDALA The amygdala is an almond-­shaped collection of nuclei in the medial portion of the anterior temporal lobe. It is involved in the emotional interpretation of external sensory information and internal states. It provides individual-­specific behavioral and emotional responses, particularly those involving fear and aversive responses. The amygdala is subdivided into corticomedial nuclei and basolateral nuclei (which receive afferents and project axons to target structures) and the central nucleus, which provides mainly efferent projections to the brainstem. Afferents to the corticomedial nuclei arrive primarily from subcortical limbic sources, including the olfactory bulb, septal nuclei, and hypothalamic nuclei (VM, LHA); the thalamus (intralaminar nuclei); the bed nucleus of the stria terminalis; and extensive numbers of autonomic nuclei and monoamine nuclei of the brainstem. Afferents to the basolateral nuclei arrive mainly from cortical areas, including extensive sensory association cortices, the prefrontal cortex, the cingulate cortex, and the subiculum. 5HT, 5-­hydroxytryptamine [serotonin]; NE, norepinephrine.

CLINICAL POINT The amygdala is a subcortical collection of nuclei in the medial anterior temporal lobe. It is involved in the emotional interpretation and “flavoring” of external sensory information and internal states. Afferents to corticomedial nuclei come from subcortical limbic structures, and afferents to basolateral nuclei derive mainly from cortical structures. Most cases in humans of bilateral destruction of the amygdala occur with trauma or temporal lobe surgery for seizures, and they involve destruction of more than just amygdaloid nuclei. On the basis of primate studies and observations in humans, it appears that amygdaloid lesions result in placid behavior, lack of fear even when confronted with normally fear-­provoking stimuli, and withdrawal from social contacts. The normal integration of emotional reactive and cognitive processing is disrupted. Studies have found that patients with bilateral amygdaloid damage cannot recognize facial expressions in others that indicate fear and do not learn or remember events with strong emotional context better than those without such emotional context, as is normally the case. In patients with bilateral temporal lobe damage involving extensive cortical and subcortical neuronal destruction, Klüver-­Bucy syndrome can occur. This syndrome is characterized by placid behavior, loss of fear of potentially dangerous objects, compulsive exploration of the environment (particularly orally), visual agnosias, inappropriately directed hyperphagia (of nonedible items), and hypersexuality. In some cases, loss of consolidation of memory (hippocampal involvement) and cognitive deficits are also seen.   

Autonomic-Hypothalamic-Limbic Systems Bed nucleus of the stria terminalis

471

To brainstem: Nucleus tractus solitarius Dorsal motor nucleus of X Raphe nuclei (5HT) Locus coeruleus (NE) Parabrachial nuclei Periaqueductal gray Reticular formation

Stria terminalis

Striatum (rostral areas) Caudate nucleus Putamen

Corpus callosum

Frontal lobe regions: Frontal cortex Prefrontal cortex Septal nuclei

Th M H

Nucleus accumbens

Substantia innominata (with nucleus basalis ACh neurons) Ventral amygdalofugal pathway Corticomedial nuclei of the amygdala

To cingulate cortex

Basolateral nuclei of the amygdala

Subiculum Entorhinal cortex

Central nucleus of the amygdala H = Hypothalamus: Preoptic area Anterior hypothalamic area Ventromedial nucleus Lateral hypothalamic area Paraventricular nucleus

Inferior temporal cortex (e.g., visual areas)

Th = Thalamus: Medial dorsal nucleus M = Midline thalamic nuclei

  16.35 MAJOR EFFERENT CONNECTIONS OF THE AMYGDALA Efferents from the corticomedial nuclei project through the stria terminalis and are directed mainly toward subcortical nuclei, such as septal nuclei, the mediodorsal (medial dorsal) nucleus of the thalamus, the hypothalamic nuclei, the bed nucleus of the stria terminalis, the nucleus accumbens, and the rostral striatum. Efferents from the basolateral nuclei project through the ventral amygdalofugal pathway to cortical regions, including the frontal cortex, the cingulate cortex, the inferior temporal cortex, the subiculum, and the entorhinal cortex, and to subcortical limbic regions, including hypothalamic nuclei, septal nuclei, and the cholinergic nucleus basalis in substantia innominata. The central amygdaloid receives input mainly from internal amygdaloid connections and sends extensive efferents through the ventral amygdalofugal pathway to autonomic nuclei and monoaminergic nuclei of the brainstem, the midline thalamic nuclei, the bed nucleus of the stria terminalis, and the cholinergic nucleus basalis.

CLINICAL POINT Efferents from the corticomedial nuclei are directed mainly to subcortical limbic nuclei. Efferents from the basolateral nuclei are directed through the ventral amygdalofugal pathway to extensive cortical regions and subcortical structures. The central amygdaloid nucleus sends extensive efferents to brainstem nuclei associated with the machinery of emotional responsiveness provoked by amygdaloid activation. This central nucleus receives its input mainly from other amygdaloid nuclei. Amygdaloid stimulation has been performed in humans (for epilepsy surgery) and in experimental animals. Corticomedial stimulation produces a freezing response (cessation of voluntary movement), automated gestures (lip smacking), and parasympathetic activation that leads to voiding and defecation. Basolateral stimulation produces the vigilance responses of becoming alert and scanning the environment. These responses most likely reflect the outflow of the amygdala to brainstem circuitry that coordinates behavior appropriate to the emotional context of the stimuli. Conditioned fear responses and reactions to stressors require coordinated interaction of neuroendocrine outflow, autonomic reactivity, and behavioral activity. In humans, amygdaloid stimulation results in feelings associated with fear and anxiety. 5HT, 5-­hydroxytryptamine [serotonin]; NE, norepinephrine.   

472

Systemic Neuroscience

Olfactory bulb Septal nuclei Hypothalamic nuclei (LHA, VM) Thalamic nuclei (intralaminar) Bed nucleus of ST Brainstem Parabrachial nucleus Periaqueductal gray VTA (DA) Raphe nuclei (5HT) Locus coeruleus (NE) NTS

Septal nuclei Bed nucleus of ST Thalamus (MD) Hypothalamus Preoptic area AHA VM LHA PVNp Nucleus accumbens Striatum (rostral) Caudate Putamen

Corticomedial nuclei

Central nucleus

Thalamus (MD) Prefrontal cortex Cingulate cortex Subiculum Sensory association cortex Temporal lobe sensory association cortex Cerebral Entorhinal cortex cortex Insular cortex Medial frontal cortex

AHA = Anterior hypothalamic area DA = Dopamine DMN of X = Dorsal motor (autonomic) nucleus of X 5HT = 5-Hydroxytryptamine (serotonin) LHA = Lateral hypothalamic area MD = Medial dorsal nucleus of thalamus

Basolateral nuclei

Bed nucleus of ST Substantia innominata (nucleus basalis)

Midline thalamic nuclei Brainstem NTS DMN of X Raphe nuclei (5HT) Locus coeruleus (NE) Parabrachial nuclei Periaqueductal gray Reticular formation Substantia innominata (nucleus basalis) Septal nuclei Hypothalamus Frontal cortex Entorhinal cortex Subiculum Cingulate cortex Inferior temporal cortex

NE = Norepinephrine NTS = Nucleus tractus solitarius PVNp = Paraventricular nucleus, parvocellular ST = Stria terminalis VM = Ventromedial VTA = Ventral tegmental area

 

16.36 SUMMARY OF MAJOR AFFERENTS, EFFERENTS, AND INTERCONNECTIONS OF THE AMYGDALA The corticomedial amygdala is connected reciprocally mainly with subcortical limbic forebrain structures and receives extensive additional inputs from brainstem autonomic and monoaminergic nuclei. The basolateral amygdala is connected reciprocally with extensive regions of limbic and association cortex and has additional efferents to subcortical limbic forebrain regions. Both the corticomedial and basolateral nuclei send axons to the central nucleus of the amygdala. The central

nucleus has massive descending efferents to extensive autonomic and monoaminergic nuclei of the brainstem as well as to some subcortical limbic forebrain regions. These interconnections with extensive regions of the cortex, the limbic forebrain regions, and the autonomic/limbic brainstem nuclei provide the integrated circuitry that permits analysis of both external and internal information and provides an emotional and interpretive context for the initiation and control of appropriate behavioral and emotional responses. See Fig. 15.26 for a brief discussion of the extended amygdala, including the bed nucleus of the stria terminalis and nucleus accumbens.

Autonomic-Hypothalamic-Limbic Systems

AFFERENTS

473

Precommissural fornix

Major afferents from: Hippocampal CA pyramidal cells Amygdaloid nuclei Corticomedial nuclei via stria terminalis Basolateral nuclei via ventral amygdalofugal pathway Ventral tegmental area Hypothalamus Preoptic area Anterior hypothalamic area Paraventricular nucleus Lateral hypothalamic area Septal nuclei Locus coeruleus (NE; not shown)

Corpus

callo s um

Stria terminalis

Fornix

Ventral amygdalofugal pathway Amygdala

Hippocampus

Stria medullaris thalami Habenular nuclei

Ventral tegmental area

Hypothalamus EFFERENTS Major efferents to: Hippocampal CA regions Fornix Dentate gyrus (ACh path) Via fornix Via stria Habenular nuclei medullaris Medial dorsal nucleus thalami of the thalamus Ventral tegmental area Via median Hypothalamus forebrain bundle Preoptic area Anterior hypothalamic area Ventromedial nucleus Lateral hypothalamic area Septal nuclei

Corp

us callosum

Hypothalamus Median forebrain bundle

Thalamus (medial dorsal) Dentate gyrus Hippocampus Ventral tegmental area

 

16.37 MAJOR AFFERENT AND EFFERENT CONNECTIONS OF THE SEPTAL NUCLEI The septal nuclei are subcortical nuclei initially implicated by early ablation and stimulation studies in the regulation of emotional responsiveness such as rage behavior. In experimental studies, the septal nuclei appear to play a role in emotional behaviors, sexual behavior, aggressive behavior, modulation of autonomic functions, and attention and memory functions (from the cholinergic neurons). Afferents to the septal nuclei arrive mainly from the hippocampus, the corticomedial and basolateral amygdala, the ventral tegmental nucleus in the midbrain, and several hypothalamic nuclei. Efferents from the septal nuclei distribute mainly to the hippocampus and dentate gyrus (via the fornix), the habenular nuclei (via the stria medullaris thalami), the medial dorsal nucleus of the thalamus (via the stria medullaris thalami), the ventral tegmental area (via the median forebrain bundle), and several hypothalamic nuclei. CLINICAL POINT In some humans with ischemic damage involving the septal area, rage behavior has been observed. This is consistent with early experimental studies in rodents in which septal lesions resulted in

exaggerated reactivity to both appropriate and innocuous stimuli (sham rage). In contrast, implanted electrodes in the septal nuclei for electrical self-­stimulation studies resulted in prolonged and repeated stimulation, indicative of pleasurable responses. Efferent connections to the habenula and, via its efferent pathways to the brainstem such as the fasciculus retroflexus (habenulopeduncular tract), and connections to the hypothalamus and brainstem through the descending median forebrain bundle represent the descending regulatory circuitry from the septal nuclei through which some of the associated behaviors are accomplished. The recent findings that a cholinergic cell group in the septum, along with the bed nucleus of the stria terminalis, sends axons via the fornix to the hippocampal formation, and that these are commonly found to have degenerated in the brains of patients with AD, raise the possibility that these cholinergic neurons are contributors to the process of consolidation of immediate and short-­term memory into long-­term traces. Damage to the entire collection of cholinergic neurons (including nucleus basalis of Meynert) produces such memory deficits, but experimental studies of selective lesions of cholinergic neurons in the septal nucleus and bed nucleus of the stria terminalis did not result in profound loss of such memory function. It is likely that the cholinergic projections to the hippocampal formation and the cerebral cortex function as a distributive system and affect memory function through an influence on the entire circuitry involved in cognitive and memory functions.   

474

Systemic Neuroscience Bed nucleus of stria terminalis (BNST)

Thalamic nuclei (e.g., centromedian)

Stria terminalis

Major inputs to BNST

From insular cortex (not visible)

Medial prefrontal cortex (PFC) Septal nuclei Nucleus accumbens

Periaqueductal gray

Ventromedial prefrontal cortex (vmPFC)

Rostral raphe nuclei Locus coeruleus

Organum vasculosum of the lamina terminalis (OVLT)

Parabrachial nucleus Brainstem areas

Hypothalamus Nucleus basalis in substantia innominata Outputs from BNST to: Humoral and circumventricular areas Neuroendocrine regulatory areas Zones of central autonomic control Behavioral control systems Thalamo-cortical feedback loops Orofacial motor control

Amygdala

Nucleus solitarius Hippocampus

A1 noradrenergic cell group

 

16.38 BED NUCLEUS OF THE STRIA TERMINALIS The bed nucleus of the stria terminalis (BNST), a limbic forebrain structure, consists of multiple clusters of neurons surrounding the caudal portion of the anterior commissure. Its caudal region, at the end of the stria terminalis, is adjacent to the amygdala, and its rostral region is ventral to the septal area and the dorsal preoptic area. Its interconnections coordinate physiological functions and behaviors related to autonomic, neuroendocrine, and motor systems. The BNST is an integrative site where descending cortical information and ascending exteroceptive and interoceptive information come together. Major inputs to the BNST derive from cortical areas (medial prefrontal, infralimbic, and insular), forebrain areas (nucleus accumbens, substantia innominata, lateral septal area), hippocampus, amygdala (basomedial and central nuclei, which connect reciprocally), circumventricular organs (subfornical organ, organum vasculosum of the lamina terminalis), thalamic regions (centromedian, other nonspecific regions), numerous hypothalamic areas, and brainstem areas (periaqueductal gray, rostral raphe nuclei, parabrachial nuclei, locus coeruleus, nucleus solitarius, A1 noradrenergic cell group). The BNST monitors inputs related to stressors, blood pressure, blood volume, and other ongoing physiological parameters.

Projections from the BNST include humoral and circumventricular areas, neuroendocrine regulatory areas, zones of central autonomic control, behavioral control systems, thalamo-­cortical feedback loops, and orofacial motor control sites. Behavioral involvement of the BNST includes monitoring uncertain, nonimminent fear states (amygdala involved in defined fear states), and modulating aggressive behaviors, social attachment, mating and parental activities, goal-­directed and addictive behaviors (through the dopamine connections from the midbrain ventral tegmental area), pain reactivity, and visceral regulatory functions. The BNST has been identified as a component of psychiatric-­related disorders such as anxiety, social dysfunction, posttraumatic stress, mood disorders, and others. BNST neurons utilize many neurotransmitter systems, including norepinephrine, serotonin, acetylcholine, nitric oxide, opioid peptides, endocannabinoids, and others. See the reference for an excellent review: Dong HW, Swanson LW: Projections from bed nuclei of the stria terminalis, anteromedial area: cerebral hemisphere integration of neuroendocrine, autonomic, and behavioral aspects of energy balance. J Comp Neurol 494:75–107, 2006.

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475

Cingulate cortex

Afferent connections Efferent connections

Association areas of parietal cortex

Fornix Corpus callosum

Association areas of frontal cortex ANT

MD

Septal nuclei

Mammillothalamic tract

Mammillary body Association areas of temporal cortex Subiculum Entorhinal cortex

Amygdala (basolateral nuclei) Hippocampus

ANT = Anterior nuclei of the thalamus MD = Medial dorsal nucleus of the thalamus

  16.39 MAJOR CONNECTIONS OF THE CINGULATE CORTEX The cingulate cortex is located above the corpus callosum. This cortical region is involved in the regulation of autonomic functions (respiratory, digestive, cardiovascular, pupillary), some somatic functions (motor tone, ongoing movements), and emotional responsiveness and behavior. Lesions in the cingulate cortex, like lesions in the orbitofrontal cortex, result in indifference to pain and other sensations that have emotional connotations, and in social indifference. Afferents to the cingulate cortex arrive from association areas of the frontal, parietal, and temporal lobes; the subiculum; the septal nuclei; and the thalamic nuclei (mediodorsal, anterior). Efferents from the cingulate cortex project to association areas of frontal, parietal, and temporal lobes and to limbic forebrain regions, such as the hippocampus, the subiculum, the entorhinal cortex, the amygdala, and septal nuclei. These limbic forebrain regions send extensive projections to the hypothalamus for regulation of autonomic and somatic regions of the brainstem and spinal cord.

CLINICAL POINT The anterior cingulate cortex may participate in selecting appropriate responses to conflicting stimuli. Inputs to the cingulate cortex derive from many regions of frontal, parietal, and temporal cortex, the subiculum; the septal nuclei; and the medial dorsal thalamus (prefrontal connections). Efferent connections project back to many of these same regions as well as to the amygdala, subiculum, and entorhinal cortex. Through these efferent connections, circuitry to the brainstem can coordinate appropriate autonomic and somatic functions. Lesions in the cingulate cortex result in indifference to pain and other sensations that have strong emotional connotations; they produce social indifference and apathy, eliminate emotional intonation in speech, and cause personality changes. Bilateral anterior cingulate lesions, or cingulotomies, have been done as “psychosurgery” to alleviate intractable pain and to incapacitate anxiety, obsessive-­ compulsive behavior, and intractable depression. Lesions in the posterior cingulate cortex result in diminished ability to perform spatial navigation.   

476

Systemic Neuroscience

Outline of insular cortex (ghosted)

Bed nucleus of stria terminalis

Anterior cingulate gyrus

Sensory cortices (representative) and multisensory cortical integration areas (representative) - polysynaptic

Efferent projections from insular cortex Reciprocal connections

Afferent inputs to insular cortex Medial prefrontal cortex

Habenula

Medial dorsal thalamic nucleus Brainstem nuclei (see text) vmPFC Nucleus accumbens Lateral hypothalamic region Amygdala Parahippocampal regions (e.g., entorhinal cortex) Nucleus solitarius (baroreceptors and chemoreceptors)

Central sulcus of insula Circular sulcus of insula

Insula

Short gyri Limen Long gyrus

 

16.40 INSULAR CORTEX The insular cortex, sometimes called the “fifth lobe of the brain,” is a viscerosensory cortex located deep in the lateral fissure, continuous anteriorly with the ventromedial prefrontal cortex (vmPFC), also called the orbitofrontal cortex. Afferent projections to the insular cortex include (1) viscerosensory inputs and inputs from chemoreceptors and baroreceptors; (2) multisensory inputs, through the thalamus and cortex, for somatosensory, trigeminal, taste, olfaction, vision, and some interoceptors; (3) nucleus basalis (cholinergic) in substantia innominata; (4) cortical areas involved in multisensory integration; and (5) numerous brainstem nuclei and sites (periaqueductal gray, parabrachial nuclei, dopaminergic ventral tegmental area, noradrenergic locus coeruleus, and serotonergic raphe nuclei). Efferent projections from the insular cortex are mainly reciprocal interconnections with (1) limbic structures (basolateral

amygdala, lateral BNST), (2) parahippocampal regions such as the lateral entorhinal cortex, (3) cortical regions (medial prefrontal, anterior cingulate), (4) nucleus accumbens, (4) medial dorsal (MD) thalamic nucleus, (5) lateral hypothalamic region, and (6) habenula. The insular cortex links sensory processing and emotional recognition and feelings and can assist with subsequent motor and autonomic reactivity. The insular cortex also aids in risk prediction and decision making related to addictive behaviors and uncertain situations. It participates, with several other limbic and cortical structures, with fear responses and anxiety responses, social interactions, and complex emotional responses such as empathy. In situations where the insular cortex is damaged or disrupted, the patient can perceive sensory information, such as pain, but is unable to react emotionally to it, showing altered or absent emotions.

Dorsolateral prefrontal cortex (dlPFC)

Cingulate cortex

Somatosensory cortex (polysynaptic)

Retrosplenial cortex Dorsolateral prefrontal cortex (dlPFC) (image projected from lateral surface)

Striatum Medial dorsal thalamic nucleus

Hypothalamus Ventromedial prefrontal cortex (vmPFC) (=orbitofrontal cortex)

Visual cortex (polysynaptic)

Hippocampus Amygdala Connections of dlPFC

Reciprocal connections of vmPFC Inputs to vmPFC from sensory cortex (somatosensory, visual, auditory, olfactory, etc.)

Parahippocampal gyrus, entorhinal cortex, and other temporal lobe areas

  16.41 PREFRONTAL CORTEX The prefrontal cortex (PFC) consists of two major anatomical and functional regions, the ventromedial (vmPFC), also called the orbitofrontal cortex, and the dorsolateral (dlPFC). VENTROMEDIAL (ORBITOFRONTAL) PREFRONTAL CORTEX

The vmPFC is reciprocally connected with medial dorsal (MD) thalamic nucleus, cortical areas (entorhinal, perirhinal, parahippocampal, some temporal lobe area), amygdala (central and basolateral), and some hypothalamic areas. Inputs to the vmPFC also include sensory integration cortex (pyriform cortex) and many sensory cortical areas (olfactory [uncus], taste, somatosensory SI and SII, visual, and auditory). The vmPFC participates in reward and emotional reactivity in decision making, expectations, and adaptive learning and can regulate autonomic reactivity via the dopamine mesocortical system. It also is a component of perception of pleasure, aggressive behavior, and complex sensory integration. Damage to the vmPFC, which occurs in traumatic brain injury (TBI), can result in behavioral disinhibition and aggression and abuse, poor decision making, poor social interactions, compulsive behaviors (addictive behaviors), and lack of empathy. The vmPFC is involved in psychiatric disorders such as schizophrenia, mood disorders, obsessive-­compulsive disorder, addictive behaviors, and borderline personality disorder. 

DORSOLATERAL PREFRONTAL CORTEX

The dlPFC is connected with cortical areas (vmPFC, primary and secondary sensory association cortical areas, cingulate cortex [anterior and posterior, retrosplenial cortex, premotor cortex), hippocampus, striatum thalamic areas, and the lateral cerebellum. The dlPFC is the “Mr. Spock” of Star Trek, the rational decision maker, carrying out logical cognitive assessment in an unemotional manner. The dlPFC directs executive functions, abstract reasoning, and complex planning and is able to inhibit impulsive amygdaloid-­driven activities and behaviors. It is a major site for working memory and deductive reasoning, as well as behavioral strategies such as lying and deception. The dlPFC directs many activities that people define as “intelligence.” Damage to the dlPFC results in a loss of drive, ambition, and motivation, leading to disinterest and loss of attention. Spontaneous activities and conversation are often lost. There is an increase in addictive behaviors, depression, and indications of major life stress. Pathways for communication from the more rostral regions of PFC include the cingulum, the extreme capsule, and the uncinate fasciculus. Pathways for communication from the more caudal regions of PFC include the superior longitudinal fasciculus, the occipitofrontal fasciculus, and the arcuate fasciculus. The activation of the dlPFC and vmPFC is inversely correlated.

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Systemic Neuroscience

Key Regions Associated with Limbic and Cortical Reactivity in the Limbic–Hypothalamic–Autonomic Axis Region

Functional

Prefrontal cortex

• Regulates complex cognitive, emotional, and behavioral function • Planning and reasoning (not intellectual ability) • Anticipatory goal orientation and predicting future outcomes • Guiding appropriate social behaviors • Determining right from wrong, especially dorsolateral prefrontal cortex

Orbitofrontal • Sensory integration (with temporal lobe): smell, taste, touch cortex (part of • Rewards, response to winning or losing prefrontal cortex) • Cognitive processing and decision making • Involved in compulsive behaviors, repetitive behaviors, drives • Impulse control and response inhibition, emotional reactivity • Modulates body changes associated with emotion (e.g., anxiety) • Participates with nucleus accumbens and the amygdala in regulating compulsive behaviors, repetitive behavior, and drives Anterior cingulate • Helps to regulate affect and emotionally uncomfortable circumstances cortex • Helps to detect errors and failure to reach goals • Aids in decision making, and anticipation and preparation for activities • Helps to regulate physiological processes (heart rate, blood pressure) • Interconnects emotional limbic system with cognitive prefrontal cortex Posterior cingulate cortex

• Contributes to human awareness, internally driven cognition • Active role in thinking and planning for the future • Focusing of attention • Participates in episodic memory retrieval • Participates in pain awareness

Parahippocampal gyrus

• Memory encoding and retrieval • Helps navigation in the environment • Encodes collective environmental scenes, not individual components • Right side: helps to identify social context, such as sarcasm

Entorhinal cortex

• Helps with memory and navigation, role in declarative memories (episodic, personal, semantic) and spatial memory • Processes familiarity of signals involved in conditioning

Dorsal subiculum

• Helps to regulate the hypothalamo–pituitary–adrenal axis

Insular cortex

• Role in consciousness, body homeostasis, and perception • Role in emotion, empathy, and compassion • Perception (body warmth and coldness, abdominal distention, bladder fullness, dyspnea sensation, unpleasant smells) • Perception of vestibular sensation, balance, and vertigo • Role in laughter, crying, emotional response to music

Uncus, periamygdaloid cortex

• Olfaction

 

16.42 KEY FOREBRAIN REGIONS ASSOCIATED WITH LIMBIC AND CORTICAL REACTIVITY AND THEIR FUNCTIONAL ROLES Several forebrain areas, both cortical and subcortical, are important in control of emotional responsiveness, cognition, learning and memory, internal and external responsiveness, decision making, and other behavioral roles. Some of their functional roles are summarized in this table. Many of these

regions utilize connectivity with the hypothalamus and its visceral and neuroendocrine outflow to accomplish behavioral goals and intended activities. For a further insightful discussion of many of these forebrain areas and their integrative activity, see the reference: Sapolsky RM: Behave: The Biology of Humans at Our Best and Worst. New York: Penguin Press; 2017.

Autonomic-Hypothalamic-Limbic Systems A. Distribution of olfactory epithelium (blue area)

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B. Schema of section through olfactory mucosa

Olfactory Receptors Olfactory bulb Cribriform plate of ethmoid bone

Septum

Lateral nasal wall

Cribriform plate Schwann cell Olfactory gland Unmyelinated olfactory axons Basement membrane Sustentacular cells Endoplasmic reticulum Nucleus Olfactory cells Dendrites Terminal bars (desmosomes) Olfactory rod (vesicle) Villi Cilia Mucus

  OLFACTORY SYSTEM 16.43 OLFACTORY RECEPTORS Olfactory receptors are found in a patch of olfactory epithelium that lines the medial and lateral walls of the roof of the nasal cavity. Olfactory receptor cells are primitive, specialized, bipolar neurons whose nuclei are in the base of the epithelium. A dendritic process extends toward the epithelial surface, widening into a rod with 10 to 30 motile cilia that extend into the mucous cover. Odorants act on receptors (G protein–coupled) on these cilia and bring about a slow, depolarizing generator potential. Odorant interactions with receptors are complex, often requiring odorant-­binding proteins to carry the odorant through the mucus. The bipolar neurons of the olfactory epithelium are CNS neurons; they are unusual because they undergo continuous replacement and turnover from basal stem cells in the epithelium. The unmyelinated olfactory axons cluster together in groups (collectively enwrapped by a single Schwann cell sheath) before passing through the cribriform plate. Injuries to the cribriform plate can tear these axons and result in anosmia.

CLINICAL POINT Anosmia, the loss of smell, may not be obvious to a patient; it may present with a blunting of the taste of food. The most common cause of anosmia is a cold, followed by allergic rhinitis. Unilateral anosmia not attributable to local nasal problems suggests involvement of the olfactory nerves, bulb, or tracts and stria. Trauma causing injury to the cribriform plate is the most common cause of olfactory nerve damage. Impairment of olfactory discrimination but with intact ability to detect odors points to possible involvement of forebrain structures, such as limbic circuitry in Wernicke-­Korsakoff syndrome, in the prefrontal cortex, in cortical areas damaged by neurodegenerative conditions such as AD, or in thalamic regions. Loss of smell and taste are both immediate and longer term sequelae of COVID-19 viral infection.   

480

Systemic Neuroscience Efferent fibers Afferent fibers Granule cell (excited by and inhibiting to mitral and tufted cells)

Subcallosal (parolfactory) area Septal area and nuclei Fibers from contralateral olfactory bulb

Mitral cell

Fibers to contralateral olfactory bulb

Recurrent process Tufted cell

Anterior commissure

Periglomerular cell

Medial olfactory stria

Glomerulus

Olfactory trigone and olfactory tubercle

Olfactory nerve fibers

Anterior perforated substance Habenula Lateral olfactory stria Lateral olfactory tract nucleus Hypothalamus Piriform lobe Hippocampal fimbria Dentate gyrus Uncus (olfactory cortex) Parahippocampal gyrus

Olfactory epithelium Olfactory nerves Olfactory bulb

Hippocampal formation Amygdala (in phantom)

Olfactory tract Anterior olfactory nucleus

Entorhinal area

Cribriform plate of ethmoid bone Lateral olfactory stria

 

16.44 OLFACTORY PATHWAYS Primary sensory axons from bipolar neurons pass through the cribriform plate and synapse in the olfactory glomeruli in the glomerular layer of the olfactory bulb. The glomeruli are the functional units for processing specific odor information. The olfactory nerve fibers synapse on the dendrites of the tufted and mitral cells, the secondary sensory neurons that give rise to the olfactory tract projections. Periglomerular cells are interneurons that interconnect the glomeruli. Granule cells modulate the excitability of tufted and mitral cells. Centrifugal connections (from serotonergic raphe nuclei and the noradrenergic locus coeruleus) modulate activity in the glomeruli and periglomerular cells. The olfactory tract bypasses the thalamus and projects to the anterior olfactory nucleus, the nucleus accumbens, the primary olfactory cortex (in the uncus), the amygdala, the periamygdaloid cortex, and the lateral entorhinal cortex. The olfactory cortex has interconnections with the orbitofrontal cortex, the insular cortex, the hippocampus, and the lateral hypothalamus.

CLINICAL POINT The olfactory bulb and tract can be damaged by meningiomas of the olfactory groove or, less commonly, of the sphenoid ridge. These tumors produce Foster-­Kennedy syndrome, which consists of ipsilateral anosmia, ipsilateral optic atrophy resulting from direct pressure, and papilledema caused by increased intracranial pressure. If the ipsilateral optic nerve is completely atrophic, papilledema will not be observed on that side. The olfactory bulb and tract also can be damaged by tumors of the frontal bone, pituitary tumors with frontal extension, frontal tumors such as gliomas that act as mass lesions, aneurysms at the circle of Willis, and meningitis. These conditions are distinguished from the olfactory groove meningiomas by the additional symptoms they cause.   

Section IV GLOBAL BRAIN

FUNCTIONS

17.  Global Brain Functions

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17

GLOBAL BRAIN FUNCTIONS

17.1 Dementia

17.9 Traumatic Brain Injury

17.2 Alzheimer’s Disease: Distribution of Pathology in the Brain

17.10 Aphasias and Cortical Areas of Damage

17.3 Alzheimer’s Disease: Pathology

17.11 Aphasias: Magnetic Resonance Images and Characteristic Language Dysfunction

17.4 Neuropsychiatric Disorders: Schizophrenia

17.12 Brain Substrates of Addictive Behaviors

17.5 Neuropsychiatric Disorders: Major Depressive Disorder and Bipolar Disorder

17.13 Memory Circuits

17.6 Neuropsychiatric Disorders: Panic and Anxiety Disorders 17.7 Neuropsychiatric Disorders: Posttraumatic Stress 17.8 Neuropsychiatric Disorders: Obsessive-­Compulsive Disorder

17.14 Consciousness and Coma Assessment 17.15 Differential Diagnosis of Coma 17.16 Aging and the Nervous System

483

484

Global Brain Functions A. Alzheimer's disease Gyral atrophy of frontal lobe regions

B. Frontotemporal dementia

Relative sparing of primary motor and sensory cortices

Atrophy of frontal and/or temporal areas Relative sparing of occipital lobe

Atrophy of temporoparietal area

Hippocampal atrophy (more pronounced in older patients) Gyral atrophy (more pronounced in younger patients) Widening of sulci Thinning of cortical mantle

Atrophy of olfactory bulbs and tracts

T1-weighted MRIs demonstrating significant atrophy in the frontal (left) and temporal lobes (right) in a patient with frontotemporal dementia

Ventriculomegaly, especially temporal horn of lateral ventricle

D. Vascular dementia

Arteriolar intracranial disease

C. Dementia with Cortical Lewy bodies Lewy bodies

and loss of dopamine projections to frontal cortex and basal ganglia result in dementia

Lewy bodies are found in substantia nigra as well as other brainstem nuclei and cortex

Dopamine Lewy body dementia

Neuron

Extracranial large Subcortical (lacunar) infarcts vessel disease cause signs and symptoms of subcortical dementia E. Treatable dementias Subdural Brain hematoma tumor

Lewy bodies are intracellular inclusions that appear as an eosinophilic inclusion with a halo when stained with hemotoxylin and eosion (left). Newer immunostaining techniques using antibodies to alpha-synuclein densely label Lewy bodies (right).

17.1 DEMENTIA

Cortical infarcts may cause focal signs and symptoms related to area of cortex involved

Intracranial medium size vessel disease

Lewy body

Dopamine Normal

Bilateral infarcts usually required for development of dementia

 

Global Brain Functions

17.1 DEMENTIA (CONTINUED) Dementia is a group of symptoms affecting memory, thought processes, and social interactions to a sufficient extent to interfere with daily life. It is accompanied by cognitive changes such as memory loss, confusion, getting lost, inattention, diminished problem-solving ability, impaired reasoning, loss of organizational skills, and loss of coordination. Psychological changes also are seen, such as depression, anxiety, agitation, anger, inappropriate behaviors, and personality changes. The onset of dementia is usually subacute or chronic. Altered consciousness does not occur until late in the disease. Psychotic behavior is uncommon in dementia. Alzheimer’s disease (AD) is the most common form of dementia. The cortex commonly demonstrates atrophy, with sparing of sensory, motor, and occipital cortices. The cortex and other areas such as the hippocampus demonstrate aberrant amyloid-­beta deposits, extracellular neuritic plaques, and intracellular neurofibrillary tangles. See Plates 17.2 and 17.3 for details of AD and its pathology. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy, with loss of neurons and neuronal connections. Patients demonstrate altered cognition, altered decision making and judgment, disinhibition and impulsivity, altered language capabilities, and personality and behavioral changes. Dementia with Lewy bodies, constituting 10% to 15% of dementias, is accompanied by abnormal changes in the synaptic protein alpha-­synuclein (Lewy bodies) in the brainstem (especially substantia nigra, pars compacta) and many areas of cerebral

485

cortex. Lewy bodies are sometimes found with plaques and neurofibrillary tangles in AD. Patients often experience visual hallucinations and striking images of animate objects and may exhibit cognitive impairment. Symptoms of Parkinson’s disease (rigidity, resting tremor, bradykinesia, postural instability) may occur, along with depression, anxiety, and autonomic dysfunction (orthostatic hypotension, dizziness, syncope). Vascular dementia is the second most common form of dementia and may accompany small and/or large vessel disease. A single stroke may precipitate dementia. Gradual occurrence of small vessel disease may precipitate damage to subcortical white matter from multiple lacunar infarcts and bring about progressive cognitive impairment, including loss of attention and ability to focus, slowed thinking, impaired organizational ability, and diminished problem-­solving ability. Vascular dementia is sometimes referred to as multi-infarct dementia (caused by multiple strokes) or Binswanger’s disease (subcortical arteriosclerotic encephalopathy [SAE]), small vessel disease caused by damage to white matter, such as seen in longstanding hypertension. Treatable dementias, appearing with cognitive decline and intellectual impairment, may occur from other causes such as traumatic brain injury (TBI), brain tumors, subdural hematomas, normal-­pressure hydrocephalus, metabolic encephalopathy, or depression. Such dementias may be accompanied by headache, seizures, gait disturbances, past history of TBI, changes in consciousness or presence of sleepiness, and incontinence.

486

Global Brain Functions

Hippocampus In neocortex, primary involvement of association areas (especially Nucleus temporoparietal and frontal) with relative sparing of primary sensory basalis cortices (except olfactory) and motor cortices Olfactory bulb

Amygdala Locus ceruleus

Dura mater Pia-arachnoid

-Amyloid peptide deposition in cortical and leptomeningeal CA1 arterioles I II III

CA2

CA4

Raphe nuclei Pathologic involvement of limbic system and subcortical nuclei projecting to cortex CA3 Subiculum

In hippocampus, neurofibrillary tangles, neuronal loss, and senile plaques primarily located in layer CA1, subiculum, and entorhinal cortex

SP IV V VI

Entorhinal cortex

Presubiculum

NFT

Association cortex In association cortex, neurofibrillary tangles (NFTs) and synaptic and neuronal loss predominate in layer V. Senile plaques (SPs) occur in more superficial layers

Characteristic pathologic findings in the brain of a patient with Alzheimer′s disease: Neuritic plaque and neurofibrillary tangle. Neuritic plaques (bottom arrows) are extracellular deposits of amyloid in the brain. Neurofibrillary tangles (top arrow) are aggregates of hyperphosphorylated tau protein.

 

17.2 ALZHEIMER’S DISEASE: DISTRIBUTION OF PATHOLOGY IN THE BRAIN The characteristic pathology in the brain in AD is neuritic (amyloid) plaques (extracellular deposits) and neurofibrillary tangles (intracellular aggregates of hyperphosphorylated tau protein in neurons). Although these are described as the characteristic pathologic features of AD, some severely cognitively impaired individuals have normal amounts of plaques and tangles, and some individuals with extensive autopsy-­confirmed plaques and tangles were cognitively intact before death. Neuritic plaques are usually abundant in AD, particularly in frontal and parietal cortical regions, found particularly in upper layers of the cortex. Neurofibrillary tangles are abundant in neurons in AD, starting in the medial temporal lobe (amygdaloid region, entorhinal cortex), expanding into the hippocampal

formation and cingulate cortex, and in late stages affecting widespread areas. Neurons with intracellular tangles are abundant in layer V of affected regions of cortex. Clinical findings accompanying these pathologies include cognitive impairment, memory deficits, poor judgment and decision making, disorientation, and language impairment. In early stages of AD, the CA1 sector of the hippocampus, the subiculum, and the entorhinal cortex are susceptible to neuronal damage from both plaques and tangles; hence the early presence of memory deficits, especially short-­term memory deficits. Some cortical areas remain relatively spared from pathology from plaques and tangles in AD, including sensory cortices (somatosensory, auditory, visual) and motor cortex. See Plate 16.31 Clinical Point.

Global Brain Functions

487

Selective loss of corticocortical and subcorticocortical projections Normal

Alzheimer′s disease Loss of corticocortical projection neuron

Corticocortical projection neuron

Neurofibrillary tangle

Corticocortical projections

Subcorticocortical projections

Loss of corticocortical projection

Preservation of some intracortical neurons

Nucleus basalis (acetylcholine) Loss of subcortical neurons projecting to cortex

Locus ceruleus (norepinephrine) Raphe nuclei (serotonin) Noncortical projections Corticocortical projection neurons project to neurons in distant areas of cortex. They receive subcorticocortical projections from neurons in subcortical nuclei.

Control

0.5

Preservation of noncortical projection neurons Alzheimer-related loss of subcorticocortical projection neurons results in loss of those circuits and cognitive dysfunction.

AD

1.0

1.5

2.0

2.5

PET imaging with florbetapir reveals the presence of amyloid plaque deposits in the brain of an individual with a clinical diagnosis of Alzheimer disease (shades of red) compared to a cognitively normal older adult with little to no evidence of amyloid (lighter red and yellow).

Coronal T1-weighted MRI scan showing atrophy of the hippocampus bilaterally (arrows), with enlargement of the temporal horns of the lateral ventricles. Global atrophy is evident with widening of the sulci and enlargement of subarachnoid spaces.

 

17.3 ALZHEIMER’S DISEASE: PATHOLOGY Pathological changes seen in AD include enlarged ventricles and the lateral fissure, with significant cortical atrophy and hippocampal atrophy, loss of cortico-­cortical connections, and widened cortical sulci. Cellular pathology includes amyloid-­beta

deposits, extracellular neuritic plaques, and intracellular neurofibrillary tangles. Also present is a significant subcortical loss of serotonergic (raphe nuclei), noradrenergic (locus coeruleus), and cholinergic (nucleus basalis) nuclei and their projections to the cortex.

