Deep Brain Stimulation and Epilepsy [1st edition] 9781000105742, 1000105741, 9781000127621, 1000127621, 9781000148954, 1000148955, 9781003076421, 1003076424

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DEEP BRAIN STIMULATION AND EPILEPSY Edited by

Hans 0 Liiders MD PhD Professor and Chairman Department of Neurology The Cleveland Clinic Foundation Cleveland, 0 H

USA

@ CRcpress ~

Taylor & Francis Group Boca Raton London New York

CRC Press is an imprint of the Taylor & Francis Group, an informa business

© 2003 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business First published in the United Kingdom in 2004 by Martin Dunitz, an imprint of the Taylor and Francis Group, 11 New Fetter Lane, London EC4P 4EE Tel.: +44 (0) 20 7583 9855 Fax.: +44 (0) 20 7842 2298 E-mail: [email protected] Website: http://www.dunitz.co.uk All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. A CIP record for this book is available from the British Library. ISBN 1 84184 259 1 Distributed in the USA by Fulfilment Center Taylor & Francis 10650 Toebben Drive Independence, KY 41051, USA Toll Free Tel.: +1 800 634 7064 E-mail: [email protected] Distributed in Canada by Taylor & Francis 74 Rolark Drive Scarborough, Ontario M1R 4G2, Canada Toll Free Tel.: +1 877 226 2237 E-mail: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel.: +44 (0)1264 332424 E-mail: [email protected] Composition by EXPO Holdings, Malaysia Printed and bound in Spain by Grafos SA Arte Sobre Papel

CONTENTS

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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I Historical overview: brain stimulation and epilepsy 1 Brain stimulation and epilepsy: basic overview and novel approaches

Jürgen Lüders, Imad Najm and Hans O Lüders . . . . . . . . . . . . . . . . . . . . . . . . . .

3

II Pathogenesis of brain stimulation: animal studies 2 The basal ganglia: an overview

Thyagarajan Subramanian . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21

3 The subthalamic nucleus: anatomy and neurophysiology

Thomas Wichmann . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29

4 Brain stimulation and epilepsy: electrical stimulus characteristics

Mark T Rise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

45

5 Electrically excitable nerve elements: excitation sites in peripheral

and central stimulation

Warren M Grill. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55

6 Control of neuronal activity by electrical fields: in vitro models of epilepsy

Dominique M Durand and Marom Bikson. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67

7 The nigral control of epilepsy: basal ganglia circuitry as a substrate for

seizure control

Karen Gale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

87

8 High frequency direct cortical electrical stimulation: an animal model of

induced acute focal seizures

Hiroshi Shigeto, Imad Najm Atthaporn Boongird, Dileep R Nair, Candice Burrier,

Kenneth B Baker and Hans O Lüders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

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CONTENTS

III Pathogenesis of brain stimulation: human studies

9

Cortico-coritcal evoked potentials Riki Matsumoto, Dileep R Nair, Eric LaPresto, Imad Najm,

William Bingaman, Hiroshi Shibasaki and Hans O Lüders . . . . . . . . . . . . . . . . . 105

10 Repetitive transcranial magnetic stimulation

Gregor Thut and Alvaro Pascual-Leone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

11 High frequency subthalamic nucleus stimulation

Erwin B Montgomery, John T Gale and Kenneth B Baker . . . . . . . . . . . . . . . . . . 129

12 Cortical-evoked potentials from deep brain stimulation

Kenneth B Baker and Erwin B Montgomery Jr. . . . . . . . . . . . . . . . . . . . . . . . . . . 143

13 EEG recording from the subthalamic nucleus in patients with epilepsy

Dudley S Dinner, Silvia Neme and Hans O Lüders . . . . . . . . . . . . . . . . . . . . . . . 157

14 EEG and the anterior thalamic nucleus

Brian Litt and Stephen Cranstoun . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

IV Effect of brain stimulation on epileptic seizures: animal experiments 15 Absence seizures in the GAERS model: subthalamic nucleus stimulation Alim-Louis Benabid, Laurent Vercueil, Karine Bressand, Maurice Dematteis,

Abdelhamid Benazzouz, Lorella Minotti and Philippe Kahane. . . . . . . . . . . . . . . 189

16 Focal limbic seizures induced by kainic acid: effects of bilateral subthalamic nucleus stimulation Andrew Pan, Atthaporn Boongird, Takaheru Kunieda, Imad Najm and

Hans O Lüders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

17 Focal stimulation versus deep brain stimulation Tatsuya Tanaka, Kiyotaka Hashizume, Atsuko Matsuo, Tomoyuki Urino,

Hiroshige Tsuda, Koichi Kato, Akira Hodozuka and Hirofumi Nakai . . . . . . . . . 209

18 The anterior thalamus and the pentylenetetrazol (PTZ) model

Marek A Mirski, David L Sherman and Wendy C Ziai. . . . . . . . . . . . . . . . . . . . . 215

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CONTENTS

V Effect of brain stimulation on epileptic seizures: human studies 19 Vagal nerve stimulation: surgical technique

William E Bingaman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

20 Vagal nerve stimulation: effects on seizures

Douglas Labar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

21 Therapeutic prospects and safety of transcranial magnetic stimulation

in epilepsy

Frithjof Tergau and Bernhard Steinhoff . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263

22 Direct cortical electrical stimulation in the treatment of epilepsy Dileep R Nair, Riki Matsumoto, Hans O Lüders, Richard Burgess,

William Bingaman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275

23 Electrical neuromodulation of the epileptic focus in cases of temporal lobe seizures Francisco Velasco, Ana Luisa Velasco, Marcos Velasco, Luisa Rocha and

Diana Menes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

24 Anterior thalamic nucleus stimulation: surgical procedure

Gordon Baltuch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

25 Anterior thalamic nucleus stimulation: issues in study design

Robert S Fisher. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305

26 Surgical procedure for subthalamic nucleus stimulation

Joshua M Rosenow, Atthaporn Boongrid, Nicholas M Boulis, Ali Rezai . . . . . . . 321

27 Subthalamic nucleus and substantia nigra pars reticulata stimulation: the Grenoble experience Alim-Louis Benabid, Adnan Koudsie, Stephan Chabardes, Laurent Vercueil,

Abdelhamid Benazzouz, Lorella Minotti, Jean-François Le Bas,

Philippe Kahane, Anne de Saint Martin and Edouard Hirsch . . . . . . . . . . . . . . . . 335

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CONTENTS

28 Subthalamic nucleus stimulation in patients with intractable epilepsy: the Cleveland experience Silvia Neme, Erwin B Montgomery Jr, Ali Rezai, Kathy Wilson and Hans O Lüders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

VI Brain stimulation: future prospects 29 The future of brain stimulation for seizure control William Heetderks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363

vi

Contributors

Kenneth B Baker PhD Section of Epilepsy Department of Neurology, S90 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA

William Bingaman MD Head, Section of Epilepsy Surgery Department of Neurosurgery, S80 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA

Gordon H Baltuch MD PhD FRCS (C) Assistant Professor, Department of Neurosurgery University of Pennsylvania 3400 Spruce Street, 5 Silverstein Pavillion Philadelphia, PA 19103 USA

Atthaporn Boongird MD Section of Epilepsy Department of Neurology The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA

Alim-Louis Benabid MD Professor, Department of Neurosciences University of Grenoble U318 INSERM-UJFG, Pavillon B BP 217, F38043 Grenoble Cedex 9 France

Nicholas M Boulis MD Section of Stereotactic and Functional Neurosurgery Department of Neurosurgery The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA

Abdelhamid Benazzouz Department of Neurosciences University of Grenoble U318 INSERM-UJFG, Pavillon B BP 217, F38043 Grenoble Cedex 9 France Marom Bikson Department of Neurophysiology University of Birmingham Birmingham UK

Karine Bressand Department of Neurosciences University of Grenoble U318 INSERM-UJFG, Pavillon B BP 217, F38043 Grenoble Cedex 9 France Richard Burgess MD PhD Department of Neurology The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA

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CONTRIBUTORS

Candice Burrier Section of Epilepsy Department of Neurology, S90 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Stephan Chabardes Centre Hospitalier Universitaire U318 INSERM-UJFG, Pavillon B BP 217, F38043 Grenoble Cedex 9 France Stephen Cranstoun MS Neuroengineering Research Laboratory Department of Bioengineering University of Pennsylvania 3320 Smith Walk, Suite 120 Philadelphia PA 19104 USA Anne de Saint Martin Centre Hospitalier Universitaire U318 INSERM-UJFG, Pavillon B BP 217, F38043 Grenoble Cedex 9 France Maurice Dematteis Department of Neurosciences University of Grenoble U318 INSERM-UJFG, Pavillon B BP 217, F38043 Grenoble Cedex 9 France Dudley S Dinner MD The Cleveland Clinic Foundation Department of Neurology, S51 9500 Euclid Avenue Cleveland, OH 44195 USA

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Dominique M Durand MD Professor, Departments of Biomedical Engineering and Neurosciences Director, Neural Engineering Center Case Western Reserve University Wickenden Building, Room 112 Cleveland, OH 44106-4912 USA Robert S Fisher MD PhD Maslah Saul MD Professor of Neurology Director, Stanford Comprehensive Epilepsy Center Stanford Medical Center 300 Pasteur Drive, Room AS343 Stanford, CA 94305-5235 USA John T Gale Center for Functional and Restorative Neuroscience Department of Neurology The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Karen Gale PhD Professor, Department of Pharmacy Director, Interdisciplinary Program in Neuroscience Georgetown University W215 Research Bldg. 3970 Reservoir Rd NW Washington, DC 20007 USA Warren M Grill PhD Assistant Professor of Biomedical Engineering Department of Biomedical Engineering Case Western Reserve University Wickenden Building, Room 114 Cleveland, OH 44106-4912 USA

CONTRIBUTORS

Kiyotaka Hashizume Department of Neurosurgery Asahikawa Medical College 2-1 Midorigaoka-Higashi Asahikawa 078-8510 Japan

Adnan Koudsie Centre Hospitalier Universitaire U318 INSERM-UJFG, Pavillon B BP 217, F38043 Grenoble Cedex 9 France

William Heetderks MD PhD Program Director, Repair and Plasticity National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2209 Rockville Pike, MD 20852 USA

Takaheru Kunieda MD Section of Epilepsy Department of Neurology, S90 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA

Edouard Hirsch Centre Hospitalier Universitaire U318 INSERM-UJFG, Pavillon B BP 217, F38043 Grenoble Cedex 9 France

Douglas Labar MD PhD Director, Comprehensive Epilepsy Center New York Presbyterian Hospital-Cornell 525 East 68th Street New York, NY 10021-4873 USA

Akira Hodozuka Department of Neurosurgery Asahikawa Medical College 2-1 Midorigaoka-Higashi Asahikawa 078-8510 Japan

Eric LaPresto MSc Department of Neurosurgery, S80 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA

Philippe Kahane Department of Neurosciences University of Grenoble U318 INSERM-UJFG, Pavillon B BP 217, F38043 Grenoble Cedex 9 France

Jean-François Le Bas Centre Hospitalier Universitaire U318 INSERM-UJFG, Pavillon B BP 217, F38043 Grenoble Cedex 9 France

Koichi Kato Department of Neurosurgery Asahikawa Medical College 2-1 Midorigaoka-Higashi Asahikawa 078-8510 Japan

Brian Litt MD Departments of Neurology and Bioengineering University of Pennsylvania 3400 Spruce Street, 3 West Gates Building Philadelphia, PA 19104-4204 USA

ix

CONTRIBUTORS

Hans O Lüders MD PhD Professor and Chairman Department of Neurology, S90 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Jürgen Lüders MD Department of Neurosurgery The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Riki Matsumoto MD PhD Medical Staff Human Brain Research Center and Department of Neurology Kyoto University Graduate School of Medicine 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 Japan Atsuko Matsuo Department of Neurosurgery Asahikawa Medical College 2-1 Midorigaoka-Higashi Asahikawa 078-8510 Japan Diana Menes Department of Nuclear Medicine National Medical Center Instituto Mexicano del Seguro Social Mexico Lorella Minotti Department of Neurosciences University of Grenoble U318 INSERM-UJFG, Pavillon B BP 217, F38043 Grenoble Cedex 9 France

x

Marek A Mirski MD PhD Director, Neuroscience Critical Care Unit Chief, Division of Neuroanesthesiology and Critical Care Medicine, Neurology, Neurosurgery John Hopkins Medical Institutions 600 N Wolfe St Meyer 8-140 Baltimore MD 21287 USA Erwin B Montgomery Jr MD Center for Functional and Restorative Neuroscience Departments of Neurology and Neuroscience, S90 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Dileep R Nair MD Section of Epilepsy Department of Neurology, S90 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Imad Najm MD Section of Epilepsy Department of Neurology, S90 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Hirofumi Nakai Department of Neurosurgery Asahikawa Medical College 2-1 Midorigaoka-Higashi Asahikawa 078-8510 Japan

CONTRIBUTORS

Silvia Neme MD Epilepsy Fellow Section of Adult Epilepsy Department of Neurology, S51 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Andrew Pan MD Section of Epilepsy Department of Neurology, S90 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Alvaro Pascual-Leone MD PhD Laboratory for Brain Stimulation Beth Israel Deaconess Medical Center 330 Brookline Avenue, Kirstein Building KS 454 Boston, MA 02215 USA Ali Rezai MD Section of Stereotactic and Functional Neurosurgery Department of Neurosurgery The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Mark T Rise PhD Senior Principal Scientist Neurostimulation Research, N10 Neurological Business Medtronic, Inc 800 53rd Avenue NE Minneapolis, MN 55421-1200 USA Luisa Rocha Department of Pharmacobiology Centro de Investigación y Estudios Avanzados Instituto Politécnico Nacional Mexico

Joshua M Rosenow MD Fellow, Functional and Restorative Neurosurgery Departments of Neurology and Neuroscience, S90 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA David L Sherman PhD Biomedical Engineering John Hopkins Medical Institutions 600 N Wolfe St Meyer 8-140 Baltimore MD 21287 USA Hiroshi Shigeto MD PhD Section of Epilepsy Department of Neurology, S90 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Bernhard Steinhoff Epilepsy Center Kork Kehl-Kork Germany Thyagarajan Subramanian MD Staff Neurologist and Director, Neural Transplantation and Gene Therapy Program Department of Neurology, S90 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Tatsuya Tanaka MD DMSc Department of Neurosurgery Asahikawa Medical College 2-1 Midorigaoka-Higashi Asahikawa 078-8510 Japan

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CONTRIBUTORS

Frithjof Tergau MD Department of Clinical Neurophysiology University of Göttingen Robert-Koch-Strasse 40 37075 Göttingen Germany Gregor Thut PhD Laboratory for Brain Stimulation Beth Israel Deaconess Medical Center 330 Brookline Avenue, Kirstein Building KS 454 Boston, MA 02215 USA Hiroshige Tsuda Department of Neurosurgery Asahikawa Medical College 2-1 Midorigaoka-Higashi Asahikawa 078-8510 Japan Tomoyuki Urino Department of Neurosurgery Asahikawa Medical College 2-1 Midorigaoka-Higashi Asahikawa 078-8510 Japan Ana Luisa Velasco MD Unit for Stereotactic and Functional Neurosurgery Hospital General De Mexico Creston 116 Pedregal DF 01900 Mexico Francisco Velasco MD Chief of Neurology and Neurosurgery Unit for Stereotactic and Functional Neurosurgery Hospital General De Mexico Creston 116 Pedregal DF 01900 Mexico

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Marcos Velasco MD Unit for Stereotactic and Functional Neurosurgery Hospital General De Mexico Creston 116 Pedregal DF 01900 Mexico Laurent Vercueil Centre Hospitalier Universitaire U318 INSERM-UJFG, Pavillon B BP 217, F38043 Grenoble Cedex 9 France Thomas Wichmann MD Associate Professor Department of Neurology Emory University 1639 Pierce Drive, Suite 6000, WMRB Atlanta, GA 30322-0001 USA Kathy Wilson RN Department of Neurology The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 USA Wendy C Ziai MD Departments of Anesthesiology and Critical Care Medicine and Neurology John Hopkins Medical Institutions 600 N Wolfe St Meyer 8-140 Baltimore MD 21287 USA

Section I

Historical overview: brain stimulation and epilepsy

1 Brain stimulation and epilepsy: basic overview and novel approaches Jürgen Lüders, Imad Najm and Hans O Lüders

Introduction Many patients with medically intractable epilepsy still remain poor candidates for surgery involving resection of epileptogenic tissue. Alternative approaches to treating these patients have been sought, including electrical stimulation of various structures in both the central and peripheral nervous system. Electrical stimulation of the nervous system for therapeutic purposes dates back to the 18th century. Jallabert used sparks to treat arm paresis, Floyer used electrical shocks in an attempt to reverse blindness, and Kite report­ edly revived the drowned with electrical shocks.1 More recently, stimulation of the nervous system has also been performed in an attempt to treat epilepsy. This includes, in the central nervous system, stimulation of the cerebellum, deep brain nuclei, such as the subthalamic nucleus, the caudate nucleus, posterior hypo­ thalamus, thalamic nuclei (centro-median nucleus, anterior thalamic nucleus), and direct focal stimulation of epileptogenic tissue (including direct cortical stimulation and hip­ pocampal stimulation). In the peripheral nervous system, stimulation of the vagal nerve and the trigeminal nerve has been performed. In this chapter, we give an historical overview of the use of electrical stimulation as a thera­

peutic modality for medically intractable epilepsy. We also introduce a novel approach to the stimulation of epileptogenic tissue by stimulating white matter tracts directly con­ nected to epileptogenic tissue. This approach results in seizure control through overdriving the epileptogenic zone (such as stimulating the fornix to overdrive the hippocampus in limbic epilepsy).

Stimulation in the central nervous system Cerebellum In 1938, Walker demonstrated that stimula­ tion of the cerebellum alters the electroen­ cephalogram,2 and in 1949 Moruzzi and Magoun reported that high frequency stimu­ lation of cerebellar cortex decreased decere­ brate rigidity in cats.3 These studies led to many experiments trying to determine if cere­ bellar stimulation may be used in the treat­ ment of epilepsy. The results of animal studies, however, were unclear. Some experiments showed a reduction of seizures and others demonstrated no effect or even an increase in seizure frequency. As early as 1955, Cooke and Snider reported arrest of focal cortical seizures with

3

BRAIN STIMULATION AND EPILEPSY

stimulation of the cerebellar cortex.4 Dow also reported a decrease of seizures with cerebellar stimulation in a cobalt-induced seizure model in the rat.5,6 Many other reports of cerebellar stimulation preventing seizure activity in various animal models have been published including pentylenetetrazol (PTZ) induced seizures and penicillin induced cortical spiking.7–11 These reports are counterbalanced by other animal studies showing no preven­ tion of seizure activity by cerebellar stimula­ tion. Grimm demonstrated no change in seizure activity with deep cerebellar nuclei stimulation in a cobalt-induced seizure model.12 Meyers found no prevention of seizure activity in models using PTZ, peni­ cillin, enflurane, or chloralose.13 Based on the positive antiseizure effects reported in some animal studies, Cooper began uncontrolled studies using cerebellar stimulation in humans in 1977.14–17 Between 1977 and 1987 a total of 11 uncontrolled studies were performed on a total of 112 patients.17–26 Excellent results were reported with 30 (27%) patients becoming seizure-free, 59 (53%) having a significant improvement in their seizure activity, and only 23 (20%) remaining unchanged. These results, however, were not confirmed in two controlled studies performed by Van Buren and Wright.27,28 Van Buren stimulated the cerebellum in five patients in a double-blind fashion. They initially observed an increase in seizure activity and at 10 months showed no change in seizure frequency. Wright stimulated 12 patients, all of them demonstrated no signif­ icant change in seizure frequency. Although the uncontrolled studies demonstrated an excellent response, the failure of the controlled studies to demonstrate a significant change in seizure fre­ quency led to discontinuation of cerebellar stimulation for the treatment of medically intractable epilepsy.

4

Deep brain structures Caudate nucleus Several animal studies have reported that stimulation of the caudate nucleus decreases seizure activity. LaGrutta reported that stimu­ lation of the caudate nucleus reduces hip­ pocampal spike frequency and amplitude in a cat model of focal penicillin.29 Caudate stimu­ lation has also been demonstrated to decrease seizure activity in the primate in an aluminum hydroxide model of focal epilepsy.30 In humans, several uncontrolled studies have reported the efficacy of caudate stimulation. Sˇramka reported in 1976 that five of six patients had improvement in their seizures with intermittent stimulation of the caudate.31 Chkhenkeli implanted electrodes in the caudate nucleus or thalamus in 74 patients and reported seizure improvement with low frequency stimulation of the caudate nucleus.32 In 1988, Gabasˇvili reported that high amplitude, low frequency stimulation of the caudate nucleus stopped epileptic seizures in six patients who had been in status epilepti­ cus for four to seven days.33 No controlled studies of caudate stimulation in humans have been performed. Posterior hypothalamus In 1994, Mirski and Fisher reported that high frequency stimulation of the posterior hypo­ thalamus significantly increased the threshold for PTZ-induced seizures in the rat.34 They felt that this effect was mediated through the ante­ rior thalamic nucleus. Further studies have focused on the anterior thalamic nucleus, which they considered as an easier and safer target. Thalamic nuclei Anterior thalamic nucleus. In 1980, Cooper reported that stimulation of the anterior nuclear group of the thalamus may help

STIMULATION IN THE CENTRAL NERVOUS SYSTEM

decrease seizure activity in humans with limbic epilepsy.35 In 1988, Sussman reported her results on five patients with intractable epilepsy who underwent stimulation of the anterior thalamic nucleus.36 She observed an improvement in seizure activity in three of five patients in an uncontrolled study. More recent animal studies have demonstrated that high frequency stimulation of the anterior thalamic nucleus in the rodent increases the threshold for PTZ-induced seizures.37 No controlled studies have been performed to evaluate the efficacy of anterior thalamic nucleus stimulation in humans.

Centro-median thalamic nucleus. In 1987, Marcos and Francisco Velasco reported a marked reduction in seizures with stimulation of the centro-median (CM) thalamic nucleus in humans.38 This was an uncontrolled study of five patients with intractable epilepsy. In 1989, Chkhenkeli and Sˇramka reported that stimulation of the CM thalamic nucleus prevents cortical epileptiform discharges.39 Based on these promising results, Fisher performed a placebo-controlled pilot study to determine the efficacy of CM thalamic stimulation in patients with intractable seizures.40 Seven patients were stimulated and showed a 30% reduction in seizure frequency. This reduction in seizure frequency was not statistically significant. Subthalamic nucleus In the early 1980s, the nigral control of epilepsy system (NCES) was described.41,42 The subthalamic nucleus (STN) is believed to play a large role in this system. Convincing experimental evidence reports tonic activity of the STN,43–45 which would suggest that the NCES is chronically inhibited by the STN under resting conditions. The STN has also recently been targeted effectively and safely

for deep brain stimulation (DBS) in humans for the treatment of Parkinson’s disease. For these reasons, there has been interest in target­ ing the STN for the treatment of epilepsy. In 1998, Vercueil reported the efficacy of bilat­ eral high frequency stimulation of the STN in suppressing seizures in the Genetic Absence Epilepsy Rat of Strasbourg (GAERS).46 Bilateral STN stimulation was also shown to significantly reduce the seizure activity in a rat model of epilepsy with unilateral kainic acid injection into the amygdala.47 Studies at the Cleveland Clinic Foundation, Ohio (CCF), using a subcutaneous injection of kainic acid in the rat, have demonstrated a significant reduction in the generalization of seizures.48 A few uncontrolled studies have been performed evaluating the efficacy of bilateral STN stimu­ lation in humans with pharmacologically intractable epilepsy. Benabid has reported the efficacy of bilateral STN stimulation in treat­ ing epilepsy after implanting four patients, with follow-ups ranging from 2 to 30 months.49 Bilateral stimulation of the STN was performed in five patients at the CCF which was effective in decreasing seizure fre­ quency in two of these patients.50 In 2001, Alaraj reported the effectiveness of bilateral STN stimulation in one patient who continued to have improvement after one year.51 No con­ trolled human studies of bilateral STN stimu­ lation in patients with medically intractable epilepsy have been performed.

Direct stimulation of the epileptogenic zone Cortical stimulation Intra-operative electrical stimulation of the cerebral cortex was first performed by Fedor Krause to help guide cortical resections during epilepsy surgery.52 Since that time, extraoperative electrical cortical stimulation has

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BRAIN STIMULATION AND EPILEPSY

become available. Invasive epilepsy monitor­ ing techniques, such as subdural grids and depth electrodes, have been developed to help determine the epileptogenic zone and func­ tional areas of the cerebral cortex. Its has been long known that stimulation of the cerebral cortex can produce afterdischarges that can evolve into clinical seizures. These same tech­ niques can be used to stimulate the cerebral cortex in an attempt to prevent or terminate seizure activity. In 1999, Lesser reported that brief bursts of pulse stimulation could be used to abort afterdischarges.53 Based on these find­ ings, preliminary animal and human studies have been performed to evaluate the efficacy of cortical stimulation in the treatment of epilepsy. Tanaka reported that high frequency stimulation (100 Hz) of the sensorimotor cortex in a rat cortical model of kainic acid induced seizures was ineffective in preventing seizures. However, low frequency stimulation (1 Hz) was effective in preventing seizures in three out of seven rats.54 Nair has started a protocol at the CCF to evaluate the efficacy of direct cortical stimulation to treat focal epilepsy in humans. A seizure detection system developed at the CCF is being used to deliver a stimulus immediately after seizure activity has been detected (‘closed loop’). Preliminary results have shown that cortical stimulation can decrease the duration of focal seizures, particularly in patients in whom the seizure onset zone is very limited (Dr Nair, personal communication;55). Hippocampal stimulation Hippocampal sclerosis (HS) is a common cause of pharmacologically intractable epilepsy and not infrequently those patients with HS are not surgical candidates due to either bilateral hippocampal involvement, or concerns with memory deficits when the focus is located in the dominant hippocampus.

6

Velasco et al. reported promising results with hippocampal stimulation in uncontrolled human studies.56 Ten patients underwent sub­ acute hippocampal electrical stimulation during pre-surgical evaluation with subdural electrodes and showed a significant decrease in the number of seizures per day. They also reported a significant decrease in the number of interictal spikes after five days of stimula­ tion. This team is now performing a doubleblind study evaluating chronic stimulation of the hippocampus.

Stimulation in the peripheral nervous system Vagal nerve stimulation In 1985, Zabara first reported on vagal nerve stimulation (VNS) and its role in the treatment of epilepsy.57,58 His results were confirmed by Woodbury in a rat model of epilepsy. 59 Lockard also reported encouraging results of VNS in a primate model of partial seizures.60 The first vagal nerve stimulator for the treat­ ment of epilepsy was implanted in a human in November 1988.61 A randomized controlled study of 125 patients who underwent VNS demonstrated a reduction in seizure frequency of 24.5% with high stimulation parameters (30–90 seconds on followed by 5–10 minutes off) and a reduction of only 6.1% with low stimulation parameters (30 seconds of stimu­ lation at 1 Hz followed by 90 minutes off).62 This difference was statistically significant. In addition, many large uncontrolled clinical studies have been performed to evaluate VNS effect in both adult and pediatric popula­ tions.63–74 These studies reported that VNS reduces the frequency of seizures by ~30% during the first three months of stimulation and ~40% after 2–3 years of stimulation. VNS

OVERVIEW OF ATTEMPTED TARGETS

has been compared to the efficacy of adding another antiepileptic medication without the adverse side effects of adding new medications.75

Trigeminal nerve stimulation Trigeminal nerve stimulation in the treatment of epilepsy was reported by Fanselow et al. in 2000.76 They reported a decrease of seizure activity in a rat model of PTZ-induced seizures with trigeminal nerve stimulation. Further studies have yet to be performed.

Overview of attempted targets Efficacy Animal studies Many animal studies have been performed stimulating the aforementioned targets. These studies vary in efficacy from reporting a statis­ tically significant change in seizure frequency or duration to no change at all. Although many animal studies report a statistically sig­ nificant efficacy, the magnitude of the decrease in seizure frequency is usually only relatively small. Babb studied stimulation of deep cere­ bellar nuclei on hippocampal cobalt epilepsy in the cat. Although considered successful, the study ‘was statistically reliable in only a frac­ tion of the preparations where it appeared to occur’.7 Evaluating animal studies involving stimulation of the cerebellum reveals only marginal reduction in seizure frequency or no change at all.9,12,13 Many other animal studies have been performed reporting effective pre­ vention of seizure activity stimulating the caudate, posterior hypothalamus, anterior thalamic nucleus, subthalamic nucleus, direct cortical stimulation, and vagal nerve stimula­

tion.29,30,34,37,46,47,54,59,60 Although many report a significant reduction in seizure frequency, none demonstrate a reproducibly marked decrease in seizures or complete seizure control. Human studies Uncontrolled studies. Many uncontrolled studies have been reported for stimulation of the nervous system to treat medically intractable epilepsy in humans. Stimulation targets in humans include the cerebellum,14–26,77,78 caudate nucleus,31–33 anterior thalamic nucleus,35,36 centro-median thalamic nucleus,38 subthalamic nucleus,50,51,79 direct cortical stimulation (Dr Nair personal communication;55), direct hippocampal stimulation,56 and the vagal nerve.63–74 Efficacy of stimulation in most of these uncontrolled studies showed an excellent control of epilepsy.

Controlled studies. Few controlled studies have been performed stimulating the nervous system in humans to treat epilepsy. The results have been disappointing. Two studies have been performed stimulating the cerebellum with no significant change in seizure frequency.27,28 One pilot study has been performed stimulating the centro-median thalamic nucleus which demonstrated no significant change in seizure frequency.40 One controlled study has been performed evaluating the efficacy of vagal nerve stimulation which reported a significant but only relatively small decrease in seizure frequency of approximately 25% with high stimulation parameters.62

Mechanisms Several mechanisms have been proposed to explain how stimulation of the various targets

7

BRAIN STIMULATION AND EPILEPSY

outlined above prevent seizure activity. The nigral control of epilepsy system (NCES) includes in its circuitry the STN, the substan­ tia nigra pars reticulata (SNr), and the dorsal midbrain antiepileptic zone (DMAZ) located in the deep layers of the superior colliculi (see Figure 1.1A). Under resting conditions, tonic glutamatergic input from STN keep the SNr firing at a high rate. The GABAergic inhibitory output from SNr maintains a con­ stant inhibition of the DMAZ. Reduced activ­ ity of the DMAZ is also related to a dimin­ ished seizure protection, but the direct mechanism by which the DMAZ exerts its antiseizure effect is unknown. Animal studies

have shown that a decrease of the tonic output from STN or of the SNr will result in disinhi­ bition of the DMAZ with a corresponding antiseizure effect (see Figure 1.1B). Benabid et al.79 speculated that high frequency stimula­ tion of STN produces a functional inhibition of STN that resulted in activation of the NCES with the corresponding antiseizure effect. A second possible antiseizure effect would be direct anterograde cortical inhibition which can be elicited by stimulation of deep cerebellar nuclei. There is also evidence that direct anterograde cortical stimulation can suppress epileptic seizures and this is the assumed mechanism of action when stimulatC

C

Cerebral cortex

Cerebral cortex

Caudate nucleus

Caudate nucleus Internal capsule

Internal capsule

Putamen

Putamen

Globus pallidus:

Globus pallidus: lateral segment

Thalamus

medial segment

medial segment

Zona incerta

Zona incerta X

Subthalamic nucleus Substantia nigra:

Substantia nigra: pars compacta

SN pars reticulata

SN pars reticulata Pedunculopontine tegmental nucleus Superior Colliculus

Superior Colliculus

NMDA

Subthalamic nucleus

pars compacta

Pedunculopontine tegmental nucleus

(A)

lateral segment

Thalamus

NMDA

GABA

GABA

(B)

Figure 1.1 (A) Schematic diagram showing the main components of the nigral control of epilepsy system, including in its circuitry the subthalamic nucleus (STN), the substantia nigra pars reticulata(SNr), and the dorsal midbrain antiepileptic zone (DMAZ) located in the deep layers of the superior colliculus. (B) Schematic diagram showing a decrease in output from the STN with a resultant disinhibition of the DMAZ and a resultant antiseizure effect.

8

THE ‘OVERDRIVE’ CONCEPT

ing targets within the circuit of Papez, such as the anterior thalamic nucleus, or when stimu­ lating the central median nucleus of the thala­ mus. Stimulation of these nuclei will produce evoked potentials at the cortical level as an expression of cortical activation. The recruit­ ing response evoked by stimulation of the anterior thalamic nucleus is one example of these evoked responses. It is also likely that vagal nerve stimulation mediates its effect through activation of thalamic, brainstem, and limbic structures.80,81 It is also important to mention that direct stimulation of the epilep­ togenic focus is an alternative method to suppress seizures by excitation. Finally, antidromic cortical stimulation is another pos­ sible mechanism by which basal ganglia stimu­ lation may prevent seizures. Baker et al.82 have shown that STN stimulation in humans can elicit relatively short latency cortical evoked potentials that most probably are generated by antidromic stimulation of cortico-STN fibers.

believe that at this point, the risks, costs, and inconvenience of having a stimulator implanted does not justify the improvement expected from brain stimulation on seizure intensity or seizure frequency. As previously described, the main antiepileptogenic effect of nervous system stimulation is most likely the excitatory or inhibitory activation of neurons in the epilep­ togenic zone. The fact that the magnitude of this effect is relatively limited, with essentially no report of complete seizure control, is most probably an expression of the limited activa­ tion of epileptogenic neurons achieved by these methodologies. We would expect stimu­ lation of the vagal nerve and also activation of the NCES only to reach a minority of the epileptogenic neurons in an indirect pathway (Figure 1.2). Stimulation of other deep brain nuclei that are connected directly in an antero­ grade or orthodromic fashion with the cortex (anterior thalamic nucleus, STN, etc.) will directly influence cortical epileptogenic zones,

The ‘overdrive’ concept All the mechanisms of action discussed above exert their seizure control by either antero­ grade or antidromic stimulation or inhibition of the cortex. This is also most likely true for the nigral control of epilepsy system, although the precise final pathway by which the DMAZ reaches the cortex remains poorly defined. Detailed analysis of the experimental evi­ dence supporting the antiseizure effect of the different methodologies outlined above indi­ cates very clearly that the magnitude of the antiseizure effect is consistently very limited. It seems that the different methodologies have a statistically significant effect of reducing seizure frequency and/or intensity but that this is too small to greatly improve quality of life in patients with intractable epilepsy. We

Figure 1.2 Schematic diagram showing stimulation of deep brain nuclei causing diffuse cortical stimulation.

9

BRAIN STIMULATION AND EPILEPSY

brain will only affect a small percentage of the epileptogenic neurons, with very limited stimulation of neurons not directly underly­ ing a subdural electrode or epileptogenic tissue buried in cortical sulci. Preliminary results obtained at the Cleveland Clinic on stimulation of the epileptogenic focus in patients with implanted subdural electrodes for pre-surgical evaluation, demonstrated that closed loop stimulation was most effective in reducing seizure duration in one case (out of four) in which the epileptogenic zone was relatively small and almost com­ pletely covered by subdural electrodes.55 (See Figure 1.4). All these observations led us to the conclu­ sion that the optimization of seizure control by brain stimulation would require two conditions:

Direct focus stimulation with subdural electrodes

(A)

Electrical stimulation Seizure escape

(B)

Figure 1.3 (A) Schematic diagram showing stimulation of subdural electrodes with a relatively poor stimulation coverage of the epileptogenic zone. (B) Schematic diagram showing seizure ‘escape’ during direct electrical stimulation of the epileptogenic area.

but will also only reach a minority of the epileptogenic neurons in the focus (Figure 1.2). The same is also true for direct stimula­ tion of the epileptogenic zone by subdural or depth electrodes. As shown in Figure 1.3, sub­ dural electrodes which cover the surface of the

10

1 Activation of all the epileptogenic neurons in the epileptogenic zone 2 The use of supramaximal stimulus intensity to assure that the epileptogenic activity in the activated neurons is actually completely blocked To meet these criteria, we have proposed a new approach of brain stimulation for seizure control which we have termed ‘overdrive’. To

pair of stimulation EEG seizure onset

Figure 1.4 Representation of subdural electrodes used in an attempt to directly stimulate the epileptogenic cortex.

THE ‘OVERDRIVE’ CONCEPT

Fornix stimulation

Orthodromic Antidromic

Figure 1.5 Schematic diagram showing overdrive of the epileptogenic zone by stimulation of the corpus callosum.

implement the overdrive of the epileptogenic zone we had to resolve two problems: 1 Find a target that would result in stimula­ tion of all the epileptogenic neurons within an epileptogenic zone. After considering numerous possibilities we concluded that in most instances the ideal target would be a white matter tract that is connected (ortho­ or antidromically) to the majority, if not all, of the neurons in the epileptogenic zone. Specifically, the corpus callosum was con­ sidered as the ideal target for many cortical epileptogenic areas (Figure 1.5) and the fornix for hippocampal foci (Figure 1.6). As shown in Figure 1.6, the fornix is a massive white matter tract with close to one million fibers (approximately the same number of fibers contained in the optic nerves) that connect the hippocampus with the hypo­ thalamus and the mamillary tract. This tract also contains fibers that connect the hypothalamus with the hippocampus and

Figure 1.6 Schematic diagram showing hippocampus overdrive by fornix stimulation.

there is extensive crossing between the left and right fornices. Pyramidal neurons in CA1-CA4 and pyramidal neurons from the subiculum feed into the fornix assuring that its stimulation will reach most neurons in the hippocampus. Figure 1.7 demonstrates the concept of white matter stimulation for epileptogenic zone overdrive comparing it

Direct stimulation of epileptic zone White matter stimulation for epileptic zone overdrive

Figure 1.7 Schematic diagram showing the concept of white matter stimulation for epileptic zone overdrive.

11

12 Direct anterograde cortical stimulation Nigral control of epilepsy system or antidromic cortical stimulation Direct stimulation of epileptogenic focus Direct stimulation of epileptogenic focus Direct anterograde cortical stimulation through activation of

thalamic, brainstem,

and limbic structures Direct anterograde cortical stimulation through desynchronization of cortical and thalamic structures Direct anterograde and retrograde stimulation of epileptogenic focus

Sramka et al.31 Chkhenkeli32 Mirski & Fisher34

Velasco et al.38

Caudate

Jürgen and Lüders (present authors), Najm

White matter tract stimulation (‘Overdrive’)

Table 1.1 Deep brain stimulation and epilepsy: summary of studies.

Fanselow et al.76

Zabara57, Penry & Dean61 Woodbury & Woodbury59 Lockard et al.60

Lesser et al.53, Nair et al.55 Velasco et al.56

Benabid et al.79 Bressand et al.48 Vercueil et al.46

Trigeminal nerve stimulation

Direct cortical stimulation Direct hippocampal stimulation Vagal nerve stimulation

Centro-median thalamic nucleus Subthalamic nucleus

Cooper et al.35

Direct anterograde cortical inhibition or stimulation Direct anterograde cortical stimulation Direct anterograde cortical stimulation Direct anterograde cortical stimulation

Walker2, Moruzzi and Magoun3

Cerebellum

Posterior hypothalamus Anterior thalamic nucleus

Proposed mechanism

Primary authors

Structure stimulated

No human studies to date

No human studies to date

No completed human studies to date Significant seizure reduction Significant seizure reduction

Significant seizure reduction No human studies to date One uncontrolled study demonstrated seizure reduction in 3 out of 5 patients Significant seizure reduction Significant seizure reduction

Significant seizure reduction

Efficacy (uncontrolled human studies)

No human studies to date

No human studies to date

Significant seizure reduction

No completed human studies to date No controlled studies

No controlled studies

No significant change

No human studies to date No controlled studies

No controlled studies

No significant change

Efficacy (controlled human studies)

REFERENCES

Cortex Epileptogenic zone Subdural stimulation Overdrive Deep brain stimulation

Figure 1.8 Schematic diagram showing a comparison of the different methods that have been used to control seizures by stimulation.

Intensity of stimulation mV

with direct stimulation of the epileptogenic zone with subdural electrodes. Figure 1.8 compares the different targets used for brain stimulation in patients with a cortical epileptogenic zone, illustrating the superior coverage that can be achieved with the overdrive methodology.

3

2

1

1Hz

10Hz

130Hz Frequency

Figure 1.9 Preliminary results in a rat representing the relationship of stimulation intensity required to induce seizure activity at specific frequencies.

2 Use a supramaximal stimulus that is unlikely to elicit epileptic seizures. Preliminary results of corpus callosum stim­ ulation revealed that seizures are most easily elicited by relatively high frequency stimulation (more than 5 Hz) which most likely leads to hypersynchronization by temporal summation (Shigeto et al. in preparation) (Figure 1.9). To overcome this difficulty we chose low frequency stimula­ tion (1 Hz) which permits high intensity stimulation without inducing seizures. Preliminary results using the overdrive tech­ nique with bilateral stimulation of the fornix in a rat model of acute systemic kainic acid seizures has yielded encouraging results that will be published elsewhere (Lüders et al. in preparation).

References 1. Rowbottom M, Susskind C. Electricity in medi­ cine: history of their interaction. San Francisco: San Francisco Press, 1984. 2. Walker AE. An oscillographic study of the cerebello-cerebral relationship. J Neurophysiol 1938;1:16–23. 3. Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1949; 1:455–73. 4. Cooke PM, Snider RS. Some cerebellar influences on electrically-induced cerebral seizures. Epilepsia 1955;4:19–28. 5. Dow RS. Extrinsic regulatory mechanisms of seizure activity. Epilepsia 1965;6:122–40. 6. Dow RS, Fernandez-Guardiola A, Manni, E. The infleunce of the cerebellum on experimental epilepsy. Electroencephalogr Clin Neurophysiol 1962;14:383–98. 7. Babb TL, Mitchell AG, Crandal PH. Fastigio­ bulbar and dentato-thalamic influences on hippocampal cobalt epilepsy in the cat. Electroencephalogr Clin Neurophysiol 1974; 36:141–54.

13

BRAIN STIMULATION AND EPILEPSY

8. Hablitz JJ, Rea G. Cerebellar nuclear stimulation in generalized penicillin epilepsy. Brain Res Bull 1976;1:599–601. 9. Hutton JT, Frost JD Jr, Foster J. The influence of the cerebellum in cat penicillin epilepsy. Epilepsia 1972;13:401–8. 10. Mitra J, Snider RS. Effects of hippocampal afterdischarges on Purkinje cell activity. Epilepsia 1975;16:235–43. 11. Mutani R, Bergamini L, Doriguzzi T. Experimental evidence for the existence of an extrarhinencephalic control of the activity of the cobalt rhinencephalic epileptogenic focus: 2. Effects of the paleocerebellar stimulation. Epilepsia 1969;10:351–62. 12. Grimm RS, Frazee JG, Bell CC. Quantitative studies in cobalt model epilepsy: the effects of cerebellar stimulation. Int J Neurol 1970; 7:126–40. 13. Myers RR, Burchiel KJ, Stockard JJ, et al. Effects of acute and chronic paleocerebellar stimulation on experimental models of epilepsy in the cat: studies with enflurane, pentylenete­ trazol, penicillin, and chloralose. Epilepsia 1975;16:257–67. 14. Cooper IS, Snider RS. The effect of varying the frequency of cerebellar stimulation in epilepsy. In: Cooper IS, Riklan M, Snider RS (eds) The cere­ bellum. Epilepsy and behavior. New York: Plenum, 1974, 245–56. 15. Cooper IS, Amin I, Gilman S. The effect of chronic cerebellar stimulation upon epilepsy in man. Trans Am Neurol Assoc 1973;98:192–6. 16. Cooper IS, Amin I, Riklan M, et al. Chronic cerebellar stimulation in epilepsy. Clinical and anatomical studies. Arch Neurol 1976; 33:559–70. 17. Cooper IS, Amin I, Upton A, et al. Safety and effi­ cacy of chronic cerebellar stimulation. Appl Neurophysiol 1977;40:124–34. 18. Amin I. The reduction of spasticity, involuntary movements, and seizures using a fully implantable cerebellar stimulator. In: Davis R, Bloedel JR (eds) Cerebellar stimulation for spastc­ ity and seizures. Boca Raton, FL: CRC Press, 1984, 211–13. 19. Bidzinski J, Bacja T, Ostrowski K, et al. Effect of cerebellar cortex electrostimulation on the fre­ quency of seizures in drug-resistant epilepsy. Neurol Neurochir Pol 1981;15:605–9.

14

20. Davis R, Gray E, Engle H. The reduction of seizures in cerebral palsy and epileptic patients using chronic cerebellar stimulation. Acta Neurochir 1984;33(Suppl):161–7. 21. Dow RS, Smith W, Maukonen L. Clinical experi­ ence with chronic cerebellar stimulation in epilepsy and cerebral palsy. Electroencephalogr Clin Neurophysiol 1977;43:906 [Abstract]. 22. Fenton GW, Fenwick PBC, Brindley GS. Chronic cerebellar stimulation in the treatment of epilepsy: a preliminary report. In: Penry JK (ed) Epilepsy, The Eighth International Symposium. New York: Raven, 1977, 333–40. 23. Gilman S, Dauth GW, Tennyson VM. Clinical, morphological, biochemical, and physiological effects of cerebellar stimulation. In: Hambrecht FT, Reswick JR (eds) Functional electrical stimu­ lation. New York: Marcel Dekker, 1977, 191–226. 24. Klun G, Stojanovic V, Strojnik P. Chronic cere­ bellar stimulation in the treatment of epilepsy. In: Wullenweber R, Klinger M, Brock (eds) Advances in neurosurgery. Berlin: Springer, 1987, 205–9. 25. Levy LF, Auchterlonie WC. Chronic cerebellar stimulation in the treatment of epilepsy. Epilepsia 1979;20:235–45. 26. Madrazo I, Rosas VH. Chronic cerebellar stimu­ lation for reduction of grave behavioral changes and seizures in psychiatric patients. In: Davis R, Bloedel JR (eds) Cerebellar stimulation for spas­ ticity and seizures. Boca Raton, FL: CRC Press, 1984, 273–80. 27. Van Buren JM, Wood JH, Oakley J, et al. Preliminary evaluation of cerebellar stimulation by double-blind stimulation and biological crite­ ria in the treatment of epilepsy. J Neurosurg 1978;48:407–16. 28. Wright GD, McLellan DL, Brice JG. A doubleblind trial of chronic cerebellar stimulation in twelve patients with severe epilepsy. J Neurol Neurosurg Psychiatry 1984;47:769–74. 29. La Grutta V, Sabatino M, Gravante G, et al. A study of caudate inhibition on an epileptic focus in the cat hippocampus. Arch Int Physiol Biochim 1988;96:113–20. 30. Oakley JC, Ojemann GA. Effects of chronic stimulation of the caudate nucleus on a preexist­ ing alumina seizure focus. Exp Neurol 1982; 75:360–7.

REFERENCES

31. Sˇramka M, Fritz G, Galanda M, et al. Some observations in treatment stimulation of epilepsy. Acta Neurochir (Wien):1976;257–62. 32. Chkhenkeli SA. Inhibitory influences of caudate stimulation on the epileptic activity of human amygdala and hippocampus during temporal lobe epilepsy. Physiol Hum Anim 1978;4: 406–11. 33. Gabasˇvili VM, Chkhdenkeli SA, Sramka M. The treatment of status epilepticus by electrostimu­ lation of deep brain structures. Presented at: First European Congress of Neurology, 1988, Prague. 34. Mirski MA, Fisher RS. Electrical stimulation of the mammillary nuclei increases seizure threshold to pentylenetetrazol in rats. Epilepsia 1994; 35:1309–16. 35. Cooper IS, Upton AR, Amin I. Reversibility of chronic neurologic deficits. Some effects of electri­ cal stimulation of the thalamus and internal capsule in man. Appl Neurophysiol 1980;43: 244–58. 36. Sussman NM, Goldman HW, Jackel RA, et al. Anterior thalamic stimulation in medically intractable epilpesy: II. Preliminary clinical results. Epilepsia 1988;29:677 [Abstract]. 37. Mirski MA, Rossell LA, Fisher RS. Electrical stimulation of thalamic anterior nucleus raises seizure threshold in an experimental model of generalized epilepsy. Neurology 1994; 44(Suppl):A235. [Abstract] 38. Velasco F, Velasco M, Ogarrio C, et al. Electrical stimulation of the centromedian thal­ amic nucleus in the treatment of convulsive seizures: a preliminary report. Epilepsia 1987; 28:421–30. 39. Chkhenkeli SA, Sˇramka, Sˇramka M. Therapeutic stimulation of the non-specific thalamic system for the treatment of some forms of epilepsy. Presented at: IXth Congress of Neurological Surgery, 1989, New Delhi, India 40. Fisher RS, Uematsu S, Krauss GL, et al. Placebocontrolled pilot study of centromedian thalamic stimulation in treatment of intractable seizures. Epilepsia 1992;33:841–51. 41. Gale K. Mechanisms of seizure control mediated by gamma-aminobutyric acid: role of the substan­ tia nigra. Fed Proc 1985;44:2414–24. 42. Iadarola MJ, Gale K. Substantia nigra: site of anticonvulsant activity mediated by gamma­ aminobutyric acid. Science 1982;218:1237–40.

