Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders [1 ed.] 9781622570836, 9781613241523

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Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders, edited by Justin L. Song, Nova Science

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders, edited by Justin L. Song, Nova Science

NEUROSCIENCE RESEARCH PROGRESS

THALAMUS

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ANATOMY, FUNCTIONS AND DISORDERS

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Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders, edited by Justin L. Song, Nova Science

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Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders, edited by Justin L. Song, Nova Science

NEUROSCIENCE RESEARCH PROGRESS

THALAMUS

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ANATOMY, FUNCTIONS AND DISORDERS

JUSTIN L. SONG EDITOR

Nova Science Publishers, Inc. New York Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders, edited by Justin L. Song, Nova Science

Copyright © 2011 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book. Library of Congress Cataloging-in-Publication Data Thalamus : anatomy, functions, and disorders / editor, Justin L. Song. p. ; cm. Includes bibliographical references and index. ISBN 978-1-62257-083-6 (E-Book) 1. Thalamus. I. Song, Justin L. [DNLM: 1. Thalamus. WL 312] QP383.5.T43 2011 611'.81--dc22 2011009078

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Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders, edited by Justin L. Song, Nova Science

Contents vii 

Preface

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Chapter I

Chapter II

Current Use of Thalamic Surgeries for Treating Movement Disorders Ryoma Morigaki, Shinji Nagahiro, Ryuji Kaji and Satoshi Goto  Innervation of Anterior Thalamic Nuclei by Mammillothalamic Tract during Perinatal Development: Carbocyanine Dye Tracing Study Irina G. Makarenko 

Chapter III

Thalamic Stroke Prakash R. Paliwal and Vijay K. Sharma 

Chapter IV

Complex Pathology in the Thalamus Following Cerebral Ischemia Mikko Hiltunen and Jukka Jolkkonen 

Chapter V

Chapter VI

Giantic Calyciform Synapses in the Nucleus Reticularis Thalami Bertalan Csillik, Elizabeth Knyihár-Csillik and András Mihály  Thalamic Changes in Temporal Lobe Epilepsy Chun Kee Chung and Chi Heon Kim 

Index

Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders, edited by Justin L. Song, Nova Science

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33  65 

83 

99 

121  133 

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders, edited by Justin L. Song, Nova Science

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Preface In this book, the authors present topical research in the study of the anatomy, functions, and disorders of the thalamus. Topics discussed include the current use of stereotactic thalamic surgeries that modulate neural activities; innvervation of anterior thalamic nuclei by mammillothalamic tract during perinatal development; thalamic stroke; complex pathology in the thalamus following cerebral ischemia; giantic calyciform synapses in the nucleus reticularis thalami and thalamic changes in temporal lobe epilepsy. (Imprint: Nova Biomedical Press) Chapter I - Recent advances in the understanding of functional motor brain circuits as well as neuroimaging and neurosurgical techniques provide a growing body of evidence suggesting that stereotactic surgery (e.g., deep brain stimulation or ablation surgery) is a powerful and safe therapeutic option for medically intractable Parkinson’s disease and other movement disorders. For more than 50 years, the ventrolateral thalamus has been a major target for stereotactic interventions in the treatment of movement disorders. It plays a pivotal role in the basal ganglia-thalamo-cortical circuit, which is involved in motor brain functions. The entire output of the basal ganglia is directed to the motor cortex via the ventrolateral thalamus where the basal ganglia and cerebellar projections terminate predominantly in the nucleus ventralis oralis (Vo nucleus) and the nucleus ventralis intermedius (Vim nucleus), respectively. This review introduces the current use of stereotactic thalamic surgeries that modulate the neural activities of the Vo complex nucleus and the Vim nucleus for treating movement disorders. Chapter II - The anterior thalamic nuclei (ATN) occupy a central position among the interconnected structures that form the limbic system and specifically are known as an important parts of “Papez circuit”. Afferent projections to the anterior thalamic nuclei from the mammillary nuclei of the

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Justin L. Song

hypothalamus form the largest known ascending input. It is organized as a large compact fiber bundle known as the mammillothalamic tract that was decribed in different adult vertebrates but there are only few studies on its development. This study was aimed to describe the schedule of the mammillothalamic tract perinatal development in the rat using carbocyanine dye tracing. This method is unique for such purposes because it works on the fixed brain tissue and thus is applicable to fetal and early neonatal material. To reveal mammillothalamic tract DiI or DiA crystals were inserted in the mammillary bodies. Fetal (E14 - E21) and neonatal (P0 – P10) rat brains were used. Serial vibratome sections were analyzed using fluorescent and confocal microscopy. On E15-16, DiI insertion into the primordium of the MB resulted in the labeling only mammillotegmental tract and no signs of the growing mammillothalamic tract could be recognized at the level of the posterior hypothalamus. First fibers of the mammillothalamic tract being the collaterals of the mammillotegmental tract axons start bifurcate from the mammillotegmental tract on E17. At a short distance from the mammillary body the axons of the mammillothalamic tract gather tightly and form a thick bundle on E18. Confocal microscopy revealed growth cones on the ends of most axons. The mammillothalmic tract enters the ventral region of the anterior thalamus on E20 – E21 and starts to form first terminal arborizations in the anteromedial and anteroventral nuclei. Specific topographic organization of the mamillothalamic projections described in adult rats was visualized since P2. Unilateral connections of the medial mammillary nucleus with the anteromedial and anteroventral thalamic nuclei develop from E20 to P6. Bilateral projections from the lateral mammillary nucleus to the anterodorsal thalamic nuclei develop later after the formation of the thalamic decussation (beginning on P2). On P6 –P10 all anterior thalamic nuclei have dense innervation from the mammilary nuclei. Thus, MB innervation of the anterior thalamic nuclei is completed during the first postnatal week and later did not change significantly. Chapter III - Thalamus has been labeled as the "Grand Central Station" of the brain because virtually all incoming information travels through it before reaching the cerebral cortex and all areas of the cortex project to the thalamus. Compared to the uncommon non-vascular insults like Korsakoff’s syndrome due to the thiamine deficiency, vascular insults constitute the commonest source of injury to the thalamus. Thalamus is predominantly supplied by multiple small vessels originating from the posterior cerebral and communicating arteries, with significant variations and overlap. The stroke syndromes are not specific to individual nuclei because most vascular lesions

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Preface

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are fairly large that result in a great deal of overlap of symptoms due to infarction or hemorrhage from a particular artery. The structure-function relationship is too complex and the information about the functional anatomy of thalamus has been largely derived from patients evaluated after thalamotomy and insertion of thalamic stimulation devices. Recent advances in functional imaging with magnetic resonance imaging and sophisticated use of diaschisis for analyzing the corticothalamic connectivity have significantly improved our understanding. In general, injury to the left side may be associated with language deficits in language, verbal intellect and verbal memory while a right-sided injury results in visuospatial deficits and impaired nonverbal intellect. Bilateral injury is associated with severe memory impairment. Other deficits due to the thalamic injuries include confusion, delirium, visual hallucinations, peduncular hallucinosis and cognitive deficits. We discuss functional areas of thalamus, their vascular supply and clcinical presentations due to various acute ischemic and hemorrhagic lesions. Chapter IV - Focal cerebral ischemia in the cortex leads to secondary pathology in areas distant from the infarct. The thalamus is spared from acute ischemic damage, but because of its synaptic connections to the cortex, delayed retrograde degeneration of thalamocortical neurons occurs. In addition to degenerative process, thalamic pathology includes parallel inflammatory reaction, impaired calcium homeostasis, complex alterations in β-secretasemediated amyloid precursor protein processing, and increased angiogenesis. Together, these result in a unique pathology remote from the initial insult that has intriguingly similar features to those in Alzheimer’s disease. The causal relationships between different pathologies and their functional meaning are poorly understood. Given the integral role of the thalamus in the flow and processing of sensorimotor information, damage to the thalamus or its projections is likely to have detrimental consequences. Further understanding of the secondary pathology in the thalamus is expected to aid drug development that aims at neurorestoration following various neuronal insults. Chapter V - The reticular nucleus (RTN), resembling an eggshell, surrounds the upper, posterior and inferior aspects of the thalamus. RTN is known to occupy a strategic position between the neocortex and the specific thalamic nuclei, is located at the crossroads between thalamus and the cortex. RTN, the “guardian of the gate” is strategically situated between the cortex and the specific thalamic nuclei. Cell-to-cell GABA-ergic interactions in the reticular nucleus are known to be crucial in establishing synchronized thalamocortical oscillations, instrumental in sleep spindles.

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Chapter VI - The seizure network is wider than the seizure onset zone and chronic seizure activity may alter the properties of a seizure network. The effect of chronic seizure activity on the adjacent brain has been the subject of numerous investigations. The thalamus is known to have a strong anatomical connection to the medial temporal area and is known to modulate seizures. In addition to an anatomical connection, physiological connection has also contributed to changes in the thalamus. Electrical stimulation revealed that the thalmus was closely connected to the hippocampus in animal study. Thalamic changes occurring in TLE have been thought to be associated with neuronal loss, gliosis and extracellular edema. Many investigators tried to show change of thalamus with various imaging studies. The volume of thalamus was decreased especially in patients with medial temporal lobe epilepsy (TLE) in a volumetric study and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) also showed thalamic hypometabolism in patients with medial TLE. These findings showed close connection of thalamus with medial temporal structure. The authors recently analyzed diffusion property of thalamus with diffusion tensor imaging study in pathologically and clinically confirmed medial and lateral TLE patients. This result showed that diffusivity of thalamus was increased in bilateral thalamus and the change was remarkable in medial TLE patients. It is controversial whether the thalamic changes are a result of recurrent seizures or are an inherent characteristic of a seizure network. The degree of change was correlated with seizure onset age or duration and this finding may suggest that thalamic changes might be the result of recurrent seizures. However, such a finding was not consistent. These results imply that such changes might be an inherent characteristic of a seizure network. However, without longitudinal observation, the authors could not differentiate whether the thalamic changes are a result of recurrent seizures or are an inherent characteristic of the network. Considering the results from previous studies and ours, they suggest that the thalamic abnormality is initially present as a bilateral gliosis or neuronal loss in patients with medial and lateral TLE, and that repetitive electrical discharges from the hippocampus in meidal TLE further increase diffusivity in the ipsilateral thalamus, e.g., by causing increased gliosis or cell death.

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In: Thalamus: Anatomy, Functions and Disorders ISBN 978-1-61324-152-3 Editor: Justin L. Song, pp. 1-31 © 2011 Nova Science Publishers, Inc.

Chapter I

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Current Use of Thalamic Surgeries for Treating Movement Disorders Ryoma Morigaki1,2, Shinji Nagahiro1,2, Ryuji Kaji1,3 and Satoshi Goto1,3* 1

Parkinson Disease and Dystonia Research Center, Tokushima University Hospital, University of Tokushima, Japan 2 Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima, Japan 3 Department of Clinical Neuroscience, Institute of Health Biosciences, University of Tokushima, Japan

Abstract Recent advances in the understanding of functional motor brain circuits as well as neuroimaging and neurosurgical techniques provide a *

Correspondence to: Satoshi Goto, MD, PhD Parkinson Disease and Dystonia Research Center, Tokushima University Hospital, University of Tokushima. Department of Clinical Neuroscience, Institute of Health Biosciences, University of Tokushima, Tokushima 7708503, Japan E-mail: [email protected]. Tel: +81-88-633-7149/Fax: +8188-632-9464

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Ryoma Morigaki, Shinji Nagahiro, Ryuji Kaji, et al. growing body of evidence suggesting that stereotactic surgery (e.g., deep brain stimulation or ablation surgery) is a powerful and safe therapeutic option for medically intractable Parkinson’s disease and other movement disorders. For more than 50 years, the ventrolateral thalamus has been a major target for stereotactic interventions in the treatment of movement disorders. It plays a pivotal role in the basal ganglia-thalamo-cortical circuit, which is involved in motor brain functions. The entire output of the basal ganglia is directed to the motor cortex via the ventrolateral thalamus where the basal ganglia and cerebellar projections terminate predominantly in the nucleus ventralis oralis (Vo nucleus) and the nucleus ventralis intermedius (Vim nucleus), respectively. This review introduces the current use of stereotactic thalamic surgeries that modulate the neural activities of the Vo complex nucleus and the Vim nucleus for treating movement disorders.

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Introduction Because the ventrolateral (VL) nucleus of the thalamus plays a crucial role in motor control, it is an anatomical target for stereotactic surgeries for the treatment of movement disorders. It preferentially receives afferent fibers from the cerebellum, basal ganglia, cerebral cortices, and spinal cord and projects their efferents toward the cerebral cortices and basal ganglia. Extensive studies on primate brains provide strong evidence that the thalamic VL nucleus has 2 major functional territories: the nucleus ventralis intermedius (Vim nucleus) and the nucleus ventralis oralis (Vo nucleus) (Hassler, 1959). The Vo nucleus is subdivided into the ventrooralis anterior (Voa) nucleus and the ventrooralis posterior (Vop) nucleus. The Vim nucleus preferentially receives the excitatory cerebellothalamic inputs that originate in the cerebellar nuclei, whereas the Vo complex nucleus receives inhibitory pallidothalamic inputs from the globus pallidus internus (GPi) (Asanuma et al., 1983a, b; Anderson and Turner, 1991; Kultas-Ilinsky and Ilinsky, 1991; Ilinsky et al., 2002). This review introduces the current use of thalamic surgeries that modulate neural activities of the Vim and Vo nuclei for treating movement disorders.

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1. Surgical Anatomy of the Motor Thalamus

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Accumulating evidence in humans and non-human primates suggests that the thalamic VL nucleus acts not only as a relay but also as a region for convergence and functional integration of all inputs from the cerebellum, GPi, cortex, and spinal cord. The afferents from the cerebellum and the GPi innervate the thalamic VL nucleus in a topographic manner (for reference see, Figure 1). The differentially weighted influences on these thalamic inputs originating from the cerebellum and basal ganglia could be important when considering the effects of thalamic surgery, including adverse events.

Figure 1. Major fiber connections of the Vim and Vo nuclei in movement disorders. Abbreviations: PMc, primary motor cortex; SMA, supplementary motor area; PM, premotor cortex; GPe, globus pallidus externa, STN, subthalamic nucleus; GPi, globus pallidus internus; SNr, substantia nigra pars reticulata.

1.1. Cerebellothalamic Connections Cerebellothalamic connections have been suggested to play a critical role in tremor genesis (Timmermann, 2007; Mure et al., 2011). There is a posterior-to-anterior gradient in the heightened density of the cerebellothalamic afferents in the thalamic VL nucleus (Percheron et al., 1996; Sakai et al., 1996; Galley et al., 2008) (Figure 2A). The Vim nucleus receives a massive number of afferent fibers from the contralateral cerebellum (Lang et al., 1979; Asanuma et al., 1983 a, b; Berkley, 1983) and sends its efferent projections predominantly to the deep area of the motor cortex (e.g. primary

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motor cortex), which responds to passive joint movements (Butler et al., 1992; Vitek et al., 1994; Jones, 2007). The neurons within the Vim nucleus are distributed in a somatotopic fashion: the facial-, forelimb-, and hindlimbreceptive fields are arranged in the medial to lateral direction (Strick, 1976; Asanuma et al., 1983b; Vitek et al., 1994; Ohye, 1997). The cerebellothalamic pathway plays a role in the fine spatial and temporal tuning of coordinated movements as well as in the learning and retention of new motor skills. Thus, functional interference might also be achieved in deep cerebellar nuclei and affect activities in the striatum and cerebral cortices via the VL nucleus related to the ongoing and intended movements (Rispal-Padel 1987 a, b; Craig, 2008).

Figure 2. Afferent fiber inputs to the thalamic VL nucleus on the axial view. Note a gradient pattern of the cerebellothalamic innervations (A, red), or of the pallidothalamic inputs (B, blue). Abbreviations: Vim, ventralis intermedius; Voa, ventrooralis anterior; Vop, ventrooralis posterior, a, anterior; l, lateral; m, medial; p, posterior.

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1.2. Pallidothalamic Connections The thalamic Vo nucleus receives massive afferents from the ipsilateral ventrolateral part of the GPi (Kuo and Carpenter, 1973;Ilinsky and Kultasilinsky, 1987; Kultas-Ilinsky et al., 1997; Sidibé et al., 1997; Nakano, 2000) via the ansa lenticularis and fascicularis lenticularis (Nauta and Mehler, 1966; Starr et al., 1998; Galley et al., 2008) and projects its efferent fibers toward cortical regions such as the primary motor, premotor, and supplementary motor cortical areas (Ilinsky and Kultas-ilinsky,1987; Nakano, 2000). There is an anterior-to-posterior gradient in the heightened density of the pallidothalamic afferents in the VL nucleus (Figure 2B). Sakai et al. (1996) revealed a wide intermingling of the cerebellothalamic and pallidothalamic projections within the VL nucleus, suggesting that it transgresses the cytoarchitectonic boundary between the Voa and Vop where the cerebellothalamic and pallidothalamic afferents are demarcated (Asanuma et al., 1983 a, b).

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1.3. Spinothalamic Connections The spinothalamic tract in primates is thought to consist of anatomically and functionally different components (Craig, 2006; Craig and Zhang, 2006; Craig, 2008). The spinothalamic inputs of the VL nucleus originate entirely from the laminae V and VII neurons of the spinal cord. The spinothalamic inputs to the posteroventral part of the VL nucleus highly innervate in a posterior-to-anterior gradient, suggesting coexistence with the cerebellothalamic inputs that have the same gradient pattern. These findings suggest that the posteroventral part of the VL nucleus is not simply a relay of the primary cerebellothalamic inputs; rather, it might be the site of the convergence of movement-related activities conveyed by the spinothalamic and cerebellothalamic pathways (Craig, 2008).

1.4. Thalamostriatal Connections The thalamic ventral motor nuclei send their projections, which are largely collaterals of the thalamocortical efferent axons, to the sensorimotor territory within the striatum (Smith et al., 2009). The sensorimotor striatum receives highly topographic convergent inputs from the ventral motor thalamus and

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multiple cortical regions such as the primary motor, premotor, and supplementary motor areas (McFarland and Haber, 2000, 2001). These lines of evidence indicate possible interactions between the thalamic and cortical inputs at the striatum level and suggest that the thalamic ventral motor nuclei act not only as relay nuclei but also as highly ordered nuclei that may provide positive feedback to the sensorimotor striatum (Smith et al., 2004). It is suggested that this feedback system sustains the disinhibition of ongoing specific thalamocortical circuits until its goal is achieved; alternatively, it might reinforce or facilitate the selective basal ganglia circuit that suppress unwanted movements (McFarland and Haber, 2000).

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1.5. Thalamocortical Connections In the thalamic VL nucleus, the territory innervated by the pallidal afferents sends its projections predominantly to the primary motor and posterior premotor cortices, whereas the territory innervated by the cerebellar afferents sends its projections predominantly to the primary motor, premotor, and pre-supplementary motor cortices (Rouiller et al., 1994; Sakai et al., 2002; Morel et al., 2005). It seems that there is a divergence and convergence of projections from the pallidal and cerebellar afferent receiving thalamic areas to multiple areas of the motor and premotor cortices (Morel et al., 2005). Different sets of cortico-thalamo-basal ganglia loops are suggested to have specialized functions depending on the cortical areas participating in these loops (Alexander and Crutcher, 1990). Reciprocal thalamocortical connections play a role in maintaining these parallel processing loops. Functionally segregated parallel loops could be integrated via the non-reciprocal connections between the striatum and substantia nigra and within the convergent spots of the corticostriatal projections arising from functionally different cortical areas (Harber and Calzavara, 2009). Similar integration may also occur via the non-reciprocal thalamocortical connections between the thalamus and cortex, which terminate in the superficial and deep cortical layers. Their terminals could influence the different cortical areas that in turn, project toward the striatum sending efferents back to the thalamus. In addition, the non-reciprocal corticothalamic projections terminate in the thalamic regions participating in other processing loops (McFarland and Haber, 2002). The convergent spots of afferent terminals from different cortical areas may also occur in the thalamus similar to that in the striatum (Haber, 2003; Haber and Calzavara, 2009).

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1.6. Thalamic Local Circuitry The ventrolateral thalamus largely consists of medium-sized neurons that project glutamatergic excitatory axons. There are also GABAergic inhibitory interneurons that form local circuits within the thalamus (Ilinsky et al., 1997, 2002). In the cerebellar afferent-receiving area, the thalamocortical projecting neurons receive glutamatergic excitatory afferents from the deep cerebellar nuclei, which also give excitatory collateral branches to the local circuit neurons that possess many dendro-dendritic synapses providing complex feedforward inhibition or excitatory inputs to the thalamocortical projecting neurons. In the pallidal afferent-receiving area, the thalamocortical projecting neurons receive GABAergic inhibitory afferents from the GPi. These pallidothalamic projections also provide inhibitory collateral branches to the local circuit neurons that provide inhibitory outputs to the projecting neurons located in the Vim nucleus. The thalamocortical projections also provide excitatory branches to the thalamic reticular nucleus, which in turn provides feedback inhibition to the thalamocortical projecting neurons (Ilinsky et al., 1997). The corticothalamic afferents provide excitatory glutamatergic inputs over the entire ventrolateral thalamus. Type 1 corticothalamic fibers give rise to synapses on distal dendrites of thalamocortical projecting neurons, whereas type 2 corticothalamic fibers provide synaptic contacts on proximal dendrites of projecting neurons and on the dendrites of local circuit neurons that provide feedforward inhibition. The reticular nucleus receives excitatory inputs from the cortex and provides GABAergic inhibitory synapses on the thalamocortical projecting neurons. In addition, about 50% of synapses of the reticular nucleus establish feedforward disinhibitory connections to the proximal dendrites of the projecting neurons via the synapses on the local circuit neurons. The spinothalamic afferents do not provide synapses on the local circuitry neurons (Ilinsky, 2002). Thus, the local thalamic circuitry may be involved in a significant amount of processing, especially by increasing the temporal resolution of the afferent information before projecting to the cortices. These local inhibitory neurons are also required for network synchronization (Huguenard, 1999).