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Global Brain Functions

Enlargement of ventricles

Dorsolateral prefrontal cortex (dlPFC)

Inferior parietal cortex

Lateral ventricle

Angular gyrus

Posterior cingulate Striatum cortex (image projected) Third ventricle Corpus callosum Dorsolateral prefrontal cortex (dlPFC) (image projected from lateral surface)

Thalamus Ventral tegmental area

Ventromedial prefrontal cortex (vmPFC)

Raphe nuclei

Amygdala Hippocampus Medial temporal cortex Neural Pathways Involved in Schizophrenia Substantia nigra Prefrontal cortex

Positive Symptoms (delusions, hallucinations)

Anterior parahippocampal gyrus

Mesolimbic pathway

5-HT receptor blockers (e.g., risperidone) increase release of DA to alleviate negative symptoms.

Negative Symptoms (flat affect, apathy) Mesocortical pathway

Tegmentum

D2 receptor blockers (e.g., haloperidol) inhibit DA action and alleviate positive symptoms. Adverse Effects (e.g., parkinsonism) Nigrostriatal pathway

DA

Tegmentum (Inhibited in schizophrenia)

DA

Tegmentum (disinhibited in schizophrenia)

Striatum

Nucleus accumbens

Nucleus accumbens

Prefrontal cortex

Corpus striatum DA

Substantia nigra Inhibited DA release results in loss of inhibition of excitatory acetylcholine neurons in corpus striatum.

  17.4 NEUROPSYCHIATRIC DISORDERS: SCHIZOPHRENIA Schizophrenia is a major psychiatric disorder, with a genetic component, characterized by delusions, hallucinations, disorganized speech and thoughts, psychomotor disturbances, and often cognitive impairment. Positive symptoms (delusions and hallucinations) and negative symptoms (catatonic behavior, social withdrawal, blunted affect, alogia, and avolition) are seen. Patients sometimes have difficulty distinguishing fantasy from reality and show reduced insight and awareness of their illness. Cognitive impairment may include deficits in episodic memory, attention, executive functions, and intellectual ability. These many symptoms may be variable in their appearance and severity but usually have a drastic effect on personal relationships and business and professional relationships. Schizophrenia has a lifetime prevalence of approximately 1%, typically appears at 20 to 35 years of age, and is more frequent in men than in women. Approximately 15% of patients with schizophrenia commit suicide.

Areas of the brain involved in schizophrenia include: 1.  Prefrontal cortex (both ventromedial prefrontal cortex [vmPFC] and dorsolateral prefrontal cortex [dlPFC]) and its connections with temporal cortex, parietal cortex, and striatum 2. Medial temporal cortex 3.  Other cortical areas—posterior cingulate cortex, inferior parietal cortex, angular gyrus, anterior parahippocampal gyrus, and cortico-­cortical excitatory pathways 4. Corpus callosum—slower interhemisphere processing 5.  Hippocampus—disorganized pyramidal neurons in CA1, CA2, subiculum, entorhinal cortex 6. Amygdala—diminished emotionality 7. Thalamus—especially dorsal and medial dorsal (MD) regions 8. Striatum—striatal enlargement may result from antipsychotic meds 9. Enlarged lateral and third ventricles—may be the consequence of neuronal loss 10. Ventral tegmental area (VTA) and its mesolimbic and mesocortical pathways 11. Raphe nuclei—dorsal raphe nucleus, central superior nucleus

Global Brain Functions

489

Dorsolateral prefrontal cortex (dlPFC) Insular cortex

Striatum Cingulate (image projected) cortex

Dorsolateral prefrontal cortex (dlPFC) (image projected from lateral surface)

Thalamus Ventral tegmental area Raphe nuclei

Ventromedial prefrontal cortex (vmPFC)

Locus coeruleus

Nucleus accumbens Amygdala Hippocampal formation (including subiculum)

 

17.5 NEUROPSYCHIATRIC DISORDERS: MAJOR DEPRESSIVE DISORDER AND BIPOLAR DISORDER Major depressive disorder (MDD) is a common neuropsychiatric disorder, with onset often in early adulthood, that occurs in approximately 5% of the population. MDD is more prevalent in women and is associated with a genetic component. Many medical conditions may provoke MDD. The clinical onset includes at least 2 weeks with sadness and a loss of pleasure (anhedonia), accompanied by at least five of the following symptoms: (1) diminished concentration, (2) lethargy and fatigue, (3) altered appetite and weight changes, (4) sleep dysfunction, (5) restlessness, (6) feelings of worthlessness or guilt, (7) difficulty making decisions or thinking, and (8) suicidal thoughts or an actual attempt. MDD is a chronic illness with a tendency to recur, sometimes becoming worse at it progresses. A major treatment approach is pharmacologic, such as the use of selective serotonin reuptake inhibitors (SSRIs). Brain areas involved in MDD include: 1. Prefrontal cortex—both vmPFC and dlPFC 2. Insular cortex 3. Cingulate cortex and its connections regulating autonomic and neuroendocrine systems 4. Corticolimbic connections 5. Hippocampal formation, including the subiculum

6. Amygdala 7. MD thalamus and its connections to PFC, amygdala, and striatum 8. Striatum 9. Nucleus accumbens and its midbrain dopaminergic (DA) mesolimbic connections for reward and motivation 10. Raphe nuclei—dorsal raphe nucleus and central superior nucleus (serotonergic) 11. Locus coeruleus and its noradrenergic connections 12. VTA and its dopaminergic mesolimbic and mesocortical connections Bipolar disorder often appears as recurrent manic episodes seen before a major depressive disorder. Bipolar I disorder is the occurrence of one or more full-­blown manic episodes, accompanied by expansive or irritable mood, grandiosity, racing thoughts, excess energy and a decreased need for sleep, distractibility, poor judgment, and risk-­taking. Bipolar II disorder involves prior hypomanic behavior and depressive episodes but no major manic episode. In some situations, both manic/hypomanic and depressive components may occur together. Areas of the brain involved in bipolar disorder include many of the areas noted above for MDD, including PFC, cingulate cortex, reduced cortical thickness (frontal, temporal, and parietal), hippocampal CA regions, amygdala, and ventral striatum.

490

Global Brain Functions

Dorsolateral prefrontal cortex (dlPFC) Insular cortex Striatum Bed nucleus of stria (image projected) terminalis

Anterior cingulate cortex Dorsolateral prefrontal cortex (dlPFC) (image projected from lateral surface)

Thalamus Ventral tegmental area Raphe nuclei

Ventromedial prefrontal cortex (vmPFC)

Hypothalamus GABA activity in multiple brain areas (not shown)

Locus coeruleus

Amygdala Hippocampus

 

17.6 NEUROPSYCHIATRIC DISORDERS: PANIC AND ANXIETY DISORDERS Panic disorder involves multiple episodes of intense anxiety and associated physical symptoms. These physical symptoms include palpitations, dyspnea and shortness of breath, dizziness, tachycardia, sometimes chest pain, and others. The patient is fearful of being away from help, fearful of social interactions, and frightened by the prospect of catastrophic outcomes such as a heart attack or stroke. Anxiety disorder is characterized by uncontrollable worry, far greater than the actual situation would warrant. This disorder involves 6 months or more of uncontrollable worry and at least three of the following characteristics: (1) restlessness and edginess, (2) irritability, (3) fatigue, (4) disrupted sleep, (5) poor concentration, and (6) muscle tension. Anxiety disorder may persist for many years and has some genetic component. Several brain areas are involved in panic and anxiety disorders:

1. Fear-­processing circuitry of the amygdala, anterior cingulate cortex, and insular cortex, demonstrating increased activity 2.  Prefrontal cortex and MD nucleus of the thalamus—can inhibit or blunt the fear-­processing circuitry, demonstrate diminished activity 3.  Bed nucleus of the stria terminalis—help to drive autonomic reactivity with connectivity through the amygdala and hypothalamus 4. Hippocampus—altered processing of fear-­related learning and memory and threats 5. Amygdala and its stimulation of the hypothalamo-­pituitary-­ adrenal (HPA) stress axis 6. Hypothalamus and its regulatory circuitry for the HPA axis and the autonomic nervous system 7. Raphe nuclei (rostral) and its serotonergic connections 8. Locus coeruleus and its noradrenergic connections 9. GABA activity in multiple brain areas

Global Brain Functions Coronal section

491

Lateral ventricle (elevated CRH and NE in CSF and brain) Caudate nucleus Basal ganglia (caudate nucleus, putamen, globus pallidus; Bed nucleus of stria image projected) terminalis

Thalamus Putamen Globus pallidus

Hippocampus

Hypothalamus

Thalamus Ventromedial prefrontal cortex (vmPFC)

Hypothalamus

Olfactory bulb Optic nerve Amygdala Hippocampus (decreased volume) Vestibulocochlear nerve

  17.7 NEUROPSYCHIATRIC DISORDERS: POSTTRAUMATIC STRESS Posttraumatic stress (PTS), often referred to as posttraumatic stress disorder (PTSD), is a debilitating and often long-­term neuropsychiatric disorder in reaction to a traumatic event or ongoing events. PTS is seen in both men (5%+) and women (10%+) and often occurs in combat veterans (25%+). PTS can occur following rape, violent assault, life-­threatening experiences, and other severe traumas. A principal characteristic of PTS is the repeated and intrusive recall of the trauma (with hallucinations, striking images, flashbacks, nightmares). Blunted emotional reactivity and a sense of detachment occur, often accompanied by hopelessness and a lack of positive outlook. Hyperreactivity (hyperarousal, hypervigilance, startle responses, outbursts of anger) is also seen. PTS also is accompanied by impaired social interactions, emotional interactions, and cognitive functioning, seriously affecting personal and professional relationships. Impaired learning and memory, and inattention, also occur. PTS often is accompanied by depression, anxiety, substance abuse, and suicide; these accompanying problems may diminish or resolve when the underlying PTS is treated successfully. Current therapeutic approaches include pharmacology (often SSRIs), behavioral therapy, and psychotherapy. A more recent approach involves connecting the patient with PTS with a support animal for which the patient has responsibility, such as a horse, which provides support and close interactions with the animal, other patients with PTS, and the program staff.

Neurological involvement in PTS includes: 1. Increased corticotropin-releasing factor (or hormone; CRH) in the brain and cerebrospinal fluid (CSF), accompanied by decreased adrenocorticotropic hormone in the pituitary and decreased cortisol in the serum. There is enhanced sensitivity to negative feedback by cortisol. 2. Elevated CRH acts on the basolateral amygdala, enhancing memory consolidation for traumatic events. 3. Elevated norepinephrine (NE) is present in the CSF, also enhancing memory consolidation for fear-­ associated and trauma-­associated events. 4. Decreased hippocampal volume (from elevated CRH) and enhanced sensitivity of CRH receptors, leading to hippocampal neuronal apoptosis via excitotoxic damage. This also blunts the suppression of stress responses. 5.  Amygdala—receives convergence of damaging trauma-­ induced hyperstimulation via CNs I, II, and VII and drives fear responses to the trauma, especially through continuing activation of the cranial nerves associated with sensory components of the initial trauma. The amygdala on the left side may be hyperresponsive in PTS. Lesions of the amygdala on the right side result in loss of fear responses. 6. vmPFC (ventromedial prefrontal cortex)—underresponsive in PTS and cannot counter the overactivity of the amygdala 7. Hypothalamus—drives autonomic reactivity 8. Bed nucleus of the stria terminalis (BNST)—involved in autonomic regulation (associated with the amygdala and hypothalamus), uncertain fear-­related reactivity, aggressive behaviors, and altered social attachments. 9. Cortico-­basal ganglia-­thalamic-­cortical loops.

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Global Brain Functions

Dorsolateral prefrontal cortex (dlPFC)

Basal ganglia/striatum (image projected)

Anterior cingulate cortex Dorsolateral prefrontal cortex (dlPFC) (image projected from lateral surface)

Thalamus Ventral tegmental area

Ventromedial prefrontal cortex (vmPFC)

Amygdala Hippocampus

 

17.8 NEUROPSYCHIATRIC DISORDERS: OBSESSIVE-­COMPULSIVE DISORDER Obsessive-­compulsive disorder (OCD) is characterized by intrusive and unwanted thoughts and obsessions, which provoke activities and rituals that are meaningless and inappropriate. The obsessive thoughts and compulsive behaviors are disturbing to the patient and greatly interfere with normal life. Obsessions often relate to cleanliness and fear of the presence of “germs,” resulting in endless handwashing and cleaning rituals. Some obsessions center on detailed organization and orderliness of objects in the environment, with repeated checking to ensure that everything is exactly as desired. OCD also may lead to hoarding and accumulation of clutter. OCD sometimes is accompanied by anxiety and mood disorders, such as bipolar disorder. OCD is often chronic and disrupts behavioral life and daily activities. The lifetime prevalence is approximately 2%. Early onset of OCD may be foreshadowed by Tourette’s syndrome and tic disorders. There may be a genetic component to OCD.

Several neural structures and brain circuits are associated with OCD: 1.  Prefrontal cortex (PFC)–basal ganglia–thalamus–cerebral cortex loops. The dlPFC, head of the caudate nucleus, corticostriate circuitry, and thalamic circuitry demonstrate heightened metabolic activity. Diminished executive functions from the dlPFC may occur, leading to compulsive and impulsive activity. 2. vmPFC—increased activity may underlie intrusive thoughts 3. Anterior cingulate cortex—activation may lead to anxiety 4. Hippocampus—may be associated with short-­term memory dysfunction 5. Amygdala 6.  Midbrain VTA and its DA mesolimbic and mesocortical pathways 7. Increased glutamate neural activity—increased in the caudate nucleus and diminished in the anterior cingulate cortex

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Injured brain

Normal brain

Traumatic forces to the head can change the way the brain works

Healthy neuron Tau-microtubule complexes in axon

Repetitive concussions can cause chronic traumatic encephalopathy and result in loss of white matter

Microtubule Tau subunits assemble and form neurofibrils Tau bound to microtubule

Diseased neuron

Aggregated tau protein within neurofibrillary tangle

Microtubule subunits fall apart

Disintegrating microtubule

Dissociated tau subunit

  17.9 TRAUMATIC BRAIN INJURY A concussion is a TBI caused by forces impinging on the head that alter brain function but usually do not cause loss of consciousness. More than 1.5 million concussions occur per year during sports activities. Repeated concussions can result in chronic traumatic encephalopathy (CTE), with serious physical, emotional, and cognitive consequences. Symptoms of concussion include memory impairment, altered thinking, emotional changes, and physical problems such as nausea, headaches, and visual impairment. A second concussion or trauma occurring before the resolution of the initial concussion can escalate the problems, contributing to cerebral edema, severe neurological impairment, coma, or death. A problematic consideration is the lack of an accurate indicator for the full recovery from an initial concussion or vulnerability to a subsequent trauma.

CTE may occur in former athletes or individuals who have experienced repeated concussions or head trauma. CTE involves progressive brain deterioration and degenerative brain changes, including chronic accumulation of tau protein within neurofibrillary tangles, similar to what is observed in the brains of patients with AD. In addition to alterations in gray matter, CTE may be accompanied by white matter loss, even in young athletes. Significant numbers of TBI cases are seen in military combat theaters from high-­velocity rifle injuries, from shrapnel and blast injuries, and as consequences of improvised explosive devices. These patients experience severe acute edema and increased intracranial pressure, and they sometimes require mechanical ventilation. Advances in field treatment of these military personnel have led to lives being saved, but at the expense of severe sequelae from the resultant injuries.

494

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Infarct, coronal section

Clinical manifestations Broca aphasia (if on left side) Contralateral hemiplegia, hemisensory loss, gaze palsy, spatial neglect

Patient trying to find words but only producing nonfluent effortful, slow, halting speech Wernicke aphasia (if on left side) Contralateral hemianopsia or upper quadrantanopsia Constructional dyspraxia (if on right side)

Fluent phonemic mixed syllables verbally incorrect words (i.e., paraphrase errors/ ”word salad”) Global aphasia (if on left side) Contralateral gaze palsy, hemiplegia, hemisensory loss, spatial neglect, hemianopsia May lead to decreased consciousness and even coma secondary to edema

Right-handed patient with severe hemisphere deficit unable to utter any language or comprehend with hemiplegia individual

  17.10 APHASIAS AND CORTICAL AREAS OF DAMAGE Cerebral infarcts and other damage to cortical gray matter and cortical white matter (long association pathways) can result in language disorders called aphasias. This chart presents the location

and clinical manifestations of major types of aphasia, including Broca (expressive) aphasia, Wernicke’s (receptive) aphasia, and global aphasia. The location and clinical characteristics of conduction aphasia are discussed in Plate 13.26 Clinical Point.

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R

495

Clinical syndromes related to site of region

L

Broca aphasia MRI-FLAIR

Wernicke aphasia Broca aphasia

Pronunciation, speech rhythm

Dysarthria, stuttering, effortful

Speech content Repetition of speech

Angular gyrus-posterior temporal, inferior parietal Wernicke aphasia

Normal, fluent, loquacious

Global aphasia-T2 FLAIR

Angular gyrus

Global aphasia

Alexia without agraphia Alexia without agraphia

Normal

Very abnormal Normal

Missed syllables, Use of wrong or agrammatical, telegraphic nonexistent words

Often normal

Very abnormal Normal

Abnormal but better than spontaneous

Abnormal

Normal

Very abnormal Normal

Comprehension Normal of spoken language

Very abnormal

Normal

Very abnormal Normal

Comprehension Not as good as for of written spoken language language

Abnormal but better than for spoken

Very abnormal

Very abnormal Normal

Writing

Clumsy, agrammatical, misspelling

Penmanship OK but misspelling and inaccuracies

Very abnormal, spelling errors Very abnormal Normal

Naming

Better than spontaneous speech

Wrong names

Often abnormal

Other

Hemiplegia, apraxia

Sometimes hemianopsia Slight hemiparesis, trouble and apraxia calculating, finger agnosia, hemianopsia

Very abnormal Normal Hemiplegia

Abnormal reading

 Images reprinted with permission from Jones RH, et al. The Netter Collection of Medical Illustrations, Part I, Brain, 2nd Edition. Philadelphia: Elsevier, 2014.

17.11 APHASIAS: MAGNETIC RESONANCE IMAGES AND CHARACTERISTIC LANGUAGE DYSFUNCTION Aphasia is a language disorder affecting language use and language comprehension. It does not include dysarthrias, characterized by impaired articulation and the loss of ability to speak, or dysphonia, characterized by the inability to speak due to dysfunction of structures in the oral cavity or the vocal cords. The presence of aphasia is associated with dysfunction of the dominant hemisphere for language, usually the left side. The evaluation of language function includes the capabilities on the left side of the chart. The major types of aphasia considered in this chart include Broca aphasia (expressive aphasia), Wernicke aphasia (receptive aphasia), angular gyrus aphasia, global aphasia, and alexia without agraphia. MRIs, with typical lesions for these aphasias, are included at the top of the chart. Alexia without agraphia is a disconnect syndrome in which patients can write but not read; it usually occurs with strokes in the left occipital cortex that also disrupt the transfer of visual information from the right visual cortex to the left, language-­dominant hemisphere. Another type of aphasia (not represented in the table) is conduction aphasia, in which communication between Broca’s area and Wernicke’s area is disrupted, resulting in the patient’s loss of ability to repeat words, phrases, or sentences that are spoken to them. Conduction aphasia occurs with the disruption of the arcuate fasciculus (interconnecting the frontal and temporal lobes) or the supramarginal gyrus.

CLINICAL POINT Nondominant cortical hemispheric dysfunction. Damage to the nondominant hemisphere, usually the right hemisphere, often leads to left-­sided hemiplegia and many additional problems: 1. Left-­sided neglect for objects, people, written material, and sound, involving the right frontal and parietal lobes and associated thalamic connections. 2. Anosognosia—failure to recognize one’s own left-­sided hemiplegia and weakness. These individuals are susceptible to increased falls. 3. Flat affect and blunted emotional responses—unconcerned about physical deficits and future problems. 4.  Altered prosody of speech, including tone, loudness, rhythm, intonation, timbre, and word emphasis. This problem also affects music production and appreciation. 5. Prosopagnosia—difficulty recognizing familiar faces. 6. Social communication problems, including the inability to perceive emotional content of facial expression, missing nonverbal cues, and diminished abstract understanding. 7. Attention issues and difficulty focusing on tasks. 8. Cognitive difficulty with reasoning and problem solving. 9. Memory problems with recall and learning new information. 10. Disorientation to place, date, time, and topographic locations. 11. Constructional apraxia for drawing simple configurations such as a clock face. The drawing is incomplete and tails off to the left. Other apraxias (motor, ideomotor, ideational) involve damage to the dominant hemisphere. Right-­sided strokes and damage demonstrate poorer recovery than damage elsewhere, with functionally disabling problems persisting.   

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Dorsolateral prefrontal cortex (dlPFC)

Coronal section

Basal ganglia (Caudate nucleus, putamen; image projected)

Basal ganglia

Caudate nucleus

Putamen Substantia nigra Hippocampus

Anterior cingulate cortex Ventral tegmental area

Dorsolateral prefrontal cortex (dlPFC) (image projected from lateral surface)

Substantia nigra

Subcallosal gyrus Ventromedial prefrontal cortex (vmPFC)

Ventral tegmental area Nucleus accumbens

Amygdala

Hippocampus

 

17.12 BRAIN SUBSTRATES OF ADDICTIVE BEHAVIORS Addiction is a compulsion for the need or use of a habit-­forming substances (cocaine, fentanyl, other opiates, alcohol, nicotine) or activities (smoking, gambling). Addiction is driven by physiological and neurological processes interacting with environmental influences, with a genetic component. Addiction involves the repeated activation of brain reward circuitry in the presence of the addicting substance or activity. There is a three-­phase reaction with addicting substances: (1) the rush and binge (high, intoxication, euphoria), (2) withdrawal and adverse effects, and (3) anticipation and then preoccupation with the next high. These three phases utilize the same brain circuitry, but with significantly different activation or inactivation; these changes may persist even after cessation of use of the addicting substance. Addictive substances provoke greater reward, motivation, and drive than other positive stimuli. Addiction is associated with several brain circuits: 1. Reward circuitry—nucleus accumbens, ventral pallidum 2. Motivation and drive circuitry—vmPFC, subcallosal gyrus 3. Cortical circuitry—dlPFC, anterior cingulate cortex 4. Learning and memory circuitry—amygdala (basolateral) and hippocampus

5.  Habit-­ learning circuitry—caudate nucleus, putamen, and DA input from the substantia nigra, pars compacta, and its nigrostriatal pathway 6. DA circuitry from the VTA and its mesolimbic (major DA projections to nucleus accumbens, amygdala, and hippocampus) and mesocortical (PFC) components With the rush and euphoria of drug use, high amounts of DA release activate nucleus accumbens (mood), the vmPFC (motivation), and amygdala and hippocampus (emotion, learning, memory). The cognitive control circuitry of the dlPFC and anterior cingulate cortex cannot block or counter this DA surge, which reinforces the compulsive substance use. The anticipation of subsequent drug use can be even more powerful for DA release than use of the drug itself. During prolonged drug use, and especially during withdrawal, DA release plummets, removing the pleasurable and euphoric effects and initiating the negative effects. Subsequent anticipation of the next use can then reverse the DA crash and enhance DA release. Superimposed on this cycle is the influence of environment, which can modulate the DA activity. Susceptibility to addiction and the large DA activation may be partially driven by individual variation in DA D2 receptor numbers and expression.

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Possible processing circuit for recent memory Primary sensory cortices Primary somatosensory cortex

Unisensory association cortices

Polysensory association cortices

Primary visual cortex

Specific sensory input successively processed through primary sensory, unisensory, and polysensory association cortices. These cortices project directly or indirectly to entorhinal cortex, which projects to hippocampus. All sensory information indexed in hippocampus and projected back to entorhinal cortex, from which it is diffusely projected to neocortex for storage as memory.

Primary auditory cortex

CA1 CA3 Dentate gyrus

Corticocortical projections

Subiculum

Entorhinalhippocampal circuit

Perforant pathway

Neuronal loss or dysfunction in entorhinal hippocampal circuit, as in Alzheimer′s disease, may disconnect this memory processing area from input of new sensory information and from retrieval of memory stored in neocortex. Loss of corticocortical projections interferes with memory processing and may contribute to memory deficits in Alzheimer′s disease.

Olfactory bulb Amygdala (Primary olfactory cortex may project directly to entorhinal cortex) Entorhinal cortex

Korsakoff syndrome. Small hemorrhages around enlarged 3rd ventricle and shrunken mamillary bodies (arrows). Clinical features include memory loss, confabulation, confusion, peripheral neuritis, nystagmus and opthalmoplegia.

Amnesic stroke. Bilateral infarction of hippocampus and medial temporal lobes

 

17.13 MEMORY CIRCUITS Memory circuits involve multiple regions of the temporal lobe, hippocampal formation (including the entorhinal cortex), and sensory/polysensory cortical areas. Conditions such as Korsakoff

syndrome and amnestic strokes can result in damage to this circuitry.

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Full Outline of UnResponsiveness Score (FOUR) Eye response 4 = eyelids open or opened, tracking, or blinking to command 3 = eyelids open but not tracking 2 = eyelids closed but open to loud voice 1 = eyelids closed but open to pain 0 = eyelids remain closed with pain Motor response 4 = thumbs-up, fist, or peace sign 3 = localizing to pain 2 = flexion response to pain 1 = extension response to pain 0 = no response to pain or generalized myoclonus status Brainstem reflexes 4 = pupil and corneal reflexes present 3 = one pupil wide and fixed 2 = pupil or corneal reflexes absent 1 = pupil and corneal reflexes absent 0 = absent pupil, corneal, and cough reflex Respiration 4 = not intubated, regular breathing pattern 3 = not intubated, Cheyne-Stokes breathing pattern 2 = not intubated, irregular breathing 1 = breathes above ventilator rate 0 = breathes at ventilator rate or apnea Interpretation: Minimum score = 0, Maximum score = 16. The lower the score the greater the coma. Reprinted with permission from Wijdicks EFM, Bamlet WR, Maramattom BV. Validation of a new coma scale: the FOUR score. Ann Neurol 58:585-593, 2005.

17.14 CONSCIOUSNESS AND COMA ASSESSMENT A new coma scale assesses eye response, motor responses, brainstem reflexes, and respiratory responses. The original classic

 

coma scale is the Glasgow Coma Scale, using eye, motor, and verbal responses.

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Clinical features

Pathology (examples)

Normal pupils (equal, reactive) Bilateral cerebral hemisphere disease

Normal oculocephalic reflex phenomenon

Normal corneal reflex

Bilateral hemispheric swelling (small ventricles, obliterated sulci, rounded edges)

Absent or minor focal features (lateral paralysis, sensory or visual loss)

Unilateral cerebral hemisphere lesion with compression of brainstem

Third cranial nerve palsy, nonreactive pupil, ptosis

Contralateral hemiparesis

Primary brainstem lesion

Right temporal hemorrhage from trauma, with swelling of right hemisphere

Etiologies Increased subarachnoid or extracerebral pressure Meningitis Subarachnoid hemorrhage Bilateral subdural hematoma Metabolic encephalopathy Liver coma Kidney coma Carbon dioxide narcosis Hypoxia Hypoglycemia Hypercalcemia Hyponatremia Diabetic acidosis Hyperosmolar coma Toxins or drug overdose Barbiturates Alcohol Other sedative drugs Lead Multifocal cerebral disease Sequential infarctions Multiple abscesses Encephalitis Multiple areas of brain tumor Multiple cerebral contusions

Cerebral Tumor Hemorrhage Abscess Infarction Contusion Extracerebral Subdural hematoma Epidural hematoma

Infarction Hemorrhage Severe metabolic disturbance, sedative or phenytoin overdose Severe anoxia Phenytoin Narcotics

Small pinpoint pupils, absent horizontal eye movements

Rigid limbs

Large pontine hemorrhage

Vomiting Cerebellar lesion with secondary brainstem compression

Inability to walk or ataxia

Sixth cranial nerve palsy

  17.15 DIFFERENTIAL DIAGNOSIS OF COMA This chart depicts the differential diagnosis of coma.

Infarction Hemorrhage Tumor Abscess Contusion Large cerebellar hemorrhage

499

Dorsolateral prefrontal cortex (dlPFC) Insular cortex Striatum (image projected)

Ventral tegmental area

Temporal cortex Dorsolateral prefrontal cortex (dlPFC) (image projected from lateral surface)

Substantia nigra Rostral raphe nuclei

Ventromedial prefrontal cortex (vmPFC) Selective loss of cortical gray matter

Cerebellum (gray matter) Hippocampus Enlargement of ventricles

Locus coeruleus

  17.16 AGING AND THE NERVOUS SYSTEM The aging human shows great variation in the consequences of changes, usually due to genetic background, medical history and conditions, and environmental factors. The MacArthur Commission on Successful Aging noted the three most significant factors contributing to successful aging: (1) stay socially engaged, (2) stay physically active, and (3) avoid disease (refrain from smoking, substance abuse, obesity, damaging stress, and other factors that can bring about diabetes, cardiovascular disease, and other adverse health conditions). Numerous alterations in brain and brain function have been reported in normal aging (differing from Alzheimer’s disease, other dementias, and neurodegenerative diseases): 1. Diminished brain volume and gray matter loss, accompanied by enlargement of the ventricles. This loss is not uniform and most significantly affects the prefrontal cortex, striatum, temporal cortex (especially on the left side), insular cortex, cerebellum, and hippocampus. The occipital cortex and cingulate cortex appear to be least affected. 2. Increased susceptibility to neurodegenerative disease (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis), cerebrovascular disease, mild cognitive impairment, and dementia. It should be noted than many aging individuals have no evidence of any of these problems. 3. Increased damage to noradrenergic (NA), dopaminergic (DA), and serotonergic (5HT) systems due to oxidative stress and the production of damaging free radicals. Highly toxic derivatives of these monoamines can be produced by the release and subsequent reuptake into the monoamine nerve terminals, leading to gradual destruction. DA and 5HT receptors also decline with

age. NA terminals in the postganglionic sympathetic peripheral systems also can be damaged by monoamine-­derived free radical production and subsequent uptake. This can lead to loss of optimal sympathetic interactions with the cardiovascular system and with secondary lymphoid organs and natural immune cells such as natural killer cells and some T lymphocytes. Accelerated DA release, as occurs in Parkinson’s disease, or NA release, as occurs in chronic sympathetic activation during chronic stress, can accelerate this damaging process. 4. Diminished presence of other neurotransmitters such as glutamate (in parietal cortex, basal ganglia, and frontal cortex), and diminished N-­acetyl aspartate. 5. Physiological changes, including diminished brain glucose metabolism, cerebrovascular changes from ischemia, white matter lesions with some loss of myelin, and some diminished dendritic arborizations of neurons in important structures such as prefrontal cortex and hippocampus. 6. Diminished performance on tasks requiring attention and executive functions (prefrontal cortex–basal ganglia–thalamic circuitry). Deficits also occur in processing speed and problem-­solving ability, and in spatial orientation. 7. Diminished memory function, including episodic memory (e.g., recalling places and occurrences) and semantic memory (memory for meanings), both components of declarative or explicit memory. Working memory (briefly retaining a password or phone number) also may be diminished. Procedural memory (implicit memory), which aids in accomplishing some activities without conscious awareness (e.g., tying shoes or riding a bike), remain intact.

Index Page numbers followed by b indicate box (Clinical Point) and f indicate figure.

A A receptor, 41f A1 noradrenergic cell group, 474f A1 nucleus, 288f, 350, 350f A2 nucleus, 288f, 350, 350f A5 nucleus, 288f, 350, 350f A7 nucleus, 350, 350f A9 nucleus, 352 A10 nucleus, 352 Aβ plaque, 19f Abdominal celom, serosal lining (peritoneum) of, 131f Abdominal nerves, and sympathetic ganglia, 220–221, 220f Abdominal viscera, sensory neurons of, 132f, 162f Abdominopelvic splanchnic nerves, 231f Abducens internuclear neuron, 387f projection, 416f Abducens nerve (CN VI), 49f, 75f, 121f, 138f, 146f, 261f–262f, 269f–270f, 272f–274f, 293.e7f, 387f and ciliary ganglion, 275–276, 275f clinical point, 274b fibers of, 269f in orbit, 273–274 spinal tract/nucleus of, 293.e1f Abducens nucleus, 269f, 271f–272f, 275f, 281f, 387f, 404, 404f, 416f Abductor digiti minimi muscle, 196f, 202f Abductor hallucis muscle, 202f Abductor pollicis brevis muscle, 194f–195f Abductor pollicis longus muscle, 192f Aberrant pallidofugal fibers, 439f Abnormal palmar crease, 157f ACA. See Anterior cerebral artery Accelerated respiration, 456f Accessory meningeal artery, 49f, 95f Accessory nerve (CN XI), 49f, 74f–75f, 121f, 138f, 146f, 183f–184f, 270f–272f, 284–285, 284f, 404f clinical point, 284b cranial root of, 284f–285f dorsal (motor) nucleus of, 285f external branch of, 284f internal branch of, 284f spinal nucleus of, 271f–272f, 404f spinal roots of, 49f, 284f Accessory obturator nerve, 197f Accessory optic tract, 396f nucleus of, 396f Acetylcholine (ACh), 177f, 436b, 456f Acetylcholine receptor, 176f–178f Acetylcholine (ACh) synapse, 45f, 46 Acetylcholinesterase (AChE), 177f

AChE. See Acetylcholinesterase Acoustic (VIII) nerve, 281f, 293f Acoustic pathway, 295f Acoustic schwannoma, 282b ACTH. See Adrenocorticotropic hormone Actin, 178f Action potentials, 27f, 173f neuronal, 27–28, 27f conduction velocity of, 29–30, 29f in neurotransmitter release, 27, 40f propagation of, 28–29, 28f propagation of, blocking of, 28b Activated microglia, 13f, 19f Activation gate, 24f Active PKA pathway, 43f Active zone, 176f Acute stroke, 19f AD. See Alzheimer’s disease Adamkiewicz, artery of, 116f Addition, 496 Adductor brevis muscle, 200f Adductor hallucis muscle, 202f Adductor longus muscle, 200f Adductor magnus muscle, 200f–201f Adductor pollicis muscle, 196f Adenohypophysis, 106f, 296f Adenosine triphosphate (ATP), 23f aerobic metabolism of, 4b Adequate intrafascicular circulation, pressure gradient necessary for, 164f Adipose mass, 461f Adiposity signals, 461f Adrenal cortex, 44f, 232f, 452f, 464f Adrenal glands, 204f, 207f innervation of, 232–233, 232f sympathetic innervation of, 231–232, 231f Adrenal medulla, 232f, 435f, 447f, 458f, 464f Adrenals, 459f Adrenergic cell groups, 287f Adrenergic synapses, 207–208, 207f Adrenergic terminals, 218f Adrenoceptor, alpha and beta, 436b Adrenocorticotropic hormone (ACTH), 44, 439b, 452f, 453, 453b Adrenocorticotropin, 463f Adult neurogenesis, 143–144, 143f Adventitia, 174f Adventitial zone neuroeffector junction, 179f Affective behavior, diet composition and, 46b Affective disorders, noradrenergic pathways and, 350b Afferent connections, 475f Afferent fibers, 212f, 218f–219f, 222f, 480f to brainstem, 206f to spinal cord, 206f

Afferent inhibition, of stretch reflex, 251f Afferent inputs, 456f Afferent nerve calyx, 385f Aggregated tau protein, 493f Aging, and nervous system, 500, 500f Agraphia, alexia without, 495f Agrin, 178f AICA. See Anterior inferior cerebellar artery Alar (roof) plate, 131, 137f–138f, 153f derivatives of, 145–146, 145f Alcohol intoxication, and cerebellar dysfunction, 425b Alcoholic patients, cerebellar dysfunction in, 76b Aldosterone, 459f Alpha adrenoceptor, 436b Alpha-­gamma coactivation, 252b, 253, 253f Alpha motor neurons, 252f–253f, 402–403, 402f classification of axons of, 30f Alternating hemiplegias, 112b, 286b Alveolar process of maxilla, 50f Alveus, 467f of hippocampus, 70f Alzheimer’s disease (AD), 353, 484f, 485 clinical point, 353b, 467b distribution of pathology in, 354f brain, 486–487, 486f pathology of, 487–488, 487f Amacrine cell, 390f processes, 7f Amino acid synapse, 45f, 46 Amnesic stroke, 497f AMPA receptor, 26f, 36f AMPAR pathway, 42, 42f–43f Amplify cDNA, 9f Ampullae, 151f, 378f–379f cristae within, 385f opposite wall of, 385f Amygdala, 67b, 289f, 302f, 304f–306f, 322f–329f, 354f–355f, 377f, 417f, 442f–445f, 447f, 457f, 468f–469f, 473f–477f, 480f, 486f, 488f–492f, 496f–497f basolateral nuclei of, 470f–471f central nucleus of, 355f, 471f clinical point, 470b coronal sections through, 326–327, 326f–327f corticomedial nuclei of, 470f–471f development of, 140 efferents of subiculum to, 468f extended, 432b major afferent connections of, 470–471, 470f summary of, 472–473, 472f

501

502

Index

Amygdala (Continued) major efferent connections of, 471–472, 471f summary of, 472–473, 472f stimulation of, and fear and anxiety, 471b Amygdaloid bodies, 66f, 70f, 144f, 465f nuclei, 67f Amygdaloid nuclei, 70f, 432f Amyloid-­β (Aβ), ingestion of, 19f Amyotrophic lateral sclerosis, 256b, 272b Analgesic dolorosa, 72b Analyze data, 9f Anastomotic branch to median nerve, 196f Anconeus muscle, 191f–192f Anencephaly, 130b, 156f Angiotensin I, 459f Angiotensin II, 459f Angiotensinogen, 459f Angular artery, 105f Angular gyrus, 54f, 488f, 495f Angular vein, 98f Anhidrosis, 242b Anions, in neuronal cell membrane, 23 Ankle, 408f Anococcygeal nerve, 198f Anosognosia, 495b ANS. See Autonomic nervous system Ansa cervicalis, 183f–184f, 286f inferior root (descendens hypoglossi) of, 184f, 286f superior root (descendens hypoglossi) of, 184f, 286f Ansa lenticularis, 427f, 430f, 438f–439f Ansa subclavia, 210f, 217f, 219f, 221f Anterior celiac branch, 222f Anterior central artery, 117f Anterior central vein, 127f Anterior cerebellar notch, 76f Anterior cerebral artery (ACA), 100f–101f, 105f–106f, 110f–112f, 306f A1 segment, 106f A2 segment, 106f aneurysm of, 107f basal view of, 99, 99f coronal forebrain section, 102f frontal view of, 101, 101b lateral and medial views of, 108 midline portion of, 110f terminal cortical branches of, 108f territory of, colored illustration, 109, 109f Anterior cerebral artery origin, 97f Anterior cerebral veins, 122f–123f, 126f Anterior chamber, 393f endothelium of, 389f of eye, 150f, 388f Anterior choroidal artery, 99f–101f, 106f, 111f–112f aneurysm of, 107f Anterior ciliary artery, 393f Anterior ciliary vein, 389f, 393f Anterior cingulate cortex, 316f–317f, 444f, 478f, 490f, 492f, 496f Anterior cingulate gyrus, 476f Anterior clinoid process, 48f