43. DeLong MR, Crutcher MD, Georgopoulos AP. Primate globus pallidus and subthalamic nucleus: functional organization. J Neurophysiol 1985; 53:530–43. 44. Matsumura M, Kojima J, Gardiner TW, et al. Visual and oculomotor functions of monkey sub­ thalamic nucleus. J Neurophysiol 1992;67: 1615–32. 45. Wichmann T, Bergman H, DeLong MR. The primate subthalamic nucleus: I. Functional prop­ erties in intact animals. J Neurophysiol 1994; 72:494–506. 46. Vercueil L, Benazzouz A, Deransart C, et al. High-frequency stimulation of the subthalamic nucleus suppresses absence seizures in the rat: comparison with neurotoxic lesions. Epilepsy Res 1998;31:39–46. 47. Bressand K, Dematteis M, Kahane P, et al. Involvement of the subthalamic nucleus in the control of temporal lobe epilepsy: study by high frequency stimulation in rats. Soc Neurosci 1999;25:1656 [Abstract]. 48. Pan A, Boongird A, Kunieda T, et al. Focal limbic seizures induced by kainic acid: effects of bilat­ eral subthalamic nucleus stimulation. In: Lüders H (ed) Deep brain stimulation and epilepsy. London: Martin Dunitz, 2004. 49. Benabid AL, Koudsie A, Chabardes S, et al. STN and/or SNpr stimulation in intractable epilepsy: Grenoble experience. In: Lüders H (ed) Deep brain stimulation and epilepsy. London: Martin Dunitz, 2004. 50. Neme S, Montgomery E, Lüders H, et al. Seizure outcome of deep brain stimulation of the subthalamic nucleus for intractable focal epilepsy. Epilepsia 2001;42(Suppl 2):124 [(Abstract)]. 51. Alaraj A, Comair Y, Mikati M et al. Subthalamic nucleus deep brain stimulation: a novel method for the treatment of non-focal intractable epilepsy. Presented as a poster at: Neuromodulation: defining the future, 2001, Cleveland, OH. 52. Krause F. Surgery of the brain and spinal cord— based on personal experiences: Vol III [English translation]. New York: Rebman Company, 1912. 53. Lesser RP, Kim SH, Beyderman L, et al. Brief bursts of pulse stimulation terminate afterdis­ charges caused by cortical stimulation. Neurology 1999;53:2073–81.

15

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54. Tanaka T, Hashizume K, Matsuo A, et al. Focus stimulation versus deep brain stimulation. In: Lüders H (ed) Deep brain stimulation and epilepsy. London: Martin Dunitz, 2004. 55. Nair DR, Matsumoto R, Lüders H, et al. Direct cortical electrical stimulation in the treatment of epilepsy. In: Lüders H (ed) Deep brain stimu­ lation and epilepsy. London: Marin Dunitz, 2004. 56. Velasco F, Velasco AL, Velasco M, et al. Electrical neuromodulation of the epileptic focus in cases of temporal lobe seizures. In: Lüders H (ed) Deep brain stimulation and epilepsy. London: Martin Dunitz, 2004. 57. Zabara J. Peripheral control of hypersynchronous discharge in epilepsy. Electroencephalogr Clin Neurophysiol 1985;61:162. [Abstract]. 58. Zabara J. Time course of seizure control to brief repetitive stimuli. Epilepsia 1985;26:518. 59. Woodbury DM, Woodbury JW. Effects of vagal stimulation on experimentally induced seizures in rats. Epilepsia 1990;31(Suppl 2):S7–26. 60. Lockard JS, Congdon WC, DuCharme LL. Feasibility and safety of vagal stimulation in monkey model. Epilepsia 1990;31(Suppl 2): S20–6. 61. Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results. Epilepsia 1990;31(Suppl 2):S40–3. 62. The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 1995;45: 224–30. 63. Aldenkamp AP, Van de Veerdonl SHA, Majoie HJM, et al. Effects of 6 months of treatment with vagus nerve stimulation on behavior in children with Lennox-Gastaut syndrome in an open clini­ cal and nonrandomized study. Epilepsy and Behavior 2001;2:343–50. 64. Asakura T, Nakamura K, Yatsushiro K. Effect of VNS on intractable epilepsy—First trial in Japan: Presented at: 3rd European Congress of Epileptology, 1998, Warsaw, Poland. 65. Frost M, Gates J, Helmers S. Vagal nerve stimula­ tion in children with refractory seizures associ­ ated with Lennox-Gastaut syndrome. Epilepsia 2001;42:1148–52. 66. Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-

16

onset seizures: a randomized active-control trial. Neurology 1998;51:48–55. 67. Helmers S, Wheless J, Frost M. VNS therapy in pediatric patients with refractory epilepsy: retro­ spective study. J Child Neurol 2001;16:843–8. 68. Karceski S: A review of the literature and data for the VNS patient registry. CNS Spectrum 2001;6:766–70. 69. Labar D. Changes in AEDs among patients receiving vagal nerve stimulation. Neurology 2002;58:A53. 70. Lundgren J, Amark P, Blennow G, et al. VNS in 16 children with refractory epilepsy. Epilepsia 1998;39:809–13. 71. Majoie H, Berfola M, Aldenkamp A. Vagal nerve stimulation in children with therapy-resistant epilepsy diagnosed as Lennox-Gastaut Syndrome. J Clin Neurophysiol 2002;18:419–28. 72. Murphy J, Andriola M, Barron T. Left VNS in children with medically refractory epilepsy. J Pediatr 1999;134:563–6. 73. Parker A, Polkey C, Binnie C, et al. Vagal nerve stimulation in epileptic encephalopathies. Pediatrics 1999;103:778–82. 74. Patwardan R, Strong B, Bebin M, et al. Efficacy of VNS in children with medically refractory epilepsy. Neurosurgery 2000;47:1353–8. 75. Fisher RS, Handforth A. Reassessment: vagus nerve stimulation for epilepsy: a report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1999;53:666–9. 76. Fanselow EE, Reid AP, Nicolelis AL. Reduction of pentylenetetrazole-induced seizure activity in awake rats by seizure-triggered trigeminal nerve stimulation. J Neurosci 2000;20:8160–8. 77. Cooper IS, Upton AR. Effects of cerebellar stimu­ lation on epilepsy, the EEG and cerebral palsy in man. Electroencephalogr Clin Neurophysiol 1978;34(Suppl):349–54. 78. Heath RG. Cerebellar vermis stimulation: longterm response in intractable behavioral disor­ ders and epilepsy. In: Davis R, Bloedel JR (eds) Cerebellar stimulation for spasticity and seizures. Boca Raton, FL: CRC Press, 1984, 263–7. 79. Benabid AL, Minotti L, Koudsie A, et al. Antiepileptic effect of high-frequency stimulation of the subthalamic nucleus (corpus luysi) in a case of medically intractable epilepsy caused by focal

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81. Ko D, Heck C, Grafton S. Vagus nerve stimula­ tion activates central nervous system structures in epileptic patients during PET H2(15)O blood flow imaging. Neurosurgery 1996;39:426–30. 82. Baker K, Montgomery EB, Rezai A, et al. Subthalamic nucleus deep brain stimulation evoked cortical potentials: physiological and thera­ peutic implications. Mov Disord 2002;17:969–83.

17

Section II

Pathogenesis of brain stimulation: animal studies

2 The basal ganglia: an overview

Thyagarajan Subramanian

Anatomy The basal ganglia have been traditionally con­ sidered to consist of the striatum (caudate and putamen), globus pallidus (external and inter­ nal segments), thalamus, subthalamic nucleus (STN), substantia nigra (pars compacta, SNc and pars reticulata, SNr) the pedunculopon­ tine nucleus (PPN) and the connections between these nuclei. Anatomically, all these structures are located subcortically adjacent to the ventricular system. These nuclei range in size and shape and have extensive afferent and efferent connections to the cerebral cortex, cerebellum and the sensory nuclei. Based on neuroanatomical and neurophysiological studies in animal models of Parkinson’s disease (PD) and electrophysiological studies in PD patients undergoing functional brain surgery, a model of basal ganglia function and pathophysiology of PD has been proposed.1,2 According to this model (Figure 2.1), motor function is modulated by a circuit that origi­ nates in the pre- and post-central sensorimotor areas, engages the motor areas in the basal ganglia and the ventral anterior and ventrolat­ eral thalamus (VA/VL). Cortical projections terminate in the post-commisural putamen, the motor portion of the striatum. Putamenal output is in turn directed towards the basal ganglia output nuclei, globus pallidus internal

Normal

Parkinsonism

Cortex

Cortex

Putamen D1 D2

CM VA/VL

Putamen

SNc

GPe

CM VA/VL

SNc

GPe

? STN

STN GPi/SNr GPi/SNr

Brainstem Spinal cord

Brainstem Spinal cord

Figure 2.1 Schematic diagram of the basal ganglia-thalamocortical motor circuitry under normal and parkinsonian conditions. Inhibitory connections are shown in black, excitatory in grey. Degeneration of the DAergic neurons in the SN leads to differential changes in the two striatopallidal projections indicated by the thickness of the connecting arrows. In parkinsonism, GPe is underactive, whereas STN, GPi and SNr are overactive. DA, dopamine; GPe, globus pallidus external segment; GPi, globus pallidus internal segment; STN, subthalamic nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata.

21

THE BASAL GANGLIA: AN OVERVIEW

Cortex Glu

Glu

Glu

D2 and A2A receptors Striatum GABA ENK GPe GABA

D1 receptors GABA, SP DYN

Dopamine Ventral thalamus SNc

Glu PPN

GABA GPi/SNr

STN Glu

Glu

segment (GPi) and the SNr via two pathways: a ‘direct’ monosynaptic pathway and an ‘indi­ rect’ polysynaptic pathway passing through motor areas of the external pallidal segment (GPe) and the subthalamic nucleus (STN). Basal ganglia motor output is directed towards VA/VL and is thought to influence the activity of thalamocortical projection neurons.

Biochemistry Several neurotransmitter systems are active in the basal ganglia. Gamma-aminobutyric acid (GABA) and glutamate are the most common neurotransmitters followed by dopamine, acetylcholine, substance P, dynorphin and enkephalins. Dopamine (DA) plays an impor­ tant role in the regulation of basal ganglia function. There is substantial evidence that release of DA into the striatum via the nigrostriatal pathway facilitates transmission in the direct pathway by activating D1 recep­ tors and inhibits transmission over the indi­ rect pathway via activation of D2 receptors.

22

Glu

Figure 2.2 Biochemistry of the basal ganglia. Glu, glutamate; GABA, gamma-aminobutyric acid; ENK, enkephalin; DYN, dynorphin; SP, Substance P; D1, dopamine receptor type 1; D2, dopamine receptor type 2; A2A, adenosine receptor type 2A; PPN, pedunculopontine nucleus; STN, subthalamic nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; GPi, globus pallidus internal segment; GPe, globus pallidus external segment.

In addition, DA may modulate basal ganglia output through its actions at extrastriatal sites. DAergic neurons in the SN also send projections to the STN and the GPi and may affect the release of GABA in the striatoni­ gral pathway through somatodendritic release of DA.3–10 With the exception of the excitatory (glutamatergic) efferents of the STN, intrinsic and output connections of the basal ganglia are inhibitory (GABAergic) (Figure 2.2).

Electrophysiology Neurons within each basal ganglia nucleus have specific patterns of neuronal discharge. Using single cell neuronal recording, these neuronal discharge patterns can be recorded and analysed. Clinically, these signature pat­ terns (Figure 2.3) can be very useful to map specific structures for functional surgery. Neuronal firing patterns have specific ‘burst­ ing patterns’ and ‘oscillations’ in addition to specific range of frequencies.

BASAL GANGLIA PHYSIOLOGY AND PATHOPHYSIOLOGY OF PARKINSON’S DISEASE

Striatum

Motor thalamus GPe

Figure 2.3 Microelectrode recording from basal ganglia structures. Representative single unit and multi-unit discharge patterns from the basal ganglia showing typical ‘signature’ patterns. For abbreviations see Figure 2.2.

‘Border’ cell

GPi

5 mm

STN multi-unit

SNR 1 second

STN single-unit

Basal ganglia physiology and pathophysiology of Parkinson’s disease The role of the substantia nigra pars reticulata (SNr) Our understanding of the basal gangia has been largely influenced by experiments and observations in Parkinson’s disease (PD) and in animal models of PD. PD is a common degenerative disorder associated with promi­ nent abnormalities of facial, limb and axial movements, such as bradykinesia (slowness of movement), rigidity (muscle stiffness), tremor,

and postural instability. This disorder is char­ acterized by the progressive degeneration of dopamine-(DA) producing neurons in the sub­ stantia nigra (SN). Recent investigations delin­ eating the location and function of DAergic neurons and DA receptors within the basal ganglia have improved our understanding of the pathophysiology of PD and the function of the basal ganglia. The current model of basal ganglia func­ tional and anatomical organization (Figure 2.1) proposes that in parkinsonism the loss of SN DAergic cells results in the relative overac­ tivity of the ‘indirect pathway’. This leads to increased striatal inhibition of GPe, followed by disinhibition and overactivity in the STN

23

THE BASAL GANGLIA: AN OVERVIEW

neurons, which then results in increased basal ganglia output from GPi and SNr (see Figure 2.3). Increased basal ganglia output to the thalamus is thought to inhibit thalamocortical neurons which may in turn, lead to inhibition in cortical activity and to the development of parkinsonian motor signs. As a corollary, the model predicts that restoration of DAergic inputs into the striatum will lead to the diminution of the relative overactivity of the indirect pathway (i.e. diminish STN overactiv­ ity) and partially ‘normalize’ SNr activity (via the striatonigral afferents). DeLong and colleagues1 have proposed that the basal ganglia have specific segregated path­ ways or ‘loops’ that deliniate skeletomotor, occulomotor, cognitive/limbic and associatory functions. This hypothesis suggests that specific areas within individual basal ganglia nuclei have segregated function. For example, the skeletomotor loop is hypothesized to contain the somatosensory/primary and premotor cor­ tices connecting to the putamen which then projects to the GPi and SNr. The Gpi/SNr complex projects to the ventral anterior and ventral lateral thalamic nuclei which then project back to the primary motor/supplemen­ tary motor and premotor cortex. Similar ‘loops’ involving specific somatotopically orga­ nized areas within each basal ganglia nucleus are hypothesized (Figure 2.4). Recent studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have corroborated the ‘segregated pathway’ hypothesis. However, alternate hypotheses of ‘convergence’ and ‘split segregation’ have also been proposed. There appears to be growing evidence to support the notion of ‘convergence’ in the case of the SNr while most other basal ganglia nuclei appear to have ‘segregation’ of various ‘loops’. Recent experience with basal ganglia lesions and deep brain stimulation (DBS) has demonstrated that the current

24

pathophysiological mode of PD may be too simplistic. However, most research clinicians and scientists are cautious in interpreting these data more widely in the context of the current models of basal ganglia function. This cautious approach appears to be prudent because most of these data are preliminary and because current DBS technology lacks accuracy at microscopic neuroanatomical level. For example, it is virtually impossible to distin­ guish at the present time if an accurately placed STN DBS device provides electrical stimulation of the STN neurons alone or includes adjacent axons and nuclei. Further refinement in DBS technology may permit such cellular level dissection of DBS effects and then we may be able to extrapolate these results more broadly to the mechanism of basal ganglia function.

Somatodendritic DA from SNc neurons: implications for DBS Studies in rodents and cats have documented that the DAergic neurons within the SNc release DA not only in the striatum but also through their soma and dendrites within the SN.11–16 These studies have demonstrated that DA is released by neurons in the SN in a calcium-dependent, potassium depolarization­ mediated mechanism in vivo.11 Local injection of tetrodotoxin had no effect on this DA release from the SN thereby suggesting that this release was not from axon terminals. DA receptors of the D1 type have been located in high density on the GABAergic striatonigral afferent fibers that pass though the dendritic field of the SN DAergic neurons.17–19 DA pro­ duces a dose-dependent increase in the release of [3H] GABA from rodent SN that is blocked

SOMATODENDRITIC DA FROM SNc NEURONS: IMPLICATIONS FOR DBS

1. Skeletomotor loop Cerebral cortex Somatic sensory Primary motor Premotor

Thalamic nuclei Ventral anterior Ventral lateral

Putamen

GPi SNr

Caudate (body)

SNr GPi

Ventral anterior Medial dorsal

Caudate (head)

SNr GPi

Ventral anterior Medial dorsal

Ventral striatum

Ventral pallidum GPi and SNr

Medial dorsal Ventral anterior

Supplementary motor area Premotor Primary motor cortex

Figure 2.4 Schematic representation of the ‘segregated loops’ hypothesized by DeLong and colleagues1 in the basal ganglia. For abbreviations see Figure 2.2.

2. Oculomotor loop Posterior parietal Prefrontal Frontal eye field Supplementary eye field

3. Association loop

Posterior parietal Premotor Prefrontal

4. Limbic loop Medial and lateral temporal lobes Hippocampal formation Anterior cingulate orbitofrontal

by DA antagonists and mimicked by DA agonists.20–23 These findings suggest that the DA secreted by the soma and dendrites of the SN DAergic cells act on the D1 receptors on

the GABAergic striatonigral afferents. Microinjections of D1 agonists into the SN reduce the basal neuronal firing rate in the nigro­ thalamic neurons in rats.5,24–26 These findings

25

THE BASAL GANGLIA: AN OVERVIEW

support the hypothesis that DA, acting through D1 receptors, results in a net inhi­ bition of SNr output neurons. From these experiments it can be inferred that loss of somatodendritic secretion of DA results in disinhibition of the tonically active SNr neurons, resulting in increased inhibition of the thalamocortical neurons, which in turn, lead to parkinsonian motor signs.18,27 Somatodendritic release of DA has been extensively investigated in the unilateral 6­ hydroxydopamine (6-OHDA) rat model of PD.16,28,29 Direct intranigral injection of DA into parkinsonian rats augments locomotor activity and this action is blocked with a DA antagonist.30 Similarly, intranigral injections of DA agonists caused contralateral rotational behavior suggesting that DA in the SN is capable of initiating a motor response.28,29 Intranigral injection of D1 selective antagonist, SCH 23390 has been shown to block L-dopa­ induced rotational behavior.13 Yurek and his colleagues have demonstrated that rotational behavior induced by systemic administration of D1 receptor agonist and amphetamine is blocked by intranigral injection of D1 receptor antagonist SCH 23390.31,32 These data support the hypothesis that somatodendritic release of DA within the SN is an important regulator of motor control in rodents and that the loss of somatodendritic DA release in the SN may contribute to parkinsonism. Recent evidence suggests this possibility by demon­ strating an alternative means of DA release in the SN that involves the dopamine transporter (DAT).33 It appears that DAT is not only responsible for cleaning up the excess DA in the synaptic cleft (DA influx, as seen in the striatum), but may also be responsible for DA release from the synapse (DA efflux, at least in the substantia nigra). The implication of these findings pertaining to PD is that it provides possible ways to thera­

26

peutically modulate DA efflux, especially in the early stages of the disease (neuroprotective effect). Neuroprotective because in PD the STN is disinhibited (excessive firing) therefore it may be triggering the SN dendrites to produce a harmful amount of DA. Somatodendritic DA release may be important in many other ways, specifically the regulated release of somato­ dendritic DA may be beneficial to modulate STN neurons from their execessive firing either by direct effects of somatodendritic DA release diffusing to the adjacent STN which is adjacent to the SNc or via direct SNc-STN DAergic con­ nections. Therefore, replacing or preserving somatodendritic DA release in the SN may be critical for complete recovery of function in PD and perhaps suggest a putative mechanism through which DBS ameliorates parkinsonian symptoms.

Summary This brief overview of the basal ganglia dis­ cussed the current model of basal ganglia with respect to its anatomical organization, neuro­ chemistry, pharmacology and physiology. Much of the information presented in this overview is based on experiments in animal models of Parkinson’s disease and clinical studies in patients with movement disorders. Recent experiments suggest that the substantia nigra pars reticulata (SNr) may be important in modulating basal ganglia function. The SNr has also been postulated as a important player in the pathophysiology of epilepsy. A better understanding of SNr and its connections to the rest of the brain may allow us to under­ stand the possible biological basis for the use­ fulness of deep brain stimulation (DBS) in epilepsy and other neuropsychiatric disorders. Recent investigations suggest that dopamine secreted locally into the SNr via the soma and

REFERENCES

dentrites of the substantia nigra pars com­ pacta (SNc) neurons may play a significant role in modulating SNr activity.

References 1. DeLong MR. Primate models of movement disor­ ders of basal ganglia origin. Trends Neurosci 1990;13:281–5. 2. Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders Trends Neurosci 1989;12:366–75 [See comments]. 3. Geffen LB, Jessell TM, Cuello AC, Iversen LL. Release of dopamine from dendrites in rat sub­ stantia nigra. Nature 1976;260:258–60. 4. Sladek JR Jr, Parnavelas JG. Catecholamine­ containing dendrites in primate brain. Brain Res 1975;100:657–62. 5. Waszczak BL, Walters JR. Endogenous dopamine can modulate inhibition of substantia nigra pars reticulata neurons elicited by GABA iontophore­ sis or striatal stimulation. J Neurosci 1986;6:120–6. 6. Nieoullon A, Cheramy A, Glowinski J. Release of dopamine in vivo from cat substantia nigra. Nature 1977;266:375–7. 7. Cheramy A, Nieoullon A, Glowinski J. In vivo evidence for a dendritic release of dopamine in the cat substantia nigra. Appl Neurophysiol 1979;42:57–9. 8. Hery F, Soubrie P, Bourgoin S et al. Dopamine released from dendrites in the substantia nigra controls the nigral and striatal release of sero­ tonin. Brain Res 1980;193:143–51. 9. Cheramy A, Leviel V, Glowinski J. Dendritic release of dopamine in the substantia nigra. Nature 1981;289:537–42. 10. Gauchy C, Desban M, Glowinski J, Kemel ML. NMDA regulation of dopamine release from proximal and distal dendrites in the cat substan­ tia nigra. Brain Res 1994;635:249–56. 11. Cheramy A, Chesselet MF, Romo R et al. Effects of unilateral electrical stimulation of various thalamic nuclei on the release of dopamine from dendrites and nerve terminals of neurons of the two nigrostriatal dopaminergic pathways. Neuroscience 1983; 8:767–80. 12. Richards CD, Shiroyama T, Kitai ST. Electrophysiological and immunocytochemical

characterization of GABA and dopamine neurons in the substantia nigra of the rat. Neuroscience 1997;80:545–57. 13. Robertson HA. Dopamine receptor interactions: some implications for the treatment of Parkinson’s disease. Trends Neurosci 1992; 15:201–6. 14. Santiago M, Westerink BH. The regulation of dopamine release from nigrostriatal neurons in conscious rats: the role of somatodendritic autoreceptors. Eur J Pharmacol 1991;204:79–85. 15. Nedergaard S, Hopkins C, Greenfield SA. Do nigro-striatal neurones possess a discrete den­ dritic modulatory mechanism? Electrophy­ siological evidence from the actions of ampheta­ mine in brain slices. Exp Brain Res 1988; 69:444–8. 16. Hoffman AF, van Horne CG, Eken S et al. In vivo microdialysis studies on somatodendritic dopamine release in the rat substantia nigra: effects of unilat­ eral 6-OHDA lesions and GDNF. Exp Neurol 1997; 147:130–41. 17. Besson MJ, Graybiel AM, Nastuk MA. [3H]SCH 23390 binding to D1 dopamine receptors in the basal ganglia of the cat and primate: delineation of striosomal compartments and pallidal and nigral subdivisions. Neuroscience 1988;26: 101–19. 18. Abercrombie ED, DeBoer P. Substantia nigra D1 receptors and stimulation of striatal cholinergic interneurons by dopamine: a proposed circuit mechanism. J Neurosci 1997;17:8498–505. 19. Dubois A, Savasta M, Curet O, Scatton B. Autoradiographic distribution of the D1 agonist [3H]SKF 38393, in the rat brain and spinal cord. Comparison with the distribution of D2 dopamine receptors. Neuroscience 1986;19:125–37. 20. Aceves J, Floran B, Martinez-Fong D. Activation of D1 receptors stimulates accumulation of gamma-aminobutyric acid in slices of the pars reticulata of 6-hydroxydopamine-lesioned rats. Neurosci Lett 1992;145: 40–2. 21. Aceves J, Floran B, Sierra A, Mariscal S. D–1 receptor mediated modulation of the release of gamma-aminobutyric acid by endogenous dopamine in the basal ganglia of the rat. Prog Neuro Psychopharmacol Biol Psychiatry 1995;19:727–39. 22. Floran B, Aceves J, Sierra A, Martinez-Fong D. Activation of D1 dopamine receptors stimulates the release of GABA in the basal ganglia of the rat. Neurosci Lett 1990;116:136–40.

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THE BASAL GANGLIA: AN OVERVIEW

23. Reubi JC, Iversen LL, Jessell TM. Dopamine selectively increases 3H-GABA release from slices of rat substantia nigra in vitro. Nature 1977; 268:652–4. 24. Martin LP, Waszczak BL. D1 agonist-induced excitation of substantia nigra pars reticulata neurons: mediation by D1 receptors on striatoni­ gral terminals via a pertussis toxin-sensitive cou­ pling pathway. J Neurosci 1994;14:4494–506. 25. Waszczak BL, Lee EK, Tamminga CA, Walters JR. Effect of dopamine system activation on sub­ stantia nigra pars reticulata output neurons: vari­ able single-unit responses in normal rats and inhi­ bition in 6-hydroxydopamine-lesioned rats. J Neurosci 1984;4:2369–75. 26. Waszczak BL. Differential effects of D1 and D2 dopamine receptor agonists on substantia nigra pars reticulata neurons. Brain Res 1990;513: 125–35. 27. Timmerman W, Abercrombie ED. Amphetamineinduced release of dendritic dopamine in substan­ tia nigra pars reticulata: D1-mediated behavioral and electrophysiological effects. Synapse 1996;23:280–91.

28

28. Andrews CD, Woodruff GN. Turning beha­ viour following nigral injections of dopamine agonists and glycine. Eur J Pharmacol 1982;84:169–75. 29. Kelly E, Jenner P, Marsden CD. Behavioural effects mediated by unilateral nigral dopamine receptor stimulation in the rat. Exp Brain Res 1984;55:243–52. 30. Jackson EA, Kelly PH. Effects of intranigral injec­ tions of dopamine agonists and antagonists, glycine, muscimol and N-methyl-DL-aspartate on locomotor activity. Brain Res Bull 1984; 13:309–17. 31. Yurek DM, Hipkens SB. Intranigral injections of SCH 23390 inhibit amphetamine-induced rota­ tional behavior. Brain Res 1993;623:56–64. 32. Yurek DM, Hipkens SB. Intranigral injections of SCH 23390 inhibit SKF 82958-induced rota­ tional behavior. Brain Res 1994;639:329–32. 33. Falkenberger BH, Barstow KL, Mintz IM. Dendrodendritic inhibition through reversal of dopamine transport. Science 2001;293:2465–70. 34. Blakely RD. Dopamine’s reversal of fortune. Science 2001;293:2407–9.

3 The subthalamic nucleus: anatomy and neurophysiology Thomas Wichmann

Introduction The realization that abnormal activity in the subthalamic nucleus (STN) is an important feature in the pathogenesis of movement dis­ orders, such as hemiballism and parkinsonism, has resulted in considerable interest in the anatomy and physiology of the STN. Knowledge gained from these studies has found widespread clinical application, particularly with the introduction of deep brain stimulation (DBS) as treatment for parkinsonism and other movement disorders. The objective of this review is to highlight some of the anatomic and physiologic properties of the STN that may be important for an understanding of the patho­ physiology of clinical disorders.

Intrinsic discharge properties In vitro recordings of subthalamic nucleus neurons suggest that these cells have at least two different discharge modes, depending on the membrane potential.1 In a relatively depo­ larized state, these neurons discharge in a ‘single-spike mode’ at frequencies in the 10–20 Hz range, most likely driven by slowly inacti­ vating voltage-gated sodium channels, and modulated by calcium-dependent potassium currents.2,3 At more hyperpolarized potentials,

the cells discharge in a burst mode, often with regularly recurring bursts. The various excita­ tory and inhibitory inputs to the subthalamic nucleus that are described below utilize and modify these intrinsic discharge properties to produce the rich variety of discharge patterns recorded from the subthalamic nucleus under in vivo conditions.4

General anatomy The general circuitry that is involved in shaping STN discharge is shown in Figure 3.1. For more than a decade, it has been realized that the STN functions in the context of a larger network that includes the other basal ganglia structures, as well as the cerebral cortex and thalamus.5 The network is composed of several circuits that remain segregated throughout their subcortical course. Each of these circuits originates in spe­ cific cortical areas, passes through a distinct portion of the basal ganglia and thalamus, and projects back to the frontal cortical area of origin. The cortical sites of origin of these circuits define the presumed function of these circuits as ‘motor’, ‘oculomotor’, ‘associative’, and ‘limbic’. In each of the basal ganglia­ thalamocortical circuits, the striatum and STN serve as the input stage of the basal ganglia, and the internal pallidal segment (GPi) and the

29

THE SUBTHALAMIC NUCLEUS: ANATOMY AND NEUROPHYSIOLOGY

Cortex

Putamen CM/Pf D2

D1

indirect

direct SNc GPe

STN

Brainstem/ spinal cord

GPi/SNr

PPN

substantia nigra pars reticulata (SNr) as output stations. Striatal output reaches GPi/SNr via two pathways, a ‘direct’, monosynaptic route, and an ‘indirect’, polysynaptic, route that passes through the external pallidal segment (GPe) to GPi, either directly or via GPe projections to the STN.6,7 In the following, the excitatory and inhibitory inputs, and their contribution to sub­ thalamic discharge are discussed.

Inputs to the subthalamic nucleus (STN) Excitatory inputs In recent years, the STN has emerged as a major port of entry of cortical information into the basal ganglia circuitry.8 The cortico-

30

VA/VL

Figure 3.1 Simplified schematic diagram of the basal ganglia­ thalamocortical circuitry. Inhibitory connections are shown as filled arrows, excitatory connections as grey arrows. The principal input nuclei of the basal ganglia, the striatum and the STN are connected to the output nuclei, GPi and SNr. Basal ganglia output is directed at several thalamic nuclei (VA/VL and CM) and at brainstem nuclei (PPN and others). For abbreviations and further explanation of the model, see text.

subthalamic projection appears to be ipsi­ lateral9,10 and arises in large part from the primary motor cortex, with lesser contribu­ tions from the supplementary motor area (SMA), the pre-SMA, the dorsal and ventral premotor cortices, the cingulate motor area, and the prefrontal and premotor cortices.9–13 Physiologic experiments have confirmed the existence and importance of the corticosub­ thalamic projection. For instance, it has been shown that frontal cortical ablation in primates results in a significant reduction of metabolic activity in the STN.14 Physiologic experiments in rodents15 and primates16 have shown that activation of cortical afferents results in a short-latency excitation at the STN level, which is subsequently transmitted to both seg­ ments of the globus pallidus. In anesthetized rats, EEG activity, recorded over the frontal

INPUTS TO THE SUBTHALAMIC NUCLEUS (STN)

cortex, and STN activity were synchronized, and cortical ablation resulted in a more regular firing pattern in the STN.17,18 A similar rela­ tionship between cortical and STN activity has recently also been described in primates.19 It is important to note that cortical afferents impose a topographic and somatotopic orga­ nization on the basal ganglia, not only at the striatal level, but also at the level of the STN.4,5,20 The corticosubthalamic projections are topographically organized so that afferents from the primary motor cortex and cingulate motor area target the dorsolateral STN,9,12 while premotor and supplementary motor areas innervate mainly the medial third of the nucleus.9,12,13,21,22 The prefrontal (non-motor) cortices project to the medial STN.9,10,23,24 The projection from the primary motor cortex is somatotopically organized; the face area pro­ jects laterally, the arm area centrally and the leg area medially.9,11,12 Compared to this arrangement, the somatotopical representa­ tions from the supplementary motor area (SMA) to the medial STN is reversed.12 The cortical inputs determine in large part the responses of subthalamic nucleus neurons to proprioceptive and other somatosensory inputs. In primates,4 and humans undergoing stereotactic surgical procedures for treatment of movement disorders,25 a rough somatotopic arrangement was identified that corresponds well with the topography of the input from primary motor cortex, that is, responses to face examination are found laterally, responses to leg examination medially, and responses to arm examination in between. These responses are not as clear-cut as the anatomic studies suggest, likely because of the overlap between various corticosubthalamic projections. In rodents,26 some convergence of projections from different frontal cortical areas may occur, as subthalamic nucleus neurons have long dendrites that may cross boundaries of

functional territories imposed by cortical pro­ jections. However, the physiologic studies in primates and humans (see above) have indi­ cated that the responses to somatosensory examination are highly specific, so that a high degree of functional convergence of inputs appears unlikely. Excitatory inputs to the STN from the caudal intralaminar thalamic nuclei represent another important source of glutamatergic inputs to the STN. This projection respects the functional organization of the STN (as outlined above); sensorimotor neurons, originating in the thala­ mic centromedian nucleus (CM), terminate preferentially in the lateral part of the STN, whereas neurons related to limbic or associative functions, originating in the thalamic parafascicular nucleus (Pf) project to the medial STN.27–29 The thalamosubthalamic projection is excitatory and may tonically drive the activity of STN neurons, as suggested by studies invest­ igating the effects of lesions of the intralaminar thalamic nuclei on subthalamic nucleus dis­ charge rates.30 Although some CM/Pf neurons that project to the striatum send axon collater­ als to the STN,31 most of the the thalamosub­ thalamic and thalamostriatal projections arise from different CM/Pf neurons.32

Inhibitory inputs The primary inhibitory (GABAergic) input to the STN arises from the external pallidal segment (GPe). Terminals from the GPe-STN projection form symmetric synapses in all areas of the STN.33 In vitro studies have con­ firmed that GPe exerts a strong inhibitory influence on STN firing.34 The pattern and rate of inhibitory input from GPe upon STN determine the nature of the response in the STN, which may range from resetting of oscil­ latory single-spike activity in the STN after single IPSPs to profound hyperpolarization in

31

THE SUBTHALAMIC NUCLEUS: ANATOMY AND NEUROPHYSIOLOGY

the STN, terminating in rebound bursts after multiple summed IPSPs. Paradoxically, certain patterns of inhibitory input patterns from GPe, through induction of strong rebound bursts, may even result in a net increase in average discharge in the STN.34 The phenome­ non of rebound bursting may also give rise to the generation of oscillatory burst patterns in GPe and STN. In experiments in which sub­ thalamic nucleus, pallidal, striatal and cortical tissues were co-cultured, GPe and STN show synchronized bursting activity, which is inde­ pendent of striatal or cortical inputs, but can be disrupted by severing the pallidosubthala­ mic connection.35 It is thought that rebound bursts in the STN drive bursting activity in GPe, which, in turn, result in further hyperpo­ larization of STN, maintaining the oscillatory cycle. Aside from its potential role in the genera­ tion of oscillatory activity, the GPe-STN pathway is an essential component of the ‘indirect’ pathway (see above). The GPe pro­ jects topographically to the entire extent of the STN in a topographic manner. Similar to the excitatory inputs to the STN, the inhibitory input from GPe is topographically organized, so that populations of neurons within sensori­ motor, cognitive and limbic territories in the GPe are connected to populations of neurons in the same functional territories of the STN.36 Despite this clearly defined functional and anatomical topography, double anterograde tracing experiments indicate that there are some areas of overlap of inputs from function­ ally diverse regions of the pallidal complex in rats.26,37 Interestingly, recent single-cell labelling studies in primates have indicated that many GPe neurons give rise to long axons that may collateralize to varying degrees in STN, GPi and SNr,38 indicating that the concept of a single ‘indirect’ pathway, linking GPe to GPi via the STN is incorrect, and that,

32

instead, there are several such pathways, some of which may bypass the STN.

STN efferents The primary targets of the excitatory STN output projections are GPi, SNr and GPe. In the rat, most STN neurons project to both GPe (i.e. GP in rats) and GPi/SNr,39–41 while retro­ grade double-labelling methods in monkeys have suggested that subthalamic inputs to the substantia nigra and the pallidal complex arise from different populations of neurons36,42 (but see Parent and Hazrati43,44), attesting to a higher degree of functional specialization in pri­ mates. The segregation of function within the STN appears to be maintained in its output pathways, so that neurons in sensorimotor, cog­ nitive and limbic territories in the STN (as defined by their cortical and pallidal inputs) project to territories in GPe, GPi and SNr which are concerned with the same func­ tions36,45 (but see Parent and Hazrati43,44). STN projections tend to terminate distally on the dendrites of pallidal and nigral neurons, and account for approximately 10% of the total population of terminals on perikarya and dendrites in these nuclei.46 At first glance, these anatomical findings suggest that the impact of STN activity on discharge in the pallidum and nigra is limited. However, electrophysiologic studies have demonstrated that the STN output is, in fact, one of the major ‘driving forces’ of basal ganglia output.47 Experiments in primates have demonstrated that STN lesions result in a sub­ stantial reduction of pallidal discharge rates, and may convey many of the sensorimotor responses in these nuclei.48,49 As mentioned above, STN output to GPe may also be involved in maintaining oscillatory burst dis­ charges in the basal ganglia output nuclei.

PHYSIOLOGIC ROLE OF THE STN IN THE CONTROL OF MOVEMENT AND OTHER FUNCTIONS

Additional projections from the STN to the SNc,50–52 and the pedunculopontine nucleus (PPN42,50,53,54) have also been described. The STN has the potential to influence SNc activ­ ity by multiple routes (Figure 3.2),51,55–57 and it is thought that activation of the monosynap­ tic STN-SNc pathway results in increased burst discharges in the SNc, while activation of a bisynaptic pathway involving GPe lowers average discharge rates in the SNc at the same time. The direct STN-SNc route is probably not as important in primates as it is in rodents, given the relatively sparse innervation of the primate SNc by STN efferents.52 On the whole, the STN-SNc interactions are of sub­ stantial interest, because of the potential role of the STN in maintaining dopamine home­ ostasis under normal and parkinsonian condi­ tions (see below).58–60 In addition, it is con­ ceivable that electrical stimulation of the STN, as is often done in the treatment of

STN

+

+

–

PPN

+

Parkinson’s disease, may at least in part act though activation of remaining dopaminergic nigrostriatal fibers. Far less is known regarding the STN inter­ action with the PPN. Recent studies have sug­ gested that the STN may exert an excitatory drive on the PPN61 in rodents, and that lesions of the STN reduce the metabolic activity in this nucleus.62

Physiologic role of the STN in the control of movement and other functions The focus of most studies investigating the function of the STN has been its involvement in the control of movement. Given the similar organization of motor and non-motor circuits passing through the STN, it appears likely that

SNc

Figure 3.2 Influence of the STN on SNc activity. The STN may influence SNc activity via a direct monosynaptic route, or via the intercalated PPN, SNr or GPe. Inhibitory connections are shown as filled arrows, excitatory connections as grey arrows. For abbreviations, see text.

SNr

GPe

33

THE SUBTHALAMIC NUCLEUS: ANATOMY AND NEUROPHYSIOLOGY

the considerations with regard to motor control also apply to non-motor functions. The function of the STN has to be viewed in the context of the indirect pathway, or of the corticosubthalamo-pallidal pathway. According to the current model of the basal ganglia-thalamocortical circuitry, activation of striatal neurons that give rise to the direct pathway reduces inhibitory basal ganglia output with subsequent disinhibition of related thalamocortical neurons.63 This disin­ hibition results in increased activity in corre­ sponding cortical neurons, resulting in facilita­ tion of the movement. By contrast, activation of the striatal neurons that give rise to the indirect pathway, of which the STN is part of, leads to increased (inhibitory) basal ganglia output on thalamocortical neurons and to suppression of movement. Since the majority of neurons in GPi increase their discharge rate with movement, suppression of competing movements, mediated via the indirect pathway, may be a particularly important role of the basal ganglia. As part of this movement-limiting function, the STN may participate in ‘scaling’ of move­ ments, (i.e. the termination or restriction of ongoing motor activity). Indeed, discharge in the basal ganglia have been shown to correlate with the amplitude or the velocity of move­ ment.63–65 Scaling or braking of movements could be achieved by a temporal sequence of activity changes in the basal ganglia in which striatal output, via the direct pathway, would first inhibit specific neuronal populations in GPi/SNr, thus facilitating movement, followed by disinhibition of the same GPi/SNr neuron via inputs over the indirect pathway, leading to inhibition of the ongoing movement. Alternatively, the STN may participate in a ‘focusing’ in the basal ganglia.16,66 In this model, STN activity is thought to drive background activity in the basal ganglia output nuclei, which

34

would result in suppression of unintended movements. Intended movements would be allowed to proceed through spatially and tem­ porally circumscribed increases of striatal output along the direct pathway (see also dis­ cussions in Wichman et al. and Jaeger et al.4,67). While these relatively direct effects of STN activity on movement may hold true for the activity of many STN cells, this nucleus may also be part of additional higher level motor functions that have been ascribed to the basal ganglia circuitry, such as a role in movement preparation, in self-initiation (internally generated) movements, in motor (especially procedural) learning and in move­ ment sequencing.68–70

Changes in STN activity in movement disorders One of the most important reasons for the rekindled interest in the anatomy and physiol­ ogy of the STN was the discovery that this nucleus plays a significant role in the develop­ ment of hypo- and hyperkinetic movement disorders.

Parkinsonism In parkinsonism, changes in the activity along striatopallidal pathways were first suggested by studies in primates that had been rendered parkinsonian through injections of the dopaminergic neurotoxin MPTP. These studies indicated that the metabolic activity (as mea­ sured with the 2-deoxyglucose technique) is increased in both pallidal segments.71,72 This was interpreted as evidence for increased activity of the striatum-GPe connection and the STN-GPi pathway, or, alternatively, as evi­ dence for increased activity via the projections from the STN to both pallidal segments.

CHANGES IN STN ACTIVITY IN MOVEMENT DISORDERS

SNr

2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 0

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Figure 3.3 Raster displays of spontaneous neuronal activity recorded in GPe and GPi in normal and parkinsonian primates. Each of the diagrams shows a twenty-second segment of the spontaneous activity of a single neuron, displayed in 1 s intervals with each tick representing a single action potential. In parkinsonism, the neuronal activity is reduced in GPe, and increased in STN, GPi and SNr. In addition to the rate changes, there are also obvious changes in the firing patterns of neurons. For abbreviations and further explanations, see text.

35

THE SUBTHALAMIC NUCLEUS: ANATOMY AND NEUROPHYSIOLOGY

Subsequent microelectrode recordings of neu­ ronal activity in the primate MPTP model of parkinsonism showed directly that neuronal discharge is reduced in GPe, and increased in the STN, GPi and SNr (Figure 3.373–76). The changes in discharge rates in the basal ganglia have been interpreted as indicating that striatal dopamine depletion leads to increased activity of striatal neurons of the indirect pathway, resulting in inhibition of GPe, and subsequent disinhibition of STN and GPi/SNr (Figure 3.4). Inconsistencies between this model and more recent immunohistochemical studies has led to the development of alternative hypotheses, in which the observed activity changes in STN and GPi may primarily be due to altered activity via the corticosubthalamic or CM/Pf­ subthalamic projection or via dopaminergic inputs to STN itself. 77–81 Regardless of its origin, increased STN and GPi/SNr activity is thought to result in inhibition of thalamo­ cortical projection neurons. This is supported by PET studies in parkinsonian patients that have consistently shown reduced activation of motor and premotor areas.82,83 Even the earliest studies of neuronal activity in parkinsonian animals have described not only MPTP-induced changes in discharge rates in the basal ganglia, but also significant changes in discharge patterns (Figure 3.3). It was shown that the neuronal discharge in the STN and GPi/SNr becomes less regular, with the development of frequent (oscillatory or non-oscillatory) bursts.74,75 These and other abnormalities of neuronal discharge may be the result of intrinsic membrane properties of STN neurons, or the interaction between the STN and one or more of its afferents, most likely those arising in the GPe (the STN-GPe pacemaker, see above). Oscillatory activity in the STN may be of particular interest in the pathogenesis of parkinsonian tremor, although

36

it remains uncertain whether these oscillatory discharges reflect proprioceptive input to the STN (via the corticosubthalamic projection), or whether they are caused by the develop­ ment of tremor.84,85 Most recently, attempts have also been made to integrate the STN-SNc and STN­ PPN projections into models of parkinsonian pathophysiology. It has been suggested that the STN may have an excitatory effect on dopaminergic neurons in primates, and may result in increased dopamine release in the striatum (Wichmann et al., unpublished observation). Thus, the overactivity of the STN in parkinsonism may serve to compen­ sate for the dopaminergic loss in early stages of the disease.58–60 The STN-PPN interaction has recently been investigated in 6-OHDA­ treated animals, 61 in which the PPN was found to be overactive in the parkinsonian state, a finding that could be reversed by STN lesions, suggesting that the increased PPN activity in this model was, at least in part, driven by increased STN output to the PPN. STN and PPN projections to the SNc represent the most important sources of glu­ tamate in the SNc. If PPN and SNc are driven by STN activity, overactivity of this nucleus may also accelerate significantly the dopaminergic cell loss in Parkinson’s disease via excitotoxic mechanisms.86,87

Hemiballism and other hyperkinetic movement disorders The pathophysiology of hyperkinetic dis­ orders is often described as the mirror image of the pathophysiology of Parkinson’s disease (Figure 3.4). It is thought that in disorders associated with dyskinesias, basal ganglia output is reduced, resulting in disinhibition of thalamocortical systems.88,89 This is best

direct

PPN

GPi/SNr

SNc

D1

STN

direct

PPN

GPi/SNr

SNc

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Brainstem/ spinal cord

CM/Pf VA/VL

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STN

direct

PPN

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SNc

D1

Putamen D2

GPe

indirect

Brainstem/ spinal cord

CM/Pf VA/VL

Cortex

Hemiballismus

CM/Pf VA/VL

Figure 3.4 Changes in the neuronal activity in the basal ganglia-thalamocortical circuitry in movement disorders. Shown are diagrams depicting the changes encountered in parkinsonism (center), a hypokinetic disorder, and hemiballismus (right diagram), a hyperkinetic disorder. Inhibitory connections are shown as filled arrows, excitatory connections as grey arrows. Activity changes are indicated by the width of the respective arrows. In parkinsonism, STN drives the basal ganglia output structures. In contrast, hemiballismus is caused in most cases by a lesion of the STN, resulting in substantial reduction of GPi and SNr activity. For abbreviations, see text.

Brainstem/ spinal cord

STN

GPe

indirect

D2

Putamen

Cortex

Normal

CHANGES IN STN ACTIVITY IN MOVEMENT DISORDERS

37

THE SUBTHALAMIC NUCLEUS: ANATOMY AND NEUROPHYSIOLOGY

documented for hemiballism, a disorder that follows discrete lesions of the STN, which result in reduced activity in GPi in both experimental primates and in humans. 48,90 The mechanisms underlying chorea in Huntington’s disease are thought to be similar to those in hemiballism in that degeneration of striatal neurons projecting to GPe (indirect pathway) leads to disinhibition of this nucleus, resulting in increased inhibition of the STN. The functional reduction of STN activity renders GPi neurons underactive in this disease. 91,92 Drug-induced dyskinesias may also result from a similar reduction in STN and GPi activity. Support for the validity of these models comes from electrophysio­ logic 74,75,93–97 and metabolic studies in pri­ mates, and a number of PET studies investi­ gating cortical and subcortical metabolism in humans with movement disorders. 98,99 For instance, in animals with drug-induced dyski­ nesias, STN and GPi activity, as measured by electrophysiology, was found to be greatly reduced, concomitant to the expression of dyskinetic movements.95 While STN lesions result in obvious and long-lasting dyskinesias, pallidotomies, done as treatment for parkinsonian patients, rarely induce dyskinetic movements.66,100–102 This suggests that partial rather than total reduction of pallidal output to the thalamus may result in dyskinesias, and that specific alterations in discharge patterns may be particularly con­ ducive to the development of dyskinesias. Compensatory mechanisms at the thalamic or cortical level may also be at work to prevent the development of dyskinesias after complete cessation of pallidal or nigral output. For instance, in many cases, the dyskinetic move­ ments after STN lesions are transient,103 despite the continued presence of reduced and abnormal neuronal discharge in GPi.48

38

Conclusion In recent years, research into the physiology and anatomy of the STN have yielded fasci­ nating insights that may help to elucidate the physiologic role of the STN within the frame­ work of the basal ganglia circuitry and its role in the pathophysiology of some of the most disabling movement disorders. Much work needs to be done, however, to integrate the newly described physiologic and anatomic facts into the models of the larger basal ganglia circuits. The expansion of knowledge about the basal ganglia-thalamocortical cir­ cuits will greatly help to improve upon exist­ ing lesion and stimulation approaches in the treatment of diseases involving the basal ganglia.

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94. Vitek JL, Kaneoke Y, Turner R et al. Neuronal activity in the internal (GPi) and external (GPe) segments of the globus pallidus (GP) of parkin­ sonian patients is similar to that in the MPTP­ treated primate model of parkinsonism. Soc Neurosci Abstr 1993;19:1584. 95. Papa SM, Desimone R, Fiorani M, Oldfield EH. Internal globus pallidus discharge is nearly sup­ pressed during levodopa-induced dyskinesias. Ann Neurol 1999;46:732–8. 96. Lozano AM, Lang AE, Levy R et al. Neuronal recordings in Parkinson’s disease patients with dyskinesias induced by apomorphine. Ann Neurol 2000;47:S141–6. 97. Merello M, Balej J, Delfino M. Apomorphine induces changes in GPi spontaneous outflow in patients with Parkinson’s disease. Mov Dis 1999;14:45–9. 98. Brooks DJ. The role of the basal ganglia in motor control: contributions from PET. J Neurol Sci 1995;128:1–13.

99. Brooks DJ. Functional imaging in relation to parkinsonian syndromes. J Neurol Sci 1993; 115:1–17. 100. Horak FB, Anderson ME. Influence of globus pallidus on arm movements in monkeys: I. Effects of kainic-induced lesions. J Neurophysiol 1984;52:290–304. 101. Wichmann T, Kliem MA, DeLong MR. Antiparkinsonian and behavioral effects of inactivation of the substantia nigra pars reticulata in hemiparkinsonian primates. Exp Neurol 2001;167:410–24. 102. Baron MS, Wichmann T, Ma D, DeLong MR. Effects of transient focal inactivation of the basal ganglia in parkinsonian primates. J Neurosci 2002;22:592–9. 103. Hamada I, DeLong MR. Excitotoxic acid lesions of the primate subthalamic nucleus result in transient dyskinesias of the contralat­ eral limbs. J Neurophysiol 1992;68:1850–8.

43

4 Brain stimulation and epilepsy: electrical stimulus characteristics Mark T Rise

Physiological principles of neurostimulation Clinicians commonly use pharmaceutical agents that modulate neural processes in order to treat disorders of the central nervous system (CNS). Most drugs used to treat neurological disorders do so by affect­ ing synaptic transmission. However, they may not be specific in their action and cause modulation of other neural circuits not involved in the specific disorder. Often, this leads to unintended neural side effects. Electrical stimulation of the nervous system is an alternative way to modulate the subcircuits of the CNS with the possibility of greater specificity. Nerve cells convey information from one part of the CNS to another through electri­ cal phenomena. An action potential is a transient reversal in the transmembrane voltage potential of a nerve cell axon. The action potential propagates along the nerve cell membrane. Neurostimulators affect the CNS through the creation of a voltage in the neighborhood of a specific circuit of the nervous system artificially manipulating membrane voltages. Manipulation of the membrane potential through the use of the neurostimulator can cause nerve cells to

propagate action potentials orthodromically and antidromically along the axon. Alternat­ ively, appropriately applied voltages can block the propagation of action potentials. Thus, the use of implanted extracellular electrodes connected to neurostimulators to modulate the activity in selected pathways of the CNS can be palliative treatment for neurological disorders.