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2. Thalamic Vim Surgery Anatomical target for Vim surgery is illustrated in Figure 3. Vim surgery has largely been used in the treatment of medically intractable tremors. Tremor suppression is achievable irrespective of age, disease duration, or baseline disease severity (Benabid et al., 1996; Schuurman et al., 2008). The precise mechanism underlying the genesis of tremors is currently unknown. However, abnormal synchronization of neuronal firings of the basal ganglia-thalamocortical loop is suggested to be involved in parkinsonian, dystonic, and Holmes’ tremors; meanwhile, similar firings in the cerebello-thalamo-cortical loop are involved in essential, cerebellar, and Holmes’ tremors (Plaha et al., 2008). The therapeutic mechanism of thalamic Vim deep brain stimulation (DBS) also remains unclear. Four different hypotheses have been proposed for the mechanism underlying DBS with respect to tremor suppression. The first proposed mechanism is a “conduction block.” This hypothesis is supported by evidence that Vim thalamotomy has similar effects to Vim DBS (Benabid et al., 1996). The second mechanism is the activation of inhibitory axon terminals that synapse on and inhibit the projection neurons (Wu et al., 2001). The third mechanism is the superposition of continuous stimuli onto rhythmically oscillating subcortical-cortical loops (Montgomery and Baker, 2000). The last proposed mechanism is that high-frequency stimulation inhibits neuronal activities near the stimulation site but activates axonal elements leaving the target structure (Vitek, 2002). The therapeutic impacts of thalamic Vim surgery on various types of tremors are listed below.

B

A

Vo Vim

Vo Vim

Figure 3. Stereotactic targets for Vim and Vo thalamic surgeries. Targets for the Vim (red) and Vo (yellow) nuclei are shown on the axial (A) and sagittal (B) planes. Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders, edited by Justin L. Song, Nova Science

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2.1. Vim DBS Complete arrest of tremors is usually achieved immediately by continuous stimulation of the Vim nucleus at high frequency (at least 100 Hz); these effects are completely reversible (Benabid, 1996). In general, resting tremor is better controlled than action tremor, distal limb tremor better than proximal limb tremor, and upper limb tremor better than lower limb tremor (Benabid et al., 1996, 1998; Lozano, 2000). Katayama et al. (2005) postulate that the most important target site for alleviating tremor is the lateral portion of the Vim nucleus. This is where the so-called “tremor cells” that can burst discharges synchronized with the muscle discharges caused by tremors (Ohye et al., 1974; Lenz et al., 1988) may play a role in controlling parkinsonian tremor, as suggested previously (Hariz et al., 1997; Atkinson et al., 2002). The authors also describe that in essential and post-stroke tremors, tremor cells may be spread out more anteriorly and dorsally in the VL nucleus; thus, the tremor could also involve more proximal muscle components. Indeed, other reports also indicate that stimulation of a wider area spreading more anteriorly and dorsally in the VL nucleus could result in the best control of essential tremor (Nguyen et al., 1993; Kiss et al., 2003; Papavassiliou et al., 2004; Yamamoto et al., 2004). 2.1.1. Parkinson’s disease In a series of 111 limbs in 80 patients, Benabid et al. (1996) demonstrated complete or nearly complete tremor resolution in 88% of patients with Parkinson’s disease (PD) at the time of the last follow-up (range, 0.5–8 years). Other studies report similar results (Benabid et al., 1991; Blond et al., 1992; Pollak et al., 1993; Alesch et al., 1995; Benabid et al., 1998; Tasker, 1998; Schuurman et al., 2000; Krauss et al., 2001). Based on blinded assessments, Koller et al. (1997) report a significant and marked improvement in global disabilities in 58% of their patients 3 months postoperatively. Rehncrona et al. (2003) found a marked (~70%) reduction in the tremor score determined by the unified Parkinson disease rating scale (UPDRS) at a mean follow-up period of 2.1 years. With a mean follow-up period of 6.6 years, the authors also report a 64% improvement of the UPDRS tremor score in their doubleblinded study of 12 PD patients. In this series, the authors found no significant changes in the stimulus parameters and a significant (~1.8-fold) increase in the intake dosage of dopaminergic drugs compared to the preoperative baseline. Tarsy et al. (2005) report that rest and postural tremors were improved by 94% and 84%, respectively, as determined by the UPDRS score at a mean follow-

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up period of 5.5 years, during which other PD symptoms were unchanged; however, the L-dopa dose needed to be significantly increased up to about 2 times as much as that at the preoperative baseline. Pahwa et al. (2006) report that unilateral stimulation resulted in an 85% improvement in the hand tremor score in the UPDRS with a follow-up period of 5 years, whereas bilateral stimulation produced 90% and 100% improvement in the right and left hands, respectively. In a series of 46 limbs in 38 patients with a mean follow-up period of 6.6 years, Hariz et al. (2008) report a 93% improvement in the UPDRS tremor score without any significant changes in the stimulating parameters and the L-dopa dose. It was noted that PD tremor reoccurred in ~5% of the patients several weeks or years after the surgery (Benabid et al., 1996; Tasker, 1998). Thus, stable long-term tremor suppression can be obtained with Vim DBS in PD patients despite disease progression (Schuurman et al., 2008). Non-tremor PD signs usually remain unchanged after Vim stimulation during either short- or long-term follow-up periods (Blond, 1992; Benabid et al., 1996; Putzke, 2003; Pahwa, 2006). According to the disease progression, the UPDRS motor scores related to axial symptoms are indeed significantly worse within 5 years after surgery. These findings may be concordant with accumulating data suggesting that the genesis of tremors has a pathophysiology different from that of other PD symptoms such as akinesia and rigidity. However, some studies have reported that the therapeutic effects of Vim DBS on akinesia, rigidity, and L-dopa-induced dyskinesias (LID) are side effects of tremor alleviation (Blond, 1992; Tasker, 1998; Limousin et al., 1999; Putzke et al., 2003; Rehncrona et al., 2003; Pahwa, 2006). The additional benefits of Vim DBS may be attributed to the current spreading to the Vop nucleus or its related afferent fibers. Although the UPDRS-ADL scores significantly improved at the shortterm follow-up (Benabid et al., 1996; Koller et al., 1997; Hariz et al., 1999; Limousin et al., 1999; Shuurman et al., 2000; Putzke et al., 2003; Shuurman et al., 2008), they reportedly returned to the preoperative baseline at the longterm follow-up (Pahwa et al., 2006; Shuurman et al., 2008). The stimulus amplitude often needs to be increased because of progression of PD and/or the so-called “tolerance” phenomenon, which is also known as “habituation” to electrostimulation of the neuronal network (Benabid et al., 1996; Koller et al., 1997; Hariz et al., 1999). This undesirable increase in amplitude often causes paresthesia and cerebellar signs such as dysmetria and hypotonia (Benabid et al., 1996; Yamamoto et al., 2004). Regarding the neuropsychological consequences of Vim DBS, it has been suggested that there are significant improvements in verbal memory (Tröster et al., 1998; Hugdahl and Wester,

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2000; Woods et al., 2001), conceptualization, and emotional adjustment (Woods et al., 2001), whereas verbal frequency declines because of left-side stimulation (Schuurman et al., 2000). A recent report on the effects of bilateral subthalamic nucleus (STN) stimulation in patients with previous Vim surgery revealed a significant improvement in the UPDRS total motor, tremor, and ADL scores, although axial motor symptoms and neuropsychological status were unchanged (Fraix et al., 2005). Given that bilateral STN stimulation greatly improves PD motor symptoms, including tremors, Krack (1997) suggests that STN DBS is preferable to Vim DBS even in tremor-dominant PD patients. 2.1.2. Essential Tremor A high rate of limb tremor alleviation was documented in short-term follow-up studies (Blond et al., 1992; Ondo et al., 1998; Hariz et al., 1999; Koller et al., 1999; Schuurman et al., 2000; Krauss et al., 2001; Rehncrona et al., 2003). In a series by Benabid et al. (1996), 75% of 36 operated limbs exhibited complete or nearly complete tremor resolution at the 3-month follow-up. Blinded assessments showed a marked reduction in the tremor score and a significant improvement in the disability score (Koller et al., 1997; Schuurman et al., 2000; Rehncrona et al., 2003). Recent data with long-term (more than 5 years) follow-ups also demonstrated the long-lasting efficacy of Vim DBS on essential tremor (ET). Using the essential tremor rating scale (ETRS), Rehcrona et al. (2003) found that tremor and hand function scores improved by 47% and 71%, respectively, at a mean follow-up period of 6.5 years. Pahwa et al. (2006) report that in 30 limbs of 23 patients, Vim DBS resulted in 75% improvement in targeted hand tremors by unilateral stimulation, 65% improvement in the left limb, and 86% in the right limb by bilateral stimulation, with 36% and 51% improvement in ADL by unilateral and bilateral stimulation, respectively. Using the Fahn-Tolosa-Marin clinical rating scale, Zhang et al. (2008) report a 80.4% and 69.7% improvement of tremor and handwriting scores, respectively, in a series of 34 patients with a follow-up period of about 5 years. Sydow et al. (2003) report a 41% reduction in ETRS scores and a 39% improvement in the ETRS-ADL scores with a follow-up period of 6.5 years when there was small change in stimulation parameters and medication dose. Hariz et al. (2008) report a 49% and 18% reduction in ETRS scores at the follow-up periods of 1 and 7 years, respectively. Head tremor also can be treated by bilateral Vim DBS (Ondo et al., 1998; Koller et al., 1999; Taha et al., 1999), although its therapeutic efficacy is reported to vary (Limousin et al., 1999; Obwegeser et al., 2000;

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Sydow et al., 2003; Putzke et al., 2005). With respect to voice tremor, some studies report significant and marked (more than 80%) improvement (Taha et al., 1999; Obwegeser et al., 2000), whereas others report minimal changes in either short- or long-term follow up studies (Limousin et al., 1999; Sydow et al., 2003; Putzke et al., 2005). ET patients (39–51%) treated with Vim DBS showed long-lasting improvements in ADL scores over a 5-year follow-up period (Sydow et al., 2003; Pawha et al., 2006). The recurrence of ET seems to be higher than that of PD tremor (Benabid et al., 1996; Tasker, 1998; Pilitsis et al., 2008). Poor outcomes have been documented in up to 40% of ET patients (Hariz and Hirabayashi, 1997; Benabid et al., 1998; Hariz et al., 1999; Koller et al., 2001; Kumar et al., 2003). Stimulus tolerance (habituation) to DBS was found in 9% of patients (Papavassiliou et al., 2004), and such cases have been treated by subsequent thalamotomy (Oh et al., 2001). Pilitsis et al. (2008) report a correlation of tremor reccurrence with the suboptimization of lead positioning in an anteriorto-posterior direction. 2.1.3. Other Types of Tremors Vim DBS suppresses tremors in more than 60% of patients with multiple sclerosis (MS) (Schulder et al., 1999; Bitter et al., 2005; Shuurman et al., 2008). Bitter et al. (2005) demonstrated better outcomes with thalamotomy than thalamic DBS in MS patients. Given that MS tremors can have various origins depending on the locations of the responsible sclerotic lesions (Benabid et al., 1996), the authors suggest that it is necessary to influence a wide thalamic area in order to alleviate MS tremors. Vim DBS is also effective for posttraumatic and postapoplectic tremors (Broggi et al., 1993, Benabid et al., 1996; Yamamoto et al., 2004). Yamamoto et al. (2004) suggest treating the broad area affected by DBS in the Vim–Vop region for alleviating these types of tremors, similar to the treatment of MS tremor. In this context, Nguyen and Degos (1993) report an interesting finding that Vim stimulation produces a therapeutic impact on distal limb tremors, whereas Vop stimulation produces this effect on proximal limb tremors such as cerebellar postural tremor (also called action or intention tremor). 2.1.4. Myoclonus-Dystonia Syndrome There are several reports on the beneficial effects of Vim DBS on myoclonus-dystonia syndrome, characterized by both myoclonic jerks and dystonia (Kupsch et al. 1999; Trottenberg et al., 2001; Kuncel et al., 2009; Gruber et al., 2010; Oropilla et al., 2010). Gruber et al. (2010) implanted DBS

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leads into the Vim and GPi in 10 patients with this syndrome and report that the therapeutic efficacy for alleviating myoclonus of Vim DBS is comparable to that of GPi DBS. Oropilla et al. (2010) report a single patient who underwent unilateral DBS of both the Vim and GPi. The authors state that tremor, dystonia, and myoclonus were more effectively suppressed with GPi DBS than with Vim DBS and that dystonia was best alleviated with simultaneous stimulation of both the GPi and Vim. Vim DBS with a high frequency (more than 100 Hz) immediately reduces myoclonus, whereas low frequencies (10–15 Hz) worsen myoclonus (Bejjani et al., 2000; Kuncel et al., 2009). This frequency-dependent response of myoclonus to Vim DBS reportedly resembles that of tremor (Benabid et al., 1996). 2.1.5. Adverse Effects Related to Vim DBS Stimulation-related complications and their incidences in the literature concerning long-term (more than 5 years) follow-ups are described as follows: paresthesias (0–38%), dysarthria (0–36%), gait disturbance (0–19%), dystonia/hypertonia (0–16%), balance disturbance (0-8%), and cognitive dysfunction (0-3%). (Rehncrona et al., 2003; Sydow et al., 2003; Pawha et al., 2006; Tarsy et al., 2006; Hariz et al., 2008; Schuurman et al., 2008). Among these adverse effects, non-adjustable and long-lasting complications include paresthesia (0-19%), dysarthria (0-19%), dystonia (0-6%), gait disturbance (04%) and upper limb ataxia (0–4%). Pahwa et al. (2006) report that bilateral stimulation can cause persistent complications that include dysarthria, disequilibrium, and gait disturbance even if stimulus parameters are optimized. The incidence of infection in patients appears to be 0–13% throughout the postoperative course (Rehncrona et al., 2003; Sydow et al., 2003; Tarsy et al., 2005; Hariz et al., 2008; Schuurman et al., 2008). Hardware-related complications are found in 4–37% of patients (Rehncrona et al., 2003; Sydow et al., 2003; Tarsy et al., 2005; Pawha et al., 2006; Blomstedt et al., 2007; Hariz et al., 2008; Schuurman et al., 2008).

2.2. Radiofrequency Vim Thalamotomy Vim thalamotomy can produce long-term tremor suppression; its therapeutic efficacy may be comparable to that of Vim DBS (Schuurman et al., 2000, 2008). However, ablation surgery can potentially cause undesirable and irreversible tissue damage; thus, Vim thalamotomy has been largely replaced by Vim DBS. Furthermore, there is a consensus that bilateral thalamotomy

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should be considered a contraindicated procedure. However, Vim thalamotomy on 1 side could still be an option for medically intractable tremors or if (1) a patient dislikes the implantation; (2) a patient cannot cope with the stimulators; (3) the tremor involves proximal limbs, thereby necessitating extensive lesioning, as often seen in cerebellar, Holmes’, and MS tremors; and (4) habituation or tolerance to electrostimulation occurs after Vim DBS. 2.2.1. Parkinson’s Disease Vim thalamotomy on the side contralateral to the tremor results in total or nearly complete suppression of the tremor in 86–96% of patients (Kelly and Gillingham, 1980; Tasker et al., 1983; Nagaseki et al., 1986; Fox et al., 1991; Jankovic et al., 1995; Schuurman et al., 2000). However, Kelly and Gillingham (1980) report that the tremor abolition rate is reduced to less than 60% of patients 10 years after surgery. There is controversy regarding the benefits of Vim thalamotomy for alleviating non-tremor PD symptoms. Some authors state that Vim thalamotomy has no impact on any other PD symptoms (Kelly and Gillingham, 1980; Diederich et al., 1992). However, for some patients, Vim thalamotomy resulted in reduced contralateral rigidity (Kelly and Gillingham, 1980; Tasker et al., 1983; Tasker, 1998) and LID (Nagaseki et al., 1986, Fox et al., 1991; Tasker, 1998). Ohye (1997) suggests that alleviation of rigidity and LID is attributable to the additional involvement of the Vop nucleus. 2.2.2. ET and Other Types of Tremors ET can be satisfactorily suppressed by Vim thalamotomy for long periods in more than 80% of patients (Nagaseki et al., 1986; Jankovic et al., 1995). Goldman et al. (1992a) report that voice tremor was significantly improved in more than 70% of patients. Posttraumatic and cerebellar tremors may also be good candidates for Vim thalamotomy (Goldman et al., 1992b; Krauss, 1994; Jankovic et al., 1995). MS tremor reportedly responds to thalamotomy with an initial improvement of more than 90%; however, it subsequently recurred in 30% of patients (Goldman et al., 1992b). Bitter et al. (2005) report that for MS patients, thalamotomy produces better clinical outcomes but more adverse events compared to those of thalamic DBS. Some reports provide evidence that MS tremor may be more favorably alleviated by lesioning both the Vop and zona incerta (Nandi et al., 2002; Bitter et al., 2005).

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Current Use of Thalamic Surgeries for Treating Movement Disorders 15 2.2.3. Adverse Effects Related to Vim Thalamotomy Thalamotomy-related complications during long-term follow-up are as follows: dysarthria (6–25%), gait and balance disturbance (0–18%), contralateral motor weakness (0–15%), cognitive dysfunction (0–14%), upper limb dyspraxia (0-6%), and dysphasia (0-3%) (Nagaseki et al., 1986; Fox et al., 1991; Goldman et al., 1992a,b; Jankovic et al., 1995; Schuurman et al., 2008). Bilateral thalamotomy is no longer recommended because it carries a high risk of irreversible speech and cognitive complications (Tasker et al., 1983).

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2.3. Gamma Knife Thalamotomy As an alternative to radiofrequency Vim thalamotomy, gamma knife thalamotomy (GKT) is used in the treatment of intractable tremors. In general, GKT produces favorable outcomes when treating tremors, with success rates ranging from 80-100% (Elaimy et al. 2010). The beneficial effects of GKT are usually observed approximately 1 year after irradiation (Ohye et al., 2000). During long-term (more than 2 years) follow-up, complete or nearly total tremor relief was found in 50–88.3% of PD patients, 50–92% of ET patients, and 50% of MS patients. (Duma et al., 1998; Young et al., 2000; Mathieu et al., 2007; Kondziolka et al, 2008). Niranjan et al. (1999) suggest that therapeutic efficacy of GKT in alleviating tremors is equal to that of radiofrequency Vim thalamotomy. Using a clinical scale for tremors, Young et al. (2010) evaluated 161 ET patients for a mean follow-up period of 44 months and found that writing and drawing scores were significantly reduced by 58% and 51%, respectively, compared to the preoperative baseline. However, Lim et al. (2010) recently reported a blind study on 18 patients with intractable tremors, and suggest that GKT only improves the ADL scores on the Fahn– Tolosa–Marin Tremor Rating Scale but does not alleviate tremors. The major complications of GKT include paresthesia, dysarthria, and motor paresis due to lesioning or subacute/delayed edema. In series with longterm (more than 2 years) follow-up, these adverse effects were found in 0– 16.7% of patients (Duma et al., 1998; Mathieu et al., 2007; Kondziolka et al, 2008 Young et al., 2010). GKT can be considered an alternative to radiofrequency lesioning in select patients who are considered unsuitable for invasive open surgery because of anticoagulant use or advanced cardiac or respiratory diseases. Patients who refuse to undergo open surgery and/or IPG implantation may also be candidates for GKT.

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3. Thalamic Vo surgery Anatomical target for Vo surgery is illustrated in Figure 3. Based on evidence indicating that the Vo nucleus receives massive afferents originating from the GPi, Vo surgery has been widely used for treating hyperkinetic involuntary movement disorders associated with functional impairment of the thalamo-cortical-basal ganglia circuitry. The therapeutic uses of Vo surgery in the treatment of movement disorders are introduced below.

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3.1. Focal Hand Dystonia (Writer’s Cramp) Focal hand dystonia (FHD) is a primary dystonia produced by excessive co-contraction of antagonistic muscles of the hand and forearm (Sheehy and Marsden, 1982; Cohen and Hallett, 1988). Oral medications and botulinum toxin injections are the first-line treatments; however, thalamic surgery is also used to treat medically refractory FHD in a limited number of patients. Andrew et al. (1983) report a patient with dystonic writer’s cramp in whom hand dystonia was initially improved but relapsed 6 weeks after lesioning of the Vim and the nucleus ventralis caudalis internus and externus. Goto et al. (1997) first used selective Vo complex (Voa and Vop) thalamotomy in a patient with dystonic writer’s cramp in whom immediate and complete relief of dystonia symptoms was observed after surgery. This therapeutic effect of Vo thalamotomy in patients with FHD also has been documented in subsequent reports (Taira and Hori, 2003; Shibata et al., 2005). Taira and Hori (2003) report no incidence of either mortality or permanent morbidity in their series of 12 cases. Vo DBS has been recently used in patients with FHD. Fukaya et al. (2007) implanted DBS leads into the Vim nucleus passing through the Vo nucleus in 5 patients with writer’s cramp; they placed an additional single DBS lead in the GPi in 1 patient. The authors report that the therapeutic effects of thalamic DBS are better than those of GPi DBS and that bipolar stimulation of both the Vo and Vim nuclei provides the maximum benefit. Goto et al. (2008) report a patient with FHD in whom the DBS leads were simultaneously implanted into both the Vo nucleus and GPi (Figure 4). With a 3-year follow-up, the authors report that both Vo and GPi DBS produced immediate and complete relief of FHD independent of each other. Although the optimal medical or surgical therapy for FHD is debatable (Jankovic, 2006), clinical evidence suggests that

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thalamic Vo surgery is an alternative surgical option for the treatment of medically refractory FHD.