Anterior commissure, 67f, 89f, 123f, 140f, 292f, 296f–297f, 308f–309f, 324f–325f, 345f, 437f–438f, 441f, 465f, 470f, 480f in axial (horizontal) sections through forebrain, 308–309, 308f–309f in coronal section of forebrain, 324–325, 324f–325f in midsagittal section, 57f Anterior communicating artery, 96f, 99f–102f, 105f–106f, 108f, 111f aneurysm of, 107f Anterior corticospinal tract, 84f, 241f–246f, 405f, 408f, 410f, 415f minor component of, 410f Anterior cutaneous nerve, 133f Anterior ethmoidal artery, 49f Anterior ethmoidal foramen, 49f Anterior ethmoidal nerve, 49f, 274f, 276f, 357f external nasal branch of, 182f, 276f internal nasal branch of, 276f, 357f Anterior ethmoidal vein, 49f Anterior external venous plexus, 127f Anterior funiculus, 82f Anterior hepatic branch, 226f Anterior hepatic plexus, 229f Anterior horn, 241f frontal, of left lateral ventricle, 86f with lower motor neurons, 245f ventral, 405f Anterior hypothalamic area, 297f, 437f–439f, 441f, 444f, 472f Anterior inferior cerebellar artery (AICA), 99f, 101f, 105f–106f, 112f–114f, 116f, 269f syndrome, 269f Anterior inferior pancreaticoduodenal arteries, plexus on, 223f Anterior internal venous plexus, 127f Anterior interosseous nerve, 194f Anterior limb, 407f–408f of internal capsule, 66f, 405f Anterior lobe, 115f, 420f, 451f, 454f pituitary, 445f–447f of pituitary, 437f, 441f Anterior median fissure, 82f, 245f–246f Anterior medullary vein, 126f Anterior meningeal artery, from anterior ethmoidal artery, 95f Anterior meningeal vessels, sulcus for, 48f Anterior olfactory nucleus, 480f Anterior parahippocampal gyrus, 488f Anterior perforated substance, 60f, 67f, 75f, 445f, 465f, 480f Anterior pillar, 418f Anterior pituitary, 44f Anterior pituitary hormones, 171f Anterior pontomesencephalic vein, 126f Anterior pulmonary plexuses, branches to, 217f Anterior radicular arteries, 116f–118f Anterior radicular vein, 127f Anterior ramus, of brain, 54f Anterior rectus capitis muscles, 184f Anterior (pontine) reticulospinal tract, 84f

Anterior scalene muscle, 183f, 185f Anterior semicircular canal, 379f Anterior semicircular duct, 379f Anterior septal vein, 122f–124f Anterior spinal arteries, 99f, 101f, 105f, 112f, 114f, 116f–117f, 117–118, 245f– 246f, 248f, 269f anastomotic loops to, 116f branches of, supplying medulla, 258b cross-­sectional view of, 118, 118f infarct of, 118b Anterior spinal artery syndrome, 248f Anterior spinal vein, 126f–127f Anterior (ventral) spinocerebellar tract, 84f Anterior superior pancreaticoduodenal arteries, plexus on, 223f Anterior temporal diploic vein, 120f Anterior terminal (caudate) vein, 122f–124f Anterior thalamic nucleus, 312f, 445f Anterior thalamus, 329f Anterior tibial recurrent branch, 203f Anterior tubercle, 71f Anterior tympanic artery, 105f Anterior vagal trunks, 217f, 220f–223f, 226f, 229f–230f, 234f, 285f anterior gastric branch of, 223f celiac branches of, 223f, 225f–226f gastric branches of, 285f hepatic branches of, 223f, 225f, 285f Anterior white commissure, 84f, 241f–246f, 364f, 367f, 405f, 410f crosses in, 169f Anterograde, 9f Anterolateral central (lenticulostriate) arteries, 106f Anterolateral funiculus, 371f Anteromedial central (perforating) arteries, 106f Antibody, 9f Anti-­inflammatory effects, 44f Antiseizure medications, sites of action of, 36–37, 36f Anxiety disorder, 490–491, 490f Aorta, 105f, 118f, 131f, 229f arch of, 218f Aortic arch, 110f Aortic body, 417f Aortic plexus, 222f Aorticorenal ganglion, 205f, 222f, 224f–225f, 231f, 234f–236f, 238f Aphasias characteristic language dysfunction, 495–496, 495f and cortical areas of damage, 494–495, 494f magnetic resonance images, 495–496, 495f Apical dendrites, 170f, 341f Apical foramina, 278f Apoptosis, glucocorticoid regulation of, 44–45, 44f Appendicular arteries, 226f Appendicular plexus, 226f Appendix, 285f Appetite, neural control of, 460–461, 460f Aqueduct, 146f, 264f–268f, 293.e10f, 293.e11f, 293.e12f, 293.e13f, 293.e14f, 305f transition to III ventricle, 293.e13f

Index Arachnoid, 82f–83f, 119f–120f Arachnoid cell, 136f Arachnoid granulations, 51, 51f, 91f, 95f, 119f–120f, 119b indenting skull, 51f, 120f Arachnoid layer, 392f Arachnoid space, 51, 51f ARAS. See Ascending reticular activating system Arcuate eminence, 48f Arcuate fasciculus, 347f Arcuate nucleus, 355f, 461f Area postrema, 290f, 449, 449f–450f, 449b Arm inferior lateral cutaneous nerve of, 190f lower lateral cutaneous nerve of, 191f–192f medial cutaneous nerve of, 187f, 193f–194f posterior cutaneous nerve of, 190f–192f superior lateral cutaneous nerve, 190f upper lateral cutaneous nerve of, 191f–192f Arnold-­Chiari malformation, 89b, 155f–156f, 155 Arousal, reticular formation associated with, 290 Arrector muscle of hair, 175f Arterial pressure, 164f Arterial system, 95–96 of brain, 96–97, 96b basal view, 99–100, 99f circle of Willis in, 100–101, 100f coronal forebrain section, 102–103, 102f frontal view, 101–102, 101f internal carotid circulation, angiographic anatomy of, 111–112, 111f ophthalmic arteries and, 96, 96b, 98–99, 98f lateral and medial views, 108–109, 108f magnetic resonance angiography of, frontal and lateral views, 110–111, 110f meningeal, 95–96, 95f schematic of, 105–106, 105f territories of, color illustration of, 109–110, 109f hypothalamus and pituitary gland, vascular supply to, 115–116, 115f pituitary, 115–116, 115f spinal, 116–117, 116f anterior and posterior, 117–118, 117f vertebrobasilar, 99b, 112–113, 112b angiographic anatomy of, 113–114, 113f occlusive sites of, 114–115, 114f Arteriole, 12f Artery, 175f, 179f Artery of trabecula, 115f Articular twig, 199f Articularis genus muscle, 199f Ascending arousal pathways, 462f Ascending cervical artery, 105f, 116f

Ascending cholinergic pathway, 353f Ascending colon, 285f Ascending fibers, 235f–236f of CN VII, 261f Ascending pathways, of spinal cord, 84f Ascending pharyngeal artery, 105f meningeal branch of, 49f meningeal branches of, 95f Ascending ramus, of brain, 54f Ascending reticular activating system (ARAS), 289f Ascending secondary sensory axon, 17f Ascending sensory fibers, from brainstem and spinal cord, color imaging of, 348f Ascending serotonergic pathway, 351f Ascending tract of Deiters, 386f–387f, 416f Aspiny granule cell, 341f Association cortex, 486f Association fibers, of cerebral cortex, 340f, 343f bundles, 346–347, 346f clinical point, 345b–346b color imaging of, 347–348, 347f neuronal origins of, 344 pathways of, 345–346, 345f Association neuron, 132f Astrocyte end-­foot processes, 12f Astrocyte foot processes, 11f, 18f Astrocyte processes, 12f Astrocytes, 8, 8f, 11f, 17f, 21f biology of, 12–13, 12f glial process, 5f physiology, 12f in pia mater, 51 reactivity and loss, 19f Atherosclerosis, 97 common sites for, 97, 97f Athetoid movements, 308b Athetosis, 427b Atlas (C1), 50f, 79f, 81f ATP. See Adenosine triphosphate Atrial septal defect, 157f Auditory cortex, 55, 55f Auditory evoked potential, 37–38, 37f Auditory I, 345f Auditory II, 345f Auditory nuclei, 289f Auditory pathways, 408f afferent, 382–384, 382f–383f clinical point, 383b centrifugal (efferent), 384–385, 384f sound transduction in, 378–379, 378f clinical point, 378b Auditory radiations, 310f Auditory (eustachian) tube, 151f, 285f cartilage of, 48f pharyngeal opening and, 283f Auerbach’s plexuses, 227 Auricle, 378f Auricular muscles, branches to, 279f Auriculotemporal nerve, 182f, 215f, 276f, 283f Autocrine signaling, 15f Autonomic channels, 171–172, 171f

503

Autonomic-­hypothalamic-­limbic systems, 434–480 autonomic nervous system in, 435–437 hypothalamus and pituitary in, 437–438 limbic system in, 465–466 olfactory system in, 479 Autonomic nervous system (ANS), 204–205, 204f central preganglionic axons of, 132 development of, 148f, 149–150 cholinergic and adrenergic synapse, 207–208 development of, 133–134, 133f, 148f, 149–150 distribution of in abdominal nerves and ganglia, 220–221, 220f in adrenal gland, 231–233, 231f–232f in cranial nerve fibers, 270–271 in enteric nervous system, 227–228, 227f in esophagus, 221–222, 221f in eye, 212–213, 212f in female reproductive organs, 238, 238f in heart, 219–220, 219f in immune system and metabolic organs, 205–206, 205f in kidneys, ureters, and urinary bladder, 234–235, 234f in limbs, 216–217, 216f in liver and biliary tract, 229–230, 229f in male reproductive organs, 237–238, 237f in nasal cavity, 213–214, 213f in otic ganglion, 215–216, 215f in pancreas, 230, 230f in pelvic region, 233–234, 233f, 233b in pterygopalatine and submandibular ganglia, 214–215, 214f in small and large intestines, 224–225, 224f in stomach and duodenum, 223–224, 223f in tracheobronchial tree, 218–219, 218f neurons of, preganglionic and postganglionic, 436b organization of, 435f, 436–437 postganglionic axons in, 132 classification of, 22f preganglionic neurons of, 8, 204 classification of, 30f clinical point, 8b reflex pathways of, 206–207, 206f, 206b schematic of, 208–209, 208f Autonomic postganglionic neuron, 30f of sympathetic or parasympathetic ganglion, 8f Autoregulation, of blood flow to brain, 210b Axial muscles, 412f Axial rudiment, 129f Axillary nerve, 181f, 187f, 191f, 193f–194f cutaneous innervation from, 192f Axis (C2), 50f, 79f Axoaxonic ending, 8f Axoaxonic synapse, 7f

504

Index

Axodendritic ending, 8f Axodendritic inhibitory synapse, 251f Axodendritic synapse, 4, 4f, 7f, 38b Axolemma, 29f, 38f, 176f–177f Axon(s), 4f–5f, 7f, 11f, 22f, 32f–33f, 38f, 163f–165f, 169f, 172f–173f, 176f–177f, 207f, 454f alpha motor neuron, classification of, 30f demyelination of, 21b diameter of, myelination and, 30b ensheathment, myelination and, 22–23 gamma motor neuron, classification of, 30f initial segment of, 4f myelinated, 21 action potential in, 27 conduction of action potential in, 29–30, 29f NA, 5f from NA sympathetic postganglionic neurons, 5f peripheral, development of, 132–133, 132f in peripheral nerve, 5f tau-­microtubule complexes in, 493f undergoing dissolution, 163f unmyelinated action potential in, 27 conduction of action potential in, 27, 29f myelination of, 27 Axon hillock, 4f, 38f Axon terminal, 172f, 177f Axonal outgrowth, 15f Axoplasm, 23f, 27f, 29f, 176f Axosomatic ending, 8f Axosomatic inhibitory synapse, 251f Axosomatic synapse, 4f, 7f, 38b Azygos vein, 217f

B B receptor, 41f Back muscles, excitatory endings to, 386f Bacterial infection, 19f Barbiturates, 36f Basal body, 385f Basal ganglia, 351f, 354f, 405f, 427–428, 466f, 491f–492f, 496f in axial (horizontal) section, 312–313, 312f–313f circuitry and neurochemistry in, 428–429, 428f clinical point, 66b, 308b, 427b cognitive loop in, 431f connections of, 427–428, 427f horizontal sections of, 66–67, 66f motor loop in, 431f nucleus accumbens in, 432, 432f oculomotor loop in, 431f parallel loops in, 431–432, 431f Basal plate, 131, 137f–138f, 153f derivatives of, 145–146, 145f Basal progenitors, 142f Basal vein, 124 of Rosenthal, 122f–126f Basement membrane, 18f, 172f, 174f, 176f–177f, 376f, 385f, 454f, 479f

Basil epithelial cells, 172f Basilar artery, 96f–97f, 101f, 105f–106f, 110f, 112f–114f, 116f–117f, 269f, 300f–302f infarct of, 262b obstruction and, 114f and pontine branches, 99f Basilar groove, 75f Basilar membrane, 380f Basilar part, 48f Basilar plexus, 121f Basilar trunk, aneurysm of, 107f Basis pedunculi, 430f Basis pontis, 261f, 300f, 302f, 328f–329f, 331f with corticospinal system, 301f, 303f corticospinal tract in, 328f–329f, 331f fibers, 329f motor fibers in, 348f Basivertebral vein, 127f Basket cell, 421f–422f Basolateral dendrites, 170f, 341f Basolateral nuclei, 472f BDNF. See Brain derived neurotrophic factor Beaded varicosities, 8f Bed nucleus of stria terminalis (BNST), 445f, 470f–472f, 474–475, 474f Behavioral pathology dopaminergic pathways and, 352b noradrenergic pathways and, 350b and subcortical white matter of forebrain, 345b Bell’s palsy, 280b Benedict’s syndrome, 267b, 269f Benzodiazepines, 36f Berry aneurysms, 106b Beta adrenergic receptors, 208 Beta adrenoceptor, 436b Beta endorphin neurons, 355f, 356–357, 371, 371b Betz cell, 341f Biceps brachii muscle, 193f cervical disk herniation, 189f Biceps femoris muscle long head of, 201f short head of, 201f tendon of, 203f Bifurcation, 107f Big toe, 134f Bilateral cerebral hemisphere disease, 499f Bilateral hemispheric swelling, 499f Bile ducts, 204f, 229f, 285f Biliary tract autonomic innervation of, 229–230, 229f clinical point, 229b Bipolar cell, 7f, 390f–391f Bipolar disorder, 489–490, 489f Bipolar neurons, olfactory, 479 Bipolar recording needle, 31f Bitemporal hemianopsia, 395f Biventral lobule, 76f Bladder, 204f, 207f Blocks inflammatory transcription factors, 44f Blood-­borne information, 444f Blood-­borne inputs, 444f Blood-­brain barrier, 18–19, 18f, 18b breakdown of, 19f

Blood pressure elevation, 232f Blood pressure regulation, in hypothalamus long-­term, 459–460, 459f short-­term, 458–459, 458f Blood vessel, 8f Blood vessel lumen, 179f BMR elevation, 232f BNST. See Bed nucleus of stria terminalis Body of caudate nucleus, 439f Body of fornix, 87f, 89f, 312f–313f Body weight, signaling systems involved in regulation of, 461–462, 461f Bone, 278f, 452f Bone marrow, 17f, 464f Bony and membranous labyrinths, 379–380, 379f Botulinum toxin (BOTOX), in neurotransmitter release, 40b Bound enzyme, 9f Boutons, 7f, 21f in synapse, 38f Brachial plexus, 183f, 185f, 187–188, 187f, 216f clinical point, 187b communication to, 184f lateral cords of, 193f–194f Brachialis muscle, 191f, 193f Brachiocephalic trunk, 96f, 105f, 110f, 185f Brachioradialis muscle, 191f–192f Brain, 53–72, 152f, 459f, 461f angular branch of, 101f, 108f anterior parietal branches of, 101f, 108f anterior temporal branches of, 108f arterial supply to, 96–97, 96f ascending frontal (candelabra) branch of, 99f, 101f, 108f autoregulation of blood flow to, 210b basal surface anatomy of, with brain stem and cerebellum removed, 60–61, 60f Brodmann’s areas of, 56–57, 56f, 59f, 61–62, 61f calcarine branch of, 108f, 114f central (rolandic) branches of, 101f–102f, 108f circumventricular organs of, 449, 449b cisterns of, 86 corpus callosum of, 68–69, 68f cranial nerve primordia of, 147 deep venous drainage of, 122–123, 122f relationship to ventricles, 123–124, 123f defects of, 156f development of in 2 months, 140f in 3 months, 135f in 5 to 7 weeks, 132f in 6-­month and 9-­month, 141–142, 141f in 26-­28 days, 132f, 137–138, 137f in 36-­day-­old embryo, 138–139, 138f in 49-­day-­old embryo and 3-­month-­ old embryo, 139–140, 139f cranial nerve formation in, 147, 147f eye and orbit formation in, 150–151, 150f

Index Brain (Continued) neural proliferation and differentiation in, 135–136, 135f, 141b, 142 pituitary gland, development of, 152–153, 152f ventricle development in, 153–154, 153f diet composition and, 46b fornix of, 70–71, 70f frontal branches of, 101f functional regions of, 55–56, 55f, 55b functions of, 481–500 hemispheres of, midsagittal view of, 57b hippocampal formation in, 70–71, 70f imaging of computed tomographic, 62–63, 62f diffusion-­weighted, 69 magnetic resonance, 63f, 64–65 positron emission tomographic, 65–66, 65f injured, 493f internal frontal branches of, 108f lateral view of, 55–56, 55f–56f limbic structures of, 67–68, 67f medial (midsagittal) surface anatomy of, 57–58, 57f with brain stem removed, 58–59, 58f functional, 59, 59f medial surface of, 59–60 meninges of, 51–52, 51f normal, 493f parietooccipital branch of, 108f posterior parietal branches of, 101f, 108f posterior temporal branches of, 108f precentral (prerolandic) branches of, 101f–102f, 108f sex steroid hormones in, 439b spinal segmental medullary branches of, 105f substrates of addictive behaviors, 496–497, 496f surface anatomy of, 54–55, 54f temporal branches of, 101f–102f thalamus of, 71–72, 71f–72f topographic organization of, 55b Brain cell transplantation, 429b Brain derived neurotrophic factor (BDNF), 15f Brain primordia, adult derivatives of, 146f Brain stem at 6 months, 141 alar and basal plate derivatives in, 145–146, 145f arteries of, 114, 114f motor and preganglionic autonomic nuclei development in, 148f, 149–150 venous drainage of, and cerebellum, 126–127, 126f Brain tumor, 484f Brainstem, 254–293.e14, 73–77, 170f–171f, 432f, 446f, 458f, 472f afferent fibers to, 289f anterior anatomy of, 75–76, 75f ascending sensory fibers from, 348f cerebellum and, 291–292, 291f

Brainstem (Continued) cisterns around, 90f clinical point, 74b affective disorders and depression, 350b bulbar palsy and pseudobulbar palsy, 256b lateral medullary syndrome, 258b lateral pontine syndrome, 263b medial inferior pontine syndrome, 260b midbrain displacement and changes in brain function, 265b pontine hemorrhage, 262b unipolar depression, 351b Weber’s syndrome, Benedict’s syndrome, 267b cranial nerves, schematic distribution of sensory, motor, and autonomic fibers, 270–271 cross-­sectional anatomy of, 255–256 at genu of facial nerve, 262f at level of CN IV and locus coeruleus, 264f at level of CN X and vestibular nuclei, 259f at level of cochlear nuclei, 260b at level of decussation of pyramids, 255f at level of dorsal column nuclei, 256f at level of facial nucleus, 261f at level of inferior colliculus, 265f at level of inferior olive, 258f at level of medial geniculate body, 267f at level of midbrain, 265f at level of midbrain-­diencephalon junction, 268f at level of obex, 257f at level of pons, 255f at level of posterior commissure, 268f at level of superior colliculus, 266f at level of trigeminal motor and main sensory nuclei, 263f at medullo-­pontine junction, 260b descending connections to, 465f reticular and tegmental nuclei of, 67f efferent connections to nuclei in, 289f lower motor neuron distribution in, 404–405, 404f noradrenergic pathways of, 350–351, 350f clinical point, 350b posterolateral anatomy of, 74–75, 74f reticular formation of, 287–288 nuclei of, in brainstem and diencephalon, 288–289 pattern of nuclei in brainstem, 287–288 retinal projections to, 396–397, 396f serotonergic pathways from, 351–352, 351f clinical point, 351b tegmental cholinergic group in, 353f vestibular area of, 74f Brainstem arterial syndromes, 269–270 Brainstem auditory evoked potentials, 37, 37f Brainstem inputs, 444f

505

Brainstem nuclei, 464f, 476f Brainstem pathways, 454f Brainstem reticular formation, 445f Brainstem tegmental noradrenergic cell groups, 371f Branches to dorsum of middle and distal phalanges, 196f Branchiomotor (SVE) column, 149f Branchiomotor neurons, 148 Breast, 452f Broca aphasia, 494f–495f Broca’s area, 55f functional magnetic resonance imaging of, 349f Brodmann’s areas, of brain, 56–57, 56f on basal surface, 61–62, 61f on medial surface, 59f Bronchi, 204f, 207f Bronchial dilation, 232f Brow, 407f Brown fat, 205f Brown-­Séquard lesion, 242b Brown-­Séquard syndrome, 248f Buccal nerve, 182f, 276f Buccinator muscle, 279f, 281f, 373f Bulbar conjunctiva, 388f–389f Bulbar polio, 256b, 272b Bulbospongiosus muscle, 236f

C C1-­3 pain pathway, 375f C2 spinal nerve, 183f C3 spinal nerve, 183f C3 vertebra, 50f C5 spinal nerve, 183f C7 vertebra, 50f Ca++ ion flow, 391f Ca2+, 26f, 43f Calcaneal nerve, 181f Calcar avis, 70f–71f Calcarine cortex lower bank, 57f in midsagittal section, 57f Calcarine fissure, 54f, 59f, 398f, 460f, 468f Calcarine sulcus, 57f–58f, 60f, 465f fissure, 67f, 71f Callosomarginal arteries, 101f–102f, 108f, 111f Calmodulin, 43f Caloric nystagmus, 433b Calvaria, 51f, 119f CaMKK pathway, 43f Campylobacter jejuni enteritis, 83b Canines, 278f Capillary, 11f, 21f, 174f, 454f Capillary endothelial cell, 18f Capillary lumen, 18f Capillary plexus, of infundibular process, 115f Capillary pressure, 164f Capsulopeduncular transition zone, 440f Carbamazepine, 36f Cardiac function, hypothalamic regulation of, 457–458, 457f Cardiac muscle endings, 8f Cardiac output, 458f

506

Index

Cardiac plexus, 217f, 219f, 221f, 285f thoracic vagal branches to, 217f Cardiovascular autonomic neuropathies, 219, 219b Cardiovascular regulation centers, 456f Caroticotympanic nerve, 279f, 283f Carotid bifurcation, 97f Carotid body, 96f, 174f, 210f, 218f, 283f, 417f artery to, 174f veins from, 174f Carotid endarterectomy, 96b Carotid nerve, 98f Carotid plexus, 98f, 279f Carotid sinus, 174f, 209f–210f, 218f, 283f, 457f Carotid venograms, 124–125, 124f Carpal tunnel, medial nerve in, 164f Carpal tunnel syndrome, 195, 195f Cas9 enzyme, 10f Caspase-­1, 13f CASPR-­1, 29f CASPR-­2, 29f Catecholamine, 232, 444f–445f Catecholamine synapse, 45f, 46 Catecholaminergic neurons, 287 Cations, in neuronal cell membrane, 23 Cauda equina, 81, 81f, 81b, 83, 83f, 155f, 166f, 246f–247f, 247 Caudal brainstem areas, 354f Caudal limb, 386f Caudal lumbosacral spinal cord, 247f Caudal medulla, crosses in, 169f Caudal neuropore, 130f–131f Caudate nucleus, 66, 66f, 104f, 343f, 346f, 354f–355f, 405f, 427, 427f–429f, 471f, 491f, 496f atrophy of, 430f body of, 87f, 144f, 314f–315f, 317f, 326f–329f, 331f–332f, 440f, 466f development of, 140 head of, 66f, 70f–71f, 112f, 122f, 308f, 310f–313f, 322f–325f, 438f in axial (horizontal) section, 310–311, 310f–311f, 314–315, 314f–315f coronal section through, 322–323, 322f–323f magnetic resonance imaging of, 63f as radiologic landmark, 86 tail of, 66f, 70f, 87f, 304f, 306f, 308f–312f, 329f, 331f–332f Caudate veins, 122f–124f Cavernous plexus, 233f, 275f Cavernous sinus, 96, 96f, 98f, 106f, 111f, 115f, 121f, 274f, 451f efferent vein to, 115f, 451f rupture of internal carotid artery into, 98f Cavernous sinus thrombosis, 121b CB1 receptors, 354f CBT. See Corticobulbar tract Cecal arteries, 226f Cecal plexus, 226f Cecum, 285f Celiac ganglia, 204f–207f, 220f–226f, 228f–231f, 234f, 236f–238f Celiac ganglion, 418f, 460f

Celiac plexus, 220f–223f, 225f–226f, 234f– 235f, 238f branch of posterior vagal trunk to, 221f vagal branch to, 221f Celiac trunk, 222f, 224f, 230f Cell body, 4, 4f, 7f, 170f, 341f peptide synthesized in, 45f Cell membrane, 18f Cell of Martinotti, 341f Cellular debris, ingestion of pathogens and, 19f Cellular response, 40f Cement, of teeth, 278f Central canal, 135f, 138f, 144f–145f, 153f, 255f, 257f, 293.e1f, 293.e2f, 293.e3f of spinal cord, 153f, 292f Central chemoreceptor zone, 417f Central cholinergic pathway, in nucleus basalis (of Meynert) and in septal nuclei, 353–354, 353f clinical point, 353b Central cord syndrome, 248f Central core, 173f Central gray matter, 145f Central incisors, 278f Central lobule, 89f ala of, 76f Central mechanisms, 375f Central nervous system (CNS) astrocytes, 5f axonal transport in, 17–18, 17f, 20–21, 20f axons in, myelination by oligodendroglia, 21–22, 21f development of in 5 to 7 weeks, 132f 6-­month and 9-­month, 141–142, 141f in 26-­28 days, 132f in 49-­day-­old embryo and 3-­month-­ old embryo, 139f brain and skull defects in, 156f comparison at 5.5 weeks and adult, 144–145, 144f cranial nerve formation in, 147, 147f development of ventricles in, 153–154 eye and orbit formation in, 150–151, 150f neural proliferation and differentiation in, 135–136, 135f, 141b, 142 pituitary gland, development of, 152–153, 152f ventricle development in, 153f inflammation in, 16–17, 16f, 19–20, 19f neural tube defects in, 155–156, 155f neurons of, 8 myelinated axons of, 22f myelination of axons of, 137b nociceptive modulation in, 371, 371b origin of, 136f origin off, 136 stem cells in, intrinsic and extrinsic mechanisms of, 16–17, 16f Central norepinephrine pathways, 370f Central nucleus, 472f Central pain pathway, 374f–375f Central preganglionic axons, development of, 148f, 149–150

Central retinal artery, 388f, 393f Central retinal vein, 388f, 393f Central retinal vessels, 392f Central serotonin pathway, 370f Central (rolandic) sulcus, 54f–57f, 141f of insula, 54f Central superior raphe nucleus, 264f Central tegmental tract, 259f–268f, 293.e5f, 293.e8f, 293.e9f, 293.e10f, 293.e11f, 293.e13f, 293.e14f of CN VII, 293.e7f Centralis superior, 351f Centromedian nucleus, 372f, 427f, 431f Centromedian parafascicular complex, 428f Centromedian thalamus, 332f Centrum semiovale, 316f–319f, 318–319, 329f Cephalic flexure, 137f, 139f Cerebellar cortex, 77f, 292f, 422f, 424f, 426f Cerebellar glomerulus, 7f Cerebellar lesion, 499f Cerebellar neurons, circuitry of, 422f Cerebellar peduncles, 74, 76f, 77, 88f, 292f–293f, 293 clinical point, 74b, 293b and fourth ventricular anatomy, 88 superior and middle, 348f Cerebellar Purkinje neurons, 5f Cerebellar tonsil, 293.e3f herniation of, 52f Cerebellar uvula, 293.e7f, 293.e8f Cerebellar vermis, 300f, 303f–307f, 339f Cerebellomedullary cistern (cisterna magna), 91f Cerebellopontine angle, 282b MRI of vestibular schwannoma at, 383f Cerebellorubrothalamic tract, 267f–268f, 293. e13f, 293.e14f Cerebellovestibular pathways, 425–426, 425f clinical point, 425b Cerebellum, 254–293.e14, 59f, 71f, 73–77, 123f, 139f, 141f, 146, 146f, 247f, 291–292, 354f, 364f, 412f, 420–421, 462f, 500f afferent connections in, 422–423, 422f afferent pathways to, 423–424, 423f clinical point, 423b alcohol and dysfunction of, 76b alcohol intoxication and dysfunction of, 425b anatomical organization of, 291–292 deep nuclei and cerebellar peduncles, 293 lobes and regions, 291–292, 291f lobules, 292–293, 292f anatomy of external, 76–77, 76f internal, 77, 77f anterior lobe of, 291f cerebellovestibular and vestibulocerebellar pathways in, 425–426, 425f clinical point, 291b–293b drug toxicity in, 421b complex arrays of synapses in, 7b computed tomography scan of, 62f cortex of, 143f, 332f deep nuclei of, 289f, 422, 422f

Index Cerebellum (Continued) development of, 139, 139f efferent connections in, 289f, 293f efferent pathways in, 424–425, 424f clinical point, 424b to upper motor neuron systems, 426–427, 426f flocculonodular lobe of, 291f functional subdivisions of, 420–421, 420f lateral hemisphere of, 291f lateral view of, 292f magnetic resonance imaging of, 63f medial view of, 57f neuronal circuitry of, 421–422, 421f posterior lobe of, 291f posterior view of, 292f T2-­weighted magnetic resonance imaging of, 64f venous drainage of, 126–127, 126f Cerebral aneurysms, common site of, 106 Cerebral aqueduct, 57f, 60f, 89, 123f, 304f, 306f of Sylvius, 86f, 89f, 91f–92f, 138f, 144f–145f, 153f, 287f, 292f Cerebral arteries, 119f territory of, colored illustration, 109–110 Cerebral cortex, 34f, 54, 142f–144f, 365f–367f, 417f, 428f, 444f, 464f, 472f at 6 months, 141 afferents to, 289f areas of damage, 350, 350f association fibers of, 340f, 343f bundles, 346–347, 346f clinical point, 345b–346b color imaging of, sagittal and axial views, 347–348, 347f neuronal origins of, 344 pathways of, 345–346, 345f Brodmann’s areas of, 56 corticobulbar tract, 407f corticospinal tract, 408f efferent connections in, 289f, 343–344, 343f clinical point, 343b neuronal origins of, 344–345, 344f efferent pathways of, 405f color imaging of, 406, 406f functional characteristics of, 54b functional regions of, 54b functional magnetic resonance imaging of, 349f lateral aspect of, 407f–408f layers of, 340–341, 340f neuronal cell types in, 341–342, 341f postcentral gyrus, 372f processing of nociceptive information and, 365 projection fibers of, 343f color imaging of, 347–349, 347f–348f neuronal origins of, 344 underlying, 60 vertical columns of, 342–343, 342f Cerebral hemisphere, 51f, 119f, 140f, 146f Cerebral longitudinal fissure, 60f, 68f Cerebral palsy, 410b

Cerebral peduncle, 60f, 74f–75f, 77f, 100f, 122f, 144f, 146, 265f–269f, 293.e11f, 293.e12f, 293.e13f, 293.e14f, 297f, 304f–307f, 328f–329f, 331f, 396f, 405f, 411f, 441f Cerebral veins, 119b, 125, 125f penetrating subdural space to enter sinus, 120f Cerebrospinal fluid (CSF), 85–93 analysis of, by spinal tap, 81b circulation of, 91–92, 91f blockage of flow of, 86 from fourth ventricle, 89–90, 89b from lateral ventricles to third ventricle, 87 obstruction of, 153b composition of, 86f Cerebrovascular occlusive disease, common sites of, 97–98, 97f Cerebrovascular “strokes”, 108b Cerebrum, 365f, 367f Cervical cardiac nerves, 216f–217f, 221f Cervical dermatomes, 134 Cervical disc herniation, 189–190, 189f Cervical enlargement, 81f, 166f Cervical flexure, 137f, 139f Cervical lymph nodes, 205f Cervical nerves, 166f, 181f 1st, 81f 8th, 81f dorsal rami of, 182f Cervical plexus, 184–185, 184f clinical point, 184b in head and neck, 182–183, 182f schema, 183f, 197f in situ, 183–184, 183f ventral rami of C1, C2, and C3 forming, 286f Cervical spinal cord, 247f, 365f, 367f, 372f at gray matter organization, 241–242 lower part of, 386f magnetic resonance images of, 247 Cervical sympathetic trunk ganglia, 207f, 209f, 216f, 221f vertebral ganglion of, 221f Cervical vertebrae, arteries surrounding spinal cord and, 116f Cervicothoracic (stellate) ganglion, 210f, 217f, 219f, 221f Cervix, 238f Chandelier cell neuron, 341f Chemical neurotransmission, 45f, 46 Chemical synaptic transmission, 25f Chemogenetics, 9f Chemokines, 19f Chemosis, 98f Chiasm lesion, 394f, 400f Chiasmatic cistern, 91f Choanae, 50f Choline, 177f Choline acetyl-­transferase, 177f Cholinergic ganglion cells, 207f Cholinergic muscarinic receptor (M1-­M3), 436b Cholinergic synapses, 46, 207–208, 207f in tracheobronchial tree, 218

507

Cholinergic terminals, 218f Chorda tympani, 147f, 276f, 279f, 281f–282f, 377f, 460f Chorda tympani nerves, 209f, 214f–215f Chorea, 427b Choreiform movements, 312b Choroid, 150f, 388f, 392f–393f pigment cells of, 390f Choroid fissure, 140f Choroid plexus, 57f, 70f–71f, 86–87, 89b, 140f, 144f, 154f, 258f, 293.e4f, 308f, 310f, 312f, 466f–467f of 3rd ventricle, 87f, 89f, 91f, 292f of 4th ventricle, 89f, 91f, 145f, 292f ependymal-­pial covering of, 140f of lateral ventricle, 66f, 87f, 91f in roof of 3rd ventricle, 144f of roof of 3rd ventricle, 140f in ventricle, 339f Choroidal artery, 140f, 154f Choroidal vein, 140f, 154f Choroidal vessels, 154f Chromaffin cells, 208f medullary, 231 Chromogenic colorless substrate, 9f Chromogenic marker, 9f Chromosome 4, 430f Chronic compression, 164 Chronic traumatic encephalopathy (CTE), 493 Cilia, 479f Ciliary body, 388f–389f, 393f blood vessels of, 393f orbiculus ciliaris of, 389f Ciliary ganglion, 147f, 204f, 209, 209f, 211f–212f, 274f, 276f, 397f, 435f and extraocular nerves, 275–276, 275f motor (parasympathetic) root of, 275f nasociliary nerve root of, 212f oculomotor nerve root of, 212f sensory root of, 275f–276f sympathetic root of, 275f Ciliary muscle, 211f–212f, 275f, 388f–389f Ciliary neurotrophic factor (CNTF), 15f Ciliary processes, 388f–389f Cilium, 391f Cingulate cortex, 314f–315f, 325f, 327f, 329f, 331f–333f, 339f, 468f, 470f–472f, 475–476, 475f, 477f, 489f clinical point, 475b magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f Cingulate gyrus, 57f–58f, 60f, 67f, 318f–324f, 326f, 328f–329f, 345f, 442f–443f, 465f, 469f Cingulate sulcus, 57f Cingulum, 322f, 324f–329f, 331f–333f, 339f, 346f, 348f, 350f, 352f Circadian rhythms, hypothalamic regulation of, 438b Circle of Willis, 99, 99f and cerebral aneurysms, 106 schematic illustration and vessels in situ, 106–107, 106f Circular fibers, 389f

508

Index

Circular intramuscular plexus, 227f Circular muscle, 227f–228f Circular sulcus of insula, 54f Circulating epinephrine, uptake of, 40f Circumventricular organ, 438, 449–450, 449f clinical point, 449b Cisterna chyli, 220f Cisterna magna, 247f computed tomography scan of, 62f magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f Cisterns, magnetic resonance imaging of, 64 Cl-­ channels, 23f–24f Clarke’s column, 423f Claustrum, 66f, 144f, 308f, 310f, 312f, 322f– 324f, 326f, 328f–329f, 346f, 427f Clavicles, 180f Cleft, 152f, 296f Climbing fibers, 421–422, 421f–422f CN I. See Olfactory nerve CN II. See Optic nerve CN III. See Oculomotor nerve CN IV. See Trochlear nerve CN V. See Trigeminal nerve CN VI. See Abducens nerve CN VII. See Facial nerve CN VIII. See Vestibulocochlear nerve CN IX. See Glossopharyngeal nerve CN X. See Vagus nerve CN XI. See Accessory nerve CN XII. See Hypoglossal nerve CNS. See Central nervous system CNS excitability, 232f CNTF. See Ciliary neurotrophic factor Coccygeal nerve, 81f, 138f, 166f, 198f Coccygeal plexuses, 198–199, 198f Coccyx, 79f, 81f, 166f, 204f Cochlea, 378f spiral ganglion of, 282f Cochlear aqueduct, 379f Cochlear duct, 151f, 379f–380f basilar membrane of c, 381f containing spiral organ (Corti), 378f scala media, 385f Cochlear nerve, 378f, 380f, 383b Cochlear nuclei, 260b, 282f, 289f Cochlear receptors, 381–382, 381f Collagen space, 454f Collateral, 8f Collateral eminence, 71f Collateral ganglia, 208f, 435f, 436, 447f sympathetic, 204 Collateral ganglion, 133f Collateral sulcus, 58f, 60f Collateral sympathetic ganglion, 162f, 464f Collateral sympathetic trunk ganglion, 132f Collateral trigone, 71f Colliculi magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f Column of fornix, 58f, 66f, 70f–71f, 122f magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f

Coma assessment, 498–499, 498f differential diagnosis of, 499–500, 499f Combined systems degeneration (subacute combined degeneration), 245b Commissural axons, 344f Commissural fibers, 68, 68f of cerebral cortex, 343f neuronal origins of, 344 Commissural neuron, 132f Commissure of fornix, 70f Common annular tendon, 273f, 275f Common body and membranous limbs, 379f Common carotid artery, 105f, 110f, 174f, 183f, 209f–210f, 214f–215f, 218f, 283f bifurcation of, 96, 96b Common carotid plexus, 209f–210f Common hepatic artery, 222f, 229f Common palmar digital nerve, 196f Common peroneal nerve, 181f, 201f, 203f Complementary nucleotide probe, 9f Complex regional pain syndrome (CRPS), 370, 370b Compression-­induced denervation, 31f Compression neuropathy, 165–166 electrodiagnostic studies in, 31f Computed tomography scans, coronal and sagittal, 62–63, 62f Concussion, 493 Condensing mesenchyme, 151f Conduction velocity, 29–30, 29f evaluation, 202b studies, 31–32 Condylar canal, 49f Condylar process of mandible, 50f Condyle, 48f Cone, 390f Conjunctiva, 150f Conjunctival vessels, 393f Connective tissue, 296f Connective tissue layer, 175f Consciousness, 498–499 Contactin-­1, 29f Contralateral cerebellar cortex, 423f Contralateral hemiplegia, 100b Contralateral olfactory bulb, 480f Conus medullaris, 81f, 166f Conus medullaris syndrome, 247b Coracobrachialis muscle, 193f Cornea, 150f, 388f–389f, 393f Corneal epithelium, 150f Cornu ammonis, 70 Corona radiata, and internal capsule, 348f Coronoid process of mandible, 50f Corpus callosum, 57f–59f, 71f, 87f, 101f, 112f, 140f, 144f, 297f, 345f, 347f, 406f, 439f–443f, 465f–466f, 468f, 470f–471f, 473f, 475f, 488f anatomy of, 68–69, 68f in axial (horizontal) sections, 314–315 body of, 58f, 68f–69f, 102f, 322f–329f, 331f–333f in axial (horizontal) sections, 316–317, 316f–317f midline fibers, 69f