Neurostimulation devices The CNS is the quintessential neural network. Neurostimulation is one means to modulate the information-processing activity of the CNS. This is typically carried out to compensate for the loss of normal func­ tion due to disease or injury. Implicit in the use of neurostimulation to treat a neural disorder is a rudimentary understanding of which the part of the nervous system is affected and the type of compensation required to restore normal function. This review describes in general terms some of the basic principles of extracellular neurostimu­ lation, the criteria for stimulating without causing damage to the nervous tissue, and two applications of neuromodulation using electrical stimulation.

45

BRAIN STIMULATION AND EPILEPSY

Basic principles of neurostimulation Neurostimulation can be thought of as being a tool for treating neurological dysfunction. The particular therapeutic application will determine which part of the nervous system is activated or deactivated by stimulation. There are basic principles associated with the use of neurostimulation which aid the clinician in predicting the effects of using different stimu­ lation parameters in a safe manner with the desired outcome.

Biophysics of neurostimulation Reduced to its simplest form, a neuro­ stimulator consist of a power supply (i.e. a battery), a pair of electrodes in contact with the tissue, extension wires to connect the electrodes to the battery and a ‘switch’ that enables the power to be intermittently con­ nected to the electrodes (Figure 4.1). Ohm’s law governs the relationship between the voltage and current. Much of the basic understanding of nerve cell electro­ physiology was discovered as a result of studies carried out with intracellular elec­ trodes referenced to electrodes in the extracellular space. Neurostimulators used for neuromodulation, however, make use of extracellular electrodes to generate the voltage/current fields. Electronic switch

Current I Anode (positive electrode)

+ Voltage (V)

By convention, there are two types of electrode configurations, referred to as ‘mono­ polar’ and ‘bipolar’ stimulation. Of course, for current to flow it is necessary that there be two electrodes, a positive anode and a nega­ tive cathode. Monopolar stimulation then refers to an electrode configuration that includes an electrode of relatively small surface area located near or in the nervous tissue to be stimulated (Figure 4.2). This elec­ trode is typically the negative electrode or cathode for reasons described below. The posi­ tive electrode has a larger surface area and is located remote to the stimulation target. Typically, the outside surface or ‘case’ of the neurostimulator electronics package is used as the positive anode when performing monopo­ lar stimulation. When performing bipolar stimulation, both the positive and negative electrodes are in or near the nervous tissue tar­ geted for stimulation and have the same or similar surface areas. Neuromodulation is performed by applying intermittent, electrical stimulation. In other words, the switch in Figure 4.1 connecting the battery to the electrodes is closed then opened repeatedly as time goes on. The stimulation waveform is defined by standard parameters of stimulation (Figure 4.3). Table 4.1 lists the programmable parameters and their ranges for one model of neuro­ stimulator. The amplitude of stimulation is defined by the voltage setting (related to the

Ohm's law V=IxR

Tissue impedance (R) Cathode (negative electrode)

46

Figure 4.1 Simple equivalent circuit of a neurostimulator.

BASIC PRINCIPLES OF NEUROSTIMULATION

Figure 4.2 Schematic diagrams of neurostimulators in monopolar and bipolar configurations.

Leads

Neurostimulator

Anode +V

Electrodes Cathode – V Anode, + V

Cathode, – V

Bipolar stimulation

Monopolar stimulation

Pulse width (ms)

Stimulus pulse

Amplitude (V)

Figure 4.3 A graphical representation of an asymmetrical Lilly-type stimulation waveform applied to two electrodes with the most distal electrode programmed negative.

Charge balance

compensation

pulse

Interpulse interval = 1 / Pulse frequency

+

–

–

+

Electrode polarity

current according to Ohm’s law). The Medtronic Model 7424, for example, can be programmed with amplitudes up to 10.5 volts (Table 4.1). Typical amplitude settings will be 5 volts or less but depend on the therapeutic application. The pulse width or duration of the stimulus pulse is the time that the switch con-

necting the power supply to the tissue is closed. In other words, the time the voltage is applied to the electrodes. The stimulation frequency is defined as the number of times the stimulus pulse is applied each second. Stimulation fre­ quency settings differ for the different applica­ tions of stimulation (see below) but span the

47

BRAIN STIMULATION AND EPILEPSY

Programmable parameters

Values

Pulse amplitude (peak voltage) Rate (pps)

0–10.5 volts, programmable 2,5,10,15,20,30,33,35,40,45,50,55,60,65,70,75,80,85 90,95,100,130,135,145,160,170,185 60, 90, 120, 150, 180, 210, 270, 330, 400, 450 0.1 s to 24 h 0.1 s to 24 h 15 s to 24 h 15 s to 24 h Allows selection of 15, 20, 25, or 30 s, ramp increasing gradually from zero to the selected amplitude 15, 30, 45, 60, or 75 min stimulation periods 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, or 4.0

Pulse width (�s) Cycle on time Cycle off time Cycle on time w/SoftStart Cycle off time w/SoftStart Ramp Dose time Dose lockout time (h)

Table 4.1 Parameter options for the Medtronic Model 7424 neurostimulator.

range from 2 pulses per second (pps) to 250 pps for the various commonly used clinical applications Most neurostimulators have programmable clock capabilities that allow cycling of the stimulation therapy. Neuromodulation therapies with a carryover effect can then be cycled on and off (e.g. 15 minutes out of every hour). The more sophisticated neurostimulator systems include the ability to electronically select electrode combinations to be used for stimulation after the device has been implanted. The Medtronic Model 7426 Soletra® neurostimulator is used to stimulate nervous tissue deep in the brain to treat tremor and other motor symptoms of Parkinson’s disease. The Model 7425 Itrel® 3 is used to stimulate the spinal column to treat chronic pain. These neurostimulators provide one channel of stimulation output. A stimula­ tion output channel is defined as a single source of current/voltage stimulation pulses with a common set of parameters (e.g. the same pulse width, frequency and amplitude). While there is only one channel of stimulation, these neurostimulators have the capability to

48

independently select four independent elec­ trodes to be on or off. Those electrodes selected to be ‘on’ may be programmed to be positive (an anode) or negative (a cathode). It is also possible to program a portion of the surface of the electronics package, referred to as the ‘case’, to be an electrode. This feature is used to employ monopolar stimulation as described above. When the case is pro­ grammed to be an electrode it is restricted to be a positive electrode or anode. The Model 7427 Synergy™ stimulator is a new neurostimulator that differs from previ­ ous models by having two channels of stimu­ lation. The amplitude and pulse width may be selected independently for each channel. However, the stimulus frequency must be the same for both. Each channel is capable of connecting to four separate electrodes. Alternatively, eight electrodes may be con­ nected to one single channel. The implanted neurostimulator is pro­ grammed using a clinician programmer. The programmer communicates with the implanted electronics using a pulse width modulated code with an RF carrier frequency. The coded

STIMULATION OF NERVOUS TISSUE: SAFETY ISSUES

instructions are sent to the implanted device and the values of the various parameters can be determined by interrogating the neurostimula­ tor’s memory. Some models of neurostimulator include ‘patient programmers’ which can also communicate with the implanted neurostimula­ tor to adjust parameters within a range of values prescribed by the physician. This gives the patient an opportunity to make certain adjustments to the stimulation parameters. The patient programmer can also be used to turn the device on and off. Alternatively, some models of neurostimulator are turned on and off by passing a magnet over the skin above the neurostimulator to toggle a magnetic reed switch in the neurostimulator. Fully implantable neurostimulators, (i.e. those including an internal battery), will need to be replaced when the energy of the battery has been consumed. The longevity of the neuro­ stimulator is very dependent on the stimula­ tion parameters, since the energy delivered to the electrodes is a major portion of the con­ sumed energy. From Ohm’s law, the amount of charge consumed by the stimulus pulse for a particular voltage setting will depend on the resistance of the electrode. A larger resistance will result in a lower current drain and a longer battery life. Programming more elec­ trodes into the circuit will reduce the resis­ tance resulting in greater current usage and a shorter lifespan. In addition, certain principles should be kept in mind when programming stimulation parameters in order to obtain optimal battery life. Stimulating at wider pulse widths, higher amplitudes, and higher pulse frequencies will all contribute to shorter battery life. In general, the biophysics of extracellular electrical stimulation of nervous tissue is a complex subject and is discussed elsewhere in this book. The reader can refer to review articles by Ranck,1 or Durand,2 and the book

by Agnew and McCreery3 for more informa­ tion. However, there are several general rules or guidelines that might be useful to the clini­ cian. The first pertains to the order of recruitment of nervous tissue. When consid­ ering which nerve cells will be activated the clinician should remember: (1) nerve cells further away from the electrode will be less likely to be stimulated; (2) axons will be stimulated at lower stimulation amplitudes than nerve cell bodies (3) larger axons will respond to lower stimulus amplitudes than will smaller axons; and (4) axons with branching processes will be more easily activ­ ated than those without branching. A second key point is the orientation of nerve cells relative to the voltage field. The important parameter of the voltage determining whether a nerve cell is stimulated is the second spatial derivative of voltage along the axis of the axon. The value of the second derivative falls off rapidly with distance from the surface of the electrode. Even at maximum amplitudes there will be little effect on nervous tissue beyond 5 mm from the surface of the electrode. Nerve cell axons that are oriented in the direction of the voltage gradient will more likely be activated while axons lying along an isopotential line may not be activated. Finally, the nerve cells near the cathode (negative) will be more easily activated than those near the anode (positive). This is the reason the ‘case’ of the neurostimulator is made positive when using monopolar stimulation and the electrodes in the nervous tissue are made negative.

Stimulation of nervous tissue: safety issues Early efforts to use electrical energy to activate nervous tissue simply connected a

49

BRAIN STIMULATION AND EPILEPSY

voltage source to the tissue, such as that shown in Figure 4.1, for a brief period of time. The pulse of direct current flowed into the tissue and resulted in a voltage that activated it, but had little effect if only performed a few times. Indeed, in the 1950s Dr Lilly determined that the repeated expo­ sure of tissue to direct current could have a deleterious effect. 4 Instead, he proposed using a stimulus pulse that had two phases of current flow resulting in a net charge flow of zero. 5 A version of this waveform is shown in Figure 4.4. and charge-balanced stimulation pulses have now become the standard method of delivering stimulation pulses to excitable tissue. There are several versions of a chargebalanced waveform, some having symmetrical phases and others having asymmetrical phases. The key feature is that the charge flowing during the first phase is equal in mag­ nitude but opposite in direction to the charge flowing during the second phase so that the net charge transferred after the occurrence of each stimulus pulse is zero. In practice, the two phases of the stimulus pulse may not be perfectly balanced which results in a small amount of net charge transferred with each stimulus pulse. This charge is measured in units of coulombs.

Stimulus pulse

Compensation pulse

Figure 4.4 An asymmetrical charge-balanced waveform.

50

Even with the use of Lilly-type stimulation pulses, chronic electrical stimulation of nervous tissue can reportedly cause damage under some circumstances.6,7 Research con­ tinues to elucidate the reasons for this tissue injury. Clinicians and researchers have estab­ lished safe levels for stimulating nervous tissue using electrical energy and Agnew and McCreery7 reviewed the corresponding litera­ ture. This review has established a working definition of the boundaries for the electrical stimulation parameters that may be used to chronically stimulate nervous tissue without concern for cell damage. The stimulation parameters used in the studies Agnew and McCreery reviewed reported stimulation amplitude in different ways. Consequently, the authors considered both the charge per phase of the stimulus pulse and the charge density per phase when recording the level of stimulation. As a result of this survey the authors established a boundary on the loglog plot of charge density per phase versus charge per phase that seems to divide stimu­ lation parameters reported to cause damage from those that do not. This boundary is used as a working definition of a safety threshold for stimulating nervous tissue. Intersection with that boundary is deter­ mined by the surface area of the electrode being used, which in turn determines the safe parameter levels. The charge density per phase of a stimulus pulse is given in units of coulombs per square centimeter. It is determined by dividing the charge delivered during the stimulating phase of the stimulating pulse by the surface area of the stimulating electrode. The charge per phase is, in turn, determined by dividing the voltage amplitude by the resistance to obtain the current. The current, which is in units of amperes or coulombs of charge per second, can be multiplied by the number of seconds

DEEP BRAIN STIMULATION

the stimulus pulse is applied to obtain the charge per phase. Charge density = [(Voltage/Resistance) × Pulse width]/Surface area The length of time the stimulus is applied is simply the programmed value of the pulse width. Product manuals for the neurostimula­ tor devices provide guidelines to assist the clinician to ensure that stimulation parameters are not set so high as to pose a risk to the nervous tissue being stimulated.

Spinal cord stimulation A neurostimulator used primarily to stimulate the spinal cord is the Itrel® 3. However, a newer model stimulator, the Synergy® has

recently been added to the list of neurostimu­ lator options. The Synergy® differs from the Itrel® 3 in that the user can program two ‘channels’ or programs of stimulation. (See Figure 4.5.) These stimulation programs may include different values for pulse width and amplitude settings.

Deep brain stimulation The term ‘deep brain stimulation’ (DBS) dates back to the 1970s. It is generally used to refer to electrical stimulation therapies that require placement of the stimulating lead into the brain using stereotaxic techniques. The orig­ inal therapy that led to the development of DBS technology was electrical stimulation of the sensory thalamus to treat chronic pain.12 More recently, the techniques have been Figure 4.5 Neurostimulator and lead systems used for spinal cord stimulation to treat chronic pain. The Itrel 3® and Synergy® are neurostimulators. The Synergy® EZ is a patient programmer. Percutaneous leads (top) and surgical leads (bottom) are also shown (Reproduced with permission from Medtronic, Inc.).

51

BRAIN STIMULATION AND EPILEPSY

employed to stimulate the ventral intermediate thalamic nucleus of the thalamus to treat tremor,13 the subthalamic nucleus,14 and the internal portion of the globus pallidus15 to treat the motor symptoms of Parkinson’s disease. Other authors in this book describe the experimental use of DBS to treat epilepsy by stimulating in the centre median or ante­ rior nucleus of the thalamus or the subthala­ mic nucleus. In contrast to stimulating targets deep within the brain, electrodes could be placed on the surface of the cortex either over the dura or just under it. In this case, the elec­ trode is more likely to appear similar to the surgical leads seen at the bottom of Figure 4.5. The neurostimulators used for DBS are the Model 7426 Soletra® stimulator or the Model 7428 Kinetra®, which at the time of writing is not yet approved for sale in the US but is available in other countries. The Kinetra® is a dual-channel stimulator as described above. There are two options for leads (see Figure 4.6). The Model 3387 lead has four electrodes each 1.5 mm long separated by

1.5 mm thus spanning a linear distance of 10.5 mm. The Model 3389 lead has the same four electrodes separated by only 0.5 mm spanning a total of 7.5 mm. In both cases the leads are 1.27 mm in diameter. There are Introducer Kits that facilitate stereotaxic place­ ment of the leads using the more popular stereotaxic frames. The leads are connected to an extension wire, which is tunneled under the skin down to a subclavicular pocket where the neurostimulator is placed (see Figure 4.7).

Conclusion Neurostimulation technology can be used by the clinician to artificially depolarize or hyperpolarize nervous tissue. It is based on the fundamental electrical properties of the nervous system. Knowledge of the basic prin­ ciples enables the clinician to achieve the desired interactions with specific circuits within the quintessential neural network to compensate for dysfunction. Figure 4.6 Deep brain stimulation leads. Model 3387 (top) and Model 3389 have different electrode separation. (Reproduced with permission from Medtronic, Inc.)

52

SUMMARY

Figure 4.7 Unilateral deep brain stimulation to treat tremor. (Reproduced with permission from Medtronic, Inc.)

Summary The explosion in understanding of how the central nervous system (CNS) works affords new opportunities for interacting with the CNS to compensate for dysfunction due to disease or injury. ‘Restorative neuroscience’ is a term that describes methods to accom­ plish that interaction based on principles of nerve cell physiology. One approach to restorative neuroscience is the use of electri­ cal stimulation. The treatment of epilepsy is

an application of neurostimulation being currently investigated. This chapter provided a detailed description of neurostimulation technology, including neurostimulators and leads, systems used to program neurostimulators, and characteristics of the stimulation parameters. The reader should gain an understanding of the basic biophysical and physiological principles that are the underpinning of neurostimulation systems and a familiarity with the terminology associated with this therapeutic approach.

53

BRAIN STIMULATION AND EPILEPSY

References 1. Ranck, JB Jr. Which elements are excited in elec­ trical stimulation of mammalian central nervous system: A review. Brain Res 1975;98:417. 2. Durand DM. Electrical stimulation of excitable tissue. In: Bronzino JD (ed) The biomedical engineering handbook. Boca Raton, FL: CRC Press, 1995, 229. 3. Agnew WF, McCreery DB. Neural prostheses fundamental studies. Englewood Cliffs, NJ: Prentice Hall, 1990. 4. Lilly JC, Austin GM, Chambers WW. Threshold movements produced by excitation of cerebral cortex and efferent fibers with some parametric regions of rectangular current pulses (cats and monkeys). J Neurophysol 1952;15:319–41. 5. Lilly JC, Hughes, JR, Ellsworth CA Jr, Galkin TW. Brief, noninjurious electric waveform for stimulation of the brain. Science 1955;121:468–9. 6. Pudenz RH, Bullara LA, Dru D, Talalla A. Electrical stimulation of the brain: II. Effects on the blood-brain barrier. Surg Neurol 1975;4:265. 7. Agnew WF, McCreery DB, Yuen TGH, Bullara LA. Effects of prolonged electrical stimulation of the central nervous system. In: Agnew WF, McCreery DB (eds) Neural prostheses fundamen­ tal studies. Englewood Cliffs, NJ: Prentice Hall, 1990, 226.

54

8. Mortimer JT, Shealy CN, Wheeler C. Experimental nondestructive electrical stimulation of the brain and spinal cord. J Neurosurg 1970;32:553. 9. Shealy CN, Mortimer JT, Reswick JB. Electrical inhibition of pain by stimulation of the dorsal columns. Anesth Analg 1967;46:489. 10. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150:971. 11. North RB, Fowler K, Nigrin DJ, Szymanski, R. Patient-interactive, computer-controlled neurological stimulation system: clinical efficacy in spinal cord stimulator adjustment. J Neurosurg 1992;76:967. 12. Hosobuchi Y. Subcortical electrical stimulation for control of intractable pain in humans. J Neurosurg 1986;64:543. 13. Benabid AL, Pollak P, Gervason C, et al. Longterm suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991;337:391. 14. Limousin P, Pollak P, Benazzouz A, et al. Effect on Parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 1995; 345:91. 15. Kumar R, Lozano AM, Montgomery E, Lang AE. Pallidotomy and deep brain stimulation of the pallidum and subthalamic nucleus in advanced Parkinson’s disease. Mov Disord 1998;13:73–82.

5 Electrically excitable nerve elements: excitation sites in peripheral and central stimulation Warren M Grill

Introduction Electrical stimulation of the nervous system has been employed extensively as an experi­ mental treatment for epilepsy, as well as a host of other neurological disorders. The effects of electrical stimulation on nervous tissue have been known for over a century, but the theory to explain the effects of extracellular stimula­ tion on neural tissue was only derived after the development of classical electromagnetic field theory and the development of cable models of nerve cells. The fundamental under­ standing provided by quantitative analysis is required for rational design and interpretation of therapies employing electrical stimulation. A nerve cell or a nerve fiber can be artificially stimulated (and a propagating action potential generated) by depolarization of the cell’s (fiber’s) membrane. The propagating action potential reaches the terminal of the neuron leading to release of neurotransmitter that can impact the postsynaptic cell. Depolarization can be achieved by a direct outward flowing current injected across the membrane or by generation of an extracellular potential distrib­ ution that results in an outward flowing transmembrane current. Electrical current pulses delivered through extracellular electrodes located in the vicinity of the nerve cell bodies or fibers can be used to create extracellular poten­

tials in the tissue that in turn may lead to the generation of an action potential. Alternately, extracellular potentials may modulate or block ongoing neuronal firing. The distribution of extracellular potentials is dependent on the electrode geometry, the electrical properties of the extracellular tissue, and the stimulation amplitude, and the effect of the potentials on neurons is dependent on the nerve cell type, its size and geometry, as well as the temporal char­ acteristics of the stimulus. The objective of this chapter is to present the biophysical basis for electrical stimulation of neurons in the peripheral and central nervous systems. The focus is on using funda­ mental understanding of both the electric field and its effects on neurons to determine the site of neuronal excitation or modulation in the peripheral nervous system, where electrodes are placed around bundles of myelinated nerve fibers, and in the central nervous system where electrodes are placed among heterogeneous populations of neuronal elements including cells, axons, dendrites.

Modeling of neuronal stimulation Computational modeling provides a powerful tool to study extracellular excitation of central

55

ELECTRICALLY EXCITABLE NERVE ELEMENTS

nervous system (CNS) neurons. The volume of tissue stimulated, both for fibers and cells, and how this changes with electrode geometry, stimulus parameters, and the geometry of the neuronal elements is quite challenging to determine experimentally. Using a computer model enables these parameters to be exam­ ined under controlled conditions, and enables determination of the effects of stimulation on all the different neural elements around the electrode simultaneously. Further, welldesigned modeling studies enable generation of experimentally testable hypotheses on the effects of stimulation conditions on the pattern and selectivity of neuronal stimulation within the nervous system. However, the strengths of modeling are tempered by the necessary simplifications made in any reason­ able model, and models should be coupled as closely as possible to experimental work. The utility of modeling in analysing neural stimulation has been demonstrated by previ­ ous field-neuron models of cochlear stimula­ tion which were able to replicate experimental activation patterns and document the effects of changes in electrode geometry and stimulus parameters.1–3 Similarly, integrated fieldneuron models of epidural spinal cord stimu­ lation have been used to explain clinical pat­ terns of paresthesias,4–7 and used to design novel electrode geometries for selective stimu­ lation of targeted neural elements.8–9 These examples demonstrate the utility of computerbased modeling in understanding and control­ ling neural elements activated by electrical stimulation. Computational modeling of the effects of extracellular stimulation on neurons involves a two-step approach. The first step is to calculate the electric potentials generated in the tissue by passage of current through the electrode. The second step is to determine the effect(s) of those potentials on the surrounding neurons.

56

Electrical potentials generated in neuronal tissue Passage of current through neuronal tissue generates potentials in the tissue (recall Ohm’s law: V = I × R). The pattern and magnitude of the potentials are dependent on the electrode geometry. For example, the potential gener­ ated by a monopolar point source can be determined analytically using the relationship: Ve(r) =

I 4

r

where I is the stimulating current, is the con­ ductivity of the tissue medium, and r is the electrode to node distance (Figure 5.1). In con­ trast, the potentials generated by a cylindrical electrode contact, as used in a deep brain stim­ ulating lead, fall off much more slowly in space than those of the monopolar point source. The extracellular potentials are also dependent on the electrical properties of the tissue. The white matter of the CNS and peripheral nerve tissue is anisotropic with a higher conductivity parallel to the nerve fibers (~ 0.01 siemens/cm) than transverse to the nerve fibers (~ 0.001 siemens/cm), while grey matter is isotropic with conductivity between 0.0017 and 0.0033 siemens/cm. Spatial varia­ tions in the electrical properties of the tissue can cause changes in the patterns of activa­ tion.10 In most cases, to simulate accurately the extracellular potentials generated by extracellular stimulation requires a numerical solu­ tion using a discretized model (e.g. with the finite element method).

Electrical circuit cable models of neurons The second step in calculating the effects of extracellular stimulation is to determine the

PERIPHERAL NERVE STIMULATION

A

Figure 5.1 Computational modeling of the effects of extracellular stimulation on neurons involves a two-step approach. (A) The first step is to calculate the electric potentials generated in the tissue by passage of current through the electrode. Although a simple analytical solution exists for the potential generated by a point source electrode, it differs substantially from the potential generated by a deep brain stimulating electrode. (B) The second step is to determine the effect(s) of those potentials on the surrounding neurons. Cable models are constructed to represent neurons as electrical circuits.

1.2

Potential

1

Point source DBS electrode

0.8 0.6 0.4 0.2 0 0

2

4 6 Distance

8

gi

gj

gk

Ei

Ej

Ek

10

B

response of the neurons to the extracellular potentials. Cable models, which represent neurons as electrical circuits, are used to cal­ culate the effects of extracellular potentials on neurons. The process of developing neuronal cable models is illustrated in Figure 5.1B. Based upon the known geometry of a neuron obtained from morphological studies, a series of equivalent cylinders are used to represent the neuronal geometry. Each cylinder is in turn replaced by a ‘compartment’, representing the neuronal membrane, and a resistor represent­ ing the intracellular space. Thus, the model becomes a series of membrane compartments, connected by resistors. Each compartment is itself an electrical circuit that includes a capac­

Cm

itor representing the membrane capacitance of the lipid bilayer, resistors representing the ionic conductances of the transmembrane pro­ teins (ion channels), and batteries representing the differences in potential (Nernst Potential) arising from ionic concentration differences across the membrane. A differential equation describing the electrical potential in the cable as a function of position and time is then solved numerically.

Peripheral nerve stimulation Electrical stimulation of the vagus nerve with a surgically implanted circumneural cuff

57

ELECTRICALLY EXCITABLE NERVE ELEMENTS

bipolar cuff electrode is used for the treatment of intractable epilepsy.11 The vagus nerve is composed of a comparatively homogeneous population of myelinated nerve fibers with diameters between 2 �m and 12 �m, with the large majority of fibers having a diameter of 2–6 �m.12,13 Electrical stimulation of sufficient magnitude will lead to generation and bidirec­ tional propagation of action potentials from the electrode site.

old current, Ith, and the fiber diameter, D, is shown in Figure 5.2D and is given by:

Larger diameter nerve fibers have lower thresholds for excitation

The triphasic shape of the second difference of the extracellular potentials gives rise to a triphasic pattern of change in transmembrane potential. During stimulation with a cathodic current the nerve fibers are depolarized imme­ diately beneath the electrode (this is where action potential initiation will occur), and hyperpolarized in regions lateral to the elec­ trode. However, during stimulation with an anodic current, the portion of the nerve fiber nearest to the electrode is hyperpolarized by inward current flow. It is observed that typi­ cally the current thresholds for excitation with an anodal current are 5–8 times larger than the threshold current for direct cathodal stim­ ulation (Figure 5.3A). What explains this dif­ ference in thresholds? There are two ways that membrane hyperpolarization can lead to neuronal excitation: ‘virtual cathodes’ and anode ‘break’ excita­ tion (see below). Virtual cathodes arise from the triphasic form of the transmembrane potential generated by stimulation. While the part of the fiber immediately under the elec­ trode is hyperpolarized by inward current flow, this region of hyperpolarization is sur­ rounded by two flanking regions of depolar­ ization arising from outward current flow (Figure 5.3B). If the applied anodal current is sufficient to bring the depolarized portion of the membrane to threshold, then action

An example of the response of myelinated nerve fibers to extracellular stimulation is shown in Figure 5.2. The extracellular poten­ tials generated at each node of Ranvier of a 4 �m and an 8 �m diameter nerve fiber by a point source electrode were calculated. The maximum potential is the same in both fibers, but the change in potential between nodes is much larger in the 8 �m fiber, as the nodes of Ranvier are further apart in larger diameter nerve fibers (the distance between nodes of Ranvier is approximately equal to 100 times the fiber diameter). This is seen more clearly in Figure 5.2B, which illustrates the magnitude of the second difference of the extracellular potentials along each of the fibers. The second difference of the extracel­ lular potentials is the source term that drives membrane polarization. 14,15 The larger second difference for the 8 �m diameter nerve fiber gives rise to larger changes in transmembrane potential (Figure 5.2C). Thus, during extracellular stimulation, larger diameter nerve fibers have a lower threshold for excitation than smaller diameter nerve fibers, as a result of their larger internodal spacing. The relationship between the thresh­

58

Ith(D) = ID + a — √D where ID and a are constants.

Effects of stimulus polarity on threshold and excitation site

PERIPHERAL NERVE STIMULATION

C

Normalized potential

1

Normalized transmembrance potential

A 4 μm 8 μm

0.5

0 D

0.4 0.2

0.8 0.6 0.4 0.2 Depolarized 0 Hyperpolarized

–0.2

–12 200

–8

–4

0 4 Node#

8

12

180 Threshold current (μA)

Normalized second difference of the extracellular potential

B

1

0 –0.2 –0.4 –0.6 –0.8 –1

160 140 120 100 80

–1.2

60 –12

–8

–4

0 4 Node#

8

12

4

6

8 10 12 14 16 18 Nerve fiber diameter (μm)

20

Figure 5.2 Excitation of myelinated peripheral nerve fibers. (A) Normalized extracellular potentials at each node of Ranvier in 4 �m and 8 �m diameter nerve fibers from a point source electrode. (B) Magnitude of the second difference of the extracellular potentials which is the source term driving membrane polarization for the fibers as a function of the node number. The magnitudes of the second difference of the extracellular potentials were normalized to the peak value for the 8 �m fiber to illustrate that the source term is smaller in the smaller diameter nerve fiber. (C) Profile of transmembrane potential generated in the 4 �m and 8 �m nerve fibers. Again, the transmembrane potentials were normalized to the peak value in the 8 �m fiber to illustrate the difference between the two diameters. (D) Threshold current as a function of the nerve fiber diameter for excitation of nerve fibers lying 1 mm from a point source electrode in medium with conductivity of 0.0017 siemens/cm and pulses 0.1 ms in duration.

59

ELECTRICALLY EXCITABLE NERVE ELEMENTS

Percent activation (%)

A 100 80 60 40 20

cathodic stimuli

0

anodic stimuli 1

10

100

Stimulus amplitude (μA)

Transmembrane potential

B

Depolarized Hyperpolarized

–12

–8

–4

0

4

8

Figure 5.3 Effect of stimulus polarity on excitation of myelinated peripheral nerve fibers. (A) Input-output curves from a population model containing 50 axons randomly positioned around a point source stimulating electrode. The curves are the percentage of fibers activated as a function of the stimulation amplitude for 0.2 ms duration monophasic cathodic pulses and monophasic anodic pulses. (Modified from McIntyre and Grill, 2000.16) (B) Profile of transmembrane potential generated in a myelinated nerve fiber by an extracellular anodic electrode. The nerve fiber is hyperpolarized immediately under the electrode and depolarized at the flanking nodes by the virtual cathodes (arrows).

12

Node

potential initiation will take place at the virtual cathodes. Anode break excitation arises from the voltage-dependent properties of the sodium conductance. During membrane hyperpolar­ ization, the sodium channels are deinactivated. Following termination of the pulse and the release of hyperpolarization, the membrane potential recovers toward the rest potential. Due to the slow time constant of inactivation as compared to activation, the sodium channels remain in a de-inactivated state, while the level of activation recovers toward its resting value. This puts the mem­ brane is a hyperexcitable state, as compared to rest, and the influx of sodium during the

60

return of membrane potential toward rest can result in generation of an action potential. Since this excitation occurs at the termination of the current pulse, it is referred to as ‘break’ excitation. Because the time constant of inacti­ vation is quite long, anode break excitation generally requires long duration hyperpolariz­ ing pulses (≥0.5 ms).

Central nervous system stimulation During stimulation of peripheral nerves it is clear which neuronal elements are activated. However, the CNS contains a heterogeneous

CENTRAL NERVOUS SYSTEM STIMULATION

population of neuronal elements including local cells projecting locally around the electrode as well as those projecting away from the region of stimulation, axons passing by the electrode, and presynaptic terminals projecting onto neurons in the region of the electrode. Effects of stimulation can be mediated by activation of any or all of these elements and include both direct effects of stimulation on postsynaptic ele­ ments, as well as indirect effects mediated by electrical stimulation of presynaptic terminals that mediate the effects of stimulation via synaptic transmission. Two principal questions thus arise during stimulation of the CNS: what neuronal elements are activated by extracellular stimulation?, and how can targeted elements be stimulated selectively?

B

C

D

Percent activation (%)

100 A 80 60 40

20

0

100 80 60 40 20 0

1

Effect of polarity on CNS stimulation In the peripheral nervous system different stimulus polarities produced substantial changes in the threshold as well as changes in the site of action potential initiation. Similar, but more pronounced effects occur during CNS stimulation. Figure 5.4 shows the results of a computational study to determine which neuronal elements are activated by extracellu­ lar stimulation in the CNS.16 A population model was used to compare activation of local cells to activation of passing fibers with differ­ ent stimulation waveforms. These data show that the threshold for activation of passing fibers is less than the threshold for activation

activation of cells activation of fibers

10

100 1 10 Stimulus amplitude (mA)

100

Figure 5.4 Excitation of local cells and fibers of passage is dependent on the stimulus polarity. Input-output curves from a population model containing 50 local cells and 50 axons of passage randomly positioned around a point source stimulating electrode. The curves are the percentage of local cells and percentage of fibers of passage activated as a function of the stimulation amplitude using four different stimulus waveforms: (A) 0.2 ms duration monophasic cathodic pulses; (B) 0.2 ms duration monophasic anodic pulses; (C) asymmetrical biphasic pulse with an anodic phase 0.2 ms in duration followed by a cathodic phase 0.02 ms in duration; (D) asymmetrical biphasic pulse with a cathodic phase 1.0 ms in duration followed by an anodic phase 0.1 ms in duration. (Modified from McIntyre and Grill, 2000.16)

61

ELECTRICALLY EXCITABLE NERVE ELEMENTS

of local neurons when using cathodic pulses. However, when using anodic pulses, the threshold for activation of local cells is less than the threshold for activation of passing fibers. The basis for this effect can be under­ stood by comparing action potential initiation in local cells using cathodic and anodic stimuli.

Site of action potential initiation in central neurons Computation models were used to determine the site of action potential initiation during Cathodic stimulus

extracellular stimulation of CNS neurons.16,17 Figure 5.5 shows the response of a model neuron to extracellular stimulation with cathodic and anodic stimuli delivered through an electrode placed 1 mm above the cell body. In both cases, even though the electrode is positioned directly over the soma, action potential initiation occurred in the axon, a finding consistent with recent in vitro results from cortex.18,19 With 0.1 ms duration cathodic stimuli action potential initiation occurred at the second node of Ranvier from the cell body (arrow), and with 0.1 ms dura­ tion anodic stimuli action potential initiation

Anodic stimulus

20 mV 1 ms

62

Figure 5.5 Action potential initiation in CNS neurons by cathodic and anodic stimuli. Each trace shows transmembrane voltage as a function of time for different sections of the neuron. During threshold stimulation with an electrode positioned 1 mm over the cell body, action potential initiation occurs at a node of Ranvier of the axon. With cathodic stimuli (duration 0.1 ms) action potential initiation occurred at the second node of Ranvier from the cell body (arrow). With anodic stimuli (duration 0.1 ms) action potential initiation occurred in the third node of Ranvier from the cell body (arrow).

CENTRAL NERVOUS SYSTEM STIMULATION

occurred in the third node of Ranvier from the cell body (arrow). During the cathodic stimu­ lus pulse, the node of Ranvier where action potential initiation occurred was hyperpolar­ ized by the stimulus (arrowhead in Figure 5.5). Following termination of the stimulus, the cell body and dendritic tree discharged through the axon, leading to action potential initia­ tion.17 Thus, with cathodic stimuli action potential initiation occurred in a part of the neuron that was hyperpolarized by the stimu­ lus, and this indirect mode of activation increases the threshold for activation of local cells with cathodic stimuli. Conversely, with anodic stimuli, the site of action potential ini­ tiation was at the node that was most depolar­ ized by the stimulus (arrow in Figure 5.5). Note that this mode of excitation is identical to the ‘virtual cathode’ mechanism described for activation of myelinated nerve fibers with anodic stimuli. The difference in the mode of activation of local cells is the basis for the dif­ ference in threshold between cathodic and anodic stimuli. The finding that action potential initiation is in the axon has three important implications for CNS stimulation. First, since excitation occurs in the axon there is little difference in the extracellular chronaxie times for excita­ tion of local cells and excitation of passing axons.20 Therefore, chronaxie time is not a sensitive indicator of the neuronal element that is stimulated. Second, the axon may still fire even when the cell body is hyperpolarized, for example by inhibitory synaptic inputs.20 Therefore, extracellular unit recordings of cell body firing may not accurately reflect the output of the neuron. Finally, since action potential initiation occurs at some distance from the site of integration of synaptic inputs, the effects of co-activation of presynaptic fibers may be less than expected.21

Waveforms for selective stimulation of CNS neuronal elements Previous experimental evidence demonstrates that different neuronal elements have similar thresholds for extracellular stimulation and illustrates the need for design of methods that enable selective stimulation. In vitro measure­ ments in cortical brain slices indicate that cells and fibers have similar thresholds for activa­ tion.18,19 Similarly, in vivo measurements using microstimulation indicate that fibers and cells have similar thresholds for cathodic rectangu­ lar stimuli.22–24 Recent computational studies of the excitation of CNS neurons indicate that with conventional rectangular stimuli, axons of passage and local cells respond at similar thresholds.16,17,21 Also, the thresholds for gen­ erating direct and synaptic excitation of neurons in the spinal cord,22 red nucleus,25 and cortex26 were quite similar. Thus, with conventional stimulation techniques, the thresholds for activation of different neuronal elements are very close, and it is difficult to isolate stimulation of particular neurons. Stimulus waveforms can be designed explic­ itly to take advantage of the non-linear con­ ductance properties of neurons and thereby increase the selectivity between activation of different neuronal elements. Biphasic asym­ metrical stimulus waveforms capable of selec­ tively activating either local cells or axonal elements consist of a long duration low ampli­ tude pre-pulse followed by a short duration high amplitude stimulation phase. The long duration pre-pulse phase of the stimulus is designed to create a sub-threshold depolariz­ ing pre-pulse in the non-target neurons and a hyperpolarizing pre-pulse in the target neurons.16 Recall that during cathodic stimu­ lation, the site of excitation in axons is the

63

ELECTRICALLY EXCITABLE NERVE ELEMENTS

depolarized node of Ranvier, while the site of excitation in local cells is a node of Ranvier that is hyperpolarized by the stimulus. Conversely, with anodic stimuli, the site of excitation in local cells is a depolarized node of Ranvier, and that the most polarized node of passing axons is hyperpolarized by the stimulus. Thus, the same polarity pre-pulse will produce opposite polarization at the sites of excitation in local cells and passing axons. The effect of this subthreshold polarization is to decrease the excitability of the non-target population and increase the excitability of the target population via alterations in the degree of sodium channel inactivation.27 Therefore, when the stimulating phase of the waveform is applied, the neuronal population targeted for stimulation will be activated with greater selectivity (Figure 5.4). Asymmetrical chargebalanced biphasic cathodic phase first stimu­ lus waveforms result in selective activation of local cells, while asymmetrical chargebalanced biphasic anodic phase first stimulus waveforms result in selective activation of fibers of passage. Further, charge-balancing is achieved as required to reduce the probability of tissue damage and electrode corrosion.

Discussion Electrical stimulation of the peripheral nervous system (PNS) is used clinically to treat epilepsy, and electrical stimulation of the central nervous system (CNS) is under investi­ gation to treat this condition. Successful appli­ cation of electrical stimulation to treat nervous system disorders as well as interpreta­ tion of the results of stimulation requires understanding of the cellular level effects of stimulation. Quantitative models provide a means to understand the response of neurons to extracellular stimulation. Further, accurate

64

quantitative models provide powerful design tools that can be used to engineer stimuli that produce a desired response. The results presented in this chapter high­ light differences in the effects of stimulus polarity and sites of excitation in peripheral and central stimulation. During stimulation of peripheral nerves the threshold difference between cathodic and anodic stimuli arises due to a shift in the site of excitation from the most polarized portion of the axon to the flanking regions polarized by ‘virtual elec­ trodes’. During CNS stimulation action poten­ tials are initiated in the axons of local cells, even for electrodes positioned over the cell body. The threshold difference between cathodic and anodic stimuli arises because of differences in the mode of activation. Anodic stimuli cause depolarization of the axon and excitation via a ‘virtual cathode’, as occurs during PNS stimulation. Cathodic stimuli cause hyperpolarization at the site of excita­ tion and the action potential is initiated during repolarization. This difference in excitation mechanism was exploited to design novel asymmetrical biphasic stimulus pulses that increased the selectivity between excitation of local cells and axons of passage. In this chapter the focus was on the direct effects of stimulation within the central nervous system. However, several other factors should be considered when designing therapies or interpreting results of CNS stimu­ lation. First, the threshold for activation of presynaptic terminals projecting into the region of stimulation is often less than or equal to the threshold for direct excitation of local cells.21,22,25,26 Thus, indirect effects medi­ ated by synaptic transmission may alter the direct effects of stimulation on the post­ synaptic cell.21 Further, antidromic activation of axon terminals can lead to widespread acti­ vation or inhibition of targets distant from the

REFERENCES

site of stimulation through axon collaterals. Second, synapses may have activity-dependent transmission properties (i.e. synaptic depres­ sion) that influence the downstream effects of local stimulation.28,29 Finally, stimulation may cause activity-dependent changes in the local ionic milieu that can modulate neuronal excitability.30 These ‘indirect’ effects of stimu­ lation must be considered when electrodes are placed within the heterogeneous environment of the CNS.

Acknowledgments Preparation of this chapter was supported by National Institutes of Health Grant R01 NS­ 40894. The author acknowledges the collabo­ rative efforts of Dr Cameron McIntyre in modeling the effects of extracellular stimula­ tion on CNS neurons, and thanks are due to Ms Amanda Adams for assistance in prepar­ ing some of the figures.

References 1. Finley CC, Wilson BS, White MW. Models of neural responsiveness to electrical stimulation. In: Miller JM, Spelman FA (eds) Cochlear implants: models of the electrically stimulated ear. New York, Springer, 1990, 55–96. 2. Frijns JHM, de Snoo SL, ten Kate JH. Spatial selectivity in a rotationally symmetric model of the electrically stimulated cochlea. Hearing Res 1996;95:33–48. 3. Frijns JHM, de Snoo SL, Schoonhoven R. Potential distributions and neural excitation pat­ terns in a rotationally symmetric model of the electrically stimulated cochlea. Hearing Res 1995;87:170–86. 4. Coburn B. Electrical stimulation of the spinal cord: two-dimensional finite element analysis with particular reference to epidural electrodes. Med Biol Eng Comput 1980;18:573–84. 5. Coburn B. A theoretical study of epidural electri­ cal stimulation of the spinal cord: II. Effects on

long myelinated fibers. IEEE Trans Biomed Eng 1985;32:978–86. 6. Sin WK, Coburn B. Electrical stimulation of the spinal cord: a further analysis relating to anatom­ ical factors and tissue properties. Med Biol Eng Comput 1983;21:264–9. 7. Struijk JJ, Holsheimer J, van Veen BK, Boom HBK. Epidural spinal cord stimulation: calcula­ tion of field potentials with special reference to dorsal column nerve fibers. IEEE Trans Biomed Eng 1991;38:104–10. 8. Holsheimer J, Nuttin B, King GW et al. Clinical evaluation of paresthesia steering with a new system for spinal cord stimulation. Neurosurgery 1998;42:541–7. 9. Struijk JJ, Holsheimer J, Spincemaille GH et al. Theoretical performance and clinical evaluation of transverse tripolar spinal cord stimulation. IEEE Trans Rehab Eng 1998;6:277–85. 10. Grill WM. Modeling the effects of electric fields on nerve fibers: influence of tissue electrical properties. IEEE Trans Biomed Eng 1999;46: 918–28. 11. The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for the treatment of medically intractable seizures. Neurology 1995;45:224–30. 12. Guo Y-P, McLeod JG, Baverstock J. Pathological changes in the vagus nerve in diabetes and chronic alcoholism. J Neurol Neurosurg Psychiatry 1987;50:1449–53. 13. Al-Kureischi K. Verlauf und Nervenfaserarten des Truncus Vagalis des Menschen. Acta Anat 1979; 103:252–8. 14. Rattay F. Analysis of models for extracellular fiber stimulation. IEEE Trans Biomed Eng 1989;36:676–82. 15. Warman EN, Grill WM, Durand D. Modeling the effects of electric fields on nerve fibers: deter­ mination of excitation thresholds. IEEE Trans Biomed Eng 1992;39:1244–54. 16. McIntyre CC, Grill WM. Selective microstimula­ tion of central nervous system neurons. Ann Biomed Eng 2000;28:219–33. 17. McIntyre CC, Grill WM. Excitation of central nervous system neurons by nonuniform electric fields. Biophys J 1999;76:878–88. 18. Nowak LG, Bullier J. Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter: I. Evidence from chronaxie measure­ ments. Exp Brain Res 1998;118:477–88.

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19. Nowak LG, Bullier J. Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter: II. Evidence from selective inactiva­ tion of cell bodies and axon initial segments. Exp Brain Res 1998;118:489–500. 20. Grill WM, McIntyre CC. Extracellular excitation of central neurons: implications for the mecha­ nisms of deep brain stimulation. Thalamus and Related Systems 2001;1:269–77. 21. McIntyre CC, Grill WM. Extracellular stimula­ tion of central neurons: influence of stimulus waveform and frequency on neuronal output. J Neurophysiol 2002;88:1592–1604. 22. Gustafsson B, Jankowska E. Direct and indirect activation of nerve cells by electrical pulses applied extracellularly. J Physiol 1976;258:33–61. 23. Ranck JB. Which elements are excited in electri­ cal stimulation of mammalian central nervous system: a review. Brain Res 1975;98:417–40. 24. Roberts WJ, Smith DO. Analysis of threshold cur­ rents during microstimulation of fibers in the spinal cord. Acta Physiol Scand 1973;89:384–94.

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25. Baldissera F, Lundberg A, Udo M. Stimulation of pre- and postsynaptic elements in the red nucleus. Exp Brain Res 1972;15:151–67. 26. Jankowska E, Padel Y, Tanaka R. The mode of activation of pyramidal tract cells by intracortical stimuli. J Physiol 1975;249:617–36. 27. Grill WM, Mortimer JT. Stimulus waveforms for selective neural stimulation. IEEE Eng Med Biol 1995;14:375–85. 28. Castro-Alamancos MA, Connors BW. Thalamo­ cortical synapses. Prog Neurobiol 1997;51: 581–606. 29. Urbano FJ, Leznik E, Llinas RR. Cortical activa­ tion patterns evoked by afferent axons stimuli at different frequencies: an in vitro voltage-sensitive dye imaging study. Thalamus and Related Systems 2002;1:371–8. 30. Bikson M, Lian J, Hahn PJ et al. Suppression of epileptiform activity by high frequency sinusoidal fields in rat hippocampal slices. J Physiol 2001;531:181–91.

6 Control of neuronal activity by electrical fields: in vitro models of epilepsy Dominique M Durand and Marom Bikson

Introduction The causes of epilepsy involve a large and complex array of physiological processes. The genetic component of epilepsy for example has recently been recognized; sodium, potassium, and calcium channels have been found to be associated with certain types of epilepsy. 1,2 Head trauma, infection, stroke, hypoxia, dysplasia and various chemical imbalances in the brain can also cause epilepsy. 3 The large number of clinical manifestation has led to the develop­ ment of many in vivo and in vitro animal models of epilepsy, each reproducing some aspect of the disease. These models have been used extensively to study the mech­ anisms of epilepsy and to screen anticon­ vulsant treatments.3,4 Several of these models rely on drugs that produce imbalance between excitation and inhibition by either blocking inhibitory synaptic pathways (e.g. penicillin, picrotoxin and bicuculline, all GABA blockers) or enhancing excitatory synaptic function (e.g. kainic acid and NMDA). Other convulsive drugs increase neuronal excitability by directly effecting intrinsic membrane proper­ ties (e.g. veratridine, 4-aminopyridine). Manipulation of extracellular ionic activities (e.g. high potassium and low calcium) can

also lead to spontaneous epileptiform activity in vitro, by increasing neuronal excitability and/or synchronization mechanisms. The mechanisms of in-vitro epileptogenesis have been studied extensively and are reviewed elsewhere.4,5 Twenty-five per cent of epilepsy patients do not respond to anticonvulsant drugs or suffer unacceptable side effects as a result of medication.3 In some cases (about 100 000 patients/year in the US), surgical resection can eliminate seizures provided that the focus can be clearly identified and the resection will not produce serious behavioral and psychological impairments. Electrical stimu­ lation has recently become available as an alternative to surgery. High frequency stimu­ lation of the vagus nerve and certain deep brain structures can reduce seizure frequency. However, the mechanisms of action have not been elucidated. Basic studies examining the effect of electrical stimulation on nervous system function have revealed that some stimulation paradigms have anticonvulsant properties.6,7 This is somewhat paradoxical since electrical stimulation of nervous tissue has tradition­ ally been used to excite axons and neurons for the purpose of studying basic mechanisms or to replace a function lost following injury.8,9 The in vitro brain slice preparation

67

CONTROL OF NEURONAL ACTIVITY BY ELECTRICAL FIELDS

is a powerful tool for developing and analysing electrical stimulation protocols because of: (1) readily identifiable structure and targets; (2) precise control of stimulus location and orientation (see below); (3) access to identifiable excitatory neurons, inhibitory interneurons and glia for intra­ cellular recording; (4) use of ion-selective and optical imaging approaches; and (5) rapid screening of various stimulation paradigms. The purpose of this chapter is to review the results of several groups that have demonstrated and analysed the suppression of epileptic activity in vitro with electrical fields (using several classes of stimulation protocols). In addition, we review the theoretical background on electrical field neuronal interaction as it relates to the sup­ pression of neuronal activity. The effect of long-duration low amplitude pulse, shortduration high amplitude single pulse, chaos control, and periodic low or high frequency electrical stimulation on the suppression of neural activity is reviewed. The mechanisms and clinical implementation of these methods of suppression are discussed.