Figure 4. Electrode locations and stimulation results in a patient with focal hand dystonia. (A, B) Frontal (A) and lateral (B) views of the radiologic location of the deep brain stimulation implanted in the Vo nucleus (Vo) and globus pallidus internus (GPi). ML, midline; AC, anterior commissure, PC, posterior commissure. (C, D) Without stimulation, the patient’s left hand showed spontaneous dystonic postures characterized by flexion deformity of the fingers and wrist. A paper cup held in the left hand was crushed involuntarily. (E, F) Thalamic Vo stimulation alone immediately and completely suppressed the left-hand dystonia.

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3.2. Generalized Dystonia Before the emergence of pallidal DBS, thalamotomy was used for treating severe generalized dystonia. In a large series by Cooper (1976), Vo thalamotomy produced a marked improvement in 24.5% of patients and mildto-moderate improvement in 45.2% of patients with a mean follow-up period of 7.9 years. Other series also report unfavorable outcomes and a high rate of irreversible complications that occurred especially after bilateral lesioning (Gros et al., 1976; Andrew et al., 1983; Tasker et al., 1988; Yamashiro and Tasker, 1993; Cardoso et al., 1995; Yoshor et al., 2001). Additional lesioning of the centromedian nucleus provides further improvement in some patients (Cooper, 1976; Andrew et al., 1983). Individual body regions are somatotopically arranged in the thalamus, with the leg region being represented in the outmost lamella and the trunk, arm, and orofacial regions in the deeper lamella across multiple subnuclei of the thalamus. This indicates that only minimal improvement is conferred by small lesions (e.g., thalamotomy) in patients with generalized dystonia (Vitek et al., 1994; Vitek, 1998). With the increasing success of bilateral GPi DBS for generalized dystonia, the globus pallidus is now the primary target for treating generalized dystonia (Jankovic, 2006).

3.3. Hemichorea and Ballism Chorea/ballism is characterized by brief, irregular, non-rhythmic muscle contractions that produce poorly patterned movements involving the more distal limbs in chorea and the more proximal limbs in ballism (Fahn, 1998). A small number of cases exhibit long-term suppression of this hyperkinetic disorder after Vo thalamotomy (Cardoso et al., 1995; Goto et al., 2001), Vo thalamotomy combined with lesioning of the zona incerta (Krauss and Mundinger, 1996), and thalamic DBS (Thompson et al., 2000). Appropriate sizing and accurate positioning of the stereotactic lesion is suggested to be of the utmost importance for obtaining maximum benefit (Goto et al., 2001).

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Conclusion Currently, thalamic Vim DBS is one of the first-line treatments for various medically intractable tremors. Although its therapeutic impact on ADL outcome gradually decreases, its impact on long-term tremor suppression is promising. Among the surgical options for treating PD, STN DBS is currently considered the most effective procedure when the disease progression is taken into consideration, even in patients with tremor-predominant PD (Krack et al., 1997). However, tremor-predominant PD originally has a better clinical prognosis because of its slower progression (Louis et al., 1999); therefore, Vim DBS could still be optimal for this type of PD, particularly in aged or cognitively impaired patients. The main advantage of Vim DBS is characterized by less permanent side effects even after bilateral stimulation. Moreover, Vim DBS could suppress PD tremor directly without any significant changes in L-dopa dose. Because of the potential risk of undesirable and irreversible tissue damage caused by radiofrequency Vim thalamotomy, the use of this therapy may be limited to select patients who cannot undergo Vim DBS or obtain satisfactory results with Vim DBS. GKT may be an alternative to radiofrequency Vim thalamotomy, but its use may be further limited to specific patients who cannot undergo radiofrequency Vim thalamotomy or Vim DBS. Data on the therapeutic effects of Vo surgery for movement disorders are limited. However, accumulating evidence suggests that Vo thalamotomy and DBS are valuable surgical options for alleviating medically refractory FHD. Vo surgery may also relieve chorea/ballism; however, our experience is limited, and further clinical data are needed to determine its efficacy in comparison with GPi DBS. The current opinion is that GPi DBS is the first line of surgical treatment for severe generalized dystonia.

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Current Use of Thalamic Surgeries for Treating Movement Disorders 21 sensory pathways in lateral diencephalon. J Comp Neurol. 220(2), 229251. Bittar RG, Hyam J, Nandi D, Wang S, Liu X, Joint C, Bain PG, Gregory R, Stein J, Aziz TZ (2005). Thalamotomy versus thalamic stimulation for multiple sclerosis tremor. J Clin Neurosci. 12(6), 638-642. Blomstedt P, Hariz GM, Hariz MI, Koskinen LO (2007). Thalamic deep brain stimulation in the treatment of essential tremor: a long-term follow-up. Br J Neurosurg. 21(5), 504-509. Blond S, Caparros-Lefebvre D, Parker F, Assaker R, Petit H, Guieu JD, Christiaens JL (1992). Control of tremor and involuntary movement disorders by choronic stereotactic stimulation of the ventral intermediate thalamic nucleus. J Neurosurg. 77(1), 62-68. Broggi G, Brock S, Franzini A, Geminiani G (1993). A case of posttraumatic tremor treated by chronic stimulation of the thalamus. Mov Disord. 8(2), 206-208. Butler EG, Horne MK, Hawkins NJ (1992). The activity of monkey thalamic and motor cortical neurones in a skilled, ballistic movement. J Physiol. 445, 25-48. Cardoso F, Jankovic J, Grossman RG, Hamilton WJ (1995). Outcome after stereotactic thalamotomy for dystonia and hemiballismus. Neurosurgery, 36(3), 501-508. Cohen LG, Hallett M (1988). Hand cramps: clinical features and electromyographic patterns in a focal dystonia. Neurology, 38(7), 10051012. Cooper IS (1976). 20-year followup study of the neurosurgical treatment of dystonia musculorum deformans. Adv Neurol. 14, 423-452. Craig AD (2006). Retrograde analyses of spinothalamic projections in the macaque monkey: input to ventral posterior nuclei. J Comp Neurol. 499(6), 965-978. Craig AD, Zhang ET (2006). Retrograde analyses of spinothalamic projections in the macaque monkey: input to posterolateral thalamus. J Comp Neurol. 499(6), 953-964. Craig AD (2008). Retrograde analyses of spinothalamic projections in the macaque monkey: input to the ventral lateral nucleus. J Comp Neurol. 508(2),315-328. Diederich N, Goetz CG, Stebbins GT, Klawans HL, Nittner K, Koulosakis A, Sanker P, Strum V (1992). Blinded evaluation confirms long-term asymmetric effect of unilateral thalamotomy or subthalamotomy on tremor in Parkinson’s disease. Neurology, 42(7), 1311-1314.

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Current Use of Thalamic Surgeries for Treating Movement Disorders 23 Gros C, Frerebeau P, Perez-Dominguez E, Bazin M, Privat JM (1976). Long term results of stereotaxic surgery for infantile dystonia and dyskinesia. Neurochirurgia (Stuttg), 19(4), 171-178. Gruber D, Kühn AA, Schoenecker T, Kivi A, Trottenberg T, Hoffmann KT, Gharabaghi A, Kopp UA, Schneider GH, Klein C, Asmus F, Kupsch A (2010). Pallidal and thalamic deep brain stimulation in myoclonusdystonia. Mov Disord. 25(11), 1733-1743. Haber SN (2003). The primate basal ganglia: parallel and integrative networks. J Chem Neuroanat. 26(4), 317-330. Haber SN, Calzavara R (2009). The cortic-basal ganglia integrative network: the role of the thalamus. Brain Res Bull. 78(2-3), 69-74. Hariz MI, Hirabayashi H (1997). Is there a relationship between size and site of the stereotactic lesion and symptomatic results of pallidotomy and thalamotomy? Stereotact Funct Neurol. 69, 28-45. Hariz MI, Shamsgovara P, Johansson F, Hariz G, Fodstad H (1999). Tolerance and tremor rebound following long-term chronic thalamic stimulation for Parkinsonian and essential tremor. Stereotact Funct Neurosurg. 72(2-4), 208-218. Hariz GM, Blomstedt P, Koskinen LO (2008). Long-term effect of deep brain stimulation for essential tremor on activities of daily living and healthrelated quality of life. Acta Neurol Scand. 118(6), 387-394. Hariz MI, Krack P, Alesch F, Augustinsson LE, Bosch A, Ekberg R, Johansson F, Johnels B, Meyerson BA, N’Guyen JP, Pinter M, Pollak P, von Raison F, Rehncrona S, Speelman JD, Sydow O, Benabid AL (2008). Multicentre European study of thalamic stimulation for parkinsonian tremor: a 6 year follow-up. J Neurol Neurosurg Psychiatry, 79(6), 694699. Hassler R (1959). Introduction to stereotaxic operation with an atlas of the human brain. In: G. Schaltenbrand and P. Bailey (Eds.), Anatomy of the thalamus. (pp230-290). Stuttgart, Thieme. Hugdahl K, Wester K (2000). Neurocognitive correlates of stereotactic thalamotomy and thalamic stimulation in Parkinsonian patients. Brain Cogn. 42(2), 231-252. Huguenard JR (1999). Neuronal circuitry of thalamocortical epilepsy and mechanisms of antiabsence drug action. Adv Neurol. 79, 991-999. Ilinsky IA, Kultas-Ilinsky K (1987). Sagittal cytoarchitectonic maps of the Macaca mulatta thalamus with a revised nomenclature of the motorrelated nuclei validated by observasions on their connectivity. J Comp Neurol. 262(3), 331-364.

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Ilinsky IA, Yi H, Kultas-Ilinsky K (1997). Mode of termination of pallidal afferents to the thalamus: a light and electron microscopic study with anterograde tracers and immunocytochemistry in Macaca mulatta. J Comp Neurol. 386(4), 601-612. Ilinsky IA, Kultas-Ilinsky K (2002). Motor thalamic circuits in primates with emphasis on the area targeted in treatment of movement disorders. Mov Disord. 17 (suppl 3), s9-s14. Jankovic J, Cardoso F, Grossman RG, Hamilton WJ (1995). Outcome after stereotactic thalamotomy for parkinsonian, essential, and other types of tremor. Neurosurgery, 37(4), 680-687. Jankovic J (2006). Treatment of dystonia. Lancet Neurol. 5(10), 864-872. Jones EG (2007). The thalamus: volume ΙΙ. 2007; Second edition. pp 12971447. New York, Cambridge University Press. Katayama Y, Kano T, Kobayashi K, Oshima H, Fukaya C, Yamamoto T (2005). Difference in surgical strategies between thalamotomy and thalamic deep brain stimulation for tremor control. J Neurol. 252(suppl 4),17-22. Kelly PJ, Gillingham FJ (1980). The long-term results of stereotaxic surgery and L-dopa therapy in patients with Parkinson’s disease. A 10-year follow-up study. J Neurosurg. 53(3), 332-337. Kiss ZH, Davis KD, Tasker RR, Lozano AM, Hu B, Dostrovsky JO (2003). Kinaesthetic neurons in thalamus of humans with and without tremor. Exp Brain Res. 150(1), 85-94. Koller W, Pahwa R, Busenbark K, Hubble J, Wilkinson S, Lang A, Tuite P, Sime E, Lazano A, Hauser R, Malapira T, Smith D, Tarsy D, Miyawaki E, Norregaard T, Kormos T, Olanow W (1997). High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol. 42(3), 292-299. Koller WC, Lyons KE, Wilkinson SB, Pahwa R (1999). Efficacy of unilateral deep brain stimulation of the VIM nucleus of the thalamus for essential tremor. Mov Disord. 14(5), 847-850. Koller W, Lyons KE, Wilkinson SB, Troster AI, Pahwa R (2001). Long-term safety and efficacy of unilateral deep brain stimulation of the thalamus in essential tremor. Mov Disord. 16(3), 464-468. Kondziolka D, Ong JG, Lee JY, Moore RY, Flickinger JC, Lunsford LD (2008). Gamma knife thalamotomy for essential tremor. J Neurosurg. 108(1), 111-117.

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Current Use of Thalamic Surgeries for Treating Movement Disorders 25 Krack P, Pollak P, Limousin P, Benazzouz A, Benabid AL (1997). Stimulation of subthalamic nucleus alleviates tremor in Parkinson’s disease. Lancet, 350, 1675. Krauss JK, Mohadjer M, Nobbe F, Mundinger F (1994). The treatment of posttraumatic tremor by stereotactic surgery. Symptomatic and functional outcome in a series of 35 patients. J Neurosurg. 80(5), 810-819. Krauss JK, Mundinger F (1996). Functional stereotactic surgery for hemiballism. J Neurosurg. 85(2), 278-286. Krauss JK, Simpson RK Jr, Ondo WG, Pohle T, Burgunder JM, Jankovic J (2001). Concepts and methods in chronic thalamic stimulation for treatment of tremor: technique and application. Neurosurgery, 48(3), 535543. Kultas-Ilinsky K, Ilinsky IA (1991). Fine structure of the ventral lateral nucleus (VL) of the Macaca mulatta thalamus: cell types and synaptology. J Comp Neurol. 314(2), 319-349. Kumar R, Lozano AM, Sime E, Lang AE (2003). Long-term follow-up of thalamic deep brain stimulation for essential and parkinsonian tremor. Neurology, 61(11), 1601-1604. Kuncel AM, Turner DA, Ozelius LJ, Greene PE, Grill WM, Stacy MA (2009). Myoclonus and tremor response to thalamic deep brain stimulation parameters in a patient with inherited myoclonus-dystonia syndrome. Clin Neurol Neurosurg. 111(3), 303-306. Kuo JS, Carpenter MB (1973). Organization of pallidothalamic projections in the rhesus monkey. J Comp Neurol. 151(3), 201-236. Kupsch A, Trottenberg T, Meissner W, Funk T (1999). Neurostimulation of the ventral intermediate thalamic nucleus alleviates hereditary essential myoclonus. J Neurol Neurosurg Psychiatry, 67(3), 415-416. Lang W, Büttner-Ennever JA, Büttner U (1979). Vestibular projections to the monkey thalamus: an autoradiographic study. Brain Res. 177(1), 3-17. Lenz FA, Tasker RR, Kwan HC, Schnider S, Kwong R, Murayama Y, Dostrovsky JO, Murphy JT (1988). Single unit analysis of the human ventral thalamic nuclear group: correlation of thalamic “ tremor cells” with the 3-6 Hz component of parkinsonian tremor. J Neurosci. 8(3), 754764. Lim SY, Hodaie M, Fallis M, Poon YY, Mazzella F, Moro E (2010). Gamma knife thalamotomy for disabling tremor: a blinded evaluation. Arch Neurol. 67(5), 584-588.

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Current Use of Thalamic Surgeries for Treating Movement Disorders 27 Nandi D, Chir M, Liu X, Bain P, Parkin S, Joint C, Winter J, Stein J, Scott R, Gregory R, Aziz T (2002). Electrophysiological confirmation of the zona incerta as a target for surgical treatment of disabling involuntary arm movements in multiple sclerosis: use of local field potentials. J Clin Neurosci. 9(1), 64-68. Nauta WJ, Mehler WR (1966). Projections of the lentiform nucleus in the monkey. Brain Res. 1(1), 3-42. Nguyen JP, Degos JD (1993). Thalamic stimulation and proximal tremor. A specific target in the nucleus ventrointermedius thalami. Arch Neurol. 50(5), 498-500. Niranjan A, Jawahar A, Kondziolka D, Lunsford LD (1999). A comparison of surgical approaches for the management of tremor: radiofrequency thalamotomy, gamma knife thalamotomy and thalamic stimulation. Stereotact Funct Neurosurg. 72(2-4), 178-184. Obwegeser AA, Uitti RJ, Turk MF, Strongosky AJ, Wharen RE (2000). Thalamic stimulation for the treatment of midline tremors in essential tremor patients. Neurology, 54(12), 2342-2344. Oh MY, Hodaie M, Kim SH, Alkhani A, Lang AE, Lozano AM (2001). Deep brain stimulator electrodes used for lesioning; proof of principle. Neurosurgery, 49(2), 367-369. Ohye C, Saito U, Fukamachi A, Narabayashi H (1974). An analysis of the spontaneous rhythmic and non-rhythmic burst discharges in the human thalamus. J Neurol Sci. 22(2), 245-259. Ohye C (1997). Functional organization of the human thalamus, stereotactic interventions. In: Sterade M, Jones EG, McCormick DA (Eds.), Thalamus vol. Ӏ Ӏ : Experimental and clinical aspects (pp517-542). Amsteredam, Elsevier. Ohye C, Shibazaki T, Ishihara J, Zhang J (2000). Evaluation of gamma thalamotomy for parkinsonian and other tremors: survival of neurons adjacent to the thalamic lesion after gamma thalamotomy. J Neurosurg. 93(suppl 3), 120-127. Ondo WG, Jankovic J, Schwartz K, Almaguer M, Simpson RK (1998). Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson’s disease tremor. Neurology, 51(4), 1063-1069. Oropilla JQ, Diesta CC, Itthimathin P, Suchowersky O, Kiss ZH (2010). Both thalamic and pallidal deep brain stimulation for myoclonic dystonia. J Neurosurg. 112(6), 1267-1270. Pahwa R, Lyons KE, Wilkinson SB, Simpson RK Jr, Ondo WG, Tarsy D, Norregaard T, Hubble JP, Smith DA, Hauser RA, Jankovic J (2006).

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Current Use of Thalamic Surgeries for Treating Movement Disorders 31 Wu YR, Levy R, Ashby P, Tasker RR, Dostrovsky JO (2001). Does stimulation of the GPi control dyskinesia by activating inhibitory axons? Mov Disord. 16(2), 208-216. Woods SP, Fields JA, Lyons KE, Koller WC, Wilkinson SB, Pahwa R, Tröster AI (2001). Neuropsychological and quality of life changes following unilateral thalamic deep brain stimulation in Parkinson’s disease: a oneyear follow-up. Acta Neurochirurgica (Wien), 143(12), 1273-1277. Yamamoto T, Katayama Y, Kano T, Kobayashi K, Oshima H, Fukaya C (2004). Deep brain stimulation for the treatment of parkinsonian, essential, and poststroke tremor: a suitable stimulation method and changes in effective stimulation intensity. J Neurosurg. 101(2), 201-209. Yamashiro K, Tasker RR (1993). Stereotactic thalamotomy for dystonic patients. Stereotact Funct Neurosurg. 60(1-3), 81-85. Yoshor D, Hamilton WJ, Ondo W, Jankovic J, Grossman RG (2001). Comparison of thalamotomy and pallidotomy for the treatment of dystonia. Neurosurgery, 48(4), 818-824. Young RF, Jacques S, Mark R, Kopyov O, Copcutt B, Posewitz A, Li F (2000). Gamma knife thalamotomy for treatment of tremor: long-term results. J Neurosurg. 93(suppl 3), 128-135. Young RF, Li F, Vermeulen S, Meier R (2010). Gamma knife thalamotomy for treatment of essential tremor: long-term results. J Neurosurg. 112(6), 1311-1317. Zhang K, Bhatia S, Oh MY, Cohen D, Angle C, Whiting D (2010). Long-term results of thalamic deep brain stimulation for essential tremor. J Neurosurg. 112(6), 1271-1276.

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In: Thalamus: Anatomy, Functions and Disorders ISBN 978-1-61324-152-3 Editor: Justin L. Song, pp. 33-63 © 2011 Nova Science Publishers, Inc.

Chapter II

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Innervation of Anterior Thalamic Nuclei by Mammillothalamic Tract during Perinatal Development: Carbocyanine Dye Tracing Study Irina G. Makarenko* N.K. Koltzov Institute of Developmental Biology Russian Academy of Sciences Vavilov Str. 26, Moscow 119334, Russian Federation

Abstract The anterior thalamic nuclei (ATN) occupy a central position among the interconnected structures that form the limbic system and specifically are known as an important parts of “Papez circuit”. Afferent projections to the anterior thalamic nuclei from the mammillary nuclei of the hypothalamus form the largest known ascending input. It is organized as a large compact fiber bundle known as the mammillothalamic tract that *

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Irina G. Makarenko was decribed in different adult vertebrates but there are only few studies on its development. This study was aimed to describe the schedule of the mammillothalamic tract perinatal development in the rat using carbocyanine dye tracing. This method is unique for such purposes because it works on the fixed brain tissue and thus is applicable to fetal and early neonatal material. To reveal mammillothalamic tract DiI or DiA crystals were inserted in the mammillary bodies. Fetal (E14 - E21) and neonatal (P0 – P10) rat brains were used. Serial vibratome sections were analyzed using fluorescent and confocal microscopy. On E15-16, DiI insertion into the primordium of the MB resulted in the labeling only mammillotegmental tract and no signs of the growing mammillothalamic tract could be recognized at the level of the posterior hypothalamus. First fibers of the mammillothalamic tract being the collaterals of the mammillotegmental tract axons start bifurcate from the mammillotegmental tract on E17. At a short distance from the mammillary body the axons of the mammillothalamic tract gather tightly and form a thick bundle on E18. Confocal microscopy revealed growth cones on the ends of most axons. The mammillothalmic tract enters the ventral region of the anterior thalamus on E20 – E21 and starts to form first terminal arborizations in the anteromedial and anteroventral nuclei. Specific topographic organization of the mamillothalamic projections described in adult rats was visualized since P2. Unilateral connections of the medial mammillary nucleus with the anteromedial and anteroventral thalamic nuclei develop from E20 to P6. Bilateral projections from the lateral mammillary nucleus to the anterodorsal thalamic nuclei develop later after the formation of the thalamic decussation (beginning on P2). On P6 –P10 all anterior thalamic nuclei have dense innervation from the mammilary nuclei. Thus, MB innervation of the anterior thalamic nuclei is completed during the first postnatal week and later did not change significantly.