Corpus callosum (Continued) clinical point, 324b color imaging of, 69–70, 69f fibers in, 348f computed tomography scan of, 62f in coronal section, 320–321, 320f–321f development of, 140 genu of, 60f, 66f, 68f, 123f, 310f–311f, 313f–314f, 320f–321f in axial (horizontal) section, 314–315, 314f–315f lateral fibers of, 69f magnetic resonance imaging of, 63f rostrum of, 102f, 122f, 312f splenium of, 66f, 70f, 89f, 112f, 114f, 122f–123f, 126f, 292f, 310f–313f, 315f, 339f, 347f in axial (horizontal) section, 314–315, 314f–315f in coronal section, 338–339, 338f–339f in sagittal view, 347f T2-­weighted magnetic resonance imaging of, 64f Corpus striatum, 34f, 102f, 140f, 144f, 430f, 488f Corrugator supercilii muscle, 279f, 281f Cortex, 231f, 446f Cortical association bundles, 346–347, 346f Cortical association fibers, 69f Cortical association neurons, 341f Cortical efferent fibers, 406f Cortical gyrus computed tomography scan of, 62f magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f Cortical hormones, 452f Cortical input, 423f Cortical interneurons, 341f Cortical mantle, thinning of, 484f Cortical neurons, 17f, 142, 366f electrical firing patterns of, 34–35, 34f epileptic firing pattern of, 34f Cortical primordium, of suprarenal gland, 131f Cortical projection, 427f Cortical projection fibers, 347f to subcortical structures, 342f Cortical upper motor neuron, 170f Cortical white matter magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f Corticoautonomic fibers, 343f Corticobulbar fibers, 427f Corticobulbar pathway, 405f, 408f Corticobulbar tract (CBT), 343f, 407–408, 407f clinical point, 409b Corticobulbospinal system, 343f Corticocortical afferent, 342f Corticocortical axons, 344f Corticocortical efferents, 342f Corticocortical projections, 469f, 487f, 497f neuron, loss of, 487f Corticohypothalamic fibers, 343f Corticohypothalamic pathways, 463f

Index Corticolimbic fibers, 343f Corticomedial nuclei, 472f Corticonigral fibers, 343f Corticonuclear axons, 405f Corticonuclear fibers, 145f, 343f, 371f Corticonuclear pathway, 405f Cortico-­olivary fibers, 343f Corticopontine fibers, 145f, 343f Corticoreticular afferents, 289f Corticoreticular fibers, 416f Corticoreticular pathways, 413–414, 413f Corticoreticulospinal system, 343f Corticorubral connection, 426f Corticorubral fibers, 427f Corticorubral pathway, 405f Corticorubrospinal system, 343f Corticospinal axons, 405f Corticospinal connection, 426f Corticospinal (pyramidal) fiber, 8f Corticospinal fibers, 145f, 427f Corticospinal pathway, 405f, 408f Corticospinal system, 293.e7f, 293.e10f Corticospinal tract (CST), 84, 170f, 260f– 264f, 269f, 293f, 293.e7f, 293.e8f, 293.e9f, 343f, 408f, 409–410, 415f clinical point, 409b fibers, 300f, 302f terminations of, in spinal cord, 410–411, 410f, 415 Corticostriatal connections, 431 Corticostriatal projection, 427f Corticostriate fibers, 343f Corticosubthalamic fibers, 343f Corticotectal fibers, 343f Corticothalamic axons, 344f Corticothalamic projections, 343f Corticotropin releasing hormone (CRH), 44 Cortisol, 44f, 232f, 464, 464f Costal cartilage, 186f Costocervical trunk, 105f Costo-­transverse ligaments, 186f Cough receptors, 218f Cranial fossa, 48f Cranial nerves, 270–271 I (olfactory), 270f II (optic), 270f, 273 III (oculomotor), 211f, 270f, 273, 275–276, 275f IV (trochlear), 270f, 273, 275–276, 275f V (trigeminal), 270f, 276f, 277–278 VI (abducens), 270f, 273, 275–276, 275f VII (facial), 211f, 270f, 273, 279–280, 279f VIII (vestibulocochlear), 270f, 282–283, 282f bipolar cell of, 8f IX (glossopharyngeal), 211f, 270f, 283–284, 283f X (vagus), 270f, 285–286, 285f XI (accessory), 270f, 284–285, 284f XII (hypoglossal), 270f, 286–287, 286f neuron components of, 148–149, 148f and nuclei, 270–271, 270f, 271b, 272f clinical point, 270b–271b distribution of sensory, motor, and autonomic fibers, 270–271 lateral view of, 272–273 primordia of, 147–148, 147f

Cre enzyme, 10f Cre-­Lox technology, 10f CRH. See Corticotropin releasing hormone Cribriform plate, 48f, 479f of ethmoid bone, 273f foramina of, 49f Cricoid cartilage, 50f Cricothyroid muscle, 285f Crista, section of, 385f Crista galli, 48f Crossed rubrospinal fibers, 411f Crown, of teeth, 278f CRPS. See Complex regional pain syndrome Crura of fornix, 70f, 112f Crural interosseous nerve, 202f Crus cerebri, 145f Crus of fornix, 58f, 66f, 339f CRUSH, 370f Crush injury, in spinal cord, 244b Crypt, 376f CSF. See Cerebrospinal fluid CST. See Corticospinal tract CT (computed tomography) scans, coronal and sagittal, 62–63, 62f CTE. See Chronic traumatic encephalopathy Culmen, 89f Cuneate nucleus, 145f, 365f–366f, 405f Cuneate tubercle, 74f, 88f Cuneocerebellar tract, 364f, 423f Cuneus, 57f–58f apex of, 60f Cutaneous blood vessel constriction, 456f Cutaneous cervical nerve, 181f Cutaneous innervation, 193f–194f, 196f, 199f–200f Cutaneous nerves, 175f femoral and lateral, 199–200, 199f posterior, 201–202, 201f of head and neck, 182–183, 182f Cutaneous receptors, of peripheral nerve, 172–173, 172f Cuticle, 175f, 385f Cytokines, 19f and influences on hypothalamus and other brain regions, 448–449, 448f, 448b Cytoplasm, 18f minute masses of, 14f Cytoplasmic protrusion, 172f Cytosol, 44f

D Damage cells, ATP from, 13f Damaged organelles, 20f DAMPs, 19f Dandy-­Walker syndrome, 153b DBS. See Deep brain stimulation Decerebrate posturing, 433b Decerebration, in vestibulospinal tracts, 412b Declive, 89f Decorticate posturing, 433b Decussation, of pyramids, 255f Deep brain stimulation (DBS), 429f Deep cerebellar nuclei, 289f, 293, 293f, 339f, 421f

509

Deep cervical artery, 105f, 116f Deep middle cerebral veins, 120f, 122f–123f, 126f Deep middle temporal artery, 120f Deep middle temporal vein, 120f Deep nucleus, 422f Deep peroneal nerve, 181f, 203f lateral branch of, 203f medial branch of, 203f Deep petrosal nerve, 209f, 213f–214f, 279f, 283f, 357f Deep temporal nerves, 276f Degenerating axons, 163f Dejerine Roussy syndrome, 72b Dejerine’s syndrome, 75b Delayed inflammatory response, 19f Deltoid muscle, 191f cervical disk herniation, 189f Dementia, 430f, 484 with Lewy bodies, 484f, 485 treatable, 484f, 485 Demyelination axonal diameter and, 21b clinical disorders associated with, 346b Dendrites, 4, 4f–5f, 7f, 38f, 287f, 341f, 479f Dendritic crest synapse, 7f Dendritic spine synapse, 7f Dendritic spines, 4f, 7f Dendritic trees, 77f Dendrodendritic synapse, 7f Denervated skeletal muscle fibers, clinical point, 402b Denervation positive waves, 31f Dental caries, 157f Dental pulp, containing vessels and nerves, 278f Dentate gyrus, 44f, 58f, 67f, 70, 70f–71f, 87f, 355f, 465f–468f, 473f, 480f of hippocampus, 16f Dentate nucleus, 77f, 88f, 261f–262f, 292f–293f, 293.e7f, 424f–426f Denticulate ligament, 82f Dentinal tubules, 278f Dentine, 278f Depolarization, 24f, 27, 32f Depolarizing (Na+) current, 28f Depression, noradrenergic pathways and, 350b Depressor anguli oris muscle, 281f Depressor labii inferioris muscle, 279f Depressor septi muscle, 279f Depressor supercilii muscle, 279f Dermal papilla, 172f, 175f Dermal sinus, in spina bifida occulta, 155f Dermatome(s), 134–135, 134f distribution of, peripheral nerves in, 180–181, 180f of upper limb, 188–189, 188f Dermatomyotome, 133f Dermis, 175f Descemet’s membrane. See Posterior limiting lamina Descending cholinergic pathway, 353f Descending colon, nerves from inferior hypogastric plexuses to, 233f Descending fibers, 235f–236f

510

Index

Descending hypothalamic connections, 297f, 441f Descending noradrenergic bundle, 350f Descending norepinephrine pathway, 371f Descending (spinal) nucleus of V, 154f Descending palatine nerves, 214f Descending pathway, 212f of spinal cord, 84f Descending serotonergic pathway, 351f Descending serotonin pathway, 371f Descending upper motor neuron axon, 17f Descending upper motor neuron tracts, in spinal cord, terminations of, 415–416, 415f Desmosomes, 172f Developmental neuroscience, 128–158 Diabetic neuropathy, and delayed gastric emptying, 222b Diaphragm, 197f, 217f, 229f innervation of, 185f slip of origin of, 186f Diaphragma sellae, 274f Diaphragmatic pleura, 185f Diencephalon, 140f, 153f, 294–298, 444f–445f at 28 days, 137f at 36 days, 138, 138f at 49 days, 139, 139f adult derivatives of, 146, 146f comparison of, at 5.5 weeks and adult, 144f at junction with midbrain, 268f reticular nuclei in, 288–289 Differentiated somatic cells, 17f Diffusion, 23f Diffusion tensor imaging (DTI), 69 Diffusion-­weighted imaging (DWI), 69 Digastric muscle, 183f, 373f posterior belly of, 279f Digital nerves, 195f Dilation, of retinal veins, papilledema, and progressive loss of vision, 98f Dilator muscle of pupil, 212f, 389f Dilator pupillae muscle, 275f Diploic veins, 119, 119f–120f Direct lateral vein, 122f–123f Disintegrating microtubule, 493f Dissociated tau subunit, 493f Distal anterior cerebral artery, aneurysm of, 107f Distal colon, 204f Distal phalanges, branches to dorsum of, 194f Diurnal rhythms, hypothalamic regulation of, 438b Dividing satellite cell, 22f dlPFC. See Dorsolateral prefrontal cortex DNA strand, 9f Dopamine, 45f, 232f, 430f, 472f, 484f Dopamine median forebrain bundle, 432f Dopaminergic cell groups, 287f Dopaminergic nerve terminals, 428f Dopaminergic neurons, 17f, 287 Dopaminergic pathways, from midbrain and hypothalamus, 352–353, 352f clinical point, 352b Dorsal accessory olivary nucleus, 258f, 293.e4f

Dorsal accessory olive, 256f, 258f, 293.e2f, 293.e4f Dorsal acoustic stria, 382f Dorsal alar plate, 144f, 154f Dorsal antebrachial cutaneous nerve, 181f Dorsal cochlear nucleus, 37f, 260f, 271f–272f, 293.e6f, 382f, 384f Dorsal column, 162f neuronal organization of, 366–367, 366f Dorsal column afferent, 369f Dorsal column interneurons, 366f Dorsal column nuclei, 366f in brainstem, 256f Dorsal column system in brainstem, color imaging of, 348f and epicritic modalities, 365–366, 365f clinical point, 368b Dorsal digital nerves, 192f Dorsal funiculus, 132f Dorsal (sensory) ganglion, 132f Dorsal gray column, 144f Dorsal horn, 145f, 149f, 169f, 354f–355f, 448f of spinal cord, 240 Dorsal horn interneuron, 250f Dorsal hypothalamic area, 297f, 437f, 439f, 441f Dorsal interosseous muscle, EMG of, 31f Dorsal limb, 386f Dorsal longitudinal fasciculus, 296f–297f, 441f, 443f–446f, 463f Dorsal mesentery, 131f Dorsal motor nucleus of CN X, 417f, 435f, 445f, 447f–448f, 457f, 464f, 471f–472f of vagus, 144f, 154f Dorsal nasal artery, 105f Dorsal noradrenergic bundle, 350f Dorsal nucleus, 444f of CN X, 298 of vagus, 224f Dorsal ramus, 83, 83f, 133f, 162f, 186f–187f lateral branches of, 186f medial branches of, 186f of spinal nerve, 132f Dorsal raphe nucleus, 264f–266f, 293.e11f, 293.e12f Dorsal respiratory nucleus, 417f Dorsal root, 82, 82f–83f, 82b, 132f–133f, 162f, 169f, 186f, 214f–215f, 245f–246f Dorsal root entry zone, 245f Dorsal root ganglion, 8b, 82f–83f, 132, 133f, 162f, 224f, 229f, 250f, 366f, 370f, 448f, 460f afferent pain neuron of, 371f in primary sensory neuron cell body, 168f Dorsal scapular artery, 183f Dorsal scapular nerve, 187f, 191f Dorsal spinal ganglion, 131f Dorsal spinocerebellar tract (DSCT), 145f, 241f–246f, 255f–257f, 293.e1f, 293. e2f, 293.e3f, 362f, 364f, 423f inferior cerebellar peduncle with, 257f Dorsal subiculum, 478f Dorsal tegmental decussation, 414f Dorsal tegmental nucleus, 445f

Dorsal trigeminal lemniscus (dorsal trigeminothalamic tract), 372f Dorsal trigeminothalamic tract. See Dorsal trigeminal lemniscus Dorsal vagal nucleus, 145f, 219f, 235f Dorsolateral fasciculus (Lissauer’s zone), 84f, 241f–246f, 372f Dorsolateral prefrontal cortex (dlPFC), 477f, 488f–490f, 492f, 496f, 500f Dorsomedial nucleus, 297f, 437f, 441f Dorsum sellae, 48f DREADD (designer receptor exclusively activated by designer drug), 9f DSCT. See Dorsal spinocerebellar tract DTI. See Diffusion tensor imaging Duct of gland, 376f Ductus deferens, 233f, 237f Ductus plexus, 237f Ductus reuniens, 151f, 379f Duodenum, 285f Dura mater, 51, 51f, 82f–83f, 91f, 95f, 114f, 119f–120f, 140f, 167f, 379f, 392f, 486f branch to, 118f inner layer of, 51f meningeal arteries and relationship to, 95–96, 95f venous sinuses of, 119 Dural sac, 155f termination of, 166f Dural sinus, 374f DWI. See Diffusion-­weighted imaging Dynein, 20f Dynorphin neurons, 356 Dynorphins, 355f Dysautonomic polyneuropathy, 220b Dysphagia, 419b α-­Dystroglycan, 178f β-­Dystroglycan, 178f

E Ear, development of, 151–152, 151f Eardrum, 151f Ectoderm, 130f–131f optic area of, 129f Ectodermal structures, and nerves, 147f Edinger-­Westphal nucleus, 211f–212f, 212, 266f–267f, 271f–272f, 275f, 293. e12f, 293.e13f, 397f, 435f in accommodation of lens, 388b EEG. See Electroencephalography Efferent connections, 475f Efferent fibers, 480f Efferent hypophyseal veins, 106f Efferent nerve ending, 385f Efferent neurons, 341f axon of, 341f Efferent olivocochlear fibers, 384f 8th thoracic spinal nerve, 222f Elastic fibers, 175f Electrical discharges, in seizures, types of, 36–37, 36f Electrode, 35f Electroencephalography (EEG), 34–36, 35f Electromyography, 31–32 Embolic strokes, 103, 108b

Index Emboliform nucleus, 77f, 262f, 293f, 424f–426f fiber from, 411f Embolism, 103f Embryoid bodies, 17f Embryonic stem cells, 10f Emissary veins, 49f, 119, 119f–120f Enamel, 278f Encapsulated endings, 8f, 174f Encephalocele, 156f End feet, 5f End-­foot processes, 12f Endogenous cannabinoid system, 354–355, 354f Endogenous opiates, 371b Endogenous opioid systems, 355f beta-­endorphin, dynorphins, and met-­enkephalin, 355–357, 355f–356f Endogenous pain control system, impaired inhibition in, 375f Endogenous spinal cord stem cells, in situ modulation of, 17f Endogenous stem cells, 17, 17f Endolymphatic appendage, 151f Endolymphatic duct, 49f, 151f in vestibular aqueduct, 379f Endolymphatic sac, 151f, 379f Endoneurial edema, 164 Endoneurium, 163, 165f Endoplasmic reticulum, 170f, 479f Endosome, 20f Endothelial cells, 12f, 174f Endothelium, 454f Energy balance, 461f Energy expenditure, 461f Enkephalin interneurons, 371b Enkephalin neuron, 370f–371f Enkephalins, 207 Enteric nervous system cross-­sectional view, 228–229, 228f, 228b longitudinal view, 227–228, 227f Enteric plexus, 206f Enteric plexus ganglia, 133f Entorhinal area, 480f Entorhinal cortex, 70f, 87f, 304f, 306f, 332f, 352f, 355f, 466, 466f–472f, 475f, 477f–478f, 486f, 497f afferent and efferent connections of, 469–470, 469f inputs to, 467f–468f perforant pathway from, 467f pyramidal cell layer of, 466f Entorhinal-­hippocampal circuit, 469f, 497f Eosinopenia, 232f Epaxial muscles, 133f Ependyma, 11f, 16f, 87f Ependymal cells, central canal around, 17f Ependymal stem cells, proliferation of, 17f Epicranium, 51f Epicritic modalities, dorsal column system and, 365–366, 365f Epicritic sensation afferent, clinical point, 362b dorsal column system and, clinical point of, 368b loss of, 240b, 242b

Epicritic trigeminal projections, in trigeminal sensory system, 372 Epidermis, 172f, 175f Epididymis, 237f Epidural hematoma, 52, 95 Epidural space, 51f, 83, 83f, 119f–120f, 127b Epiglottis, 50f, 376f–377f Epinephrine, 208f, 231f–232f, 464, 464f Epineurium, 163, 165f normal, 165f Epiphysis, 139f–140f Episcleral artery, 393f Episcleral space, 388f Episcleral vein, 393f Epithelium, 376f Epitympanic recess, 378f EPSP. See Excitatory postsynaptic potential Epstein-­Barr syndrome, 83b Equivalent circuit diagrams, 27f Erectile dysfunction, autonomic, 237b Erector spinae muscle, 186f Esophageal plexus, 217f, 221f–222f, 285f sympathetic branch to, 217f Esophagus, 221f, 226f, 285f nerves of, 221–222, 221f recurrent branch of left inferior phrenic artery and plexus to, 225f Estrogen, 452f Ethmoid bone, 48f cribriform plate of, 357f, 479f–480f Excitatory endings, 386f, 412f–413f, 416f, 421f, 424f–425f Excitatory feedback circuits, 34 Excitatory fibers, 26f, 32f–33f Excitatory interneuron, 386f, 411f–413f Excitatory neurotransmitter, 40f Excitatory postsynaptic potential (EPSP), 25, 25f Excitatory presynaptic neuron, 36f Excitatory summation, 33f Excitatory synapse, 251f, 386f, 412f regulation of synaptic strength at, 42–43, 42f Executive anticipatory cortical function, 61f Exiting fibers of CN III, 266f–267f of CN VII, 261f Exogenous stem cells, 17, 17f Expanded axon terminal, 172f Explicit memory, clinical pathology of, 468b Extensor carpi radialis brevis muscle, 191f–192f Extensor carpi radialis longus muscle, 191f–192f Extensor carpi ulnaris muscle, 191f–192f Extensor digiti minimi muscle, 192f Extensor digitorum brevis muscle, 203f Extensor digitorum longus muscle, 203f Extensor digitorum muscle, 191f–192f Extensor hallucis brevis muscle, 203f Extensor hallucis longus muscle, 203f Extensor indicis muscle, 192f Extensor muscles, 411f–412f Extensor pollicis brevis muscle, 192f Extensor pollicis longus muscle, 192f Extensors, 403f

511

External acoustic meatus, 50f, 378f–379f External auditory meatus, 151f External capsule, 66f, 308f, 310f, 312f, 322f, 324f–325f, 328f–329f External carotid artery, 95f, 105f, 174f, 183f, 209f–210f, 214f–215f, 374f External carotid plexus, 209f–210f, 214f External cuneate nucleus, 257f–258f, 293.e3f, 293.e4f, 423f External genitalia, 204f External intercostal membrane, 186f External intercostal muscle, 186f posterior intercostal membrane on, 186f External limiting membrane, 135f External medullary lamina, 72f External nasal branch, 357f External oblique muscle, 186f External segments, of lentiform nucleus, 66f External sheath, 175f External terminal filum, 166f Extracellular fluid, 23f, 27f Extracellular potential, 28f Extrafusal muscle fiber, 252f–253f, 252b Extrafusal skeletal muscle fibers, neuromuscular junctions on, 402f Extraneural pressure, 164f Extraocular muscles, 150f Extraocular nerves, and ciliary ganglion, 275–276, 275f Extreme capsule, 66f, 308f, 310f, 312f, 322f, 324f, 328f–329f Extrinsic inflammatory stimuli, inflammatory response to, 16f, 19 Extrinsic stimuli, response to, 19f Eye, 204f anatomy of, 388–389, 388f anterior and posterior chambers of, 389–390, 389f arteries and veins in, 393–394, 393f optic chiasm in, 394–395, 394f optic nerve in, 392–393, 392f retinal layers in, 390–391, 390f autonomic distribution to, 212–213, 212f development of, 150–151, 150f Eye movements, central control of, 416–417, 416f Eyeball, 273f Eyelid, 407f Eyelid primordia, 150f Ezogabine, 36f

F Facial artery, 105f, 183f, 209f, 214f Facial canal, 282f Facial colliculus, 74b, 88f Facial muscles, 279f Facial nerve (CN VII), 49f, 74f–75f, 98f, 121f, 126f, 138f, 146f, 204f, 209f, 213f–215f, 261f, 269f–272f, 276f, 281f, 293f, 293.e7f, 404f, 435f buccal branches of, 280f–281f cervical branch of, 280f–281f cervicofacial division of, 280f clinical point, 280b communication to, 283f fibers of

512

Index

Facial nerve (Continued) motor, 279f orbital, 273 parasympathetic, 279f parotid, 280–281, 280f sensory, 279f sympathetic, 279f genu of, 293f lesions of, 281–282, 281f main trunk of, 280f marginal mandibular branch of, 280f–281f motor nucleus of, 145f, 269f, 279f motor root of, 279f, 282f temporal branch of, 280f, 281–282 temporofacial division of, 280f zygomatic branches of, 280f–281f Facial nerve (VII) fibers, 372f, 375f, 377f– 378f, 384f Facial nerve nucleus, 405f, 411f, 413f Facial nucleus, 271f–272f, 281f, 384f, 404f Facial plexus, 209f Facial (anterior facial) vein, 98f Facial veins, 174f, 183f Falx cerebelli, 126f Falx cerebri, 51f, 102f, 119f, 121, 121f, 126f, 140f Familial dysautonomia, 131b Fascial sheath of eyeball (Tenon’s capsule), 388f Fascicle, 163f–164f Fasciculation, 31f Fasciculi cuneatus, 169f Fasciculi gracilis, 169f Fasciculus cuneatus, 74f, 84f, 88f, 145f, 241, 241f–242f, 245f, 255f–256f, 292f–293f, 293.e2f, 365f Fasciculus gracilis, 74f, 84f, 88f, 145f, 241, 241f–246f, 255f–256f, 292f–293f, 293.e2f, 365f Fasciculus lenticularis, 427f, 430f, 439f Fasciculus proprius, 84 Fasciculus retroflexus, 67f, 443f, 445f, 465f Fasciculus thalamicus, 430f Fast anterograde axonal transport, 17f, 20f Fast retrograde axonal transport, 17f, 20f Fastigial nucleus, 77f, 293f, 424f–426f Fat tissue, 452f Felbamate, 36f Femoral nerve, 181f, 197f, 199f–200f anterior cutaneous branches of, 199f posterior, 201–202, 201f Fenestrated capillary, 454f Fenestrated vasculature, of brain, 449, 449b Fetal alcohol syndrome, 157, 157f Fibers of CN IV, 264f of CN V, 263f of CN VI, 262f of CN VII, 261f–262f, 293.e7f of CN VIII, 260f of CN IX, 260f of CN X, 257f–259f, 293.e3f, 293.e4f, 293. e5f of CN XII, 257f–258f, 293.e3f, 293.e4f Fibrillation, 31f Fibroblast, 174f, 454f Fibrous astrocytes, 12

Fibula, head of, 203f Fields of Forel, 439f 5th intercostal nerve, 217f 5th thoracic sympathetic trunk ganglion, 217f Fight-­or-­flight response, 463–464, 463f Filaments of dorsal root, 82f of nerve root, 81f of ventral root, 82f Filiform papillae, 376f Filum terminale, 81, 81f, 83f Fimbria, 66f, 466f–468f of hippocampus, 70f–71f Fimbria of fornix, 310f Fimbria of hippocampus, 87f Fingers, 408f 1st cervical nerve, 138f 1st cervical somite, 130f–131f First dorsal interosseous muscle, 31f 1st intercostal nerve, 187f First jejunal artery, plexus on, 223f 1st left lumbar splanchnic nerve, 226f 1st lumbar nerve, 138f 1st lumbar splanchnic nerve, 235f 1st occipital somite, 130f 1st rib, 50f 1st sacral nerve, 138f 1st sacral sympathetic trunk ganglion, 233f 1st spinal nerve (C1) dorsal roots of, 74f ventral roots of, 75f 1st thoracic nerve, 138f 1st thoracic somite, 131f 1st thoracic sympathetic trunk ganglion, 212f Fissure, brain, 54 Flaccid paralysis, 402b Flexed posturing, 430f Flexor carpi radialis muscle, 194f Flexor carpi ulnaris muscle, 196f Flexor digiti minimi brevis muscle, 196f, 202f Flexor digitorum brevis muscle, 202f Flexor digitorum longus muscle, 202f Flexor digitorum profundus muscle, 194f, 196f Flexor digitorum superficialis muscle, 194f Flexor hallucis brevis muscle, 202f Flexor hallucis longus muscle, 202f Flexor muscles, 411f–412f Flexor pollicis brevis muscle, 194f–196f Flexor pollicis longus muscle, 194f Flexor reflex interneuron, 250f Flexor retinaculum, 194f, 202f Flexor tendons, in carpal tunnel, 195f Flexor withdrawal reflex, 251f, 363, 363f Flexors, 403f Flocculonodular lobe, 420f, 426f Flocculus, 75f–76f, 291f, 420f, 425f–426f Fluorescence, 9f Fluorescent marker, 9f Fluorophore, 9f Foliate papillae, 376f–377f Folium, 89f Follicle-­stimulating hormone (FSH), 439b, 452f, 453, 453b Food intake, 461f signaling systems involved in regulation of, 461–462, 461f

Foot, 180f lateral margin of, 180f Foramen cecum, 48f–49f, 376f Foramen lacerum, 49f Foramen magnum, 49f, 284f Foramen of Luschka, choroid plexus of 4th ventricle at, 75f Foramen of Vesalius, 49f Foramen ovale, 49f–50f Foramen rotundum, 49f Foramen spinosum, 49f–50f Foramina in base of adult skull, 49–50, 49f clinical point, 49b of ventricles, 86 Forceps major, 69f Forceps minor, 69f Forearm anterior branch, 193f articular branch, 193f lateral cutaneous nerve of, 190f, 193f medial cutaneous nerve of, 187f, 193f–194f posterior branch, 193f posterior cutaneous nerve of, 191f–192f Forebrain, 129f adult derivatives of, 146–147, 146f associated with limbic and cortical reactivity, 478–479 axial (horizontal) sections of at anterior commissure and caudal thalamus, 308–309, 308f–309f at basal ganglia and internal capsule, 312–313, 312f–313f at centrum semiovale, 318–319, 318f–319f at corpus callosum, 314–315, 316f–317f at dorsal caudate, splenium, and genu of corpus callosum, 314–315, 314f–315f at head of caudate and midthalamus, 310–311, 310f–311f at mid pons level, 300f–301f, 301–302 at midbrain level, 304–305, 304f–305f at rostral midbrain and hypothalamic level, 306–307, 306f–307f at rostral pons level, 302–303, 302f–303f coronal sections of at amygdala/anterior limb of internal capsule, 326–327, 326f–327f at anterior commissure/columns of fornix, 324–325, 324f–325f at caudal pulvinar and superior colliculus, 336–337, 336f–337f at caudate nucleus/nucleus accumbens, 322–323, 322f–323f at geniculate nuclei, 334–335, 334f–335f at genu of corpus callosum, 320–321, 320f–321f at mammillary body, 328–329, 328f–329f

Index Forebrain (Continued) at mammillothalamic tract/substantia nigra, rostral hippocampus, 330–331, 330f–331f, 330b at midthalamus, 332–333, 332f–333f at splenium of corpus callosum, 338–339, 338f–339f development of, 137, 137f at 7 weeks through 3 months, 140–141, 140f hippocampal formation in, 466 horizontal sections of, 66 hypothalamic regions of, 442–443, 442f lateral surface anatomy of, 54f, 55–56 Brodmann’s areas in, 56–57, 56f functional regions in, 55–56, 55f limbic structures of, 67–68, 67f medial surface anatomy of, 57–58, 57f neural plate of, 130f neurotransmission in, and brainstem central cholinergic pathways, 353–354, 353f dopaminergic pathways, 352–353, 352f noradrenergic pathways, 350–351, 350f serotonergic pathways, 351–352, 351f pathways, 454f ventricular anatomy in, 87–88 Fornix, 67f, 67b, 70–71, 70f, 140f, 144f, 296f–297f, 348f, 353f, 437f, 441f–442f, 446f, 463f, 465f–466f, 468f, 473f, 475f body of, 58f, 70f, 292f, 439f–440f columns of, 308f–311f, 313f, 324f, 326f–329f, 331f–333f, 438f–440f commissure of, 140f in coronal section of forebrain, 324–325, 324f–325f magnetic resonance imaging of, 63f in medial view, 57f T2-­weighted magnetic resonance imaging of, 64f Foster-­Kennedy syndrome, 480b FOUR. See Full Outline of UnResponsiveness Score 4th lumbrical muscles, 196f 4th sacral nerve, perineal branch of, 198f 4th thoracic sympathetic trunk ganglion, 219f 4th ventricle, 76f–77f, 89f, 92f, 123f, 126f, 135f, 138f, 144f–146f, 153f–154f choroid fissure of roof of, 154f choroid plexus protruding through lateral aperture of, 154f choroidal point and choroidal artery to, 112f development of, 154–155, 154f ependymal floor of, 154f ependymal roof of, 154f floor of, 143f lateral recess of, 154f outline of, 112f roof of, 139f vein of lateral recess of, 126f Fourth ventricle, 57f, 258f, 260f–263f, 292f–293f, 293.e4f, 293.e5f, 293.e7f, 293.e8f, 293.e9f, 300f–303f, 339f tenia of, 292f

Fovea centralis, 393f in macula, 388f Free nerve endings, 8f, 162f, 168f, 172f, 174f–175f Frontal bone, 48f Frontal cortex, 311f, 313f, 405f, 471f–472f association areas of, 475f Frontal crest, 48f Frontal diploic vein, 120f Frontal encephalocele, 156f Frontal eye fields, 55f, 405f, 416f Frontal forceps (forceps minor), 68f Frontal horn, of lateral ventricle, 102f Frontal lobe, 54f, 59f, 141f, 310f, 314f–316f, 318f–319f, 399f association areas of, 468f of brain, 56f computed tomography scan of, 62f medial surface of, 59f regions, 471f gyral atrophy of, 484f Frontal nerve, 273f, 275f–276f Frontal opercula, 54f Frontal pole, 60f of brain, 54f lateral ventricle, 90f magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f Frontocingulate pathway, 345f Frontoparietal opercula, 54f Frontopolar artery, 101f, 108f, 111f Frontopontine pathway, 408f Frontotemporal dementia, 484f, 485 Frontothalamic pathway, 408f FSH. See Follicle-­stimulating hormone Full Outline of UnResponsiveness Score (FOUR), 498f Fungiform papillae, 376f–377f Funiculus, 84, 84b Furrow, 376f Fused neural folds, 130f–131f

G G protein-­coupled receptors, 39f GABA reuptake, 12f GABAA receptor, 26f GABAB receptor, 26f GABAergic neurons, 17f Gabapentin, 36f Galea aponeurotica, 51f, 119f Galen, great cerebral vein of, 121, 121f–126f, 123, 292f Gallbladder, 204f, 285f Gallstones, development of, 229b GALT. See Gut-­associated lymphoid tissue Gamma motor neurons, 252f–253f, 253, 402–403, 402f classification of axons of, 30f Ganglion, 458f Ganglion cell layer, 390f Ganglion cells, 207f Gastrocnemius muscle, 201f–202f Gastroduodenal artery, 222f, 225f, 229f Gastroduodenal plexus, 225f, 229f Gastrointestinal tract, 207f

513

Gastro-­omental (gastroepiploic) arteries, plexus on, 223f GBS. See Guillain-­Barré syndrome GDNF. See Glial cell-­line derived neurotrophic factor Gelatinous cupula, 385f Gelatinous otolithic membrane, 385f Gemmules, 4f Gene expression, 10f of interest, 10f Generator potential, 173f Geniculate bodies, 88f, 292f, 460f Geniculate ganglion, 209, 279f, 281f, 377f of facial nerve, 271f, 282f–283f Geniculate nuclei clinical point, 334b in coronal section, 334–335, 334f–335f Geniculum, 213f Genioglossus muscle, 286f Geniohyoid muscle, 183f–184f, 286f Genitofemoral nerve, 181f, 197f, 200f femoral branch of, 197f genital branch of, 197f Genomics, 9f Genu, 58f, 69f of corpus callosum, 70f magnetic resonance imaging of, 63f midline fibers, 69f T2-­weighted magnetic resonance imaging of, 64f of internal capsule, 66f Germinal epithelium, of future gonad, 131f GH. See Growth hormone Ghrelin, 461f Giant pyramidal cells, 411f Gingival (gum) epithelium, 278f Gingival groove, 278f Glabrous skin, 172f Glands, 227f Glassy membrane, 175f Glaucoma, and optic nerve damage, 389b Glial capsule, 7f Glial cell, types, 11–12, 11f Glial cell-­line derived neurotrophic factor (GDNF), 15f Glial process, 4f, 7f, 38f Glial scar formation, 12f Glioblast, 136, 136f Gliomedin, 29f Gliotransmitters, 12 Global aphasia, 494f–495f Globose, 426f fiber from, 411f nuclei, 424f–425f Globose nucleus, 77f, 262f, 293f Globus pallidus, 66f, 87f, 104f, 295f, 308f, 310f–311f, 324f–325f, 327f, 343f, 346f, 354f, 405f, 427, 427f–429f, 432f, 438f–440f, 491f afferents to, 289f external segment, 326f, 328f–329f internal segment, 326f, 328f–329f magnetic resonance imaging of, 63f Globus pallidus internal segment, 431f Glomerulus, 421f, 480f

514

Index

Glossopharyngeal nerve (CN IX), 49f, 74f–75f, 121f, 138f, 146f, 174f, 204f, 207f, 209f–210f, 214f–215f, 260f, 270f–272f, 279f, 283–284, 285f, 372f, 377f, 404f, 435f carotid sinus branch of, 209f–210f, 283f clinical point, 283b dorsal motor nucleus of, 405f inferior ganglia of, 283f lingual branches of, 283f petrosal (inferior) ganglion of, 377f pharyngeal branches of, 283f superior ganglia of, 283f tonsillar branches of, 283f vagal branch to carotid sinus branch of, 285f Glossopharyngeal neuralgia, 283b Glucagon secretion, 230 Glucocorticoid, in regulation of neurons and apoptosis, 44–45, 44f Glucose production, 461f Glutamate, 12f, 26f, 42, 45f, 207 release, 36f Glutamatergic neurons, 17f Glutamine, 12f Glycogenesis, 12f Glycogenolysis, 232f GM1 ganglioside, 29f GnRH. See Gonadotropin-­releasing hormone Golgi apparatus, 4, 4f Golgi (inner stellate) cell, 421f Golgi cell axon, 7f Golgi cell dendrite, 7f Golgi cells, 421, 421f–422f Golgi tendon organ, 253f Golgi tendon organ reflex, 363, 363f Gonadotropin-­releasing hormone (GnRH), 439b G-­protein coupled metabotropic glutamate receptors (mGluRs), 42 Gracile nucleus, 145f, 365f–366f, 405f, 423f Gracile tubercle, 74f, 88f Gracilis muscle, 200f Graded potentials, 7 in neurons, 25–26 Granular cell, in cerebellum, 168f Granular layer, 421f Granulated vesicles, 172f Granule cell layer, 16f Granule cells, 44f, 342f, 421, 421f–422f, 425f, 480f dendrites, 7f Gray matter, 82f of spinal cord, 84, 84f, 240–241, 403f at cervical level, 241–242 development of, 148, 148f lower motor neuron organization and control, 250–251 at lumbar level, 241–242 neuronal cell groups, 240 at sacral level, 241–242 somatic reflex pathways, 251–252 at thoracic level, 241–242 Gray ramus communicans, 132f, 162f, 197f–198f, 204f, 206f–207f, 210f, 212f, 214f, 216f–217f, 219f–222f, 224f, 233f–238f, 435f

Great auricular nerve, 181f–184f Great cerebral vein cistern of, 91f of Galen, 57f, 89f Great superficial petrosal nerve, 98f Great toes, medial side of, 180f Greater occipital nerve, 181f–182f, 184f Greater (major) palatine branches, 357f Greater palatine nerves, 209f, 213f, 357f Greater petrosal nerve, 49f, 209f, 213f–214f, 273f, 279f, 281f–283f, 357f, 377f hiatus of canal of, 49f sulcus of, 48f Greater sciatic foramen, 201f Greater splanchnic nerves, 221f, 225f, 234f, 237f–238f Greater thoracic splanchnic nerve, 204f, 224f Greater wing, 48f Groin regions, 180f Growth factors, 15f Growth hormone (GH), 439b, 452f, 453, 453b Guillain-­Barré syndrome (GBS), 83b, 185b, 271b Gustatory (Ebner’s) gland, duct of, 376f Gut, 131f, 133f Gut-­associated lymphoid tissue (GALT), 205f, 464f Gyri, of brain, 54 in medial view, 57f topographic organization of, 55b Gyrus fasciolaris, 67f, 465f Gyrus rectus, 57f

H Habenula, 66f–67f, 289f, 309f, 443f, 465f, 476f, 480f Habenular commissure, 57f, 71f, 89f, 292f, 308f Habenular nuclei, 473f Habenular trigone, 71f, 88f, 292f Hair, 172f Hair cells, 382f, 385f in organ of Corti, 380–381, 380f, 380b structure and innervation of, 385f type I, 385f in vestibular apparatus, 380–381 in vestibular receptors, 385 Hair cuticle, 175f Hair follicles, 172f, 175f, 204f, 207f innervation of, 216 papilla of, 175f Hair matrix, 175f Hair shaft, 175f Hair tufts, 385f Hallpike maneuver, 379b Hallux, 134 Hamulus, of pterygoid process, 50f Hand, 180f Head anterior, 374f caudate nucleus, T2-­weighted magnetic resonance imaging of, 64f and neck autonomic distribution to lateral view, 210–211, 210f medial view, 209–210, 209f schematic, 211–212, 211f