Electrical fields and current generated by electrical stimulation The electrodes used for in vitro suppression of abnormal neuronal activity generate either ‘localized’ or ‘uniform’ fields. 7 For localized fields, a constant current or constant voltage source is connected to a small tip monopolar or bipolar electrodes (Figure 6.1). Uniform fields are generated by placing a section of brain tissue to be stimu­ lated between two large parallel electrodes (called ‘field electrodes’) through which a

68

known current is passed (Figure 6.2). The relationship between the electrical field and current is simple for homogenous tissue (see below) but can be quite complex when the conductivity of the tissue is a function of direction or location. The current density, voltage and electrical field distributions can be obtained from the quasi-static formula­ tion of the Maxwell equations.10,11

Localized fields (homogenous tissue) Assuming a monopolar point source elec­ trode generating a current (I) located at a distance (r) from the recording point, the voltage (V), referenced to a distal electrode is given by: V=

1 4

I r

(1)

where is the conductivity of the tissue, assumed to be homogenous. The electrical field (E) and the current density (J) generated at any point in a homo­ geneous medium are given by: E=

1 4

I r2

ur

J = Eur

(2) (3)

where ur is a unit radial vector. Therefore, the electrical field decays as 1/r2 compared to 1/r for the voltage.

Uniform fields (homogenous tissue) For uniform fields, a voltage source V0 is located between two large electrodes sepa­

ELECTRICAL FIELDS AND EXCITABLE TISSUE

A

Figure 6.1 (A) Membrane polarization by a localized electrode. The electrode is localized in the somatic layer and generating a positive current (anode). The current enters the cell in the Hyperpolarization somatic region thereby producing hyperpolarization and leaves the cell in the dendrite causing depolarization. Cathode Since most of the sodium channels are located in the somatic region, the cell is Depolarization moved away from threshold, and the firing of the cell is suppressed. (B) The polarity is reversed and the cell is moved closer to threshold.

B

Depolarization

Anode

Hyperpolarization

Out

Out +

–

–

+

In

In

rated by a distance d. The voltage (at distance x from the anode) and electrical field is given by: V=

V0 x d

V E= 0 d

(4)

(5)

Note that for uniform fields: (1) there is zero field in the direction parallel to the stimulating electrodes; and (2) the amplitude of the electric field (between the stimulating electrodes) is not a function of position (x). Voltages generated in non-homogeneous

media can also be calculated using the theory of images,11,12 or using numerical approxima­ tions such as boundary element of finite element methods.13

Electrical fields and excitable tissue When electrical fields and currents are gener­ ated in the vicinity of the neurons and axons, the current lines generated by the sources in the extracellular space will enter and exit the neural membrane generating passive sinks and sources, respectively. As the current leaves the membrane, the membrane capacitance is

69

CONTROL OF NEURONAL ACTIVITY BY ELECTRICAL FIELDS

A Current generator

+ Amplification e

od

ctr

le ee

–

ir

lw

C Ag

–

Ag

ells

1c

CA s

ell

cc

Re

w

flo d

iel

Ef

B

C Anode

Cathode

Depolarization

E

Hyperpolarization

E

Depolarization Hyperpolarization

Anode

70

Cathode

Figure 6.2 Membrane polarization with a uniform field. The current flow generated by a uniform electrode is different than that generated in the monopolar case (see Figure 6.1). (A) Uniform electrical (E) fields are generated using two wire electrodes located on either side of the neural tissue (hippocampal slice). (B) A cathode is located close to the basilar dendrites and the anode close to the apical dendrites. Current enters the apical dendrites generating membrane hyperpolarization and leaves the cell in the somatic and basilar region generating membrane depolarization. (C) The current direction or cell orientation is reversed, generating hyperpolarization in the soma and therefore suppression of neuronal firing.

ELECTRICAL FIELDS AND EXCITABLE TISSUE

discharged and the membrane is depolarized. Similarly, as the current enters the membrane, the charge on the capacitance is increased and the membrane is depolarized (see Figure 6.1). For simple structures, the transmembrane current flow can be calculated by deriving the effect of the field analytically.14 Compart­ mental analysis can be used to represent more complex anatomical structures. A compart­ ment of length x can be modeled at rest by a capacitance (Cm) in parallel with a series combination of a battery (Er) for the resting potential and a resistance (Rm) simulating the combined resistance at rest of all the mem­ brane channels.11 Non-linear ionic channel conductances can be added in parallel with the membrane resistance and capacitance. The important variable is the transmembrane potential (Vm) and it is defined as the differ­ ence between the intracellular voltage and the extracellular voltage (Ve). Note that the extracellular voltage can be first calculated using the equations given above and applied at each node as indicated. Applying Kirchoff’s law at each compartment, one obtains the following non-homogenous cable equation which gives the transmembrane voltage at each compart­ ment as a function of time:15

A2

2

Vm x

2

−T

dVm − Vm = −A2 dt

2

Ve

x2

(6)

The space constant of the membrane depends only on the geometric and electric properties of the membrane.

A=

s 1 Rm d , 2 Ras

(7)

S is the specific membrane resistance, where Rm S Ra the axoplasmic specific resistance, and d the

diameter of the dendrite. Tm is the time constant of the membrane and is given by:

T m = RmC m

(8)

The term on the right side of equation (6) is the forcing function and is the product of the square of the space constant and the second spatial derivative of the extracellular voltage. The source term indicates that the transmembrane voltage depends on the second order derivative of the extracellular voltages generated along the membrane. Therefore, as confirmed by experiments, the orientation of cell bodies with respect to the electrical field affects the longitudinal field amplitude, and thus the efficacy of the applied field. For example, a dendrite or axon located perpen­ dicular to the induced field lines would not be affected by stimulation. The forcing function also indicates that the membrane voltage is affected by the external field only if the voltage has a non­ zero second order spatial derivative. Thus, a uniform field along an ideal cylindrical cell body would have no effect even in the pre­ sence of non-zero potentials. However, if the membrane terminates, branches, or bends (as with dendrites and axons), then uniform applied electric fields can generate a non­ zero driving force and produce excitation or inhibition. At the boundary (cell body, bending site or sealed end), the driving func­ tion is not proportional to the second spatial derivative but to the first spatial derivative of the extracellular voltage. Therefore, at these boundaries the membrane is prefe­ rentially polarized. These results apply to both electrical fields induced directly by electrodes,14 and fields induced indirectly by magnetic stimulation.16 If the amplitude of the applied field is below threshold, the transmembrane can be described by equation

71

CONTROL OF NEURONAL ACTIVITY BY ELECTRICAL FIELDS

(6) since the membrane properties are modeled by passive elements.

Effect of electrical fields on nervous tissue: membrane polarization The effect of constant low amplitude (sub­ threshold) externally applied currents or fields (referred to as DC fields) on neural excitability has been documented in many neuronal systems. Most studies, examining Purkinje cells, 17,18 hippocampal dentate granule, 19 and pyramidal neurons, 20,21 and cortical neurons, 22,23 used uniform fields applied with large field electrodes placed on the surface of the cortex for in vivo experi­ ments or across the tissue for in vitro studies. The effect of localized fields have been studied in the hippocampus. 24–26 All these reports showed how DC fields could decrease or increase neuronal excitability. The results of studies, in combination with theoretical analysis (see above), have yielded a consistent theory on how applied fields induce mem­ brane polarization. The mechanism of the local field effects is illustrated in Figure 6.1. When an anode is located next to the soma of the cell (anodic local stimulation), the current must enter the soma and causes hyperpolarization (Figure 6.1A). The current must exit the membrane in the dendritic regions of the cell causing depolarization. However, since there are few sodium channels in the apical dendrites, the neuron is not neces­ sarily excited. The net effect is therefore a decrease in neuronal excitability. Currents applied through monopolar electrodes should generate radial localized fields that decay rapidly with distance (equation 2). Since the current density is high only near the electrodes,

72

it is expected that the method should produce large transmembrane currents locally,27,28 If the stimulating electrode is positioned near distal dendritic tufts, anodic stimulation can result in current flowing out of the soma, leading to neu­ ronal excitation. In the case of uniform electric fields, the field is generated by two long electrodes located on either side of the brain slice (see Figure 6.2A). When the anode is located on the side of the cell with the smallest dendrite (anodic field stimulation), the current enters the cell nears the anode and produces hyperpolarization in the smaller (basal) dendrite and somatic region of the cell (Figure 6.2B). The current leaves the cell in the larger (apical) dendrites and produces depolarization without excitation since there are only few sodium channels in that region. Therefore, the asymmetry of the dendritic tree facilitates sup­ pression of the neuronal firing by hyperpolar­ izing the somatic region. If the anode and the cathode are reversed, neuronal excitation is produced (Figure 6.2C). As long as the stimu­ lated tissue lies between the two large elec­ trodes, its exact location does not matter. If the targeted cells lie parallel to the electrodes (and hence perpendicular to the induced uniform electrical field), the electric field has no effect (see above); therefore, for uniform field stimulation, the orientation of the elec­ trodes and cells is crucial. It is important to emphasize that the above basic theory applies generally only for constant low amplitude electric fields. Alternating (bi­ phasic) or high amplitude fields may modulate membrane polarization, and hence neuronal exitability, in a more complex manner because of the non-linear properties of neuronal and glial membranes. However, it is important to emphasize that in all cases the effect of electrical fields on nervous function is mediated first by an induced polarization of cell membranes.

SUPPRESSION OF NEURAL ACTIVITY BY DIRECT CORTICAL LOCALIZED ELECTRICAL FIELDS

In studies examining the effect of uniform fields, stimulation intensity is generally reported as the amplitude of the electric field (e.g. mV/mm) perpendicular to the stimulating elec­ trodes (which is, by definition, constant between the electrodes). For studies using local stimula­ tion, intensity is reported in injected current amplitude (e.g. �A) which can be related to field strength (at any given distance from the elec­ trode) using equation (2) (see below). Since epileptic activity is characterized by hyperexcitability, low amplitude anodic DC fields, which can inhibit neuronal firing, should have anticonvulsive properties. The following two sections summarize reports in which epilep­ tiform activity was suppressed successfully in vitro using low amplitude local and field DC stimulation. Subsequent sections summarize results using more complicated stimulation waveforms.

Suppression of neural activity by DC localized electrical fields The effects of localized constant (DC) electrical fields have been tested on three in vitro models of epilepsy: penicillin,24 high potassium,25 and low calcium.26

Effect of localized fields on the penicillin model Penicillin can induce epileptiform activity by blocking the GABA-mediated inhibitory pathways. Evoked activity by a stimulation electrode located in the stratum radiatum gen­ erates multiple population spikes in the pres­ ence of a low dose of penicillin (Figure 6.3A). A long duration anodic electrical current pulse generated by a second electrode located in the

somatic region of the CA1 layer can signifi­ cantly attenuate the amplitude of the evoked potentials (Figure 6.3B).24 Transmembrane potentials, obtained by measuring the differ­ ence between the intracellular and extracellular potentials, showed that during anodic stimula­ tion, neurons were hyperpolarized. These data indicate not only that applied currents can inhibit activity but that this inhibition is pro­ duced with current amplitudes that do not gen­ erate excitation. Further increases in the ampli­ tude of the anodic current can generate excitation at the onset of the pulse; therefore, for local stimulation, there is a window of amplitudes were DC current can generate inhi­ bition without excitation (Figure 6.3C). Reversal of the amplitude of the DC current (cathodic stimulation) enhanced epileptiform activity (not shown).

Effect of localized fields on the high potassium model Hippocampal slices exposed to a raised (8–10 mM) extracellular potassium concentra­ tion generate spontaneous epileptiform activ­ ity similar to interictal activity observed in humans with epilepsy.29 The effect of local stimulation was tested on the spontaneous activity generated using the high potassium model of epilepsy.25 When a spontaneous event was detected, a DC current pulse was applied with a monopolar electrode positioned in the CA1 somatic layer. The amplitude of the high potassium events was reduced with increasing anodic current amplitudes. Complete inhibition could be generated in 94% of the slices with a mean minimum current amplitude 12.5 ± 3.8 �A. Intracellular recordings showed that, as in the case of peni­ cillin and low calcium, the membrane of the neurons was hyperpolarized by the anodic current thereby suppressing neuronal firing.

73

CONTROL OF NEURONAL ACTIVITY BY ELECTRICAL FIELDS

Blocking

A

Extracellular Intracellular

Orthodromic

CA1 cells

le cell s

Granu

B

Orthodromic current

Blocking current 41 μA 27 μA

5 mV

15 μA

5 ms Control

C

Inhibition 100 Inhibition window

80 60 %

Excitation

40 20 0

0

20

40

60

80

Figure 6.3 Effect of applied localized fields on epileptiform activity induced by penicillin. (A) Schematic of hippocampal slice and electrodes. Epileptic activity was triggered by an orthodromic electrode in the stratum radiatum and recorded by an extracellular microelectrode located in the CA1 region. The blocking electrode was located on the surface of the slice close to the recording electrode. Here, and in the following figures, application of long-duration electrical field pulse results in a step increase in the extracellular voltage (stimulus artifact). (B) With no current applied in the blocking electrode, the extracellular response shows the characteristic multiple spikeevoked potential. As the current is increased, the activity is attenuated until complete suppression is obtained with a current of 41 �A. (C) As the current is further increased, excitation is generated at the onset of the pulse. Therefore, the plot of percentage inhibition as a function of current from 20 slices shows a window of current for which suppression is obtained without excitation. (Modified from Kayyali and Durand, 1991.24)

Blocking current (μA)

Localized fields in the low calcium model During epileptic seizures, the extracellular calcium concentration is known to decrease.30

74

In brain slice preparations, lowering Ca2+ blocks chemical synaptic transmission,31 but leads to the development of spontaneous nonsynaptic epileptiform activity that approx­ imates ictal epileptiform activity.32–35 Low Ca2+

SUPPRESSION OF NEURAL ACTIVITY BY DIRECT CORTICAL LOCALIZED ELECTRICAL FIELDS

A

5 mV 4s

C

8.8 μA

5.9 μA

100 90 80 70 60 50 40 30 20 10 0

% slices blocked

B

0

1

2

4.4 μA

3 4 5 6 7 Current (μA)

8

Figure 6.4 Effect of localized fields on epileptiform activity induced by low calcium solutions. (A) Two examples of low calciuminduced activity with (top) and without (bottom) population spikes superimposed on a spontaneous slow shift in the baseline. (B) The arrow indicates a normal event. As the anodic current in increased, the event is blocked. (C) Cumulative histogram showing the relationship between the percentage slices blocked at a given current amplitude. (Modified from Warren and Durand, 1998.26)

9 10

4 mV

2.9 μA 1s –2.9 μA

non-synaptic bursts are characterized extracel­ lularly by prolonged negative potential shifts, sometimes with superimposed high frequency population spikes (Figure 6.4A). Ephaptic effects are partly responsible for the synchro­ nization of the neural activity suggesting that applied currents would be highly effective in modulating low calcium ictal events. Localized fields, generated by passing current into a small diameter monopolar electrode positioned in the somatic region, could inhibit epileptiform activity induced using the low calcium epilepsy model. The current amplitudes required for total inhibition are lower than

those required to block penicillin or high potas­ sium-induced activity. The minimum current for fully blocking an event was as low as 1 �A and spontaneous events were fully blocked in 90% of the slices with a current amplitude of 9 �A (Figure 6.4C).26 The electrical field gener­ ated by a monopolar sources is given by equa­ tion (6). A current of 1 �A generates an electric field of 2 V/m at a distance of 200 �m, assum­ ing a homogenous and isotropic medium of 200 ohm cm. This number is similar to the minimum electric field required to suppress low Ca2+ activity using uniform fields (minimum amplitude of 1.8 V/m, see below).

75

CONTROL OF NEURONAL ACTIVITY BY ELECTRICAL FIELDS

The suppression of low-Ca2+ activity is not only dependent on stimulation polarity but also on the exact position of the stimulating electrode along the cell dendritic axis. 36 Intracellular recording showed mechanism of suppression to be depolarization block. 36 Because synaptic function is blocked in the low-Ca 2+ model, successful suppression of activity (at very low stimulation intensities) confirms that DC field effects are not medi­ ated by excitatory or inhibitory neurotrans­ mitter release.

Suppression of neural activity by direct cortical uniform electrical fields Since uniform fields have been effective at con­ trolling neuronal excitability in normal tissue (see above), it is likely that uniform fields would also be effective at controlling epilepti­ form activity. This hypothesis has been tested using two in vitro models of epilepsy: high potassium and low calcium.

Suppression with uniform direct cortical fields in the high potassium model of epilepsy Gluckman et al. showed that anodic electri­ cal fields as low as 5 mV/mm applied with field electrodes can completely suppress high potassium-induced epileptiform activity. 37 High potassium burst frequency increased linearly with field amplitude during cathodic stimulation and decreased with increasing anodic fields. The mechanism for activity suppression and enhancement is consistent with membrane polarization, as described above. Similar results were obtained by Duong and Chang.38 76

Suppression with uniform direct cortical fields in the low calcium model of epilepsy Ghai et al. (2000) studied the effects of exogenous DC fields applied via field elec­ trodes on spontaneous low Ca2+ bursting.39 Spontaneous epileptiform activity could be suppressed for the duration of an anodic stimulus. The mean minimum field required to suppress spontaneous activity in low calcium was 1.8 mV/mm (n = 30) and a field amplitude of approximately 5 mV/mm could suppress 100% of the activity in 90% of the slices. Field amplitudes capable of complete suppression were clearly subthreshold. The suppression efficacy was dependent on the orientation of the neuronal tree with respect to the electric field. In a majority of the slices, the trailing edge of the suppressing field pulses caused excitation of the tissue through an ‘anodic rebound’ effect. Low calcium burst frequency increased lin­ early with field amplitude during cathodic stimulation and decreased with increasing anodic fields.39 Using uniform fields, the minimum field amplitude required for full suppression of low Ca2+ activity (1.8 V/m) is considerably lower than the one required to suppress high potassium induced epileptiform activity.37 One explanation for this effect is that extracellular resistance in low calcium is increased (as a result of cell swelling) such that applied field effects are enhanced. Consistent with this hypothesis, a 10% decrease in per­ fusate osmolarity (which causes further cell swelling and increases extracellular resistance) resulted in an average 50% decrease in the minimum field required for full suppression of low Ca2+ bursts, while a 14% increase in osmolarity resulted in an average 76% increase in the minimum electrical field ampli­ tude required for full suppression.39

CONTROL OF NEURONAL DYNAMICS

Control of neuronal dynamics by low frequency and single-pulse stimulation Although both local and uniform direct corti­ cal (DC) field techniques can clearly suppress neuronal activity, these methods require that the electrical field is applied continuously. Moreover, the orientation of the neural struc­ ture with respect to the applied field is crucial to the suppression. Other potential anticon­ vulsant stimulation methods employing single narrow pulses, that disrupt the dynamics of the neuronal activity, could overcome these limitations. Three different stimulation methods that involve the modulation of the dynamics of the neural network, using single or low frequency short-duration pulses, have been proposed for the suppression of synchronized activity: phase resetting, chaos control, and periodic low frequency stimulation.

Phase resetting and neural desynchronization Small amplitude pulses can alter (or ‘reset’) the phase of an oscillating system. Phaseresetting analysis has been used extensively to study cardiac rhythms and predict singularities in the dynamics of the heart.40–42 An analysis of the relationship between the stimulus timing and amplitude and the response of the system, has shown that, for some systems, one can predict the existence of a ‘singular stimu­ lus’ capable of disrupting (or ‘annihilating’) periodic oscillating activity.42 Using a com­ puter simulation of a spontaneously firing pyramidal cell (in high potassium solution), Hahn and Durand showed that a single pulse, with precise timing and amplitude, could anni­ hilate firing indefinitely.43 This phenomenon

can be explained by the concept of bistability. In increased potassium solution (in a small range of parameter settings), the neural model has two stable attractors, one corresponding to a resting potential and the other for repeti­ tive firing. The singular stimulus can move the system from a repetitive firing state to a silent, resting state. The phase resetting method was tested in vitro using the penicillin model of epilepsy. A stratum radiatum electrode was used to trigger an evoked epileptiform response and a somatic electrode was used to generate a short-duration phase-resetting pulse (Figure 6.5A). The results show that a ‘resetting’ pulse with the appro­ priate timing and amplitude could generate a large decrease in the amplitude of the evoked epileptiform population spikes (Figure 6.5B).28 The effect could not be explained by membrane polarization (as with DC fields), since the pulse was clearly not long enough to suppress the activity, or by increased synaptic inhibition (since inhibition was blocked by penicillin). Intracellular recordings revealed that neural firing was not suppressed; rather, the neurons were still active but their firing was desynchro­ nized by the application of the resetting pulse (Figure 6.5C). Desynchronization of a popula­ tion relies, in part, on the slightly different distance of each neuron and the stimulating electrode; since the degree of membrane polar­ ization is a function of distance (equation 2) each neuron will be affected slightly differently by a single pulse. It is therefore possible to interfere with the dynamics of a hyperexcitable system with a single stimulus that shifts the system from a stable periodic synchronized oscillation into a ‘stable’ unsynchronized fixed point. However, for either annihilation or desynchronization to be successful, the method requires the existence of at least two stable modes. Chaos control could potentially over­ come these limitations.

77

CONTROL OF NEURONAL ACTIVITY BY ELECTRICAL FIELDS

A Somatic-stimulating electrode

Recording electrode CA1 cells

Stratum radiatum electrode

Granule cells

B

Stratum, radiatum + somatic stimulation

3 mV 5 ms

Somatic electrode Somatic radiatum electrode C

Singular 40 mV 10 ms

78

Figure 6.5 Phase resetting and singularity in the penicillin model of epilepsy. A penicillin event is induced by an orthodromic electrode located in the stratum radiatum and monitored with an extracellular electrode located in the CA1 region of the hippocampal slice. A narrow pulse is applied with a stimulating electrode located close to the recording electrode in the somatic region. (B) Activation of the somatic electrode with just the right delay and amplitude (singular pulse) produces nearly complete suppression of the penicillininduced population spikes. (C) The mechanism for this suppression was attributed to a desynchronization of the neuronal population. Dual intracellular recordings showed that, during the application of the singular pulse, the relative phase of the neuronal firing is changed producing a more uniform firing distribution and suppression of the extracellular activity. (Modified from Durand and Warman, 1994.28)

HIGH FREQUENCY STIMULATION

Chaos control

High frequency stimulation

Spontaneous epileptiform activity generated using the high potassium interictal model sat­ isfies some of the criteria for deterministic chaos, and therefore chaos control algo­ rithms could be applied. Schiff et al. employed low frequency pulsed stimuli with timing derived from a chaos control algo­ rithm with the aim of reducing the periodic­ ity of high potassium activity in the CA3 region. 44 Their results showed that the system could be made more periodic or more chaotic by using a strategy of anti-control. Therefore, the dynamics of the neuronal network can be affected by applied current pulses chosen appropriately. However, it is not known to what extent the neuronal firing of the cells that generate the epileptic events was inhibited by the stimulus.

The stimulation techniques discussed above, using constant long-duration DC or low fre­ quency short-duration pulses are effective at reducing abnormal neural activity in several in vitro animal epilepsy models; moreover, in most cases, their mechanism is well character­ ized. However, there is no reported clinical implementation of (subthreshold) membrane polarization, phase resetting or chaos-control methods. Another method to suppress neu­ ronal activity, high frequency stimulation, has been used clinically for almost two decades, yet animal studies have only recently begun to shed light on its mechanism of action. Although high frequency stimulation applied to brain structures has been shown to decrease the frequency of seizure activity in patients with epilepsy,48 the mechanisms underlying its antiepileptic effects are not known. The effect of high frequency fields has been examined using several evoked,49 and spontaneous in vitro epilepsy models.36,50 Bawin et al. investigated the effects of uniform high frequency sinusoidal fields on evoked low Ca2+ and penicillin-induced burst­ ing.49 They reported that high frequency stimu­ lation (3–5.5 mV/mm, 60 Hz) could depress evoked responses for several minutes after ter­ mination of stimulation. In contrast to studies using uniform direct cortical fields (see above), they found the efficacy of sinusoidal fields was not orientation-dependent. They speculated that ‘the field induced rise in [extracellular] K+ may be important in the modulation of bursting in a epileptic focus’. Bikson et al. studied the effect of uniform high-frequency sinusoidal fields (20–50 Hz, 50–250 mV/mm) on spontaneous epilepti­ form activity using the zero Ca+2, low Ca+2, high K +, and picrotoxin epilepsy models

Periodic low frequency stimulation Low frequency periodic stimulation of the Schaffer collateral input to CA1 has been shown to inhibit the generation of electro­ graphic seizures in three hippocampal models of epilepsy: high potassium,45,46 magnesiumfree, and 4-aminopyridine.47 Stimulation in a narrow frequency band (1.0–1.3 Hz) can suppress or reduce the frequency of high potassium-induced ictal episodes. 45–46 0.25–1.5 Hz stimulation could suppress both magnesium-free and 4-aminopyridine-induced seizure-like bursts.47 A proposed explanation for this effect was an interruption of the processes leading to seizure initiation with long (>1–4 s) time constants. Suppression was reversible arguing against an induced change in synaptic efficacy, such as in longterm depression.

79

CONTROL OF NEURONAL ACTIVITY BY ELECTRICAL FIELDS

Extracellular potassium concentration

Current generator

A + Amplification and subtraction

–

+

Potassium-selective electrode

–

Field electrode

w

flo d

iel

Ef

B

2 mM K+

1 mV

Stimulation C Field 10/20 mV 5s

Transmembrane 20 mV 5s Transmembrane­ low-pass filtered

80

Figure 6.6 (A) Intracellular and extracellular potassium measurements during suppression of spontaneous epileptiform activity in hippocampal slices with high frequency fields. Experimental set­ up: (B) Top trace: potassium (K+) recording, bottom trace: extracellular field recording. During spontaneous low Ca2+ epileptiform activity high frequency stimulation (bar) resulted in a large K+ increase during stimulation and suppression of activity. Poststimulation suppression of activity was associated with a decrease in K+ below baseline levels. (C) Top trace: field recording, middle/bottom trace: transmembrane potential. During spontaneous picrotoxin epileptiform activity suprathreshold high frequency stimulation resulted in the depolarization block of CA1 pyramidal cells and suppression of spontaneous activity. (Modified from Bikson et al., 2001.50)

DISCUSSION

(Figure 6.6A). 50 They found that high fre­ quency stimulation could suppress completely epileptiform activity for the duration of the stimulation and for up to several minutes after termination of stimulation (Figure 6.6B). Successful suppression of reduced Ca2+ (non­ synaptic) bursting indicated that neurotrans­ mitter release was not required for this effect. Suppression was always associated with an increase in extracellular potassium (Figure 6.6B). In each model of epilepsy, suppression efficacy was not orientation-dependent. The use of sinusoidal stimulation and off line fil­ tering allowed monitoring of intracellular and extracellular potentials during high frequency stimulation. The high frequency stimulation was associated with significantly membrane depolarization (about 20 mV) (Figure 6.6C) suggesting that a depolarization block is responsible for the suppression. However, intracellular sinusoidal stimulation at a similar frequency failed to induce depolariza­ tion block indicating this effect is a network phenomenon (e.g. involving a population of neurons, interneurons, and/or glia). Experiments using localized stimulation with monopolar electrodes showed similar results for hippocampal epilepsy models. 36 Both sinusoidal and (more clinically relevant) pulsed stimulation protocols were shown to suppress epileptiform activity while inducing extracellular potassium and depolarization block of neurons. However, with the localized fields the suppression could be localized to the region around the monopolar-stimulating electrode.

Discussion As outlined in this review, electrical stimula­ tion can be used to inhibit neuronal firing and suppress epileptiform activity in vitro; signifi­

cant progress has been made towards under­ standing the anticonvulsive mechanism of low amplitude direct (DC), single-pulse, and low frequency stimulation paradigms However, these protocols are rarely (or never) used in a clinical setting. The potentials and present lim­ itations for implementing these protocols in vivo are discussed. There is still significant debate over the mechanism of high frequency stimulation-induced suppression in vivo; this is a particularly critical issue as high frequency protocols are currently used exclusively in clinical treatment. The relevance of the recent in vitro finding that epileptiform activity is suppressed by depolarization block36,50 to this debate is also discussed.

Suppression by membrane polarization Low amplitude DC fields, applied both locally (using monopolar electrodes) and globally (using field electrodes) can effectively suppress neuronal activity in every model of epilepsy tested. The main advantages of this method are that: (1) the current amplitude is very low (a few �A) can inhibit a large group of neurons); and (2) the suppression mechanism (polariza­ tion) is well established from in vitro studies and computer simulations. However, DC stim­ ulation has several severe disadvantages. Suppression with DC fields is critically depen­ dent on the orientation of the applied electrical field, the anatomy of the neurons, and the posi­ tion of the electrode(s) with respect to the neu­ ronal population. To generate somatic hyperpolarization using uniform fields, the neurons must be either unipolar or have asymmetric dendritic arborization. For anodic monopolar stimulation, the electrode must be located close to the cell body in order to generate somatic hyperpolarization. Another disadvantage of DC stimulation is that it has no long-term

81

CONTROL OF NEURONAL ACTIVITY BY ELECTRICAL FIELDS

(after stimulation is turned off) anticonvulsant effects; moreover, excitation rebound of spon­ taneous activity can occur at the termination of the stimulation.39 Partially because of this, suc­ cessful DC stimulation protocols must employ long-duration monophasic currents, which can generate non-reversible chemical reactions leading to damage of both the neural tissue and the electrode.8 Several approaches can be used to minimize the current (charge) used during DC stimulation and improve stimulation efficacy: (1) DC fields can be triggered by the initiation of spontaneous activity;51 (2) An ‘adaptive’ approach has recently be shown effective in controlling ictal bursting, where activity is monitoring and fields proportional to the event amplitude are applied;52 although this approach does not use constant (DC) fields, the mechanism of suppression is still presumably somatic hyperpolarization; (3) Short DC pulses applied at the onset of the epileptiform event can suppress its development.26 The efficacy of the DC suppression method was recently demonstrated in vivo.53 This method could be applied clinically in the hip­ pocampus with an anode located along the hippocampus in order to inhibit the basal den­ drites and the somatic region of the CA1 neurons. However, it is likely that this method would produce excitation in other regions, such as the CA3 layer. Suppression of the CA3 region would also be possible but more diffi­ cult due to the non-uniform anatomy of that region.37 Thus, low amplitude DC stimulation protocols have some potential for clinical implementation, provided that the stimulation can be applied in a targeted fashion and without significant electrochemical damage. The fundamental difference between DC and other stimulation protocols reviewed here, is that effective DC fields (50 �A local) suprathreshold stimula­ tion (they are also, as a result, not as highly orientation, polarity, and location-dependent). By taking advantage of the non-linear dynamic properties of tissue, epileptic activity can be controlled with these approaches.

Suppression based on the non­ linear dynamics properties of the neural tissue Single-pulse or low frequency trains of pulses that rely on non-linear dynamic properties also have potential for clinical implementation since they minimize the duration of the stimu­ lation (and thus tissue and electrode damage) and could potentially affect the behavior of a whole network. However, their effectiveness depends critically on the properties of the system. The phase-resetting/annihilation method, for example, depends on the exis­ tence of at least two states in the system; one of them must be a resting state or attractor where the network stops oscillating. Very few such systems have been identified and there is no guarantee that a bi-stability can be found in any given neuronal network (especially in the presence of noise). Moreover, bi-stability does not necessarily imply a decrease in excitability. In the hippocampal penicillin model of epilepsy, a single pulse can produce a large reduction of the amplitude of the popu­ lation spikes through a desynchronization mechanism but without any noticeable reduc­ tion in neuronal firing rate.28 However, as neural synchronization is a hallmark of epilep­ tic seizures, desynchronization alone could play an important role in seizure reduction. In vitro studies indicate that low frequency periodic stimulation can reduce seizure

CONCLUSIONS

frequency.45–47 The main drawback of this technique is that, in most cases, electrographic seizures were replaced by stimulus-induced afterdischarges raising concerns about the in vivo/clinical outcome of such paradigms. Although clinical (subdermal) cerebellar, vagal, and deep brain stimulation are effective only at high frequencies (see Durand and Bikson, 2001 for a review7), low (0.5 Hz) fre­ quency transcranial magnetic stimulation (TMS) has been shown to reduce seizure latency and frequency in both in vivo animal models,54 and clinical trials.55 However, in contrast to the in vitro studies, low frequency TMS has long-term (after stimulation is turned off) anticonvulsant effects, which were attributed to the phenomenon of long-term depression (LTD). LTD, a persistent depres­ sion in synaptic excitation, has been demon­ strated in vitro (in the absence of convulsants) after trains of low frequency stimulation.

High frequency stimulation Clinically, high frequency stimulation of deep brain structures, like the subthalamic nucleus (STN), mimics the effect of lesioning that same structure, suggesting that electrical stimulation is suppressing neuronal activity. This hypothesis has been supported by in vivo animal studies.56 Using a blanking amplifier, Kiss et al. showed that thalamic neurons were depolar­ ized and stopped firing during high frequency stimulation.57 Beurrier et al. found that after termination of high frequency stimulation STN neurons recovered slowly from a depo­ larization, during which time their excitability was reduced for several minutes; the reduction in excitability was mediated through nonsynaptic mechanisms.58 Two studies in the hip­ pocampus (see above) revealed that during high frequency stimulation, extracellular po­ tassium increases leading neuronal suppression

by depolarization block, independent of synaptic function.36,50 After stimulation was turned off, epileptiform activity was sup­ pressed for several additional minutes (until potassium returned to baseline). Whether depolarization block (mediated in part by extracellular potassium increases) plays a role in clinical deep brain stimulation (DBS) remains to be tested. However, currently used DBS protocols are most likely causing a large extracellular potassium rise, which in turn will dramatically affect cellular function. In addi­ tion, other effects of high frequency extracellular stimulation observed experimentally could also promote depolarization block, such as extracellular Ca2+ concentration reduction, depolarizing GABA-induced synaptic poten­ tials, and swelling. Moreover, it is interesting to note that in vivo, stimulation of the thala­ mus can raise potassium concentration both locally and in connected cortical regions, potentially leading to neuronal suppression in the cortex as well as in the thalamus.59 Experiments in corticothalamic slices, contain­ ing portions of the STN and pathways con­ necting the STN to the cortex, are currently being performed to study directly the local and distal effects of thalamic stimulation.60 Several additional mechanisms have been proposed to explain DBS, such as selective activation of inhibitory pathways or interfer­ ence with normal propagation of information through the neuronal circuit; however, these mechanisms have yet to be tested in vitro.61

Conclusions In vitro studies have revealed that suppres­ sion of epileptiform activity can be achieved by disrupting the patterns of neuronal firing (with short low frequency stimuli) or re­ ducing neuronal firing either through tonic

83

CONTROL OF NEURONAL ACTIVITY BY ELECTRICAL FIELDS

hyperpolarization or depolarization of neu­ ronal membranes (with DC of high frequency stimuli). One common theme to emerge from in vitro studies is the importance of nonsynaptic mechanisms in suppression of epileptiform activity. In vitro epilepsy models provide an important basis for further devel­ opment, characterization, and comparison of these different stimulation methodologies, with the ultimate goal of improving clinical outcome. Lastly, because implantable stimu­ lators can readily be reprogrammed, future stimulation paradigms could employ a com­ bination of suppression techniques, cus­ tomized for efficacy in each patient and (by use of feedback monitoring) each seizure.

Summary Epilepsy is a devastating disease affecting approximately 1 per cent of the world’s popu­ lation. Anticonvulsant drug therapy is an effective tool to suppress seizures but 25 per cent of the patients are either not responsive or suffer major side effects. For some patients, surgical resection is a potential treatment, but can also be associated with serious complica­ tions. Recently, electrical stimulation has proved to be an effective alternative to resec­ tion in specific cases. Over the past two decades, numerous electrical stimulation pro­ tocols have been developed using animal models of epilepsy that can reduce or com­ pletely suppress electrographic seizures. In this chapter, several methods to generate suppres­ sion of abnormal neural activity with electrical fields are discussed. The review is focused on those stimulation paradigms that have been tested in vitro in order to assess their under­ lying mechanisms. In particular, the anticon­ vulsant effects of direct cortical (DC) electrical fields, low frequency, high frequency, chaos

84

control and desynchronization protocols are discussed. The effect of electrical fields was tested on a variety of in vitro animal epilepsy models including low calcium, high potas­ sium, penicillin, and picrotoxin. Both the underlying mechanisms and the potential for clinical implementation are discussed.

Acknowledgements We thank the Whitaker foundation, the National Institute of Health and the National Science Foundation for providing financial assistance for some of the work mentioned in this review.

References 1. Steinlen OK, Noebels JL. Ion channel and epilepsy in man and mouse. Curr Opin Genet Dev 2000;10:286–91. 2. Wallace RH, Wang DW, Singh R et al. Febrile seizures and generalized epilepsy associated with a mutation in the NA+-channel beta1 subunit gene SCN1B. Nat Genet 1998;19, 65:1078–85. 3. Fisher RS. Epilepsy. In: Enna SJ, Coyle JT (eds), Pharmacological management of neurological and psychiatric disorders. New York: McGrawHill, 1998. 4. Durand D. Ictal patterns in animal models of epilepsy. J Clin Neurophys 1993;10:181:297. Durand D. Electrical stimulation can inhibit syn­ chronized neuronal activity. Brain Res 1986;382: 139–44. 5. Jefferys, JGR. Nonsynaptic modulation of neu­ ronal activity in the brain: electric currents and extracellular ions. Physiol Rev 1995;75:689–723. 6. Weinstein S. The anticonvulsant effect of electric fields. Curr Neurol Neurosci Rep 2001;1:155–61. 7. Durand DM, Bikson M. Suppression and control of epileptiform activity by electrical stimulation: a review. Proc IEEE 2001;89:1065–82. 8. Agnew WF, McCreery, DB. Neural prostheses: fundamental studies, Englewood Cliffs, NJ: Prentice Hall, 1990.

REFERENCES

9. Grill WM, Kirsch RF. Neuroprosthetic applica­ tions of electrical stimulation. Assist Technol 2000;12:6–20. 10. Plonsey R. Bioelectrical phenomena. New York: McGraw-Hill, 1969. 11. Durand D. Electrical Stimulation of excitable tissue. In: Biomedical engineering handbook. Boca Raton, CRC Press, 1995. 12. Nunez PL. Electric fields in brain: the neuro­ physics of EEG. Oxford University Press, 1981. 13. Johnson: Numerical methods for bioelectric field problems. In: Bronzino (ed) Biomedical engineer­ ing handbook. Boca Raton, CRC Press, 1994. 14. Tranchina D, Nichelson C. A model for the polarization of neurons by extrinsically applied electric fields. Biophys J 1986;50:1139–56. 15. Rattay F. Analysis of models for external stimula­ tion of axons. IEEE Trans Biomed Eng 1986; 10:974–7. 16. Nagarajan S, Durand DM. A generalized cable equation for magnetic stimulation. IEEE Trans Biomed Eng 1996;43:304–12. 17. Chan CY, Nicholson C. Modulation by applied electric fields of Purkinje and stellate cell activity in the isolated turtle cerebellum. J Physiol 1986;371:89–114. 18. Chan CY, Hounsgaard J, Nicholson C. Effects of electric fields on transmembrane potential and excitability of turtle cerebellar Purkinje cells in vitro. J Physiol 1988;402:751–71. 19. Jefferys JGR. Influence of electric fields on the excitability of granule cells in guinea-pig hip­ pocampal slices. J Physiol 1981;319:143–52. 20. Bawin SM, Mahoney MD, Sheppard AR, Adey WR. Influences of sinusoidal electric fields on excitability in the rat hippocampal slice. Brain Res 1984;323:227–37. 21. Bawin SM, Sheppard AR, Mahoney MD et al. Comparison between the effects of extracellular direct and sinusoidal currents on excitability in hippocampal slices. Brain Res 1986;362:350–4. 22. Denney D, Brookhart JM. The effects of applied polarization on evoked electro-cortical waves in the cat. Electroenceph Clin Neurophysiol 1962; 14:885–97. 23. Purpura DP, Malliani A. Spike generation and propagation initiated in dendrites by tranship­ pocampal polarization. Brain Res 1966;1:4030–6. 24. Kayyali H, Durand D. Effects of applied currents on epileptiform bursts in vitro. Exp Neurol 1991;113:249–54.

25. Nakagawa M, Durand D. Suppression of sponta­ neous epileptiform activity with applied currents. Brain Res 1991;567:241–7. 26. Warren RJ, Durand DM. Effects of applied cur­ rents on spontaneous epileptiform activity induced by low calcium in the rat hippocampus. Brain Res 1998;806:186–95. 27. Ranck JB. Which elements are excited in electri­ cal stimulation of mammalian central nervous system: a review. Brain Res 1975;98:417. 28. Durand D, Warman E. Desynchronization of epileptiform activity by extracellular current pulses in rat hippocampal slices. J Physiol 1994; 71:2033–45. 29. Traynelis SF, Dingledine R. Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. J Neurophysiol 1988;59: 259–76. 30. Heinemann U, Lux HD, Gutnick MJ. Extracellular free calcium and potassium during paroxysmal activity in the cerebral cortex of the rat. Exp Brain Res 1977;27:237–43. Holsheimer J. Electrical conductivity of the hip­ pocampal CA1 layers and application to current source density analysis. Exp Brain Res 1989; 77:69–78. 31. Jones RSG, Heinemann U. Abolition of the orthodromically evoked IPSP of CA1 pyramidal cells before the EPSP during washout of calcium from hippocampal slices. Exp Brain Res 1987; 65:676–80. 32. Haas HL, Jefferys JGR. Low-calcium field burst discharges of CA1 pyramidal neurons in rat hippocampal slices. J Physiol 1984;354: 185–201. 33. Jefferys JGR, Haas HL. Synchronized bursting of CA1 hippocampal pyramidal cells in the absence of synaptic transmission. Nature Lond 1982; 300:448–50. 34. Snow RW, Dudek FE. Evidence for neuronal interactions by electrical field effects in the CA3 and dentate regions of rat hippocampal slices. Brain Res 1986;367:292–5. 35. Yaari Y, Konnerth A, Heinemann U. Spontaneous epileptiform activity of CA1 hip­ pocampal neurons in low extracellular calcium solutions. Exp Brain Res 1983;51:153–6. 36. Lian J, Bikson M, Sciortino C, Stacey WC, Durand DM. Local suppression of epileptiform activity by electrical stimulation in rat hippocampus in vitro. J Physiol 2003;547:427–34.

85

CONTROL OF NEURONAL ACTIVITY BY ELECTRICAL FIELDS

37. Gluckman BJ, Neel EJ, Netoff TI, Ditto WL, Spano ML, Schiff SJ. Electric field suppression of epileptiform activity in hippocampal slices. J Neurophysiol 1996;76:4202–5. 38. Duong DH, Chang T. The influence of electric fields on the epileptiform bursts induced by high potassium in CA3 region of rat hippocampal slices. Neurolog Res 1998;20:542–548. 39. Ghai RS, Bikson M, Durand DM. Effects of applied electric fields on low-calcium epileptiform activity in the CA1 region of rat hippocampal slices. J Neurophysiol 2000;84:274–80. 40. Jalife J, Antzelevitch C. Phase resetting analysis and annihilation of pacemaker activity in cardiac tissue. Science 1979;206:695–7. 41. Guevara MR, Jongsma HJ. Three ways of abolishing automaticity in sinoatrial node: ionic modeling: nonlinear dynamics. Am J Physiol 1992;262:H1268–86. 42. Winfree AT. When time breaks down. Princeton University Press, 1987. 43. Hahn PJ, Durand DM. Bistability dynamics in simulations of neural activity in high-extracellular­ potassium conditions. J Comput Neurosci 2001;11:5–18. 44. Schiff SJ, Jerger K, Duong DH et al. Controlling chaos in the brain. Nature 1994;370:615–20. 45. Jensen MS, Yaari Y. The relationship between interical and ictal paroxysms in an in vitro model of focal hippocampal epilepsy. Ann Neurol 1988;24:591–8. 46. Jerger K, Schiff SJ. Periodic pacing of an in-vitro epileptic focus. J Neurophysiology 1995;73:876–9. 47. Barbarosie M, Avoli M. CA3-driven hippocampal­ entorhinal loop controls rather than sustains in vitro limbic seizures. J Neurosci 1997;17:9308–14. 48. Loddenkemper T, Pan A, Neme S, et al. Deep brain stimulation in epilepsy. J Clin Neurophysiol 2001;18:514–32. 49. Bawin SM, Abu-Assal M, Sheppard AR et al. Long-term effects of sinusoidal electric fields in penicillin-treated rat hippocampal slices. Brain Res 1986;399: 194–9. 50. Bikson M, Lian J, Hahn PJ et al. Suppression of epileptiform activity with high frequency sinu­ soidal fields. J Physiol, in press.

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51. Ghai R, Durand D. Electric field suppression of low calcium epileptiform activity in the rat brain. Soc. Neurosc, 1998 [Abstract]. 52. Gluckman BJ, Nguyen H, Weinstein SL, Schiff SJ. Adaptive electric field control of epileptic seizures. J Neurosci 2001;21:590–600. 53. Weiss SRB, Eidsath A, Li XL et al. Quenching revisited: low level direct current inhibits amygdala-kindled seizures. Exp Neurol 1998; 154:185–92. 54. Akamatsu N, Fueta Y, Endo Y et al. Decreased susceptibility to pentylenetetrazol-induced seizures after low-frequency magnetic stimulation in rats 2001;14: 153–6. 55. Tergau FU, Naumann W, Paulus BJ, Steinhoff BJ. Low frequency repetitive transcranial magnetic stimulation improves intractable epilepsy. Lancet 1999;353:2209. 56. Benazzouz A, Piallat B, Pollak P, Benabid A. Responses of substantia nigra pars reticulata and globu pallidus complex to high frequency stimu­ lation of the subthalamic nucleus in rats: electro­ physiological data. Neurosci Lett 1995;189: 77–80. 57. Kiss ZHT, Mooney DM, Hu, B. Cellular basis of deep brain stimulation: an intracellular study in rat thalamus. Soc Neurosci Abst 2000;477:16. 58. Beurrier C, Bioulac B, Audin J, Hammond C. High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J Neurophysiol 2001;85:1351–6. 59. Heinemann U, Gutnick MJ. Relation between extracellular potassium concentration and neu­ ronal activities in cat thalamus (VPL) during projection of cortical epileptiform discharge. Electroencephalogr Clin Neurophysiol 1979; 47:345–7. 60. Bikson M, McIntyre CC, Lacey MG, Fox JE, Jefferys JQR. Role of extracellular potassium concentration changes in the modulation of neu­ ronal firing during high frequency stimulation of the subthalamic nucleus in vitro. Soc Neurosci Abst 2003. 61. Montgomery EB, Baker KB. Mechanisms of deep brain stimulation and future technical develop­ ments. Neurolog Res 2000;22:259–66.

7 The nigral control of epilepsy: basal ganglia circuitry as a substrate for seizure control Karen Gale

Introduction During the past decade, it has become increas­ ingly evident that the neural substrates of seizure initiation and propagation in the brain are considerably more complex than originally envisioned. Likewise, the neural substrates available for seizure control can be found beyond traditional territories. Through the analysis of experimental seizure models, it has become clear that different types of seizures, and even different components of a seizure, depend on separable neural circuits. Moreover, the regulation of seizure propaga­ tion can be achieved through neural circuits that do not necessarily contribute directly to seizure propagation. Basal ganglia, thalamic, and brainstem nuclei that are not part of the seizure-generating network can, nevertheless, determine the susceptibility of other net­ works to enter into seizure discharge (for a detailed review of the relevant literature, see Proctor and Gale, 1998 1). The fact that stimulation of the afferent vagus has been found to have therapeutic impact in treating seizures in patients with epilepsy, argues that brainstem circuits (which are the direct targets of afferent vagal nerve fibers) can regulate forebrain seizure susceptibility in the human brain. Yet we know relatively

little about the ways in which brainstem nuclei may interact to permit or prevent the development of a seizure in the forebrain. While it is clear that seizure propagation in forebrain circuits can take place in the absence of any connections with the brain­ stem,2,3 in the presence of those connections, selective inhibition or activation of specific groups of brainstem neurons impedes seizures. Three brainstem nuclei for which there is evidence of anatomical inter­ connections will be the focus of the current discussion (see Figure 7.1): the substantia nigra (SN); the deep layers of the superior colliculus (SC); and the subthalamic nucleus (STN). These nuclei are located in the mid­ brain and each has been implicated in seizure control.

STN

SN

SC

Figure 7.1 Simplified relationships between the subthalamic nucleus (STN), substantia nigra (SN), and superior colliculus (SC).

87

THE NIGRAL CONTROL OF EPILEPSY

Species differences: rats vs primates Much of the functional neuroanatomy of seizure propagation and control in subcortical circuits comes from studies conducted in rat models. While a few notable laboratories have conducted experimental epilepsy studies in cats and in non-human primates, only rarely are direct comparisons made to rats. Consequently, the information derived from rodent studies cannot easily be compared to primate studies, especially since different ques­ tions are often asked. Recently, procedures for evaluating focally evoked seizures in monkeys, which can be analysed in parallel with an analogous model in rats, has permitted the evaluation of neural substrates of seizure control in the primate brain using site-specific focal application of reversible drugs and, moreover, has allowed for the direct compari­ son of effects in rodents versus primates. In the process of conducting these experi­ ments, we have discovered: (1) the specific pharmacological response profile within a given brain region can be strikingly different (and even opposite) between rat and monkey; (2) the anatomical routes via which partial seizures progress to become generalized are distinct for the rodent versus primate brain; and (3) the elaboration and topographical sorting of connections within a single nucleus, such as the substantia nigra (SN), in the primate brain allows for rich intranuclear sitespecificity of far greater complexity than can be achieved (or evaluated) in the rat brain.

Focally evoked seizure model The focally evoked model of seizures first developed in the rat by the unilateral applica­ tion of bicuculline into the deep layers of the rostral piriform cortex,4 was extended to the

88

monkey in a series of experiments identifying a comparable epileptogenic site in the monkey brain.5–7 The site, which has been referred to as ‘area tempestas’ (AT), is comparable in both rat and monkey to the extent that: (a) relatively low doses of bicuculline when focally applied unilaterally evoke propagated seizures that have the characteristics of complex partial seizures; and (b) as function­ ally defined by the response to bicuculline, the site is highly circumscribed (100 Hz) electrical DC stimulation on seizure induction remains unknown. We applied DC electrical stimulation on the rat brain. ADs and both focal and secondary generalized electrocorticographic and behavioral seizures were induced at various

100

high frequency currents. AD induction thresh­ old and duration were not significantly different in rats stimulated at frequencies ranging from 50 Hz to 800 Hz.