Introduction The anterior thalamic nuclei (ATN) occupy a central position among the interconnected structures that form the limbic system. According to their connectivity ATN and MB are thought to be functionally related to the limbic “Papez circuit” (Papez, 1937; Mark et al., 1995; Vertes et al., 2001). The MB and the anterior thalamic nuclei take part in mnemonic functions, spatial information processing and navigation (Sziklas and Petrides, 1998; Vertes et al., 2001; Vann and Aggleton, 2003, 2004). Topographical organisation of the thalamic afferents and efferents is contralateral, and the lateralisation of the

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thalamic functions affects both sensory and motoric aspects (Herrero et al, 2002). Several human disorders accompanied by a loss of memory such as Korsakoff’s and Wernicke’s syndromes have been assigned to disturbances of the MB and their main fiber tracts (Kopelman, 1995; Vann and Aggleton, 2004; Yoneoka et al., 2004). Afferent projections to ATN from the mammillary body (MB) form the largest known ascending input to ATN and are thought to provide feedback concerning the effects of limbic cortex on activity in the hypothalamus (for review, Issacson, 1982; Morgane et al., 2005). Efferent fibers from the mammillary nuclei projecting to the anterior thalamic nuclei are organized in the large compact fiber bundle - the mammillothalamic tract that has been exhaustively studied in many species (Cowan, 1954; Guillery, 1957; Fry et al., 1963; Raisman, 1966; Krieckhaus, 1967; Niimi et al., 1972; Cruce, 1975; Seki and Zyo, 1984). Mammillary bodies (MB) - the source of this projection system represent a large paired structure of the posterior hypothalamus located in the ventrocaudal diencephalon of vertebrates. Cytoarchitectonically each of them consists of medial (MM) and lateral (ML) mammillary nuclei (Gurdjian, 1927; Shibata, 1992; Allen and Hopkins, 1988) and MM in the rat is divided into the pars medianus, pars medialis, pars lateralis, and pars posterior (Bleier and Byne, 1985). Morphology and connections of the MB were studied in detail in adult vertebrates of different (Watanabe and Kawana, '80; Hayakawa and Zyo,'85, '86). The earliest description of the MB projection systems was performed by Ramón y Cajal (1895, 1903) based on Golgi preparations. The major output of the MB neurons is represented by the principal mammillary tract, which divides after a short ascending course into two thick compact bundles: the mammillotegmental and mammillothalamic tracts. The first one bends caudally and reaches the ventral and dorsal tegmental nuclei of Gudden (Nauta, '58; Ban and Zyo, '63), and the second grows in the rostrodorsal direction to the anterior thalamic nuclei. The major efferent fibers from the mammillary nuclei project to the anterior thalamic nuclei via the mammillothalamic tract that has been exhaustively studied in many species (Cowan, 1954; Guillery, 1957; Fry et al., 1963; Krieckhaus, 1967; Niimi et al., 1972; Cruce, 1975; Seki and Zyo, 1984). The first suggestion that these tracts are formed by axonal branching of the mammillary neurons was provided by Fry (1966, 1970) and Fry and Cowan (1972), using a retrograde cell degeneration method. Later doublelabeling studies in rats using injections of different fluorescent tracers (Fast Blue and Nuclear Yellow) into the ATN and midbrain tegmental nuclei clarified fine details of these collateral

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projection systems (Takeuchi et al., 1985; Hayakawa and Zyo, 1989). They determined that most of the MB neurons project to both the anterior thalamus and the tegmentum via these tracts and only a small part of the MB neurons sends axons only to the anterior thalamus through the mammillothalamic tract. Although mammillary projections to the anterior thalamic nuclei are predominantly unilateral there are some sparse to the contralateral side. Specific topography of the mammillothalamic projections was clear described. It was shown that the medial mammillary nucleus projects ipsilaterally to the anteromedial and anteroventral thalamic nuclei, whereas the lateral mammillary nucleus projects bilaterally to the anterodorsal thalamic nuclei (Seki and Zyo, 1984; Shibata, 1992; Guison et al., 1995; Gonzalo-Ruiz et al., 1998). Development of the MB fiber tracts was described only in mice. The mammillotegmental tract can be recognized in mice at about E10, being one of the first tracts to develop in the central nervous system (Mastick and Easter, 1996). Much later, on E17, axons of the mammillotegmental tract generate collaterals that contribute to the formation of the mammillothalamic tract reaching the anterior thalamic nuclear group by E20 (Valverde et al., 2000). Analysis of Golgi staining of the diencephalon provided the data that MB axonal projection systems in mice appear completely developed during the first postnatal days (Valverde, 1998). Recent observations in mice indicate that the guidance of the mammillothalamic tract axons is regulated by the transcription factors Pax-6, Foxb1, Sim1 and Sim2 (Wehr et al., 1997; Alvarez-Bolado et al., 2000; Valverde et al., 2000; Marion et al., 2005). There are only two works describing formation of the MB and their fiber systems in the rat (Coggeshall, 1964; Alpeeva and Makarenko, 2007). Coggeshall (1964) using conventional histologic and neuromorphologic silver impregnation methods provided general data that the mammillotegmental and mammillothalamic tracts can be distinguished on E13 and E19, respectively. Our previous DiI tracing study of the MB connections confirmed that development of the mammillotegmental tract in rats takes place during prenatal ontogeny earlier than E14 – the earliest day studied (Alpeeva and Makarenko, 2007). Our preliminary data demonstrated that the labeling of the mammillothalamic tract is observed on the late prenatal stages, but the starting point of its formation was not determined (Alpeeva and Makarenko, 2009). This chapter reavaluate our study undertaken using fluorescent carbocyanine dye tracing method to examine the development of projections from the mammillary nuclei to the anterior thalamic nuclei.

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Experimental Procedures Wistar rats provided by the Scientific Center of Biomedical Technology Russian Academy of Medical Sciences (Stolbovaya) mated overnight were used in our studies. The day of conception (sperm visualization in the female vagina) was defined as E0 and the day of birth as P0. Fetuses and postnatal animals were used at different developmental stages: from E14 to E21 and from P0 to P20 respectively. Totally 70 cases were analyzed for this study (E15 – n7; E16 – n5; E17 – n3; E18 – n7; E19 - n5; E20 – n4; E21 – n4; P1 – n6; P2 – n7; P3 – n5; P6 – n4; P8 – n3; P10 – n5 and control n6). All animal procedures were made under intraperitoneal anesthesia with pentobarbital (50 mg/kg body weight). All protocols of the manipulations with the animals have been approved by the animal care committee of Institute of Developmental Biology of Russian Academy of Sciences and experiments were carried out in accordance with European Communities Council Directive of 24 November 1986 (86/609/EEC).

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Fixation On early embryonic stages (E14-E15) fetuses were removed from the uterus, decapitated and dissected brains fixed by the immersion in 4% paraformaldehyde in 0.1 M sodium phosphate buffer (pH 7,2-7,4) for 12-24 hours at room temperature. Older fetuses (E16-E21) and postnatal rats were perfused transcardially, first with saline, and then with 4% paraformaldehyde. The brains were removed from the skull and immersed in the same fixative at room temperature for at least 24 hours – 2 month for carbocyanine dye procedures. For immunocytochemical experiments postfixation was shorter and did not exceed 12 – 20 hours at room temperature.

Carbocyanine Dye Insertion and Material Processing Lipophilic carbocyanine tracers 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) and/or 4-(4-dihexadecylaminostyryl)-Nmethylpyridinium iodide (DiA) (Molecular Probes, USA) were used for this study. Crystalls of DiI (DiA in few cases) were inserted into the fixed brain under a dissecting microscope using thin glass microelectrode.

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Methodology of the carbocyanine dye application can vary depending of the exact task and age of the animal. Brain meninges were removed from ventral hypothalamic surface in the place of future insertion, the brain was gently dried by filter paper before an insertion. Usually crystals of the marker were inserted into the whole fixed brain in the small incision on the ventral surface of the MB unilaterally or bilaterally (Figure 1). In some cases, DiI and DiA were inserted into the MB of the same brain (Figure 1). Few brains were divided along a midsagittal plane and DiI crystals were placed on the medial mammilary nucleus, or applicated on the region of the midbrain tegmentum on the postnatal brains. Several control cases with DiI insertions rostrally to MB in the caudal mediobasal hypothalamus or caudally in the interpeduncular nucleus were prepared for comparison with exact MB applications.

Figure 1. Photographs of the fetal and postnatal rat brains of different ages with carbocyanine dye insertions into the mammillary bodies. Arrow indicates the place of DiA insertion, arrow heads – the places of DiI insertion on E20. Scale bar 1mm.

Brains with DiI were stored for 3-24 month in the paraformaldehyde in a dark at room temperature for DiI retrograde and anterograde diffusion along the neuronal membranes. Long storage mentioned previously as the main disadvantage of the DiI tracing method (Lucas, et

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al., 1998; Vercelly et al., 2000) is very important as it helps avoid negative results and makes sure that the marker had reached neurons even at a large distance from the place of insertion. Additionally it helps to label fine details of the neuronal morphology such as growth cone or terminal brush. After the storage brains were photographed under a dissecting microscope equipped with digital photo camera for documentation of the insertion places.

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Sectioning and Microscopy Serial 80 – 100µm-thick vibratome brain sections were made in the coronal or sagittal planes, mounted on slides (Super Frost/Plus), coverslipped with mowiol (Calbiochem, Germany) and stored at 4°C in the dark. Sections were examined under Leica DM RXA2 epifluorescent photomicroscope (Germany), using a rhodamine filter set for viewing the orange-red DiI fluorescence and fluorescein one for the yellow-green DiA fluorescence. The ultraviolet filter was used for the analysis of the specific location of DiI and DiA crystals in the brain that was proved to be helpful in our previous study (Makarenko, 2007, 2008). Sections were photographed with Olympus DP70 digital photo camera (Japan). The digital images were processed using Photoshop 7.0 software (Adobe, USA). Regions and nuclei of the adult and developing brain were identified according to the brain atlases (Paxinos, et al., 1991; Paxinos and Watson, 1997). Some sections of the diencephalon were scanned additionally with the confocal microscope Leica TCS SP (Germany). Confocal images were processed using the standard Leica LCS software.

Results Carbocyanine Dye Distribution in the Place of their Insertion into the Mammillary Bodies on Different Developmental Stages Transport of DiI from the place of crystals insertion looked in the whole brain as a diffuse or patch-like pinc staining (DiA – yellow). In each case, region including place of insertion was analyzed first on the sections using specific filter sets for DiI and DiA to identify its position and volume. We

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have found, that ultraviolet filter was very helpful for identifying exact position of the marker crystals for visualizing the real size of the dye diffusion around them (Figure 2 A) in comparison to that visible with the rhodamine filter. It was also useful in the cases with double labeling using both markers (Figure 2 C) because it demonstrated simultaneously 2 dyes in the same section. Rhodamine filter revealed very high brightness of DiI and more faintly DiA in the place of insertion (Figure 2 D). Fluorescein filter showed mostly DiA (Figure 2 E).

Figure 2. Low-magnification photomicrographs of the coronal sections of the hypothalamus demonstrated places of DiA and DiI insertions into the mammillary bodies on E15 (A, B) and P2 (C-E) visualized with different filter sets: ultraviolet (A, C); rhodamine (B, D) and fluoresceine (E). MB – mammillary body. Arrow – principal mammillary tract. Scale bar 200 μm.

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Figure 3. Low-magnification photomicrographs of the sagittal brain sections demonstrating that DiI inserted in the mammillary body (MB) without the damage of its fiber capsule localizes mostly inside MB (A, C), but after an insertion into the mediobasal hypothalamus (MBH) did not spread inside MB (B). DiI insertion caudally into interpeduncular nucleus (IPN) did not provide the marker diffusion into MB and as a result visualizes only habenulointerpeduncular tract (Hit) but not mammillotegmental tract. Scale bar 200μm.

On early embryonic stages DiI insertion into the presumptive MB just rostral to the midbrain flexure usually revealed a thick bundle of labeled fibers running in dorsal direction from the place of the dye application. It was recognized as a principal mammillary tract. On the coronal sections visualization of this bundle was used as a criterion of a good MB insertion (Figure 2 A, B). On the sagittal brain sections this bundle turned caudally along the midbrain flexure (Figure 3A). We identified this bundle as the mammillotegmental tract with its initial part named the principal mammillary tract. On embryonic stages E15 – E19 when MB fiber capsule was not developed the tracer could easily spread from the site of insertion and distribute to the adjacent regions of the posterior hypothalamus (Figure 3 A).

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On the later prenatal and postnatal stages (E20 – E21 onwards), the MB were surrounded by the capsule of nerve fibers, which restricted the dye spreading outside the MB when the marker was placed specifically inside it (Figure 3 C). In these cases, efferent mammillary axons gathered in the MB tracts were clearly visualized and only few additional labeled neurons were found in the supramammillary and posterior hypothalamic regions. When dorsal or lateral parts of the MB capsule were damaged during the dye insertion and DiI diffused out of the MB, not only mammillothalamic and mammillotegmental tracts were labeled, additional fiber systems were also observed but were subtracted from the main results of this study. The control cases with DiI location in the regions adjacent to MB confirmed that only MB insertions give rise for the mammillothalamic and mammillotegmental tracts. In the case with DiI insertion in the mediobasal hypothalamus rostrally to the MB, the capsule prevented distribution of the marker inside them and this resulted in absence of the MB tracts labeling (Figure 3 B).

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Prenatal Development of the Mammillothalamic Tract On E15-16, DiI insertion into the primordium of the MB resulted in the labeling of only mammillotegmental tract. No signs of the growing mammillothalamic tract could be recognized at the level of the posterior hypothalamus (Figure 3 A, 4 A). The first fibers of the mammillothalamic tract became visible on E17 (Figure 4 B). On E18, the mammillothalamic tract was visualized on sagittal sections as a thick compact short (approximately 200 µm long) bundle of axons (Figure 4 C). Later on E19 the mammillothalamic tract became longer but still was located within the hypothalamus (Figure 4 D). On E20 – E21, DiI insertions into the MB revealed that mammillothalamic tracts reached the ventromedial region of the anterior thalamus. Rostral end of the mammillothalamic tract thickened as its axons began to form the network in the presumptive anteromedial thalamic nucleus that was most obvious on sagittal sections (Figure 4 E). As there were too many labeled axons in the principal mammillary tract confocal scanning was used to find points of bifurcation of the MB fibers. Only confocal microcopy with high resolution demonstrated these features and showed that they grew from the mammillotegmental tract in rostrodorsal direction forming an angle of about 80 degree with its axons.

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Figure 4. Low-magnification photomicrographs of sagittal brain sections following DiI insertions into the MB on five consecutive prenatal stages (A – D). On E16 DiI reveals only mammillotegmental tract without signs of bifurcation (A). The first axons of the mammillothalamic tract (arrow head) bifurcating from the mammillotegmental tract on E17 (B). The mammillothalamic tract growing in the rostrodorsal direction through the hypothalamus and ventral thalamus on E18 (C), E19 (D) and on E21 (E) entering the ventral region of the anterior thalamus. Scale bar 200 μm.

Fine confocal analysis revealed that unlike the fibers of the mammillotegmental tract that were gathered in compact isolated fascicles, separate axons of the mammillothalamic tract were spreaded between unlabeled cell bodies of the posterior and dorsal hypothalamus (Figure 5 A). Alomost all axons of the mammillothalamic tract had growth cones at the ends on E18-19 (Figure 5 B, C). Coronal sections through the thalamus on the last prenatal stages demonstrated that bilateral DiI insertions in MB labeled mamillothalamic tracts on both sides of the brain. They reached the ventral level of the anterior

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thalamus and occupied anteromedial thalamic nuclei on the proper side but there were no fibers crossing the midline (Figure 6).

Figure 5. Low-magnification confocal image demonstrating the place of origin of the mammillothalamic tract from the thick axon bundles of the principal mammillary and mammillotegmental tracts (A). High magnification confocal image representing the growing distal tip of the mammillothalamic tract with growth cones on the ends of its axons shown in Figure 4 D (B) and enlarged growth cones (C arrows). Scale bar 80 μm for panel A, 20 μm for panel B, 8 μm for panel C.

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Figure 6. Low-magnification photomicrographs of the coronal sections of the anterior thalamus on E20 following bilateral DiI insertion into MB revealed labeled fibers in both mammillothalamic tracts without crossing through the midline of the brain (A, B). High magnification confocal image representing demonstrating the first terminal branching of the mammillothalamic fibers in the anteromedial thalamic nucleus. Scale bar 100 μm for panels A and B, 80 μm for panel C.

To prove that mammillothalamic tract is formed by collaterals of MB axons directed to midbrain nuclei several brains (on E15 and E19) received DiI applications on the midbrain tegmentum. In all cases, the mammillotegmental tract was visualized on the sagittal brain sections and numerous retrogradely labeled neurons were ualized in it. On E19 tegmental DiI applications stained not only the mammillotegmental tract but additionally the fibers of the mammillothalamic tract (Figure 7).

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Figure 7. Low-magnification photomicrograph of the sagittal brain section on E19 following DiI insertions into the midbrain tegmentum revealed labeled fibers in both mammillotegmental and mammillothalamic tracts and retrogradely labeled neurons in MB. Scale bar 200 μm.

Postnatal Development of the Mammillothalamic Tract and Formation of the Innervation of the Anterior Thalamic Nuclei by Its Axons On early postnatal ages DiI insertions in MB usually occupied both medial and lateral mammillary nuclei. In all cases mamillothalamic tract contained numerous labeled MB axons that formed innervation inside two ventral anterior thalamic nuclei (Figure 8 A, B). On P1 – P2, MB axons expanded their terminal arborizations mainly in the ipsilateral to the insertion anteromedial and anteroventral thalamic nuclei (Figure 8 B). These fibers occupied mostly ventromedial region of the anteroventral thalamic nucleus and continued to grow toward its lateral and dorsal borders (Figure 8 C). Sparse labeled fiber bundle crossed midline of the thalamus above anteromedial nucleus and followed laterally along anteroventral thalamic nucleus in the direction of anterodorsal nucleus (Figure 8 B, D) which had no innervation at this age. This decussation was formed by the MB axons that penetrated the anteromedial thalamic nucleus and grew contralaterally to the anterodorsal thalamic nuclei. The rest part of the mammillothalamic tract axons penetrated the anteromedial thalamic nucleus and reached the ispilateral

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anterodorsal thalamic nucleus. Terminal arborizations of the mammillothalamic tract fibers had not been visualized in the anterodorsal thalamic nuclei yet.

Figure 8. Low-magnification photomicrographs of sagittal (A) and coronal (B) brain sections on P2 following DiI insertions into MB revealed labeled fibers in mammillothalamic tract (A) that innervated only anteromedial and anteroventral thalamic nuclei. Scale bar 200 μm. High-magnification confocal images of the coronal brain sections representing labeled terminal network of the MB fibers in the anterior thalamic nuclei on P2 revealed after DiI insertion into the MB. Short white arrows indicate MB axons growing towards the lateral and dorsal borders of the anteroventral thalamic nucleus, long white arrows indicate MB axons growing through the anteromedial thalamic nucleus to the anterodorsal thalamic nucleus (C, D). Scale bar 80μm.

These observations were detailed in the experiment with simultaneous DiI and DiA insertions into the MB of the same brain on P2. DiI occupied both the medial and lateral mammillary nuclei of the left MB and DiA was located specifically in the medial mammillary nucleus on the right side (Figure 9 A). DiI-positive terminal network was observed in the ipsilateral anteromedial and

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anteroventral thalamic nuclei and ingrowing labeled fibers – in the anterodorsal thalamic nuclei on both sides of the brain (Figure 9 B, C). Fibers labeled with DiA were visualized only in the anteromedial and anteroventral nuclei on the right side of the thalamus (Figure 9 D). The quality of the terminal labeling with DiA (Figure 5 D) was lower than with DiI (Figure 9 B, C).

Figure 9. Low-magnification photomicrographs of the coronal brain sections representing visualization of DiI and DiA following insertion of two markers into the MB of the same brain on P2. Coronal section of the MB with DiI (black arrows) and DiA (black arrow heads) insertions visualized using ultraviolet filter (A) : DiI (left side) locates in the lateral mammillary nucleus and the lateral region of the medial mammillary nucleus; DiA (right side) locates in the medial region of the medial mammillary nucleus (D). Panels B – D demonstrated images of one section through the anterior thalamic nuclei visualizing with rhodamine (B, C) and fluoresceine filters (D). Whole section (B) demonstrated DiI distribution in the fibers of the dorsal thalamic decussation (d) then growing to the anterodorsal thalamic nuclei (AD) on both sides and innervation of the ipsilateral anteromedial and anteroventral thalamic nuclei enlarged on panel C. High-magnification photomicrograph representing the right part of the section shown in B visualized using fluorescein filter to visualize DiA labeling in the anteromedial and anteroventral thalamic nuclei. DiA labeling is also visible in rhodamine filter as a pale red staining in the right anteromedial and anteroventral thalamic nuclei Scale bar 200 μm.

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On P3 – P4, labeled fibers of the mammillothalamic tract reached the dorsal and lateral borders of the anteroventral and anterodorsal thalamic nuclei and began to form terminal network in the later. By P5 – P6, the density of fluorescent mammillothalamic tract terminal arborizations in all three nuclei of the anterior thalamus grew significantly. Increased volume of the MB in the postnatal rat brain allowed us to make restricted insertions into the separate MB nuclei and even their parts. In the case when the place of DiI application occupied only the medial part of the medial mammillary nucleus and did not spread to its lateral part and to the lateral mammillary nucleus (Figure 10 A), terminal labeling was observed in the ipsilateral anteromedial thalamic nucleus and the dorsomedial part of the ipsilateral anteroventral thalamic nucleus and were not seen in the anterodorsal thalamic nuclei (Figure 10 B).