Head (Continued) bony framework of, 50–51, 50f cutaneous nerves of, 182–183, 182f pain-­sensitive structures of, 374–375, 374f posterior, 374f Head mesenchyme, 147f Head of caudate nucleus, 309f Hearing loss, 378b Heart, 204f, 207f, 285f, 459f autonomic neuropathies and, 219b innervation of, 219–220, 219f Heart rate, 458f Heat, production of, 456f Heat loss, regulation of, 456f Helicotrema, 378f of cochlea, 379f Hematoma, 52, 52f Hemorrhage, 93f Hemorrhagic strokes, 103 Hepatic artery branch, 229f Hepatic plexus, 223f, 225f pyloric branch from, 285f via lesser omentum, 221f Hepatic triad, 229f Hepatocytes, 205f Hering-­Breuer reflex, 218f Herniated disc, 80 compression nerve root, 189f Herniated lumbar nucleus pulposus, clinical features of, 167f Herniation cervical disc, 189–190, 189f lumbar disc, 167–168, 167f Herring bodies, 454f hESC. See Human embryonic stem cells Heubner, artery of, 101b Hiatus of adductor canal, 200f High-­affinity uptake carrier, 40f Hilus, 16f Hindbrain, 129f, 137f–138f adult derivatives of, 146–147, 146f Hip, 408f Hippocampal commissure, 345f Hippocampal cortex, 140f Hippocampal fimbria, 480f Hippocampal formation, 70–71, 70f, 304f–309f, 328f–329f, 331f–332f, 339f, 432f, 438f, 440f, 442f–443f, 466, 468b, 480f, 489f afferent and efferent connections in, 468–469, 468f anatomy of, 466–467, 466f CA regions of, 466f clinical point, 466b–467b fimbria of, 58f, 466f information processing in, 67b magnetic resonance imaging of, 63f neuronal connections in, 467–468, 467f T2-­weighted magnetic resonance imaging of, 64f temporal lobe and, 467b Hippocampal pyramidal cells, 444f Hippocampal sulcus, 70f Hippocampal veins, 123f

Index Hippocampus, 44f, 66f–67f, 70f–71f, 87f, 114f, 140f, 143f, 343f, 353f–355f, 465f, 473f–475f, 477f, 486f, 488f, 490f–492f, 496f, 500f CA regions of, 468f fimbria of, 67f, 70f, 465f inputs to, 468f rostral, in coronal section, 330–331, 330f–331f, 330b hiPSC. See Human induced pluripotent stem cells Hirschsprung’s disease, 131b Histamine, 207 Holoprosencephaly, 139b Homeostasis, autonomic maintenance of, 206b Homunculus, 365 Hook bundle of Russell, 424f–425f Horizontal canal, plane of, 385f Horizontal cell, 390f–391f Horizontal cell neuron, 341f Horizontal fissure, 76f Horizontal (lateral) gaze center, 288 Horizontal semicircular canal, 385f, 387f Horner’s syndrome, 242b, 258b Human disease, transgenic mouse models of, 10f Human embryo, 17f Human embryonic stem cells (hESC), 17f Human induced pluripotent stem cells (hiPSC), 17f Hunger neural control of, 460–461, 460f signal, 461f Huntington’s chorea, 430f Huntington’s disease, 312b neurotransmitter involvement in, 430–431, 430f Hyaloid artery, 150f Hyaloid canal, 388f Hydrocephalus, 89b, 92–93, 92f, 153b normal pressure, 93 5-­Hydroxytryptamine (serotonin), 444f–445f, 472f Hyoglossus muscle, 286f Hyoid bone, 50f Hypaxial muscles, 133f Hyperglycemia, 232f Hyperpolarization, 23 Hyperreflexic responses, 38b Hypertonic state, 38b Hypogastric nerves, 204f, 220f, 224f, 234f–238f Hypoglossal canal, 49f Hypoglossal nerve (CN XII), 49f, 74f–75f, 121f, 138f, 145f–146f, 183f–184f, 269f–272f, 286–287, 286f, 293.e3f, 293.e4f clinical point, 286b fibers, 269f ipsilateral, clinical point in, 75b meningeal branch of, 286f Hypoglossal nerve trigone, 88f Hypoglossal nucleus, 144f–145f, 154f, 269f, 271f–272f, 286f, 404f–405f of CN Xll, 259f, 293.e5f

Hypoglossal trigone, 74f Hypophyseal fossa, 48f Hypophyseal portal system, 171f, 446f in the median eminence, 447f primary plexus of, 115f, 451f secondary plexus of, 115f, 451f Hypophyseal portal vasculature, 451–452, 451f Hypophyseal portal veins, 452f Hypophyseal stalk, 296f Hypophysis, 61f, 129f, 139f, 296f, 443f anterior lobe of, 140f Hypopituitarism, 453b Hypothalamic area, 296f Hypothalamic artery, 106f, 452f Hypothalamic inputs, 470f Hypothalamic nuclei, 296f, 443f, 472f clinical point, 298b illustration of, 297f, 298 Hypothalamic-­pituitary-­adrenal (HPA) axis, 44, 44f Hypothalamic sulcus, 57f, 137f–138f, 144f, 296f, 437f Hypothalamic vessels, 115f, 451f Hypothalamo-­pituitary-­adrenal (HPA) axis, 453b, 463, 464b Hypothalamohypophyseal tract, 296f Hypothalamo-­pituitary-­adrenal system, 298b Hypothalamus, 44f, 57, 67f, 87f, 144f, 146, 171f, 224f, 293.e14f, 296f, 326f– 329f, 343f, 346f, 352f, 354f–355f, 367f, 427f, 430f, 432f, 442f, 444f–445f, 447f, 465f, 468f, 470f–474f, 477f, 480f, 490f–491f afferent pathway associated with, 289f, 443–444, 443f, 443b schematic diagram of, 444–445, 444f anatomy of, 437–438, 437f appetite and hunger, 460–461, 460f arterial supply to, 454f autonomic and endocrine regulation by, 296–297, 298b axial (horizontal) sections of, MRI of, 306–307, 306f–307f cardiac function and, 457–458, 457f clinical point, 298b, 438b, 440b connections of, 446–447, 446f cytokine influences in, 448–449, 448f, 448b dopaminergic pathways from, 352, 352f clinical point, 352b efferent pathway associated with, 289f, 443–444, 443f, 443b schematic diagram of, 445–446, 445f fight-­or-­flight response, 463–464, 463f forebrain regions associated with, 442–443, 442f and limbic structures, 67b, 465 long-­term blood pressure, 459–460, 459f magnetic resonance imaging of, 63f mammillary zone of, 440–441, 440f neuroimmunomodulation and, 464–465, 464f nuclei located within, 296f–297f, 298, 298b, 437 paraventricular nucleus of, 447–448, 447f, 447b

515

Hypothalamus (Continued) preoptic and supraoptic zones of, 438–439, 438f regulation by, 439b diurnal and circadian rhythm, 438b of food intake, body weight, and metabolism, 461–462, 461f releasing factors secretion, 439b of sleep and waking states, 462–463, 462f sleep-­wake cycle, 438b retinal projections to, 396–397, 396f schematic reconstruction of, 441–442, 441f short-­term blood pressure, 458–459, 458f thermoregulation and, 456–457, 456f tuberal zone of, 439–440, 439f vascular supply to, 115–116, 115f vasculature to, 448f Hypothenar muscles, 196f Hypoxia, 103f

I Ia afferent, 402f Ia (Aα) fibers, 252f Ib (Aα) fibers, 252f IC. See Internal capsule ICA. See Internal carotid artery II (Aβ) fibers, 252f III (Aδ) fibers, 252f Ileocolic artery, 225f–226f Ileocolic plexus, 225f–226f Iliacus muscle, 197f–199f muscular branches to, 197f Iliohypogastric nerve, 181f, 197f, 200f Ilioinguinal nerve, 181f, 197f, 200f Immature neuron, 16f Immune system, autonomic innervation of, 205–206, 205f, 228 Immunohistochemistry, 9f In situ hybridization, 9f Inactivation gate, 24f Incisive canal, 357f Incontinence, 93f Increased cardiac output, 232f Incus, 151f, 282f, 378f–379f, 384f Induced pluripotent stem cells (iPSCs), 17, 17f Indusium griseum, 67f–68f, 465f Infarct, 103f Inferior alveolar nerve, 209f, 215f, 276f, 373f Inferior anastomotic vein, of Labbé, 122f, 124f Inferior articular process of L1 vertebra, 80f of L3 vertebra, 80f Inferior cerebellar hemispheric vein, 126f Inferior cerebellar peduncle, 74f, 126f, 145f, 258f–262f, 269f, 282f, 293f, 293.e3f, 293.e4f, 293.e5f, 293.e7f, 293.e8f, 332f, 364f, 382f, 396f, 423f–424f with dorsal spinocerebellar tract, 258f, 293.e3f, 293.e4f Inferior cerebral vein, 122f opening of, 121f

516

Index

Inferior cervical sympathetic cardiac nerve, 210f, 219f Inferior cervical vagal cardiac branches, 219f Inferior cluneal nerve, 201f Inferior colliculus, 37f, 57f, 71, 71f, 74f, 88f–89f, 265f–266f, 275f, 292f–293f, 382f, 384f, 396f, 405f auditory cortex to, 405f brachia of, 74f brachium of, 71f, 265f–267f, 293.e11f, 293. e12f, 293.e13f, 382f, 384f, 396f commissure of, 266f Inferior constrictor muscle, of pharynx, 285f Inferior dental plexus, 276f Inferior extensor retinaculum, 203f Inferior fovea, 88f Inferior frontal gyrus, 54f, 320f–321f Inferior frontal sulcus, 54f Inferior ganglion, 215f of vagus nerve, 284f–286f Inferior gluteal artery, 198f Inferior horn, 86f of lateral ventricle, 16f, 71f, 87f, 304f–305f, 440f Inferior hypogastric (pelvic) plexus, 204f, 224f, 234f–238f nerves from, 226f Inferior hypophyseal artery, 106f, 115f, 451f, 454f lateral branch of, 115f, 451f medial branch of, 115f, 451f Inferior lateral nasal nerves, 213f Inferior longitudinal fasciculus, 348f Inferior macular arteriole, 393f anatomy of, 392f outer sheath of, 388f Inferior macular venule, 393f Inferior (inferolateral) margin of cerebrum, 54f Inferior medullary velum, 57f, 76f, 89f, 145f, 292f Inferior mesenteric artery, 220f, 224f, 226f, 233f Inferior mesenteric ganglia, 204f–205f, 207f, 220f, 224f, 226f, 228f, 233f–234f, 236f–238f Inferior mesenteric plexus, 220f, 226f, 233f Inferior nasal fibers, 394f Inferior nasal retinal arteriole, 393f Inferior nasal retinal venule, 393f Inferior oblique muscle, 275f, 416f branch of oculomotor nerve to, 274f Inferior occipitofrontal fasciculus, 346f Inferior olivary nucleus, 144f–145f, 154f, 257f–260f, 293.e3f, 293.e4f, 293.e5f, 411f Inferior olive, 258f, 396f, 423f–424f Inferior ophthalmic veins, 98f Inferior pancreaticoduodenal arteries, 222f, 225f–226f plexus on, 223f Inferior pancreaticoduodenal plexus, 225f–226f Inferior parietal cortex, 488f Inferior parietal lobule, 54f Inferior petrosal sinus, 49f, 121f sulcus of, 48f

Inferior phrenic arteries, 225f Inferior phrenic plexuses, 225f Inferior rectal nerve, 224f Inferior rectal plexus, 233f Inferior rectus muscle, 275f, 416f branches to, 274f Inferior retrotonsillar vein, 126f Inferior sagittal sinus, 51f, 120f–124f, 126f, 140f Inferior salivatory nucleus, 211f, 215f, 283f, 435f Inferior semilunar lobule, 76f Inferior temporal cortex, 471f–472f Inferior temporal gyrus, 54f, 60f Inferior temporal retinal arteriole, 393f Inferior temporal retinal venule, 393f Inferior temporal sulcus, 54f, 60f Inferior thalamic peduncle, 438f Inferior thalamostriate veins, 123f, 126f Inferior thyroid artery, 105f, 183f Inferior vena cava, 217f Inferior ventricular veins, 123f Inferior vermian artery, 112f–113f Inferior vermian vein, 126f Inferior vermis, 76f Inferior vertebral notch, of L2 vertebra, 80f Inferior vestibular nucleus, 259f–260f, 293. e5f, 386f Inflammatory cytokines, 456f and influences on hypothalamus and other brain regions, 448b Infrahyoid muscles, 373f Infraorbital nerve, 182f, 213f, 275f–276f superior alveolar branches of, 276f Infraspinatus muscle, 191f Infratemporal fossa, 50f Infratrochlear nerve, 182f, 274f, 276f Infundibular process, 152f, 296f capillary plexus of, 451f Infundibular recess, 138f, 153f Infundibular stalk, 75f Infundibular stem, 296f Infundibulum, 106f, 138f–140f, 152f, 296f, 437f Infusion of fibroblast growth factor-­2 (FGF-­2), 17f Inguinal (Poupart’s) ligament, 197f Inguinal lymph nodes, 205f Inguinal regions, 180f Inhibin, 452f Inhibitory endings, 386f, 412f–413f, 416f, 421f, 424f–425f Inhibitory factor, 445f Inhibitory fibers, 26f, 32f–33f Inhibitory interneurons, 386f–387f Inhibitory postsynaptic potential (IPSP), 25, 25f Inhibitory presynaptic neuron, 36f Inhibitory synapse, 32, 251f Initial segment, 38f Inner epineurium, 163f Inner hair cell, 380f Inner nuclear layer, 390f Inner plexiform layer, 390f Innermost intercostal muscle, 186f window cut in, 186f

Insula, 54, 54f, 75f, 102f, 141f, 144f, 469f, 476f central sulcus of, 476f circular sulcus of, 476f in lateral (sylvian) sulcus, 141f Insular cortex, 66f, 289f, 308f, 310f–313f, 322f–329f, 331f–332f, 470f, 476–477, 476f, 478f, 489f–490f, 500f magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f Insulin, 461f Insulin-­like growth factor 1 (IGF-­1), 15f Insulin secretion, 230 Intact axons, 163f Intercavernous (circular) sinus, 121f Intercostal nerves, 186f, 216f anterior cutaneous branch of, 186f anterior cutaneous branches of, 186f collateral branch of, 186f lateral cutaneous branch of, 186f Intercostobrachial nerve, 181f Interglobular spaces, 278f Interleukin-­1β, sleep-­wakefulness control and, 290 Intermediate acoustic stria, 382f Intermediate column, 129f Intermediate dorsal cutaneous nerve, 203f Intermediate gray, 240, 241f, 244f–246f Intermediate mesoderm, 129f Intermediolateral cell column, 231f, 240f, 242f–243f, 403f, 445f in lateral horn, 447f Intermediolateral nucleus presynaptic sympathetic cell bodies in, 213f sympathetic preganglionic cell bodies in, 214f–215f Intermesenteric nerves, 224f Intermesenteric (abdominal aortic) plexus, 220f, 225f–226f, 233f–238f renal and upper ureteric branches from, 234f Intermuscular stroma, 227f Internal acoustic meatus, 49f, 279f, 282f, 378f Internal arcuate fibers, 145f, 256f–257f, 293. e2f, 293.e3f, 365f Internal auditory (labyrinthine) artery, 99f, 101f Internal capsule (IC), 66f, 87f, 140f, 144f, 300, 346f, 372f, 407f–408f, 411f, 427f anterior limb of, 102f, 308f, 310f–313f, 322f–327f, 438f in axial (horizontal) section, 312–313, 312f–313f cleft for, 66f clinical point, 326b corona radiata and, 348f corona radiata coalescing into, 348f in coronal section, 326–327, 326f–327f genu of, 310f–312f, 327f magnetic resonance imaging of, 63f posterior limb of, 114f, 310f–313f, 328f–329f, 331f, 365f, 367f T2-­weighted magnetic resonance imaging of, 64f

Index Internal carotid artery (ICA), 49f, 96, 96b, 98f–99f, 101f–102f, 105f–106f, 110f, 114f–115f, 121f, 150f, 174f, 183f, 209f–210f, 212f–215f, 274f–275f, 283f, 286f, 374f, 451f aneurysm of, 107f caroticotympanic branch of, 105f cervical segments of, 111f circulation, angiographic anatomy of, 111–112, 111f groove for, 48f meningohypophyseal trunk and, 95f ophthalmic arteries and, 98–99, 98f siphon portion of, 97f Internal carotid nerve, 209f–210f, 213f–214f, 216f Internal carotid plexus, 49f, 209f, 212f, 275f sympathetic root from, 274f Internal cerebral veins, 71f, 120f, 122f–126f Internal genu, of facial nerve, 272f Internal intercostal muscle, 186f Internal jugular vein, 98f, 124, 124f–125f, 174f, 183f, 286f Internal limiting membrane, 135f Internal medullary lamina, 72f, 295f Internal nasal branch, 357f Internal occipital crest, 48f Internal occipital protuberance, 48f Internal occipital vein, 123f Internal pudendal artery, 198f Internal segments, of lentiform nucleus, 66f Internal sheath, 175f Internal spinal arteries, 117f Internal spinal veins, 127f Internal surface of orbital part, 48f Internal terminal filum, 166f Internal thoracic artery, 105f, 185f Interneurons, 8, 8f, 168f, 170f, 251f axons of, 341f Internode, 29f, 164f asymmetric distortion of, 164f Interoceptors, 174–175, 174f Interossei, cervical disk herniation, 189f Interpeduncular cistern, 91f Interpeduncular fossa, 328f posterior perforated substance in, 75f Interpeduncular nucleus, 67f, 265f, 288f, 293. e11f, 443f, 445f, 465f Interproximal spaces, of teeth, 278f Interstitial nucleus of Cajal, 268f, 293.e14f, 405f, 414f, 416f Interstitiospinal tract, 414–415, 414f, 414b Interthalamic adhesion, 57f, 67f, 71f–72f, 86f, 123f, 295f, 297f, 437f, 439f, 441f, 465f Interventricular foramen, 67f, 71f, 140f, 153f, 292f, 296f, 438f, 465f in midsagittal view, 57f of Monro, 89f–90f, 92f, 122f–123f, 332f Intervertebral disc space, 80f Intervertebral discs, 79, 79f herniation of, 82b Intervertebral foramen, 80f Intervertebral vein, 127f Intestinal inhibition, 232f Intestines, 204f Intima, 174f

Intracellular cGMP, hydrolysis of, 391f Intracellular potential, 28f Intracellular transduction, 391f Intracerebral hemorrhage, 103f hypertensive, 103 Intracortical neurons, preservation of, 487f Intracranial aneurysms, 107–108, 107f Intracranial vessels, 204f Intraculminate vein, 126f Intraembryonic coelom, 129f Intrafascicular pressure, 164f Intrafusal muscle fibers, 252f–253f, 252b Intralaminar nuclei, 72f, 288f, 295f, 365f, 470f Intramural ganglia, 204, 208f, 435f, 436, 447f vagal efferents to, 448f Intraparietal sulcus, 54f Intrinsic damage inflammatory response to, 16f, 19 response to, 19f Intrinsic muscle, 376f Intrinsic proteinopathy, response to, 19f Ion movements, 25f Ionic balance, 12f Ionotropic receptors, 39f iPSCs. See Induced pluripotent stem cells Ipsilateral flaccid paralysis, 117 Ipsilateral hypoglossal nerve, clinical point in, ipsilateral, clinical point in, 75b Ipsilateral medial lemniscus, clinical point in, 75b Ipsilateral optic nerve lesion, 400f Ipsilateral pyramid, clinical point in, 75b Ipsilateral spastic paralysis, 117 IPSP. See Inhibitory postsynaptic potential Iridocorneal angle, 388f–389f, 393f Fontana, trabecular meshwork and spaces of, 389f Iris, 150f, 388f–389f, 393f folds of, 389f major arterial circle of, 389f, 393f minor arterial circle of, 389f, 393f Irritant receptors, 218f Ischemic episode, neuronal damage in, 4b Ischemic strokes, 103 Ischio-­coccygeus muscle, 198f Isodendritic neurons, 8b Isolate individual cells, 9f IV (unmyelinated) fibers, 252f

J Joint receptors, 252–253 Jugular foramen, 49f, 121f, 283f–285f Jugum, 48f Junctional fold, 176f–177f Juxtaparanode, 29f

K K+ buffering, 12f K+ channels, 23f–24f K+ conductance, 27f K+ voltage-­gated channels, 29f Keratinized tip of papilla, 376f Kidneys, 232f, 459f brown fat, 204f and upper ureters, autonomic innervation of, 234–235, 234f

517

Kinesin, 20f Kinocilium, 385f Klüver-­Bucy syndrome, 470b Knee, 408f Knee joint anterior branch of, 200f articular branch of, 200f cutaneous branch of, 200f posterior branch of, 200f Korsakoff amnestic syndrome, 440b Korsakoff syndrome, 497f Krause’s end bulb, 172f Krebs cycle, 45f

L L3 spinal nerve, 238f L3 vertebra, body of, 80f Labyrinthine (internal acoustic) artery, 49f, 106f Lacosamide, 36f Lacrimal artery, 105f Lacrimal glands, 204f, 211f, 214f, 273f, 281f, 435f Lacrimal nerve, 273f–276f palpebral branch of, 182f Lactate, 12f Lacunar infarcts, 104–105, 104f, 108b Lamellated capsule, 173f Lamina, 72f, 79f 7 nuclei, 288f of L4 vertebra, 80f Lamina affixa, 71f Lamina cribrosa, 392f Lamina propria, of gingiva, 278f Lamina terminalis, 57f, 60f, 67f, 89f, 138f, 140f, 153f, 292f, 437f, 465f Laminae of Rexed, 240, 240f at cervical level, 241 at lumbar level, 241–242 at sacral level, 241–242 at thoracic level, 241–242 Laminar layer, 392f Laminin, 178f Lamotrigine, 36f Large acoustic Schwannoma, 383f Large cerebellar hemorrhage, 499f Large intestine innervation of, autonomic, 224–225, 224f nerves of, 226–227, 226f Large pontine hemorrhage, 499f Large pyramidal cell, 342f, 344f Larynx, 204f, 218f, 377f, 407f Lateral antebrachial cutaneous nerve, 181f Lateral apertures, 154f foramen of Luschka, 91f–92f, 123f Lateral atrial vein, 123f Lateral basal nucleus, 240f, 403f Lateral calcaneal branches, 201f Lateral cerebellar hemisphere, 56f, 300f–302f, 339f Lateral cerebral (sylvian) fissure, 102f middle cerebral artery and branches, deep in, 101f Lateral cervical nucleus (C1-­C2 only), 365f Lateral cord hemisection, 248f

518

Index

Lateral corpus callosum fibers, radiating to cortical gyri, 69f Lateral corticospinal tract, 84f, 145f, 241f– 246f, 248f, 255f, 293.e1f, 405f, 408f, 410f–411f, 415f Lateral (accessory) cuneate nucleus, 145f, 364f Lateral cutaneous nerve, 133f Lateral dorsal cutaneous nerve, 201f, 203f Lateral epicondyle, 192f Lateral femoral cutaneous nerve, 181f, 199f–200f Lateral fissure, 54f–56f, 60f, 311f, 313f, 318f–325f, 327f–329f, 331f, 343f, 346f Lateral funiculus, 82f, 132f clinical point, 242b, 364b dorsal and ventral spinocerebellar pathways in, 364b Lateral geniculate body (LGB), 60f, 66f, 71f–72f, 74f–75f, 100f, 122f, 126f, 267f–268f, 271f, 293.e14f, 295f, 396f, 398f, 400f and nuclei of thalamus, 295f Lateral geniculate nucleus, 37f, 267f–268f, 293.e13f, 293.e14f, 306f–307f, 332f–333f projection on, 398f Lateral glossoepiglottic fold, 376f Lateral gray column, 144f Lateral hemisphere, 420f, 426f of cerebellum, 303f Lateral horn, 84, 149f, 242f–243f with intermediolateral cell column, 245f Lateral hypophyseal veins, 115f, 451f Lateral hypothalamic area (LHA), 268f, 289f, 297f, 377f, 437f–441f, 438, 444f–445f, 460f, 470f, 472f Lateral hypothalamic region, 476f Lateral hypothalamus, 446f, 457f Lateral incisors, 278f Lateral intermuscular septum, 191f Lateral lemniscus, 37f, 145f, 264f–265f, 293. e10f, 293.e11f, 382f, 384f nuclei of, 382f, 384f nucleus of, 37f Lateral lenticulostriate arteries, 99f, 101f– 102f, 111f–112f Lateral longitudinal striae, 68f Lateral mammillary nucleus, 440f Lateral medullary syndrome, 258b, 269f Lateral mesencephalic vein, 126f Lateral midbrain reticular formation, 445f Lateral muscles, 410f Lateral nasal wall, 479f Lateral occipitotemporal gyrus, 58f, 60f Lateral olfactory stria, 480f Lateral olfactory tract nucleus, 480f Lateral orbitofrontal artery, 99f, 101f, 108f Lateral parabrachial nucleus, 263f, 293.e9f Lateral pectoral nerve, 187f Lateral plantar nerves, 181f, 201f–202f Lateral plate, 129f of pterygoid process, 50f Lateral pontine syndrome, 263b, 269f

Lateral posterior superior nasal branches, 357f Lateral preoptic area, 438f Lateral preoptic nucleus, 297f, 441f Lateral pterygoid nerves, 276f Lateral pterygoid plate, 50f Lateral recess, 88f, 292f Lateral rectus capitis muscles, 184f Lateral rectus muscle, 273f, 275f, 387f, 416f tendon of, 388f Lateral reticular formation, 367f, 371f–372f, 413f nuclei and, 287f Lateral reticular nucleus, 288f, 411f, 423f–424f Lateral reticulospinal tract, 84f, 413f, 415f Lateral sacral artery, 116f Lateral semicircular canal, 379f prominence of, 378f Lateral semicircular duct, 379f ampulla of, 282f Lateral spinothalamic tract, 248f Lateral stria, olfactory, 67f Lateral sulcus, 141f, 144f Lateral sural cutaneous nerve, 201f–203f branches of, 203f Lateral tegmental CA nuclei, 444f Lateral telocele, 140f Lateral thalamic nuclei, 312f Lateral thalamus, 114f, 332f Lateral ventricle, 70f, 92f, 100f, 123f, 135f, 138f, 140f, 153f, 297f, 343f, 441f, 466f, 488f, 491f anterior horn of, 310f–311f, 438f–440f atrium of, 308f–309f body of, 143f, 314f–317f, 326f–329f, 331f–333f choroid plexus of, 100f, 112f, 122f computed tomography scan of, 62f frontal pole of, 312f, 314f–315f, 320f–325f inferior horn of, 123f, 143f, 327f–329f, 331f magnetic resonance imaging of, 63f post horn of, 123f site of, T2-­weighted magnetic resonance imaging of, 64f temporal horn of, 466f–467f temporal pole of, 310f–313f, 329f trigone of, 339f Lateral vestibular nucleus, 261f–262f, 293f, 293.e7f, 293.e8f, 386f–387f somatotopical pattern in, 412f Lateral vestibulospinal tract, 241f–244f, 386f, 412f, 415f Latissimus dorsi muscle, 186f Least splanchnic nerves, 225f, 234f, 237f–238f Least thoracic splanchnic nerve, 224f Left 7th thoracic sympathetic trunk ganglion, 222f Left anterior cerebral arteries, 96f, 108f, 111f Left anterior inferior cerebellar arteries, 96f Left aorticorenal ganglion, 220f, 226f, 237f Left ascending pharyngeal artery, posterior meningeal branch of, 96f Left cerebral hemisphere, 140f–141f frontal lobe of, 141f

Left colic artery, 220f, 226f Left colic plexus, 220f, 226f Left common carotid artery, 185f Left common iliac artery, 220f Left common iliac plexus, 220f Left gastric artery, 222f–223f, 225f–226f sympathetic fibers along esophageal branch of, 221f Left gastric plexus, 223f, 225f–226f Left gastroepiploic artery, 222f Left greater splanchnic nerve, 221f, 223f, 226f, 230f Left greater thoracic splanchnic nerves, 217f, 220f, 222f, 229f Left hypogastric nerves, 226f, 233f Left inferior colliculi, 126f Left inferior phrenic arteries, 223f, 226f sympathetic fibers along, 221f Left inferior phrenic plexus, 223f, 226f Left internal auditory (labyrinthine) artery, 96f, 112f Left internal carotid artery, 108f, 112f Left interventricular foramen (of Monro), 86f Left lateral aperture (foramen of Luschka), 86f Left lateral brachial vein, 126f Left lateral recess, 86f Left lateral ventricle, 86f, 153f body of, 86f central part of, 153f Left least splanchnic nerves, 226f Left lesser splanchnic nerves, 223f, 226f Left lesser thoracic splanchnic nerves, 217f, 220f Left lower permanent teeth, 278f Left lowest thoracic splanchnic nerve, 220f Left lumbar sympathetic trunk, 226f Left middle cerebral arteries, 96f, 108f Left middle meningeal artery, 96f Left occipital artery, mastoid branch of, 96f Left pericardiacophrenic artery, 185f Left phrenic nerve, 185f Left posterior cerebral arteries, 96f with anterior and posterior temporal branches, 112f terminal cortical branches of, 108f Left posterior inferior cerebellar arteries, 96f inferior vermian branches of, 113f left hemispheric branch of, 113f Left posterior spinal artery, 112f, 118f Left pulvinars, 112f, 126f Left recurrent laryngeal nerve, 185f, 217f, 221f, 285f Left renal artery, 226f Left renal plexus, 226f Left sacral plexus, 220f Left subclavian artery, 185f Left superior cerebellar arteries, 96f Left superior colliculus, 112f, 126f Left suprarenal plexus, 226f Left sympathetic trunk, 217f, 220f, 230f Left thalamus cut surface of, 126f lateral and medial geniculate bodies of, 112f Left transverse sinus, 126f

Index Left upper permanent teeth, 278f Left vagus (X) nerve, 185f, 217f Left vertebral artery, 112f posterior meningeal branches of, 96f Lemniscal channels, 169–170, 169f Lens, 150f, 388f–389f, 393f capsule of, 388f–389f nucleus of, 389f Lens placode, 129f, 147f, 150f Lens vesicle, 150f Lenticulostriate arteries, 102f Lentiform nucleus, 66f, 87f, 405f, 427f Leptin, 461f Lesser occipital nerve, 181f–184f Lesser omentum anterior and posterior layers of, 223f branch from hepatic plexus to cardia via, 223f Lesser palatine nerves, 209f, 213f, 357f Lesser petrosal nerve, 49f, 215f, 273f, 276f, 279f, 283f hiatus of canal of, 49f sulcus of, 48f Lesser splanchnic nerves, 225f, 234f, 237f–238f Lesser thoracic splanchnic nerve, 204f, 224f, 235f Lesser wing, 48f Levator anguli oris muscle, 279f, 281f Levator ani muscle, 198f nerve to, 198f Levator labii superioris alaeque nasi muscle, 279f Levator labii superioris muscle, 279f Levator palpebrae superioris muscle, 273f–275f Levator scapulae muscles, 183f–184f, 191f Levator veli palatini muscle, 285f, 418f Levetiracetam, 36f Lewy body, 430f Lewy body dementia, 484f, 485 LGB. See Lateral geniculate body LH. See Luteinizing hormone LHA. See Lateral hypothalamic area Ligand-­gated ion channels, 39f in neurotransmitter release, 40, 40f Ligand-­gated Na+ channel, 40f Light-­activated protein, 9f viral vector delivers gene for, 9f Limb distal part of, 403f proximal part of, 403f Limb rotation, in nervous system development, 134–135, 134f Limbic cingulate cortex, 59f Limbic forebrain, 67–68, 67f, 446f, 463f–464f afferent and efferent connections in, 289f amygdala in, 472 anatomy of, 465–466, 465f cingulate cortex of, 475–476 clinical point in, 67b hippocampal formation in, 466 structures, 171f Limbic lobe, 59f Limbs of stapes, 378f Limen, 54f

Limen of insula, 102f Linea alba, 186f Lingual artery, 105f, 183f, 214f Lingual glands, 376f Lingual gyrus, 57f–58f, 60f Lingual nerve, 209f, 214f–215f, 276f, 279f, 281f, 377f Lingual tonsil, 376f Lingual vein, 174f Lingula, 77f, 89f, 291f, 420f Lipolysis, 232f Lips, 407f Lissauer’s zone. See Dorsolateral fasciculus Lissencephaly, 141b Little finger, 180f Little toe, lateral margin of, 180f Liver, 204f–205f, 285f, 459f, 461f autonomic innervation of, 229–230, 229f clinical point, 229b LMNs. See Lower motor neurons Lobes, of brain, 54 medial surface of, 59f Lobulated nucleus, 172f Local anesthesia, blocking of action potential by, 28b Local microglia, activation of, 19f Locus coeruleus, 88f, 263f–264f, 288f, 290f, 293.e9f, 293.e10f, 350f, 352f, 355f, 371f, 375f, 444f–445f, 447f, 470f–471f, 474f, 486f–487f, 489f–490f, 500f noradrenergic neurons in, 350 varicose axon of, 421f Long ciliary nerves, 209f, 212f, 274f–276f Long gyrus, 54f Long hypophyseal portal veins, 106f, 115f, 451f Long posterior ciliary artery, 393f Long smooth philtrum, 157f Long thoracic nerve, 187f Longitudinal (interhemispheric) fissure, 112f, 122f Longitudinal intramuscular plexus, 227f Longitudinal muscle, 227f–228f Longitudinal vessels, 163f Long-­term potentiation, 468b Longus capitis, 183f Longus capitis muscles, 183f–184f Longus colli muscles, 183f–184f Lower intercostal nerves, 185f Lower limb, 386f, 412f anterior surfaces of, 180f dermatome, 134f inner surfaces of, 180f outer sides of, 180f posterior sides of, 180f somatic innervation of cutaneous femoral nerve in, 199–200, 199f obturator nerve, 200–201, 200f peroneal nerve in, 203–204, 203f sciatic and posterior femoral nerves, 201–202, 201f tibial nerve, 202–203, 202f Lower limb bone marrow, 205f

519

Lower lumbar sympathetic trunk ganglia, 216f Lower motor neuron palsies, 272b Lower motor neuron (LMN) syndrome, 402b Lower motor neurons (LMNs), 84b, 168f, 170–171, 170f, 208f, 240, 402–403, 422f, 426f alpha and gamma, 252b, 253, 402–403, 402f in anterior horn, 241f–244f clinical point, 7b, 256b, 272b development of, 132 distribution of in brainstem, 271, 404–405, 404f in spinal cord, 403–404, 403f of phrenic nucleus, 417f in somatic reflex actions and pathways, 362 somatic reflex pathways, 251 synaptic endings of, 38b Lower subscapular nerve, 191f Lower thoracic sympathetic trunk ganglia, 216f Lowest thoracic splanchnic nerve, 204f, 235f Lumbar arteries, 116f Lumbar cistern, 79, 81, 81b, 91, 247, 247f Lumbar disc herniation, 167–168, 167f Lumbar disc protrusion, 166f Lumbar enlargement, 166f Lumbar nerve, 166f 1st, 81f 5th, 81f Lumbar plexopathy, 197b Lumbar plexus, 197–198, 197f, 199f Lumbar spinal cord, 365f, 367f gray matter organization in, 241–242 Lumbar splanchnic nerves, 204f, 220f, 224f, 233f, 238f Lumbar vertebrae arteries surrounding spinal cord and, 116f radiography of, 80–81, 80f Lumbosacral enlargement, 81f Lumbosacral trunks, 197f–200f Lumbrical muscles, 194f–195f Lumen, 227f Lunate sulcus (inconstant), 54f Lungs, 204f, 459f left, root of, 185f right, root of, 185f Luschka, foramina of, 86, 88, 153b obstruction of, 89b Luteinizing hormone (LH), 439b, 452f, 453, 453b Lymph follicles, 376f Lymph nodes, 464f Lymph space, 252f Lymphoid organs, 204f Lyse cells, purify mRNA, 9f Lysosome, 4f

M M1-­M3 muscarinic receptors, 436b Macrophages, 19f Macula, 385f, 392f–393f fovea centralis, 388f section of, 385f

520

Index

Magendie, foramen of, 86, 88, 153b obstruction of, 89b Magnetic gait, 93f Magnetic resonance angiography, of brain arterial system, frontal and lateral views, 110–111, 110f Magnetic resonance imaging (MRI) of aphasias, 495–496, 495f functional, of cerebral cortex, 349–350, 349f high-­resolution axial sections at anterior commissure and caudal thalamus, 308f–309f at basal ganglia and internal capsule, 312f–313f at centrum semiovale, 318f–319f at corpus callosum, 316f–317f at dorsal caudate, splenium, and genu of corpus callosum, 314f–315f at head of caudate and midthalamus, 310f–311f at mid pons level, 300, 300f–301f at midbrain level, 304f–305f at rostral midbrain and hypothalamic level, 306f–307f at rostral pons level, 302f–303f high-­resolution coronal sections at amygdala/anterior limb of internal capsule, 326f–327f at anterior commissure/columns of fornix, 324f–325f at caudal pulvinar and superior colliculus, 336f–337f at caudate nucleus/nucleus accumbens, 322f–323f at geniculate nuclei, 334f–335f at genu of corpus callosum, 320f–321f at mammillary body, 328f–329f at mammillothalamic tract/substantia nigra, rostral hippocampus, 330f–331f at midthalamus, 332–333, 332f–333f at splenium of corpus callosum, 338f–339f T1-­weighted of brain, axial and sagittal views, 63–64, 63f of brainstem, caudal to rostral cross-­sections, 255 T2-­weighted of brain, axial and sagittal views, 64–65, 64f of spinal cord, sagittal sections, 247 of ventricles, axial and coronal views, 90–91, 90f Magnocellular, 431f Magnocellular neuron, 454f Main cuneate nucleus, 423f Major depressive disorder (MDD), 489–490, 489f Malleus, 151f, 379f, 384f head, 378f head of, 282f Malocclusion, 157f

Mammillary body, 57f–58f, 60f–61f, 67f, 70f, 75f, 89f, 139f, 144f, 268f, 292f–293f, 306f, 328f, 437f, 465f, 468f, 475f in coronal section, 328–329, 328f–329f Mammillary complex, 297f, 441f Mammillary nuclei, 466f Mammillary peduncle, 289f, 440f, 444f Mammillary recess, 144f Mammillotegmental tract, 443f, 445f, 468f Mammillothalamic fasciculus, 58f Mammillothalamic tract, 67f, 296f–297f, 329f, 439f–441f, 445f–446f, 463f, 465f, 468f, 475f in coronal section, 330–331, 330f–331f, 330b Mandible, 50f ramus of, 280f Mandibular nerve, 49f, 182f, 209f, 214f–215f, 273f, 275f–276f, 277, 283f, 373f, 377f meningeal branch of, 49f, 273f sensory root and motor root of, 372f Mandibular notch, 50f Marginal artery, 226f Marginal plexus, 226f Marginal sinus, 179f Masked facies, 93f Masklike facies, 430f Masseter muscle, 280f Masseteric nerves, 276f Mast cell, 454f Mastoid angle, 48f Mastoid emissary vein, 120f Mastoid foramen, 49f Mastoid process, 50f, 280f Mature granule cell neuron, 16f Maxillary artery, 95f, 105f, 209f, 214f–215f Maxillary nerve, 49f, 98f, 182f, 209f, 214f– 215f, 273f–276f, 277, 357f, 372f–373f, 377f entering foramen rotundum, 213f meningeal branch of, 273f Maxillary plexus, 209f Maxillary sinus, 213f Maximal contraction, 31f MCA. See Middle cerebral artery MD. See Muscular dystrophy MDD. See Major depressive disorder Meatal plug, 151f Media, 174f Medial accessory olivary nucleus, 257f–258f, 293.e3f, 293.e4f Medial accessory olive, 256f–258f, 293.e2f, 293.e3f, 293.e4f Medial antebrachial cutaneous nerve, 181f Medial atrial vein, 123f Medial basilar infarct, 269f Medial brachial cutaneous nerve, 181f Medial calcaneal branches, 201f–202f Medial dorsal cutaneous nerve, 203f Medial dorsal nucleus, 431f, 470f of thalamus, 444f, 446f Medial dorsal thalamic nucleus, 445f, 476f–477f Medial dorsal thalamus, 329f, 332f Medial eminence, 74f, 88f