References 1. Lüders H, Lesser RP, Dinner DS, et al. Localization of cortical function: new information from extraoperative monitoring of patients with epilepsy. Epilepsia 1988;29(Suppl 2):S56–65.

REFERENCES

2. Lesser RP, Kim SH, Beyderman L, et al. Brief bursts of pulse stimulation terminate afterdischarges caused by cortical stimulation. Neurology 1999;53:2073–81. 3. Fisher RS Animal models of the epilepsies. Brain Res Rev 1989;14:245–78. 4. Loscher W. Animal models of epilepsy for the development of antiepileptogenic and diseasemodifying drugs. A comparison of the pharma­ cology of kindling and post-status epilepticus models of temporal lobe epilepsy. Epilepsy Res 2002;50:105–23. 5. Holmes GL, Khazipov R, Ben-Ari Y. Seizureinduced damage in the developing human: rele­ vance of experimental models. Prog Brain Res 2002;135:321–34. 6. Sankar R, Shin D, Liu H, et al. Epileptogenesis during development: injury, circuit recruitment, and plasticity. Epilepsia. 2002;43(Suppl 5):47–53.

7. Bragin A, Wilson CL, Engel J. Rate of interictal events and spontaneous seizures in epileptic rats after electrical stimulation of hippocampus and its afferents. Epilepsia 2002;43(Suppl 5):81–5. 8. Riban V, Bouilleret V, Pham-Le BT, et al. Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy. Neuroscience 2002;112:101–11. 9. Bragin A, Wilson CL, Engel J Jr. Increased afterdischarge threshold during kindling in epileptic rats. Exp Brain Res 2002;144:30–7. 10. Infante C, Cartier L, Motles E. Comparative study of the epileptogenic effect of kainic acid injected into the cerebral cortex, hippocampus and amygdala in adult cats chronically implanted. Arch Ital Biol 2002;140:31–40.

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Section III

Pathogenesis of brain stimulation: human studies

9 Cortico-cortical evoked potentials Riki Matsumoto, Dileep R Nair, Eric LaPresto, Imad Najm, William Bingaman and Hans O Lüders

Introduction Cortical electrical stimulation, first performed by Bartholow in 1874, has become a gold standard method to explore various cortical functions and has greatly aided the field of functional neurosurgery to preserve eloquent cortices.1 Standard cortical stimulation has been performed with a train of biphasic square wave pulses with a stimulus duration of 0.1–0.5 ms at a rate of 10 to 50 Hz. Each train of electrical stimuli is delivered to the cortex for a duration lasting from 2 to 5 seconds. Together with direct cortical elec­ trical stimulation, the various advancements in the last decade in functional neuroimaging techniques, such as positron emission tomo­ graphy (PET) and functional magnetic reso­ nance imaging (fMRI), has brought additional insight into the functional organization of the human brain. In contrast with increasing knowledge of various brain functions associ­ ated with various cortical regions, there is very little understanding regarding human intercortical neural connectivity. This is mostly due to the fact that there is a limited repertoire of suitable anatomic techniques that can be used in the living human brain.2 At present, human functional connectivity has mainly come from extrapolation from studies performed in other species.

Most of the research on white matter connec­ tivity such as cortico-cortical and cortico­ subcortical connections has been conducted in the non-human primate brains using a variety of invasive tracer techniques. Retrograde and anterograde tracer techniques were introduced in the early 1970s with horseradish peroxidase (HRP) as the tracer and have revolutionized the understanding of connections in the non-human primate brain.3,4 Functional connectivity has also been investigated using electrical stimula­ tion in monkeys. Intracortical microstimulation techniques have evaluated orthodromic or antidromic responses in the remote cortical regions via cortico-cortical connections.5,6 In addition, a technique based on tracing the spread of experimentally induced seizures, namely strychnine neuronography, was used to study neural pathways in non-human primates before the advent of modern anatomic track-tracing techniques.7–10 Intracortical connections in humans have been studied almost exclusively by gross anatomic dissections.11 Diffusion-weighed MRI, with its ability to visualize fiber trajecto­ ries, has the same limitation as gross dissec­ tion to track fibers into specific grey matter regions due to the low signal-to-noise ratio at the grey-white matter junction.12,13 Knowledge of the link between functional brain regions and anatomical fiber connections

105

CORTICO-CORTICAL-EVOKED POTENTIALS

is essential to an integrated understanding of the organization of the human nervous system not only in basic systems neuroscience but also in the field of epileptology. Similar to what was revealed in experimentally induced seizures by the strychnine neuronography in non-human primates, we occasionally encounter propaga­ tion or spread pattern of interictal spikes or seizures into areas remote from the epilepto­ genic focus. For example, as predicted by Ajmone-Marson and Ralston in 1957, seizures originating in the occipital lobes can have mul­ tiple spread patterns.14 Interictally, spikes can be frequently recorded from the temporal area as a spread pattern from the occipital region via cortico-cortical connection. EEG seizures, when recorded from scalp, can be also observed as a temporal pattern with clinical semiology consistent with seizures arising from the temporal lobe (automatism with loss of consciousness). On the other hand, suprasyl­ vian spread to the lateral frontoparietal area produces focal sensory or motor seizures. Therefore, knowledge of the underlying physi­ ological cortico-cortical connections is essential for a better understanding of pathological con­ nections involved in the spread or propagation of epileptic discharges. Several attempts have been made recently to track neuronal connectivity in the living human brain by stimulating the cortex with transcranial magnetic stimulation (TMS) and recording indirect hemodynamic responses by PET. Stimulation of the frontal eye field by TMS elicited hemodynamic responses from the remote higher visual cortices in the occipitoparietal areas.15 Other authors have confirmed connectivity pattern established in non-human species between the primary motor area and the adjacent lateral premotor and somatosensory (S1 and S2) areas.16 Although the activation via intercortical connection was recorded as indirect hemodynamic change by

106

group analysis, these studies have shed light on the neural connectivity study in vivo in humans. Direct cortical electrical stimulation has been shown to activate neurons in the motor cortex using not only conventional repetitive stimulation but also with single pulse stimula­ tion. Direct cortical stimulation with single electric pulses through subdural electrodes elicited motor evoked potentials in awake patients with medically intractable partial epilepsy or multiple system atrophy.17,18 It is speculated that the cortical stimulation gener­ ated direct and indirect orthodromic dis­ charges in pyramidal neurons, thus activating the corticospinal pathway. We have recently developed a novel method which we termed ‘cortico-cortical evoked potential’ (CCEP), to track the cortico-cortical connections in vivo in patients with intractable partial epilepsy during the invasive pre-surgical evaluation with subdural electrodes. In contrast to the conventional 50 Hz repetitive stimulation,19 1 Hz repetitive stimulation makes it possible to record neural activity from the adjacent and remote cortical regions after each stimu­ lus as an epicortical-evoked potential. In con­ trast to TMS-PET studies that record indirect hemodynamic change by group analysis, this method enables us to investigate functional connectivity directly in each individual patient by recording neural activity with excellent time and spatial resolution of sub­ dural electrodes (center-center inter-electrode distance is 1 cm). Repetitive square wave electric pulses were employed with a pulse width of 0.3 ms and a frequency of 1 Hz. Stimulation with alternat­ ing polarity was employed to: (1) reduce the stimulus artifacts; (2) avoid charges building up at the cortex for safety; and (3) avoid the polarization of platinum electrodes which can

CASE 1: INTRACTABLE TEMPORAL LOBE EPILEPSY

lessen the actual current density.18 Bipolar stimulation for two adjacent electrodes was delivered at 80% of the intensity that pro­ duced clinical signs or afterdischarges (ADs) during the standard 50Hz cortical stimulation. If no clinical signs or ADs were present at 15 mA with the standard stimulation parame­ ters, the stimulus intensity was set at 10–12 mA. If excessive artifact was recorded, the intensity was set lower by 1 mA until arti­ facts became small enough to permit recording of evoked responses. Continuous electro­ corticogram (ECoG) was recorded, and all the subdural electrodes were referenced to a scalp electrode placed on the skin at the mastoid process contralateral to the side of implanta­ tion (Axon Epoch 2000 Neurological Workstation, Axon Systems Inc, NY, USA). The bandpass filter for data acquisition was set to 1–1000 Hz with a sampling rate of 2500 Hz for each channel. ECoGs were aver­ aged using the stimulus onset as the trigger. In each session, at least two blocks of 20–100 responses each were averaged separately to confirm the reproducibility of the response. ECoG was simultaneously monitored with a digital encephalograph (Vangard, Cleveland, OH, USA) to detect EEG seizures or ADs. Anatomical location of each electrode was evaluated with a three-dimensional MRI co­ registration technique reported elsewhere.20,21 No tasks were performed during the examina­ tion period, thus allowing patients to be sitting or lying down in bed. Illustrative cases are described below.

Case 1: Intractable temporal lobe epilepsy A 33-year-old right-handed man with med­ ically intractable partial epilepsy since age 7 underwent invasive video-EEG monitoring

with subdural electrodes placed at the lateral frontoparietal and lateral and basal temporal areas. Habitual seizures started with an aura consisting of a tingling sensation in his chest, spreading to his arms and legs. Seizures were then followed by a left face tonic seizure, finally evolving into a generalized tonic-clonic seizure. While interictal epileptiform dis­ charges were widely spread over the right hemisphere, the EEG seizures started with an electrodecremental pattern in the lateral and basal temporal areas, followed in 2 seconds by a paroxysmal fast activity in Plate D maximum at electrode D1. Standard 50 Hz electrical stimulation at electrode D1 elicited a habitual aura. Bipolar stimulation of elec­ trodes D1 and D2 were performed to investi­ gate cortico-cortical connections in the tem­ poral area in an attempt to better understand the spike propagation. CCEPs were recorded from the basal and lateral temporal areas (Figure 9.1). Stimulation of electrodes D1 and D2 elicited CCEPs from the adjacent elec­ trodes with its maximum at electrode D5/6, peaking latency at 12 ms. CCEPs were also recorded from Plate E with its maximum at E4, though with smaller amplitude and longer peak latency. No clear focal potentials were recorded from the lateral temporal area at Plate B. To investigate short and long cortico­ cortical connections in the frontoparietal area, pairs of electrodes in Plate C were stim­ ulated. CCEPs were recorded from the poste­ rior half of Plate C in the inferior frontal gyrus (IFG) and from a part of Plate A in the inferior parietal area (Figure 9.2). In Plate C, large short-latency CCEPs were recorded from the electrodes close to the pair of stimu­ lation (Figure 9.2). The largest CCEPs were obtained from electrodes adjacent to the pair of stimulation with a peak latency of 12–14 ms. With regards to long cortico­ cortical connections, stimulation at Pair 3 in

107

CORTICO-CORTICAL-EVOKED POTENTIALS

8 5

D 4

E 6

1

1

Plate E 6 Plate D 8

4 39 ms

12 ms stim 12 ms 5

Pair of stimulation Recording electrode

1 stim

300 μV

–

1

20 ms

Figure 9.1 CCEPs recorded from the basal temporal area (Plates D and E) by stimulating electrodes D1 and D2 (symptomatogenic zone of the habitual aura revealed by standard 50 Hz stimulation) in Case 1. Stimulation elicited short-latency CCEPs from the electrodes D5, D6 (adjacent to the stimulating electrodes) as well as from Plate E (maximum at E4). The vertical bar corresponds to the time of stimulation. Two trials (black and grey lines) were superimposed. Black circles denote the recording subdural electrodes co-registered with 3-D MRI.

the posterior part of inferior frontal gyrus elicited CCEPs in the posterior part of the inferior parietal area with the first negative peak at 25–37 ms followed by a larger late negative potential. On the other hand, no clear activity was recorded when the anterior part of inferior frontal gyrus (Pair 1) was stimulated. These studies showed the presence of the interconnection within the ventral prefrontal/premotor area (by short cortico­ cortical connections) and the fronto–parietal circuit between the ventral prefrontal/premotor and posterior inferior parietal areas (by long cortico–cortical connections).

Case 2: Intractable frontal lobe epilepsy A 17-year-old right-handed man with intractable frontal lobe epilepsy underwent

108

invasive monitoring with subdural electrodes to localize the epileptogenic zone and for functional mapping of eloquent areas. His seizures started with an undescribable aura, followed by a bilateral asymmetric tonic seizure and then by a hypermotor seizure. To investigate the connection between the orbitofrontal and mesial frontal areas, CCEPs were performed by stimulating the mesial frontal area and recording the evoked poten­ tial potentials from the orbitofrontal area. Two pairs were stimulated. Stimulation at Pair 1 in the mesial prefrontal area elicited CCEPs suggestive of a dipole activity which peaked at 47 ms in the lateral orbitofrontal sulcus. No clear dipole activity was recorded by stimulating Pair 2 located posteriorly in the mesial premotor area (Figure 9.3). This study shows long cortico-cortical connections between anterior mesial frontal and orbito­ frontal areas.

CONCLUSION

Plate A

Plate C

CS

15 ms

Pair 1

A C Sylv

B 13 ms

CS

106 ms 120 ms

stim

A

stim

B

Pair 2 C

124 ms

37 ms

Sylv

CS

25 138 ms 106 ms

stim

Pair 3

A C

12 ms

26 119 ms

stim

B

Sylv

dorsal rostral

300 μV

– 50 ms

Figure 9.2 CCEPs recorded from the right frontoparietal area by stimulating the right inferior frontal gyrus in the prefrontal area in Case 1. In addition to large short-latency CCEPs (peak latency 12–15 ms) observed in the electrodes adjacent to the electrode pair of stimulation, CCEPs were recorded remotely at the posterior part of the inferior parietal area with the early and late negative potentials peaking at 25–37 ms and 106–138 ms, respectively. The response was site-specific: stimulation of Pair 3 and, to a lesser degree, Pair 2 elicited CCEPs while Pair 1 did not. CS, central sulcus; Sylv, sylvian fissure. Other conventions are the same as Figure 9.1.

Conclusion The present cortico-cortical evoked potentials (CCEPs) studies revealed short and long cortico-cortical connections in vivo. The largest CCEPs with the shortest latency (P7 T8>F8 F8>T8 F7>Fp1

Distribution

124 (73–172) 90 (52–130) 73 (38–113) 71 (50–108) 35 (34–38) 41 (34–55)

Amplitude (�V)

Scalp EEG

86 (81–113) 105 (81–116) 120 (69–150) 73 (62–99) 108 (91–113) 93 (77–98)

Duration (ms) LSTN 0–3 LSTN 0–3 LSTN 0–3 RSTN 0–3 RSTN 0–3 LSTN 0–3

Distribution

259 (101–355) 183 (132–299) 167 (54–370) 93 (64–114) 176 (112–200) 76 (70–84)

Amplitude (�V)

STN EEG

100 (73–139) 109 (96–118) 134 (91–172) 92 (62–109) 102 (89–112) 92 (88–94)

Duration (ms)

Table 13.2 Distribution, amplitude and duration of the sharp waves recorded from the scalp and subthalamic nucleus (STN) electrodes.

PS

LB PW

Patient

HUMAN STUDIES

161

EEG RECORDING FROM THE SUBTHALAMIC NUCLEUS

Figure 13.2 Simultaneous scalp and bilateral subthalamic nucleus (STN) EEG recording of LB. Left temporal derivation electrodes all referenced to the P4 electrode in channels 1–4 demonstrate a sharp wave of negative polarity in the left temporal region. The left STN contacts 0–3 also referenced to P4 demonstrate the presence of a sharp wave of positive polarity recorded at the same time.

Fp1–P4

F7–P4

T7–P4

P7–P4

LSTN0–P4 LSTN1–P4 LSTN2–P4 LSTN3–P4 RSTN0–P4 RSTN1–P4 RSTN2–P4 RSTN3–P4 100 uV

1s

Figure 13.3 Sharp wave of negative polarity recorded in the left temporal region maximum at T7>F7, with a simultaneous positive polarity sharp wave in the left subthalamic nucleus (STN) electrode contacts. The scalp sharp wave precedes the STN sharp wave by 14 ms.

Fp1–P4

F7–P4

T7–P4

P7–P4

LSTN0–P4 LSTN1–P4 LSTN2–P4 LSTN3–P4 RSTN0–P4 RSTN1–P4 RSTN2–P4 RSTN3–P4 50 uV

1/2 s

rare occasions, the scalp and STN sharp waves appeared simultaneously. In Patient AD, no sharp waves were recorded from the scalp or the STN. However, the EEG demonstrated continuous slowing over the left frontal region. There were fre­ quent intermixed polyspikes recorded in the left fronto-central region maximum at F3, C3.

162

The patient also had polyspikes occurring bilaterally in the fronto-central regions. In association with the bilateral polyspikes recorded at the scalp, there were also bilateral polyspikes recorded at the left and right STN electrodes (Figure 13.5). The activity at the STN electrodes appeared of opposite polarity to the scalp recorded polyspikes.

HUMAN STUDIES

Figure 13.4 Scalp-recorded sharp wave with its peak recorded 11 ms after the STN recorded a sharp wave of positive polarity.

Fp1–P4

F7–P4

T7–P4

P7–P4

LSTN0–P4 LSTN1–P4 LSTN2–P4 LSTN3–P4 RSTN0–P4 RSTN1–P4 RSTN2–P4 RSTN3–P4 50 uV

1/2 s

Figure 13.5 Bipolar scalp EEG montage demonstrates bilateral polyspikes higher in the left frontal region, with simultaneous recording of activity recorded at the subthalamic nucleus (STN) electrode contacts bilaterally.

Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 Lstn0–Lstn1 Lstn1–Lstn2 Lstn2–Lstn3 Rstn0–Rstn1 Rstn1–Rstn2 Rstn2–Rstn3

In addition, spikes were seen recurring independently in the left and right STN elec­ trodes without any reflection at the scalp elec­ trodes (Figure 13.6A,B). These spikes were of negative or positive polarity. They were of shorter duration than the sharp waves recorded from the STN, were high in ampli­ tude and were stereotyped in morphology.

50 uV 1 s

The mean values and ranges of the amplitude and duration are shown in Table 13.3. The spikes were recorded bilaterally from patients PW and PS who had sharp waves recorded bilaterally over the scalp. But from patient LB who had unilateral sharp waves over the left temporal region, the isolated STN spikes were recorded predominantly at the left STN

163

EEG RECORDING FROM THE SUBTHALAMIC NUCLEUS

Figure 13.6 (A) EEG demonstrating the spikes from the right subthalamic nucleus (STN) electrodes without associated sharp waves at the scalp surface. (B) STN electrode contacts referenced to the PZ scalp electrode demonstrating involvement of all right-sided contacts by a negative right STN spike.

A LSTN0–RSTNO Fp1–F7 F7–T7 T7–P7 P7–O1 Fp2–F8 F8–T8 T8–P8 P8–O2 Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 20 uV

1s

B LSTN0–Pz LSTN1–Pz LSTN2–Pz LSTN3–Pz RSTN0–Pz RSTN1–Pz RSTN2–Pz RSTN3–Pz 100 uV

(98%) and rarely at the right STN electrode (2%). They recurred frequently, at a rate of 3–6 per 10 seconds. The patient with Parkinson’s disease (without epilepsy) had extremely rare spikes recorded from the STN electrodes of negative or positive polarity, approximately once every 120 seconds. These spikes were not reflected at the scalp surface

164

1s

electrodes. The patient, AD, had no isolated STN spikes recorded. The frequency of the spikes in the three patients with epilepsy was much higher than in the patient with Parkinson’s disease. There was an increase in the spike frequency in all patients in stage 1 non-rapid eye movement (NREM) sleep, 3–6 times the waking spike

DISCUSSION

Patient

LB PW PS

STN EEG Distribution

Amplitude (�V)

Duration (ms)

RSTN-LSTN RSTN-LSTN RSTN-LSTN

180 (128–273) 129 (97–190) 158 (106–278)

74 (43–94) 60 (54–75) 55 (39–73)

Table 13.3 Amplitude and duration of isolated spikes recorded at the subthalamic nucleus (STN) electrodes.

rate.39 The epilepsy patients were recorded in all stages of sleep and demonstrated a further increase in stage 2 NREM sleep spike fre­ quency up to 7–11 times the waking rate. There was a dramatic decrease in the spike fre­ quency in stage 3/4 NREM sleep and also in REM sleep. In patient PW, 22 clinical seizures were recorded and were characterized by flexion of the neck and shoulders followed by a generalized tonic-clonic seizure of brief dura­ tion (10 seconds). The ictal EEG demonstrated rhythmic beta activity (15–18 Hz) of 40–60 �V intermixed with spikes distributed over the left frontal region. This activity was recorded simultaneously from the left STN electrodes at a similar frequency. AD had multiple right face clonic seizures recorded, each lasting 20–40 seconds. The EEG onset was from the left fron­ tocentral region consisting of polyspikes and paroxysmal alpha frequency activity evolving to rhythmic 4–5 Hz theta activity in the same region. Recordings from the STN electrodes showed that the paroxysmal scalp activity was also recorded from the ipsilateral STN elec­ trode contacts, maximum at contacts 1 and 2 (Figure 13.7A–C). It was difficult to study the relationship of the polarity of the ictal activity at the scalp and the STN due to its rhythmicity. PS had one clinical seizure that was recorded on scalp EEG but STN recordings were not obtained simultaneously.

Discussion Positive sharp waves were recorded from the subthalamic nucleus (STN) electrodes in close temporal relationship to the negative sharp waves recorded from the scalp electrodes over­ lying the frontal or temporal regions in the patients with intractable epilepsy. With many discharges the STN sharp waves occurred with a short delay after the scalp recorded interictal epileptiform discharges, (IEDs) as shown in Figure 13.3. This pattern suggests that there is spread of the epileptiform activity from the cortex to the STN along a direct pathway. This is consistent with data from animal experiments of a direct cortico-STN pathway. A direct glutamatergic pathway from the cere­ bral cortex to the STN has been demonstrated in rats and monkeys.40 Some studies have shown that the projections from the cortex are widespread and bilateral. In one animal study, both ipsilateral and contralateral cortical stim­ ulations resulted in STN excitations.41 The possibility that this excitation was indirect due to polysynaptic excitations was excluded by various chemical lesion studies. The seizures recorded in patient AD showed that the ictal EEG activity was recorded from the scalp over the left fronto-central region and simultane­ ously from the ipsilateral STN electrode con­ tacts. This finding also supports the spread of

165

EEG RECORDING FROM THE SUBTHALAMIC NUCLEUS

Figure 13.7A–C Ictal EEG from patient AD. At the onset of one of his clinical seizures there is rhythmic alpha activity distributed over the left frontocentral region, followed by rhythmic theta activity. Simultaneous recording from the subthalamic nucleus (STN) electrodes demonstrated rhythmic activity recorded from the left STN contacts.

A Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 Lstn0–Lstn1

Lstn1–Lstn2

Lstn2–Lstn3

Rstn0–Rstn1

Rstn1–Rstn2

Rstn2–Rstn3

50 uV

1s

B Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O4 Lstn0–Lstn1

Lstn1–Lstn2

Lstn2–Lstn3

Rstn0–Rstn1

Rstn1–Rstn2

Rstn2–Rstn3

the ictal activity along a pathway from the cortex to the ipsilateral STN. In a few dis­ charges, the STN sharp waves preceded the scalp-recorded sharp waves. This may be explained by the initial cortical epileptiform activity located in a sulcus or restricted to a small region of cortical tissue, and initially is not recorded at the scalp; the activity spreads

166

50 uV

1s

to the STN where it is first recorded. Then, the cortical activity spreads to involve a greater amount of cortical tissue, and is subsequently recorded at the scalp. A similar explanation may account for the simultaneous occurrence of the STN and the scalp-recorded sharp waves. The activity at the STN always appears ipsilateral to the scalp-recorded epileptiform

DISCUSSION

C

Figure 13.7A–C – continued Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 Lstn0–Lstn1

Lstn1–Lstn2

Lstn2–Lstn3

Rstn0–Rstn1

Rstn1–Rstn2

Rstn2–Rstn3

activity. The low amplitude deflections at the contralateral STN contacts probably reflect activity of the reference electrode. The scalp-recorded sharp waves were always negative in polarity whereas the STN sharp waves were always of positive polarity. The one possibility is that the scalp and STN electrodes were recording opposite poles of a dipole. However, this is very unlikely because the STN sharp waves were recorded only uni­ laterally. The contralateral STN is in close proximity to the ipsilateral STN and equidis­ tant from the cortex and no activity was recorded from the contralateral STN that one would expect under that circumstance. A second possibility is that the epileptiform activity spreads to the STN and we are then recording only the positive pole of this inde­ pendent activity at the STN. In some of the STN sharp waves the ampli­ tude of the activity was similar at all four STN contacts. This may be explained by the fact that the activity recorded may be along the corticoSTN pathway as it is entering the STN or is in the STN at a short but equal distance from the

50 uV

1s

four contacts. However, in other sharp waves the maximum was at one electrode contact as demonstrated in Figure 13.2, that is consistent with recording of a near-field potential. The spikes restricted to the STN were seen at both the left and right STN electrodes in those patients who had IEDs in both hemispheres. But in patient LB, who had IEDs only in the left temporal region, STN spikes were seen almost exclusively from the left STN. These spikes may represent spread to the STN of IEDs which are restricted to a very small core of cortical tissue so that they are not recorded at the scalp surface. An alternative hypothesis is that these spikes reflect extreme hyperexcitability of the STN pool of neurons in patients with epilepsy. The rare contralateral STN spikes seen in patient LB may represent spread of the IEDs to the contralateral STN from the cortex or may represent some irritability in the neuronal pool of the contralateral STN related to insertion of the depth electrode. The relationship of the isolated STN spikes and sleep is similar to that of scalp IEDs and sleep, which also supports the hypothesis that the isolated STN spikes

167

EEG RECORDING FROM THE SUBTHALAMIC NUCLEUS

represent a pool of extremely hyperexcitable STN neurons as part of a diffuse hyperexcitability that occurs in epilepsy patients with cortical spikes that are not seen at the scalp. The recording of extremely rare spikes in the STN in the Parkinson’s disease patient sug­ gests that isolated STN spikes may result from insertional injury, but this is probably a minor contribution to the frequent spikes recorded from the STN of the patients with intractable epilepsy. It is also possible that rare spikes in the STN may represent a normal finding. In summary, in this chapter we describe the EEG findings performed in epilepsy patients who underwent STN placement of deep brain electrodes for HFS in the management of their intractable focal epilepsy. The sharp waves at the ipsilateral STN in close temporal relation­ ship to the scalp recorded sharp waves, as well as the spread of unilateral ictal EEG activity to the ipsilateral STN support the presence of a direct pathway from the cortex to the ipsi­ lateral STN in humans as has been described in animals.

References 1. Ben Menachem E, Hellstrom K, Waldton C, Augustinsson LE. Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to 5 years. Neurology 1999;52:1265–7. 2. Brorson LO, Wranne L. Long-term prognosis in childhood epilepsy: survival and seizure progno­ sis. Epilepsia 1987;28:324–30. 3. Hauser WA, Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia 1975;16:1–66. 4. Annegers JF, Hauser WA, Elveback LR. Remission of seizures and relapse in patients with epilepsy. Epilepsia 1979;20:729–37. 5. Camfield C, Camfield P, Gordon K, et al. Outcome of childhood epilepsy: a populationbased study with a simple predictive scoring system for those treated with medication. J Pediatr 1993;122:861–8.

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6. Shafer SQ, Hauser WA, Annegers JF, Klass DW. EEG and other early predictors of epilepsy remission: a community study. Epilepsia 1988; 29:590–600. 7. Cooper IS, Amin I, Gilman S. The effect of chronic cerebellar stimulation upon epilepsy in man. Trans Am Neurol Assoc 1973;98:192–6. 8. Cooper IS, Amin I, Riklan M, et al. Chronic cerebellar stimulation in epilepsy. Clinical and anatomical studies. Arch Neurol 1976;33:559–70. 9. Fisher RS, Uematsu S, Krauss GL et al. Placebocontrolled pilot study of centromedian thalamic stimulation in treatment of intractable seizures. Epilepsia 1992;33:841–51. 10. Velasco F, Velasco M, Marquez I, Velasco G. Role of the centromedian thalamic nucleus in the genesis, propagation and arrest of epileptic activ­ ity. An electrophysiological study in man. Acta Neurochir Suppl (Wien) 1993;58:201–4. 11. Velasco M, Velasco F, Velasco AL, et al. Effect of chronic electrical stimulation of the centro­ median thalamic nuclei on various intractable seizure patterns: II. Psychological performance and background EEG activity. Epilepsia 1993;34:1065–74. 12. Velasco F, Velasco M, Velasco AL, Jimenez F. Effect of chronic electrical stimulation of the cen­ tromedian thalamic nuclei on various intractable seizure patterns: I. Clinical seizures and paroxys­ mal EEG activity. Epilepsia 1993;34:1052–64. 12a.Velasco F, Velasco M, Velasco AL, et al. Electrical stimulation of the centromedian thala­ mic nucleus in control of seizures: long-term studies. Epilepsia 1995;36:63–71. 13. Velasco F, Velasco M, Ogarrio C, Fanghanel G. Electrical stimulation of the centromedian thalamic nucleus in the treatment of convulsive seizures: a preliminary report. Epilepsia 1987;28:421–30. 14. Velasco M, Velasco F, Velasco AL, et al. Epileptiform EEG activities of the centromedian thalamic nuclei in patients with intractable partial motor, complex partial, and generalized seizures. Epilepsia 1989;30:295–306. 15. Sussman NM, Goldman HW, Jackel RA et al. Anterior thalamic stimulation in medically intractable epilpesy: II. Preliminary clinical results. Epilepsia 1988;29:677 [Abstract]. 16. Cooper IS, Upton AR, Amin I. Reversibility of chronic neurologic deficits. Some effects of electri­ cal stimulation of the thalamus and internal capsule in man. Appl Neurophysiol 1980;43:244–58.

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17. Sramka M, Chkhenkeli SA. Clinical experience in intraoperational determination of brain inhibitory structures and application of implanted neurostimulators in epilepsy. Stereotact Funct Neurosurg 1990;54–55:56–9. 18. Garant DS, Gale K. Lesions of substantia nigra protect against experimentally induced seizures. Brain Res 1983;273:156–61. 19. Iadarola MJ, Gale K. Substantia nigra: site of anticonvulsant activity mediated by gamma­ aminobutyric acid. Science 1982;218:1237–40. 20. Depaulis A, Vergnes M, Marescaux C. Endogenous control of epilepsy: the nigral inhibitory system. Prog Neurobiol 1994;42:33–52. 21. Zhang H, Rosenberg HC, Tietz EI. Injection of benzodiazepines but not GABA or muscimol into pars reticulata substantia nigra suppresses pentylenetetrazol seizures. Brain Res 1989;488: 73–9. 22. Zhang H, Rosenberg HC, Tietz EI. Anticonvulsant actions and interaction of GABA agonists and a benzodiazepine in pars reticulata of substantia nigra. Epilepsy Res 1991;8:11–20. 23. La Grutta V, Sabatino M. Substantia nigra­ mediated anticonvulsant action: a possible role of a dopaminergic component. Brain Res. 1990; 515:87–93. 24. Sabatino M, Gravante G, Ferraro G, et al. Inhibitory control by substantia nigra of general­ ized epilepsy in the cat. Epilepsy Res 1988;2:380–6. 25. Boda B, Szente MB. Stimulation of substantia nigra pars reticulata suppresses neocortical seizures. Brain Res 1992;574:237–43. 26. Benazzouz A, Piallat B, Pollak P, Benabid AL. Responses of substantia nigra pars reticulata and globus pallidus complex to high frequency stimulation of the subthalamic nucleus in rats: electrophysiological data. Neurosci Lett 1995; 189:77–80. 27. Benazzouz A, Hallett M. Mechanism of action of deep brain stimulation. Neurology 2000;55: S13–16. 28. Beurrier C, Bioulac B, Audin J, Hammond C. High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J Neurophysiol 2001;85:1351–6. 29. Windels F, Bruet N, Poupard A et al. Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in

substantia nigra and globus pallidus in the normal rat. Eur J Neurosci 2000;12:4141–6. 30. Baker KB, Montgomery EB Jr, Rezai AR, Burgess R, Luders HO. Subthalamic nucleus deep brain stimulus evoked potentials: physiological and thera­ peutic implications. Mov Disord 2002;17:969–83. 31. Handforth A, DeGiorgio CM, Schachter SC et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology 1998;51:48–55. 32. Veliskova J, Velsek L, Moshe SL. Subthalamic nucleus: a new anticonvulsant site in the brain. Neuroreport 1996;7:1786–8. 33. Vercueil L, Benazzouz A, Deransart C et al. Highfrequency stimulation of the subthalamic nucleus suppresses absence seizures in the rat: compari­ son with neurotoxic lesions. Epilepsy Res 1998;31:39–46. 34. Krack P, Limousin P, Benabid AL, Pollak P. Chronic stimulation of subthalamic nucleus improves levodopa-induced dyskinesias in Parkinson’s disease. Lancet 1997;350:1676 [Letter]. 35. Limousin P, Pollak P, Benazzouz A et al. Bilateral subthalamic nucleus stimulation for severe Parkinson’s disease. Mov Disord 1995; 10:672–4. 36. Limousin P, Krack P, Pollak P et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998;339:1105–11. 37. Guridi J, Rodriguez-Oroz MC, Lozano AM et al. Targeting the basal ganglia for deep brain stimu­ lation in Parkinson’s disease. Neurology 2000;55:S21–28. 38. Dinner DS, Neme S, Nair D et al. EEG and evoked potential recording from the subthalamic nucleus for deep brain stimulation of intractable epilepsy. Clin Neurophysiol 2002;113:1391–402. 39. Dinner DS, Neme S, Montgomery EB Jr, et al. Isolated subthalamic nucleus spikes: are they epileptogenic? Epilepsia 2001;42(Suppl 7):44 [Abstract]. 40. Parent A, Hazrati LN. Functional anatomy of the basal ganglia: I. The cortico-basal ganglia­ thalamo-cortical loop. Brain Res Rev 1995;20: 91–127. 41. Rouzaire-Dubois B, Scarnati E. Bilateral cortico­ subthalamic nucleus projections: an electrophysi­ ological study in rats with chronic cerebral lesions. Neuroscience 1985;15:69–79.

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14

EEG and the anterior thalamic nucleus

Brian Litt and Stephen Cranstoun

Introduction There is rapidly increasing interest in develop­ ing implantable stimulation devices for treat­ ing intractable epilepsy. In particular, high fre­ quency electrical stimulation has been demonstrated to be of potential therapeutic benefit in this disorder by desynchronizing neural activity.1 A variety of targets have been pursued, including the vagus nerve, hypothala­ mus, basal ganglia and the subthalamic (STN), centro-median (CM) and anterior thalamic nuclei (AN). Our group is currently participat­ ing in a pilot study of the antiepileptic effects of AN stimulation in humans. We have to date implanted three patients, and reviewed record­ ings from three additional patients, with AN stimulation devices who have intractable partial epilepsy and have either failed or are not candidates for surgical treatment. We have recorded spontaneous seizures from simulta­ neous scalp and AN electrodes, and are cur­ rently analysing field recordings obtained during and after surgical implantation. This summarizes our early experience recording EEG from the anterior thalamic nucleus. The main reasons for recording spon­ taneous EEG or evoking responses from AN include: (1) verifying lead placement within the target nucleus at the time of surgery by evoking a ‘recruiting response’ when adjust­

ment of electrode position is still possible; (2) recording spontaneous activity from AN in order to understand mechanisms underlying the generation and modulation of epileptiform activity; and (3) exploring the possibility of AN as central place for monitoring for seizure onset. In this way, seizure detection and/or prediction algorithms may be applied to these recordings in order to trigger a warning or therapeutic response. Although pilot clinical studies of brain stimulation therapy for epilepsy and movement disorders have enabled researchers to obtain thalamic record­ ings from humans, there is a longstanding tradition of basic research in thalamic physiology—this is beyond the scope of this chapter.2–7

Background The anterior thalamic nucleus (AN) is a com­ ponent of the circuit of Papez, a group of interconnected structures in the limbic system demonstrated to have a role in cognition, memory and epilepsy.8–10 Although the func­ tion of the AN in these circuits is not exactly clear, there is considerable interest in record­ ing both single unit and field potentials from this region, with the goal of understanding its function in health and disease.8 A great

171

EEG AND THE ANTERIOR THALAMIC NUCLEUS

driving force behind the resurgence of clinical research in this area is the recent success of functional brain stimulation in humans to treat neurological disease, particularly tremor, movement disorders, and most recently in epilepsy. In the early 1980s, Cooper et al. described the theoretical benefits of stimula­ tion in this region for treating epilepsy.11 Experiments in animals later suggested that high frequency stimulation of AN had an inhibitory, antiepileptic effect on brain regions electrically coupled to this region.9,12 Based on these experiments, pilot trials of AN stimula­ tion for epilepsy are underway, including recording from and stimulating AN in humans. Early results from these studies suggest sufficient safety, tolerability,13 and perhaps efficacy14 to promote clinical human trials of this therapy. This brief chapter sum­ marizes recent experience in recording field potentials from electrodes stereotaxically placed in AN and recording evoked responses on the scalp resulting from low frequency stimulation of AN.

Validating electrode placement in the anterior thalamic nucleus: the recruiting response The procedure for implanting chronic elec­ trodes in thalamus involves stereotaxic surgery in which coordinates from a standard stereo­ taxic atlas of the human brain are adapted, or ‘morphed’ to a high resolution magnetic reso­ nance imaging (MRI) scan of a particular subject. Verification of lead placement can be performed in several different ways: 1. Monitoring single unit potentials for firing patterns of characteristic nuclei; this is

172

useful in subthalamic nucleus (STN) implantation. Since the typical surgical approach to the anterior thalamic nucleus (AN) requires inserting electrodes through the lateral ventricles, single unit recordings are used to identify when electrodes have entered thalamic tissue, but as of yet, have not been reported to demonstrate a specific pattern of activity to distinguish AN from other regions, such as the dorsal medial (DM) thalamus. 2. Suprathreshold electrical stimulation to produce characteristic sensory symptoms, as is employed during implantation of elec­ trodes in STN to treat parkinsonism. This method has not been useful for AN implants, as nuclei capable of generating sensory symptoms with suprathreshold stimulation are not sufficiently close to AN to facilitate localization. 3. Post-operative MRI imaging, when the electrodes are determined to be MRI-safe. This technique is commonly used to verify placement post-operatively, when it is no longer possible to easily change electrode position. 4. Evoking a recruiting response in the neocor­ tex by low frequency thalamic stimulation. The thalamic recruiting response was first identified by Dempsey and Morison in 194215 and was used by Velasco et al. to verify place­ ment of electrodes in the centro-median nucleus (CM) in a pilot study of a stimula­ tor.16 They reported a dramatic decrease in seizure frequency after 7 to 33 months of intermittent stimulation. Fisher et al. also per­ formed a small trial of CM stimulation and found more moderate decreases in seizures with continual stimulation over three months.17 This study used pre-operative MRI coupled with stereotaxic surgery to place stimu­ lation electrodes but not intra-operative elec­

RECRUITING RESPONSE IN THE OPERATING ROOM

trophysiology, raising the possibility that dif­ ferences in lead placement may have accounted for the different responses to therapy in these two studies. The success of a stimulation device may depend greatly on correct placement of stimulating electrodes. It is important to note that the recruiting response is not specific to one nucleus in the thalamus, but has been reported to be gener­ ated by stimulation in at least CM, DM and AN thalamus. The number and location of the group of cells essential for generating the recruiting response is unknown. The recruiting response is reported to have a characteristic appearance, including fronto­ central distribution, anterior maximum, gradual onset within several (~2–4) seconds after the onset of stimulation and increasing sharpness with increasing stimulation ampli­ tude, sometimes approaching generalized spike and slow wave discharges, depending upon a number of factors, such as the anes­ thetic/sedation used during implantation, loca­ tion of the stimulating electrodes, concomitant medications, type of epilepsy, etc.

Recruiting response in the operating room Three patients with refractory partial epilepsy were implanted with deep brain stimulation (DBS) electrodes (Model 3382, Medtronic, Inc, Minneapolis, MN) in the anterior thala­ mic nuclei bilaterally at Pennsylvania Hospital of the University of Pennsylvania. This was performed as part of a pilot clinical trial, under an investigational device exemption (IDE) granted by the US Food and Drug Administration (FDA) to determine safety and tolerability, gather pilot information on efficacy, and to formulate procedures for elec­ trode placement and stimulation protocols for

this device. Human protocols all were reviewed and approved by the University of Pennsylvania’s Office of Research Administration. The AN was pre-operatively targeted bilaterally using a combination of high resolution MRI and a human stereotaxic atlas, as discussed above. Intra-operative single unit recording was used to determine entry into the AN region on each side (stimu­ lation electrodes were implanted bilaterally) after passing through the lateral ventricle in all three patients. Figure 14.1 displays an elec­ trode trajectory through, along with single unit recordings from, the anterior (AN) and dorsal medial (DM) thalamic nuclei in a single patient. DBS electrodes were placed along the tracts giving the best microelectrode record­ ings. Similar to the findings of Velasco et al. for CM thalamus stimulation, stimulating the AN in a monopolar montage generated a recruiting response that increased to a steady state over the ~2–4 seconds following the onset of stimulation, was maximal in the frontal and central leads of scalp EEG bilater­ ally, and of highest amplitude ipsilateral to the side of stimulation. In two patients, the F3 and F4 recording electrodes could not be properly placed due to the location of burrholes required for implantation, so that double distance electrode montages were used (i.e. Fp1-C3 and Fp2-C4). Thresholds for producing a visible recruit­ ing rhythm were determined as a function of stimulation voltage, frequency and pulse width. A single American Board of Clinical Neurophysiology certified expert reader (BL) interpreted EEGs in the operating room for the presence of the recruiting rhythm. In one patient, the relationship between pulse width and recruiting rhythm threshold was docu­ mented. In two patients frequency-response of the recruiting rhythm was recorded. In all patients, recruiting rhythm was produced by

173

EEG AND THE ANTERIOR THALAMIC NUCLEUS

Electrode track (circles = recordings)

OO

DM

AM

Caudate (lateral to plane) Lat vent In ventricle (no units)

Hypoth

Red

In anterior nucleus

In dorsal median 0.1 s

monopolar stimulation at different electrode depths spanning the AN on each side, and cor­ related with stereotaxic coordinates to verify functional electrode placement in the AN. The electrode depths through which the recruiting rhythm was evoked were recorded and used to select the deep brain stimulation electrode contacts positioned at the same depths for chronic stimulation postoperatively.

Results Deep brain stimulation (DBS) microelectrodes did not produce reliable recruiting responses on surface EEG using bipolar stimulation. Therefore, we first implanted a unipolar macroelectrode, which generates a larger elec­ tric field, and stimulated a recruiting rhythm prior to placement of the DBS electrode. It is important to note that the permanent DBS electrode can be used to stimulate a recruiting response when set in a monopolar montage referenced to the stimulator unit housing. We determined that the actual location of the ‘per­ manent’ DBS electrodes may vary ±1 mm,

174

Figure 14.1 Computer atlas diagram of implantation trajectory for the anterior thalamic nucleus (AN) and microelectrode recordings from AN and dorsal median (DM) thalamus. The figure is reproduced courtesy of Dr Robert Fisher of the Barrow Neurological Institute, Phoenix, AZ, USA, and displays a computer atlas of the anatomy and trajectory for stereotaxic implantation of simulation electrodes in the AN thalamus. The tracing also demonstrates single unit recordings from AN and DM obtained during implantation.

compared to the best location of the macroelectrode for evoking the recruiting response, due to potential movement during stylette removal. Figure 14.2 displays MRI scans from two study patients illustrating placement of the ‘permanent’ DBS electrode in the anterior thalamic nucleus in both transverse (A) and sagittal (B) views. In all three patients, recruiting rhythms were obtained at frequencies of 2–20 Hz with thresholds between 0.5 and 4.0 volts. In one patient, no recruiting rhythm could be elicited during administration of general anesthesia, but this activity returned, using the same stim­ ulating parameters, when anesthesia was significantly reduced and when the patient was awake. In this same patient, suprathreshold stimulation generated generalized spike and wave activity phase locked to the stimulation frequency. In most cases, stimulation gener­ ated bilateral responses but the recruiting rhythm was most easily seen ipsilateral to stimulation. Figure 14.3 displays a typical recruiting response in the left frontal region during stimulation of the left AN.

RECRUITING RESPONSE IN THE OPERATING ROOM

A B Figure 14.2 An MRI showing 4-contact DBS electrode placement in the anterior thalamic nucleus (AN). Post­ operative verification of placement of ‘permanent’ 4-contact DBS electrodes in the AN in patients 1 (A) and 3 (B). 5 volts Fp1–F3 F3–C3

50 μV 4 volts

1s

Fp1–F3 F3–C3 3 volts Fp1–F3 F3–C3 2 volts

Figure 14.3 Recruiting response in the left frontal region. Recruiting rhythm is demonstrated at a range of stimulation voltages ipsilateral to stimulation of the left anterior thalamic nucleus (AN). Stimulation frequency is set to 5 Hz and pulse width to 90 �s. In this patent, note that the tracing begins after onset of the recruiting response, approximately 4 s after stimulation commences.

Fp1–F3 F3–C3

Effect of stimulation frequency In two patients (2 and 3) we explored the effect of stimulation frequency on the recruiting response. In patient 3, stimulation fre-

quency was varied between 2 Hz and 20 Hz, and the stimulation voltage was slowly increased by 0.5 V every 30 s until the recruit­ ing response was clearly seen by eye. This was

175

EEG AND THE ANTERIOR THALAMIC NUCLEUS

Frequency (Hz) 2 5 10 20

Voltage threshold (V) 1.0 2.5 1.5 1.0

In patient 3, the pulse width was fixed to 90 �s. Frequency was set as shown and stimulation voltage was increased gradually in 0.5 V increments until the recruiting response was visible by eye. Voltage was not increased faster than 30 s intervals during the trial.

Table 14.1 Recruiting response threshold as a function of frequency.

done in order to determine the stimulation threshold as a function of frequency. Pulse width was fixed at 90 �s for these trials. Table 14.1 demonstrates no apparent relationship between recruiting rhythm threshold and stim­ ulation frequency. The thresholds listed in

Table 14.1 are typical of those found in all study patients, although thresholds sometimes varied to as high as 4 V, depending on stimu­ lation parameters, electrodes and montage chosen and anesthetic/sedation state of the patient. Figure 14.4 demonstrates the recruit­ ing response at several different frequencies in patient 3. In patient 2, in order to assess the effect of stimulation frequency on the magnitude of recruiting response, electrical stimulation was set at 6 V, to be clearly suprathreshold (the patient’s threshold at 5 Hz was 4.0 V), and the recruiting rhythm was recorded at three stimu­ lation frequencies. The AN was stimulated one side at a time using a 90 �s pulse width and the voltage threshold was found. Table 14.2 shows the frequency-dependent stimulation thresholds. Recruiting response was seen for frequencies up to 20 Hz, with a maximal response occurring in the 7–10 Hz range for all three study patients.

5 Hz, 6 volts FP2–C4 C4–P4 50 μV 1s 7 Hz, 6 volts FP2–C4 C4–P4 50 μV 1s 8 Hz, 6 volts FP2–C4 C4–P4 50 μV 1s

176

Figure 14.4 Recruiting response vs frequency. The amplitude of the recruiting response increases with increasing frequency to a range of 50–70 �V at a fixed stimulation of 6 V in this patient. Response amplitude peaked in the 7–10 V range for this patient (3), and then diminished with increasing frequency.

RECRUITING RESPONSE IN THE OPERATING ROOM

Frequency (Hz) 5 7 8

Recruiting response (�V) 20 35 50

In patient 2, stimulation pulse width was fixed to 90 �s and stimulation voltage to 6 V, using a monopolar DBS electrode. Stimulation frequency was then varied and the peak-to-peak amplitude of the recruiting response was measured. The amplitude of the recruiting response increased at stimulation frequencies up to 7–10 Hz, before declining in amplitude gradually (not shown). The recruiting response was still visible at stimulation frequencies of 20 Hz. No testing above that frequency was undertaken.

Pulse width (ms) 90 150 180 210

Voltage threshold (V) 4.0 3.5 3.0 3.0

In patient 2, stimulation frequency was fixed at 5 Hz and pulse width was varied from 90 �s to 210 �s. Voltage threshold for the recruiting response was then determined at each pulse width according to the protocol outlined in the text (voltage was raised by 0.5 V starting at 0 V, and increased at 30 s intervals until a recruiting response was visible). No increase in response was noted above pulse widths of 180 �s.

Table 14.2 Recruiting response amplitude as a function of stimulation frequency.

Table 14.3 Recruiting response threshold as a function of pulse width.