Figure 10. Low-magnification photomicrographs of the coronal brain sections showing two representative cases on P6 with restricted DiI insertions providing specific distribution of the terminal labeling in the anterior thalamic nuclei. Case 1 – the place of DiI insertion into the medial part of the medial mammillary nucleus (A). Case 1 - terminal labeling in the anteromedial thalamic nucleus and the dorsomedial part of the anteroventral thalamic nucleus and absence of the labeling in the anterodorsal thalamic nucleus following DiI insertion shown in A (B). Photomicrograph of the section shown on B made using ultraviolet filter representing the topography of the anterior thalamic nuclei (C).

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Unilateral DiI insertion into the MB, which occupied the lateral part of the medial mammillary nucleus and the lateral mammillary nucleus (Figure 10 D, E), resulted in terminal labeling in all three ipsilateral anterior thalamic nuclei and in the anterodorsal thalamic nucleus on the contralateral side (Figure 10 F). Comparing with the previous case lateral MB insertion provided more substantial terminal labeling in the anteroventral nucleus with maximal density in its ventrolateral part and significant projections to the anterodorsal thalamic nuclei on both sides of the brain.

Figure 11. Low-magnification photomicrographs of the sagittal brain section representing DiI insertion into MB and resulted labeling of the mamillothalamic tract and innervation of the anterior thalamic nuclei on P10 (A) and coronal section (B) showing labeled terminal network in all anterior thalamic nuclei following bilateral DiI insertion into the MB. Scale bar 200 μm.

Case 2 - the place of DiI insertion into the lateral part of the medial mammillary nucleus and the lateral mammillary nucleus visualized using rhodamine (D). and ultraviolet (E) filters. Case 2 - terminal labeling in the ipsilateral anteromedial and anteroventral thalamic nuclei and bilateral anterodorsal thalamic nuclei following DiI insertion shown in D; (F). Scale bar 200 μm. On P8 – P11, labeled mammillothalamic tract became curved dorsally on the border between the hypothalamus and the thalamus that was obvious on sagittal sections (Figure 11 A). The bright fluorescent network of terminals that filled all three anterior thalamic nuclei became very dense; the nuclei were

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sharply defined against the surrounding dark unlabeled tissue on the coronal (Figure 11 B) and sagittal (Figure 12) sections.

Figure 12. Low-magnification photomicrographs of the serial sagittal sections through the anterior thalamus on P10 demonstrating distribution of terminal network of the MB fibers in three anterior thalamic nuclei. The most lateral section (A). Scale bar 200 μm. Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders, edited by Justin L. Song, Nova Science

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As at these ages mammillothalamic projection system was totally developed we have made comparison of the cases with unilateral and bilateral DiI insertion into MB. It was obvious that unilateral insertions with diffusion to both mammillary nuclei (Figure 13, C) provide labeling of all tree anterior thalamic nuclei on the same side and revealed only anterodorsal thalamic nucleus on the contralateral side (Figure 13 B, C). In the cases with similar bilateral insertions in the MB (Figure 13 F) labeling of the terminal network was observed in all anterior thalamic nuclei on both sides with slight difference depending on the amount of the marker on each side (Figure13 D, E).

Figure 13. Low-magnification photomicrographs of the coronal brain sections from 2 cases representing innervation of the anterior thalamic nuclei after unilateral DiI insertion covered medial and lateral mammillary nuclei on the right side on P8 (A – C) and bilateral covered whole MB on P10 (B). Scale bar 200 μm. Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders, edited by Justin L. Song, Nova Science

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Figure 14. High-magnification confocal images of the brain sections representing labeled terminal network in the anterior thalamus following DiI insertion into the MB on P10. Axons of the mammillary neurons (arrow) growing to the anteromedial thalamic nucleus and formed there terminal network (A). Terminal arborizations of the mammillothalamic fibers surrounding unlabeled neurons (asterisks) of the anteroventral thalamic nucleus (B). Single terminal bunches of the mammillothalamic axons at the margin of the anteromedial thalamic nucleus (C, D). Scale bar 40 μm.

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Confocal scanning of the sections of anterior thalamic nuclei revealed fine beaded axons entering them from mamillothalamic tract (Figure 14 A) and numerous terminal arborizations filling the neuropile surrounding thalamic neurons (Figure 14 B). Single terminal bunches could be seen close to the margin of the anteromedial thalamic nucleus where the density of the terminals was not so high (Figure 14 C, D).

Discussion This is our new successive study of the development of the rat hypothalamic efferent projection system (mammillothalamic projections) using carbocyanine dye tracing. Diffusion along the axons of the mammillothalamic tract resulted in heavy labeling of the terminal network in anterior thalamic nuclei but not in the neurons at all ages that confirms that all axons of this tract belong to the mammillary neurons.

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Methodological Issues In the last two decades, long-chain dialkylcarbocyanine (DiI) and dialkylaminostyryl (DiA) dyes have been widely used for anterograde and retrograde neuronal tracing (Godement et al, 1987; Lukas et al., 1998; Vercelli et al., 1999; Makarenko, 2008). The main advantage of this method comparing with previous neuroanatomical approaches is that it can be used on the fixed brain tissue avoiding stereotaxic marker insertion into the brain in vivo. This feature makes it applicable for studies in fetuses and pups and was proven in our current and previous studies of different hypothalamic projection systems (Makarenko, 2007, 2008; Makarenko et al., 2000, 2001, 2002, 2005). Storage of the brains with DiI insertions in the paraformaldehyde at room temperature over a long period is necessary for the diffusion of the tracer along the neuronal processes and increases the probability of complete labeling of studied projection systems. Our recent data support the view that DiI labeling is more successful for tracing long fiber systems than DiA (Trukhacheva and Alexandrova, 1999; Vercelli, 2000) as it provides bright, stable and more complete labeling of all neuronal processes. DiA reveals mainly retrogradely labeled neuronal bodies and thick axonal tracts but fails to stain the fine network of separate fibers (Makarenko, 2007). This was proved

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in the experiments with insertions of DiI and DiA into the MB on different sides of the same brain. Amount of the marker inserted in the brain and exact place of insertion resulted in significant difference of the labeling. Large insertions are useful for general evaluation of the consequent formation of the hypothalamic connections. For this purpose we have used dye insertions which cover the whole part of the hypothalamus or other place of interest. It is important in fetuses when the process of neuronal migration is not finished and this approach gives us the possibility to avoid negative results. We have found that dye distribution in the place of insertion depends of the morphological features of this region and presence of the fiber tracts and capsules may prevent marker distribution to the adjacent structure. This was true in the case of MB insertions were fiber capsule if not damaged prevent DiI spreading in both directions on postnatal ages. The fading of the dye labeling in the sections was mentioned as one of the problems (Vercelly, 2000) but this problem deals with the mounting medium used. It can be prevented by using anti-fading mounting mediums such as vectashield. We recommend the mowiol (Calbiochem) which can be prepared and stored in aliquots in the freezer and which polimeraized on the slides at room temperature. Vibratome sections with DiI label can be stored after coverslipping in mowiol for several months without fading of the tracer labeled structures. Opinions differ widely on how DiI works as a tracer of the adult brain connections. Several authors wrote that it is often ineffective in mature animal brain (Balthazart et al., 1994; Vercelli et al., 2000) but provides good results in the studies of the human postmortem brain tissue (Dai et al., 1998). Our preliminary data (not shown) demonstrated that the quality of visualization of the MB connections in P20 and older rats decreased comparing with fetuses and pups, especially in the region of terminal arborizations in the anterior thalamus. This phenomenon can probably be explained by the fact of gradual changes of the neuronal membranes taking place during brain ontogeny, especially with myelination which in several major fiber tracts was described to start in the first postnatal week and to be completed by P40 – P70 (Jacobson, 1963; Hamano et al., 1998). Thus we did not use for this study cases older than P10.

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Perinatall Development of the Mammillothalamic Tract and Formation of the Innervation of the Anterior Thalamic Nuclei by Its Axons The mammillothalamic tract is one of the main projection systems of the MB. It was shown earlier that the axons of the MB neurons start to grow and form the tracts even before the MB becomes an independent brain structure surrounded by a fibrous capsule (Coggeshall, 1964; Alpeeva and Makarenko, 2007). Our recent results confirmed existing notion about the prenatal beginning of the mammillothalamic tract development (Coggeshall, 1964; Valverede et al., 2000). The study of Coggeshall (1964) was based on conventional histological and neuromorphological methods that are nonspecific for nervous tract tracing that is why he described appearance of the first mammillothalamic tract fibers only on E19. DiI tracing revealed that in fact this happens in rats already on E17. We have shown that the mammillothalamic tract was visualized both after DiI insertions into MB and also after DiI application on the developing midbrain tegmental nuclei made on sagittally divided brain. This confirmed the data obtained in adult rats and mice that two main MB tracts are formed by the axons of the same neurons and the fibers of the mammillothalamic tract represent the collaterals of mamillotegmental axons (Van der Kooy et al., 1978; Takeuchi et al., 1985; Hayakawa and Zyo, 1989; Valverde et al., 2000). There is evidence that various nervous tracts start to grow sending fist pioneer axons with growth cones that are guided by different types of specific molecules expressed in the brain during perinatal ontogeny (Tessier-Lavigne and Goodman, 1996; Anderson and Key 1999). Visualization of the did not show leading axons fare forwad from the top of the growing mammillothalamic tract on E17-20. Confocal microscopy revealed an interesting fact that all axons of this compact bundle have growth cones and hence grow simultaneously intermingled with the cells of the posterior hypothalamus and gathered more tightly in the thalamus. As the neurons of the thalamus are known to be born between E15 and E17 (Altman and Bayer, 1988) and separate nuclei of the anterior thalamus can be defined on E21 (Coggeshall, 1964) that coincides with the mammillothalamic tract growth, it can be supposed that these processes are interrelated. The first fibers of the mammillothalamic tract were shown to begin bifurcating from the mammillotegmental bundle on E17. This probably means that the newly born neurons of the thalamus begin to establish a gradient of chemoattractant, which acts selectively on the mammillotegmental fibers and stimulates them to

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form collaterals. The fibers of the mammillothalamic tract may also be attracted to the anterior thalamus by the chemical substances that are produced by the glial cells situated on the border between the thalamus and the hypothalamus (Valverde et al., 2000). We have first demonstrated the process of perinatal (E20/21 – P5/10) formation of the innervation of the anterior thalamic neurons by MB axons (Alpeeva and Makarenko, 2009). Specific spatial organization of the mammillary nuclei projections to the anterior thalamus described in adult rodents and macaque monkeys (Cruce, 1975; Seki and Zyo, 1984; Vann et al., 2007) was observed from the fist days after birth. Fibers of the mammillothalamic tract can be divided into three portions consequently innervating different anterior thalamic nuclei. The axons of the first portion begin to brunch in the ipsilateral anteromedial and anteroventral thalamic nuclei during the last prenatal (E20-21) and first postnatal days. They are known to arise from the neurons of the medial mammillary nucleus (Seki and Zyo, 1984; Hayakawa and Zyo, 1989). Those of the second one pass through the anteromedial nucleus and enter the ipsilateral anterodorsal thalamic nucleus on P2 but form terminal network there during next 2 – 3 days. At the same time fibers of the third portion grow through the ipsilateral anteromedial thalamic nucleus and cross the thalamic midline to reach the contralateral anterodorsal thalamic nucleus. These bilateral projections were described originating from the lateral mammillary nucleus (Watanabe and Kawana, 1980; Guison et al., 1995; Gonzalo-Ruiz et al., 1998). Our material provides clear evidence that terminal labeling in the anterodorsal thalamic nucleus was observed only in the cases with DiI insertions occupying the lateral mammillary nucleus. Thus, MB innervation of the anterior thalamic nuclei is completed during the first postnatal week and later did not change significantly. The medial mammillary nucleus of adult rats is divided at least into four parts with specific pattern of their thalamic projections (Seki and Zyo, 1984; Allen and Hopkins, 1988; Shibata, 1992). Although DiI tracing method could not provide restricted insertions inside any specific part of this nucleus without diffusion of the dye into the others, we succeeded in obtaining some cases on P6 with preferential labeling of the medial or lateral region of the medial mammillary nucleus, and demonstrated specific topographic organization of their projections to the anteroventral thalamic nucleus. More lateral insertions into the medial mammillary nucleus provided terminal labeling mostly in the ventrolateral part of the anteroventral thalamic nucleus, whereas more medial insertions resulted in terminal labeling in its dorsomedial part.

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Thus, our data schedules the growth of the mammillothalamic tract in the rat from E17 and describes formation of the anterior thalamic nuclei innervation from E20 to P8-10. Bilateral projections from the lateral mammillary nucleus to the anterodorsal thalamic nucleus are formed later than unilateral ones from the medial mammillary nucleus to the anteromedial and anteroventral thalamic nuclei. Dense innervation of the anterodorsal thalamic nucleus was revealed by P5. Unique spatial and temporal pattern of the perinatal development of the ascending mammillary body projections to the anterior thalamic nuclei may reflect the importance of these connections within the limbic circuitry.

Acknowledgments

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The authors would like to thank Elena Alpeeva for participation in tracing of the mammilary body connections. This work was supported by research grants of Russian Foundation for Basic Research #07-04-00798 and #1104-00788.

Abbreviations for Figures AD AM AT AV AV AV d hit IP LM MB MM mtg mth pm 3V

anterodorsal thalamic nucleus anteromedial thalamic nucleus anterior thalamus anteroventral thalamic nucleus dm anteroventral thalamic nucleus, dorsomedial part vlanteroventral thalamic nucleus, ventrolateral part decussation of the mammillothalamic tract habenulointerpeduncular tract interpeduncular nucleus lateral mammillary nucleus mammillary body medial mammillary nucleus mammillotegmental bundle mammillothalamic tract principal mammillary tract third ventricle

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Cowan, WM; Gottlieb, DI; Hendrickson, AE; Price, JL; Woolsey, TA. The autoradiographic demonstration of axonal connections in the central nervous system. Brain Res, 1972 37, 21-51. Cruce, J.A. An autoradiographic study of the projections of the mammillothalamic tract in the rat. Brain Res, 1975 85, 211-219. Dai, J; Swaab, DF; Van Der Vliet, J; Buijs, RM. Postmortem tracing reveals the organization of hypothalamic projections of the suprachiasmatic nucleus in the human brain. J Comp Neurol, 1998 400, 87–102. Fry, WJ; Krumins,R; Fry, FJ; Thomas, G; Borbely, S; Ades, H.Origins and distributions of some efferent pathways from the mamillary nuclei of the cat. J Comp Neurol, 1963 129:195-258. Fry, WJ. Mammillary complex of cat brain-aspects of quantitative organization. Anat Rec, 1966 154, 175-84. Fry, WJ. Quantitative delineation of the efferent anatomy of the medial mammillary nucleus of the cat. J Comp Neurol. 1970 139, 321-336. Godement, P; Vanselow, J; Thanos, S; Bonhoeffer, F. A study in developing visual systems with a new method of staining neurons and their processes in fixed tissue. Development, 1987 101, 697-713. Gonzalo-Ruiz, A ; Morte, L ; Sanz, JM. Glutamate/aspartate and leuenkephalin immunoreactivity in mammillothalamic projection neurons of the rat. Brain Res Bull, 1998 47, 565-574. Guillery, RW. Degeneration in the hypothalamic connexions of the albino rat. J. Anat, 1957 91, 91-115. Guison, N.G; Ahmed, A.K; Dong, K; Yamadori, T. Projections from the lateral mammillary nucleus to the anterodorsal thalamic nucleus in the rat. Kobe J Med Sci, 1995 41, 213-220. Gurdjian, E.S. The diencephalon of the albino rat. J Comp Neurol, 1927 43, 1114. Hamano, K; Takeya, T; Iwasaki, N; Nakayama, J; Ohto, T; Okada, Y. A quantitative study of the progress of myelination in the rat central nervous system, using the immunohistochemical method for proteolipid protein. Brain Res Dev Brain Res, 1998 108, 287-293. Hayakawa, T; Zyo, K. Afferent connections of Gudden's tegmental nuclei in the rabbit. J Comp Neurol. 1985 235,169-81. Hayakawa, T; Zyo, K. Subcortical afferents to the nucleus reticularis tegmenti pontis in the rabbit: a retrograde horseradish peroxidase study. Okajimas Folia Anat Jpn. 1986 63, 159-177.

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Hayakawa, T; Zyo, K. Retrograde Double-Labeling Study of the Mammillothalamic and the Mammillotegmental Projections in the Rat, J Comp Neurol, 1989 284,1-11. Herrero, MT; Barcia, C; Navarro, JM. Functional anatomy of thalamus and basal ganglia. Childs Nerv Syst, 2002 18, 386-404. Issacson, RL. The Limbic System. 1982 New York: Plenum Press. Jacobson, J. Sequence of myelinization in the brain of the albino rat. A. Cerebral cortex, thalamus and related structures. J Comp Neurol, 1963 121, 5-29. Kopelman, MD. The Korsakoff syndrome. Br J Psychiatr, 1995 166, 154–173. Krieckhaus, EE. The mamillary bodies their functions and anatomical connections. Acta Biol Exp. (Warsaw) 1967 27, 319-337. Lukas, JR; Aigner, M; Denk, M; Heinzl, H; Burian, M; Mayr, R. Carbocyanine postmortem neuronal tracing: Influence of different parameters on tracing distance and combination with immunocytochemistry. J Histochem Cytochem, 1998 46, 901–910. Makarenko, IG. Prenatal carbocyanine dye tracing of septo-hypothalamic connections. Brain Res, 2007 1130, 38-47. Makarenko, IG. DiI tracing is a useful tool for studies of the hypothalamic connections during perinatal development. In Neural Pathways Research. Chapter II. F.L. Pichler, ed. Nova Sci. Publishers, New-York, 2008 pp. 31-71. Makarenko, IG; Ugrumov, MV; Derer, P; Calas, A. Projections from the hypothalamus to the posterior lobe in rats during ontogenesis: 1,1'dioctadecyl-3,3,3', 3'-tetramethylindocarbocyanine perchlorate tracing study. J Comp Neurol, 2000 422, 327-337. Makarenko, IG; Ugrumov, MV; Calas, A. Axonal projections from the hypothalamus to the median eminence in rats during ontogenesis: DiI tracing study. Anat Embryol (Berl), 2001 204, 239-252. Makarenko, IG; Ugryumov, MV; Kalas, A. Involvement of accessory neurosecretory nuclei of hypothalamus in the formation of hypothalamohypophyseal system during prenatal and postnatal development in rats. Russ J Devel Biol, 2002 33, 37-42. Translated from Ontogenez, 2002 33, 43-49. Makarenko, IG; Ugrumov, MV; Calas, A. Axonal projections from the hypothalamus to the pituitary intermediate lobe in rats during ontogenesis: DiI tracing study. Brain Res Dev Brain Res, 2005 155, 117-126.

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Marion, JF ; Yang, C; Caqueret, A ; Boucher, F; Michaud, JL. Sim1 and Sim2 are required for the correct targeting of mammillary body axons. Development, 2005 132, 5527-5537. Mark, LP; Daniels, DL; Naidich, TP; Hendrix, LE. Limbic connections. Am J Neuroradiol, 1995 16, 1303-1306. Mastick, GS; Easter, SS. Initial Organization of Neurons and Tracts in the Embryonic Mouse Fore- and Midbrain. Devel Biol, 1996 173, 79-94. Morgane, PJ; Galler, JR; Mokler, DJ. A Review of Systems and Networks of the Limbic Forebrain/Limbic Midbrain, Prog Neurobiol, 2005 75, 143160. Nauta, WJH. Hippocampal projections and related neural pathways to the midbrain in the cat. Brain, 1958 81, 319-340. Niimi, K; Koizuka, M; Kawamura, S; and Abe, K. Efferent projections of the mamillary body in the cat. Okajimas Fol Anat Jpn, 1972 49, 129-156. Papez, JW. A proposed mechanism of emotion. Arch Neurol Psychiatr, 1937 38, 725–743. Paxinos, G; Tork, I; Tecon, LH; Valentino, KL. Atlas of the developing rat brain. San Diego: Academic Press Inc, 1991. Paxinos, G; Watson, T. The rat brain in stereotaxic coordinates. Acad. Press, New York. 1997 Powell, TPS; Cowan, WM. The origin of the mammillothalamic tract in the rat. J Anat, 1954 88, 489-497. Powell, TPS; Guillery, RW; Cowan, WM. A quantitative study of the fornixmamillo-thalamic system. J Anat, 1957 91, 419–437. Raisman, G. Neural connections of the hypothalamus. Brit Med Bull, 1966 22, 197-201. Ramón y Cajal, S. Apuntes para el studio del bulbo raquídeo, cerebelo y orígen de los nervios encefálicos. Anales Soc. Española Historia Natural, 1895 24, 5-118. Ramón y Cajal, S. Estudios talámicos. Trab Lab Invest Biol Univ Madrid, 1903 2, 31-69. Seki, M; Zyo, K. Anterior Thalamic Afferents from the Mammillary Body and the Limbic Cortex in the Rat. J Comp Neurol, 1984 229, 242-256. Shibata, H. Topographic organization of subcortical projections to the anterior thalamic nuclei in the rat. J Comp Neurol, 1992 323, 117-127. Sziklas, V; Petrides, M. Memory and the region of the mammillary bodies. Prog Neurobiol, 1998 54, 55-70.