Medial epicondyle, 191f Medial forebrain bundle, 444f, 465f Medial frontal gyrus, 57f Medial frontal lobe, 470f Medial geniculate body (MGB), 37f, 60f, 66f, 71f–72f, 74f, 100f, 122f, 126f, 145f, 267f–268f, 293.e14f, 295f, 382f, 384f and nuclei of thalamus, 295f Medial geniculate nucleus, 267f–268f, 293. e13f, 293.e14f, 306f–307f, 332f–333f Medial hypothalamus, 446f Medial inferior pontine syndrome, 260b Medial lemniscus, 145f, 169f, 256f–269f, 293f, 293.e2f, 293.e3f, 293.e4f, 293.e5f, 293.e7f, 293.e8f, 293.e9f, 293.e10f, 293.e11f, 293.e12f, 293.e14f, 300f, 302f, 365f–366f of CN VII, 293.e7f decussation of, 145f, 365f ipsilateral, clinical point in, 75b Medial lenticulostriate arteries, 99f, 101f– 102f, 111f–112f Medial longitudinal fasciculus, 77f, 84f, 89f, 145f, 241f–244f, 256f–268f, 287f, 292f–293f, 293.e2f, 293.e3f, 293.e4f, 293.e5f, 293.e7f, 293.e8f, 293.e9f, 293.e12f, 301f, 414f, 416f ascending fibers in, 386f Medial longitudinal striae, 68f Medial mammillary nucleus, 440f Medial medullary reticular formation, 413f Medial medullary syndrome, 269f Medial midbrain syndrome, 269f Medial muscles, 410f Medial occipitotemporal gyrus, 58f, 60f Medial olfactory stria, 480f Medial orbitofrontal artery, 101f, 108f, 111f Medial parabrachial nucleus, 263f, 293.e9f, 417f Medial pectoral nerve, 187f Medial plantar nerves, 181f, 201f–202f Medial pontine reticular formation, 396f, 413f Medial pontine syndrome, 269f Medial prefrontal cortex (PFC), 433b, 457f, 474f, 476f Medial preoptic area, 438f Medial preoptic nucleus, 297f, 441f Medial pterygoid muscle, 280f Medial pterygoid nerves, 276f Medial pterygoid plate, hamulus of, 50f Medial rectus motor neurons, 387f Medial rectus muscle, 273f, 275f, 387f, 416f branches to, 274f tendon of, 388f Medial reticular formation, 287f, 372f Medial reticulospinal tract, 415f anterior, 413f pontine, 84f Medial septal nucleus, 353f Medial stria, olfactory, 67f Medial striate artery, 106f Medial sural cutaneous nerve, 201f–202f Medial temporal cortex, 488f Medial temporal lobes, 114f Medial thalamic nuclei, 312f

Index Medial thalamus, 114f Medial vestibular nucleus, 259f–260f, 262f, 293.e5f, 386f–387f Medial vestibulospinal fibers, 386f, 412f, 415f Median aperture foramen of Magendie, 86f, 91f of Magendie, 89f, 92f, 123f, 292f Median eminence, 152f, 296f, 445f, 449, 449f–450f, 449b, 464f Median forebrain bundle, 67f, 289f, 297f, 441f, 443f, 445f–446f, 463f, 473f Median glossoepiglottic fold, 376f Median nerve, 181f, 187f, 190f, 193f–195f, 194–195 in carpal tunnel, 195f palmar branch, 190f palmar cutaneous branch of, 195f sensory distribution of, 195f Median raphe, 145f Median sacral artery, 116f Median sulcus, 88f Median telocele, 140f roof of, 140f Mediastinal pleura, 185f Medulla, 37f, 49f, 56f–57f, 59f, 89f, 114f, 139f, 141f, 146, 146f, 204f, 207f, 213f, 215f, 219f, 224f, 231f, 235f, 247f, 282f, 292f, 329f, 332f, 364f, 371f, 382f, 396f, 407f–408f, 411f, 413f, 424f arterial syndromes of, 269f axial anatomy of at genu of facial nerve, 262f at level of CN X and vestibular nuclei, 259f at level of cochlear nuclei, 260b at level of dorsal column nuclei, 256f at level of facial nucleus, 261f at level of inferior olive, 258f at level of obex, 257f at pontine junction, 260b at spinal cord transition area, 255f clinical point bulbar palsy and pseudobulbar palsy, 256b lateral medullary syndrome, 258b medial inferior pontine syndrome, 260b comparison of, at 5.5 weeks and adult, 144f computed tomography scan of, 62f lateral reticular formation of, 288f lower, 365f–367f lower part of, 377f, 405f, 423f magnetic resonance imaging of, 63f middle part of, 405f nuclei, 288 T2-­weighted magnetic resonance imaging of, 64f upper part of, 423f Medullary cardiovascular centers, 443f Medullary lamina, 430f Medullary pyramids, 329f Medullary reticular formation, 371f–372f, 411f, 445f Medullary reticulospinal tract, 413f Megacolon, chronic, clinical point, 228b

Meissner’s corpuscle, 172f, 175f Meissner’s plexuses, 227 Melanocyte, 175f Melanocyte-­stimulating hormone (MSH), 452f, 453 Membrane organelles, 20f Membranous labyrinth, 385f Memory circuits, 497–498, 497f Meningeal arteries, 95–96 tear in, hematoma and, 52 Meningeal branch, 186f Meningeal veins, 119–120, 120f Meninges, 49f arterial system of, 96–97, 96f and relationship to skull and dura, 95–96, 95f of brain, 51–52, 51f of spinal cord, 82 Meningocele, 155, 155f Meningohypophyseal trunk, tentorial branch (cut) and dorsal meningeal branch of, 95f Meningomyelocele, 130b, 155, 155f Mental nerve, 182f, 276f Mental retardation, 157f Mentalis muscle, 279f Meridional fibers, 389f Merkel cell, 172f Merkel’s disc, 172f Mesencephalic nucleus, 377f of trigeminal nerve, 263f, 266f, 271f–272f, 276f, 373f Mesencephalic reticular formation, 352, 396f, 424f Mesencephalon, 153f at 28 days, 137, 137f at 36 days, 138, 138f at 49 days, 139, 139f adult derivatives of, 146f comparison of, at 5.5 weeks and adult, 144f Mesenchyme, 150f Mesenteric branches, 225f Mesenteric lymph nodes, 205f Mesenteric nerves, 228f Mesentery, 228f Mesoappendix, 225f Mesocortical pathway, 352f, 488f Mesolimbic pathway, 352f, 488f Mesonephros, 131f Mesothelial septum, in posterior median sulcus, 82f Metabolic organs, autonomic innervation of, 205–206, 205f Metabolic syndrome, chronic stressors and, 229b Metabolism, signaling systems involved in regulation of, 461–462, 461f Metabotropic receptors, 39f in neurotransmitter release, 40, 40f Metacoele, 153f Metanephrine, 232f Metencephalon, 138, 138f, 153f at 49 days, 139, 139f adult derivatives of, 146f myelencephalon, 146f

521

Met-­Enkephalin neurons, 356 Meyer’s loop, 398f, 400f and visual loss, 398b Mg2+, 26f MGB. See Medial geniculate body Microcephaly, 157f Microglia, 8, 136 activated, 19f age-­related “priming” of, 19f biology of, 13–14, 13f Microglial cell, 11f Microgyria, 141b Microneuron, 4 Microtubule, 20f, 493f subunits, 493f Microtubule segments, pre-­assembly of, 20f Microvilli, 376f Midbrain, 37f, 57f, 114f, 129f, 137f–138f, 365f, 367f, 371f–372f, 382f, 407f–408f, 411f, 414f, 437f adult derivatives of, 146–147, 146f arterial syndromes of, 269f axial anatomy of, 304–305, 304f–305f at level of inferior colliculus, 265f at level of medial geniculate body, 267f at level of superior colliculus, 266f clinical point, 265b, 267b, 304b computed tomography scan of, 62f dopaminergic pathways from, 352, 352f clinical point, 352b lateral reticular formation of, 288f magnetic resonance imaging of, 63f nuclei of, 288 T2-­weighted magnetic resonance imaging of, 64f Midbrain colliculi, 57 Midbrain tegmentum, 446f Middle cerebellar peduncle, 74f–75f, 126f, 145f, 260f–264f, 293f, 293.e7f, 293. e8f, 293.e10f, 301f, 348f, 396f, 423f crossing fibers of, 261f, 263f Middle cerebral artery (MCA), 100f, 105f–106f, 110f–112f, 114f, 328f aneurysm of, 107f basal view of, 99, 99f branches of, 110f coronal forebrain section, 102f in frontal view, 101 lateral and medial views of, 108 multiple branches of, 111f obstruction of, 100b territory of, colored illustration, 109–110, 109f Middle cerebral artery origin, 97f Middle cervical sympathetic cardiac nerve, 210f, 219f Middle cervical sympathetic ganglion, 221f Middle cervical sympathetic trunk ganglion, 210f, 219f Middle colic artery, 225f–226f Middle colic plexus, 225f–226f Middle constrictor muscle, of pharynx, 285f Middle ear, 212f Middle frontal gyrus, 54f, 320f–321f

522

Index

Middle meningeal artery, 49f, 51f, 95f, 105f, 120f, 209f, 374f parietal (posterior) and frontal (anterior) branches of, 95f skull fracture crossing, 52f Middle meningeal plexus, 209f Middle meningeal vein, 49f, 51f, 120f–121f Middle meningeal vessels, sulcus of, 48f Middle phalanges, branches to dorsum of, 194f Middle rectal artery, 226f Middle rectal plexus, 226f Middle scalene muscle, 183f Middle temporal area, 399f Middle temporal gyrus, 54f Middle ureteric branch, 234f Midline fibers, 406f Midline groove (median sulcus), 376f Midline (median) nuclei, 72f, 288f, 295f Midline thalamic nuclei, 471f–472f Migraine headaches, mechanism of, 375–376, 375f Migrating neuroblasts, 135f–136f Miosis, 242b Mitochondria, 4, 4f, 14f, 23f, 38f, 172f, 176f, 391f Mitochondrion, 172f, 177f Mitral cell, 480f Modified pyramidal cell, 344f Modiolus of cochlea, 380f Molars, 278f Molecular layer, 16f, 421f Monoamine oxidase inhibitors, 350b Monocarboxylate Transporter 1 (MCT1), 14f Monro, foramen of, 86 Mossy cell axon, 7f Mossy fibers, 421–422, 421f–422f, 425f, 467f Motor (recording electrodes), 31f Motor area, 442f Motor axon, 41f Motor cerebral cortex, 411f Motor control of speech, 345f Motor cortex, 55f, 340f corticobulbar, 407 corticospinal, 409 efferent pathways of, 405 functional magnetic resonance imaging of, 349f Motor end plate, 8f with Schwann cell cap, 8f Motor end plates, 176f Motor fibers, 184f Motor interneuron, 423f Motor (autonomic) nerve, 175f Motor nerve fibers, of cranial nerves, 270–271 Motor neuron(s), 5f, 32f, 386f, 412f–413f classification of axons of, 30f development of, 148f, 149–150 to limbs, 240f myelination of axons of, 21 normal, 165f permanently impaired, 165f representation of, 403f schematic representation of, 250f to trunk and neck, 240f undergoing central chromatolysis, 165f

Motor nucleus of trigeminal nerve, 373f Motor-­sensory, 345f Motor signs (weakness), 189f Motor systems, 401–433 basal ganglia in, 427–428 cerebellum in, 420–421 lower motor neurons in, 402–403 upper motor neurons in, 405–406 Motor units, 402b Movement disorders, 312b, 427b surgical approaches to, 429–430, 429f, 429b MRI. See Magnetic resonance imaging MSH. See Melanocyte-­stimulating hormone Mucosa, 227f–228f Mucosal glands, 227f Mucous cells, 179f Mucous glands, 376f Mucus, 479f Müller cell, 7f, 390f Multipolar cell, 8f Multipolar neurons, 227f Multipolar somatic motor cell of anterior horn of spinal cord, 8f nuclei of cranial nerves III, IV, V, VI, VII, IX, X, XI, or XII, 8f Multisensory association areas, of cortex, 55f basal surface of, 61f Muscarinic receptors, 208 M1-­M3, 436b Muscle, 452f Muscle spindles, 8f, 168f, 252–253, 402f detail of, 252f Muscle stretch reflex, 363, 363f clinical point, 253b, 362b Muscular dystrophy (MD), 178b Muscularis mucosae, 227f–228f Musculocutaneous nerve, 187f, 193–194, 193f–194f MuSK, 178f Myasthenia gravis, 176b Mycoplasma pneumoniae, 83b Myelencephalon, 138, 138f, 153f at 49 days, 139, 139f thin root of, 138f Myelin, 29f, 163f, 169f Myelin sheaths, 5f, 8f, 14f, 29f, 38f, 165f, 173f, 177f, 385f in neuronal function, 21b Myelinated afferent fiber, of spinal nerve, 8f Myelinated axon, 21, 163 action potential in, 27 conduction of action potentials in, 27, 29f Schwann cells associated with myelin sheaths of, 21f Schwann sheath surrounding, 22f Myelinated fascicles, 5f Myelinated fibers, 8f, 29f–30f Myelinated nerve fibers, 29f, 164f Myelinated somatic motor fiber, of spinal nerve, 8f Myelination, 21–22, 21f development of, 22–23, 22f triggering of, by axonal diameter, 30b Myenteric (Auerbach’s) plexus, 227, 227f–228f

Myenteric plexuses, 460f Mylohyoid muscle, 183f, 373f Mylohyoid nerve, 276f, 418f Myofibrils, 176f

N Na+ channels, 14f, 23f–24f, 26f, 178f Na+ conductance, 27f Na+ voltage-­gated channels, 29f Nares, 407f Nasal cavity, autonomic innervation of, 213–214, 213f Nasal mucosal glands, 211f, 435f Nasal retina, 392f nerve fibers of, 392f Nasal septum, 357f Nasalis muscle, 279f Nasociliary nerve, 209f, 212f, 273f–276f sensory root from, 274f Nasociliary nerve root, 209f Nasopalatine nerve, 213f, 357f Nasopharynx, 378f Nauta’s limbic midbrain, 445f Near vision, pupillary regulation in, 210 Neck, of teeth, 278f Neocortex, cell migration in, 142–143, 142f, 142b Neopallial cortex, 140f Nerve compression, 164–165 pressure gradients, 164–165 Nerve fiber bundles, 163f Nerve fibers, 163f, 174f, 380f, 385f, 402f, 464f bundles, 392f emerging from taste buds, 376f layer, 390f, 392f Nerve growth factor (NGF), 15f Nerve impulse, 31f Nerve injury, Sunderland classification of, 165f Nerve of pterygoid canal, 209f Nerve plexus, 172f, 376f Nerve roots, 82, 167f Nerve terminals, 464f Nervous system aging and, 500, 500f autonomic-­hypothalamic-­limbic systems, 434–480 central brain in, 53–72 brain stem and cerebellum in, 73–77 spinal cord in, 78–84, 239–253 ventricles and cerebrospinal fluid in, 92 cranial nerves of, 270–271 motor systems of, 401–433 neurons in, 1–46 sensory systems of, 359–400 skull and meninges of, 47–52 vasculature of, 94–127 Nervus intermedius, 98f, 121f, 270f, 279f, 377f motor root of, 282f Neural branch, 117f Neural circuitry, of swallowing, 418–420, 418f

Index Neural crest, 130f–133f derivatives of, 136–137, 136f formation of, 129–130, 129f and neural tube development, 131, 131f future, 130f Neural folds, 130f Neural groove, 130f Neural growth factors, 12f Neural plate, 130f in 21-­ or 22-­day-­old-­embryo, 130 appearance of, 129f formation of, 129–130, 129f forming neural tube, 129f Neural proliferation, and differentiation, 135–136, 135f, 142 Neural stalk, 296f Neural stem cells, 17f Neural tube, 133f at 5 weeks, 135f defects of, 155–156, 155f derivatives of, 136–137, 136f development, 131, 131f formation of, 129–130, 129f walls of, 135–136, 135f Neurilemma, 176f Neurilemmal cell, 22f Neuritic plaques, in Alzheimer’s disease, 486 Neuroblasts, 16f, 136 Neurodegenerative process, response to, 16f, 19, 19f Neuroectoderm, 150f Neuroeffector junction, on smooth muscles, 162f Neuroendocrine regulation by hypothalamus, 298b of pituitary gland, 298b Neuroepithelial cells, 142f Neuroepithelial progenitor cells, 142 Neurofibrillary tangles (NFTs), 486f–487f Neurofilaments, 38f Neurogenesis, 142–143, 142f, 142b Neurohistology, neuronal structure and, 5–6, 6f Neurohypophyseal hormones, 454–455, 454f Neurohypophyseal tract, 454f Neurohypophysis, 106f, 146f, 296f, 450f Neuroimmunomodulation, 464–465, 464f Neuromediators, 207 Neuromuscular junction, 15f, 41f, 132, 176–177, 176f physiology of, 177–178, 177f structures and proteins in, 178–179, 178f Neuron(s), 11f, 13f, 484f action potentials of, 27–28, 27f association, 341f autocrine and paracrine signaling between and among, 15f cell types, 8–9, 8b cortical electrical firing patterns of, 34–35, 34f types of, 341–342, 341f current flow in, 25f differentiation of in 5 to 7 week embryo, 132f in 26-­28 day embryo, 132f

Neuron(s) (Continued) diseased, 493f energy and metabolic requirements of, 4b genetic models for studying, 10–11 glial cell types in, 11–12 glucocorticoid regulation of, 44–45, 44f graded potentials in, 25–26 growth factors and trophic factors of, 15–16, 15f inhibitory and excitatory, 33 maintenance of, 15f membrane potential and sodium channels in, 24–25, 24f metabolic support of, 12f molecular signaling in, mechanisms of, 39–40, 39f molecular techniques for studying, 9–10 properties of, 1–46 anatomical and molecular, 4–5 electrical, 23–24 resting potential in, 23–24, 23f reticular formation, 5f signal transduction of, 42–43, 42f structure of, 4–5, 5f summation of input to, 33 in superior mesenteric-­celiac ganglion, 5f synapses of, 7–8 types of, 7–8 ultrastructure, 6–7 Neuronal cell bodies, 5f, 22f Neuronal differentiation, 15f Neuronal dysfunction, 19f Neuronal loss, 19f Neuropathic pain, mechanisms of, 370–371, 370f Neuropathies, diagnosis of, 31 Neuropeptide Y, 41f Neuropeptides, 46, 207 Neuropsychiatric disorder major depressive disorder and bipolar disorder, 489–490, 489f obsessive-­compulsive disorder, 492–493, 492f panic and anxiety disorders, 490–491, 490f posttraumatic stress, 491–492, 491f schizophrenia, 488–489, 488f Neurosecretory vesicles, 454f Neurospheres, 17f Neurotransmission chemical, 45f, 46 at cholinergic synapses, 207 and neuromuscular junction, 176–177, 176f Neurotransmitter(s), 7, 354f amino acid, 46 chemical, synaptic morphology in, 38 co-­localization and release of, 41f excitatory and inhibitory, 25 multiple, 41–42, 41f non-­linearity of release of, 41f norepinephrine, 207 preganglionic and postganglionic, 436b release, 40–41, 40f and signaling properties, 38–39 Neurotransmitter receptors (NTR), 354f Neurotransmitter-­receptor mismatch, 41, 41f

523

Neurotubules, 4f, 38f Neurulation, 130–131, 130f failure of, 130b Neutrophilia, 232f Neutrophils, 19f NF-­155, 29f NF-­186, 29f NFTs. See Neurofibrillary tangles NGF. See Nerve growth factor Nicotinic cholinergic receptors, 436b Nicotinic receptors, 207–208 Nigrostriatal pathway, 352f Nipples, level of, 180f Nissl substance, 8f Nitric oxide, 221 NLRs. See NOD-­like receptors NMDA receptor, 26f, 36f NMDAR. See N-­methyl-­D-­aspartate receptor N-­methyl-­D-­aspartate receptor (NMDAR), 42, 42f Nociceptive afferent, 369f Nociceptive axons descending control of ascending, 371 in spinothalamic and spinoreticular systems, 368 clinical pathology of, 368b spinal cord processing of, 369–370, 369f trigeminal, 372 Nociceptive processing, spinal mechanism of, 369f Nodal cells, endings, 8f Node, 38f Node of Ranvier, 5f, 14f, 21, 21f, 29–30, 29f, 163, 164f NOD-­like receptors (NLRs), 13f Nodose ganglion, 209 Nodule, 89f, 291f, 420f, 425f–426f Noncortical projections, 487f neurons, preservation of, 487f Nondominant cortical hemispheric dysfunction, 495b Nonspecific thalamic nuclei (centromedian), 367f Noradrenergic bundles, 444f Noradrenergic cell groups, 287f Noradrenergic pathways, in brainstem, 350–351, 350f clinical point, 350b Noradrenergic (NA) postganglionic sympathetic nerve fibers, 179f Norepinephrine, 208f, 231f–232f, 436b, 464, 464f, 472f Norepinephrine axon, 41f, 45f, 46 Normal midline structures, shift of, 52f Normal sleep, EEG, 35f Normetanephrine, 232f Nose, nerves of, 357, 357f Notochord, 129, 129f, 131f NT. See Neurotransmitter(s) NTR. See Neurotransmitter receptors Nuclear bag fiber, 252f, 402f Nuclear cell columns, of spinal cord, 240f Nuclear chain fiber, 252f, 402f Nuclear signaling, regulation of, 43–44, 43f Nuclei cuneatus, 169f

524

Index

Nuclei gracilis, 169f Nucleic acid “bar” codes, 9f Nucleolus, 4f Nucleus, 4f, 391f, 479f of CN III, 266f–267f of CN IV, 265f of CN VI, 261f–262f, 293f, 293.e7f of CN VII, 261f–262f, 293f, 293.e7f of CN XI, 255f, 293.e1f of CN XII, 256f–259f, 293.e2f, 293.e3f, 293.e4f, 293.e5f of facial nerve, 373f of hypoglossal nerve, 373f of solitary tract, 271f, 279f and tractus solitarius, 293.e4f Nucleus accumbens, 322f–323f, 352f, 354f– 355f, 432f, 445f, 468f, 471f–472f, 474f, 476f, 488f–489f, 496f connections of, 432, 432f coronal section through, 322–323, 322f–323f dopaminergic neurotransmission in, and associated emotions and behavior, 322b, 352b Nucleus ambiguus, 144f–145f, 154f, 256f– 258f, 269f, 271f–272f, 283f–285f, 284b, 293.e2f, 293.e3f, 293.e4f, 404f–405f, 404, 407f, 417f Nucleus basalis, 290f, 324f–325f, 486f–487f of Meynert, 353f cholinergic pathways originating in, 353 Nucleus centralis superior, 264f–266f, 293. e10f, 293.e11f, 293.e12f Nucleus cuneatus, 255f–258f, 293.e1f, 293.e2f, 293.e3f, 293.e4f Nucleus dorsalis, 403f of Clarke, 240f, 242f–243f, 245f Nucleus gracilis, 255f–257f, 293.e1f, 293.e2f, 293.e3f Nucleus intercalatus, 297f, 440f–441f Nucleus of Darkschewitsch, 268f, 293.e14f Nucleus of Edinger-­Westphal, 144f–145f Nucleus of muscle cell, 176f Nucleus of Schwann cell, 176f Nucleus posterior marginalis, 240f, 403f Nucleus prepositus, 260f Nucleus proprius, 241f–246f of posterior horn, 240f, 403f Nucleus pulposus, 167f herniated, impingement of, 79 Nucleus raphe dorsalis, 264f, 287f, 293.e10f, 355f, 375f Nucleus raphe magnus, 261f, 355f, 375f Nucleus raphe obscurus, 260f Nucleus raphe pallidus, 260f midline neurons, 287f Nucleus raphe pontis, 263f, 293.e9f Nucleus reticularis tegmenti pontis, 396f, 423f Nucleus solitarius, 256f–260f, 269f, 293.e2f, 293.e3f, 293.e4f, 293.e5f, 293.e6f, 355f Nucleus tractus solitarius, 144f, 154f, 290f, 444f–445f, 447f–448f, 457f, 460f, 464f, 470f–472f, 474f, 476f Nucleus VPL (ventral posterolateral), 169f

Nutrient-­related signals, 461f Nystagmus, 379b, 387–388, 387f clinical point, 433b

O Obesity, clinical point, 223b Obex, 88f, 257f, 292f–293f Object recognition pathway, 399f Obscurus, 351f Obsessive-­compulsive disorder, 492–493, 492f Obstructive hydrocephalus, potential lesion sites in, 92f Obturator externus muscle, 200f Obturator internus muscle, 198f nerve to, 198f Obturator nerve, 181f, 197f–200f, 200–201 Occipital artery, 95f, 105f branch of, 49f mastoid branch of, 95f Occipital bone, 48f Occipital condyle, 286f Occipital cortex, 394f Occipital diploic vein, 120f Occipital emissary vein, 120f Occipital encephalocele, 156f Occipital eye fields, 416f Occipital lobe, 54f, 56f, 59f, 141f, 304f–310f, 312f–313f, 315f–319f, 399f of brain, 56f computed tomography scan of, 62f lesion, 400f medial surface of, 59f projection on left, 398f Occipital nerve, 182f Occipital pole, 54f, 60f Occipital sinus, 121f, 126f sulcus of, 48f Occipital-­temporal association fibers, 347f Occipitofrontal fasciculi, superior and inferior, 346f Occipitofrontalis muscle, 279f, 281f Occipitotemporal sulcus, 58f, 60f Oculomotor control, 416 Oculomotor nerve (CN III), 49f, 75f, 89f, 121f, 138f, 145f–146f, 204f, 209f, 212f, 266f–267f, 269f–274f, 292f, 297f, 304f, 387f, 404f, 416f, 435f, 441f and ciliary ganglion, 275–276, 275f clinical point, 75b, 209b, 274b, 388b compression of, 52f fibers of, 269f in orbit, 273–274, 273b inferior division of, 274f–275f motor (parasympathetic) root from, 274f superior division of, 274f–275f Oculomotor nerve root, 209f Oculomotor nucleus, 144f–145f, 271f–272f, 275f, 396f, 404f, 416f Odontoblast layer, of teeth, 278f 5-­OH-­tryptamine, 45f 5-­OH-­tryptophan, 45f Olecranon, 191f Olfactory bulb, 16f, 60f–61f, 67f, 141f, 146f, 345f, 357f, 442f–444f, 463f, 469f– 470f, 472f, 479f–480f, 486f, 491f, 497f clinical point, 60b, 480b

Olfactory cells, 479f Olfactory cortex, 61f, 480 Olfactory epithelium, 480f distribution of, 479f Olfactory fear-­conditioning, 16f Olfactory gland, 479f Olfactory lobe, 139f–140f Olfactory memory, 16f Olfactory mucosa, schema of section through, 479f Olfactory nerve (CN I), 270f, 357f and projections into CNS, 357, 357f clinical point, 357b Olfactory nerve bundles, 49f Olfactory nerve fibers, 480f Olfactory nerves, 480f Olfactory pathways, 480, 480f Olfactory placode, 129f, 147f Olfactory receptors, 479–480, 479f clinical point, 357b, 479b Olfactory-­related projection, 444f Olfactory rod, 479f Olfactory sulcus, 60f Olfactory tract, 58f, 60f–61f, 67f, 75f, 297f, 357f, 441f, 443f, 480f clinical point, 480b Olfactory trigone, 480f Olfactory tubercle, 480f Oligodendrocyte(s), 8f, 11f, 17f, 21f–22f biology of, 14–15, 14f central myelination of axons of, 21 fused layers of, 14f maturation, 14f physiology, 14f precursor cells, 14 Oligodendrocyte progenitor cells (OPCs), 16, 16f Olive, 74f–75f, 141f, 154f, 272f Olivopontocerebellar atrophy, 423b “Omics”, 9f Omohyoid muscle, 183f–184f, 286f OPCs. See Oligodendrocyte progenitor cells Ophthalmic artery, 98f, 105f–106f, 111f–112f, 212f aneurysm of, 107f and internal carotid, 98–99, 98f Ophthalmic nerve, 49f, 182f, 209f, 212f, 214f–215f, 273f–276f, 277, 372f– 374f, 377f tentorial (meningeal) branch of, 273f Opioid analgesia, central nervous system, 371b Opponens digiti minimi, 196f Opponens pollicis, 194f–195f Optic canal, 49f Optic chiasm, 37f, 57f, 60f–61f, 67f, 75f, 89f, 102f, 106f, 123f, 146f, 273f–274f, 292f, 296f–297f, 323f–324f, 394–395, 394f, 396f–398f, 400f, 437f–438f, 441f, 465f clinical point, 60b damage affecting, 395–396, 395f invading, 395f Optic cup, 138f–139f, 147f, 150, 150f, 153f Optic disc, 393f blind spot, 392f

Index Optic nerve (CN II), 37f, 49f, 58f, 60f–61f, 112f, 121f, 126f, 139f, 150f, 212f, 270f, 273, 273f–275f, 297f, 304f, 322f, 388f, 392–393, 392f–393f, 395f–398f, 400f, 437f, 441f, 491f clinical point, 272f glaucoma in, 389b visual field deficit resulting from, 396b and optic chiasm, 394 prechiasmatic, 394f and retina, 392–393 retinal cell axons passing via, 390f Optic pathway, 394f Optic radiations, 310f–313f, 339f, 394f, 396f, 400f magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f Optic recess, 57f, 86f of 3rd ventricle, 140f Optic stalk, 138f, 140f, 150f, 153f Optic tract, 37f, 60f–61f, 70f, 74f–75f, 87f, 100f, 126f, 267f–268f, 293.e13f, 293. e14f, 295f, 306f, 325f–329f, 394f–398f, 400f, 438f–440f, 466f clinical point in, 60b fibers of, 268f lesion, 400f termination sites for fibers in, 271f Optic vesicle, 137f, 150f Optogenetics, 9f Optokinetic nystagmus, 433b Ora serrata, 388f–389f, 393f Oral ectoderm, 152f Orbicularis oculi muscle, 150f, 279f, 281f Orbicularis oris muscle, 279f, 281f, 373f Orbit development of, 150–151, 150f nerves of, 272f, 273–274, 273b, 274f Orbital gyri, 60f Orbital sulcus, 60f Orbitofrontal cortex, 305f–309f, 442f, 445f, 463f, 469f, 478f projections, 443f Organ of Corti, 380–381, 380f clinical point, 380b Organum vasculosum of the lamina terminalis (OVLT), 438, 448f–450f, 449, 449b, 474f Oropharyngeal membrane, 129f Osseous cochlea, 380f Osseous spiral lamina, 380f Ossicle condensations, 151f Otic capsule, 379f Otic ganglion, 147f, 204f, 209, 209f, 211f, 214f–215f, 276f, 279f, 283f, 377f, 435f schematic of, 215–216, 215f Otic vesicle, 151f Otoconia, 385f Outer epineurium, 163f Outer hair cells, 380f Outer nuclear layer, 390f Outer plexiform layer, 390f Outer segment, of photoreceptor, 391f Outer stellate cell, 421f–422f

Oval (vestibular) window, base of stapes in, 378f Ovarian artery, 238f Ovarian plexus, 238f Ovary, 238f, 452f OVLT. See Organum vasculosum of the lamina terminalis Oxcarbazepine, 36f Oxytocin, 454–455, 454f

P Pachygyria, 141b Pacinian corpuscles, 162f, 169f, 172f–173f, 173–174, 175f Pain sensation, 374f temperature, 362f, 367f, 372f Pain modulation, endogenous and exogenous, 371 Pain perception, 375f Pain referral, pain-­sensitive structures of head and, 374–375, 374f Palatine nerves, 214f, 276f Palatine tonsil, 376f Palatoglossal arch, 376f Palatoglossal muscle, 376f Palatoglossus, 285f Palatopharyngeal arch, 376f Palatopharyngeal muscle, 376f Palatopharyngeus, 285f Paleocerebellum, 76b Pallidal projection, 427f Pallidotegmental tract, 289f Pallidothalamic connections, 431 Pallidotomy/DBS site (PVL), 429f Palmar and dorsal interossei muscles, 196f Palmar digital branches, 190f Palmar digital nerves, 194f Palmaris brevis, 196f Palmaris longus muscle, 194f PAMPs, 19f Pancreas, 204f, 285f, 461f autonomic innervation of, 230–231, 230f Panic disorder, 490–491, 490f Papez circuit, 67b, 446f Papilla, 278f Parabrachial nucleus, 288f, 290f, 355f, 367f, 444f–445f, 447f, 470f–471f, 474f Paracentral artery, 101f, 108f Paracentral lobule, 57f, 59f Paracrine signaling, 15f Paraganglion cells, 448f Parahippocampal cortex, 87f Parahippocampal gyrus, 58f, 60f, 67f, 70f, 355f, 442f, 465f, 477f–478f, 480f Parahippocampal regions, 476f Parallel fibers, 421f Paramedian midbrain syndrome, 269f Paramedian penetrating artery, 269f Paramedian reticular formation, 287f Paraneoplastic syndrome, 424b Paranode, 29f Paraolfactory gyrus, 322f Parapontine reticular formation (PPRF), 288f, 387f Parasympathetic (GVE) column, 149f

525

Parasympathetic efferent output, 458f Parasympathetic fibers, 204f, 206f–207f, 212f, 218f–219f, 222f Parasympathetic ganglion, postganglionic neuron of, 21f Parasympathetic nervous system (PsNS), 445f distribution of, 208–209, 208f in abdomen, 220 in eye, 212 in head and neck, 209 in immune system and metabolic organs, 205–206, 205f in kidneys, ureters, and urinary bladder, 234–235, 234f in kidneys and upper ureter, 235–236, 235f in limbs, 216–217, 216f in liver and biliary tract, 229–230, 229f in nasal cavity, 213–214, 213f in otic ganglia, 215–216, 215f in pancreas, 230–231, 230f in pelvic region, 233–234, 233f, 233b in pterygopalatine and submandibular ganglia, 214–215, 214f in small and large intestines, 224–225, 224f in stomach and duodenum, 222–223, 222f in tracheobronchial tree, 218–219, 218f postganglionic neurons of, 436b preganglionic neurons of, 436b Parasympathetic (vasodilation) outflow, 375f Parasympathetic postganglionic fibers, 214f Parasympathetic postsynaptic fibers, 215f Parasympathetic preganglionic fibers, 214f Parasympathetic preganglionic neurons, 403f Parasympathetic presynaptic fibers, 215f Parasympathetic terminal ending, 179f Paraterminal gyrus, 57f, 67f, 465f Paraventricular nuclei (PVN), 296, 296f–297f, 298b, 355f, 437f, 438, 439f, 441f, 444f–445f, 447f, 452f, 454f, 457f, 472f in neuroimmunomodulation, 464b regulation of, in hypothalamus, 447–448, 447f, 447b Paravermis, 291f, 420f, 426f Paravertebral anastomosis, 118f Paraxial column, 129f Parenchyma, 5f cells scattered throughout, 17f Parietal bone, 48f Parietal cortex, association areas of, 475f Parietal emissary vein, 120f Parietal lobe, 54f, 59f, 141f, 314f–319f, 339f, 399f of brain, 56f clinical point, 399b computed tomography scan of, 62f visual pathways in, 399–400, 399f Parietal neocortex, 354f Parietocingulate pathways, 345f Parietooccipital sulcus, 54f, 57f, 141f Parkinson’s disease, 352b clinical point, 428b neurotransmitter involvement in, 430–431, 430f pharmacological treatment of, 429b

526

Index

Parotid duct, 280f Parotid gland, 183f, 204f, 211f, 215f, 281f, 283f, 435f facial nerve fibers in, 280–281, 280f Paroxysmal depolarization shift (PDS), 36f Pars compacta, 427f, 431f of substantia nigra, 352, 428b Pars distalis, 152f, 296f Pars inferior, 151f Pars intermedia, 152f, 296f Pars nervosa, 152f Pars reticularis, 427f Pars reticulata, 431f Pars superior, 151f Pars tuberalis, 152f, 296f Partial depolarization, 33f Parvocellular, 431f Patent microtubules, 165f Patent vessels, 165f Pathogens, 19f phagocytosis of, 13f response to injury or, 13f Pathological nystagmus, 433b PCA. See Posterior cerebral artery PDS. See Paroxysmal depolarization shift Pectinate ligament, 389f Pectineus muscle, 199f Pedicle, 79f of L3 vertebra, 80f Pedunculopontine nucleus, 428f Pedunculopontine tegmental nuclei, 290f Pelvic nerve, 228f, 463f Pelvic splanchnic nerves, 133, 198f, 204f, 207f, 224f, 226f, 233f–238f Penis cavernous nerves of, 237f dorsal nerve of, 233f posterior nerves of, 237f Peptide synapse, 45f, 46 Perforant pathway, 468f Perforated substance, anterior and posterior, 60f Perforating cutaneous nerve, 198f Periamygdaloid cortex, 478f Periaqueductal gray, 264f–268f, 287f–288f, 293.e10f, 293.e12f, 293.e13f, 293. e14f, 306f, 355f, 371, 371f, 371b, 375f, 444f–445f, 470f–471f, 474f deep layers of, 367f Periarteriolar lymphatic sheath, 179f Periaxonal space, 22f Pericallosal arteries, 101f–102f, 108f, 111f Perichoroidal space, 388f–389f Pericranium, 119f Periglandular plexus, 227f Periglomerular cell, 480f Perineum, 180f Perineurium, 163f, 165f Periodontium, 278f Peripheral arterioles, 207f Peripheral axons, development of, 132–133, 132f Peripheral blood elements, recruitment of, 19f Peripheral cranial blood vessels, 204f Peripheral mechanisms, 375f

Peripheral nerve(s), 162–163, 448f anatomy of, 163–164, 163f classification of, 30–31, 30f compression of, 165–166 cutaneous distribution of, 181–182, 181f cutaneous receptors, 172–173, 172f degeneration of, in compression injury, 165–166 destructive lesions in, 162b interoceptors of, 174–175, 174f lemniscal sensory channels of, 169–170, 169f motor channels, 170–171, 170f neuroeffector junctions of, 179–180, 179f neuromuscular junctions of, 176–177, 176f organization of, at spinal cord, 162–163, 162f Pacinian corpuscle receptors of, 173–174, 173f reflex and cerebellar sensory channels of, 168–169, 168f somatic, 180–181 spinal nerve roots of, and related vertebrae, 166–167, 166f Peripheral nerve injury, 165–166 Peripheral nervous system (PNS), 8f, 159–238 autonomic, 208–209, 208f autonomic channels, 171–172, 171f axonal transport in, 17–18, 17f, 20–21, 20f cutaneous receptors, 172–173, 172f development of in 5 to 7 weeks, 132f in 21-­or 22-­day-­old-­embryo, 130, 130f in 24 day embryo, 131f in 26-­28 day embryo, 132f development of peripheral axons in, 132–133, 132f limb rotation and dermatomes in, 134–135, 134f neural crest, formation of, 129–130, 129f neural plate, formation of, 129–130, 129f neural proliferation and differentiation, 135–136, 135f, 142 neural tube, formation of, 129–130, 129f neurulation, 130–131, 130f somatic versus splanchnic nerve development, 133–134, 133f interoceptors of, 174–175, 174f motor channels, 170–171, 170f myelination of, 21–22, 21f neuroeffector junctions of, 179–180, 179f neuromuscular junctions of, 176–177, 176f Pacinian corpuscle receptors of, 173–174, 173f preganglionic neurons of, 208 somatic, 180–181 Peripheral neurons, 17f myelinated axon of, 22f unmyelinated axons of, 22f Peripheral neuropathies, clinical point of, 362b