Effect of pulse width A larger pulse width provides more stimula­ tion energy for a given frequency, stimulating more nuclear neurons. In patient 2 we varied the stimulation pulse width and determined the voltage threshold for eliciting a recruiting response. A stimulation frequency of 5 Hz was used and the voltage increased from 0 V, in 0.5 volt increments, until a response was detected. Table 14.3 illustrates the effect of pulse width on recruiting rhythm threshold. Threshold was reduced with increasing pulse width until the width was 180 ms after which increasing pulse width did not affect the threshold. It is important to note that all of the data above represent stimulation trials during electrode implantation to help guide proper electrode placement, and were limited in time and scope so as to not delay the implantation procedure. Each measurement, however, was collected twice to verify relia­

bility. Precision of measurements was to +0.5 V. Electrode position The principal objective of evoking the recruit­ ing rhythm in the operating room was to verify placement of electrodes in the AN. After being driven into the lateral ventricle by a servo-controlled device attached to a stereo­ taxic frame, the first tissue encountered from which single units may be recorded should be the AN. Ventral and medial to AN is the dorsal medial nucleus of the thalamus (DM) and ventrally, the ventral anterior (VA) nucleus. It is unclear if electrode position can be determined within the AN solely from the recruiting response since these other nuclei appear to be capable of generating a similar response. There is some suggestion that it may be possible to distinguish AN from DM by single unit recording (see Figure 14.1),

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however, this has not been demonstrated. If electrode placement is too shallow or lateral to AN, placing contacts within the ventricle, no recruiting response should be elicited. In all three study patients, post-operative MRI identified whether contacts of the DBS elec­ trode were within the AN on each side. These results were compared to intra-operative evoked recruiting responses for each patient. In patient 1, DBS electrodes elicited a recruiting rhythm on the left side in bipolar mode between contacts 0 and 1 only, using 8 Hz and 5 Hz stimulation with 90 �s pulse width and 5 V amplitude. Contacts 1–2 and 2–3 configurations failed to generate a recruit­ ing rhythm. Inspection of post-operative MRI determined that only contacts 0 and 1 were within the AN. In patient 2, no recruiting rhythm was seen with any electrode or stimulating pattern in the left side. Due to previous surgery and implanted electrodes, the surgeon had to take an alternative approach, which led to elec­ trode placement slightly lateral to AN. Post­ operative MRI showed that all four contacts were outside of AN on this side. Macroelectrode stimulation elicited recruiting rhythms for all stimulating parameters in the right side. Images show that all four DBS con­ tacts were in AN. Patient 3 displayed bilateral recruiting rhythms using macroelectrodes. Post-operative MRI showed that all four contacts were in the thalamus, but the contacts 0 and 1 may have been placed in DM nucleus. This highlights one of the difficulties with using the recruiting rhythm for placing AN electrodes: other thala­ mic nuclei may elicit equivalent responses making it difficult to delineate responses from AN from other nuclei. Thresholds were equiv­ alent for a variety of electrode locations, rela­ tive to the target, even some of which may be in DM.

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Summary Elicitation of a cortical recruiting rhythm from stimulation of AN during lead placement may be a valuable adjunct to imaging based on stereotaxic MRI during surgical implantation. In our experience with three patients, we have shown that this rhythm can be seen at frontal scalp electrodes when stimulation passes a threshold dependent on a number of variables, including electrode location, frequency, pulse width and the presence of medications, such as sedatives and anesthetic agents. Amplitude of the generated response is dependent on location within the target nucleus and may provide assistance in optimizing the efficacy of local electrical stimulation. Recruiting responses were most easily elicited when the stimulating frequency was 5–10 Hz and the pulse width greater than 150 �s. Response amplitude was also dependent upon electrode depth, as would be expected if the electrode were just passing into the nucleus from the lateral ventricle. From this set of preliminary results, we can recommend the following procedure for utiliz­ ing the recruiting rhythm to assist in electrode placement in AN. 1. Initially, use monopolar stimulation to generate recruiting responses. Monopolar stimulation generates a spherical electric field, which is larger and less dispersed than the cylindrical field generated by bipolar stimulation for a given stimulation voltage, and appears to be more effective in generating an evoked response. 2. We recommend using stimulation frequen­ cies between 7 Hz and 10 Hz, and avoid­ ing stimulation frequencies near the domi­ nant alpha frequency, so evoked rhythms can be easily delineated from natural rhythms.

DISCUSSION

3. An initial pulse width of 90 �s should be sufficient to generate a recruiting rhythm, but increasing width to 180 �s can be used to stimulate more of the surrounding tissue, if the recruiting rhythm cannot be elicited otherwise. 4. Begin stimulation at deeper sites and retract the electrode until no recruiting rhythm is seen, presumably when the contact exits the thalamus into the ventri­ cle. The most superficial position where a response is seen should be the position of the most distal electrode contact. This will guarantee that all contacts are in the nucleus or deeper, assuming the trajectory takes the electrode through AN. Again, the presence of a recruiting response identifies that the stimulating electode(s) is within the thalamus, not that it is necessarily in a particular nucleus. 5. Stimulation voltage can be increased stepwise until a recruiting rhythm is seen. In general this should occur with stimula­ tion less than 5 V. Overstimulating may result in generalized spike and wave activity.

Discussion Dempsey and Morison first described the recruiting rhythm generated by thalamic stim­ ulation.15 It is attributed to alpha frequency stimulation of the generalized thalamic system (intralaminar, centro-median, and anterior nuclei), which has broad projections to neo­ cortex. The anterior thalamic nucleus (AN) is involved in the classical circuit of Papez, which includes limbic-thalamic connections, making it appealing to hypothesize that stimu­ lation in this region might modulate hip­ pocampal activity, perhaps even preventing a temporal lobe focus from generating seizures

or preventing localized synchronous activity in this region from generalizing. Stimulating AN can generate a recruiting response in frontal scalp EEG, maximal ipsilateral to the side of stimulation, so use of this rhythm can be used as a functional correlate to imaging during stereotaxic implantation of stimulating electrodes.

Recording spontaneous EEG from AN We recorded spontaneous seizures from scalp electrodes and anterior thalamic nucleus (AN) contacts (three in the nucleus on each side) in two patients. The most illustrative of these recordings was obtained from a patient with right frontal onset seizures with sec­ ondary bisynchrony, validated by implanta­ tion with subdural strips and a grid. These recordings demonstrate several important points: 1. Depth recordings from AN provide fidelity similar to that obtained from intracranial hippocampal depth and subdural strip electrodes. Figure 14.5 demonstrates a brief tonic seizure recorded on scalp elec­ trodes and from three contacts in AN bilaterally. In Figure 14.5, the AN tracings are displayed in a referential montage to a linked mastoid reference. It is important to note the presence of bisynchronous activity in AN bilaterally, including polyspikes and then the tonic discharge characterizing the seizure. While the reference may contribute greatly to this activity, making it difficult to tell what is coming from AN and what is coming from the reference, double dis­ tance electrodes recorded referentially to linked mastoid electrodes did not display the same waveforms. Another important point regarding Figure 14.5 is the polarity

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Fpl–F7 F7–T3 T3–T5 T5–O1 Fp2–F8 F8–T4 T4–T6 T6–O2 Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 *Cz–Pz *LA0 *LA1 *LA2 *LA3 *RA0 *RA2 *RA3

50 μV 1s

Figure 14.5 Spontaneous tonic seizure recorded simultaneously from scalp electrodes and depth electrodes in the anterior thalamic nucleus (AN) bilaterally. Tonic seizure in a patient with a symptomatic generalized epilepsy, right frontal focus with secondary bisynchrony. The AN electrodes are labelled left (LA) and right (RA), with the distal most contact numbered 0. The RA1 electrode has been deleted, as it was high impedance, and activity in it was difficult to distinguish from artifact. AN electrodes are recorded against a linked-ears reference, making it difficult to determine exactly how much activity was recorded from AN and how much from the reference (see text). Note that the fidelity of the AN recording is comparable to other intracranial electrodes. Also of note, the gain of the bottom 7 tracings is 3 times that of the top bipolar recording (150 �V/mm instead of 50 �V/mm). Note: channel Cz-Pz has been shortened, for ease of viewing, to make a line between scalp and AN channels.

of the epileptiform discharges. There has been considerable discussion raising concerns that epileptiform activity recorded from AN and STN in the few patients tested so far have demonstrated positive polarity, when recorded with an inactive reference (linked ears in this case). We propose that this is not a cause of great concern, as the potentials being recorded in these nuclei are not ‘open’ fields, as is the normal with potentials recorded in cortex or even hippocampus, but rather

180

‘closed’ fields, from scattered cells not arranged in a laminar structure. For this reason, these recordings support the conclusion that fields corresponding to epilep­ tiform activity recorded from these nuclei originate within the nuclei themselves, rather than being volume conducted from some location outside of these regions. 2. Epileptiform discharges emanating from the frontal lobe and simultaneously recorded from AN bilaterally in humans appear to lateralize in AN ipsilateral to the

DISCUSSION

Fp1–F7 F7–T3 T3–T5 T5–O1 Fp2–F8 F8–T4 T4–T6 T6–O2 O1–O2 Fp1–F2 F3–C3 C3–P3 P3–O1 Fp2–F4 F4–C4 C4–P4 P4–O2 *LA0 *LA1 *LA2 *LA3 *RA0 *RA2 *RA3 *LA0–LA1 *LA1–LA2 *LA2–LA3 *RA0–RA2 *RA2–RA3 LA0–LA1 LA0–LA2 *LA0–LA3 *RA0–RA2 *RA0–RA3

50 μV 1s

Figure 14.6 Lateralization of interictal epileptiform discharges in the anterior thalamic nucleus (AN). A focal epileptiform discharge is marked on the scalp over the left frontal region, with phase reversal over the F3 electrode (upper arrow) and on bipolar recording in the thalamus in the left AN electrodes (lower arrow). Note that the sensitivity of the top 16 channels is 7 �V/mm, the next 7 channels (AN referenced to linked ears) is 20 �V/mm, and the bottom 10 bipolar channels in AN 3 �V/mm. Note also that a clear lead from the left thalamus is not seen in the referential contacts, perhaps due to spread of the field.

side of origin of these discharges in the frontal cortex. Figures 14.6 and 14.7 demonstrate epileptiform activity lateral­ ized on the scalp which is also lateralized in AN when bipolar montaging is used during recording from AN electrodes. 3. The anterior thalamus may play a role in seizure propagation. In simultaneous recordings from the scalp and AN in patient 1 (Figure 14.8), epileptiform dis-

charges appeared to begin in the right frontal region, spread to the left frontal region, then to move to the thalamus within approximately 15–20 ms. Of inter­ est, AN stimulation did not significantly reduce the number of this patient’s seizures, but rather modulated them so that they were more often partial than gen­ eralized (as was the case prior to implanta­ tion), and significantly reduced falls. This

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EEG AND THE ANTERIOR THALAMIC NUCLEUS

*Fp1–F7 *F7–T3 *T3–T5 *T5–O1 *Fp2–F8 *F8–T4 *T4–T6 *T6–O2 *Cz–Pz *O1–O2

50 μV 1s

*LA0–LA1 *LA0–LA2 *LA0–LA3 *RA0–RA2 *RA0–RA3

Figure 14.7 Regional lateralization of epileptiform activity in the anterior thalamic nucleus (AN). A burst of polyspikes is seen in the scalp electrodes maximal in the right anterior temporal region, with considerable spread of the field to the left mid-temporal area. In the bipolar (AN) electrodes (actually referenced to the deepest contact on each side), predominance of the field in right AN is demonstrated.

improvement in the patient’s condition was hypothesized to be due to disruption of seizure spread through the thalamus, there­ fore limiting secondary generalization of seizures. In addition to the conclusions noted above, these very early recordings from humans implanted with AN electrodes suggest that not only does it appear that AN electrodes may be useful for brain stimulation in treat­ ment trials for epilepsy, but that recording from these electrodes may provide important clues as to mechanisms of seizure propaga­ tion in the human brain, and the role of the anterior thalamus in this process. Given that recordings from AN were of excellent quality and comparable to other recordings obtained from intracranial EEG electrodes, our experi­

182

ence suggests that it may be worthwhile to investigate the possible use of thalamic recordings for the purposes of seizure detec­ tion and perhaps prediction. While it may appear that not all of cortically generated interictal epileptiform activity is conducted to the thalamus, all seizures in the patients we monitored were seen in AN electrodes. The utility of this type of monitoring may also be dependent on the location of the ictal onset zone, and whether or not this region projects to AN. For example, our patients with frontal lobe epilepsy all appeared to have seizure spread to AN relatively early. It is unclear if this would be the case with seizures that originate more posteriorly, although AN has many connections to regions all over the brain through the circuit of Papez, and other white matter tracts.

DISCUSSION

Fp1 Fp2 F3 F4 F3 F4 C3 C4 O1 O2 F7 F8 T3 T4 T5 T6 *LA1 *LA2 *LA3 *RA2 *RA3 *ECG1 *ECG2 of30 M1 M2

50 μV 1s

Figure 14.8 Temporal relationship between frontal scalp and anterior thalamic nucleus (AN) discharges. The tracing, with time scale expanded, shows several discharges originating in the frontal regions with some, but not all, conducted to the AN bilaterally. In several of these interictal discharges (e.g. see arrows) onset appears to be in the right frontal region, followed by rapid spread to the left frontal region then to AN. Although the recording technique (e.g. reference of AN electrodes to linked mastoid reference) raises questions about accurately localizing AN fields, the timing of the discharges should remain unchanged.

Again, it is important to emphasize the very preliminary nature of the observations related above. While they may prove somewhat useful in helping aid localization of electrodes implanted in thalamus, and provide food for thought for those interested in thalamic neuro­ physiology and the neurophysiology of epilepsy, further, more detailed and extensive experimental observations will need to be made, within the constraints of appropriately supervised clinical trials, to validate and expand on our observations.

Suggested protocol for anterior thalamic nucleus intraoperative physiology: evoking the recruiting response I. Initial stimulation settings a. Pulse width: 90 microseconds. b. Frequency: 7 hertz.

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EEG AND THE ANTERIOR THALAMIC NUCLEUS

(i) may measure anywhere from 2 Hz to 20 Hz (ii) maximum amplitude is provoked at 7–10 Hz (iii) adjust stimulation frequency away from dominant background rhythm to maximize signal-to-noise ratio (iv) prime numbers (e.g. 5,7, 13 Hz) are best, to avoid harmonics of noise. c. Amplitude: Begin stimulation at 0 volts and increase slowly to threshold (where response is seen). Record threshold value for each location and continue to stimulate up to 5 V, so as to expose each patient to the same amount of stimulation (for clini­ cal trials). Usual thresholds are in the range of 2–4 V. Hold each stimulation for at least 10 seconds at each location once the recruiting response is seen. For clinical trials it may be desirable to set a specific duration for viewing and recording the response, such as 20 s. It is important to remember that the recruiting response takes at least 2–5 s to become apparent on the EEG after initiating stimulation. d. Use monopolar electrode for stimulation. e. EEG montage: Use longitudinal bipolar montage. If the approach requires that F3 and F4 cannot be used due to the location of burr holes in the operative field, use Fp1-C3 and Fp2–C4 in the montage, or place F3′ and F4′ lateral to their usual locations. f. Affix electrodes with collodion prior to sur­ gical implantation after the stereotaxic frame has been affixed to the patient’s skull and targeting in the MRI scanner has been completed. We do this in the operating room, although a preparation room with proper ventilation will do.

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II. Stimulation mapping a. Position monopolar electrode at projected deepest location of most distal contact of the DBS electrode. Stimulate according to the above parameters. As noted above, record coordinates of stimulation location and voltage at which the recruiting response is first seen (threshold). Increase voltage gradually, stopping briefly at 0.5 volt intervals starting at 0.5 V and go up to 5.0 V, holding each stimulation for 10 s. b. Note position and threshold on EEG record. c. Retract electrode by 2 mm and repeat pro­ cedure for a span of 2 cm (10 times), or until the electrode no longer evokes a recruiting response (it is out of the nucleus). d. If this procedure fails to generate a recruit­ ing rhythm, careful consideration should be given to trying another track/approach from the same coordinates. Prior to changing location, another option is to gradually increase the pulse width and repeat the pro­ cedure, to a maximum of 180 microseconds.

Acknowledgements We would like to extend our deepest gratitude to the six patients involved in this study without whom advancement in this field would not be possible. The authors would like to acknowledge Marc Dichter, Gordon Baltuch, Jacqueline French, Mary Ann Brodie, Delight Matthews and Raeleen Dolan for their contributions to this pilot trial. Dr Litt’s work is supported by the Whitaker Foundation, the American Epilepsy Society,

REFERENCES

the Epilepsy Foundation, the Charles Henry Dana Foundation, and by National Institutes of Health Grants RO1NS041811-01 and RO1MN062298-02. Stephen Cranstoun was supported by the National Institutes of Health (NIH) under Grant T32-GM07517, and cur­ rently by the National Science Foundation (NSF) Graduate Research Fellowship.

References 1. Mirski M, Fisher R. Electrical stimulation of the mammillary nuclei increases seizure threshold to pentylenetetrazol in rats. Epilepsia 1994;35: 1309–16. 2. Steriade M, Contreras D. Spike-wave complexes and fast components of cortically generated seizures: I. Role of neocortex and thalamus. J Neurophysiol 1998;80:1439–55. 3. Steriade M, Contreras D, Amzica F, Timofeev I. Synchronization of fast (30–40 Hz) spontaneous oscillations in intrathalamic and thalamocortical networks. J Neurosci 1996;16:2788–808. 4. Steriade M, Curro Dossi R, Contreras D. Electrophysiological properties of intralaminar thalamocortical cells discharging rhythmic (approximately 40 HZ) spike-bursts at approxi­ mately 1000 HZ during waking and rapid eye movement sleep. Neuroscience 1993;56:1–9. 5. Contreras D, Curro Dossi R, Steriade M. Bursting and tonic discharges in two classes of reticular thalamic neurons. J Neurophysiol 1992; 68:973–7. 6. Contreras D, Steriade M. State-dependent fluctu­ ations of low-frequency rhythms in corticothala­ mic networks. Neuroscience 1997;76:25–38.

7. Destexhe A, Contreras D, Steriade M. Corticallyinduced coherence of a thalamic-generated oscil­ lation. Neuroscience 1999;92:427–43. 8. Vertes RP, Albo Z, Viana Di Prisco G. Thetarhythmically firing neurons in the anterior thala­ mus: implications for mnemonic functions of Papez’s circuit. Neuroscience 2001;104:619–25. 9. Mirski MA, Ferrendelli JA. Anterior thalamic mediation of generalized pentylenetetrazol seizures. Brain Res 1986;399:212–23. 10. Mirski MA, McKeon AC, Ferrendelli JA. Anterior thalamus and substantia nigra: two distinct structures mediating experimental generalized seizures. Brain Res 1986;397:377–80. 11. Cooper IS, Upton AR, Amin I, et al. Evoked metabolic responses in the limbic-striate system produced by stimulation of anterior thalamic nucleus in man. International J Neurology 1984;18:179–87. 12. Jenkins TA, Dias R, Amin E, et al. Fos imaging reveals that lesions of the anterior thalamic nuclei produce widespread limbic hypoactivity in rats. J Neuroscience 2002;22:5230–8. 13. Hodaie M, Wennberg RA, Dostrovsky JO, Lozano AM. Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia 2002;43:603–8. 14. Kerrigan J, Fisher R. Personal communication. 15. Dempsey E, Morison R. The production of rhyth­ mically recurrent cortical potentials after local­ ized thalamic stimulation. Am J Physiol 1942; 135:293–300. 16. Velasco F, Velasco M, Velasco AL, et al. Electrical stimulation of the centromedian thala­ mic nucleus in control of seizures: long-term studies. Epilepsia 1995;36:63–71. 17. Fisher R, Uematsu S, Krauss G, et al. Placebocontrolled pilot study of centromedian thalamic stimulation in treatment of intractable seizures. Epilepsia 1992;33:841–51.

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Section IV

Effect of brain stimulation on epileptic seizures: animal experiments

15

Absence seizures in the GAERS model: subthalamic nucleus stimulation Alim-Louis Benabid, Laurent Vercueil, Karine Bressand, Maurice Dematteis, Abdelhamid Benazzouz, Lorella Minotti and Philippe Kahane

Introduction

Animal models of epilepsy

Epilepsy is a term derived from the Greek word ‘epilepsia,’ which means ‘to seize.’ In current usage, epilepsy refers to a variety of neurological disorders characterized by recur­ rent seizures. It is a common neurological dis­ order having a prevalence of 0.5–1%. It can affect people of any age, sex, or race. It is esti­ mated that nearly 2.5 million people in the United States have epilepsy. Approximately 50% of seizures are of the partial type and the majority of these arise in the temporal lobe. In patients with intractable temporal lobe epilepsy, magnetic resonance imaging (MRI) can frequently identify hippocampal sclerosis, and surgery can render 60–70% of these cases seizure-free. Surgery is an invasive procedure associated with complications, such as quad­ rantanopia. However, a significant proportion of patients with drug-resistant epilepsy are not candidates for epilepsy surgery. Therefore, other therapeutic approaches must be found. Clinical and experimental observations suggest that seizures can be controlled by neu­ ronal structures, particularly those involved in motor control. The nigro-striatal system seems to be particularly important as a network capable of controlling seizures.

Only selected animal models of epilepsy emulate human epilepsy. These include status epilepticus injury causing partial-onset epilepsy, several genetic epilepsy models of generalized epilepsy, and models of cortical dysgenesis. Many human disorders associated with seizures do not have animal models. The following brain abnormalities can cause epilepsy in mammals. Focal injuries Most of the time, focal injuries produce partial-onset seizures. Models of cortical dysgenesis Cortical dysgenesis (CD) is a human cause of epilepsy that has been well studied with animal models Disruption of any of the steps involved in the formation of the neocortex can result in CD. In utero irradiation of rats is one model in which CDs and heterotopias occur. In another model, methylazoxymethanol (MAM) treated rats demonstrate increased numbers of bursting neurons in the hippocampus and neocortex, as well as heterotopic bridges.

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Models of limbic epilepsy Status epilepticus model. This is an initial precipitating injury. Several animal models of temporal lobe epilepsy (TLE) involve a down­ stream consequence of brain damage induced by an acute episode of status epilepticus, which can be triggered through two main mechanisms: (1) administration of a chemical convulsant (pilocarpine1 or kainic acid); or (2) electrical stimulation. Several weeks after status epilepticus, secondary generalized seizures occur spontaneously. These seizures usually persist for the entire lifespan, and tend to be of limbic origin, frequently in the hip­ pocampus. Typical patterns of hippocampal sclerosis (HS) are observed, and include neu­ ronal loss and circuit rearrangements, particu­ larly sprouting of mossy fibers.

Kindling model. This has many desirable fea­ tures in several mammalian species. It is clearly progressive, through five behavioral stages, which can be manipulated separately. Hippocampal kindling progresses much more slowly than amygdala kindling. Models of drug resistance. It is not clear whether mechanisms of drug resistance are operative from the start of treatment, or whether there is a progressive development of drug resistance during the course of treatment. Drug resistance is likely to be a multifactorial process,2 including genetic factors (e.g. poly­ morphisms), disease-related factors (e.g. etiol­ ogy of the seizures), and drug-related factors (e.g. loss of anticonvulsant efficacy during treatment). Overexpression of multi-drug transporters may be one important mecha­ nism: brain expression of the multiple drugresistance gene, MDR1 (encoding the multidrug transporter P-glycoprotein), is markedly increased in the majority of drug-resistant epileptic patients.3 There are selected animal

190

models which express drug-resistance charac­ teristics, namely, a pharmacoresistant sub­ group of amygdala-kindled Wistar rats,4 the pilocarpine model of TLE,5 and the 6 Hz corneal stimulation seizure model.6 Genetic models of epilepsy We lack adequate animal models for temporal lobe epilepsy (TLE) without hippocampal scle­ rosis (HS), and for dual pathology. There are many genetic epilepsy animal models, such as the Genetic Absence Epilepsy Rat of Strasbourg (GAERS), the Genetically EpilepsyProne Rat (GEPR), various mutant mice (including DBA/2, E1, quaking, tottering, lurcher, and staggerer), the Mongolian gerbil, epileptic baboons (like the Papio-papio, which has a spontaneous photosensitive epilepsy). Genetic models may have some features similar to human epilepsy. GAERS rats, and GEPR rats in particular, have many desirable characteristics. They mimic human seizures and the human response to drugs. The seizures are predictable and reproducible. GAERS rats are an interesting model with EEG and behavioral aspects similar to human absence epilepsy. Absence seizures in this model are suppressed by all antiabsence drugs. Absence seizures occur spontaneously, have a duration of approximately 20 seconds, and are characterized by generalized spike and wave discharges (SWD), concomitant with behavioral arrest.7 The epileptiform discharges are facilitated by noradrenergic and dopamin­ ergic decrements and GABAergic increments. They are suppressed by ethosuximide and other antiabsence drugs, but are exacerbated by phenytoin and other anticonvulsant drugs. Progress in the understanding of the role of the basal ganglia in the control of seizures has been advanced using this genetic model of generalized non-convulsive seizures.8 The cortex and the reticular nucleus and the ven­

THE NIGRAL CONTROL OF EPILEPSY

trobasal relay nuclei of the thalamus play an important role in the development of SWD. In contrast, in the GEPR rat model, three types of convulsive seizures occur: (1) general­ ized tonic-clonic seizures; (2) partial seizures; and (3) partial seizures with secondary tonic­ clonic generalization. GEPR rats have a predis­ position to sound-induced seizures which can be assessed by an audiogenic response score (ARS). (0, no response; 3, moderate seizures exhibiting clonic convulsions; 9, complete tonic extensions). Anticonvulsant treatment lowers the ARS score. GEPR rats respond to a broad spectrum of drugs, and also to those useful in generalized tonic-clonic and partial seizures, but not to baclofen and chlorpro­ mazine. In GEPR rats there is a deficiency of noradrenaline, serotonin, and probably GABA, and possibly an excess of glutamate. The tottering mouse exhibits features of generalized epilepsy including generalized spike-waves on EEG and absence-like seizures. ‘EL mice’ are the only genetic animal models that express seizure-associated damage to the hippocampus, a region of the brain commonly damaged by epilepsy in humans. 31 P-labelled oligonucleotide probes specific for low voltage activated calcium channels bind more in the GAERS rat in different brain regions than in non-epileptic control strains, but the difference of distribution is marginally significant.9 Studies in the ventro-posterior (VP) thalamus and nucleus reticularis thalami (NRT) neurons from control rats and GAERS rats have also shown that there is an overexpression of the �1 G mRNA subunit in GAERS as compared to controls. The �1 H subunit is also overexpressed in the NRT of adult and juvenile rats, but all other subunits, such as �1I and �1E, are not abnormal in GAERS rats. During the past two years, the genetic muta­ tions responsible for epilepsy in several differ­

ent mouse models, including the tottering and stargazer mice were identified. The stargazer mutation,10 interferes with proper functioning of calcium channels, allowing overexcitation of neurons that leads to seizures. A second form of seizure, known as ‘slow-wave epilepsy’, because of its characteristic pattern of electrical recordings from the brain, is caused by a mutation that inactivates the sodium-hydrogen transporter.

The nigral control of epilepsy The nigral control of epilepsy systems is the most advanced conceptual scheme of endoge­ nous control of epileptogenicity.11–14 Since the beginning of the 1980s, the substantia nigra (SN) has been considered to be a key structure in the control of epileptic seizures. Although the SN is not critical in the initiation of seizures, its inhibition by local injection of GABA-mimetic drugs results in antiepileptic effects. This finding led Karen Gale to suggest that the ‘. . . substantia nigra may contain synapses capable of modifying the development and propagation of a seizure, regardless of the neural mecha­ nisms responsible for the seizure initiation’.15,16 The SN, located in the ventral midbrain is com­ posed of two main subnuclei: (1) the pars com­ pacta (SNc), which contains dopaminergic neurons which project primarily to the stria­ tum; and (2) the pars reticulata (SNr), which contains GABAergic neurons projecting to: (i) the ventro-medial nucleus of the thalamus; (ii) the intermediate and deep layers of the superior colliculus (SC); and (iii) the pedunculopontine and laterodorsal nuclei of the ventral tegmen­ tum The nigro-collicular pathway (connecting the SNr to SC) exerts a tonic inhibition of the SC and a decrease of SNr activity results in disinhibition of collicular neurons,17 and plays a major role in the modulation of seizures. In dif­

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ABSENCE SEIZURES IN THE GAERS MODEL

ferent models of epileptic seizures, lesion of the SC antagonizes the antiepileptic effects obtained by injecting a GABA agonist into the SN. Activation of SC neurons by local injection of glutamate agonists or GABA antagonists also results in significant antiepileptic effects.18–20 The antiepileptic effects resulting from disinhibition of the SC neurons remain to be elucidated. Circuits modulating the nigro­ collicular pathway may exert a control on epileptic seizures.

The modulating effect of basal ganglia activity on absence seizures The substantia nigra pars reticulata (SNr), one of the main output structures of the basal ganglia, receives a monosynaptic GABAergic projection from the striatum and a polysynaptic (through globus pallidus pars externa (Gpe)) glutamatergic excitatory input from the sub­ thalamic nucleus. Activation of the direct striato-nigral pathway releases GABA in the SNr, resulting in a transient suppression of the tonic inhibition of SNr neurons on their targets. Through these direct and indirect succession of synapses, the striatum can modulate the SNr neurons. The subthalamic nucleus is a key element of the indirect striato-nigral pathway.21 Although the cellular details of activation of either D1 or D2 receptors in the striatum are not yet fully understood, several data have shown that intrastriatal application of D1 agonists increases the activity of the direct pathway, whereas application of D2 agonists decreases the activity of the indirect pathway and blocks seizures in different models of convulsions.22

The direct striato-nigral pathway Substantia nigra pars reticulata (SNr) neurons have a spontaneous high tonic activity.23 The

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modulation of absence seizures through inhi­ bition of the SNr by the direct GABAergic striato-nigral pathway was elucidated initially by intranigral injections of GABAA agonists which induced antiepileptic effects. Intrastriatal bilateral injection of NMDA, as well as D1 agonists, suppresses absence seizures, and even more efficiently, seizures induced by nucleus accumbens stimulation. Striatal activation by either glutamate or D1 agonists increases the release of GABA in the SNr and decreases SNr activity, inducing a decrease of seizures. Blockade of the GABAA receptors in the SNr, as well as of the D1 receptors in the striatum, increases absence seizures in GAERS rats.

The indirect striato-nigral pathway The above described model predicts that due to glutamatergic excitation of the substantia nigra pars reticulata (SNr) from the subthala­ mic nucleus (STN) input activation of the indi­ rect striato-nigral pathway should control epileptic seizures. In GAERS rats, injections of NMDA antagonist in the SNr-suppressed absence seizures. High frequency stimulation or bilateral injection of a GABA agonist in the STN suppresses the activity of the SNr and the spike and wave discharges (SWD). Injection of a GABAA antagonist into the globus pallidus or the ventral pallidum resulted in seizure sup­ pression in GAERS rats. This suppression of absence seizures correlated with a decrease of glutamate levels in the SNr, suggesting that the antiepileptic effects induced by disinhibition of the pallidum is mediated through a reduction of activity of the STN. Conversely, an increase in the occurrence of absence seizures was observed after injections of a GABAA agonist into the ventral pallidum. Intrastriatal injec­ tions of D2 agonists suppressed absence

TREATMENT OF EPILEPSY IN ANIMAL MODELS BY HIGH FREQUENCY STIMULATION

seizures in GAERS rats and blockade of D2 receptors by intrastriatal antagonists signifi­ cantly increases absence seizures. Suppression of seizures is associated with disinhibition of neurons in the intermediate and deep layers of the superior collicus (SC). Furthermore, a marked suppression of absence seizures was obtained after com­ bined intranigral injections of muscimol, a GABA A agonist and small doses of CGP 40116, an NMDA antagonist. Systemic injection of dopamimetics also suppress absence seizures, whereas injection of dopamine antagonists and lesions of dopaminergic neurons within the SNc and ventral tegmental area (VTA) aggravate absence seizures in GAERS rats. The most effective targets for modulation of absence seizures by intracerebral microin­ jections were located relatively ventrally, both at the striatal (nucleus accumbens) and palli­ dal (ventral pallidum) levels. The fact that more ventrally located circuits are involved in the control of absence seizures is in agreement with both clinical and experimental observa­ tions, indicating the importance of the moti­ vational state in the occurrence of absence seizures. Activation of neurons in the stria­ tum, by injection of either an NMDA agonist,24 or a GABA antagonist,25 has been shown to block seizures induced by pilo­ carpine. This suppression of seizures was reversed by the subsequent injection of a GABA antagonist in the SNr. As for the indi­ rect pathway, intranigral injections of NMDA antagonists have been shown to suppress myoclonic, tonic-clonic, or partial seizures with secondary generalization.26 The critical role of the STN in these antiepileptic effects was confirmed using local injections of a GABA agonist in models of generalized tonic­ clonic seizures or partial seizures with sec­ ondary generalization.21,27

Treatment of epilepsy in animal models by high frequency stimulation of the subthalamic nucleus Why the subthalamic nucleus (STN)? The key role of STN in the organization of the basal nuclei led to attempts to manipulate this nucleus in order to activate the nigral control of epilepsy system in animal models. Why high frequency stimulation (HFS)? It has been known for many centuries that electrical stimulation produces excitation of the nervous system. In the Latin era (circa 79AD), excitation of the sensorimotor affer­ ents in humans was induced by natural sources of electricity, such as torpedo fish. This was also used clinically as a treatment in some forms of rheumatism. In 1804, Jean Aldini in Bologna, using batteries designed by Alessandro Volta, conducted an experiment where he attached a conductor to the scalp of a subject and reported the sensations described by the subject. Aldini suggested that electrical stimulation might have a therapeutic role. This type of experiment eventually led to electrical stimulation of the thalamus and spinal cord, and more recently the premotor cortex for the treatment of pain. High frequency electrical stimulation has been applied for several decades for the treat­ ment of movement disorders. HFS of various targets of the basal ganglia (Vim (ventral intermedius), CM-Pf (centrum medianum­ parafascicularis), internal pallidum, GPi (globus pallidus pars interna), STN) mimics ablative surgery in patients suffering from these dis­ orders. The ability of HFS of the basal ganglia to reproduce the same effect as lesions suggests that it induces the equivalent of inhibition of these structures. The mechanism by which

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ABSENCE SEIZURES IN THE GAERS MODEL

electrical stimulation inhibits cells is still un­ known. Possible mechanisms include ‘jamming’, inhibition of calcium and sodium voltagedependant channels, or an alteration of the neuronal firing pattern by inducing electrical activity comprising bursts in the gamma range. Extracellular recordings in different nuclei of the basal ganglia in rats,28 suggest that HFS inhibits not only the stimulated target, such as the sub­ thalamic nucleus (STN), but also the GPi (entopeduncular nucleus in the rat), and the substantia nigra pars reticulata (SNr). The inhi­ bition of these last two targets should result in a decrease of the gabaergic output to the ventro­ lateral (VL) thalamic nucleus, inducing a disin­ hibition of the thalamo-cortical activity. At the same time, decrease of the SNr GABAergic pro­ jection to the superior colliculus (SC) cells leads to its disinhibition. How could this be applied in the control of epilepsy? We have evaluated the effect of HFS of the STN in GAERS rats and compared these effects with those of lesions. HFS of the STN has also been investigated in models of limbic epilepsy in rats. The results confirm that inactivation of the STN by HFS is able to induce a significant suppression of absence seizures and to alter the course of the spike-wave discharge, together with the associ­ ated absence behavior. Chronic bilateral HFS of the STN is equivalent to bilateral ablation of the STN. However, chronic inactivation of the STN tends to become progressively less efficient. These experimental data have opened new per­ spectives for the treatment of intractable epilep­ sies in humans. Preliminary clinical applications to human refractory epilepsies have produced significant and long-lasting reduction in number and severity of seizures in these patients Karen Gale15 in Washington and Depaulis and Marescaux in Strasbourg,29 have shown that there is a nigral control of epilepsy. Injection in the SNr of GABA agonists or MNDA antagonists, as well as injection of

194

GABA antagonists in the SC is able to induce an antiepileptic effect in several animal models, and particularly in the GAERS model. This suggests that the inhibitory-like effect of HFS applied in the SNr or STN would also have an antiepileptic effect. According to the parallel processing model,30,31 inhibition of the STN should induce an inhibition of the SNr, thus validating the use of HFS in the STN to obtain an antiepileptic effect. This hypothesis has been corroborated by preliminary experiments in normal rats,32 where the effects of HFS of the STN on the superior colliculus has been studied. These studies showed that HFS inhibits the activity in the STN, decreasing the glutamatergic output to the substantia nigra with a decreased firing of that structure. Decreased GABAergic output of the SNr leads to a tran­ sient increase of activity in the SC during and immediately after HFS of the STN.

Effects of subthalamic nucleus stimulations in the GAERS rat High frequency stimulation (HFS) of the sub­ thalamic nucleus (STN) has been tested in vivo in the GAERS rat.33 The experiments showed that HFS of the STN interrupts bursts of spike and wave discharges (SWDS), and the associ­ ated absence behavior. The stimulus intensity necessary to obtain suppression of SWDs is lower than the stimulus intensity that induces suppression of absence behavior. This suggests that the lower stimulus intensity interrupts the EEG activity reflected on the surface EEG. However, it is likely that neuronal epileptic firing, which is not detectable by surface EEG, still continues and produces clinical absences. Higher stimulus intensities eventually lead to

DISCUSSION

suppression of clinical symptoms. In these experiments, the mean duration of the seizures was decreased, although this was not statisti­ cally significant. The total duration of seizures (mean duration of seizures multiplied by their number), however, was significantly decreased. The effect on total seizure duration was intensity-related. Subthreshold stimulation did not make any difference in the control studies. Stimulation slightly above the threshold signif­ icantly reduced the total duration of the seizure, and at higher stimulus intensities, the total duration of seizures was significantly decreased even further. Lesions produced by excitotoxic injection of kainic acid in the STN also reduced significantly the mean duration of seizures compared to bilateral injection of saline in the STN nuclei. Unilateral lesions of the STN induced a 25% reduction of seizures while bilateral destruction of the STN reduced seizures by 37.5%.

Effects of hippocampal and subthalamic nucleus stimulation in temporal lobe epilepsy Limbic epileptic seizures were elicited by uni­ lateral injection of kainic acid (8.15 ng) in the amygdala of rats (Berger’s model). The record­ ing was done from amygdala, hippocampus, and cortical structures. The status epilepticus induced by kainic acid injection in the amyg­ dala was interrupted for several dozen seconds by 130 Hz, 1 mA, 10 s hippocampal stimula­ tion. This would suggest a ‘flip-flop’ mecha­ nism, switching the equilibrium from the status epilepticus to normal EEG, and then to status epilepticus again. Preliminary experiments of subthalamic nucleus (STN) stimulation used in this same

temporal lobe epilepsy model, showed a trend to decrease the seizure duration in two animals, and in two other animals, a statisti­ cally significant reduction, suggesting that STN stimulation might also be effective in this model of temporal lobe epilepsy in rats.

Discussion Relevance of these data regarding the existence of the nigral control of epilepsy systems There is a large body of experimental evidence in support of the existence of the nigral system having output pathways, projections from the substantia nigra pars reticulata to the superior colliculus, which can influence the cortical excitability and the epileptogenicity in several models of epilepsy. Pharmacological manipu­ lation of this system can be replicated by inhi­ bition of the efferent output by high frequency stimulation of the subthalamic nucleus and substantia nigra pars reticulata. The direct link between this endogenous system and the epileptic phenomenon is still unclear. Although previous data tend to support the concept of a universal mechanism, capable of influencing all types of epilepsy, it is possible that there are animal models of epilepsy that cannot be controlled by this system. Moreover, it is still unknown what the rela­ tionship is between the nigral control of the epilepsy system and other targets, which when stimulated, affect seizure frequency (mamillo­ thalamic structures, vagal system).

Human therapeutic applications Preliminary human studies have already been carried out, even though animal models have not solved all problems or answered all ques­

195

ABSENCE SEIZURES IN THE GAERS MODEL

tions. However, the results of pilot human studies are encouraging. Fifteen years experi­ ence in the use of high frequency stimulation of deep brain nuclei in the treatment of move­ ment disorders has shown that the method is safe, that it is totally reversible and titratable, and that it offers a large degree of flexibility and adaptability, allowing exploration of numerous targets and several paradigms. To date, the effectiveness of closed loop modes of stimulation (triggered by the onset of the seizures) has still not been adequately evalu­ ated in humans. Deep brain stimulation seems to be a promising new therapeutic modality for patients with intractable epilepsy, but it is unlikely that it will replace current medical or resective surgical treatments.

Conclusion A better understanding of neuronal networks involved in the endogenous control of epilep­ togenicity could lead to identification of key targets which when stimulated could effec­ tively modulate cortical excitability. In this chapter, we have presented evidence that high frequency stimulation of the subthalamic nucleus (STN) can trigger a nigro-striatal antiepileptic effect on absence-like seizures in GAERS rats. In addition, status epilepticus in a temporal lobe epilepsy model can be reduced by hippocampal, as well as high frequency stimulation of the subthalamic nucleus. These data support human studies testing therapeuti­ cal applications of deep brain stimulation in patients with intractable epilepsy.

References 1. Turski L, Ikonomidou C, Turski WA, et al. Review: cholinergic mechanisms and epileptogen­ esis. The seizures induced by pilocarpine: a novel

196

experimental model of intractable epilepsy. Synapse 1989;3:154–71. 2. Löscher W, Schmidt D. Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clin­ ical considerations. Epilepsy Res 1988;2:145–81. 3. Tishler DM, Weinberg KT, Hinton DR, et al. MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia 1995;36:1–6. 4. Löscher W. Animal models of intractable epilepsy. Prog Neurobiol 1997;53:239–58. 5. Glien M, Brandt C, Potschka H, Löscher W. Effects of the novel antiepileptic drug levetirac­ etam on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy. Epilepsia 2002;43:350–7. 6. Brown WC, Schiffman DO, Swinyard EA, Goodman LS. Comparative assay of antiepileptic drugs by ‘psychomotor’ seizure test and minimal electroshock threshold test. J Pharmacol Exp Ther 1953;107:273–83. 7. Danober L, Deransart C, Depaulis A, et al. Pathophysiological mechanisms of genetic absence epilepsy in the rat. Prog Neurobiol 1998;55:27–57. 8. Deransart C, Marescaux C, Depaulis A. Involvement of nigral glutamatergic inputs in the control of seizures in a genetic model of absence epilepsy in the rat. Neuroscience 1996;71:721–8. 9. Talley E, Solorzano G, Depaulis A, et al. Low­ voltage-activated calcium channel subunit expres­ sion in a genetic model of absence epilepsy in the rat. Mol Brain Res 2000;75:159–65. 10. Letts, VA, Felix R, Biddlecome GH, et al. The mouse stargazer gene encodes a neuronal Ca2+­ channel gamma subunit. Nature Genetics 1998; 19:340–7. 11. Depaulis A, Vergnes M, Marescaux C, et al. Evidence that activation of GABA receptors in the substantia nigra suppresses spontaneous spike-and-wave discharges in the rat. Brain Res 1988;448:20–9. 12. Depaulis A, Snead OI, Marescaux C, Vergnes M. Suppressive effects of intranigral injection of mus­ cimol in three models of generalized non-convul­ sive epilepsy induced by chemical agents. Brain Res 1989;498:64–72. 13. Depaulis A, Vergnes M, Marescaux C. Endogenous control of epilepsy: the nigral

REFERENCES

inhibitory system. Prog Neurobiol 1994;42: 33–52. 14. Deransart C, Vercueil L, Marescaux C, Depaulis A. The role of basal ganglia in the control of gen­ eralized absence seizures. Epilepsy Res 1998;32: 213–23. 15. Gale K. Mechanisms of seizure control mediated by gamma aminobutyric acid: role of the substan­ tia nigra. Fed Proc 1985;44:2414–24. 16. Garant DS, Gale K. Substantia nigra-mediated anti-convulsant actions: role of nigral output pathways. Exp Neurol 1987;97:143–59. 17. Chevalier G, Vacher S, Deniau J, Desban M. Disinhibition as a basic process in the expression of striatal functions: I. The striato-nigral influence on tecto-spinal: tecto-diencephalic neurons. Brain Res 1985;334:215–26. 18. Depaulis A, Liu Z, Vergnes M, et al. Suppression of spontaneous generalized non-convulsive seizures in the rat by microinjection of GABA antagonists into the superior colliculus. Epilepsy Res 1990;5: 192–8. 19. Gale K, Pazos A, Maggio R, et al. Blockade of GABA receptors in superior colliculus protects against focally evoked limbic motor seizures. Brain Res 1993;603:279–83. 20. Redgrave P, Dean P, Simkins M. Intratectal gluta­ mate suppresses pentylenetetrazole-induced spike­ and-wave discharges. Eur J Pharmacol 1988;158: 283–7. 21. Veliskova J, Velsek L, Moshe SL. Subthalamic nucleus: a new anticonvulsant site in the brain. Neuroreport 1996;7:1786–8. 22. Wahnschaffe U, Löscher W. Anticonvulsant effects of ipsilateral but not contralateral microin­ jections of the dopamine D2 agonist LY 171555 into the nucleus accumbens of amygdala-kindled rats. Brain Res 1991;553:181–7. 23. Nakanishi H, Kita H, Kitai S. Intracellular study of substantia nigra pars reticulata neurons in an in vitro slice preparation: electrical membrane properties and response characteristics to subthal­ amic nucleus stimulation. Brain Res 1987;437: 45–55.

24. Cavalheiro E, Turski L. Intrastriatal N-methyl-D­ aspartate prevents amygdala kindled seizures in rats. Brain Res 1986;377:173–6. 25. Turski L, Cavalheiro EA, Bortolotto ZA, et al. Dopamine-sensitive anticonvulsant site in the rat striatum. J Neurosci 1988;8:3837–47. 26. Maggio R, Gale K. Seizures evoked from area tempestas are subject to control by GABA and glutamate receptors in substantia nigra. Exp Neurol 1989;105:184–8. 27. Dybdal D, Gale K. Anticonvulsant effects of focal inhibition of the subthalamic nucleus. 26th Annual Meeting of the Society for Neuroscience Washington, DC, November 1996. 28. Benazzouz A, Piallat B, Pollak P, Benabid AL. Responses of substantia nigra pars reticulata and globus pallidus complex to high frequency stimu­ lation of the subthalamic nucleus in rats: electro­ physiological data. Neurosci Lett 1995;189: 77–80. 29. Marescaux C, Vergnes M, Depaulis A. Genetic absence epilepsy in rats from Strasbourg—a review. J Neural Transm 1992;35(Suppl):37–70. 30. Albin R, Young A, Penney J. The functional anatomy of basal ganglia in movement disorders. Trends Neurosci 1989;12:366–75. 31. Delong M. Primate models of movement disor­ ders of basal ganglia origin. Trends Neurosci 1990;13:281–5. 32. Bressand K, Dematteis M, Kahane P, et al. Involvement of the subthalamic nucleus in the control of temporal lobe epilepsy: study by high frequency stimulation in rats [Abstract 663.3]. 29th Annual Meeting of the Society for Neuroscience, Miami, October, 1999. 33. Vercueil L, Benazzouz A, Deransart C, et al. High-frequency stimulation of the subthalamic nucleus suppresses absence seizures in the rat: comparison with neurotoxic lesions. Epilepsy Res 1998;31:39–46. 34. Berger ML, Lasmann H, Hornykiewicz O. Limbic seizures without brain damage after injection of low doses of kainic acid into the amygdala of freely moving rats. Brain Res 1989;489:261–72.

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16

Focal limbic seizures induced by kainic acid: effects of bilateral subthalamic nucleus stimulation Andrew Pan, Atthaporn Boongird, Takaheru Kunieda, Imad Najm and Hans O Lüders

Introduction

Kainic acid-induced seizures

Kainic acid, derived from the seaweed, Digenea simplex, has been used as a chemo­ convulsant to elicit both acute and chronic spontaneous, recurrent seizures in animals. This arguably provides a close representation of human temporal lobe epilepsy secondary to hippocampal sclerosis.1,2 Given either systemically or focally (intra-hippocampus, intra-amygdala, intra-ventricle), it is a potent convulsant agent that is able to elicit severe, frequent, and prolonged clinico-electrographic seizures. The resulting histological changes in this animal model closely parallel those seen in human hippocampal sclerosis. The subthalamic nucleus (STN) has extens­ ive connections in the central nervous system via the thalami, basal ganglia nuclei, cerebral cortex and the brainstem. It has recently sur­ faced as a possible target for the interruption or abolition of epileptic activity through various proposed mechanisms. This chapter will discuss the clinical and electrographic features of kainate-induced seizures in rats, the electrographic observa­ tions of STN recordings during such seizures, and the effects of bilateral STN stimulation on these seizures.

Kainic acid (KA) has been injected directly into the subcutaneous tissue, veins, peri­ toneum, hippocampus, amygdala and into the ventricles to induce seizures.1,3–13 The systemic or focal administration of KA induces distinct clinical seizure stages.1,13–15 Within the first 20–30 minutes, animals exhibit decreased activity, ‘staring’, drooling, followed by head nodding, ‘wet dog shakes’ lasting 30–60 minutes. Approximately an hour postinjection, recurrent seizures that are character­ ized by masticatory or facial movements, tremor of the forepaws, rearing and loss of postural tone ensue. These seizures increase in intensity, duration and occur at progressively shorter interictal periods. This is followed by almost continuous convulsions, lasting up to 2–5 hours. The surviving animals (up to 30% mortality) return to ‘normal’ for a silent period of between 5 and 21 days before up to half to almost all animals begin to exhibit spontaneous (or during handling), recurrent limbic seizures. 15,16 Recurrent injections of kainic acid lead to more severe clinical seizures.9 Electroencephalographically (EEG), the interictal and ictal epileptiform activity ini­

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FOCAL LIMBIC SEIZURES INDUCED BY KAINIC ACID

tially remains confined to the hippocampus and amygdala before generalization to involve other non-limbic structures.1,3,5,15,16 Goto et al. studied the spread of intra-hippocampal kainate-induced seizures (injection) by quanti­ fying local cerebral blood flow and demon­ strated initial seizure spread to the contralat­ eral hippocampus, followed by activation of the ipsilateral amygdala, other limbic struc­ tures, striatum and sensorimotor cortex.17 Subsequent spread of seizure activity was recorded to the ipsilateral globus pallidus, substantia nigra, subthalamic nucleus, thala­ mus, septum and parietal cortex. This corre­ sponds to the stages of clinical seizure activity (i.e. initial staring and individual limbic seizures to later generalized motor convul­ sions). Over time and with unilateral kainic acid injections, contralateral hippocampal interictal and ictal epileptiform discharges also develop.11 Histologically, the changes after kainic acid induced seizures are most prominent in the hippocampus, amygdala, piriform lobe, septum and medial thalamus. Early changes include shrinking and pyknosis of neuronal perikarya and dendritic swelling with pro­ nounced edema of astrocytes and microglial proliferation. Interest in KA as a convulsant first stemmed from the proposed selective action of kainate on neuronal cell bodies, sparing axons and fibers of passage, though the latter has since been disputed. Increasing neuronal cell loss is appreciated with increas­ ing survival of the animal. In the later stages, with the neuronal loss in the CA3 (more than CA1 and CA4) region of the hippocampus, synaptic reorganization similar to that seen in humans occurs, with sprouting of mossy fibers in the dentate gyrus.1,11,18–20 This likely leads to the spontaneous, recurrent clinical seizures observed later post-kainic acid injection.