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Takeuchi, Y; Allen, GV; Hopkins, DA. Transnuclear transport and axon collateral projections of the mamillary nuclei in the rat. Brain Res Bull, 1985 14, 453-468. Tessier-Lavigne, M; Goodman, CS. The molecular biology of axon guidance. Science, 1996 274, 1123-1133. Trukhacheva, AA, Aleksandrova, MA. The development of thalamocortical connections studied by using carbocyanine dyes in the early ontogeny of rats. Ontogenez, 1999 30, 210-219 [Article in Russian]. Valverde, F. Golgi atlas of the postnatal mouse brain. Springer, New York 1998. Valverde, F; Garcia, C; Lopez-Mascaraque, L; De Carlos, JA. Development of the mammillothalamic tract in normal and Pax-6 mutant mice. J Comp Neurol, 2000 419, 485-504. Van der Kooy, D; Kuypers, HG; Catsman-Berrevoets, CE. Single Mammillary Body Cells with Divergent Axon Collaterals. Demonstration by a Simple, Fluorescent Retrograde Double-Labeling Technique in the Rat. Brain Res, 1978 158, 189-196. Vann, SD; Aggleton, JP. Evidence of a spatial encoding deficit in rats with lesions of the mammillary bodies or mammillothalamic tract. J Neurosci, 2003 23, 3506-3514. Vann, SD; Aggleton, JP. The mammillary bodies: two memory systems in one? Nat Rev Neurosci, 2004 5, 35-44. Vann, SD; Saunders, RC; Aggleton, JP. Distinct, parallel pathways link the medial mammillary bodies to the anterior thalamus in macaque monkeys. Eur J Neurosci, 2007 26, 1575-1586. Vercelli, A; Repici, M; Garbossa, D; Grimald, A. Recent techniques for tracing pathways in the central nervous system of developing and adult mammals. Brain Res Bull, 2000 51, 11-28. Vertes, RP; Albo, Z; Prisco, GV. Theta-rhythmically firing neurons in the anterior thalamus: implications for mnemonic functions of the Papez’s circuit. Neurosci, 2001 104, 619-625. Watanabe, K; Kawana, E. A horseradish peroxidase study on the mammillothalamic tract in the rat. Acta Anat, 1980 108, 394–401. Wehr, R; Mansouri, A; de Maeyer, T; Gruss, P. Fkh-5-deficient mice show dysgenesis in the caudal midbrain and hypothalamic mammillary body. Development, 1997 124, 4447–4456. Yoneoka, Y; Takeda, N; Inoue, A; Ibuchi, Y; Kumagai, T; Sugai, T ; Takeda, K; Ueda, K. Acute Korsakoff syndrome following mammillothalamic tract infarction. J Neuroradiol, 2004 25, 964-968.

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In: Thalamus: Anatomy, Functions and Disorders ISBN 978-1-61324-152-3 Editor: Justin L. Song, pp. 65-81 © 2011 Nova Science Publishers, Inc.

Chapter III

Thalamic Stroke Prakash R. Paliwal and Vijay K. Sharma*

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Division of Neurology, Department of Medicine, National University Health System, Singapore

Abstract Thalamus has been labeled as the "Grand Central Station" of the brain because virtually all incoming information travels through it before reaching the cerebral cortex and all areas of the cortex project to the thalamus. Compared to the uncommon non-vascular insults like Korsakoff’s syndrome due to the thiamine deficiency, vascular insults constitute the commonest source of injury to the thalamus. Thalamus is predominantly supplied by multiple small vessels originating from the posterior cerebral and communicating arteries, with significant variations and overlap. The stroke syndromes are not specific to individual nuclei because most vascular lesions are fairly large that result in a great deal of overlap of symptoms due to infarction or hemorrhage from a particular artery. The structure-function relationship is too complex and the information about the functional anatomy of thalamus has been largely derived from patients evaluated after thalamotomy and insertion of thalamic stimulation devices. Recent advances in functional imaging with *

Corresponding author: Dr. Vijay Sharma, Division of Neurology, Department of Medicine, National University Health System, Singapore 119074, Email- [email protected], Tel- +65 6772 2516, Fax- +65 6872 3566.

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Prakash R. Paliwal and Vijay K. Sharma magnetic resonance imaging and sophisticated use of diaschisis for analyzing the corticothalamic connectivity have significantly improved our understanding. In general, injury to the left side may be associated with language deficits in language, verbal intellect and verbal memory while a right-sided injury results in visuospatial deficits and impaired nonverbal intellect. Bilateral injury is associated with severe memory impairment. Other deficits due to the thalamic injuries include confusion, delirium, visual hallucinations, peduncular hallucinosis and cognitive deficits. We discuss functional areas of thalamus, their vascular supply and clcinical presentations due to various acute ischemic and hemorrhagic lesions.

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Keywords: Thalamus, thalamic stroke, posterior cerebral artery

Thalamus has been referred as the "Grand Central Station" of the brain because it receives virtually all the incoming information before relaying it to the cerebral cortex. Furthermore, wide network of connections transmit the information from all areas of the cerebral cortex to the thalamus. Thus, knowledge of thalamic anatomy and connections is critical in understanding thalamic influence on cortical functions and in the interpretation of functional brain imaging studies [1]. This knowledge is also important to understand various clinical manifestations of thalamic stroke. Disruption of the vascular supply is the commonest cause of thalamic dysfunction. Most vascular lesions are fairly large so it affects multiple nuclei and tracts so usually patient present with overlap of clinical features seen in each vessel territory. The first clinic-pathologic study of thalamic stroke was published in 1906 by Dejerine and Roussy [2] who emphasized sensorimotor disturbances. They described three patients with thalamic stroke who developed delayed onset choreo-athetosis and hemi-ataxia. That cognitive deficits may occur after isolated thalamic vascular lesions were described twenty years later [3, 4].

Thalamic Blood Supply The details of thalamic arterial blood supply were first studied by Duret [5] and later by Foix et al. [6] Almost 50 years later, detailed arterial network and the anatomic variations in thalamic blood supply were revisited by Percheron [7-11]. There are four major vascular territories each supplying one

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particular group of thalamic nuclei. They are Tuberothalamic, Inferolateral, Paramedian and Posterior Choroidal arteries (Figure 1). There may be significant variation in terms of origin of these branches and there extent of supply.

Figure 1. Arterial branches supplying the Thalamus. Posterior cerebral arteries (PCA) constitute the terminal bifurcation of basilar artery (BA). All the arterial branches supplying thalamus arise from the PCA. Paramedian arteries originate from P1 segment of PCA as inferior ramus (1), middle ramus (2) and superior ramus (3). Tuberothalamic artery (4) is usually a branch from the posterior communicating artery (PCOM). Posterior choroidal arteries usually arise from the P2 segment of PCA as 1-2 medial posterior choroidal arteries (4), 5-10 inferolateral arteries (6) and 1-6 branches of lateral posterior choroidal arteries (7).

Tuberothalamic artery, also known as the Polar artery supplies anterior parts of the thalamus [7, 12]. Paramedian arteries can be in pairs or arise as one common trunk and are responsible for perfusion of the paramedian territory of thalamus [9, 13]. Inferolateral part of thalamus is supplied by Thalamogeniculate artery while the posterior regions of the thalamus are supplied by posterior choroidal artery [14]. Since, many anomalies are common in the number of arteries and their perfusion territories, clinical manifestations may vary widely.

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Tuberothalamic Artery Infarction

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Tuberothalamic artery arises from middle third of the posterior cerebral artery (PCA) [15]. However, it may be absent in 1/3rd cases and its function is performed by the Paramedian arteries [7, 12]. Within thalamus it follows course of mammilothalamic tract. This artery supplies the reticular nucleus, ventral anterior nucleus (VA), rostral part of the ventrolateral nucleus (VL), ventral pole of the medial dorsal nucleus (DM), mamillothalamic tract, ventral amygdalofugal pathway, ventral part of the internal medullary lamina, and anterior thalamic nuclei: anteromedial (AM), ventral anterior (VA), and ventral posterior (VP) (Figure 2). Infarction in the territory of this vessel is characterized clinically by severe neuropsychological deficits [16-18]. The symptoms may be fluctuating level of consciousness, confusion or euphoria. Other characteristic features include impairmed recent memory, inability to learn the new things, apathy and temporal disorientation, especially in left sided lesions [21]. One specific type of behavioral change described with tuberothalamic artery stroke is ‘Palipsychism’ manifested by parallel expression of mental activities [21].

Figure 2. Anatomical segments of Thalamus. This line diagram shows lateral (A) and dorsal (B) of thalamus and their nuclei. Various thalamic nuclei represented in the figure are dorsomedial (DM), ventral anterior (VA, ventral lateral (VL), ventral posterior (VP), pulvinar (P). Inferior lateral (IL) nucleus is visible in the dorsal view (B).

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and hippocampus [19]. Language disturbances are seen more commonly in patients with left thalamic lesions. These may include anomia, decreased fluency and impaired comprehension and constructional apraxia. Sometimes, fluent paraphasic speech may be seen, often associated with neologism and perseveration. Reading and repetition may be relatively preserved. One of the unique presentations of the tuberothalamic artery involvement is emotional facial paresis in patients with normal volitional movement. Left thalamic lesion may cause acalculia in addition to buccofacial and limb apraxia [20]. Although, mild-to-moderate weakness is a common feature, sensory disturbances are rare.

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Paramedian Artery Infarction Paramedian arteries arise from the proximal PCA [22]. Tatu et al grouped these arterial branches into inferior, middle and superior rami [23]. Although, paramedian arteries may supply variable extents of thalamus, the main perfusion territories include the dorsomedial nucleus, internal medullary lamina, and intralaminar nuclei. In some patients, even the paraventricular nuclei, posteromedial part of ventrolateral nuclei and ventromedial part of the pulvinar (Figure 2) may also be supplied by the paramedian arteries. Stoke resulting from the occlusion of paramedian artery produces neuropsychological symptoms in form of disturbances of arousal and memory. Impairment of arousal may last for few days and may be associated with confusion, aggression, agitation and apathy [13, 16-18]. Speech and language impairments may also be seen and are characterized by hypophonia, dysprosody and frequent perseveration. Although, fluency of speech is severely reduced, syntactic structure may be preserved with normal repetition, called as adynamic aphasia of Guberman and Stuss [24]. Paramedian artery arise from P1 segment of the PCA on each side separately but in a considerable proportion of patients it may arise from common trunk from one of the P1 PCAs and supply both thalami, described as the ‘Artery of Percheron’. Occlusion of this variant can present with bilateral thalamic infarction and severe manifestations, especially somnolence (Figure 3) [25]. Bilateral infarction in territory of this vessel produces severely impaired orientation, confusion, hypersomnolence, deep coma, “coma vigil” or akinetic mutism and severe memory impairment with perseveration and confabulation. It is also associated with eye movement abnormalities [13, 16, 17, 26]. In some cases, it may have inappropriate social behavior, impulsive

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aggressive outburst, emotional blunting, loss of initiative and absence of spontaneous thoughts and mental activities [27, 28]. This occurs due to loss of psychic self activation as a result of disconnection in thalamofrontal projections. Prominent disorientation in time known as ‘chronotaraxis’ has also been described [29, 30]. Initial manifestation in bilateral thalamic infarctions due to paramedian artery occlusion may be quite severe [31].

Figure 3. Vertebrobasilar system and origin of one of the variants (azygous) of artery of Percheron. A schematic diagram represents ‘azygous variant’ of the artery of Percheron, originating from the right posterior cerebral artery and supply both thalami.

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Amnestic syndrome with adjuvant behavioral abnormalities, called ‘thalamic dementia’ has been described in patients with paramedian thalamic involvement [32]. However, similar clinical syndromes may occur due to thiamine deficiency, Creutzfeldt-Jakob disease, fatal familial insomnia [33]and transient global amnesia [34]. Neurological signs in thalamic infarction include asterixis, complete or partial vertical gaze paresis, loss of convergence, pseudo–sixth nerve palsy, bilateral internuclear ophthalmoplegia, miosis and intolerance to bright light [18, 24]. Thalamic infarctions can also manifest as complete ophthalmoplegia [35], due to the involvement of the oculomotor nuclei or fascicles and supranuclear vertical gaze palsy due to involvement of the rostral interstitial nucleus of the medial longitudinal fasciculus. Occasionally, loss of all abduction movements of the eyes may occur due to a lesion of the abducens motorneurons. However, loss of abducting eye movements may also be due to psuedoabducent palsy , as it occurs in absence of abducent lesion [36]. Artery of Percheron infarction can give rise to bilateral paramedian infarction (Figure 4) with or without midbrain involvement due to anatomic variation in blood supply. It can give rise to characteristic ‘V-shaped’ hyperintense signal intensity on axial diffusion-weighted (DWI) and fluid attenuated inversion recovery (FLAIR) images along the pial surface of the midbrain in the interpeduncular fossa. This neuroimaging sign of artery of Percheron infarction has been reported to have sensitivity of be around 67% [37].

Figure 4. Bilateral thalamic infarction in patient after acute ‘top-of-the’ basilar artery thrombosis. Comupterized tomographic angiography (CTA) of the brain shows a filling defect in the distal basilar artery (A) in a patient who presented with drowsiness and quadriparesis of 2 hours duration. Although, the patient remained drowsy, power in the extremities recovered completely during intravenous tissue plasminogen activator infusion. CTA performed 3 hours later confirmed complete recanalization of the basilar artery (B). MRI of the brain showed bilateral thalamic infarcts on diffusion-weighted imaging (C).

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Some other variants of paramedian artery may be seen in some cases. In cases where the tuberothalamic artery is absent, paramedian arteries may supply its territory. Thalamus is usually supplied by the perforating branches of the superior rami. On the other hand, the inferior rami supply pons and midbrain and their involvement often result in ‘locked-in syndrome’.

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Inferolateral Artery Infarction Inferolateral arteries are group of arteries which arises from the P2 segments of PCA [7, 18]. The three main branches of the inferolateral artery are- the medial geniculate, principal inferolateral, and inferolateral pulvinar arteries. These branches supply the external half of medial geniculate nucleus, the major part of the ventral posterior nuclei and the rostral and lateral parts of the pulvinar, respectively. Patients with inferolateral artery infarction present with the characteristic thalamic syndrome of Dejerine and Roussy [2]. All modalities of sensation may be affected and hemiparesis and ataxia may also be seen [2, 38, 39]. Sensory loss is usually of variable extent and in some cases pain may persist for a long time after the acute event. Post-lesion pain in the syndrome of Dejerine and Roussy is more common in patients with right thalamic lesion [40]. Owing to the complexity of the number and perfusion territories of penetrating arteries, the resultant small vessel strokes present with variable manifestations. Speech is rarely involved in stroke involving the inferolateral arteries. Although, cognitive impairment and psychiatric features are not the usual feature, some patients may develop cognitive impairment with verbal long-term memory impairment, especially following lateral thalamic involvement. These presentations are more common with right sided lesions [41].

Posterior Choroidal Artery Infarction Posterior choroidal artery originates from the P2 segment of PCA. Through its many branches, it supplies subthalamic nucleus, midbrain, medial half of the medial geniculate nucleus, posterior parts of the intralaminar nuclei and the pulvinar nuclei [7, 11, 13, 18, 23]. The clinical features of infarction from the occlusion of posterior choroidal artery are not well defined. Patients may present with quadrantonopia with impaired fast phase of optokinetic

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response on the side of lesion, especially when lateral geniculate nucleus is involved [18]. Some patients may have hemisensory loss, transcortical aphasia and memory deficits [42]. In patients with infarcts restricted to pulvinar, a complex hyperkinetic motor syndrome may be observed that includes ataxia, rubral tremor, dystonia, myoclonus, and chorea. This syndrome has been described as ‘jerky dystonic unsteady hand’ [43]. Although, spatial neglect may also occur in lesions of the right pulvinar, it is more common in patients in whom lateral dorsal and ventrolateral nucleus are also involved [44].

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Variants of Thalamic Infarction Wide range of clinical presentations are seen in patients with thalamic infarctions due to extremely variable vascular supply. These anatomical variant may be grouped as antero-median, central and postero-lateral territories. Antero-median territory combines anterior and paramedian territory, central territory combines central part of all 4 conventional territories and postero-lateral combines infero-lateral and posterior territories. Cognitive impairment, altered consciousness and vertical eye paresis are the most frequent signs with antero-median infarction. Central territory infarction present with variable clinical signs including unresponsiveness, cognitive impairment, eye movement abnormalities and contralateral sensory disturbances. Although, sensory disturbances are predominant in posterolateral territory infarctions, weakness, ataxia and cognitive impairment are not seen commonly with this territory involvement [45].

Combined Polar and Paramedian Artery Infarction Polar artery are extremely variable and in up to one-third of patients, its territory is supplied by the paramedian artery and hence, the clinical manifestations are often combination of the dysfunction of these two arteries [7-9, 13, 18, 46, 47]. Clinical dysfunction is mainly neuro-behavioral. Patients can present with severe retrograde and anterograde amnesia, apraxia, dysgraphia and vertical gaze palsy. Although, amnesia may occur in infarctions of either vascular territory, it is less severe and improves with time. However, amnesia is severe in infarctions of combined polar and paramedian arteries and recovery is less apparent [48].

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Other Uncommon Manifestations Wide range of presentations have been reported with thalamic infarctions, largely depending upon the specific regions involved. Altered odour perception [49] and disorders of smell, taste, and food intake [50] have been described occasionally in patients with infarctions of dorsomedial and intralaminar thalamic nuclei. Kim et al described a case of anterior thalamic infarction with micrographia and attributed it to the involvement of lenticulothalamic circuit [51]. Various movement disorders like dystonia-athetosischorea and action tremors of delayed onset have been described after thalamic stroke [52]. These involuntary movements are believed to be due to loss of proprioception [53]. Similarly, involvement of cerebello-rubro-thalamic cortical tract may lead to jerky hand tremors, seen more commonly with large vessel occlusion [52]. It occurs in a delayed manner due to unbalanced recovery in motor power and seen in lesions of lateral and posterior part of thalamus with variable capsular involvement. Cerrato et al described a case of complex myoclonus involving palate and upper limb in a patient with lateral thalamic infarction [54]. Lapez et al described a case of the ‘alien hand syndrome’ in a patient with right lateral thalamic involvement [55]. This was described as ‘posterior alien hand syndrome’ that is due to sensory ataxia and hemineglect syndrome, entirely different from its more classical anterior or motor variant.

Thalamic Venous Infarction Cerebral venous thrombosis involving the deeper veins has been reported to cause bilateral thalamic infarction. Krolak–Salmon et al described a case that presented with apathy, poor insight, slowness of thought, and amnesia. It mimicked bilateral paramedian thalamic infarcts. As seen with other venous infarcts, their patient achieved relatively good outcome for memory and cognitive functions [56].

Thalamic Hemorrhage Clinical presentations in thalamic hemorrhage are similar to the ischemic lesions and depend on the location of tissue injury. Hemorrhages larger than 2

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cm in diameter and/or 4 mL in volume are usually considered as large. Patients with thalamic hemorrhages more than 3.3 cm in size usually die within 1 month [57-59]. Similar to the ischemic lesions, thalamic hemorrhages are also classified as antero-lateral, postero-lateral, medial and dorsal. Postero-lateral thalamic hemorrhage is the commonest location for thalamic hemorrhage and most of the bleeds in this region are large [60]. Hypertension constitutes the most common risk factor for thalamic hemorrhage [61] and thalamic hemorrhages usually develop during daily activities, corresponding to typical circadian rhythm [62]. Thalamic hemorrhage may lead to intraventricular extension and present with headache, vomiting and nuchal rigidity. Intraventricular extension of thalamic hemorrhage correlates with its size, volume and extension to other areas. It is associated with poor prognosis for survival [60] as up to 52% of patients with intraventricular hemorrhage do not survive [63]. Altered consciousness and cognitive impairment are more common with antero-medial thalamic lesions as compared to postero-lateral lesions. Coma and stupor at the onset of stroke in such cases are associated with poor outcome and higher risk of mortality [57-59] Speech disturbances may also occur with thalamic hemorrhage and range from motor aphasia to global aphasia and even mutism. Motor deficits are seen in 93% to 100% of patients with thalamic hemorrhage [58, 59, 63], either direct involvement of adjacent internal capsule or indirect pressure effects. Sometimes, thalamic hemorrhages may resemble a pure sensory stroke [64]. Ocular signs are quite commonly seen in patients with thalamic hemorrhage and include horizontal or upward gaze palsy, skew deviation or fixed pupils [65, 66]. Eye signs occur more commonly with postero-lateral infarctions. Horizontal gaze disturbances occur as a result of interruption of the descending fibers from the frontal eye field at the posterior thalamus. On the other hand, vertical gaze dysfunctions correspond to the involvement of intralaminar and dorsomedial nucleus, along with coexisting upper midbrain lesion.

Prognosis in Thalamic Hemorrhage Clinical outcomes after thalamic hemorrhage correlate with volume of hematoma, loss of consciousness at onset, presence of motor weakness, intraventricular extension and hydrocephalus [67, 68]. In general, mortality

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and motor recovery after thalamic hemorrhage is relatively better than the 1 cortical or subcortical strokes in children [69, 70] as well as adults [63, 71]. However, the data on the prognosis of post-stroke thalamic pain and neuropsychiatric impairment are insufficient.

Conclusion Although the clinical presentations of thalamic stroke may be divided into individual vascular syndromes, considerable overlaps are observed because of the variations in the vascular anatomy and their resultant lesions. However, clinical-anatomic correlations can be inferred from the disturbances of various connections within the thalamus as well with other brain structures.