Peripheral resistance, 458f Peripheral vessel, 204f Perirhinal cortex, 469f Peritoneum, 225f inferior extent of, 237f–238f Perivascular macrophage, 18f Perivascular pericyte, 11f, 18f Periventricular arcuate nucleus, 439f Periventricular hypothalamus, 446f Periventricular nucleus, 297f, 439f, 441f Peroneal nerve, 203–204, 203f Peroneus brevis muscle, 203f Peroneus longus muscle, 203f Perspiration, 456f Pes hippocampus, 70f–71f PET. See Positron emission tomography (PET) scanning Petrosal ganglion, 209 Petrosal sinuses, 121b Petrosal vein, 121f, 126f Petrous artery, 111f Petrous part, 48f pH balance, 12f Pharyngeal arch cranial nerve components, 148 Pharyngeal arches, 149f and nerves, 147f Pharyngeal branch, 357f Pharyngeal nerve, 214f Pharyngeal plexus, 209f–210f, 283f, 285f, 418f Pharyngeal wall, 418f Pharyngotympanic (auditory) tube, 378f–379f Phase contrast phenomena, 110 Phenytoin, 36f Pheromone-­linked behavior, 16f Phosphorylation, of CaMKII, 42f Phosphorylation enhances AMPAR conductance, 42f Photoreceptors, 390f, 391–392 inner segment of, 391f Phrenic ganglion, 229f Phrenic nerve, 183f–185f, 185–186, 187f, 210f clinical point, 185b pericardial branch of, 185f phrenicoabdominal branches of, 183f Pia, 82 Pia-­arachnoid mater, 486f Pia mater, 11f, 21f, 51, 51f, 82f–83f, 87f, 119f–120f, 135f Pia mater cell, 136f Pial arterial plexus, 118f peripheral branches from, 118f zone supplied by both central branches and branches from, 118f zone supplied by penetrating branches from, 118f Pial cell, 135f Pial layer, 392f Pial venous plexus, 127f PICA. See Posterior inferior cerebellar artery Pigment epithelium, 389f–390f Pigmented retina, 150f Pillar (rod) cells, 380f Pilomotor fibers, 216 Pineal gland, 57f, 66f, 71, 71f, 74f, 88f–89f, 146f, 292f, 339f, 449, 449f–450f, 449b

Index Pineal recess, 86f, 153f Piriform lobe, 480f Piriformis muscle, 198f Pituicyte processes, 454f Pituicytes, 152 Pituitary efferent pathways, 445f Pituitary gland, 57f, 59f–60f, 121f, 274f, 296f, 450f, 456f anterior clinical point, 453b hormone secretion of, 452f, 453 anterior lobe of, 296f–297f basal view of, 60f blood supply of, 451f development of, 152–153, 152f hypothalamus and, 296–297 neuroendocrine regulation of, 298b posterior, 449f, 449b clinical point, 454b hormones by, 454–455, 454f posterior lobe of, 296f–297f vascular supply to, 115–116, 115f Pituitary stalk, 273f Pituitary tumors, 453b Placebo effect, 442b Placodes, 148 Plantaris muscle, 201f–202f Plasma glucose, 461f Plasma membrane, 391f Plasma osmolality, 455f Plasticity, synaptic, 38b Platysma muscle, 279f, 281f Pluripotent stem cells, induced, 17f Polio, 84b Polysensory association cortices, 469f, 497f Polysynaptic connections, 417f Polysynaptic (flexor) reflex, 168f, 250f Pons, 56f–57f, 59f, 74f–75f, 89f, 104f, 114f, 139f, 141f, 146f, 215f, 247f, 281f, 292f, 297f, 364f–365f, 367f, 372f, 377f, 396f, 405f, 407f, 413f–414f, 417f, 441f, 462f arterial syndromes of, 269f axial anatomy of at genu of facial nerve, 262f at junction with medulla, 260b at junction with midbrain, 264f at level of facial nucleus, 261f at level of trigeminal motor and main sensory nuclei, 263f rostral, 302–303, 302f–303f clinical point, 262b lateral pontine syndrome, 263b medial inferior pontine syndrome, 260b pontine hemorrhage, 262b computed tomography scan of, 62f floor of fourth ventricle, 332f lateral reticular formation of, 288f magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f Pontine, 445f Pontine arteries, 106f branches of, 112f Pontine flexure, 139f

Pontine hemorrhage, 262b Pontine nuclei, 260f–265f, 293f, 293.e7f, 293. e8f, 293.e9f, 293.e10f, 293.e11f, 405f, 423f, 426f Pontine reticular formation, 288f, 372f Pontine taste area (parabrachial nucleus), 377f Pontine tegmentum, 300f–303f Pontine tract, 84f Pontocerebellar connections, 405f Pontocerebellar fibers, 145f Pontomedullary reticular formation, 424f Popliteus muscle, 202f nerve to, 202f Portal veins, 115f, 451f Positron emission tomography (PET) scanning, 65–66, 65f Post-­central branch, 117f Postcentral cerebral cortex, 427f Postcentral gyrus, 54f, 141f, 365f, 367f, 373f Postcentral sulcus, 54f, 141f Postchiasmatic nerve, 394f Postcommissural fornix, 67f, 444f, 465f, 468f Posterior area, 297f, 441f Posterior auricular artery, 95f, 105f Posterior auricular nerve, 279f–281f occipital branch of, 279f Posterior canal, plane of, 385f Posterior celiac branch, 222f Posterior central artery, 117f Posterior central vein, 127f Posterior cerebellar notch, 76f Posterior cerebral artery (PCA), 101f, 105f–106f, 110f–111f, 113f–114f, 116f, 269f, 304f, 306f aneurysm of, 107f in basal view, 99, 99f calcarine branches of, 113f compression of, 52f lateral and medial views of, 108 P1 segment, 106f P2 segment, 106f parieto-­occipital branches of, 111f, 113f posterior temporal branches of, 111f, 113f territory of, colored illustration, 109–110, 109f Posterior chamber, 393f of eye, 388f Posterior cingulate cortex, 478f, 488f Posterior clinoid process, 48f Posterior column syndrome, 248f Posterior columns, 248f Posterior commissure, 57f, 71f, 89f, 292f–293f at level of midbrain-­diencephalon junction, 268f Posterior communicating artery, 99f–101f, 105f–106f, 108f, 111f–115f, 451f aneurysm of, 107f Posterior cranial fossa, arteries of, 112f Posterior cutaneous nerve, 133f Posterior ethmoidal artery, 49f meningeal branch of, 95f Posterior ethmoidal foramen, 49f Posterior ethmoidal nerve, 49f, 274f, 276f Posterior ethmoidal vein, 49f Posterior external venous plexus, 127f

527

Posterior femoral cutaneous nerve, 181f, 201f Posterior fossa, dura of, 374f Posterior fossa hematoma, 52f Posterior hepatic plexus, 229f Posterior horn, 86f of lateral ventricle, 66f, 70f–71f nucleus proprius, 240f of right lateral ventricle, 112f Posterior (dorsal) horn interneurons, 405f, 411f, 413f Posterior hypothalamic area, 268f, 437f, 440f Posterior inferior cerebellar artery (PICA), 99f, 101f, 105f, 112, 112f–114f, 116f–117f, 269f aneurysm of, 107f syndrome, 269f Posterior inferior nasal branch, 357f Posterior intercostal arteries, 116f, 118f dorsal ramus of, 118f Posterior internal venous plexus, 127f Posterior interosseous nerve, 192f Posterior lateral choroidal arteries, 100f, 112f–113f Posterior lateral nasal nerves, 209f Posterior limb, 407f–408f of internal capsule, 66f, 308f, 405f, 439f–440f Posterior limiting lamina (Descemet’s membrane), 389f Posterior lobe, 115f, 420f, 451f–452f, 454f of pituitary, 437f, 441f veins, 115f, 451f Posterior medial choroidal artery, 100f to choroid plexus of 3rd ventricle, 112f Posterior median sulcus, 88f Posterior meningeal artery, 49f Posterior meningeal vessels, sulcus of, 48f Posterior mesencephalic vein, 123f, 126f Posterior nasal nerves, 214f Posterior orbitofrontal cortex, 444f Posterior perforated substance, 60f Posterior pericallosal artery, 108f, 113f Posterior pericallosal vein, 123f Posterior pillar, 418f Posterior pituitary, 445f–447f Posterior pulmonary plexuses, branches to, 217f Posterior radicular arteries, 116f–118f Posterior radicular vein, 127f Posterior ramus, of brain, 54f Posterior semicircular canal, 379f, 385f Posterior semicircular duct, 379f ampulla of, 282f Posterior septal vein, 123f Posterior spinal arteries, 99f, 101f, 116f–118f, 117–118, 245f anastomotic loops to, 116f in cross section, 118f Posterior spinal vein, 126f–127f Posterior (dorsal) spinocerebellar tract, 84f Posterior superior alveolar nerves, 213f Posterior superior nasal nerves, 213f Posterior temporal diploic vein, 120f Posterior terminal (caudate) vein, 122f–124f Posterior vagal branch to lesser curvature, 221f

528

Index

Posterior vagal trunks, 220f–222f, 225f–226f, 229f–230f, 234f celiac branch of, 223f celiac branches of, 225f–226f Posterolateral fissure, 76f Posterolateral funiculus, 371f Posterolateral thalamic syndrome, 72b Posteromedial central arteries paramedian, 106f perforating, 106f Postganglionic axons, 132 autonomic classification of, 30f myelination of, 21 Postganglionic fibers, 231f Postganglionic parasympathetic cholinergic nerve fibers, 207f Postganglionic parasympathetic fibers, 205f, 213f Postganglionic parasympathetic neurons, 436b Postganglionic sympathetic fibers, 205f, 213f, 370f Postganglionic sympathetic neurons, 132f, 436b Postlunate fissure, 76f Postnatal neurogenesis, 143f Postotic somites, 147f Postsynaptic cell, 38f Postsynaptic inhibition, 32–33, 32f Postsynaptic membrane, 25f, 38f, 176f–177f Postsynaptic neuron, 26f, 36f, 354f Postsynaptic receptor, 40f Posttraumatic stress, 491–492, 491f neurological involvement in, 491 Potassium channel, 36f PPRF. See Parapontine reticular formation Preaortic ganglia, 232f Preaortic sympathetic ganglion, 131f Precentral cerebral cortex, 427f Precentral gyrus, 54f, 141f, 373f Precentral sulcus, 54f, 57f, 59f, 141f Precentral vein, 126f Prechiasmatic sulcus, 48f Precommissural fornix, 67f, 432f, 444f, 465f, 468f, 473f Preculminate vein, 126f Precuneal artery, 108f Precuneus, 57f Prefrontal area, 442f Prefrontal cortex, 443f, 470f–472f, 477–478, 477f–478f, 488f dorsolateral, 477–478 ventromedial (orbitofrontal), 477 Prefrontal lobe, 345f Prefrontal neocortex, 354f Preganglionic autonomic neuron, Boutons of association neurons synapsing with, 21f Preganglionic cholinergic nerve fibers, 231f Preganglionic neurons, autonomic, 8 classification of, 30f clinical point, 8b Preganglionic parasympathetic fibers, 205f, 213f Preganglionic parasympathetic neurons, 436b

Preganglionic sympathetic axon, 464f Preganglionic sympathetic fibers, 205f, 213f, 370f Preganglionic sympathetic neurons, 162f, 171f, 436b Preganglionic vagal efferents, 464f Pre-­laminar branch, 117f Prelaminar layer, 392f Premolars, 278f Premotor cerebral cortex, 411f Premotor cortex, 55f Premotor lobe, 345f Preoccipital notch, 54f Preoptic area, 355f Preoptic hypothalamic areas, 290f Preoptic nuclei, 437f Preotic somitomeres, 147f Prepontine cistern, 91f Prepyramidal fissure, 76f Pressure gradients, nerve compression and, 164–165 Presubiculum, 486f Presynaptic autoreceptor, 40f Presynaptic GABAergic neuron, 26f Presynaptic inhibition, 32–33, 32f, 363, 363f Presynaptic membrane, 25f, 38f, 176f Presynaptic neuron, 26f, 354f Presynaptic receptor, 45f Presynaptic terminal, 42f–43f Pretectal nucleus, 397f Pretectum, 212f, 268f, 293.e14f, 396f Prevertebral ganglion, 463f Primary afferents, somatosensory, 369 Primary auditory cortex, 55f, 469f, 497f Primary brainstem lesion, 499f Primary fissure, 76f, 291f–292f, 423f Primary hypophyseal portal system, 115b Primary motor cortex, 55f, 59f, 407f–408f, 411f Primary sensory axon, 168f in taste pathways, 377 Primary sensory cell body, 168f Primary sensory cortex neurons, 169f Primary sensory cortices, 469f, 497f Primary sensory neuron cell body, 168f Primary sensory neurons, 169f Primary somatosensory cortex, 55f, 469f, 497f Primary somatosensory unmyelinated afferents (C fibers), 368 Primary trigeminal region, of motor cortex, 55f Primary visual cortex, 37f, 55f, 59f, 61f, 469f, 497f basal surface of, 61f Primitive streak, 130f Principal mammillary fasciculus, 440f Principal neurons, 366f Principal sensory nucleus of trigeminal nerve, 373f Principal sensory trigeminal nucleus, 372f Procerus muscle, 279f Progesterone, 452f Progressive neuronal degeneration, in cerebellum, 423b Progressive synaptic dysfunction, slow, chronic inflammation with, 19f

Projection cells of layer V, 341f Projection fibers, of cerebral cortex, 343f color imaging of, 347–349, 347f neuronal origins of, 344 Projection neurons, 8 Prolactin (LTH), 452f, 453 Promontory, 378f Pronator quadratus muscle, 194f Pronator teres muscle, 194f Proper dorsal digital nerves, 203f Proper palmar digital branches, 190f Proper palmar digital nerves, 196f Proprioception, 362f, 365f dorsal column system and, 365f in trigeminal sensory system, 372f Proprioceptive fibers, 184f, 250f Prosencephalization, 139b Prosencephalon at 28 days, 137, 137f, 137b at 36 days, 138, 138f Prosopagnosia, 495b Prostatic plexus, 233f–234f, 236f–237f Protein, dietary, in mood and affective behavior, 46b Proteinopathy, intrinsic, response to, 16f, 19 Proteomics, 9f Protoplasmic astrocytes, 12 Proximal cerebral arteries, 374f Proximal subclavian artery, 97f Pseudobulbar palsy, 256b PsNS. See Parasympathetic nervous system Psoas major muscle, 197f–199f Psoas muscles, muscular branches to, 197f Psychiatric disorders, 352b Pterygoid canal, nerve of, 213f–214f, 276f, 279f, 283f, 357f, 377f Pterygoid plexus, 98f Pterygomandibular raphe, 50f Pterygopalatine fossa, 50f lateral posterior superior nasal branches in, 213f medial posterior superior nasal branches in, 213f pterygopalatine ganglion in, 213f Pterygopalatine ganglion, 147f, 204f, 209f, 210, 211f, 214f, 279f, 281f, 283f, 357f, 377f, 435f autonomic innervation through, 213 ganglionic branches and, 276f Pterygopalatine nerves, 209f Ptosis, 157f Pudendal nerve, 198f, 224f, 233f–234f, 236f–238f Pulmonary MALT, 205f, 464f Pulmonary plexus, 218f, 221f, 285f thoracic vagal branches to, 217f Pulsating exophthalmos, 98f Pulvinar, 60f, 66f, 71f–72f, 74f, 88f, 100f, 122f, 268f, 292f–293f, 295f, 308f–310f, 312f, 396f caudal, in coronal section of forebrain, 336f–337f Pupillary constrictor muscle, 211f Pupillary dilator muscle, 211f Pupillary light reflex, 209b, 212, 212f, 397–398, 397f

Index Pure autonomic failure, 204b Purinergic receptor regulated channels, 13f Purkinje cell, 77f, 421f–422f, 425f axon, 421f dendrites of, 421f neurons, 421–422, 421f–422f Purkinje cell layer, 77f Purkinje cell neurons, 8b Purkinje neurons, 5f Pus, 93f Putamen, 66f, 87f, 104f, 308f–313f, 322f–329f, 331f, 343f, 346f, 354f–355f, 405f, 427f–428f, 438f–440f, 471f, 491f, 496f magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f PVL. See Pallidotomy/DBS site PVN. See Paraventricular nuclei Pyramid(s), 75f, 89f, 141f, 144f–145f, 154f, 255f–260f, 293.e1f, 293.e2f, 293.e3f, 293.e4f, 293.e5f and anterior corticospinal fibers, 145f decussation of, 75f, 145f, 255f–256f, 292f–293f, 293.e2f ipsilateral, clinical point in, 75b Pyramidal cell, 4, 8f of hippocampal formation, 466 Pyramidal cell neurons efferent connections of, 344f sensitivity of, to damage, 69 types of, 341f Pyramidal cells, 341f Pyramidal decussation, 89f Pyramidal neuron, 170f Pyramidal process of palatine bone, 50f Pyramidal tract, 84f, 348f Pyramidal tract syndrome, 75b Pyramids, 405f–406f, 411f decussation of, 371f, 405f, 408f

Q Quadrangular lobule, 76f Quadratus femoris, nerve to, 198f Quadratus lumborum muscle, 197f Quadratus plantae muscle, 202f Quadriceps femoris, 199f Quadrigeminal bodies, development of, 139 Quantal release, neurotransmitter, 40

R Radial glia, 12 Radial glial cells, 142f Radial glia-­like cells (B cells), 16f Radial nerve, 181f, 187f, 191f, 193f–194f cutaneous innervation from, 192f dorsal digital branches, 190f in forearm, 192–193, 192f superficial branch of, 190f, 192f Radicular arteries, 23 in cross-­section of spinal cord, 118 Radiolabeled marker, 9f Rami communicans, 82f–83f, 186f Raphe dorsalis, 351, 351f Raphe magnus, 351, 351f

Raphe nuclei, 154f, 260f, 287f–288f, 290f, 293.e7f, 293.e10f, 371f, 427f, 470f–471f, 486f–490f Raphe obscurus, 351f Raphe pallidus, 351f Raphe pontis, 351f Rapid inflammatory response, 19f Rapsyn, 178f Rathke’s pouch, 152f Receptors cochlear, 381–382, 381f cutaneous, 172–173, 172f photo, 391–392, 391f somatosensory, 363f taste sensory, 376–377, 376f vestibular, 385–386, 385f Reciprocal signaling, 15f Reciprocal synapse, 7f “Recovered memory”, 468b Recruitment by convergence, 369f Rectal plexus, 226f, 234f Rectosigmoid artery, 226f Rectosigmoid plexus, 226f Rectus abdominis muscle, 186f Rectus capitis anterior muscles, 183f Rectus capitis lateralis, 183f Rectus femoris muscle, 199f Recurrent artery (of Heubner), 99f–102f, 106f, 108f Recurrent excitatory circuit, 34f Recurrent inhibition, 363, 363f of tendon organ reflex, 251f Recurrent inhibitory circuit, 34f Recurrent laryngeal nerves, 210f, 221f, 418f Recurrent meningeal branch, 206f Recurrent process, 480f Red blood cell, 18f Red nucleus, 60f, 144f–145f, 266f–269f, 271f–272f, 293.e12f, 293.e13f, 297f, 306f, 397f, 404f–405f, 411f, 424f, 426f, 430f, 441f Reflex connections, 171f Reflex evaluation, 202b Reflex pathways autonomic, 206–207, 206f somatic, in gray matter, 251–252 Reflex signs, 189f Reflex sympathetic dystrophy (RSD), 370, 370b Regressing cells, 151f Reissner’s membrane, distort, 381f Releasing factor, 445f Remodeling, synaptic, 38b Renal artery, 222f, 235f–236f Renal ganglia, 231f, 234f–237f Renal plexus, 234f–236f Renin, 459f Renshaw cell bias, 251f, 363, 363f Renshaw interneuron, 8f Repolarization, 24f Repolarizing (K+) current, 28f Respiration, central control of, 417–418, 417f clinical point, 417b Respiratory centers, 456f Respiratory nuclei, 287f–288f “Resting” microglia, 13f

529

Resting potential, neuronal, 23–24, 23f Resting state, of neuron, 33f Reticular formation (RF), 145f, 259f–260f, 265f, 287–288, 293.e5f, 293.e11f, 297f, 355f, 382f, 384f, 396f, 405f, 441f, 443f–444f, 471f afferent and efferent connections to, 289–290, 289f noradrenergic neurons in, 350 nuclei of, in brainstem and diencephalon, 288–289 pattern of nuclei in brainstem, 287–288 sleep-­wakefulness control in, 290–291, 290f Reticular layer, 175f Reticular nucleus, 295f, 426f Reticulocerebellar tract, 423f Reticulospinal pathways, 413–414, 413f Reticulospinal tracts, 245f–246f, 415f, 433b lateral (medullary), 241f–244f medial (pontine), 241f–244f Retina, 37f, 390–391, 392f–393f, 444f axons at surface of, 390f ciliary part of, 388f–389f clinical point, 390b cerebrovascular disease in, 393b complex arrays of synapses in, 7b as derivative of CNS, 137b inner plexiform layer of, 7f left, projection on, 398f and optic nerve, 392–393, 392f optic part of, 388f–389f photoreceptors of, 391–392, 391f Retinal artery, 393f Retinal fibers, 394f Retinal nerve fibers, 392f topography of, 392f Retinal vein, 393f Retino-­geniculo-­calcarine pathway, 398–399, 398f Retinohypothalamic pathway, 444f Retrograde, 9f Retrolaminar layer, 392f Retromandibular (posterior facial) vein, 98f, 174f Retrosplenial cortex, 477f Retrotonsillar fissure, 76f Reverse transcribe mRNA to cDNA, 9f RF. See Reticular formation Rhinal sulcus, 58f, 60f Rhomboid fossa, of 4th ventricle, 74f Rhomboideus major muscle, 191f Rhomboideus minor muscle, 191f Rhombomeres, 149f Ribosomes, 4f Right 6th thoracic sympathetic trunk ganglion, 222f Right adrenal plexus, 220f Right anterior cerebral arteries, 96f, 108f, 111f Right anterior inferior cerebellar arteries, 96f Right aorticorenal ganglion, 220f, 226f Right ascending pharyngeal artery, 96f Right carotid sinus, 96f Right cerebral hemisphere, 140f medial surface of, 140f Right colic artery, 225f–226f

530

Index

Right colic plexus, 225f–226f Right common carotid artery, 96f, 185f Right costocervical trunk, 96f Right deep cervical artery, 96f Right deep temporal artery, 96f Right external carotid artery, 96f Right facial artery, 96f Right gastric artery, 222f–223f, 225f Right gastric plexus, 223f, 225f Right gastroepiploic artery, 222f Right greater splanchnic nerve, 221f, 226f Right greater thoracic splanchnic nerves, 217f, 220f, 222f–223f, 229f–230f Right hypogastric nerves, 226f, 233f Right inferior hypogastric (pelvic) plexus, 226f, 233f Right inferior phrenic arteries, 220f, 223f, 226f Right inferior phrenic plexus, 220f, 223f, 226f Right inferior thyroid artery, 96f Right internal carotid artery, 96f, 108f Right internal iliac artery, 226f Right internal iliac plexus, 226f Right internal thoracic artery, 96f Right interventricular canal, 153f Right lateral ventricle, 86f–87f, 153f Right least splanchnic nerves, 226f Right lesser splanchnic nerves, 226f Right lesser thoracic splanchnic nerves, 217f, 220f, 222f Right lingual artery, 96f Right lowest thoracic splanchnic nerve, 217f, 220f, 222f Right maxillary artery, 96f Right middle cerebral arteries, 96f Right middle meningeal artery, 96f Right occipital artery, 96f Right olfactory lobe, opening of cavity of, 140f Right ophthalmic artery, 96f Right optic stalk, opening of, 138f Right optic vesicle, opening of, 137f Right pericardiacophrenic artery, 185f Right phrenic nerve, 185f, 220f, 229f Right plexus, 220f Right posterior auricular artery, 96f Right posterior cerebral arteries, 96f, 108f parieto-­occipital and calcarine branches of, 112f Right posterior communicating artery, 96f Right posterior inferior cerebellar arteries, 96f inferior vermian branches of, 113f Right posterior pericallosal artery, 112f Right posterior spinal artery, 118f Right pulvinars, 112f Right recurrent laryngeal nerve, 221f, 285f Right renal artery, 220f Right renal plexus, 220f Right rubrospinal tract, 415f Right sacral plexus, 226f Right subclavian artery, 96f, 185f Right superficial temporal artery, 96f Right superior cerebellar arteries, 96f Right superior laryngeal artery, 96f Right superior thyroid artery, 96f

Right sympathetic trunk, 217f, 220f, 230f, 233f sacral part of, 220f Right telencephalic vesicle opening of, 138f Right temporal hemorrhage, 499f Right temporal tumor, EEG, 35f Right testicular artery, 220f Right testicular plexus, 220f Right thalamostriate vein, 87f Right thalamus, 126f Right thyrocervical trunk, 96f Right ureter, 220f, 233f Right ureteral plexus, 233f Right vagus (X) nerve, 185f, 217f Right vertebral arteries, 96f anterior meningeal branch of, 96f posterior meningeal branches of, 96f Rigidity, 430f Ring finger, 180f Risorius muscle, 279f, 281f RNA strand, 9f Rod, 390f Roof plate, 144f, 154f Root, of teeth, 278f Root (central) canals, containing vessels and nerves, 278f Rostral limb, 386f Rostral raphe nuclei, 474f, 500f Rostral spinocerebellar tract (RSCT), 241f, 364f, 423f Rostral thalamus, 328f–329f Rostral ventrolateral medulla (RVLM) nuclei, 288f Rostrum, 58f Rotational nystagmus, 433b Rough endoplasmic reticulum, 4f Round (cochlear) window, 378f–379f RSCT. See Rostral spinocerebellar tract RSD. See Reflex sympathetic dystrophy Rubromedullary fibers, 411f Rubrospinal tract, 84f, 241f–246f, 411–412, 411f, 415f clinical point, 433b Ruffini terminals, 172f Rufinamide, 36f

S SA node, 458f Saccular aneurysms, 106b Saccule, 151f, 282f, 378f–379f, 385f plane of, 385f Sacral cord, 224f Sacral foramen, 80f Sacral nerve 1st, 81f 5th, 81f Sacral nerves, 166f Sacral parasympathetic nucleus, 244f, 246f Sacral plexopathies, 198b Sacral plexus, 198–199, 198f, 233f–238f Sacral spinal cord, 435f clinical point, 244b, 247b gray matter organization in, 241–242 Sacral splanchnic nerves, 198f, 224f, 234f, 236f

Sacral sympathetic trunk, 216f, 226f Sacrum, 79f arteries surrounding spinal cord and, 116f Salivary glands, 207f Salivation, autonomic regulation of, 211b Salivatory nuclei, 211b, 435f superior and inferior, 271f–272f Salpingopharyngeus muscle, 285f Saltatory conduction, 14, 21, 28 Saphenous nerve, 181f, 199f, 202f infrapatellar branch of, 199f medial crural cutaneous branches of, 199f Sarcolemma, 176f–177f folds of, 176f Sarcoplasm, 176f–177f Sartorius muscle, 199f Satellite cells, 8, 8f, 21f “Satiety center”, 460f SCA. See Superior cerebellar artery Scala tympani, 378f–380f Scala vestibuli, 378f–380f Scalene, 183f Scalenus anterior muscles, 184f Scalenus medius muscles, 184f Scapular nerve, 191–192, 191f SCG. See Superior cervical ganglion Schaffer collaterals, 467f Schizophrenia, 488–489, 488f Schlemm’s canal. See Scleral venous sinus Schwalbe’s line, 389f Schwann cell, 479f Schwann cell cap, 179f Schwann cell process, 176f Schwann cell sheaths, 163 Schwann cells, 8, 8f, 172f, 176f–177f myelination of axons by, 21 Schwannoma, acoustic, 282b Sciatic nerve, 201f peroneal segment of, 201f tibial segment of, 201f Sclera, 150f, 388f–389f, 392f–393f lamina cribrosa of, 388f Scleral spur, 388f–389f Scleral venous sinus (Schlemm’s canal), 388f–389f, 393f SCO. See Subcommissural organ Sebaceous gland, 172f, 175f 2nd lumbar spinal nerve, 236f 2nd lumbar splanchnic nerve, 234f 2nd lumbar sympathetic trunk ganglion, 233f 2nd thoracic sympathetic trunk ganglion, 219f Second order neuron, 375f, 461f Secondary (postpyramidal) fissure, 76f Secondary sensory neurons, 168f–169f Secondary somatosensory cortex, 55f Secretory product, axonal transport of, 454f Seizures origin and spread of, 34–35, 34f types of electrical discharges in, 36–37, 36f Sella turcica, 48f Semicircular canals, 151f clinical point of, 379b Semicircular ducts, 378f Semimembranosus muscle, 201f Seminal vesicle, 233f

Index Semitendinosus muscle, 201f Sensory (recording electrodes), 31f Sensory analysis, 345f Sensory association inputs, 470f Sensory axons, myelination of, 21 Sensory cells, from neural crest, 132f Sensory channels lemniscal, 169–170, 169f reflex and cerebellar, 168–169, 168f Sensory cortex, 340f, 366f, 377f Sensory cortices, 476f Sensory fibers, 184f Sensory ganglion of X, 448f Sensory input, 290f Sensory loss, 189f Sensory nerves, 175f Sensory neuroblast, 133f Sensory neuron, 8f cell body, 21f primary, 8 Sensory pathway, 408f Sensory systems, 359–400 auditory, 378–379 bony and membranous labyrinths, 379–380, 379f somatosensory, 362–363 taste, 376–377, 376f trigeminal, 372–373, 372f visual, 388–389 Septal area, 438f, 480f Septal nuclei, 67f, 288f, 289, 353, 355f, 443f, 445f, 465f, 468f, 470f–475f, 473, 480f afferent and efferent connections of, 289f, 473–474, 473f central cholinergic neurons of, 353 cholinergic neurons of, 473b and long-­term traces, 473b Septum, 444f, 479f Septum pellucidum, 57f, 66f–67f, 70f–71f, 102f, 112f, 122f, 144f, 296f–297f, 312f–315f, 322f–325f, 327f, 437f–439f, 441f, 465f Sequence, 9f Serial synapse, 7f Serosa, 228f Serotonergic neurons, 287 Serotonergic pathways, in brainstem and forebrain, 351–352, 351f clinical point, 351b Serotonin, synapse, 45f, 46 Serotonin-­specific reuptake inhibitors, 351b Serous cells, 179f Serratus anterior muscle, 186f 7th intercostal nerve, 222f Severe acute compression, 165f Severe chronic compression, 165f Sex steroid hormones, and brain development, 439b Sex steroids, 453b Sexual behavior, and ventromedial nucleus, 439b SGZ. See Subgranular zone Shingles, 433b Shivering, 456f

Short ciliary nerves, 209f, 212f, 274f–276f, 397f Short circumferential penetrating artery, 269f Short gastric arteries, 222f Short gyri, 54f Short hypophyseal portal veins, 115f, 451f Short palpebral fissures, 157f Short posterior ciliary artery, 392f–393f Short shuffling gait, 430f Short-­term memory, 466 Shoulder, 408f Sigmoid arteries, 226f Sigmoid colon, nerves from inferior hypogastric plexuses to, 233f Sigmoid plexuses, 226f Sigmoid sinus, 49f, 121f, 125f sulcus of, 48f “Silent lesions”, 346b Simple synapse, 7f Simplex lobule, 76f Single-­cell RNA sequencing (scRNA-­seq), 9f Single stimulus, 34f Sinus with squamous plug, 155f Sinuses, confluence of, 121f–122f, 125f–126f, 126b Skeletal muscle, 162f, 168f, 170f, 208f, 362f, 422f, 426f Skeletal muscle fibers, 402f Skin, 17f, 51f, 119f, 452f arrector pili muscles of, 162f peripheral nerves in, 175–176, 175f Skin ligaments (retinacula cutis), 175f Skin lymphoid tissue, 464f Skull, 47–52 base of, 166f foramina in, 49–50, 49f interior view of, 48–49, 48f bony framework of, 50–51, 50f computed tomography scan of, 62f defects of, 156f fractures of, 95 hematoma and, 52, 52f meningeal arteries and relationship to, 95–96, 95f meninges and, 51–52, 51f sulci of, 95 Sleep hypothalamic regulation of, 462–463, 462f reticular formation associated with, 290 Sleep-­wake cycle, hypothalamic regulation of, 438b Slow anterograde axonal transport, 17f, 20f Slow axonal transport, 20f Small arteries, 458f Small arterioles, 458f Small emissary vein, 49f Small intestine, 285f innervation of, autonomic, 224–225, 224f nerves of, 225–226, 225f Small myelinated (M) axons, 362 Small myelinated nerve fibers (A delta fibers), 368 Small pyramidal association cell, 341f Small pyramidal cell, 342f, 344f, 411f Smooth muscle, 179f vascular, 210

531

SNARE complex, 40f SNS. See Sympathetic nervous system Soft palate, 418f Soleus muscle, 201f–202f Solitarius, 470f Solitary tract, rostral part of nucleus of, 377f Solitary tract nucleus, 145f, 219f, 235f, 272f, 283, 283f, 285f, 405f Soma (cell body), 4f Somatic afferents, 448f Somatic efferents, 373f Somatic nervous system brachial plexus, 187–188, 187f cervical plexus in situ, 183–184, 183f cutaneous nerves of head and neck in, 182–183, 182f dermatomal distribution of, 180–181, 180f development of, 133–134, 133f lower limb innervation obturator nerve, 200–201, 200f peroneal nerve, 203–204, 203f sciatic and posterior femoral nerves, 201–202, 201f tibial nerve, 202–203, 202f lumbar plexus, 197–198, 197f phrenic nerve, 185–186, 185f sacral and coccygeal plexuses in, 198–199, 198f thoracic nerves in, 186–187, 186f upper limb innervation median nerve, 194–195, 194f scapular, axillary, and radial nerves, 191–192, 191f ulnar nerve, 196–197, 196f Somatic reflex pathways, in spinal cord, 251–252, 363–364, 363f Somatic sensory neuron, 22f Somatomotor (GSE) column, 149f Somatopleure, 133 Somatosensory afferents, to spinal cord, 362–363, 362f Somatosensory area, 442f Somatosensory cortex, 55f, 59f, 477f Somatosensory systems, 362–363 descending control of ascending, 371–372, 371f dorsal column and epicritic modalities in, 365–366, 365f neuronal organization of dorsal column and thalamic nuclei, 366–367, 366f neuropathic pain mechanisms in, 370–371, 370f primary afferents in, 362b spinal reflex in, 363–364 spinocerebellar, 364–365, 364f spinothalamic and spinoreticular, 367f, 369–370, 369f and protopathic modalities, 367, 367f Somatostatin, 207, 439b Somites, 129f, 148 primordia, 147f SON. See Supraoptic nucleus Sound reception, peripheral pathways for, 378–379, 378f Sound transduction, 378 clinical point, 378b

532

Index

Sound waves, 381f in organ of Corti, 380 Spastic bulbar palsy, 256b Spatial and episodic memory, 16f Spatial excitatory summation, 33–34, 33f Spatial visual pathway, 399f Specialized ending, 8f Sphenoid bone, 48f, 50f spine of, 50f Sphenoid sinus, 152f Sphenopalatine foramen, 50f Spheno-­palatine ganglion, 98f Sphenoparietal sinus, 121f Sphincter ampullae, 229f Sphincter muscle of pupil, 389f Sphincter of pupil, 212f Sphincter pupillae muscle, 275f Sphincter urethrae, 236f Spina bifida, 130b, 155 Spina bifida aperta, 155f Spina bifida occulta, 155f Spinal accessory nucleus, 241f Spinal arteries, anterior and posterior, 117–118, 117f Spinal border cells, 423f Spinal branch, 118f Spinal column bony anatomy of, 79–80 longitudinal growth of, 166b Spinal cord, 78–84, 129f, 131f–132f, 137f– 139f, 141f, 146f, 149f, 153f, 213f, 231f, 235f, 239–253, 290f, 354f, 366f, 371f, 405f, 408f, 417f, 446f, 448f in 3 months, 135f afferent and efferent connections in, 289f afferent input to, 411f afferents to, 289f anterior (ventral) view of, 82, 82f arterial blood supply to cross-­sectional view, 118, 118b, 119f longitudinal view, 116–117, 116f ascending sensory fibers from, 348f body of, 79f C7, 79f, 81f central branches to left side of, 118f central branches to right side of, 118f central canal of, 89f cervical enlargement of, 139f, 403f cervical part of, 411f–412f, 423f comparison of, at 5.5 weeks and adult, 144–145, 144f cross-­sectional anatomy of, 244f–246f in situ, 83–84, 83f defective, 155, 155f descending tracts in, 218f development of, 148 fiber tracts of, 84f gray matter of, 84, 240–241, 403f at cervical level, 241–242 at lumbar level, 241–242 at sacral level, 241–242 at thoracic level, 241–242 gross anatomy in situ, 81–82, 81f L1, 79f, 81f L5, 79f, 81f

Spinal cord (Continued) levels of, 84, 84f, 84b lower motor neuron distribution in, 403–404, 403f lower motor neuron organization and control in, 250–251 lumbar enlargement of, 403f lumbar part of, 236f, 386f, 411f–413f, 423f lumbosacral enlargement of, 139f magnetic resonance imaging of, 63f sagittal views, 247 marginal zone of, 241f–246f meninges, 82, 82f motor and preganglionic autonomic nuclei in, development of, 148f, 149–150 nuclei of medullary junction with, 288f posterior (dorsal) view of, 82, 82f S1, 81f sacral part of, 207f, 463f sacral point of, 236f secondary sensory processing in, 240b somatic reflex pathways in, 251–252, 363–364, 363f somatosensory afferents to, 362–363, 362f spinal roots, 82f T1, 79f, 81f T2-­weighted magnetic resonance imaging of, 64f T12, 79f, 81f thoracic part of, 206f, 212f, 230f, 463f thoracolumbar part of, 207f venous drainage of, 127, 127f ventral horn, 404f white matter of, 84, 241 Spinal cord infarct, 23 Spinal cord injury, 17f Spinal cord neuron., 5f Spinal cord syndromes, 248–249 Spinal cord ventral horn, 5f Spinal dorsal root ganglion, unipolar sensory cell of, 8f Spinal dura mater, 81f Spinal ganglia C1-­3, 374f Spinal ganglion, 186f, 206f, 235f–236f Spinal input, 423f Spinal intermediolateral cell column, descending tract to, 457f Spinal lemnisci, 145f Spinal muscular atrophy, 9 Spinal nerve, 82f–83f, 83, 463f 1st (C1), 284f 2nd (C2), 284f 3rd (C2), 284f 4th (C2), 284f Spinal nerve roots, 166–167, 166f relationship to vertebrae, 166–167, 166f Spinal nerve trunk, 186f Spinal nerves, ventral rami of, 197f Spinal ramus, 117f Spinal reticular zone, 240f, 403f Spinal sensory (dorsal root) ganglion, 230f Spinal shock syndrome, 244b Spinal somatic reflex pathways, 251–252 Spinal tap, 81b

Spinal tract and nucleus of trigeminal nerve, 373f Spinal trigeminal nucleus, 371f–372f Spinal trigeminal tract, 371f–372f Spinocerebellar pathways clinical point, 364b in somatosensory system, 364–365, 364f Spinocerebellar tracts, 168f, 426f Spinocervical tract, 365f Spino-­olivary tract, 84 Spinoreticular pathway, 371f Spinoreticular tract, 255f–268f, 293.e1f, 293. e2f, 293.e3f, 293.e4f, 293.e5f, 293. e7f, 293.e8f, 293.e9f, 293.e10f, 293. e11f, 293.e12f, 293.e14f Spinothalamic and spinoreticular tracts, 84f, 362f, 369f clinical point, 368b sensory processing in spinal cord, 369–370, 369f somatosensory systems of, 367f, 369–370, 369f Spinothalamic tract, 145f, 169f, 255f–269f, 293.e1f, 293.e2f, 293.e3f, 293.e4f, 293.e5f, 293.e7f, 293.e8f, 293.e9f, 293.e10f, 293.e11f, 293.e12f, 293. e14f Spinothalamic/spinoreticular anterolateral system, 241, 241f–246f damage to, 242b Spinothalamic/spinoreticular system, 367f Spinous process, 79f, 83f of L4 vertebra, 80f Spiny granule cell neuron, 341f Spiral ganglion, 380f, 382f Spiral ligament, 380f Spiral organ (Corti), 380f Spiral (helical) scanners, 62 Splanchnic nerves, 132f–133f, 162f, 205f, 217–218, 217f, 228f, 435f development of, 133–134, 133f Splanchnopleure, 133 Spleen, 205f, 464f immunocytes in marginal zone of, 5f Splenic artery, 222f–223f, 229f–230f Splenic contraction, 463f Splenic plexus, 223f Splenium, 69f of corpus callosum, 58f, 60f, 68f, 310f– 313f, 315f, 339f, 347f in axial (horizontal) section, 314–315, 314f–315f in coronal section, 338–339, 338f–339f in sagittal view, 347f “Split-­brain” surgery, 326b Spurling maneuver, 189f Squamous part, 48f Stalk, 115f, 451f Stapedius muscle, 281f, 384f nerve to, 279f Stapes in oval (vestibular) window, 379f Stellate cell neuron, 341f Stem cells in CNS, intrinsic and extrinsic mechanisms of, 16–17, 16f therapy, 17–18, 17f