200

The subthalamic nucleus (STN) and its connections The STN is a small, well-defined, densely pop­ ulated nucleus located between the zona incerta superiorly and the cerebral peduncle inferiorly. Measuring 1 mm (mediolateral) × 0.9 mm (anteroposterior) × 0.5 mm (dorsoventral) in the rat and respectively 10 mm × 9 mm × 7 mm in humans, it is sur­ rounded almost in its entirety by myelinated fibers. In rodents, neurons make up almost the whole nucleus while in primates neurons make up about 10–20% of the nucleus.21 The STN neurons are closely apposed to each other, between soma, dendrites and initial axon seg­ ments. No gap junctions have been demon­ strated between these appositions and the presence of interneurons within the STN is still controversial. STN neurons have long axons with sparse dendrites; projection neurons in the rat STN could possibly func­ tion as interneurons via intrinsic, intranuclear axon collaterals and extrinsic axon collaterals that terminate in the substantia nigra pars reticulata (SNr), globus pallidus (GP) and the entopeduncular nucleus (homologue of globus pallidus interna in primates-GPi).

Efferents of the STN The STN has significant projections to the GP and the SN (SNr more than substantia nigra pars compacta—SNc),21,22 and less prominent ones to the striatum, cortex, substantia innominata, pedunculopontine tegmental nucleus and the mesencephalic and pontine reticular formation. In rodents, significant axon collateralization occurs such that the same population of STN neurons may com­ municate with different target structures. This occurs much less in primates (10–20%) where different populations of STN neurons appear

THE SUBTHALAMIC NUCLEUS (STN) AND ITS CONNECTIONS

to have distinct systems of communication with their various target structures. The STN exerts an excitatory glutamatergic effect on its target neurons.23–25 The activity of the target structures may be modified in quantity or quality of firing.

Afferents of the STN The STN receives prominent afferents from the pallidum (globus pallidus externa—GPe in primates, GP in rodents) and cortex.21,22 Less prominent afferents include those from the centromedian parafascicular complex of the thalamus, brainstem nuclei (SN, dorsal raphe nucleus, pedunculopontine tegmental nucleus). Pallido-subthalamic afferents are GABAergic in nature. In rodents, the cortico-subthalamic afferents arise from the primary motor cortex, the prefrontal cortex (most abundant), ante­ rior and medial cingulate cortex, primary somatosensory region and less so from the insular cortex. In primates, these arise mainly from the primary motor cortex. The afferents of the STN are arranged somatotopically with the dorsolateral region more associated with motor function and the ventromedial region with oculomotor and associative motor func­ tion. In rodents and primates, the medial aspect of the STN appears to be the target of the limbic structures. Cortico-subthalamic afferents have been shown to be excitatory, glutamatergic in nature.26

STN electrophysiology: regulatory and stimulation effects In vivo recordings of rat STN neuronal activ­ ity document single-spike activity as well as burst-firing activity.27 The spontaneous irreg­ ular firing rate of the rat STN is approx­ imately 14.7 ± 0.4 spikes/s.22 STN activity in

patients undergoing deep brain stimulation therapy for Parkinson’s disease demonstrate a mean firing rate of 37 ± 17 Hz (25–45 Hz) and an irregular burst firing pattern.28 The increased and burst firing activity of the STN in patients with Parkinson’s disease is thought to result from loss of nigrostriatal dopamine neurons29,30 and may be contributory to the signs and symptoms of the disease. STN activity is modulated by its afferents. Stimulation of cortico-subthalamic afferents leads to an increase in STN activity,21 while pallido-subthalamic activation causes a decrease in STN activity. 31 Another regu­ latory influence arises from the excita­ tory glutamatergic thalamic parafascicular afferents.32–34 Direct microstimulation of the STN itself did not seem to cause abnormal movements in experimental animals.35 Tzagournissakis et al. did observe ipsiversive head turning, inter­ mittent sniffing, exploring and jaw move­ ments with increased stimulation intensity.36 Benazzouz et al. had shown that high fre­ quency stimulation (HFS) of the STN signifi­ cantly decreased the frequency of (immediate post-stimulation) extracellularly recorded STN neurons in rats in vivo.37,38 They also observed decreased activity of the SN and GP with HFS of the STN. Beurrier et al. showed that HFS with 100–250 Hz, 100 �s bipolar stimuli was able to produce a full blockade of tonic or bursting activity of STN slices in vitro.39 They postulated that this occurred as a result of depolarization blockade. Although a tempting comparison to the similar thera­ peutic results obtained by lesioning the STN and subjecting the STN to HFS in patients with Parkinson’s disease, the investigators conceded that in the clinical setting, in vivo STN stimulation may have consequential effects on the basal ganglia as a whole; HFS of the STN may mimic the clinical effects of STN

201

FOCAL LIMBIC SEIZURES INDUCED BY KAINIC ACID

lesion but may do so via mechanisms inclusive of or even different from abolition or inhibi­ tion of STN activity. Contravening evidence have arisen to support this notion. Ashby et al. did not find evidence of ‘blocking’ with HFS of the STN but that the latter may acti­ vate large fiber system(s) and leads to a thala­ mocortical inhibition.40 Tzagournissakis et al. mapped cerebral metabolic activity with uni­ lateral STN stimulation utilizing bipolar (polarity switching every half minute), 0.25 Hz 100 ms trains consisting of high fre­ quency (300 Hz, 0.5 ms, 100 �s) square wave pulses.36 They showed increased glucose uti­ lization within the STN, ipsilateral SNr and GP. Less significant elevations in glucose uti­ lization was also demonstrated within the entopeduncular nucleus, the ventromedial part of the posterior striatum and the SNc. The investigators also mentioned that stimula­ tion at lower frequencies and intensities did not induce any metabolic changes. Windels et al. showed that HFS of the subthalamic nucleus induced a significant increase of extracellular glutamate levels in the ipsilateral GP and SN.41 The effects of electrical stimulation of the STN may not be as predictable or ‘pure’ as with chemical inhibition with GABA mimetic agents. With the abundant collaterals in rodent deep brain nuclei, electrical stimula­ tion of ‘one’ structure could bring about con­ comitant simultaneous ‘direct’ stimulation effects of various surrounding structures via collaterals. Furthermore, Mclntyre and Grill showed that HFS of the STN could simultane­ ously inhibit neurons and excite axons. Altering stimulation paradigms may possibly produce different effects on the STN and its efferent targets.42 The afferents of the STN may also be affected by antidromic conduc­ tion of electrical impulses. Cortical potentials with STN stimulation have been observed in animals,43 and humans.44,45

202

Effects of high frequency stimulation of the STN on KA-induced seizures Electrical stimulation has been used to induce seizures since the 1960s,46,47 as well as investi­ gated,48–60 although rarely in a controlled manner, to disrupt seizure activity. Several targets of electrical stimulation for treatment of seizures had previously been attempted in humans and animals, including the cerebel­ lum, caudate nucleus, hippocampus and various nuclei in the thalamus. These past evaluations were rarely randomized or con­ trolled and the few that were, did not show consistently beneficial results for electrical stimulation for the treatment of epileptic seizures. The subthalamic nucleus (STN) has recently surfaced as a potential target for elec­ trical stimulation to modulate seizure activity. Being a compact nucleus with closely apposed neuronal structures, the whole nucleus lends itself to be within the field of stimulation at low stimulation intensities. With extensive evi­ dence that demonstrated the inhibitory effect of bilateral substantia nigra pars reticulata (SNr) inhibition on various animal seizure models,61 attention turned to the place of the STN within this circuit for seizure control, it being a significant glutamatergic efferent of the SNr. Deransart et al., and Velískova et al. both showed that chemical inhibition of the STN also raised seizure threshold like bilateral SNr inhibition.62,63 Vercueil et al. demon­ strated suppression of absence seizures in rats with high frequency stimulation (HFS) of the STN.64 The investigators showed only positive results with bilateral and not unilateral STN stimulation. Bressand et al. also found that bilateral HFS on STN decreased seizure activ­ ity of intra-amygdaloid kainate-induced seizures in rats.65

EFFECTS OF HIGH FREQUENCY STIMULATION OF THE STN ON KA-INDUCED SEIZURES

Effect of bilateral STN stimulation on acute KA-induced seizures We recently examined the effects of bilateral, continuous HFS of the STN on systemic kainate-induced seizures in Sprague-Dawley rats. Epidural electrodes were placed over the frontal and parietal regions of the cortex and stereotactically into the depths of the STN and hippocampi. The experimental paradigm required repetitive video-EEG recordings of the same rat in three separate sessions with intraperitoneal injections of saline (to screen

for baseline epileptiform activity), kainate (10 mg/kg, subcutaneous) without STN stimu­ lation and kainate with STN stimulation. Epileptiform activity (Figure 16.1) was termi­ nated at 1 hour post-injection with intraperi­ toneal pentobarbital in order to reduce the mortality of the rats from severe seizure activ­ ity. All epileptiform EEG data were blindly analysed and quantified. The amount of epileptiform activity was compared across all three separate sessions (with rest day in between) for the same rat and the results

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aLF–aREF 200 uV aRF–aREF aLP–aREF aRP–aREF aLH–aREF aRH–aREF aLSTN1–aREF aLSTN2–aREF aRSTN1–aREF aRSTN2–aREF aLH–aRH aLSTN1–aRSTN1

1s

Figure 16.1 (A) EEG of kainate-induced seizure. (B) Seizure onset noted in the hippocampal depth electrodes with

spread to the parietal then frontal electrodes. Note the similar polarity in the STN discharges with that

of the hippocampal and parietal (overlies the dorsal hippocampus) discharges; the frontal electrodes

record a corresponding opposite polarity. LF, left frontal; RF, right frontal; LP, left parietal;

RP, right parietal; LH, left hippocampal; RH, right hippocampal; LSTN, left STN (dual contacts 1,2);

RSTN, right STN (dual contacts 1,2).

203

FOCAL LIMBIC SEIZURES INDUCED BY KAINIC ACID

pooled for all the rats (n = 8) to appreciate the overall effect of STN stimulation. The order of these three sessions were later switched (in an additional group of 4 rats) to see if similar results could be replicated. In all 12 rats, HFS of the STN significantly delayed the onset of kainate-induced seizures (mean 19.54 min vs 8.75 min) and the proportion of secondary generalized seizures (27.71% vs 53.62%), although the proportion of focal epileptiform activity in the hippocampi showed no signifi­ cant decrease. Altering the order of the experi­ mental paradigm, that is, rats subjected to session with kainate and STN HFS first fol­ lowed by kainate alone after the mandatory rest day showed similar results but also con­ firmed that kainate injection without bilateral STN stimulation resulted in earlier onset of seizures and more severe convulsions. These effects were not modulated by the preceding session with STN HFS. Unilateral STN stimu­ lation had no effect on either the latency or the duration of the EEG seizures following KA injection.

Potential mechanisms of high frequency bilateral STN stimulation on acute status epilepticus Based on the known anatomo-functional con­ nections of the subthalamic nucleus (STN) and the potential effects of high frequency stimula­ tion (HFS), the following are possible mech­ anisms that may play a role in the reduction or delay of seizure activity: 1. Inhibition of the STN. Based on the hypothesis that a subcortical network exists to modulate cortical excitability,66,67 the proposed nigral control of epilepsy

204

system (NCES) composed of the SNpr, STN, striatum, pallidum and the superior colliculi can be activated by manipulating the activity of its various nuclei compo­ nents. Inhibition of the STN, and therefore removing tonic excitatory afferent input to the substantia nigra pars reticulata (SNr), leads to a decreased activity of the inhibitory afferents of the SNr to the supe­ rior colliculi and subsequent disinhibition of the dorsal midbrain anticonvulsant zone (DMAZ) and a resultant elevated thresh­ old to epileptiform activity. HFS may inhibit the STN via depolarization blockade, or concomitant excitation of GABAergic feedback from collaterals in the basal ganglia onto the STN. Bikson et al. recorded a stimulus-locked rise in extracellular potassium concomitant with suppression of epileptiform activity of hip­ pocampal neurons with HFS68, this may be due to disruption of potassium regulation by glial cells during HFS. 2. Antidromic activation of cortico-subthala­ mic connections disrupting cortical excitability. The activation of the subthal­ amo-cortical pathway by STN stimulation has been elegantly demonstrated by Baker and Montgomery.69 Rather than HFS inhibiting all neural elements within the STN, they demonstrated that cortical evoked potentials could be elicited instead. Disruption of cortical excitability could occur by means of cellular desynchroniza­ tion, increased cortical GABAergic or decreased cortical glutamatergic synaptic activity. This could also explain our find­ ings of decreased secondary generalized seizure activity relative to focal hippocam­ pal seizure activity. 3. Activation of STN and its efferents. This may cause an initial inhibition (from ini­ hibitory SNr afferents) and subsequent

REFERENCES

increase (direct STN afferent excitatory effect) in dopaminergic activity mediated through the substantia nigra pars com­ pacta (SNc).70 Dopaminergic SNc has been shown to be able to control hippocampal­ based epileptiform activity.71

Future directions This short review aimed to discuss recent and current work into the potential effects of sub­ thalamic nucleus (STN) stimulation on seizure activity. Continuous improvement in our understanding of the anatomical connections and electrophysiological behavior of various nuclei in the basal ganglia and their neocorti­ cal (and hippocampal) connections (or lack of), it is hoped that modulating their activity would not only yield results in movement dis­ orders but also in intractable epilepsy. The various constraints to an elegant study of the effects of electrical stimulation on deep brain nuclei have been discussed. Further metabolic and electrophysiologic investigations are needed to study the connectivity of STN with various epileptogenic structures and the poten­ tial antiepiletogenic mechanisms of STN stim­ ulation.

References 1. Ben-Ari Y. Limbic seizure and brain damage pro­ duced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 1985;14:375–403. 2. Engel J, Jr. Experimental animal models of epilepsy: classification and relevance to human epileptic phenomena. Epilepsy Res 1992;Suppl 8:9–20. 3. Ben-Ari Y, Lagowska J. [Epileptogenic action of intra-amygdaloid injection of kainic acid]. C R Acad Sci Hebd Séances Acad Sci D 1978;287: 813–16.

4. Schwarcz R, Zaczek R, Coyle JT. Microinjection of kainic acid into the rat hippocampus. Eur J Pharmacol 1978;50:209–20. 5. Ben-Ari Y, Lagowska J, Tremblay E, Le Gal La Salle G. A new model of focal status epilepticus: intra-amygdaloid application of kainic acid elicits repetitive secondarily generalized convulsive seizures. Brain Res 1979;163:176–9. 6. Pisa M, Sanberg PR, Corcoran ME, Fibiger HC. Spontaneously recurrent seizures after intracere­ bral injections of kainic acid in rat: a possible model of human temporal lobe epilepsy. Brain Res 1980;200:481–7. 7. Owen RT. Intrastriatal kainic acid- a possible model for antidyskinetic/antichoreic agents? Methods Find Exp Clin Pharmacol 1980;2: 133–7. 8. Kaijima M, Tanaka T, Daita G, et al. [A new model of epilepsy—a small epileptic focus by microinjection of kainic acid into the unilateral hippocampus in cats (author’s transl)]. No To Shinkei 1981;33:1133–40. 9. Tremblay E, Ben-Ari Y. Usefulness of parenteral kainic acid as a model of temporal lobe epilepsy. Rev Electroencephalogr Neurophysiol Clin 1984;14:241–6. 10. Araki T, Tanaka T, Tanaka S, et al. Kainic acidinduced thalamic seizure in cats—a possible model of petit mal seizure. Epilepsy Res 1992;13:223–9. 11. Babb TL, Pereira-Leite J, Mathern GW, Pretorius JK. Kainic acid induced hippocampal seizures in rats: comparisons of acute and chronic seizures using intrahippocampal versus systemic injec­ tions. Ital J Neurol Sci 1995;16:39–44. 12. Miettinen R, Kotti T, Tuunanen J, et al. Hippocampal damage after injection of kainic acid into the rat entorhinal cortex. Brain Res 1998;813:9–17. 13. Sperk G, Lassmann H, Baran H, et al. Kainic acid induced seizures: Neurochemical and histopathological changes. Neuroscience 1983; 10:1301–15. 14. Racine R. Modification of seizure activity by electrical stimulation: II. Motor seizure. Electro­ encephalogr Clin Neurophysiol 1972;32:281–94. 15. Cavalheiro EA, Riche DA, Le Gal La Salle G. Long-term effects of intrahippocampal kainic acid injection in rats: A method for inducing spontaneous recurrent seizures. Electro­ encephalogr Clin Neurophysiol 1982;53:581–9.

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16. Bragin A, Engel J, Jr., Wilson CL, et al. Electro­ physiologic analysis of a chronic seizure model after unilateral hippocampal KA injection. Epilepsia 1999;40:1210–21. 17. Goto Y, Araki T, Kato M, Fukui M. Propagation of hippocampal seizure activity arising from the hippocampus: a local cerebral blood flow study. Brain Res 1994;634:203–13. 18. Chronin EP, Dudek FE. Chronic seizures and col­ lateral sprouting of dentate mossy fibers after kainic acid treatment in rats. Brain Res 1988; 474:181–4. 19. Mathern GW, Cifuentes F, Leite JP, et al. Hippocampal EEG excitability and chronic spon­ taneous seizures are associated with aberrant synaptic reorganization in the rat intrahippocam­ pal kainate model. Electroencephalogr Clin Neurophysiol 1993;87:326–39. 20. Davenport CJ, Brown WJ, Babb TL. Sprouting of GABAergic and mossy fibers axons in the dentate gyrus following intrahippocampal kainate in the rats. Exp Neurol 1990;109:180–90. 21. Parent A, Hazrati L-N. Functional anatomy of the basal ganglia: II. The place of the subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res 1995;20: 128–54. 22. Feger J, Hassani O-K, Mouroux M. The subthal­ amic nucleus and its connections: New electro­ physiological and pharmacological data. In: Obeso JA, Delong MR, Ohye C, Marsden CD (eds) The basal ganglia and new surgical approaches for Parkinson’s disease. Advances in neurology. Philadelphia: Lippincott-Raven, 1997, 31–43. 23. Robledo P, Féger J. Excitatory influence of rat subthalamic nucleus to substantia nigra pars reticulata and the pallidal complex: electrophysi­ ological data. Brain Res 1990;518:47–54. 24. Parent A, Hazrati L-N, Smith Y. The subthalamic nucleus in primates: a neuroanatomical and immunohistochemical study. In: Cross A, Sambrook M (eds) Neural mechanisms in disor­ ders of movement. London: John Libbey, 1989, 29–35. 25. Albin RL, Aldridge W, Young AB, Gilman S. Feline subthalamic nucleus neurons contain glu­ tamate-like but not GABA-like or glycine-like immunoreactivity. Brain Res 1989;491:185–88. 26. Fujimoto K, Kita H. Response characteristics of subthalamic neurons to the stimulation of the

206

sensorimotor cortex in the rat. Brain Res 1993;609:185–92. 27. Hollerman JR, Grace AA. Subthalamic nucleus cell firing in the 6-OHDA-treated rat: basal activ­ ity and response to haloperidol. Brain Res 1992; 590:291–9. 28. Hutchison WD, Allan RJ, Opitz H, et al. Neurophysiological identification of the subthala­ mic nucleus in surgery for Parkinson’s disease. Ann Neurol 1998;44:622–8. 29. Wichmann T, DeLong MR. Physiology of the basal ganglia and pathophysiology of movement disorders of basal ganglia origin. In: Watts RL (ed) Movement disorders: Neurological principles and practice. New York: McGraw-Hill, 1997, 87–97. 30. DeLong MR. Primate models of movement disor­ ders of basal ganglia origin. Trends Neurosci 1990;13:281–5. 31. Rouzaire-Dubois B, Hammond C, Hamon B, Feger J. Pharmacological blockade of the globus pallidus-induced inhibitory responses of the sub­ thalamic cells in the rat. Brain Res 1980;200: 321–9. 32. Mouroux M, Hassani O-K, Feger J. Electrophysiological study of the excitatory parafascicular projection to the subthalamic nucleus and evidence for ipsi- and contralateral controls. Neuroscience 1995;67:399–407. 33. Mouroux M, Feger J. Evidence that the parafasci­ cular projection to the subthalamic nucleus is glu­ tamatergic. Neuroreport 1993;4:613–5. 34. Feger J, Mraovitch S, Mouroux M. The thalamic parafascicular projection to the subthalamic nucleus: a glutamatergic excitatory pathway. Neurosci Abstr 1992;18:136. 35. Wichmann T, Bergman H, DeLong MR. The primate subthalamic nucleus: I. Functional prop­ erties in intact animals. J Neurophysiol 1994; 72:494–506. 36. Tzagournissakis M, Dermon CR, Savaki HE. Functional metabolic mapping of the rat brain during unilateral electrical stimulation of the sub­ thalamic nucleus. J Cereb Blood Flow Metab 1994;14:132–44. 37. Benazzouz A, Gao DM, Ni ZG, et al. Effect of high-frequency stimulation of the subthalamic nucleus on the neuronal activities of the substan­ tia nigra pars reticulata and ventrolateral nucleus of the thalamus in the rat. Neuroscience 2000;99:289–95.

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38. Benazzouz A, Piallat B, Pollak P, Benabid AL. Responses of substantia nigra pars reticulata and globus pallidus complex to high frequency stimula­ tion of the subthalamic nucleus in rats: electro­ physiological data. Neurosci Lett 1995;189:77–80. 39. Beurrier C, Bioulac B, Audin J, Hammond C. High-frequency stimulation produces a transient blockade of voltage- gated currents in subthala­ mic neurons. J Neurophysiol 2001;85:1351–6. 40. Ashby P, Kim YJ, Kumar R, et al. Neuro­ physiological effects of stimulation through elec­ trodes in the human subthalamic nucleus. Brain 1999;122:1919–31. 41. Windels F, Bruet N, Poupard A, et al. Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat. Eur J Neurosci 2000;12:4141–6. 42. McIntyre CC, Grill WM. Selective microstimula­ tion of central nervous system neurons. Ann Biomed Eng 2000;28:219–33. 43. Maurice N, Deniau JM, Glowinski J, Thierry AM. Relationships between the prefrontal cortex and the basal ganglia in the rat: physiology of the corticosubthalamic circuits. J Neurosci 1998;18: 9539–46. 44. Montgomery EB, Baker KB. Mechanisms of deep brain stimulation and future technical develop­ ments. Neurol Res 2000;22:259–66. 45. Ashby P, Paradiso G, Saint-Cyr JA, et al. Potentials recorded at the scalp by stimulation near the human subthalamic nucleus. Clin Neurophysiol 2001;112:431–7. 46. Bancaud J, Talairach J, Morel P, Bresson M. Ammon’s horn and amygdaline nucleus: clinical and electric effects of their stimulation in man. Rev Neurol (Paris) 1966;115:329–52. 47. Bancaud J, Talairach J, Bresson M, Morel P. Epileptic attacks induced by stimulation of the amygdaloid nucleus and horn of Ammon: value of stimulation in the determination of temporal lobe epilepsy in humans. Rev Neurol (Paris) 1968;118:527–32. 48. Reimer GR, Grimm RJ, Dow RS. Effects of cere­ bellar stimulation on cobalt-induced epilepsy in the cat. Electroencephalogr Clin Neurophysiol 1967;23:456–62. 49. Wright GD, McLellan DL, Brice JG. A doubleblind trial of chronic cerebellar stimulation in twelve patients with severe epilepsy. J Neurol Neurosurg Psychiatry 1984;47:769–74.

50. La Grutta V, Sabatino M. Focal hippocampal epilepsy: effect of caudate stimulation. Exp Neurol 1988;99:38–49. 51. Krauss GL, Fisher RS. Cerebellar and thalamic stimulation for epilepsy. Adv Neurol 1993;63: 231–45. 52. Feinstein B, Gleason CA, Libet B. Stimulation of locus coeruleus in man. Preliminary trials for spasticity and epilepsy. Stereotact Funct Neurosurg 1989;52:26–41. 53. Hablitz JJ, Rea G. Cerebellar nuclear stimulation in generalized penicillin epilepsy. Brain Res Bull 1976;1:599–601. 54. Cooper IS, Amin I, Gilman S. The effect of chronic cerebellar stimulation upon epilepsy in man. Trans Am Neurol Assoc 1973;98:192–6. 55. Cooper IS, Amin I, Riklan M, et al. Chronic cerebellar stimulation in epilepsy. Clinical and anatomical studies. Arch Neurol 1976;33:559–70. 56. Cooper IS, Upton AR. Effects of cerebellar stimu­ lation on epilepsy, the EEG and cerebral palsy in man. Electroencephalogr Clin Neurophysiol 1978;34(Suppl):349–54. 57. Levy LF, Auchterlonie WC. Chronic cerebellar stimulation in the treatment of epilepsy. Epilepsia 1979;20:235–45. 58. Chkhenkeli SA, Chkhenkeli IS. Effects of thera­ peutic stimulation of nucleus caudatus on epilep­ tic electrical activity of brain in patients with intractable epilepsy. Stereotact Funct Neurosurg 1997;69(1–4):221–4. 59. Ardern S. Cerebellar stimulation for epilepsy. Nurs Times 1985;81:32–4. 60. Velasco AL, Velasco M, Velasco F, et al. Subacute and chronic electrical stimulation of the hippocampus on intractable temporal lobe seizures: preliminary report. Arch Med Res 2000;31:316–28. 61. Depaulis A, Vergnes M, Marescaux C. Endogenous control of epilepsy: the nigral inhibitory system. Prog Neurobiol 1994;42:33–54. 62. Deransart C, Le BT, Marescaux C, Depaulis A. Role of the subthalamo-nigral input in the control of amygdala-kindled seizures in the rat. Brain Res 1998;807:78–83. 63. Veliskova J, Velisek L, Moshe SL. Subthalamic nucleus: a new anticonvulsant site in the brain. Neuroreport 1996;7:1786–8. 64. Vercueil L, Benazzouz A, Deransart C, et al. High-frequency stimulation of the subthalamic nucleus suppresses absence seizures in the rat:

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comparison with neurotoxic lesions. Epilepsy Res 1998;31:39–46. 65. Bressand K, Dematteis M, Kahane P, et al. Involvement of the subthalamic nucleus in the control of temporal lobe epilepsy: study by high frequency stimulation in rats. Soc Neurosci 1999;25:1656. 66. Gale K, Iadarola MJ. Seizure protection and increased nerve terminal GABA: delayed effects of GABA transaminase inhibition. Science 1980; 208:288–91. 67. Iadarola MJ, Gale K. Substantia nigra: site of anticonvulsant activity mediated by gamma­ aminobutyric acid. Science 1982;218:1237–40.

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68. Bikson M, Lian J, Hahn PJ, et al. Suppression of epileptiform activity by high frequency sinu­ soidal fields in rat hippocampal slices. J Physiol 2001;531:181–91. 69. Baker K, Montgomery E. Cortical evoked poten­ tials from STN stimulation. Soc Neurosci Abstr 2000;26:1226. 70. Smith ID, Grace AA. Role of the subthalamic nucleus in the regulation of nigral dopamine neuron activity. Synapse 1992;12:287–303. 71. Grutta VL, Sabatino M. Substantia nigra medi­ ated anti-convulsant action: a possible role of a dopaminergic component. Brain Res 1990;515: 87–93.

17

Focal stimulation versus deep brain stimulation Tatsuya Tanaka, Kiyotaka Hashizume, Atsuko Matsuo, Tomoyuki Urino, Hiroshige Tsuda, Koichi Kato, Akira Hodozuka and Hirofumi Nakai

Introduction Recent advances in epilepsy surgery have established resective procedures as a valuable therapeutic option for patients with intractable epilepsy. However, the results obtained by using resective procedures are still not completely satisfactory. Even if surgical treatment of mesial temporal lobe epilepsy results in seizure freedom in close to 80% of the patients, there are still 20% of cases who experience recurrent seizures. Other treatment options should be considered for these patients. In previous studies, we examined the effect of prolonged stimulations of various subcortical structures prior to amygdala kin­ dling in cats.1 We found that only low fre­ quency stimulations (10 Hz) of the ventro­ lateral nucleus of the thalamus and central grey matter were effective in modifying gener­ alized seizures elicited by kindling. In the present study, electrical stimulations of differ­ ent targets were applied to rats in which focal seizures were induced by focal application of kainic acid (KA).

Materials and methods Electrical stimulations were delivered to target structures via implanted bipolar electrodes

using a 3-channel stimulator. The stimulation parameters were as follows: biphasic square wave pulses, 0.1 ms pulse duration with vari­ able frequencies. In each rat, the current inten­ sity necessary to elicit motor symptoms was measured. Stimulation intensity was set at 70% of the threshold for motor sequences.

Experiment 1 Twenty male Wistar rats were used in this study. Stereotaxic surgery was performed, and a cannula was implanted unilaterally into an amygdala to elicit limbic seizure. Bipolar recording electrodes were inserted into the ipsilateral amygdala and hippocampus. Seven days after surgery, stimulation of the amyg­ dala was tested in each rat before kainic acid (KA) injection. The threshold of the stimula­ tion that produces motor manifestation was measured. Continuous stimulation at 70% of the motor threshold was delivered. The inten­ sity of the stimulation was varied from 50 �A to 100 �A for low frequency stimulation and 100 �A to 200 �A for high frequency stimula­ tion. KA solutions (1 �g as KA) were injected using injection needles. About 30 min after the KA injection, limbic seizure status was elicited. High frequency (130 Hz) electrical stimulation and low frequency (10 Hz) were continuously applied to seven rats each before,

209

FOCAL STIMULATION VERSUS DEEP BRAIN STIMULATION

during, and after the KA injection. In the other six rats (controls), KA was injected into the amygdala but electrical stimulation was not performed.

Experiment 2 Twenty male Wistar rats were used in this study. Stereotaxic surgery was performed, and a cannula for KA injection was implanted uni­ laterally into the sensorimotor cortex. Bipolar electrodes were placed bilaterally in the senso­ rimotor cortices. Seven days after surgery, stimulation of the cortex was tested in each rat before KA injection. The threshold stimu­ lation for the motor manifestations was mea­ sured and a stimulation of 70% was delivered during the experiments. KA solutions (2 �g as KA) were injected using injection needles. After confirmation of induction of partial seizure status, electrical stimulation was applied to the cortical epileptic focus at a fre­ quency of 100 Hz in seven rats and at a fre­ quency of 1 Hz in seven rats. Stimulation was not performed in six rats. The intensity of the stimulation was varied from 10 �A to 50 �A in the high frequency group and from 1 mA to 1.5 mA in the low frequency group. Stimulation was applied for 40 min periods with rest intervals of 40 min.

Experiment 3 Twenty-two male Wistar rats were used in this study. Stereotaxic surgery was performed, and a cannula for KA injection was implanted uni­ laterally into the sensorimotor cortex. Bipolar electrodes were placed bilaterally into the sub­ thalamic nucleus (STN). Monopolar elec­ trodes were placed in both sensorimotor cor­ tices. Seven days after surgery, stimulation of the STNs was tested in each rat before KA injection. The threshold stimulation for clini­

210

cal manifestations was measured in each rat. Stimulation intensity of 70% threshold was delivered in all rats. The intensity of the stimu­ lation varied from 100 �A to 200 �A. KA solutions (2 �g as KA) were injected using injection needles. Electrical stimulation was applied to both STNs (130 Hz) before, during, and after the KA injection. In seven rats, elec­ trical stimulation (10 Hz) was tested. In the other eight rats, stimulation was applied uni­ laterally to one STN at a frequency of 130 Hz. In four of those eight rats, the STN was stimu­ lated ipsilateral to the cortical epileptic focus. In the other four rats the STN contralateral to the epileptic focus was stimulated. Stimulation was applied for 40 min periods with rest inter­ vals of 40 min. At the end of the experiments, all animals were perfused with 10% formalin solution and processed for pathological studies.

Results In Experiment 1, KA injections into the amyg­ dala produced limbic seizure status in all rats (Figure 17.1). Seizures recurred every 2–5 minutes and the clinical seizure status per­ sisted for about 8 hours, consistent with previ­ ous reports.2 In this limbic seizure model, con­ tinuous focus stimulation was applied to the ipsilateral amygdala. Both high (130 Hz) and low frequency (10 Hz) was used. A summary of the results is shown in Table 17.1. Stimulation to the amygdala induced afterdis­ charges with motor manifestation or clinical seizures at relatively low intensities even at low frequency stimulation. Therefore, it was difficult to determine whether amygdala stim­ ulation was effective in modifying the limbic seizure status. Indeed, stimulation of the amygdala promoted seizures. In two rats, however, 10 Hz stimulation did not change

DISCUSSION

Figure 17.1 EEG during limbic seizure status after kainic acid injection in the left amygdala. LCx, left motor cortex; RCx, right motor cortex; LA, left amygdala.

LCx RCx

LA

2 min

200 μV

KA focus

Stimulation

High frequency

AM

Focal Focal

promotion promotion

nc nc

Cx

STN

suppression suppression nc

nc nc nc

Bil Ipsi Contra

Low frequency

Table 17.1 Result of stimulation of the epileptic focus of subthalamic nucleus (STN) stimulation in kainic acid-induced focal seizures in rats.

the electroclinical seizures but suppressed the numbers of recurrent seizures. In Experiment 2, unilateral KA injection into the sensorimo­ tor cortex resulted in focal motor seizure status in all rats. In this model, seizures recurred every 4–5 minutes and clinical seizures persisted for about 8 hours.3 Stimulation was applied for 40 minute periods with a rest interval of 40 minutes. High fre­ quency stimulation of the cortical focus facili­ tated recurrent seizures. However, stimulation at a frequency of 1 Hz reduced the frequency of seizures and of spiking in three rats. In Experiment 3, high frequency stimulation with a strong current induced circling and other behavioral abnormalities, such as searching or biting. Consequently, the intensity of stimula­ tion was always kept at 70% of the threshold of clinical manifestations. Low frequency (10 Hz) stimulation did not modify the focal cortical seizure status. However, unilateral

high frequency (130 Hz) stimulation of the subthalamic nuclei (STNs) reduced the fre­ quency of the recurrent cortical seizures (Figure. 17.2). Moreover, unilateral stimula­ tion of the STN (130 Hz) on the side of the epileptic focus also reduced the number of recurrent seizures. Unilateral stimulation of the contralateral STN had no effect on cortical seizures. Histopathological studies confirmed the exact location of the electrodes and revealed no apparent lesion at the stimulated site.

Discussion These experiments show that electrical stimu­ lation of the epileptic focus or subcortical structures can modifiy the kindling effect, kainic acid-induced limbic seizures or cortical seizures in experimental models of epilepsy.

211

FOCAL STIMULATION VERSUS DEEP BRAIN STIMULATION

40 min STN stimulus Number of focal seizures during 40 min

40

Rat No.

35

C ×01 C ×02 C ×03 C ×04 C ×05 C ×06 C ×07

30

25

20

15 10

Figure 17.2 Effect of high frequency (130 Hz) bilateral subthalamic nucleus (STN) stimulation in kainic acid induced focal cortical seizure status in rats. Seizures were suppressed during STN stimulation.

5 0

280 min Rest 1

Stim 1

Rest 2

Stim Rest 2 3

Stim 3

Rest 4

Dempsy and Morison reported that medial thalamic stimulation (5~15 Hz) resulted in modification of cortical electrical activities.4 Tanaka et al. observed inhibition of secondary generalized seizures in a cat amygdala-kindled model.1 In their study, subcortical structures were stimulated before and during the kin­ dling stimulation. Low frequency (10 Hz) stimulation of the ventro-laterial nucleus of the thalamus and of the contralateral grey matter suppressed secondary generalized seizure in the cat amygdala-kindled nuclei (Table 17.2). Cooper et al.5 and Sussman et al.6 stimulated the ventro-anterior nucleus of the thalamus and found that the stimulations resulted in a reduction in the number of seizures in patients with generalized epilepsy. Velasco et al.7 reported that electrical stimula-

Caudate N. VL CM MRF CGM

100 Hz

10 Hz

nc nc promotion promotion nc

nc suppression nc nc suppression

Table 17.2 Effect of subcortical stimulation on kindled seizures in cats.

212

tion (1 min periods of 60 Hz stimulation with 7 min intervals) of the centro-median (CM) nucleus of the thalamus significantly reduced the number of seizures in patients with gener­ alized epilepsy. However, Fisher et al. reported that CM stimulation was not effective in a double-blind study.8 We previously studied seizure propagation in a KA-induced seizure model.2 In the present study, a KA-induced limbic seizure status model was used to examine the effectiveness of electrical stimulation. The results demonstrated that additional electrical stimulation epileptic focus induced by a KA injection facilitated the epileptic activities of the focus. High frequency stimulation actually resulted in an increase in seizure frequency and number of spike dis­ charges. However, in two out of seven rats, the seizure frequency decreased during low fre­ quency stimulation of the amygdala. Cortical electrical stimulation of the epilep­ tic focus at a high frequency had no effects on the focal cortical seizure status. Moreover, high frequency stimulation increased the seizure frequency and the number of spike dis­ charges. However, repetitive focus stimulation, with low frequencies suppressed seizures in three rats. Electrical stimulation of the cortical epileptic focus in the motor area may not be

REFERENCES

possible because of the low threshold of the motor cortex to electrical stimulation. Recent studies in animals and in humans have shown that subthalamic nucleus (STN) stimulation has an inhibitory effect on epilep­ tic activity. The inhibitory role of the GABA system in the substantia nigra pars reticulata (SNr) has been the focus of several studies.8–11 Deransart et al. demonstrated that injection of a glutamate antagonist in the SN resulted in the control of seizures in a genetic model of absence epilepsy in the rat.12 It is well known that the STN has a glutamatergic output to the SNr. This has led to studies of high fre­ quency stimulation of the STN in an attempt to control seizures in the rat amygdala­ kindled,13 or absence seizure models.14 Both studies reported seizure suppression during stimulation. In addition, Bingaman et al.15 and Minotti et al.16 applied stimulation to the STNs in patients with intractable generalized seizures and also observed a reduction in the number of seizures. In these experiments, bilateral STN stimulations (130 Hz) were found to be effective for suppression of the cortical focal seizure status in rats. During the non-stimulation period, the number of seizures increased. Moreover, unilateral stimu­ lation of the STN ipsilateral to the epileptic focus was also effective in reducing the number of seizures. Unilateral stimulation of the STN contralateral to the side of the focus, however, had no effect. Consequently, bilateral or unilateral STN stimulation on the side of the focus may be useful in patients with intractable cortical focal seizures.

Summary The effect of continuous electrical stimulations of the epileptic focus of the subthalamic nucleus were examined using a kainic acid-

induced focal seizure status model. Low fre­ quency stimulation of the cortical focus and amygdala focus suppressed focal seizure status. Bilateral high frequency (130 Hz) stim­ ulation of both STNs or of the STN ipsilateral to the epileptic focus reduced the number of seizures in rats with focal cortical seizures induced by kainic acid. Electrical stimulation of the brain at intensities which produced no side effects may become a therapeutic option in patients with intractable epilepsy who are not candidates for resective surgery.

References 1. Tanaka T, Lange H, Naquet R. Sleep, subcortical stimulation and kindling in the cat. Can J Neurol Sci 1975;2:447–55. 2. Tanaka T, Tanaka S, Fujita T, et al. Experimental complex partial seizures induced by a microinjec­ tion of kainic acid into limbic structures. Prog Neurobiol 1992;38:317–334. 3. Tanaka T, Hashizume K, Sawamura A, et al. Basic science and epilepsy: experimental epilepsy surgery. Stereotact Funct Neurosurg 2001;77:239–44. 4. Dempsy EW, Morison RS. The production of rhythmically recurrent cortical potentials after localized thalamic stimulation. Am J Physiol 1942;135:293–300. 5. Cooper IS, Upton ARM. Therapeutic implica­ tions of modulation of metabolism and functional activity of cerebral cortex by chronic stimulation of cerebellum and thalamus. Biol Psychiatr 1985; 20:811–13. 6. Sussman NM, Goldman HW, Jackel RA, et al. Anterior thalamic stimulation in medically intractable epilepsy: II. Preliminary clinical results. Epilepsia 1988;29:67. 7. Velasco F, Velasco M, Ogarrio C, et al. Electrical stimulation of the centromedian thalamic nucleus in the treatment of convulsive seizures: prelimi­ nary report. Epilepsia 1987;28:421–30. 8. Fisher RS, Uematu S, Krauss GL, et al. Placebocontrolled pilot study of centromedian thalamic stimulation in treatment of epilepsy. Epilepsia 1991;33:841–51.

213

FOCAL STIMULATION VERSUS DEEP BRAIN STIMULATION

9. Depaulis A, Vergnes M, Marescaux C. Endogenous control of epilepsy: The nigral inhibitory system. Prog Neurobiol 1994;42: 33–52. 10. Iadarola MJ, Gale K. Substantia nigra: Site of anticonvulsant activity mediated by gamma­ aminobutyric acid. Science 1982;218:1237–40. 11. Le Gal La Salle G, Kaijima M, Feldblum S. Abortive amygdaloid kindled seizures following microinjection of gamma-vinyl-GABA in the vicinity of substantis nigra in rats. Neurosci Lett 1983;36:69–74. 12. Deransart C, Marescaux C, Depaulis A. Involvement of nigral glutamatergic inputs in the control of seizures in a genetic model of absence epilepsy in the rat. Neuroscience 1996;71: 721–8. 13. Deransart C, Le B-T, Marescaux C, et al. Role of the subthalamo-nigral input in the control of

214

amygdala-kindled seizures in the rat. Brain Res 1998;807:78–83. 14. Vercueil L, Benazzouz A, Deransart C, et al. High-frequency stimulation of the subthalamic nucleus suppresses absence seizures in the rat: comparison with neurotoxic lesions. Epilepsy Res 1998;31:39–46. 15. Bingaman WE, Hadar EJ, Najm IM, et al. Chronic stimulation of the subthalamic nucleus for the treatment of medically-intractable seizures: a case report. Epilepsia 2000;41 (Suppl 7):149. 16. Minotti L, Kahane P, Da Saint-Martin A, et al. Subthalamic nucleus high frequency stimulation in medically intractable epilepsy: long-term results in three patients. Epilepsia 2001;42 (Suppl 7):206–7.

18

The anterior thalamus and the pentylenetetrazol (PTZ) model Marek A Mirski, David L Sherman and Wendy C Ziai

Introduction Epilepsy afflicts approximately 1 per cent of the world’s population—over 50 million people. Of this total, 15 per cent, or approxi­ mately 7.5 million have intractable epilepsy with current medications.1 Alternative thera­ pies, such as surgery, are limited predomi­ nantly to those with temporal lobe seizure dis­ orders amenable to simple lobectomy, with potentially beneficial results. However, for patients with deep brain origin of seizures, or with primary generalized epilepsy, other options must be identified. Focal deep brain stimulation (DBS) is con­ sidered a potentially attractive, non-destruc­ tive means of stimulating or disrupting local neuronal transmission, and has been success­ fully introduced in the management strategies for several movement disorders, most notably for tremor and Parkinsonism. DBS now has been experimentally investigated for treating intractable generalized or partial-complex seizures, with the subthalamic region and the anterior thalamic nucleus (AN) as principal targets. Although enthusiasm is high for potential improvement in seizure control in patients, the mechanisms by which DBS is effective are not entirely clear. Research is underway to better understand both the anatomical circuitry and microphysiological

changes that occur as a result of AN DBS that elicit the anticonvulsant action. Historically, stimulation of discrete brain regions has been entertained as a treatment for medically intractable epilepsy, and has been used in a limited number of patients. To date, specific foci have included the cerebellum,2,3 locus coeruleus,4 thalamic centro-median,5–8 and the vagus nerve peripheral to the central nervous system (CNS).9,10 Most recently, direct hippocampal stimulation was shown to be of possible benefit in a pilot study of 10 patients with temporal lobe epilepsy.11 The overall results, however, have been mixed. Again, perpetuating the difficulty is the limited experimental data defining suitable deep brain regions for anticonvulsant stimulation. The expression of such generalized or partial-complex seizures appears to result from disturbances in multiple anatomical systems of brain occurring in a synchronous fashion.12–24 Since the early days of electroen­ cephalography and deep brain recording, it was postulated that both forebrain and subcortical influences appeared to be important in the development of EEG and behavioral con­ vulsant activity. Early support was derived from the works by Morison et al. and Dempsey and Morison that demonstrated the existence of diffuse projection channels linking the brainstem to the entire cortex.25,26

215

ANTERIOR THALAMUS AND THE PENTYLENETETRAZOL MODEL

Through such paths, epileptic cortical general­ ized discharges could be triggered from the brainstem. Three cycle per second spike-wave complexes were elicited on cortical EEG, resembling the epileptiform discharges seen in human petit mal epilepsy. These complexes were produced by stimulating the cat anterior thalamus and intralaminar nuclei with electri­ cal pulses of the same frequency. This concept was soon to be coined the ‘centroencephalic’ theory by Penfield and Jaspar.27 The identification of specific seizure prop­ agative pathways, however, has been difficult and has limited the development of site-spe­ cific clinical therapies such as DBS. The ante­ rior thalamus complex has recently been made a target for DBS trials based on experimental and clinical evidence accumulated over the past several decades. In animal studies, the AN and its connections to cingulate cortex and caudally to the hypothalamus and brain­ stem have been linked with seizure-precipitat­ ing mechanisms.20,28,29 As early as the 1940s, Jasper and Drooglever-Fortuyn studied corti­ cal EEG responses in the region of the intralaminar nuclei in cats and observed

epileptiform activity following thalamic stimu­ lation.19 Their stimulation points overlapped with the feline AN complex. Later, Green and Morin were able to elicit cortical ictal-like recordings during mammillary stimulation, and concluded that the mammillary-AN path was an important conduit for mediation of the cortical response.28 Lesion experiments in AN have been observed to attenuate EEG seizure discharges as well as depress electrical responses in other thalamic nuclei.30,31 For several decades, there has been anecdo­ tal evidence that the AN complex in humans may mediate seizure expression, and various interventions have been shown to ameliorate either the frequency or severity of attacks.32,33 Two reports, by Upton et al. in 1987, and Sussman et al. in 1988 reported supporting human data on AN-directed DBS.34,35 Recently, neurosurgical groups in Toronto and Phoenix published their results of acute and chronic AN DBS for refractory seizures as part of a multicenter human pilot trial.36–38 The encouraging results have led to a national National Institutes of Health-sponsored investigation.

Hippocampus

Figure 18.1 Anterior thalamic nucleus. CC

HPC

B

CPU Septal region

HA

V F N

AN

Thalamus

A C

Fields of Forel MF

DL

F

B

Anterior thalamic nucleus

MTT RF MB

MP

Posterior hypothalamus mammillary body

216

LPN

DTN VTN

EVIDENCE FOR ANTERIOR THALAMIC NUCLEUS (AN) MEDIATION OF PTZ SEIZURES

Anatomically and functionally, the anterior thalamic nucleus (AN) appears well situated for the role of mediating cortico-subcortical influences (Figure 18.1). Targets of AN effer­ ents are predominantly to limbic cortical structures, namely retrosplenial, presubicular, cingulate, and anterior limbic area.39,40 Its close linkage with hippocampus—a highly epilepto­ genic region—underscores the critical relay role AN may play between brainstem-thalamus­ hippocampus-neocortex. The AN is unique amongst thalamic nuclei in not having robust connectivity with reticular thalamus, an inhibitory relay nucleus that modulates other corticothalamic activity.41–43 Thus, the corti­ cofugal and ascending synaptic activity within the path: midbrain-hypothalamus-AN-cortex is not under reticular thalamic control, and serves as a unique independent corticothalamic com­ munication stream. That AN appears to be part of the ‘paleocerebrum’ along with hippocam­ pus, an example of ‘archicortex’, supports the primitive and diffuse connectivity of these regions which may optimally support propaga­ tion of generalized seizures. As described above, experimental evidence has defined AN as an important thalamic relay for the propagation of experimental seizures.44–57 Our laboratory has expanded this research area and has been able to provide additional evidence using a variety of inves­ tigative techniques to lend further support to AN’s role in seizures, as well as shed light on the mechanisms by which AN mediates parox­ ysmal activity.

The pentylenetetrazol (PTZ) model In order to investigate the process of general­ ized seizures, an experimental model system must be selected that facilitates extensive and

thorough examination. Ideally, the experimen­ tal model would consist of a convulsant agent or stimulus that satisfies the following criteria: (1) easily administered; (2) titratable; (3) includes both behavioral and EEG mani­ festations; (4) a model for human epilepsy; (5) antagonized by clinically useful anticon­ vulsants. The major chemical generalized seizure model is pentylenetetrazol (PTZ), a compound that provides similarities between human petit mal and grand mal seizures. The mechanism of action of PTZ is not entirely clear, although evidence suggest that both membrane and synaptic physiologies are altered by this com­ pound. Among some of the actions of PTZ, the chemical has been shown to alter the Na+ currents of non-bursting neurons, reduce the transmitter-induced chloride conductance, and also act as a selective antagonist of GABA.58–60 The behavioral and EEG manifestations of PTZ seizures are generally expressed in a wellordered stereotypic sequence. After a full con­ vulsant dose, the animal—best expressed in rat and mouse—begins with hyperactivity and whisker twitching followed by myoclonic jerks, running clonic, tonic flexion and extension and recurrent clonic seizures. EEG activity features repetitive medium and high voltage spike bursts as well as periods of trains of hypersynchro­ nous discharges that are characteristic follow­ ing high doses of the convulsant.