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[64] Azouvi P, Pappata S, Baron JC. Attaque sensitive pure par hematome thalamique. Rev Neurol. 1988;144:212-214. [65] Hirose G, Kosoegawa H, Saeki M. The syndrome of posterior thalamic hemorrhage. Neurology. 1985;35:98-100. [66] Fazio C, Sacco G, Bugiani O. The thalamic hemorrhage. Eur Neurol. 1973;9:30-43. [67] Chung CS, Caplan LR, Han W, Pessin MS, Lee KH, Kim JM. Thalamic haemorrhage. Brain. 1996;119:1873-1886. [68] Kase CS. Subcortical hemorrhages. In: Donnan G, Norving B, Bamford J, Bogousslavsky J, eds. Subcortical Stroke. London, UK: Oxford University Press; 2002:347-377. [69] Garg BP, DeMyer WE. Ischemic thalamic infarction in children: clinical presentation, etiology, and outcome. Pediatr Neurol. 1995;13:46-49. [70] Brower MC, Rollins N, Roach ES. Basal ganglia and thalamic infarction in children: cause and clinical features. Arch Neurol. 1996;53:12521256. [71] Buttner T, Schilling G, Hornig CR, Dorndorf W. Thalamic infarcts: clinical aspects, neuropsychological findings, prognosis. Fortschr Neurol Psychiatr. 1991;59:479-487.

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In: Thalamus: Anatomy, Functions and Disorders ISBN 978-1-61324-152-3 Editor: Justin L. Song, pp. 83-98 © 2011 Nova Science Publishers, Inc.

Chapter IV

Complex Pathology in the Thalamus Following Cerebral Ischemia Mikko Hiltunen and Jukka Jolkkonen* Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland

Abstract Focal cerebral ischemia in the cortex leads to secondary pathology in areas distant from the infarct. The thalamus is spared from acute ischemic damage, but because of its synaptic connections to the cortex, delayed retrograde degeneration of thalamocortical neurons occurs. In addition to degenerative process, thalamic pathology includes parallel inflammatory reaction, impaired calcium homeostasis, complex alterations in βsecretase-mediated amyloid precursor protein processing, and increased angiogenesis. Together, these result in a unique pathology remote from the initial insult that has intriguingly similar features to those in Alzheimer’s disease. The causal relationships between different *

Correspondence should be sent to: Dr. Jukka Jolkkonen, Institute of Clinical Medicine – Neurology. University of Eastern Finland. P. O. Box 1627. Yliopistonranta 1 C. 70211 Kuopio, Finland. Tel: +358-40-3552519. Fax: +358-17-162048. Email: [email protected]

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Mikko Hiltunen and Jukka Jolkkonen pathologies and their functional meaning are poorly understood. Given the integral role of the thalamus in the flow and processing of sensorimotor information, damage to the thalamus or its projections is likely to have detrimental consequences. Further understanding of the secondary pathology in the thalamus is expected to aid drug development that aims at neurorestoration following various neuronal insults.

Introduction

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Neurodegeneration and plasticity after cortical ischemia has been primarily studied in the perilesional regions. However, remote areas such as the thalamus connected to the infarct are also affected [Block et al., 2005]. Delayed degeneration of corticothalamic and thalamocortical connections leads eventually to severe shrinkage of the thalamus [Fujie et al., 1990; Tamura et al., 1991]. The ongoing neurodegeneration is also associated with inflammatory reaction [Block et al., 2005]. In addition, recent evidence suggests that the thalamic pathology is far more complex (Figure 1).

Figure 1. The thalamic pathology following cerebral ischemia. Adjacent sections from the thalamus 1 month after focal cerebral ischemia show overlapping staining pattern between A) β-amyloid (Aβ), B) calcium (Alizarin red), C) microglial reaction (OX-42), and D) new blood vessels (RECA-1). Exclusively, thalamic subnuclei connected to the ischemic cortex, such as ventromedial and ventrolateral thalamic nuclei and ventroposterior lateral and ventroposterior medial nuclei, show positive staining.

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It seems that β-amyloid (Aβ) and β-amyloid precursor protein (APP) accumulates in the thalamus of rats subjected to middle cerebral artery occlusion (MCAO) [van Groen et al., 2005]. Initially, Aβ staining is diffuse but aggregates over time to plaque-like deposits similar to those in Alzheimer’s disease (AD). More interestingly and in parallel with Aβ accumulation, calcium levels are increased indicating impaired calcium homeostasis [Jolkkonen & van Groen, 2007; Mäkinen et al., 2008; Hiltunen et al., 2009]. Angiogenesis, the formation of new blood vessels, is another atypical feature in the thalamus following cerebral insults [Ling et al., 2009; Hayward et al., 2010]. Since the thalamus is the place where sensory, motor, and cognitive pathways are organized and integrated [Briggs & Usrey, 2008], the described pathology is expected to have widespread functional consequences. For example, Aβ deposits may impair sensorimotor outcome after cerebral ischemia [Clarke et al., 2007] whereas calcification and angiogenesis may have a beneficial role by removing excessively released Aβ/calcium and neuronal debris [Rodriguez et al, 2000; Hayward et al., 2010]. This review will give an update of neuropathology in the thalamus following cerebral ischemia with special emphasis on its possible functional meaning.

Alterations in APP Expression and Processing Following Focal Cerebral Ischemia According to the prevailing hypothesis, altered APP processing leading to increased Aβ production is one of the key features underlying the pathogenesis of AD [Tanzi & Bertram, 2005]. It is also a well-established fact that cerebral ischemia leads to the transient up-regulation and accumulation of APP adjacent to the ischemic lesion in the cortex and white matter [Abe et al., 1991; Koistinaho et al., 1996; Pluta et al., 2006]. Apart from the altered APP expression, it has been shown that β-secretase (BACE) mediated cleavage of APP is increased after cerebral ischemia due to the augmented BACE levels and activity [Wen et al., 2004; Tesco et al., 2007]. Moreover, cerebral ischemia induces γ-secretase activity in the ischemic hemisphere and more importantly, γ-secretase inhibition improves the neurological outcome and reduces the infarct size after MCAO in mice [Polavarapu et al., 2008]. Since an ischemic neuronal insult also affects the expression of a disintegrin and

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metalloprotease 10 (ADAM10) [Lee et al., 2006], which is the main αsecretase responsible for APP cleavage, it can be concluded that focal cerebral ischemia facilitates the amyloidogenic processing of APP and Aβ deposition. Although the above mentioned changes in APP expression and processing take place in the ischemic lesion, it was recently shown that APP and Aβ also accumulate in the ipsilateral thalamus of rats subjected to MCAO [van Groen et al., 2005]. Importantly, dense plaque-like amyloid deposits persisted in the thalamic ventroposterior lateral and ventroposterior medial nuclei (VPL/VPM) even nine months after the initial ischemic insult in the cortex. Owing to corticothalamic and thalamocortical connections between the cortex and thalamus, it is likely that the amyloid pathology observed in the thalamus is linked to the secondary degeneration known to be initiated after cerebral ischemia [Iizuka et al., 1990; Ross & Ebner, 1990; Wei et al., 2004]. Elucidation of the molecular mechanisms related to Aβ accumulation in the thalamus has revealed alterations in APP isoform expression, maturation, and processing [Hiltunen et al., 2009]. More specifically, marked increase in APP maturation has been observed, which was interpreted as an indication of enhanced APP trafficking, while the APP isoform shift from APP695 to APP751 coincided with prominent astrocyte activation 30 days after MCAO. In addition, BACE levels and activity were significantly increased seven days after MCAO in the thalamus, which again coincided with the increased calcium levels and the depletion of BACE trafficking protein, Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3). Thus, focal cerebral ischemia leads to complex pathogenic events related to APP expression and processing in the thalamus long after the initial ischemic insult. These findings also demonstrate that the underlying molecular mechanisms between cerebral ischemia and AD are intriguingly similar in terms of altered APP processing.

Inflammation in the Thalamus Following Focal Cerebral Ischemia Focal cerebral ischemia evokes inflammatory responses in the ischemic regions due to energy depletion and necrotic cell death [Zheng & Yenari, 2004; Wang et al., 2007]. These initial changes are followed by the production of reactive oxygen species (ROS) as well as inflammatory cytokines and chemokines, which again act as initiators of microglial activation and adhesion molecule expression. At the same time, adhesion molecules are responsible for

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the adherence of circulating leukocytes to the ischemic site and their subsequent infiltration to the brain parenchyma. Activated astrocytes are also observed around the perilesional area [van Groen et al., 2005]. After extracellular matrix disruption by metalloproteinases and the release of cytotoxic agents, such as nitric oxide and ROS, these adverse events ultimately lead to brain edema and cell death [Wang et al., 2007]. Compared to ischemia in the cortex, the inflammatory response in the thalamus is delayed in rats subjected to MCAO [van Groen et al., 2005]. Although the substantial activation of astrocytes and microglia was detected in the ischemic area one week after MCAO, the thalamus displayed only very few astrocytes and microglial cells. After one month, however, the situation was changed as activated astrocytes and microglial cells were present in the thalamus [van Groen et al., 2005; Hiltunen et al., 2009]. Only an astroglial scar was observed around Aβ deposits in these nuclei at nine months after MCAO [van Groen et al., 2005]. Interestingly, activation of astrocytes in the thalamus coincided with the appearance of an APP751 isoform and the increased expression of an Aβ degrading enzyme, insulin degrading enzyme (IDE) [Hiltunen et al., 2009]. Since IDE levels are shown to be increased around the amyloid plaques as a result of Aβ-triggered astrocyte activation in an AD mouse model with APP over-expression [Lee et al., 2006], it is anticipated that increased IDE expression in the thalamus of MCAO rats is a compensatory response to the increased Aβ deposition and inflammation.

Impaired Calcium Homeostasis in the Thalamus Following Focal Ischemia Impaired calcium homeostasis has been observed in a number of acute and chronic brain diseases including cerebral stroke and Alzheimer’s disease [Kuzuhara et al., 1985; Parisi et al., 1988; Ramonet et al., 2006; Bezprozvanny & Mattson, 2008]. In MCAO rats, 45Ca uptake is increased 3 days after the ischemic insult and high accumulation of 45Ca persists for at least 1 month in the VPL/VPM [Shirotani et al., 1994; Watanabe et al., 1998]. This is most likely related to the transient breakdown of the blood-brain barrier [Kim et al., 1998]. Calcium concentrations in the thalamus as measured by atomic absorption spectrometry are increased at 7 and 30 days but not 2 days after

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ischemia [Hiltunen et al., 2009]. Histological studies show that the initial diffuse calcium staining transforms over time to small calcium granules and large coral like formations, which are detectable as late as 9 months after ischemia [Jolkkonen & van Groen, 2007]. This indicates that impaired calcium homeostasis is a far more long-lasting phenomenon than previously thought. Eventually, calcium accumulation leads to secondary degeneration through inappropriate activation of several enzyme systems and mitochondrial dysfunction [Besancon et al., 2008]. Possibly independent from this, axolemmal depolarization promotes Ca2+ overload mediated primarily by the Na+/Ca2+ exchanger (NCX) operating in a reverse manner, which exacerbates axonal damage [Stys & Lopachin, 1998]. Calcification is a peculiar feature in the thalamus following cerebral ischemia. Interestingly, thalamic calcification also occurs following brain trauma [Pierce et al., 1998], global ischemia [Kato et al., 1995] and seizures [Lafreniere et al., 1992], indicating that focal cortical infarct per se is not needed for deposition. Together these data suggest that disturbed cortical electrical activity may ultimately lead to calcification of the affected structures. Glutamate driven neurotoxicity seems to play an important role in this process. This is strongly supported by the observation of calcification after microinjection of glutamate agonists into the basal ganglia [Mahy et al., 1999]. In addition to excitotoxicity, ischemia induced hypoperfusion [Dijkhuizen et al., 1998] and hypometabolism in the thalamus [Binkofski et al., 1996; Barbelivien et al., 2002] may contribute to calcification. Hypometabolism reduces energy production, which is necessary to keep calcium at basal cytoplasmic levels. On the other hand, hypoperfusion reduces pH, favoring precipitation with phosphorus and/or activation of Ca2+-permeable acidsensing ion channels [Xiong et al., 2006]. Another mechanism underlying mineralization is calcium binding to endoplasmic reticular debris in areas where neuronal damage exceeds local phagocytic capacity [Lafreniere et al., 1992]. A recent study in vitamin D knockout mice suggests the involvement of steroid hormones in thalamic calcification [Kalueff et al., 2006]. Surprisingly, calcium staining showed an overlapping distribution with Aβ in the thalamus of MCAO rats [Mäkinen et al., 2008]. Released Aβ may be incorporated into neuronal membranes, forming calcium-permeable channels [Bhatia et al., 2000; Kawahara & Kuroda, 2000]. Thus, the massive entry of Ca2+ into cells loaded by calcium permeable Aβ channels could explain the overlap seen in histochemistry. Aβ oligomers also induce calcium influx through NMDA and AMPA receptors [Kelly & Ferreira, 2006; Alberdi et al., 2010]. Impaired calcium homeostasis is hypothesized to be one mechanism

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leading to neurotoxicity of Aβ peptides [Suh & Checler, 2002; Alberdi et al., 2010].

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Angiogenesis in the Thalamus Following Focal Cerebral Ischemia A variety of angiogenic factors including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and their receptors are upregulated after stroke [Hayashi et al., 2003]. Hypoxia-inducible factor(HIF-1) and VEGF-induced new vasculature at the ischemic border becomes evident at 2-4 days after focal cerebral ischemia in rats [Hermann & Zechariah, 2009]. Angiogenesis correlates with survival in ischemic stroke patients suggesting that it is a beneficial process [Krupinski et al., 1994]. One possible mechanism is removal of neuronal debris from the peri-infarct regions [Manoonkitiwongsa et al., 2001]. Newly formed vessels are, however, leaky in the cortex, which leads to edema and possible damage to neuronal tissue [Weis & Cheresh, 2005]. Most rodent studies of hemodynamics after cerebral ischemia have focused on the peri-infarct cortex. However, recent evidence shows that hemodynamic changes also take place in the thalamus after cerebral ischemia [Hayward et al., 2010]. Early hypoperfusion in the thalamus after focal cerebral ischemia is followed by recovery partly due to angiogenesis. This is in line with a report that shows angiogenesis in the thalamus 14 days after permanent MCAO [Ling et al., 2009]. Initial hypoperfusion in the thalamus, systemic metabolic depression [Watanabe et al., 1998], retrograde excitotoxicity [Ross & Ebner, 1990], extensive edema [Nordborg et al., 1994] and/or blood-brain barrier (BBB) breakdown [Belayev et al., 1996] may all trigger angiogenesis to support the removal of necrotic brain tissue [Manoonkitiwongsa et al., 2001] and aid repair processes. Interestingly, while angiogenesis seems to be mediated by VEGF in the cortex, cadherin family adhesion proteins may play a more important role in the thalamus [Hayward et al., 2010].

Functional Implications To what extent the described pathology in the thalamus affects behavioral outcome is difficult to assess due to multiple mechanisms underlying

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functional recovery [Witte 1998]. However, given the integral role of the thalamus in the flow of sensorimotor information, the damage to the thalamus or to its projections is likely to have detrimental consequences (Figure 2). Several lines of evidence support this. Thalamic atrophy is not correlated with early behavioral impairment, but rather with the late sensory deficit shown through the adhesive-removal test and tests measuring skilled forelimb function in MCAO rats [Freret et al., 2006].

Figure 2. Interrelationships of thalamic pathology following focal cerebral ischemia. βAmyloid (Aβ) precursor protein (APP) expression and trafficking is transiently increased in the perilesional cortical neurons following focal cerebral ischemia in rats. This is reflected as an increase in APP staining around the ischemic area, in the corpus callosum in crossing axons, in descending axons leaving the lesioned area, and in the terminal zone of these axons in the thalamus. Excessively released β-amyloid forms Ca2+ permeable channels leading to neuronal Ca2+ overload and eventually cell death in the thalamus. Possibly independent from this, axolemmal depolarization promotes Ca2+ overload mediated primarily by an Na+/Ca2+ exchanger (NCX) operating in reverse manner, which exacerbates axonal damage. The described pathology in the thalamus leads to delayed impairment of sensorimotor functions.

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Table 1. Pharmacological approaches to trace the functional meaning of secondary pathology in the thalamus following cerebral ischemia in rats Treatment

Dose

Model

Outcome

Reference

Ciliary neurotrophic factor (CNTF)

0.15 or 1.5 µg/day, i.c.v., 4 weeks

distal pMCAO in hypertensive rats

cortical infarct, thalamic neuronal loss↓, improved water-maze performance

Kumon et al., 1996

Protein synthesis inhibitor (CHX)

24 or 120 µg/day, i.c.v., immediately after MCAO 300 mg/kg, s.c., biweekly, 24 h after MCAO

distal pMCAO in hypertensive rats

transient reduction in neuronal death

Watanabe et al., 1997

tMCAO (30-60 min)

infarct size↓, thalamic shrinkage↓, adhesive removal test↑

Freret et al., 2006

Carbamylerythropoetin (CEPO)

50 µg/kg, i.v., 3, 24 and 48 h after MCAO

distal pMCAO

GFAP, macrophages↓, limb-placing, foot-fault↑

Villa et al., 2007

Nogo-66 receptor antagonist (NEP1-40)

89 µg/day, i.c.v., for 1, 2 or 4 weeks, 24 h after MCAO 50 mg/kg, per os, on postoperative day 3

distal pMCAO in hypertensive rats

axonal injury↓, axonal regeneration↑

Wang et al., 2007

distal pMCAO in hypertensive rats

Aβ, gliosis, neuronal loss↓

Zhang et al., 2011

tMCAO (120 min)

Aβ, calcium↓, improvement in the cylinder test

Sarajärvi et al., unpublished data

Iron chelator, deferoxamine

γ-secretase inhibitor (DAPT) Na+/Ca2+ exchanger inhibitor, bepridil

50 mg/kg, per os, from day 2 to 28

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Sensorimotor outcome as measured by the beam-walking test is also more impaired in hAPP transgenic rats compared to wild type littermates following cerebral ischemia and this occurs in parallel with excessive Aβ load in the thalamus [Clarke et al., 2007]. The second line of evidence comes from pharmacological studies (Table 1).Delayed administration of various drugs prevents ischemia-induced pathology in the thalamus, which in turn is reflected in improved sensorimotor or cognitive functions. For example, chronic treatment of rats with an Na+/Ca2+ exchanger inhibitor, bepridil, almost completely prevents the accumulation of thalamic Aβ40/42 and calcium and this is translated to functional improvement as measured by the cylinder test degeneration [Sarajärvi et al., unpublished data]. Less is known about functional significance of thalamic pathology in stroke patients. However, it is known that the aphasic and amnestic symptoms often develop in association with retrograde thalamic degeneration [Tamura et al., 1991].

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Conclusion The thalamic pathology following cerebral ischemia includes continuous neurodegenerative processes, Aβ deposition, and impaired calcium homeostasis. This pathology is intriguingly similar to that seen in Alzheimer's disease. The pathology can be reversed by various pharmacotherapies and this in turn is reflected in improved behavioural outcome in rats. Further understanding of the secondary pathology in the thalamus is expected to aid drug development towards neurorestoration following various neuronal insults.

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van Groen, T., Puurunen, K., Mäki, H-M., Sivenius, J. & Jolkkonen, J. (2005) Transformation of diffuse β-amyloid precursor protein and β-amyloid deposits to plaques in the thalamus following transient occlusion of the middle cerebral artery in rats. Stroke 36:1551-1556. Villa, P., van Beek, J., Larsen, A.K., Gerwien, J., Christensen, S., Cerami, A., Brines, M., Leist, M., Ghezzi, P. & Torup, L. (2006) Reduced functional deficits, neuroinflammation and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives. J. Cereb. Blood Flow Metab. 27:552-63. Wang, F., Liang, Z., Hou, Q., Xing, S., Ling, L., He, M., Pei, Z. & Zengr, J. (2007) Nogo-A is involved in secondary axonal degeneration of thalamus in hypertensive rats with focal cortical infarction. Neurosci. Lett. 417:25560. Watanabe, H., Kumon, Y., Ohta, S., Nakano, K., Sakaki, S., Matsuda, S. & Sakanaka, M. (1997) Protein synthesis inhibitor transiently reduces neuronal death in the thalamus of spontaneously hypertensive rats following cortical infarction. Neurosci. Lett. 233:25-8. Watanabe, H., Kumon, Y., Ohta, S., Sakaki, S., Matsuda, S. & Sakanaka, M. (1998) Changes in protein synthesis and calcium homeostasis in the thalamus of spontaneously hypertensive rats with focal cerebral ischemia. J. Cereb. Blood Flow Metab. 18:686-696. Wei, L., Ying, D.J., Cui, L., Langsdorf, J. & Yu, S.P. (2004) Necrosis, apoptosis and hybrid death in the cortex and thalamus after barrel cortex ischemia in rats. Brain Res. 1022:54-61. Weis, S.M. & Cheresh, D.A. (2005) Pathophysiological consequences of VEGF-induced vascular permeability Nature 437:497-504. Wen, Y., Onyewuchi, O., Yang, S., Liu, R. & Simpkins, J.W. (2004) Increased beta-secretase activity and expression in rats following transient cerebral ischemia. Brain Res. 1009:1-8. Witte, O.W. (1998) Lesion-induced plasticity as a potential mechanism for recovery and rehabilitative training. Curr. Opin. Neurol. 11:655-62. Xiong, Z.G., Chu, X.P. & Simon, R.P. (2006) Ca2+ -permeable acid-sensing ion channels and ischemic brain injury. J. Membr. Biol. 209:59-68. Zheng, Z. & Yenari, M.A. (2004) Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurol. Res. 26:884-92. Zhang, Y., Xing, S., Zhang, J., Li, J., Li, C., Pei, Z. & Zeng, J. (2011) Reduction of beta-amyloid deposits by gamma-secretase inhibitor is associated with the attenuation of secondary damage in the ipsilateral

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thalamus and sensory functional improvement after focal cortical infarction in hypertensive rats. J. Cereb. Blood Flow Metab. 31:572-9.