Index Stereocilia, 385f Stereotactic frame, 429f Stereotactic needle guide, 429f Sternocleidomastoid muscle, 183f–184f, 284f Sternohyoid muscle, 183f–184f, 286f Sternothyroid muscle, 183f–184f, 286f Stimulus current, 27f STN. See Subthalamic DBS site Stomach, 204f, 461f and duodenum, innervation of, autonomic, 222–223, 222f hunger contractions in, 460f principal anterior vagal branch to lesser curvature of, 221f vagal branch from hepatic plexus to pyloric part of, 223f vagal branch to fundus and body of, 221f Stomodeum, 152f Stooped posture, 93f Strabismus, 157f Straight gyrus, 60f Straight sinus, 57f, 122–123, 122f–126f Stratum basale, 175f Stratum corneum, 175f Stratum granulosum, 175f Stratum lucidum, 175f Stratum spinosum, 175f Stress, chronic, 44f Stretch receptors, 218f Stretch reflex, 251, 251f central control of, 253 clinical point, 253b Stria medullaris, 67f, 71f, 465f Stria medullaris thalami, 443f, 473f Stria terminalis, 67f, 67b, 70f–71f, 71, 87f, 140f, 332f, 443f–446f, 465f, 470f–474f bed nucleus of, 289f, 355f, 432f, 474–475, 474f, 476f, 490f–491f Striae medullares, 88f Striatal projection, 427f Striated muscle, 207f somatic, 8f voluntary, 8f Striatopallidal connections, 431 Striatum, 352f, 427, 471f, 477f, 488f–490f, 500f efferents to, 289f Stroke volume, 458f Strokes, types of, 103–104, 103f, 103b Styloglossus muscle, 286f Stylohyoid ligament, 50f Stylohyoid muscle, 183f, 279f nerve to posterior belly of digastric muscle and to, 280f Styloid process, 50f Stylomandibular ligament, 50f Stylomastoid foramen, 279f, 281f, 283f main trunk of facial nerve emerging from, 280f Stylopharyngeus muscle, 283f, 285f Stylopharyngeus nerve, 283f Subarachnoid fluid system, 57 Subarachnoid hemorrhage, 103f, 107–108, 107f due to ruptured aneurysm, 106b

Subarachnoid space, 51f, 82f–83f, 83, 90f–91f, 119f–120f, 247f, 388f computed tomography scan of, 62f magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f Subcallosal (parolfactory) area, 57f, 67f, 465f, 480f Subcallosal gyrus, 320f–321f, 496f Subclavian artery, 105f, 110f, 116f, 183f, 210f Subclavian vein, 183f Subclavicular battery pack, 429f Subclavius muscle, 187f Subcommissural organ (SCO), 449f–450f Subcortical dementias, 430f Subcortical forebrain, 57 and human behavior, 345b Subcortical neurons, loss of, 487f Subcortical projections, 344f Subcortico-­cortical projections, 487f Subcostal muscles, 186f Subcostal nerve, 197f Subcutaneous artery, 175f Subcutaneous tissue, 175f Subcutaneous vein, 175f Subdural hematoma, 52, 52f, 93f, 119b, 484f Subdural space, 51f, 119f Subependymal veins, 123f Subfornical organ, 449, 449f–450f, 449b Subfrontal hematoma, 52f Subgranular zone (SGZ), of dentate gyrus, 16, 16f Subiculum, 70f, 87f, 444f, 466–467, 467f– 468f, 470f–472f, 475f, 486f inputs to, 467f–468f pyramidal cell layer of, 466f Sublingual gland, 204f, 211f, 214f, 279f, 281f, 435f Submandibular ganglion, 147f, 204f, 209f, 210, 211f, 211b, 214f, 276f, 279f, 281f, 435f autonomic innervation through, 214–215, 214f Submandibular gland, 183f, 204f, 214f, 279f, 281f, 435f Submucosa, 227f Submucosal (Meissner’s) plexus, 227f–228f enteric, 227 Submucous plexuses, 460f Subscapular nerves, 187f Subserous connective tissue, 227f Subserous plexus, 227f Substance P, 207 Substantia gelatinosa, 240, 240f–243f, 245f–246f, 403f enkephalin-­containing neuron in, 371f lamina II, 372f Substantia innominata, 438f, 471f–472f nucleus basalis in, 474f Substantia nigra, 34f, 60f, 145f, 265f–268f, 288f, 293.e11f, 293.e12f, 293.e13f, 293.e14f, 295f, 304f, 306f, 329f, 331f, 427f– 428f, 430f–431f, 488f, 496f, 500f in coronal section, 330–331, 330f–331f, 330b dopaminergic projection of, 427f neurochemistry in, 428b

533

Substantia nigra pars compacta, 352f Subthalamic DBS site (STN), 429f Subthalamic nucleus, 428f, 430f–431f, 440f Subthalamic projection, 427f Subthalamus, 427f Subventricular zone (SVZ), of lateral ventricles, 16, 16f Succinic semialdehyde, 36f Sudomotor fibers, 216 Sulcus of brain, 54 medial surface of, 57f of corpus callosum, 57f Sulcus limitans, 88f, 131, 131f, 137f–138f, 144f, 154, 154f Summation, of excitatory and inhibitory inputs, 33 Sunderland classification, of nerve injury, 165f Superficial cerebral veins, 119–121, 120f Superficial cervical artery, 183f Superficial cortical veins, 124f Superficial middle cerebral vein, 120f–122f Superficial peroneal nerve, 181f, 201f, 203f Superficial temporal artery, 95f, 105f, 120f, 215f frontal tributaries of, 120f parietal tributaries of, 120f Superficial temporal vein, 120f frontal tributaries of, 120f parietal tributaries of, 120f tributary of, 119f Superior anastomotic vein (of Trolard), 124f Superior articular process of L1 vertebra, 80f of L4 vertebra, 80f Superior canal, plane of, 385f Superior cerebellar artery (SCA), 99f, 101f, 105f–106f, 112, 112f–114f, 116f lateral marginal branch of, 112f Superior cerebellar peduncle, 74f, 77f, 88f, 126f, 145f, 261f–265f, 292f–293f, 293.e7f, 293.e8f, 293.e9f, 293.e10f, 293.e11f, 300f–303f, 332f–333f, 348f, 364f, 396f, 406f, 411f, 417f, 423f decussating fibers of, 266f decussation of, 77f, 304f, 411f descending fibers from, 411f–412f Superior cerebellar vein, 126f Superior cerebral vein, 119f opening of, 95f Superior cervical ganglion (SCG), 98f, 209b, 211f, 211b, 212, 213f Superior cervical sympathetic cardiac nerve, 209f–210f, 219f Superior cervical sympathetic ganglion, 214f–215f, 218f, 221f, 283f, 286f Superior cervical sympathetic trunk ganglion, 174f, 209f–210f, 212f, 219f Superior cervical vagal cardiac branches, 219f Superior choroidal vein, 122f–124f

534

Index

Superior colliculus, 60f, 71f, 74f, 88f–89f, 144f–145f, 266f–267f, 271f, 275f, 292f–293f, 293.e13f, 293.e14f, 305f–307f, 396f–397f, 405f, 414f, 416f afferents to, 289f brachia of, 74f brachium of, 71f, 268f, 293.e14f, 396f in coronal section of forebrain, 336f–337f deep layers of, 367f midbrain cross-­section at, 266f occipital eye fields to, 405f and tectospinal tract, 414b Superior constrictor muscle, of pharynx, 285f Superior extensor retinaculum, 203f Superior fovea, 88f Superior frontal gyrus, 54f, 320f–321f Superior frontal sulcus, 54f Superior ganglion, of vagus nerve, 284f–285f Superior gluteal artery, 198f Superior gluteal nerve, 198f Superior horn, of lateral ventricle, 16f Superior hypogastric plexus, 204f, 220f, 224f, 226f, 233f–238f Superior hypophyseal artery, 106f, 115f, 451f–452f anterior branch of, 115f posterior branch of, 115f Superior laryngeal nerve, 209f–210f, 218f, 221f, 285f, 377f Superior longitudinal fasciculus, 346f–347f color imaging of, 347f–348f Superior macular arteriole, 393f Superior macular venule, 393f Superior (superomedial) margin of cerebrum, 54f Superior medullary velum, 57f, 74f, 76f–77f, 88f–89f, 145f, 292f Superior mesenteric artery, 222f–225f, 230f Superior mesenteric-­celiac ganglion, 5f Superior mesenteric ganglia, 205f–207f, 220f, 222f, 225f–226f, 228f, 230f, 234f, 237f–238f Superior mesenteric plexus, 223f, 225f, 230f Superior nasal retinal arteriole, 393f Superior nasal retinal venule, 393f Superior oblique muscle, 273f, 275f, 416f Superior occipitofrontal fasciculus, 346f Superior olivary complex, 37f, 382f, 384f Superior olivary nucleus, 261f, 293.e7f Superior ophthalmic vein, 49f, 98f, 121f Superior orbital fissure, 49f Superior parietal lobule, 54f–55f Superior petrosal sinus, 98f, 121f sulcus of, 48f Superior pubic ramus, 198f Superior rectal artery, 220f, 224f, 226f, 233f Superior rectal plexus, 220f, 226f, 233f Superior rectus muscle, 273f–275f, 416f Superior retrotonsillar vein, 126f Superior sagittal sinus, 51f, 57f, 62f, 91f, 95f, 119–120, 119f–122f, 119b, 124f– 126f, 124, 140f sulcus of, 48f thrombosis in, 126b vein to, 49f

Superior salivatory nucleus, 211f, 213f–214f, 279f, 435f Superior semicircular canal, 385f Superior semicircular duct, ampulla of, 282f Superior semilunar lobule, 76f Superior tarsal muscle, 275f Superior temporal fiber, 394f Superior temporal gyrus, 54f, 469f Superior temporal retinal arteriole, 393f Superior temporal retinal venule, 393f Superior temporal sulcus, 54f Superior thalamostriate veins, 71f, 123f Superior thyroid artery, 105f, 174f, 183f Superior vena cava, 185f Superior vermian artery, 112f Superior vermian vein, 126f Superior vermis, 76f Superior vertebral notch, of L3 vertebra, 80f Superior vestibular nucleus, 261f–262f, 293. e7f, 293.e8f, 386f Supinator muscle, 192f Supplemental motor cortex, 55f, 59f Supplementary motor (premotor) area, 442f Supporting cells, 385f Supracallosal cistern, 91f Suprachiasmatic nucleus, 290f, 396f, 438f, 444f Supraclavicular nerves, 181f–184f, 190f Supraclinoid artery, 111f Supramammillary decussation, 440f Supramarginal gyrus, 54f Supraoptic nucleus (SON), 296f–297f, 437f–439f, 438, 444f–445f, 452f, 454f cell of, 454f Supraoptic recess, 324f Supraopticohypophyseal tract, 296f–297f, 441f, 445f–446f Supraorbital artery, 105f Supraorbital nerve, 182f, 273f, 276f lateral branch of, 273f–274f medial branch of, 273f–274f Supraorbital vein, 98f Suprapineal recess, 86f Suprarenal gland, 231f Suprascapular artery, 105f, 183f Suprascapular nerve, 187f, 191f Supraspinatus muscle, 191f Supratrochlear artery, 105f Supratrochlear nerve, 182f, 273f–274f, 276f Supratrochlear vein, 98f Supreme intercostal artery, 105f Sural nerve, 181f, 201f–203f Surface ectoderm, 150f Sustentacular cells, 479f SVZ. See Subventricular zone Swallowing, neural circuitry of, 418–420, 418f Swallowing disorder, 419b Sweat glands, 162f, 172f, 175f, 204f, 207f, 211f innervation of, 216 pore of, 175f Swinging flashlight test, 209b Sympathetic chain ganglia, 83, 133f, 162f, 205f, 208f, 228f, 290f, 370f, 435f, 447f, 464f collateral, abdominal nerves and, 220 lumbar, abdominal nerves and, 220 thoracic, and splanchnic nerves, 217–218, 217f, 217b

Sympathetic efferent output, 458f Sympathetic efferents, 418f Sympathetic fibers, 204f, 206f–207f, 212f, 218f–219f, 222f Sympathetic ganglia, 83f, 171f, 234f, 237f– 238f, 448f postganglionic neuron of, 21f Sympathetic nerve activity, 459f Sympathetic nervous system (SNS), 445f–446f distribution of in abdominal, 220–221, 220f in adrenal gland, 231–232, 231f in head and neck, 209, 237–238, 237f in heart, 219–220, 219f in immune system and metabolic organs, 205–206, 205f in kidneys and upper ureter, 235–236, 235f in liver and biliary tract, 229–230, 229f in pancreas, 230–231, 230f in pelvic nerves and ganglia, 233–234, 233f, 233b in small and large intestines, 224–225, 224f splanchnic nerves in, 217–218, 217f in stomach and duodenum, 222–223, 222f in tracheobronchial tree, 218–219, 218f in urinary bladder, 234–235, 234f preganglionic neurons of, 208 Sympathetic postganglionic fibers, 214f Sympathetic postsynaptic fibers, 215f Sympathetic preganglionic fibers, 214f Sympathetic preganglionic neurons, 403f Sympathetic presynaptic fibers, 215f Sympathetic rami to lumbar plexus, 216f to sacral plexus, 216f Sympathetic root, 209f Sympathetic terminal ending, 179f Sympathetic terminals, 179f Sympathetic trunk, 132f, 283f Sympathetic trunk ganglia, 186f, 197f–198f, 206f, 213f–215f, 218f, 232f, 234f–238f, 456f–457f, 463f sacral part of, 233f Sympathetic trunk ganglion, 131f Sympathetic vasoconstriction, 457f Sympathetically maintained pain, 370–371, 370f, 370b Synapses, 7–8, 7f, 12f acetylcholine, 45f, 46 adrenergic, 207–208, 207f amino acid, 45f, 46 catecholamine, 45f, 46 cholinergic, 207–208, 207f configurations of, 7b growth of, 38b inhibitory, 32 insulation of, 12f morphology of, 38–39, 38f peptide, 46 serotonin, 45f, 46 strength of, regulation of, 42–43, 42f Synaptic bouton, synaptic vesicles in, 25f Synaptic cleft, 25f, 38f, 176f–177f

Index Synaptic ending, 174f, 391f schematic of, 38f Synaptic trough, 176f Synaptic vesicles, 38f, 176f Syringobulbia, 243b Syringomyelia, 243b, 249–250, 249f

T T cells, 19f T1 vertebra, 50f TAG-­1, 29f Tanycyte, 11f Target molecule, 9f Target tissue, 15f, 171f, 208f Taste buds, 376f receptors in, 376–377, 376f Taste cells, 376f Taste pathways, 377–378, 377f clinical point, 377b Taste pore, 376f Tau, ingestion of, 19f Tau protein, hyperphosphorylation of, 10f Tear production, 210 Tectorial membrane, 380f Tectospinal tract, 84f, 241f, 256f–263f, 266f, 293f, 293.e2f, 293.e3f, 293.e4f, 293. e5f, 293.e7f, 293.e8f, 293.e9f, 293. e12f, 396f, 414–415, 414f superior colliculus and, 414b Tectum, 144f, 146f Teeth, innervation of, 278–279, 278f Tegmen tympani, 378f Tegmental nuclei, 444f Tegmentum, 144f–145f, 146, 488f Tela choroidea, of 3rd ventricle, 87f, 122f Telencephalic vesicle, 138f–140f, 153f Telencephalon, 299–358, 445f at 2 months, 140f at 6 months, 141 at 36 days, 138, 138f at 49 days, 139, 139f adult derivatives of, 146, 146f comparison of, at 5.5 weeks and adult, 144f inputs, 444f Temperature sensory pathways in spinothalamic and spinoreticular tracts, 368 spinal cord processing of, 368 trigeminal, 372f Temporal artery, 374f Temporal association cortex, 445f Temporal bone, 48f, 50f Temporal cortex, 326f, 329f, 384f, 427f, 500f association areas of, 475f Temporal excitatory summation, 33–34, 33f Temporal fossa, 50f hematoma, 52f Temporal horn, of lateral ventricle, 306f–307f Temporal lobe, 75f, 102f, 141f, 300f–310f, 323f–325f, 327f–329f, 333f, 339f, 350f, 399f of brain, 54f, 56f of cerebral hemisphere, 144f clinical point, 304b, 398b–399b herniation of, 52f visual pathways in, 399–400

Temporal lobe cortex, acoustic area of, 37f, 382f Temporal lobe sensory association cortex, 470f Temporal opercula, 54f Temporal pole, 54f, 60f–61f, 320f–322f lateral ventricle, 90f magnetic resonance imaging of, 63f T2-­weighted magnetic resonance imaging of, 64f Temporal retina, 392f Temporocingulate pathways, 345f Temporoparietal area, atrophy of, 484f Temporopontine pathway, 408f Tendon organ reflex, 251f Tenia of 4th ventricle, 88f Tenon’s capsule. See Fascial sheath of eyeball Tensor tympani muscle, 384f Tensor tympani nerve, 276f Tensor veli palatini muscle, 276f, 418f Tentorial artery, 121f Tentorium cerebelli, 121, 121f–122f, 126f, 273f, 374f Teres major muscle, 191f Teres minor muscle, 191f Terminal bars, 479f Terminal endings, 179f Terminal sulcus, 376f Terminal vein, 326f Tertiary sensory neurons, 169f Testicular artery, 237f Testicular (ovarian) artery, 234f Testicular (ovarian) plexus, 234f, 237f Testis, 237f, 452f Testosterone, 452f Thalamic impression, 153f Thalamic nuclei, 472f, 474f neuronal organization of, 366–367, 366f Thalamic projection, 427f Thalamic syndrome, 72b Thalamocortical afferent, 342f terminations, 342f Thalamogeniculate arteries, 112f Thalamoperforating arteries, 106f, 112f–113f to lateral thalamus, 114f to medial thalamus, 114f Thalamostriate vein, 120f, 122f–124f Thalamotomy/DBS site (VIM), 429f Thalamotuberal (premammillary) artery, 106f Thalamus, 34f, 57f, 66, 66f, 70f, 74f, 87f, 89f, 104f, 140f, 143f–144f, 146, 146f, 290f, 292f, 296f–297f, 308f–311f, 313f, 331f, 333f, 343f, 346f, 351f, 355f, 366f, 373f, 405f, 426f–427f, 429f–430f, 437f, 439f–442f, 444f–446f, 460f, 462f, 466f, 468f, 470f–473f, 488f–492f anatomy of, 71–72, 71f, 295–296 anterior nuclei of, 67f, 443f, 465f, 475f caudal, in axial (horizontal) section of, 308–309, 308f–309f clinical point, 295b, 334b computed tomography scan of, 62f efferents to, 289f interconnection with cerebral cortex and, 295–296, 295f

535

Thalamus (Continued) magnetic resonance imaging of, 63f medial dorsal nucleus of, 472f, 475f mid-­, 310–311, 310f–311f, 332–333, 332f–333f midsagittal view of, 57f, 59f nuclei of, 72, 72f, 288f, 295, 334b reticular nucleus of, 72f, 288 retinal projections to, 396–397, 396f T2-­weighted magnetic resonance imaging of, 64f thalamocortical radiations, 295f venous drainage of, 122, 122f ventral lateral nuclei of, 405f Thenar atrophy, 195f Thenar muscles, 194f–195f Thermoreception, 456f Thermoregulation, hypothalamus in, 456–457, 456f Thickened epineurium, 165f Thigh lateral cutaneous nerve of, 197f posterior cutaneous nerve of, 198f Thin elastic media, 174f Thin vermilion border, 157f Thinned myelin, in compressed area, 165f Third ventricle, 66f, 71f–72f, 87f–88f, 90f, 92f, 123f, 138f, 140f, 144f, 146f, 153f, 292f, 308f–310f, 324f–329f, 331f–332f, 343f, 438f–440f, 461f, 466f, 488f computed tomography scan of, 62f cut edge of tela choroidea of, 71f roof of, 140f 3rd intercostal nerve, 221f 3rd lumbar sympathetic trunk ganglion, 220f 3rd lumbrical muscles, 196f 3rd thoracic sympathetic ganglion, 221f Thoracic aortic plexus, 217f Thoracic cardiac branches, 221f Thoracic cardiac nerves, 185f, 217f Thoracic duct, 217f, 220f Thoracic greater splanchnic nerve, 418f Thoracic nerves, 166f, 186–187, 186f 1st, 81f 12th, 81f Thoracic spinal cord, 214f–215f, 218f, 247f, 414f, 435f, 447f gray matter organization in, 241–242 Thoracic splanchnic nerves, 186f, 206f, 216f, 460f Thoracic sympathetic aortic nerve, 216f Thoracic sympathetic cardiac nerves, 216f–217f, 219f Thoracic sympathetic chain, and splanchnic nerves, 217–218, 217f clinical point, 217b Thoracic sympathetic ganglionic chain, 460f Thoracic sympathetic nerve, 210f Thoracic sympathetic trunk, 221f Thoracic vagal cardiac branch, 219f Thoracic vertebrae, 116f Thoracic viscera, branch to, 132f Thoracodorsal nerve, 187f Thoracolumbar cord, 224f Thumb, 134f, 180f, 408f

536

Index

Thymus, 205f, 464f Thyrocervical trunk, 105f, 183f Thyrohyoid muscle, 183f–184f, 286f Thyroid activity, increased, 456f Thyroid cartilage, 50f, 96f Thyroid gland, 452f Thyroid hormone secretion, regulation of, 453b Thyroid hormones, 452f Thyroid-­stimulating hormone (TSH), 452f, 453, 453b Thyrotropic hormone, 456f Tiagabine, 36f Tibial nerve, 201f, 202–203, 202b Tibialis anterior muscle, 203f Tibialis posterior muscle, 202f Tic douloureux, 277b Tight junction, 18f proteins, 18f Time-­of-­flight phenomena, 110 Tissue damage, 19f TLRs. See Toll-­like receptors Toes, 408f Toll-­like receptors (TLRs), 13f Tongue, 407f dorsum of, 376f intrinsic musculature of, 286f muscles of, 373f posterior part of, 418f Tonsil, 76f, 89f, 292f, 418f Topiramate, 36f Trabecula, 115f, 451f artery of, 451f Trabecular meshwork, 389f Trabecular spaces, 389f Trachea, 50f, 204f, 207f, 285f Tracheobronchial tree, autonomic innervation of, 218–219, 218f Tractus solitarius, 256f–260f, 293.e2f, 293.e3f, 293.e4f, 293.e5f nucleus of, 373f Transcription factors, OSKM cocktail of, 17f Transcriptomics, 9f Transgenic disease model, Alzheimer’s disease, 10f Transient amplifying cells (C cells), 16f Transmitter substances, 25f Transpeduncular tract, 396f nucleus of, 396f Transtentorial herniation, 265b Transverse carpal ligament, 195f Transverse cervical artery, 105f Transverse cervical nerves, 182f–184f Transverse occipital sulcus, 54f Transverse pontine vein, 126f Transverse process, 79f of C6, 96f of L3 vertebra, 80f Transverse sinus, 121f–122f, 124, 124f–125f, 126 sulcus of, 48f Transverse temporal gyrus of Heschl, 310f Transversus abdominis muscle, 186f, 197f Transversus menti muscle, 279f Trapezius muscle, 184f, 186f, 284f Trapezoid body, 261f–262f, 293.e7f, 293.e8f, 382f, 384f of CN VII, 293.e7f

Trauma, 19f Traumatic brain injury, 493–494, 493f Tremor, 308b, 430f Triceps brachii muscle, 191f cervical disk herniation, 189f Triceps tendon, 191f Tricyclic antidepressants, 350b Trigeminal ganglion, 145f, 212f, 214f–215f, 271f–273f, 276f, 372f, 377f, 404f Trigeminal lemnisci, 145f Trigeminal mesencephalic nucleus, 372f Trigeminal motor nucleus, 263f, 372f, 405f, 413f Trigeminal nerve (CN V), 74f–75f, 121f, 126f, 138f, 145f–146f, 182f, 209f, 214f–215f, 263f, 270f–272f, 300f, 377f, 404f afferent pain fibers in, 371f articular branches of, 276f auricular branches of, 276f clinical point, 277b, 433b descending nucleus of, 212f divisions of, 277, 373f fibers, 384f mandibular branch of, 181f maxillary branch of, 181f meningeal branch of, 276f motor nuclei of, 263f, 271f–272f, 276f, 377f, 384f, 404f nasal branches of, 276f nuclei of, 145f ophthalmic branch of, 181f ophthalmic division of, 147f orbital, 273–274 pain pathway, 375f parotid branches of, 276f pharyngeal branch of, 276f sensory nuclei of, 263f, 271f–272f, 276f spinal nucleus of, 374f spinal tract and spinal nucleus of, 145f spinal tract/nucleus of, 255f–262f, 269f, 272f, 276f, 283f, 285f, 293.e2f, 293.e3f, 293.e4f, 293.e5f, 293.e7f superficial temporal branches of, 276f tentorial (meningeal) branch of, 276f Trigeminal neuralgia, 277b Trigeminal (V) nucleus, 375f Trigeminal sensory nucleus, 405f Trigeminal sensory system, 372–373, 372f Trigeminal vascular reflex, 375f Trigeminal vein, 375f Trigeminothalamic tracts, 268f, 293.e14f Trochlear nerve (CN IV), 49f, 74f–75f, 88f, 121f, 138f, 146f, 270f–274f, 292f, 404f, 416f and ciliary ganglion, 275–276, 275f clinical point, 274b orbital, 273 in pons-­midbrain, 264f Trochlear nucleus, 271f–272f, 275f, 404f, 416f Trunk, 386f, 408f somatic innervation of lumbar plexus, 197–198, 197f sacral and coccygeal plexuses in, 198–199, 198f

Tryptophan, 45f TSH. See Thyroid-­stimulating hormone Tuber, 89f Tuber cinereum, 57f, 60f, 75f, 437f Tuberal nuclei, 439f Tuberculum cinereum, 88f Tuberculum sellae, 48f Tuberohypophyseal tract, 296f–297f, 441f, 445f Tuberoinfundibular pathway, 352f Tuberosity of maxilla, 50f Tubotympanic recess, 151f Tufted cell, 480f Tympanic cavity, 151f, 213f, 282f–283f, 378f–379f Tympanic membrane, 378f–379f, 384f Tympanic nerve, 147f, 215f, 279f, 283f Tympanic plexus, 215f, 279f, 283f tubal branch of, 283f Tympanum, 281f Type I (glomus) cells, 174f Type I radial glia-­like cells, 16f Type II (sheath) cells, 174f Type II progenitor cells, 16f Tyrosine, 232f

U Ulnar nerve, 181f, 187f, 193f–194f, 196–197, 196f anastomotic branch to, 194f in Guyon’s canal, 195f Umbilical cord, 17f Umbilicus, level of, 180f Umbo, 379f UMNs. See Upper motor neurons Uncal vein, 122f Uncinate fasciculus, 346f color imaging of fibers in, 348f Uncrossed rubromedullary (rubrobulbar) fibers, 411f Uncus, 58f, 60f, 67f, 70f, 300f, 465f, 478f, 480f Unilateral cerebral hemisphere lesion, 499f Unipolar sensory cell, 8f Unisensory association cortices, 469f, 497f Unmyelinated axon terminal, 173f Unmyelinated axons, 163 action potential in, 28 conduction of action potentials in, 27–28, 29f myelination of, 22 somatosensory afferent, 362 Unmyelinated fibers, 8f, 29f Unmyelinated nerve fiber, 8f Unmyelinated olfactory axons, 479f Upper cervical spinal cord, 414f Upper limbs, 134f, 412f bone marrow, 205f dermatomes of, 134f, 188–189, 188f lateral parts of, 180f medial sides of, 180f somatic innervation of cutaneous, 190–191, 190f median nerve, 194–195, 194f scapular, axillary, and radial nerves, 191–192, 191f upper nerve, 196–197, 196f

Index Upper lumbar splanchnic nerves, 237f Upper lumbar sympathetic trunk ganglia, 216f Upper motor neuron (UMN) syndrome, 409b Upper motor neurons (UMNs), 170–171, 170f, 405–406, 422f in central control of eye movements, 416–417, 416f in central control of respiration, 417–418, 417f cerebellar efferent pathways to, 426–427, 426f clinical point, 7b bulbar palsy and pseudobulbar palsy, 256b decorticate and decerebrate posturing, 433b pontine hemorrhage, 262b upper motor neuron syndrome, 409b in cortical efferent pathways, 405–406, 405f color imaging of, 406–407 corticobulbar tract, 407–408, 407f corticoreticular tract, 413–414, 413f corticospinal tract, 408f, 409–410 interstitiospinal tract, 414–415, 414f reticulospinal tract, 413–414, 413f rubrospinal tract, 411–412, 411f tectospinal tract, 414–415, 414f vestibulospinal tracts, 412–413, 412f muscle stretch reflex and, 253b terminations of, in spinal cord, 410–411, 410f, 415–416, 415f Upper thoracic sympathetic trunk ganglia, 216f Ureter, 236f Urinary bladder, 226f, 236f autonomic innervation of, 234–237, 234f, 236f, 236b Uterine (fallopian) tube, 238f Uterovaginal plexuses, 238f Uterus, 238f Utricle, 282f, 378f–379f, 385f Utrophin, 178f Uvula, 89f, 262f, 293.e8f of cerebellum, 263f, 293.e9f

V Vagal afferents, in viscera, 448f Vagal cardiac nerves, 210f Vagal trigone, 74f, 88f Vagina, 238f Vagus efferent cardiac fibers, 457f Vagus nerve (CN X), 49f, 74f–75f, 121f, 138f, 145f–146f, 174f, 183f, 204f, 206f–207f, 209, 209f–210f, 218f– 219f, 221f, 224f, 228f, 235f, 269f–272f, 283f–285f, 285–286, 293. e4f, 293.e5f, 372f, 377f, 404f, 435f, 443f, 447f, 458f, 460f, 464f auricular branch of, 182f, 285f in brainstem, 259f celiac branches of, 285f clinical point, 285b communication to, 183f auricular branch of, 283f

Vagus nerve (Continued) dorsal motor nucleus of, 256f–259f, 269f, 271f–272f, 293.e2f, 293.e3f, 293. e4f, 293.e5f, 405f dorsal nucleus of, 460f external branch of, 285f inferior cervical cardiac branch, 285f inferior ganglion of, 221f internal branch of, 285f meningeal branch of, 285f nodose (inferior) ganglion of, 377f pharyngeal branch of, 221f, 283f, 285f superior cervical cardiac branch of, 209f–210f, 285f superior ganglion of, 221f superior pharyngeal branch of, 210f thoracic cardiac branch of, 285f vagal branches of, 285f Vallate papillae, 376f–377f Vallecula, 376f Valproate, 36f Vanillylmandelic acid, 232f Varicosities, 7f, 179f Vascular circle of Zinn-­Haller, 392f Vascular compression, 165f Vascular dementia, 484f, 485 Vascular endothelial growth factor (VEGF), 15f Vascular ischemia, 165f Vascular smooth muscle, 162f, 211f innervation of, 216 Vascular smooth muscle cell, 12f Vasculature, 5f Vasoactive intestinal peptide (VIP), 210b Vasomotor fibers, 216 Vasopressin, 454–455, 454f clinical point, 454b water balance and fluid osmolality regulation by, 455–456, 455f Vastus intermedius muscle, 199f Vastus lateralis muscle, 199f Vastus medialis muscle, 199f VEGF. See Vascular endothelial growth factor Veins, 175f, 458f bridging, 91f Venous lacuna, 51f, 95f, 120f Venous phase, 124–125, 124f Venous plexus, 127b Venous pressure, 164f Venous sinus thrombosis, 121, 121b Venous system, 119–120, 119f of brain, 122–123, 122f relationship to ventricles, 123–124, 123f of brain stem and cerebellum, 126–127, 126f carotid venograms of, 124–125, 124f magnetic resonance venography of, coronal and sagittal views, 125–126, 125f of meninges and superficial cerebrum, 119–120 sinuses of, 121–122, 121f of skull, 119 of spinal cord, 127, 127f superficial, cerebral, meningeal, diploic, and emissary, 120–121, 120f

537

Venous thrombosis, 123b Ventral amygdalofugal pathway, 432f, 443f–444f, 446f, 471f, 473f Ventral anterior nucleus, 427f, 431f Ventral basal plate, 144f, 154f Ventral cochlear nucleus, 37f, 260f, 269f, 271f–272f, 293.e6f, 382f, 384f Ventral funiculus, 132f Ventral gray column, 144f Ventral horn, 145f, 149f of spinal cord, 240–241, 245f–246f Ventral lateral nucleus, 427f Ventral lateral thalamus, 329f Ventral limb, 386f Ventral medullary cardiovascular centers, 457f Ventral noradrenergic bundle, 350f Ventral nuclei, 444f Ventral periaqueductal gray, 290f, 445f Ventral posterolateral (VPL) nucleus of thalamus, 365f, 367f Ventral posteromedial (VPM) nucleus of thalamus, 372f, 377f Ventral ramus, 83, 83f, 133f, 162f, 183f, 185f migration of, 133 of spinal nerve, 132f of T1, 219f of T11, 235f Ventral respiratory nucleus, 417f Ventral root, 82, 82f–83f, 132f–133f, 162f, 186f, 206f, 214f–215f, 236f, 245f–246f, 250f, 370f Ventral spinocerebellar tract (VSCT), 145f, 241f–246f, 255f–257f, 293.e1f, 293. e2f, 293.e3f, 364f, 423f Ventral tegmental area, 266f–267f, 288f, 293. e12f, 293.e13f, 352f, 432f, 470f, 472f–473f, 488f–490f, 492f, 496f, 500f Ventral tegmental decussation, 266f, 293.e12f, 411f Ventral tegmental nucleus, 445f Ventral thalamic nuclei, 312f Ventral trigeminal lemniscus, 372f ventral trigeminothalamic tract, 372f Ventricles, 11f, 16f, 57f, 85–93, 142f, 458f anatomy of, 86–87, 86f in coronal forebrain section, 87–88, 87f of brain, 86f development of, 153–154, 153f fourth, anatomy of, 86f lateral view, 89–90, 89f posterior view, 88–89, 88f lateral, 86 magnetic resonance imaging of, axial and coronal views, 90–91, 90f third, 86f, 87 venous drainage surrounding, 123f Ventricular septal defect, 157f Ventricular system, magnetic resonance imaging of, 64 Ventriculomegaly, 430f, 484f Ventrolateral nucleus, 431f Ventromedial hypothalamic area, 460f

538

Index

Ventromedial nucleus, 297f, 437f, 439f, 441f, 470f, 472f and sexual behavior, 439b Ventromedial prefrontal cortex (vmPFC), 474f, 476f–477f, 488f–492f, 496f, 500f Vermis, 77f, 89f, 291f–292f, 420f, 425f–426f of cerebellum, 302f Vertebrae, spinal nerve roots and related, 166–167, 166f Vertebral artery, 49f, 96, 96b, 99f, 101f, 105f–106f, 110f, 113f–114f, 116f–117f, 183f, 210f, 269f anterior meningeal branches of, 95f, 112f first segment of, 97f fourth segment of, 97f posterior meningeal branches of, 95f, 112f Vertebral body, 83f branch to, 118f Vertebral ganglion, 210f, 219f Vertebral plexus, 210f Vertebro-­basilar arteries, 374f Vertebrobasilar system, 99b, 112–113, 112f, 112b angiographic anatomy of, 113–114, 113f occlusive sites of, 114–115, 114f paramedian and short circumferential penetrating branches of, 114f tonsillohemispheric branches of, 112f–113f Vertical columns, of cerebral cortex, 342–343, 342f Vertigo, 379b Vesical plexus, 226f, 233f–234f, 236f–237f Vesicle, 20f Vestibular afferents, 426f Vestibular aqueduct, 49f Vestibular area, 88f Vestibular ganglion, 282f, 385f–386f, 412f, 423f, 425f Vestibular (Reissner’s) membrane, 380f Vestibular nerve, 378f, 386f, 412f, 416f, 423f, 425f clinical point of, 386b Vestibular nuclei, 144f–145f, 154f, 259f, 269f, 271f–272f, 282f, 289f, 293.e5f, 386f, 412f, 416f, 423f–426f Vestibular pathways, 386–387, 386f Vestibular system, 385–386 receptors, 385–386, 385f Vestibule, 378f–379f

Vestibulocerebellar pathways, 425–426, 425f clinical point, 425b Vestibulocochlear nerve (CN VIII), 49f, 74f–75f, 121f, 126f, 138f, 146f, 151f, 209f, 260f–261f, 269f–272f, 282–283, 282f, 293.e7f, 378f, 491f clinical point, 282b cochlear divisions of, 37f, 382f, 385f cochlear part of, 282f inferior division of vestibular part of, 282f superior division of vestibular part of, 282f vestibular divisions of, 385f vestibular part of, 282f Vestibulospinal tracts, 84f, 245f–246f, 386f, 386b, 412–413, 412f, 415f clinical point, 412b termination of, in spinal cord, 412 Vidian nerve, 98f Vigabatrin, 36f Villi, 479f VIP. See Vasoactive intestinal peptide Viral DNA, 9f Viral RNA, 9f Viral tracers, 9f Viral vector, 9f Virus, synaptic propagation of, 9f Visceral arterioles, 207f Visceral motor neurons, 8f myelination of axons of, 22f Visceral peritoneum, 227f Visceral sensory neuron, 22f Viscus, 206f Visual area, 442f Visual association areas, of cortex, 55f basal surface of, 61f medial surface of, 59f Visual association cortex, 59f, 61f Visual cortex, 316f–317f, 396f, 477f Visual evoked potential, 37–38, 37f Visual field deficit and lesions, 400 in optic nerve, 396b Visual fields, 400f Visual I, 345f Visual II, 345f Visual III, 345f Visual pathway, 408f Visual retina, 150f Visual system, 388–389 cerebrovascular disease in, 393b

Visual system (Continued) lesions of, 400, 400f oculomotor nerve, clinical point of, 388b optic chiasm and, 394–395, 394f optic nerve in, 389b, 392–393, 392f clinical point, 389b pathways of clinical point, 396b parietal and temporal lobes, 399–400 retino-­geniculo-­calcarine, 398–399, 398f thalamus, hypothalamus, brainstem, 396–397, 396f photoreceptors in, 391–392, 391f retina in, 390–391 clinical point, 390b Vitreous body, 388f Vitreous chamber, 393f Voltage-­gated calcium channel, 36f Voltage-­gated ion channels, 39f Vorticose vein, 393f VSCT. See Ventral spinocerebellar tract

W Waking states, hypothalamic regulation of, 462–463, 462f Wallenberg syndrome, 258b, 269f Wallerian degeneration, 165 Weber’s syndrome, 267b, 269f Wernicke aphasia, 494f–495f Wernicke-­Korsakoff syndrome, 440b, 479b Wernicke’s area, 55f White matter, 82f, 421f of spinal cord, 84, 84f, 241 White matter zone, 77f White ramus communicans, 132f, 162f, 197f, 204f, 206f–207f, 212f, 214f, 216f–217f, 219f–222f, 224f, 233f, 235f–238f, 435f Wrist, 408f

Z Zona incerta, 430f, 439f Zonisamide, 36f Zonular fibers, 389f, 393f suspensory ligament of lens, 388f Zygomatic arch, 50f Zygomatic nerve, 275f–276f Zygomaticofacial nerve, 182f, 276f Zygomaticotemporal nerve, 182f, 276f Zygomaticus major muscle, 279f Zygomaticus minor muscle, 279f

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