Evidence for anterior thalamic nucleus (AN) mediation of PTZ seizures To summarize, data using quantitative [14C]­ deoxyglucose autoradiography has identified a 217

ANTERIOR THALAMUS AND THE PENTYLENETETRAZOL MODEL

Figure 18.2 Computer digitized [14C]-deoxyglucose autoradiographs of coronal guinea pig brain sections from (A) control; (B) ethosuximide (ESM) alone; (C) PTZ alone; and (D): PTZ + ESM during threshold seizure stage. Comparison of section at the level of AN. The dark diagonal bands in (D) represent greatly increased metabolic activity in AN during early phase of PTZ EEG seizures.45

brainstem to thalamus pathway incorporating the mammillary peduncle, mammillotegmental tracts, the ventral and dorsal tegmental nuclei, mammillothalamic tracts to AN, and AN as selectively activated during threshold stages of pentylenetetrazol (PTZ) seizures in rodents (Figures 18.2 and 18.3).45 Ethosuximide (ESM) was used to retard the progression of seizure activity during the 25–40 min deoxyglucose uptake period. The increase in metabolic rate of the cellular grey matter areas, along with the unusual increase observed in the white matter tracts of the pathway, suggested that this anatomical conduit of synaptic transmission may mediate anticonvulsant activity of ESM. To test this hypothesis, the path was inter­ rupted by electrolytic lesioning of the two

218

mammillothalamic tracts (MT), which connect the hypothalamic mammillary complex with thalamic AN. Surprisingly, MT lesions resulted in a significant elevation in seizure threshold to PTZ seizures in both guinea pigs and rats.44 Similarly, lesioning the mammillary complex also led to elevations of seizure threshold, supporting the idea that the brain­ stem AN pathway facilitated seizure expres­ sion and interruptions at different points in the pathway had similar anticonvulsant action (Figure 18.4).47 These data were further corroborated using microinjection of proconvulsant and anti­ convulsant substances directly in AN. Microinjection of muscimol (GABA agonist) into either AN or the mammillary complex could prevent and terminate ongoing PTZ

EVIDENCE FOR ANTERIOR THALAMIC NUCLEUS (AN) MEDIATION OF PTZ SEIZURES

Hippocampus

CC HPC

Septal region

B HA

V F N

CPU

AN

Thalamus

A C

Fields of Forel MF

DL

F

B

MTT RF MP

MB

LPN

DTN VTN

Figure 18.3 Parasagittal outline of rodent brain illustrating the thalamic-midbrain pathway consisting of the dorsal and ventral tegmental nuclei (DTN and VTN), mammillotegmental tracts (MTT), mammillary peduncles (MP), mammillary body (MB), mammillothalamic tracts (MT), and anterior thalamic nucleus (AN). Other abbreviations: AC, anterior commissure; CC, corpus callosum; CPU, caudate­ putamen; DLF, dorsal longitudinal fasciculus; FX, fornix; HAB, habenula; HPC, hippocampus; IPN, interpeduncular nucleus; and RF, mesencephalic reticular formation.

* p < 0.005 ** p < 0.001

6

75 mg/kg PTZ Clinical seizure score

5

*

100 mg/kg PTZ

** 4

* ** **

3

** 2

1

**

0 Control Misses

All MT

Large Medium Small

Figure 18.4 Effects of 75 mg/kg and 100 mg/kg intraperitoneal PTZ on behavior in control and lesioned guinea pigs. Clinical behavior was observed and scored as follows: 0, no seizure; 1, mild clonic; 2, severe clonic (explosive motor activity); 3, severe clonic within first 10 min.; 4, severe recurrent clonic seizures; 5, steady clonic with animal on its side; and 6, same as 5 but within first 10 min.44 MT, mammillothalamic tracks.

MT

219

ANTERIOR THALAMUS AND THE PENTYLENETETRAZOL MODEL

seizures in paralyzed and ventilated rodents (Figure 18.5).46,48,52 To study behavioral effects, a longer acting agent gamma-vinylGABA (a selective GABA-transaminase inhibitor) was injected into AN. These experi­ ments also demonstrated that enhancement of GABAergic activity within AN resulted in anticonvulsant activity (Table 18.1).46 In con­ trast, kainic acid (a rigid analog of glutamate) or bicuculline (an antagonist of GABA) pro­ voked site-specific ictal responses when applied to AN (Figure 18.6). These results supported a specific facilitory role for AN in PTZ seizures and suggested the presence of glutaminergic and GABAergic transmission within the complex.

and therefore an attractive technique to pursue in patients, the anticonvulsant effects of high frequency, bilateral AN stimulation was examined in rodents. Infusion of PTZ resulted in early medium voltage EEG bursting that was not associated with behavioral ictal phenomena. Thereafter, at higher doses, stereotypic progression of motor paroxysms led to a clonic seizure, associated with high voltage synchronous EEG activity. In ANstimulated animals, the mean dose of PTZ given as continuous infusion (5.5 mg/kg/min) to elicit clonic seizures was 121±8.6 mg/kg (SE), approximately twice that observed in controls or sham-stimulated animals (57±3.1 and 63±6.8 mg/kg respectively, p 15 Hz bandwidths.

and thus can infer the relative amount of energy that is correlated with time between two sites.77 With high coherence there is little error in estimating the output of an assumed linear transfer function. Low coherence sug­ gests other factors such as contaminant signals (noise), non-linearities, and other inputs account for the uncertainty in the output time series. Simple coherence analysis is plagued, however, by potential cross-channel inter­ ference from non-linked sources.79 Volume conduction of the seizure EEG through the extracellular medium can account for high signal coherences between two regions despite lack of neuronal conduction. Thus, signal coherence between structures may be high, yet not derived from direct synaptic connec­ tions.79,81,82 Another misleading scenario is that of a common pacemaker center, synapsing with AN as well as other regions including cortex (CTX). Commonality leads to linkage associations that are not selective. Therefore, it is necessary to compare AN and CTX EEG coherences (AN/CTX) with nearby non-linked regions having limited

involvement during PTZ seizures. Removal of common input from each region provides some method of signal separation and speci­ ficity. The non-linear signal processing tech­ nique that can achieve this is known as partial coherence estimation. Through elimination of such ‘cross-talk’, partial coherence can better assess whether AN and CTX are synaptically correlated during cortical EEG and behavioral seizure expression. The posterior thalamic nuclear group (PT, consisting predominantly of pulvinar region) was selected as a sec­ ondary recording target for its thalamic loca­ tion, yet without synaptic connectivity to the AN-cortical pathway described previously.51,55 Figure 18.13A shows the progression of the cortical EEG pattern from preclonic through the clonic seizure stage, culminating at the start of the first postictal period. During the baseline periods, correlation between CTX and either AN or PT was not robust (Figure 18.13B). During cortical EEG seizures, however, a broad increase in thalamiocortical correlation was observed (coherence ratios increasing from 0.10–0.20 to 0.30–0.55),

227

ANTERIOR THALAMUS AND THE PENTYLENETETRAZOL MODEL

A

Cortex

500 0 –500

5

0

B

10

15

25

20

30

0.9

Ordinary coherence

0.8 0.7 PT AN

0.6 0.5 0.4 0.3 0.2 0.1 0.0 3

C

6

9

0.9

15

18

21

24

27

30

24

27

30

Frequency (Hz) PT AN

0.8 Ordinary coherence

12

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 3

6

9

12

15

18

21

Frequency band (Hz)

Figure 18.13 (A) Cortical EEG during 5 s preclonic period leading into a clonic seizure. The ictal period is dominated by 2–3 Hz high voltage spiking, typically lasting 25–30 s during a single clonic episode, x-axis: time (s). (B) Ordinary coherence (±SE) between anterior (AN) and posterior (PT) thalamus with cortex (CTX)-AN/CTX and PT/CTX, respectively, correlated to frequency (Hz) during baseline experimental period prior to PTZ infusion. Generally low coherence ratios are observed (T7 electrodes). The patient was not considered a candidate for surgical manage­ ment. In January 1999 he had a VNS implanted without significant benefit in his seizure fre­ quency. VNS was turned off 6 months prior to enrollment in the study. He underwent bilateral STN implantation in September 2000. The effect of constant DBS STN on his clinical seizures during an 8 month period and inter­ mittent stimulation during a 3 month period is shown in Figure 28.1D.

Results The preliminary results in patients with med­ ically intractable non-surgical focal epilepsy suggest that high frequency stimulation (HFS) of the subthalamic nucleus (STN) was effec­ tive in two patients (case studies 1 and 2), with a marked decreased in seizure frequency ranging from 42% to 75%. Constant and intermittent stimulation modes were similarly effective. These two patients also reported that STN stimulation elicited a significant decrease in seizure severity and duration. The other two patients (case studies 3 and 4) showed no effect of STN stimulation (constant or inter­ mittent) or seizure frequency. Also, these patients did not notice any change in seizure severity or duration. Side effects of stimulation consisted of tran­ sient mild twitching in the face and/or dys­ tonic posturing involving one extremity which was seen in all patients. However, these side effects were reduced or eliminated by adjust­ ment of the stimulation parameters. Neither the surgical procedure nor the stimulator system itself have caused any complications.

REFERENCES

Conclusions Deep brain stimulation (DBS) of the subthala­ mic nucleus (STN) is a possible new treatment modality for a carefully selected group of patients with pharmacologic intractable epilepsy. Further investigations regarding patient selection criteria (focal vs generalized epilepsies), stimulation modality (constant vs cycling, open loop vs closed loop), stimulation parameters and stimulation target nuclei are still needed. Indeed, only a double-blind study can establish the actual effectiveness of this treatment modality.

References 1. Hauser WA, Annergers JF, Rocca WA. Descriptive epidemiology of epilepsy: contribution of popula­ tion—based studies from Rochester, Minnesota. Mayo Clinic Proc 1996;71:576–86. 2. Foldvary N. Recognition of potential surgical can­ didates and video-electrencephalography evalu­ ation. In: The treatment of epilpesy: Principles and practice (2nd edn). 1990;73:1019–30. 3. Mattson R. The choice of antiepileptic drug in focal epilepsy. In: The treatment of epilepsy: Principles and practice (2nd edn). 1990;57: 571–8.

4. Cooper IS, Amin I, Gilman S. The effect of chronic cerebellar stimulation upon epilepsy in man. Trans Am Neurol Assoc 1973;98:192–6. 5. Cooper IS, Upton AR, Amin I. Reversibility of chronic neurologic deficits. Some effect of electrical stimulation of the thalamus and internal capsula in man. Appl Neurophysiol 1980;43:244–58. 6. Fisher RS, Uematsu S, Krauss GL, et al. Placebocontrolled pilot study of centromedian thalamic nucleus stimulation in treatment of intractable seizures. Epilepsia 1992;33:137–46. 7. Velasco M, Velasco F, Velasco AL. Centromedian­ thalamic and hippocampual electrical stimulation for control of intractable epileptic seizres. J Clin Neurophysiol 2001;18:495–513. 8. Chkhenkeli SA, Chkhenkeli IS. Effects of thera­ peutic stimulation of nucleus caudate on epileptic electrical activity of brain in patients with intractable epilepsy. Stereotact Funct Neurosurg 1997;69:221–4. 9. Benabid AL, Krack PP, Benazzouz A, et al. Deep brain stimulation of the subthalamic nucleus for Parkinson‘s disease: methodological aspects and clinical criteria. Neurology 2000;55:S40–44. 10. Kitagawa M, Murata J, Kikuchi S, et al. Deep brain stimulation of the subthalamic area for severe proximal tremor. Neurology 2000;55: 114–16. 11. Lüders HO, Acharya J, Baumgartner S, et al. Semiological seizure classification. Epilepsia 1998;39:1006–13. 12. Montgomery EB Jr, Baker KB. Mechanism of deep brain stimulation and future technical devel­ opments. Neurol Res 2000;22:259–66.

355

Section VI

Brain stimulation: future prospects

29

The future of brain stimulation for seizure control

William Heetderks

Electrical stimulation of the peripheral and central nervous system for therapeutic pur­ poses has a long history. Ancient accounts of stimulation from electric fish for treatment of headache were followed by accounts of a ‘cure’ for paralysis by electrical stimulation when electrostatic generators were developed in the 18th century. The modern era of func­ tional electrical stimulation for the treatment of neurological disorders might be said to have begun with the US Food and Drug Administration (FDA) approval of the multi­ channel cochlear implant in 1985. This was followed in the 1990s with FDA approval of deep brain stimulation (DBS) for tremor (1997), vagal nerve stimulation for epilepsy (1997), and functional electrical stimulation for hand function (1997). More recently, the FDA approved DBS for treatment of other symptoms of Parkinson’s disease (2002). The future of brain stimulation for seizure control will almost certainly depend heavily on this growing technology base as well as an expan­ sion of our scientific understanding of the disease. It is instructive to look at the evolu­ tion of some of the other therapies that utilize electrical stimulation of neural tissue as we imagine the future of brain stimulation for seizure control. The cochlear implant is perhaps the most successful neural prosthesis developed to date.

Over 75 000 implants have been placed worldwide. The indications for these devices have gradually expanded over the years as clinical results improve. The performance of the devices has steadily improved. Major advancements in design have included multi­ channel stimulation and advances in the design of the speech processor used to trans­ late sounds into patterns of electrical stimula­ tion on the array of electrodes. As a result of these developments, the majority of cochlear implant users now enjoy open-set speech com­ prehension. Research is continuing to further develop electrodes that will provide the ability to present even greater amounts of speech information to the brain. While this technology development has been occurring, the understanding of the neurobiol­ ogy of the auditory system has expanded in parallel. In many cases, results seen in cochlear implant subjects have led to new hypotheses about how sound is represented in the nervous system and about the plasticity of the auditory system. This interaction between the science and clinical work has benefited both groups. However, despite substantial progress on several fronts, there are still signif­ icant unanswered questions about cochlear implants. Probably the biggest is the continu­ ing question of how to reliably predict outcome before implantation of the device.

359

THE FUTURE OF BRAIN STIMULATION FOR SEIZURE CONTROL

Attempts to answer this question have led to several intriguing new questions about the rel­ ative importance of the fidelity of peripheral representations versus central analytic ability in understanding speech and about how infor­ mation is represented in the neural activity of a population of cells. However, we have yet to find a good predictor of outcome. The initial rationale for electrical stimula­ tion of the fibers of the auditory nerve was to provide an acoustic sensation to a deaf indi­ vidual. But the cochlear implant has other sig­ nificant effects beyond providing this immedi­ ate sensory input. In addition to giving a percept of sound, the electrical stimulation from a cochlear implant has a major role in the development of the auditory system in young children and in producing plastic changes throughout the auditory systems in adults. The presence of electrical stimuli related to acoustic events in the environment during the critical periods of speech and lan­ guage development lead to the development of an auditory system that is able to make sense of the electrical stimulation patterns. In adults, anecdotal data suggest significant improve­ ment in speech comprehension occurs over a period of a few years presumably related to reorganization of the auditory system in response to the ongoing stimuli. In animal studies there is evidence that electrical stimula­ tion from the cochlear implant has a signifi­ cant impact on the survival of fibers in the auditory nerve fibers as well as on the reorga­ nization of the central auditory pathways. Thus, the stimulation not only provides imme­ diate acoustic information but also has an impact on plasticity of the systems involved and also the survival of the systems involved. The cochlear implant has gone through a series of stages in its development. Advances in materials and electronic technology have been as essential as advances in the clinical sci­

360

ences and neurosciences in leading to the current devices and to future devices that are under development. Deep brain stimulation (DBS) for treatment of Parkinson’s disease and other movement disorders is a more recent therapy. However, it shares several features with the cochlear implant. One of the most striking similarities and perhaps the hallmark of any successful intervention is the exponential growth in the number of cases treated over time. Other shared features include the observation that the success of the therapy is ahead of our detailed understanding of the mechanism of the therapy. Another is that the initial success was achieved with ‘off-the-shelf’ technology that was not specifically designed for this application. An, as yet unanswered question is whether when devices are optimized for DBS it will lead to further improvements in outcome as has been seen with the cochlear implant. Brain stimulation for seizure control may involve both ‘state estimation’ of the condition of seizure-prone areas of the brain and ‘state transition’ from a preseizure state to a non­ preseizure state. Looking to the future of brain stimulation for seizure control I expect that we will be able to accomplish both these results before we are able to explain or under­ stand in detail what we have done. The ability to achieve a therapeutic success in some cases will also likely occur well in advance of our ability to predict which cases will succeed and which will not. It is likely that that once a foothold for detection and treatment is devel­ oped then work focused on understanding the details of what we are doing will lead to sig­ nificant improvements in the treatment, to a significant expansion of the indications for treatment, and to a better understanding of the pathophysiology of epilepsy. Also, any treatment that is designed to prevent the

THE FUTURE OF BRAIN STIMULATION FOR SEIZURE CONTROL

immediate onset of a seizure will have unan­ ticipated long-term effects on the neural organization and plasticity of the area being stimulated. These effects might be positive or negative. In the best case, we can hope that the changes might lead to resolution of the need for treatment. The NINDS is presently supporting two bio­ engineering research partnerships to investigate the potential for detection and treatment of intractable epilepsy using electrical recording and electrical stimulation and/or local (in time and space) drug delivery in the central nervous system. Several smaller projects are also being supported. In addition, the NINDS has recently announced several programs for the support of translational research aimed at developing potential new therapeutics and devices. These programs may provide an additional source of support for research on seizure control using stimulation or other approaches. Overall, the prospects for the support of further research in this area seem excellent. The impact of this research remains to be seen. Research on brain stimulation for seizure control will be interdisciplinary. To enhance collaborative work across disciplines in support of the cochlear implant, the NINDS and later the NIDCD have supported an inte­

grated research program covering a variety of issues related to the cochlear implant ranging from speech processors to electrode design to study of the protective effects of stimulation. Investigators have come together yearly for an annual meeting to discuss results and criticize (constructively) each others work. Over the past 25 years this has been an effective tool in facilitating collaboration among investigators. A similar program to bring together investiga­ tors studying DBS held its first meeting this year. This meeting included investigators looking at clinical issues, technology issues, and issues related to understanding the mecha­ nisms of action of DBS. Besides meeting on an annual basis the consortium will develop an environment and infrastructure where individ­ uals from one laboratory (especially postdoc­ toral fellows) can readily move to another lab­ oratory for a period of time to get a better understanding of the problem from the prospective of another discipline and where joint projects can be quickly initiated. Whether such strategies result in more efficient use of resources is yet to be shown. In any case, it seems that this or some other mecha­ nism may be needed to facilitate interdiscipli­ nary work in brain stimulation for seizure control as well.

361

INDEX

5-HIAA 236, 237

5-HT see serotonin

ablative techniques 129, 130

absence seizures 190

modulation by basal ganglia 192

modulation through indirect ventrally-located circuits 193

action potentials 45, 55

initiation site in CNS neurons 62–3

afterdischarges (ADs) 97, 98–9

with chronic stimulation of hippocampus 297

with direct cortical stimulation 276–7, 278

duration 100

with SAHCS 288, 289, 297

threshold of induction 100

amygdala stimulation

kindling 209, 211, 212, 213, 285

seizure induction/promotion 209, 210

AN see anterior thalamic nuclei anesthesia

in stereotactic frame placement 338

in AN stimulation surgery 312

in STN stimulation surgery 322

prophylactic 333

animal models

of drug resistance 190

of epilepsy 97, 99, 157–9, 189–91, 193–4

genetic 190–1

HFS of STN 193–4

rTMS in 266–7

SNr in seizure prevention 336

relevance 195

animal studies

efficacy, overview of 7

and mechanism of seizure prevention 8

anode ‘break’ excitation 58, 60

anodic stimuli

action potential initiation 61, 62, 63

and waveform selectivity 64

anterior temporal lobectomy 285

and alternatives 296

anterior thalamic nuclei (AN)

anatomy 216

catecholamine seizure modulation

norepinephrine 233, 235–6 serotonin 232–3, 234–6, 237

cholinergic seizure modulation 233–4

connectivity 216, 217, 232

dialysis summary 235–7

discharges 183

EEG recording from 171–85

electrode placement 173–4

excitatory amino acids 234

functions 171

GABA 234

nitric oxide 234

posterior microdialysis recovery 235–6

PTZ seizures, mediation of 217–20

in seizure propagation 181–2

anterior thalamic nuclei (AN) stimulation 9, 13, 176,

215–43, 275

animal models/studies 220–2, 306–7

anticonvulsant effect 216

human pilot trials 221–2

laboratory results 220–2

potential mechanisms 222–5

bilateral vs ipsilateral response 174

EEG recording 179–83

fidelity 179

utility 182

for epilepsy 172

ethical constraints 305, 313

history of 4

issues 305

post-operative care 302

potential mechanisms

depolarization blockade hypothesis 222–3 synaptic inhibition hypothesis 223–5

pre-operative care 299

and PTZ model 217–37

stereotactic targets 307

study design 305–19

anaesthesia, choice of 312

brain target identification 309

degree of patient/family control 310

devices to be tested 309–10

escape criteria 314–15

financial planning 317

outcome measures 313–15

patient flow time line 314

patient selection 308

placebo/blinding 313

rationale 305–8

regulatory approval 316–17

safety 315, 317

stimulation parameters 312–13

surgical methodology 310–12

targeting 310–11

surgical procedure 299–304

DBS placement 302

guiding cannula placement 301

internal pulse generator placement 302

intraoperative stimulation 302

microelectrode recording 301–2

patient selection 299

stereotactic frame fixation 299

surgical planning by Stealth system 301

target localization 299–301

363

INDEX

anterior thalamic nuclei (AN) stimulation continued

target localization, direct, using MRI scan 301

target localization, indirect, using Schaltenbrand Atlas

300–1 therapeutic potential 182

anterior thalamus, MER characteristics of 328

antibiotics in STN stimulation surgery 332

prophylactic 322, 326

antidromic cortical stimulation 9

antiepileptic drugs 296

with CSHC 295–6

rTMS, similarity to 122

and STN stimulation 349–50

and VNS 259

area tempestas 88

augmenting stimulation/response 311

auto-correlograms 138

automatic seizure blockage system 279

automatic seizure detection 280, 282

autoradiography 291, 293, 294, 306

axonal activity

compared to neuronal activity 135

during DBS 150

basal ganglia

biochemistry 22

constituents 21

electrophysiology 22

‘focusing’ by STN 34

function, model of 21–2

high frequency stimulation 193, 194

as ablation 194

input nuclei 29, 30

modulation of absence seizures 192

output stations 30

overview 21–8

physiology 23–4

current model 130–1, 139–41

segregated ‘loop’ hypothesis 24, 25

somatotopical arrangement 31

basal ganglia-thalamocortical circuits 29, 30, 34

direct pathway 130–1

effects of STN DBS 138

indirect pathway 131, 147

motor 21

in movement disorders 37

resonance frequency, reinforcement of 138

schematic representation 130

benzodiazepine receptor binding levels 291, 293–4

benzodiazepines 322, 326

bifrontal lobe epilepsy 352–3, 354

biphasic stimuli

action potential initiation 61

and waveform selectivity 63, 64

bitemporal lobe epilepsy 277–9

brain stimulation

collaboration of researchers 361

expense of 317

future for seizure control 359–61

overview

efficacy 7

history 3–7

364

mechanisms 7–9

state estimation/transition 360

stimulus characteristics see electrical stimulus

characteristics

brainstem circuits 87, 216, 218

burrholes 327

burst stimulation 145, 150–1

cable models 56–7

carbamazepine 297

catecholamine seizure modulation

norepinephrine 233, 235–6

serotonin 232–3, 234–6, 237

cathodic stimuli action potential initiation 61, 62–3 and waveform selectivity 63–4 see also virtual cathodes caudate nucleus stimulation 4, 13

CCEPs see cortico-cortical evoked potentials

cell body orientation 71

central nervous system

extracellular excitation 55–6

site of excitation/modulation 55

stimulation 60–4

effect of polarity 61–2

history 3–6

waveforms 63–4

centro-median thalamic nuclei 9

bilateral stimulation 285

history of stimulation 4–5

stimulation 13, 172

‘centrocephalic’ theory 216

cerebellum stimulation 3–4, 7, 13

chaos control 77, 79

charge-balanced waveforms 50

charge density per pulse 50–1

Charlotte Dravet’s syndrome case 337, 341, 343, 345

cholinergic seizure modulation 233–4

chronic stimulating electrodes 144

chronic stimulation of hippocampus (CSHC) 294–6

and antiepileptic drugs 295–6 method 295

circuit of Papez 171, 179

Cleveland case 1 351–2, 354

Cleveland case 2 352–3, 354

Cleveland case 3 353–4

Cleveland case 4 354

Cleveland Clinic seizure classification 349, 350

clonic seizure thresholds 237

closed loop DC stimulation 279

closed loop models of stimulation 196

cochlear implants 359–60

compartmental analysis 71

complex partial seizures 286, 294–6, 306

computational modeling

extracellular stimulation in CNS 61

information processing 135, 137

of neuronal stimulation 55–7

calculation of effects of potentals 56–7

calculation of potentials generated 56, 57

thalamic neurons 134

computed tomography (CT)

INDEX

in STN stimulation surgery 322, 323, 324

post-operative 331

cooling of neocortical surface 275–6

corpus callosum stimulation 11, 13

corpus Luysi see subthalamic nuclei

cortex

activity 30–1

DBS effect quantification 151–2

stimulation 5–6, 9, 13

cortical dysgenesis model 189

cortical electrical stimulation 105

efficacy 122

frequency-dependent effects 210, 211

see also direct cortical stimulation

cortical-evoked potentials from DBS 143–55

cortical hypersynchrony 225, 230

cortical-subcortical EEG evaluation 226–37

cortico-cortical connections 105, 109

cortico-cortical evoked potentials (CCEPs) 105–11

advantages of technique 109–10

from basal temporal area 108

from right frontoparietal area 109

tracking connections in vivo 106

cortico-subthalamic connections 165, 204

cortico-subthalamic projections 30, 31

cross-correlograms 132, 133, 139

CSHC see chronic stimulation of hippocampus

Cyberonics VNS Model 101/102 247, 251

deep brain stimulation (DBS) 4–5, 9, 67

as ablation 129, 131–5

advantages of technique 215

cortical activity quantification 151–2

devices 51–2

on different neuron components 134

effects of low vs high frequency 134

effects on ‘systems’ 138–9

electrode implantation, effect of 222

in epilepsy 157

foci 215

high frequency 137

and information processing 135–7

lack of accuracy 24

mechanisms 131, 215

mechanisms, potential

depolarization blockade hypothesis 222–3

regional blood flow studies 225

synchronization role 226

micro- vs macro-electrodes 174

movement disorders 143–4, 359–60

as research tool 130

at resonance frequency 138

role in AN chemical alterations 232

as therapeutic strategy 92–3

therapy used as research 143

unilateral 53

vs focal stimulation 209–14

deep brain stimulation-evoked potentials (DBS-EP) 143

alteration by moving contact area 152

applications, potential 151–2

creation 144–5

EEG recording 145

from GPi stimulation 151

from leads in STN 145–51

multi-phasic response 147

in Parkinson’s disease 146, 148

prolonged oscillatory nature 150

re-entrant process 150

refractory period studies 147

stimulation patterns 145

during thalamus stimulation 149, 150

tissue surrounding leads 146–7

topographical vs morphological changes 152

typical 145

depth electrodes in STN 159, 160

desynchronization 77

diathermy safety issues 316

diffusion-weighted MRI 105

direct anterograde cortical inhibition 8

direct anterograde cortical stimulation 8–9

direct cortical (DC) stimulation 105, 275–84

case study 277–9, 282–3 closed loop 279

data analysis 281

safety/efficacy 279

set-up diagram 281

effects of brief pulse stimulus 276–8

electrode placement 98

electrodes, imaging of 277

eliciting motor evoked potentials 106

high frequency 97–101

as model of neocortical seizures 99

pre-operative mapping 276

prior studies evaluating 276–9

protocol 279–83

safety parameters 276

stimulus

characteristics 98

intensity 280–1

parameters 276

suppression of neural activity 76, 81–2 thresholds for clinical seizures 281

discharge properties of STN 29, 36

dopamine

in anterior thalamic nuclei 236

in basal ganglia 22

effects of depletion 131

somatodendritic release

as motor control regulator 26

from SNc neurons 24–6

therapeutic implications 26

dopamine D1 receptors 24

dopamine transporter (DAT) 26

dopaminergic neurons in PD 23, 24

dorsal midbrain antiepileptic zone (DMAZ) 8, 9

drug resistance models 190

drug side effects, neural 45

dyskinesias see movement disorders

‘EL mice’ 191

electrical circuit cable models of neurons 56–7

electrical fields

effect on nervous tissue 72–3

and electrical stimulation current 71

365

INDEX

electrical fields continued

and excitable tissue 69–72

localized

effects on hippocampus 72

and electrical stimulation current 68, 69

and high potassium model 73

and low calcium model 74–6

and penicillin model 73, 74

suppression of neural activity 73–6

uniform 71, 72, 73

direct cortical 76

and electrical stimulation current 68–9

and high potassium model 76

and low calcium model 76

suppression of neural activity 76

electrical stimulation

of CNS sites 285–6

of epileptic focus 285

effect on epileptic activity 286–8

history of 359

paradoxical effects 67

safe parameters 50

of subthalamic area 286

electrical stimulus characteristics 45–54

electrocorticograms (ECoGs) 98

in cortico-cortical evoked potential study 107

electroencephalograph (EEG) recordings

from anterior thalamic nuclei 171–85, 308

spontaneous 179–83

in CSHC 296

in deep STN stimulation 157–69

ictal activity 165–7

individual epilepsy patients 162–5

individual PD patient 164, 167

interictal epileptiform discharges 165

in NREM sleep 164–5

polyspikes 163

in REM sleep 165

during seizures 165–6

sharp waves 160–2, 163, 165, 166–7

STN spikes 166–7

in direct cortical stimulation 279

effects of SAHCS 287, 289

responses to test stimuli 290

in kainic acid-induced seizures 199–200

kainic acid-induced seizures 203

in PTZ model 221

recruiting rhythm 311–12

spontaneous right lobe seizure 282

electroencephalograph (EEG) signals

coherence analysis 226–9, 232

between anterior/posterior thalamus 228

cortical pattern through seizure 227–9

DBS evaluation on AN electrophysiology 229–31

insight into DBS 226–37

partial coherence estimation 227, 230

power spectrum 226, 227

time delay network analysis 229, 230

electromyograph (EMG) responses to rTMS 115

electrophysiologically based treatments 152

encephalitis-induced epilepsy 354

epilepsy 189

366

animal models 97, 99, 157–9, 189–91

of drug resistance 190

genetic 190–1

high frequency stimulation of STN 193–4

causes 67

CCEPs in 107–8

DBS-EP in 146

DBS human studies 159–65

EEG findings 160–7

individual epilepsy patients 162–5

patient clinical data 159

diagnostic applications of online rTMS 121–2

drug-refractory patients 157

intractable 349

response to drugs 67

temporal lobe models 190

STN/hippocampal stimulation 195

in vitro models of epilepsy 67–86

epilepsy, intractable

frontal lobe 108

temporal lobe 107–8, 122

vagus nerve stimulation 57–8, 248

Epilepsy Monitoring Unit (EMU) 279

epileptic/epileptiform activity

by disruption/reduction of neuronal activity 83

and electric fields 73

lateralization 180–1, 182

polarity 180

epileptogenesis 285

epileptogenic zone

direct stimulation 5–6, 9, 10

overdrive 9–11, 13

ethical constraints 305, 313

ethosuxamide 218

event-related potentials 118–19

evoked potentials 143

see also specific types excitatory amino acids 234

external pallidal segment (GPe) 31–2

in basal ganglia-thalamocortical circuits 30

and subthalamic nucleus inhibition 31–2

extracellular potentials 55, 56, 59

fluoroscopic visualization 329–30

focal cooling of neocortical surface 275–6

focal injuries model 189

focal limbic seizures 199

focal stimulation vs deep brain stimulation 209–14

focally evoked seizure model 88

Food and Drug Administration (FDA)

applications to 316, 317

regulation of drugs vs devices 305

forcing function 71

fornix stimulation 11, 13

GABA 24, 234

in anterior thalamic nuclei 234

in subthalamic nuclei 31, 91–2

species differences 91, 92

in superior colliculus 92

transmission in substantia nigra 90

GABAergic drugs

INDEX

in PTZ model 218, 220

in substantia nigra 89–91

in subthalamic nuclei 158

GABAergic fibers 93

gamma-aminobutyric acid see GABA

generalized tonic-clonic seizures 191, 286

Genetic Absence Epilepsy Rat of Strasbourg (GAERS) model

158, 190–1 STN stimulation in 194–5, 344

Genetic Epilepsy-Prone Rat (GEPR) model 190, 191

genetic models of epilepsy 190–1

globus pallidus

activity in movement disorders 36, 38

activity in parkinsonism 35

DBS in 131

in parkinsonism 34

and subthalamic nucleus activity 30

see also external pallidal segment; internal pallidal

segment

glutamate antagonists in rats vs primates 89

glutamergic pathway to STN 165

Grass S88 280

Grenoble case 1 336–7, 341–2, 343, 344, 345

Grenoble case 2 337, 341, 342–3, 344

Grenoble case 3 337, 341, 343, 345

Grenoble case 4 337–8, 341, 343

Grenoble case 5 338, 341, 343, 344

Grenoble group 321

Grenoble study 335–48

grey matter, seizure control in 209

head injury case 352–3, 354

hemiballism 36, 37, 38

5-HIAA 236, 237

high frequency stimulation (HFS) 79–81, 83

direct cortical 97–101

history of 193

mechanisms of action 158, 194, 345

of STN see subthalamic nuclei stimulation, high frequency

therapeutic applications/effects 93, 195–6 see also specific areas high potassium model 83

and high frequency stimulation 79, 80, 81

and localized electrical fields 73

and uniform electrical fields 76

hippocampus

benzodiazepine receptor binding levels 293

localized field effects 72

overdrive by fornix stimulation 11

stimulation 6, 13

5-HT see serotonin

human studies, efficacy of 7

Huntington’s disease

chorea mechanism 38

GPi activity 136, 137

6-hydroxydopamine (6-OHDA) rat model 26, 36

hyperkinetic movement disorders 36

hypothalamus 4, 13

imaging, neurological see neuroimaging

impulse generators 144

in vitro brain slice preparation 67–8

in vitro models of epilepsy 67–86

infantile cerebral palsy case 337–8, 341, 343

information

encoding 135

loss/gain 135

processing

and deep brain stimulation (DBS) 135–7

schematic representation 136

interictal spikes

with CSHC 295, 297

lateralization 181

internal pallidal segment (GPi)

activity during STN stimulation 131–2, 134, 136

and basal ganglia disorders 136

in basal ganglia-thalamocortical circuits 29

DBS as alternative to pallidotomy 144

effects of STN DBS 139

and GABA-mediated seizure control 91

overactivity in PD 131

overdriving 136

relationships with other regions 138

intracortical connections research 105

intraictal spike propagation, remote 106

kainic acid 199, 219

kainic acid-induced seizures 199–200, 209–12

and cortical stimulation 210, 212–13

EEG recording 203

effects of STN HFS 202–4

histological changes 200

onset at hippocampal electrode 203

propagation 200, 212

and stimulation of amygdala 209–10, 212

and stimulation of sensorimotor cortex 211

kindled seizures 209

effect of subcortical stimulation 209–12

left frontal lobe epilepsy 354

left frontotemporal lobe epilepsy 353–4

Leksell SurgiPlan 323

Lennox-Gastaut syndrome, VNS for 257–9

Lilly-type stimulation waveform 47, 50

limbic epilepsy model 190, 209

limbic system 236–7, 306

linguistic function investigations 121

localization stimuli 276, 277

low calcium model

and high frequency stimulation 79

and localized electrical fields 74–6

and uniform electrical fields 76

low frequency stimulation 77–9 see also specific areas macronuclear model of basal ganglia physiology 140

magnetic resonance imaging (MRI)

of anterior thalamic stimulation electrodes 303

diffusion-weighted 105

in electrode placement 159, 173, 175

post-operative 178, 315, 332

safety 315–16

in AN stimulation

protocol 316

367

INDEX

magnetic resonance imaging (MRI) continued target localization 299–300

in STN high frequency stimulation 338

in STN stimulation surgery 323, 324, 325, 326

post-operative 332

magnetic stimulator, circuit diagram of 114

mammillary body

posterior hypothalamus 216

stimulation 306–7

mammillothalamic tracts 218, 219

Maxwell equations 68

Medicare and trial funding 317

Medtronic

Activa Tremor Control Unit 276

Model 3382 clinical trial 173

Model 3387 52, 144, 310

Model 3387 electrodes 350

Model 3389 52, 310

Model 3389 electrodes 341

Model 7424 47, 48

Model 7425 Itrel 3 48, 51, 350

Model 7426 Soletra 48, 52, 309

Model 7427 Synergy 48–9, 51

Model 7427 Synergy EZ 51

Model 7428 Kinetra 52, 309, 310

protocol 316

membrane depolarization 55

membrane hyperpolarization 58, 60

membrane polarization

by electrical fields 72–3

by localized electrode 69

suppression of neural activity 81

with uniform field 70

membrane potential manipulation 45

memory and CSHC 294–5, 296

MER see microelectrode recording

microelectrode recording (MER) 323, 327–8

midcommissural point determination 324

misinformation as pathophysiological mechanism 135

Mitchell’s cortical dysplasia case 337, 341, 342–3, 344

mood improvement with VNS 260

motor cortex activity

effects of STN DBS 139

relationships with other regions 138

motor-evoked potentials (MEPs) and rTMS 115–17 silent period 116–17 movement disorders

compensatory mechanisms 38

DBS research in 3

DBS therapy in 143–4

drug-induced 38

role of STN 34–8

multiple cavernous angiomas 351–2, 354

muscimol 218, 221, 286

myoclonic epilepsy case 337, 341, 343, 345

National Institutes of Health grants committee 316

Navigus burrhole ring 327, 329

Nernst Potential 57

nerve cell stimulation 55

nerve fibers 55, 58, 59

368

neural activity suppression

based on non-linear dynamic properties of tissue 82–3

by membrane polarization 81–2

by uniform fields 76

neural desynchronization 77

neuroimaging

functional, and online rTMS 120

in resurgence of ablative techniques 130

see also specific techniques neuromodulation 46

neuronal activity

control by electric fields 67–86

therapeutic implications 83

and efferent axonal activity 135

neuronal discharge/firing patterns 22–3

neuronal dynamics 77–9

neurons, models of 56–7

neurostimulation

amplitude 46–7

biophysics 46–9, 55

circuit 46

devices 45–51

deep brain stimulation 51–2 spinal cord stimulation 51

frequency 47–8

low-frequency periodic 79, 82–3

modeling 55–7

monopolar/bipolar 46, 47, 184, 210

physiological principles 45

safety issues 46–9

neurostimulator equipment 144

neurostimulators 47–8

clinician programmers 48–9, 144

deep brain stimulation 52

fully implantable 49

guidelines for clinicians 49, 51

implantation 9

patient programmers 49, 51

spinal cord stimulation 51

neurotransmitters 22–3 see also Medtronic

NIDCD research support 361

nigral control of epilepsy system (NCES) 5, 9, 191–3, 194

animal model relevance 195

and HFS of STN 336

in seizure prevention 8, 158

and STN 344

nigro-collicular pathway 191–2

nigro-striatal pathways see striato-nigral pathways

NINDS research support 361

nitric oxide 234

nocturnal frontal lobe epilepsy case 338, 341, 343, 344

norepinephrine 233, 235–6

offline rTMS

duration of effect 117, 118, 119

frequency effects 117

and motor cortex excitability 115–17

generalizability 118–19

seizure reduction 122

therapeutic utility 117–19

variability/reproducibility 119, 120, 123

INDEX

online rTMS 119–20

diagnostic applications 121

and functional neuroimaging 120

optical density readings, autoradiographic 294

optimal target of epilepsy 344–5

outcome prediction 359–60

‘overdrive’ of epileptogenic zone 9–11, 13

pain, chronic 48, 51

paired-pulse stimulation 145, 148, 151

parahippocampus 293–4

Parkinson’s disease (PD)/parkinsonism

changes in STN activity 34–6

DBS-EP in 146

globus pallidus activity 35

GPi activity 136, 137

MPTP model in primates 34–6

offline rTMS, therapeutic effects of 117

pathophysiology 23–4

current model 130–1

model 21–2

therapeutic implications 26

partial onset seizures, VNS for 255–7

partial seizures 191

see also complex partial seizures

PD see Parkinson’s disease

pedunculopontine nucleus (PPN) 33, 36

penicillin model 82

and high frequency stimulation 79

and localized electrical fields 73, 74

phase resetting 77, 78

pentylenetetrazol (PTZ) model 217–21

anterior thalamic nucleus mediation 217–20, 306–7

behavioral seizure scores 224

brain autoradiographs 218

clinical behavior in 219, 220

clonic seizure threshold comparison 237

cortical hypersynchrony 225, 231

cortical-subcortical EEG evaluation 226–37

dialysis summary 235–6

EEG recordings 221, 222, 223

mammillary body stimulation 306–7

manifestations 217

recent data 234–5

rTMS in 266–7

peripheral nervous system (PNS) 6–7, 55

stimulation 57–60, 64

phase resetting 77, 78, 82

polarity of stimulus 58, 60

effect on CNS stimulation 61–2, 64

effect on PNS stimulation 64

positron emission tomography (PET) studies 307–8

posterior hypothalamus mammillary body 216

projection channels, diffuse 215–16

PTZ model see pentylenetetrazol model

putamen activity 138, 139

putamenal output

direct pathway 22

indirect pathway 22, 23

raster displays 35

recovery cycle function 286

recovery cycles 288–9, 290

recruiting response/rhythm 172–9

amplitude 178, 184

appearance 173

EEG montage 184

electrode placement 178–9, 184, 311–12

electrode position 177–8

in individual patients 178

in left frontal region 175

in operating room 173–9

procedure 178–9

pulse width 176, 177, 183

stimulus frequency 174, 175–7, 178, 183–4

thresholds 173

stimulus location 173

suggested protocol

initial stimulation settings 183–4

stimulation mapping 184

regional cerebral blood flow (rCBF) studies 225, 286

in rTMS 264

in SAHCS 297

repetitive transcranial magnetic stimulation (rTMS) see

under transcranial magnetic stimulation

research opportunities in therapy 143

response topography 89

restorative neuroscience 53

reticular activating system (RAS) studies 306

right frontal lobe epilepsy 282

SAHCS see subacute hippocampal electric stimulation

SC see superior colliculus

Schaltenbrand Atlas 301, 324

sedation in STN stimulation surgery 322, 326

seizure classification 349, 350

seizure control

with CSHC 297

and direct striato-nigral pathway 192

future of deep brain stimulation 359–61

by GABA in substantia nigra 90

and indirect striato-nigral pathway 192–3

methods, comparison of 13

neural substrates 87

neurochemical modulation 232

optimization criteria 10

with SAHCS 296, 297

species differences 88–9, 90

substantia nigra 191

seizure detection system 6

automatic 280, 282

seizure ‘escape’ 10

seizure progression pattern in rats vs primates 88–9

seizure propagation 181–2

seizure propagation circuits

identification 216

and regulation circuits 87

seizure reduction

with CSHC 295

with rTMS 122

in SAHCS study 288

with VNS 256, 257, 259

seizure threshold 221

PTZ 224, 225

369

INDEX

seizure threshold continued

reduction with rTMS 121

seizures

‘generalized’ 89

induced acute focal, in rats 97–101

right frontal onset, EEG recordings of 179

serotonin 232–3, 234–6, 237

signal-to-noise ratio 136

in misinformation 135

single photon emission computed tomography (SPECT)

studies of epileptogenic areas 286

effects of SAHCS 289–91, 292, 297

equipment 291

single-pulse stimulation 145, 148, 151

SN see substantia nigra

SNc see substantia nigra pars compacta

SNr see substantia nigra pars reticulata

somatic hyperpolarization 81

speech arrest 121

spike and wave discharges 190–1

spinal cord stimulation devices 51

stargazer mice 191

status epilepticus

high frequency bilateral STN 204–5 and hippocampal stimulation 195

Stealth Station 301, 323

stereotactic coordinate system 323–4

in STN high frequency stimulation 338–9 stereotactic frame

placement/fixation 299, 321–3, 338

targeting discs 329

stereotaxic lead placement 51, 52, 159, 177

frameless 114

use of atlas 173, 174

stereotaxic targeting in study design 311

stimulator equipment see neurostimulator equipment

stimulus-induced artifact 132

STN see subthalamic nuclei

stochastic resonance 135

striatal output 30

striatal pathways

direct 33

indirect 34

striato-nigral pathways

direct 192

indirect 192–3

subacute hippocampal electric stimulation (SAHCS)

electrodes 286

study 286–94, 296–7

effects on benzodiazepine receptor binding 291,

293–4

electrophysical changes 288–9

subcortical stimulation 212

subdural electrode stimulation 10

subdural grids 286–7

substantia nigra pars compacta (SNc) 191

dopamine from 24

effect on subthalamic nuclei 33

substantia nigra pars reticulata (SNr) 191

activity in parkinsonism 35, 36

deep brain stimulation in 93

input from STN 158

370

role in PD/basal ganglia function 23–4 in seizure prevention

animal models 157

in animal models 336

substantia nigra (SN)

interconnections with SC and STN 87

microelectrode recording characteristics 328

seizure control 191

and GABAergic drugs 89–91

regions involved 90

species differences 90

superior colliculus in 92

subthalamic nuclei (STN) 200–2

activity in parkinsonism 35, 36

afferents 201

activation 204–5

anatomy 29–30

axon collateralization 200–1

DBS 92–3

effects of 138

in focal seizure model 147, 149–50

in Parkinson’s disease 152

DBS-EP augmentation 150–1

efferents 32–3, 200–1

electrophysiology 201–2

variability of 345

high frequency stimulation 158

inhibition 204

inputs

excitatory 30–1 inhibitory 31–2

interconnections with SN and SC 87

intrinsic discharge properties 29

location, determination of 324

location/projections 91

microelectrode recording characteristics 328

output 32

role in movement control 33–4

movement disorders 34–8

in seizure prevention 8

SN regulation 91–2

and SNc activity 33

species differences 91, 92

subthalamic nuclei (STN) stimulation 5, 275

Cleveland study 349–55

case descriptions 351–4

follow-up 351

generator activity 351

methods 349–51

patient selection 349

stimulation parameters 350–1

DBS human studies 159–65

EEG findings 160–7

individual epilepsy patients 162–5

patient clinical data 159

spread of activity 166

direct microstimulation 201

in GAERS rat 194–5

GPi activity readings 131–2

high frequency 129–41, 201–4, 213

in animal models 193–4 antiepileptic effect, evidence of 343–4

INDEX

clinical trial design 345–6

clinical trials, future 346

complications 341

continuous vs cycling 353

continuous vs intermittent 352

electrode contact coordinates 340

electrode projections 339

generator connection 339

Grenoble study clinical cases 336–8, 341–3

impulse generator connection 341

and nigral control of epilepsy 344

post-operative effects 345

potential for efficacy 345

rationale 335–6

results 341, 354

stimulus parameters 339, 341

surgical method 338–41

target/trajectory 339

high frequency bilateral 202–4

potential mechanisms 204–5

intraoperative hemorrhage 330–1

in kainic acid-induced seizures 202–4, 211, 212

in Parkinson’s disease 33, 321

post-operative infections 331

side effects 329

stimulus-induced artifact removal 132

surgical procedure 321–34

adverse effects 330–1

cable tunneling 333

final connection 330

frame placement 321–3

impulse generator implantation 332–3

patient selection/preparation 321

pin placement 322

pin slippage 323

post-operative care 331–2

pre-operative MRI scans 322

subcutaneous pocket 333

X-rays, postoperative 331

surgical technique 326–7

target planning

entry point, choice of 325

image acquisition 323

mapping to confirm optimal target 327–9

securing electrodes 329

target/trajectory 323–6

in temporal lobe epilepsy 195

sudden unexpected death in epilepsy rate 260

superior colliculus (SC)

and GABAergic nigral outputs 92

interconnections with SN and STN 87

in seizure prevention 336

supramaximal stimulus

frequency 13

intensity 10

surgical planning station 324

Taylor focal dysplasia case 336–7, 341–2, 343, 344, 345

temporal lobe epilepsy 351–2, 354

electrical modulation of epileptic focus 285–98 model 190

thalamic-midbrain pathway 219

thalamic nuclei

caudal intralaminar 31

history of stimulation 4–5

stimulation 83

thalamic recruiting response see recruiting response

thalamus

DBS in focal seizure model 149, 150

inputs/outputs in rabbits 309

therapeutic effectiveness of DBS 152

threshold of activation/excitation 63

and fiber diameter 58, 59

passing cells vs local neurons 61–2

and stimulus polarity 58, 60

tonic seizure, spontaneous 180

tottering mouse model 191

tracer techniques 105

train stimulation 145

transcranial magnetic stimulation (TMS)

convulsive 121–2

and cortical excitability 263

low frequency 83

PET and neuronal connectivity 106

repetitive (rTMS) 113–28, 275

antiepileptic drugs, similarity to 122

coils 114

demonstration of application 114

in depression 265, 266

diagnostic applications in epilepsy 121–2

duration of effect 270

effects in animal models 266–7

effects in humans 267–8

focal vs unfocal stimulation 270

future work 269–70

guidelines 115

individual tuning 123

long-term effects 267

low/high frequency 122–3, 263–4, 268–9

multicenter study, placebo-controlled 268, 269

offline see offline rTMS

online see online rTMS

online vs offline 115

principles 114

safety 113, 115, 265–6

seizure induction 265, 266

seizure reduction 267

sites of action 118

therapeutic effects 122–3, 266–8

variability with disease/individual 264, 268

safety 264–5

seizure induction 264, 265

transmembrane current flow 71

transmembrane potentials 59

tremor

stimulation parameters for inhibition 312

STN stimulation in 92–3

treatment 48, 52, 53

trigeminal nerve stimulation 7, 13

vagus nerve

anatomy 248

surgical technique 250

vagus nerve stimulation (VNS) 6–7, 13, 67, 247–53, 275

371

INDEX

vagus nerve stimulation (VNS) continued adverse effects/medical complications 248, 249, 255, 260

and antiepileptic drugs 259

benefits 260

effects on seizures 255–62 in epilepsy 157

generator programming 255–6 history of 255

indications/contraindications 247–8 for intractable epilepsy 57–8 for Lennox-Gastaut syndrome 257–9 link with thalamus 308

long-term follow-up 259

and MRI scanning 248–9 for partial onset seizures acute studies in adults 255–6 in children 256–7 patient selection 248

post-operative management 252–3 pre-operative evaluation/discussion 248–9 for refractory epilepsy in children 256–7 seizure reduction 256

372

surgical technique 249–52

cable tunneling 250, 251

electrode coils, deployment of 250–1

generator connection 252

incisions 249

subcutaneous pocket 250

system testing 252

Vanguard video-EEG monitoring system 280

ventrolateral thalamus

inhibition by GPi DBS 133–4

seizure control 209

virtual cathodes 58, 60, 63

Wahren Atlas 301, 324

waveforms of stimuli, selectivity of 63–4

white matter connectivity research 105

white matter tract stimulation 13

for epileptogenic zone overdrive 11

X-rays after STN electrode placement 331, 340

zona incerta 328