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Chapter V

Giantic Calyciform Synapses in the Nucleus Reticularis Thalami

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Bertalan Csillik, Elizabeth Knyihár-Csillik and András Mihály Department of Anatomy, University of Szeged, Hungary

Introduction The reticular nucleus (RTN), resembling an eggshell, surrounds the upper, posterior and inferior aspects of the thalamus. RTN is known to occupy a strategic position between the neocortex and the specific thalamic nuclei, is located at the crossroads between thalamus and the cortex. RTN, the “guardian of the gate” (Crick, 1984) is strategically situated between the cortex and the specific thalamic nuclei. Cell-to-cell GABA-ergic interactions in the reticular nucleus are known to be crucial in establishing synchronized thalamocortical oscillations (Steriade et al., 1993, Jones, 2002), instrumental in sleep spindles.

Problematics According to the classic immunohistochemical studies of Celio (1990) the RTN is characterized by the presence of the calcium-binding protein

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parvalbumin (PV); subsequent studies proved the coexistence of PV with numerous calcium-binding proteins, such as calcineurin, calretinin, calbindin and the inhibitory neurotransmitter gamma-amino-butyric acid (GABA) in the cytoplasms of RTN neurons. In the course of our immunohistochemical and immuno-electronmicroscopic studies (Csillik et al, 2002, 2005, 2006, 2010) however, it has been detected that, in a great number of calcium binding protein-expressing structures of the RTN, calcium binding proteins and GABA are not, as supposed earlier, located in the cytoplasms of nerve cells but rather in large, calyciform axodendritic (dendraxonic) terminals, impinging upon dendrites of nerve cells which are devoid of GABA and the calcium binding proteins listed above. Our aim was to morphologically identify GABA-ergic intercellular connections in the reticular nucleus and their role in thalamocortical circuitry, with special regards to the extrathalamic connections of RTN with the retrosplenial cortex. Finally, since it has been suggested that the GABA-synthesizing enzyme GAD (glutamic acid decarboxylase) and calcium binding proteins, in particular the one most often present in the calyciform terminals, parvalbumin (PV), are not only co-expressed in the same neuron population but also genetically regulated by a common mechanism (Schwaller et al, 2004), we decided to study the distribution of calcium binding proteins in the RTN of PV-knockout animals.

Methodology 1. Rats Investigations were carried out on 48 young adult Wistar rats, obtained from the animal house of the Albert Szent-Györgyi Medical and Pharmaceutical Center, University of Szeged. Care of the animals was in conformity with the guidelines controlling experiments and procedures in live animals, as described in the Principles of Laboratory Animal Care (NIH Publication No.85-23, revised 1985), and also complied with the guidelines of the Hungarian Ministry of Welfare. Experiments were carried out in accordance with the European Communities Council Directive (24 November 1986; 86/609/EEC) and the Guidelines for Ethics in Animal Experiments, of the Albert Szent-Györgyi Medical and Pharmaceutical Center of the University of Szeged. For gross anatomical orientation in the rat brain, the atlas of Paxinos and Watson (1982) was used.

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Immunocytochemistry For the demonstration of parvalbumin (PV), we used a polyclonal antimouse PV antibody raised in rabbits (Sigma, St. Louis, MO). Preliminary experiments showed best staining results with antibody dilutions 1:20000 l:35000. Animals were subjected to transcardial perfusion with Zamboni's picroaldehyde fixative in deep chloral hydrae anesthesia. Endogenous peroxidase activity was blocked by the application of 0.3% hydrogen peroxide diluted in methanol, for 10 min, followed by three successive rinses in 0.1 M phosphate buffer. Free-floating sections were pre-treated with blocking serum (0-1.0 M PBS [phosphate buffered saline]), 10% normal goat serum, l% BSA [bovine serum albumin] and 0.3% Triton X-100) on a shaker plate at room temperature for l hour, and then transferred into the primary antibody. Incubation was carried out at 4oC on a shaker for 36 hours, followed by three rinses in 0.1 M phosphate buffer.To detect the bound primary antibody, we used the avidin-biotin peroxidase method. Kits were obtained from Vector Laboratories (Burlinghouse, USA). The secondary antibody, biotinylated antimouse immunoglobulin was applied for 90 min. at room temperature. Three more rinses in 0.1 M phosphate buffer were followed by incubation in the avidin-biotinylated-peroxidase complex for 60 min. at room temperature. After three rinses in 0.1 M phosphate buffer, peroxidase activity was visualized by the histochemical reaction involving diamino-benzidine-tetrahydrochloride (DAB) and hydrogen peroxide (3 μl of 30% H202 to 10 ml 1% DAB). After three rinses in 0.1 M phosphate buffer, free-floating sections were dehydrated in a graded series of ethanols, cleared in xylene and coverslipped with Permount. Immunohistochemical Reaction The specificity of the immunohistochemical reaction was assessed by means of the following treatments: (1) omission of the first specific antiserum; (2) use of normal rabbit or mouse serum instead of anti-PV antiserum; (3) treatment according to the avidin-biotin complex method, from which one of the steps had been omitted; (4) preabsorbtion of the specific antibody with blocking peptide sc7447P and sc7448P at 4 ° C for 24 h. None of these specimens showed any reaction.

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2. Mice The number of normal young adult male mice, of the C57BL/6J strain was 10, while that of homozygous parvalbumin-knockout (PV -/-) mice was 8. PV deficient mice (Vecellio et al, 2000) were generated by homologous recombination. Briefly, targeted embryonic stem cells (E14; derived from 129 Ola Hsd mice) were injected into blastocysts of C57BL/6J mice, and the chimeric offspring mated to C57BL/6J animals. Heterozygous mice (PV +/-) were bred to obtain both PV +/+ and PV -/- mice, which both had a mixed 129 Ola Hsd x C57BL/6J genetic background. Genotyping was performed using genomic DNA isolated from tail biopsies. This was subjected tp PCR using primer pairs that were either specific for exon 3 (deleted in PV -/- mice) or for part of the neomycin resistant gene (absent in PV +/+ mice). Mice were housed in groups before use. All mice were adult (25-30 g) when used for experiments. Care of the animals complied with the guidelines of the Hungarian Ministry of Welfare and was in accordance with the European Communities Council Directive (November 24, 1986; 86/609/EEC), the NIH Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8523, revised 1985) and the Guidelines for Ethics in Animal Experiments, University of Szeged, Albert Szent-Györgyi Medical School. After an i.p. lethal dose of chloral hydrate, the animals were subjected to transcardial fixation with 4 % formaldehyde, 0.5 % glutaraldehyde added. Brains have been removed and processed in an ascending series of sucrose, containing 4% formaldehyde. For gross anatomical orientation in the mouse brain, the atlas of Sidman, Angevin and Pierce (1971) was used. PV immunocytochemistry, GABA IR, GABA-receptors R4 α6 and GABA receptor RA α 3, nuclear counterstaining, estimation of the intensity of the immunoreaction and statistical evaluation was performed like in our studies on rats. Oncomodulin Immunoreactivity Oncomodulin immunoreactivity was demonstrated by the same protocol, used for the demonstration of PV immunoreractivity, but instead of the antiPV serum, the anti-oncomodulin serum (parvalbumin beta, N-19), obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, USA), was used. For control experiments, the blocking peptide sc-7446P was employed. Alternatively, the anti-oncomodulin serum OM3 obtained in rabbit by SWANT (Bellinzona, Switzerland) was used. Both sera yielded identical results.

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Results

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In control experiments performed on Wistar albino rats, PV and GABA immunoreactivity in the large calyciform terminals of the RTN was conspicuous. In conventional coronal sections of the rat brain, RTN appears as a PV- immunoreactive cap encircling the posterior edge of the thalamus (Figures 1, 2). While most of the PV immunoreactive elements are nerve cell perikarya, some of the PV immunopositive profiles in RTN, though deceptively similar to PV immunopositive nerve cells equipped with large, immunonegative nuclei, were found to correspond to calyciform dendraxonic terminals which embraced cross sections of large, immuno-negative dendritic bulbs (Figures 3, 4, 5, 6, 7, 8). Local origin of calyciform terminals follows from the fact that perikarya of PV immunoreactive nerve cells were often found to be directly continuous with calyciform terminals (Figure 9a, b); it is supported also by the results of experimental transection of intrathalamoreticular pathways which did not induce any alteration in the PV IR of the calyciform terminals.

Scale bar, 90 μm. NB: PV=parvalbumin; IR=immunoreactive Figure 1. Parvalbumin immunoreactivity (PV IR) of the RTN (ret) at low power. Note strong PV IR of RTN as contrasted to the rest of the thalamus (asterisk).

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Figure 2. Topography of the recticular thalamic nucleus in the rat, according to the PaxinosWatson atlas (Sydney, New York, London, Paris, etc. 1982). Coronal; interaural 6, 7, bregma -2,3.

Scale bar, 10 μm. Figure 3. PV IR of a terminal (arrowhead), surrounding the cross section of a dendrite (arrow). The pattern is deceptively similar to a PV IR nerve cell equipped with a large immunonegative nucleus.

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Scale bar, 10 μm.

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Figure 4. The calyciform PV immunopositive complex (arrowhead) surrounds the grazing section of a dendrite (arrow).

Scale bar, 10 μm. Figure 5. The calyciform PV immunopositive complex (arrowhead) embraces a large dendrite (arrow).

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Scale bar, 10 μm.

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Figure 6. Three (partly incomplete) PV IR axonal complexes (arrowheads), surrounding large, PV-immunonegative dendrites (arrows). Arrowhead with asterisk denotes a nucleus.

Figure 7. Electron microscopy of a dendritic bulb (D) surrounded by a calyciform PV IR terminal of dendraxon (dA) containing numerou synaptic vesicles. Thalamus: Anatomy, Functions and Disorders : Anatomy, Functions and Disorders, edited by Justin L. Song, Nova Science

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The same or a similar PV and GABA immunoreactivity characterized the RTN of normal C57BL/6J mice. In genetically engineered animals, however, it was found that while PV disappeared completely not only from neuronal perikarya, but also from the calyciform presynaptic terminals themselves, GABA immunoreaction of giantic calyciform presynaptic terminals persisted. At the same time, numerous more or less varicous PV immunoreactive axons made appearence in various structures of the diencephalon; most of them in the lamina medullaris externa, surrounding the thalamus; these axons were found to contain beta-PV or oncomodulin (Csillik et al, 2010). Oncomodulinimmunopositive fibre bundles are closely related to ill-defined oncomodulinimmunoreactive cellular structures, resembling macrophages, scattered throughout the thalamus.

BV: Blood vessel Figure 8.Electron microscopy of a dendritic bulb (D) totally surrounded by PV IR dendraxonic terminals (dA) containing numerous synaptic vesicles. Arrows indicate postsynaptic densities.

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D: dendritic bulb/ Scale bar, μm.

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Figure 9. PVR IR neuron equipped with a neck-like outgrowth (arrow), surrounding a dendritic bulb (D). a) PV IR without counterstaining; b) PV IR counterstained with cresyl violet. Asterisk indicates nucleus of the PV IR neuron.

According to stereological determinations, the number of PV immunoreactive neurons in the RTN in a young adult rat was 14,700, while that of PV- immunoreactive calyciform endings amounted to 2040. Diameters of immunonegative spherical elements in the RTN (nuclei and dendritic bulbs) fall into five categories: [1] small nuclei of nondescript neurons, with a diameter of 2.5-3 μm, amounting to ~20% of the nuclear population; [2] nuclei of small fusiform cells with a diameter of 5-7 μm; this category amounted to ~24% of the nuclear population; [3] nuclei of large fusiform cells, measuring 6-8 μm in diameter; this group made up ~29% of the nuclear population, while [4] nuclei of large spherical cells had diameters of 8-9 μ m; this group amounted to 26% of the population of the nuclear population. [5] Finally, diameters of the slightly ovoid profiles of dendritic bulbs, surrounded by PV immunoreactive calyciform elements, measured 10 μ m x 12 μ m; these amounted to 12% of the total number of the population. Comparison of the surface areas occupied by the profiles of these structures (nuclei+dendritic bulbs) gave even more characteristic values: surface areas of neuronal nuclei varied between 5 μm2 and 84 μm2, while those of the dendritic bulbs varied between 68 μm2 and 101 μm2 (Figure 10). Transformation of somato-dendritic synapses into dendraxono-dendritic ones during development seems to be a physiological process (Figure 11).

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S: small nuclei of nondescript neurons SF: nuclei of small fusiforms neurons LF nuclei of large fusiform neurons LS: nuclei of large spheroid neurons D: profiles of PV immunonegative dendritic bulbs Figure 10. Percentage values of variation curves of profiles of nuclei of PV IR neurons and the profiles of dendritic bulbs surrounded by PV IR calyciform terminals in RTN of the normal rat.

Calyciform terminals in the RTN are, at the same time, GABAergic (Figures 12, 13, 14). Coexistence of GABA with PV has been well substantiated (Steriade et al, 2001). The GABA receptor on the surfaces of dendrites and dendritic bulbs, surrounded by the GABAergic calyciform terminals, belongs to the GABA-RAα6 subtype (Figure 15). Electrical stimulation of the reticular nucleus of the rat thalamus results in activation of c-fos immunoreactivity in nerve cells of the ipsilateral retrosplenial cortex after system bicuculline treatment, known to inhibit GABA receptors (Figures 16, 17). The c-fos immunoreactive neurons are mainly concentrated in lamina IV of the retrosplenial cortex. Conversely, electrical stimulation of the retrosplenial cortex induced c-fos immunoreactivity in the ipsilateral reticular nucleus of the thalamus. The results of the electrical stimulation suggest a direct synaptic connection

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between the cerebral cortex and the ipsilateral reticular thalamic nucleus and proves the role of GABA in these processes.

Nu: nucleus of parent cell P: perikaryon of parent cell N: neck-like outgrowth f the parent cell D: dendrite of the post-synaptic element Figure 11. Artist’s rendition of the transformation in the course of development, of a somato-dendritic synapse (A) into a denro-dendritic one (B).

As already mentioned, the calcium-binding proteins parvalbumin, calbindin D-28k, calretinin and calcineurin are present in subsets of GABAergic gigantic calyciform presynaptic terminals of the reticular thalamic nucleus (RTN). Previously it was hypothesized that GABA and calciumbinding proteins including parvalbumin are not only colocalized in the same neuron subpopulation, but that GABA synthesis and parvalbumin expression could be also genetically regulated by a common mechanism. For this, we analyzed GABA immunoreactivity in RTN gigantic calyciform presynaptic terminals of parvalbumin-deficient (PV-/-) mice. With respect to GABA immunoreactivity we found no differences compared to wildtype animals. However, in the brains of PV-/- mice, we observed paradoxical parvalbumin immunoreactivity in partly varicous axons in the diencephalon, mainly in the lamina medullaris externa surrounding the thalamus. A detailed immunohistochemical, biochemical and molecular biological analysis revealed this immunoreactivity to be the result of an upregulation of oncomodulin, the

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mammalian beta isoform of parvalbumin in PV-/- mice. In addition, oncomodulin was present in a sparse subpopulation of neurons in the thalamus and in the dentate gyrus.

Figure 12. GABA in RTN, a) GABA IR calyciform ending (arrow) surrounds dendritic bulb (D), b) GABA IR nondescript cell in RTN with a small nucleus (arrow with asterisk), c) GABA IR calyciform PV IR complex (arrow) embraces immunonegative dendritic bulb (D). Nuclear counterstaining with cresyl violet. Scale bar, 10 μm.

Discussion While the entire reticular nucleus of the rat is characterized by an intense PV- immunoreactivity, fine structural investigations raised doubts about the cytological identity of some of these "PV-immunoreactive perikarya". Our aim was to clear up this question. Unilateral transection of the dorsal column caused Wallerian degeneration in Goll's and Burdach's nuclei, followed by transneuronal degeneration and marked diminishment of PV-immunoreactivity in ventrolateral thalamic nuclei. At the same time, PV immunoreactivity of the RTN did not change.

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Neither did transection of thalamo-reticular pathways induce any alteration in PV immunoreactivity of RTN.

Figure 13. Dendritic profile (D) surrounded by three GABA IR dendraxons (axon-like elements, dA1, dA2, dA3), loaded with synaptic vesicles. Arrows indicate sites corresponding to presynaptic densites.

It was found that in the RTN, about 15% of the PV-immunoreactive structures are PV- immunoreactive calyciform complexes. According to double immunohistochemical staining, most of the PV- immunoreactive calyciform structures are also GABA- immunoreactive. While the somatic thalamic nuclei are directly correlated to ascending pathways, the RTN is not influenced by sensory deprivation. Impulses of specific thalamic nuclei are known to be transmitted to the cerebral cortex via GABA-ergic relay systems in RTN. Nerve cells of the RTN project to and from other thalamic nuclei, mediating intrathalamic sensory connections (Crabtree, 1999). Both the intralaminar nuclei and the dorsal relay nuclei of the thalamus project to the RTN, and both receive afférents from it (Carpenter & Sutin, 1983). We found that in RTN of the rat thalamus, calyciform presynaptic terminals establish synapses with large dendrites of PV-immunonegative nerve cells. According to Cajal (1911) cells near the border of the anterior semilunar

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and somatosensory nuclei are equipped with thick dendrites that are oriented transversely.

Figure 14. Two dendritic profiles (D1 and D2) surrounded by two GABA IR dendraxons (axon-like elements, dA), loaded with synaptic vesicles. Arrow points at presynaptic density er: endoplasmic reticulum in one of the dendrites.

According to Scheibel & Scheibel (1972). a peculiar feature to dendrites of the RTN is a system of terminal branching or 'splaying out', developing suddenly from a thick stalk. Calcium-binding protein immunoreactivity in the reticular thalamic nucleus has been noted by Celio (1990), by Frassoni et al (1991), Clémence & Mitrofanis (1992), De Biasi et al (1997), Lizier et al (1997), Amadeo et al (1998, 2001), Kakei et al (2001), but none of these authors noticed the large calyciform presynaptic structures described here. Although the PV- immunoreactive presynaptic structures bear deceptive resemblance to PV- immunoreactive cell bodies containing large empty nuclei, electron microscopic immunocytochemistry revealed that these structures are either axons, or dendrites or dendraxons (Csillik et al, 2002, 2005) studded with synaptic vesicles. Dendro-dendritic synapses were already described in the RTN (Deschenes et al, 1984; Ohara & Lieberman, 1985; Pinault, 2004).

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Figure 15. GABA receptor RAα6 IR marking surface of dendritic bulbs (asterisks) and the course of dendrites (arrow) in the RTN.

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Electrical stimulation of RTN results in expression of c-fos protein in the ipsilateral retrosplenial cortex, while electrical stimulation of the retrosplenial cortex results in c-fos expression in the ipsilateral RTN (Knyihár-Csillik et al, 2005).

Cc: corpus callusum Cx: retrosplenial cortex Scale bar, 0.1 mm. Figure 16. Immuno histochemical demonstration of c-fos in the cerebral cortex, after administration of bicuculline, following electrical stimulation of the ipsilateral retrosplenial cortex, at the sile of stimulation (apparent right). Arrow points at lamina IV of the cortex.

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Dendrites of the reticular nucleus often display signs of attachment placques and gap junctions, chacteristic of electrical transmission, as supposed by Landisman et al (2002). Parvalbumin- and GABA immunoreactive presynaptic calyciform terminals were first described by us (Csillik et al, 2005). Based on the results described above, it can be assumed that the large calyciform presynaptic complexes in the RTN, containing PV and GABA may play a part in the process of integrating and processing impulses arriving from specific thalamic nuclei as supposed by Yingling & Skinner (1976). Cell-tocell GABAergic interactions (Mihály et al, 1998) are known to be crucial in establishing synchronized thalamo-cortical oscillations (Steriade et al, 1993; Jones, 2002). The calyciform synapses in the RTN may be involved also in attentional gating (McAlonan et al, 2000), selective attention/distraction (Stehberg et al, 2001), executive attention (Kilmer, 2001) and coincidence detection, distinguishing between noxious and innocuous inputs (Llinás et al, 2002). The nucleus reticularis thalami plays an important part in transforming nociception into pain. At the level of gross anatomy, RTN is similar to a hemisphere, surrounding the lateral, superior and inferior aspects of the thalamus. Light microscopically, it is characterized by an intense parvalbumin immunoreaction which, until now, has been ascribed exclusively to large, parvalbumin immunoreactive neurons. Recent electron histochemical studies disclosed, however, that some of the structures erroneously identified as nuclei, are in reality cross sections of large dendrites, while the parvalbumin immunoreactive structures, thought to correspond to nerve cell perikarya, are, in reality, presynaptic terminals (Csillik et al, 2005). The parvalbumin immunoreactive calyciform terminals contain GABA (Csillik et al, 2006). Figure 17 Histogram demonstrating the numbers of c-fos IR neurons in the ipsi-and contralateral retrosplenial cortex, after electrical stimulation of the RTN, in bicuculline treated animals and without bicuculline, in 2500 m2 area in the different layers of the cortex (I, II, III, IV, V, VI). It has been described long ago by Peschanski et al(1980) that RTN exerts inhibition upon the noxious messages arriving at relay cells of the ventrobasal nuclei. Sensory perception is subjected to the modulatory influences of attention and distraction; the key of selective attention is the reticular nucleus which modulates thalamocortical transmission (Kilmer, 2001). Thalamocortical neurons represent the last step in the transmission of pain; nociceptive impulses are acknowledged as pain in the somatosensory cortex and in the parvocellular area of the insula, by intervention of the limbic

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system, notably the cingulum, to which the negative psychosomatic components of pain are ascribed. Two-way traffic flow of information between RTN and the cerebral cortex has been proved by means of immunocytochemical techniques combined with electrical stimulation (Knyihar-Csillik et al, 2005).

C: control; st: stimulated; NaCl: without bicuculline treatment; bicuc: after bicuculline treatment Figure 17. Asterisks denotes significant alterations (p