ISSN 1294-8322

Dialogues
in
Neuroplasticity

2004

Vo l u m e 6 . N o . 2

e

clinical neuroscience

Dialogues
Editor-in-chief Jean-Paul MACHER, MD, Rouffach, France Editorial Board Manfred ACKENHEIL, MD, München, Germany César CARVAJAL, MD, Santiago de Chile, Chile Marc-Antoine CROCQ, MD, Rouffach, France Michael DAVIDSON, MD, Tel Hashomer, Israel Margret R. HOEHE, MD, Berlin, Germany Barry D. LEBOWITZ, PhD, Rockville, Md, USA Deborah J. MORRIS-ROSENDAHL, PhD, Johannesburg, South Africa Rajesh M. PARIKH, MD, Bombay, India David RUBINOW, MD, Bethesda, Md, USA Pierre SCHULZ, MD, Chêne-Bourg, Switzerland Carol A. TAMMINGA, MD, Baltimore, Md, USA International Consultant Jorge-Alberto COSTA E SILVA, MD, Rio de Janeiro, Brazil Publication Director / Directeur de la Publication Jean-Philippe SETA, MD, Neuilly-sur-Seine, France

Editorial

D

ear Colleagues,

The known properties of the central nervous system are quite remarkable and we may confidently assume that many more fascinating aspects of the brain remain to be discovered. Until recently, the causation of mental disorders was always explained in terms of abnormalities involving familiar biological concepts, such as monoamine neurotransmission, receptor regulation, and molecular biology. The appearance of a novel explanatory model, accounting for some previously unexplained phenomena, is of tremendous interest. It has long been known that some disorders involve regional modifications that can be evidenced by studying brain structure. Neurotrophic factors preventing cell death have been shown to exist and, more recently, the process of hippocampal neurogenesis has been described. Neuroplasticity is the process that underlies neurogenesis: it leads to protein synthesis and constitutes a defense mechanism against the deleterious effects of stress. Plastic modifications of neurons and synapses have been observed thanks to the development of neuroimaging techniques, which can reach as far as the cellular level. The observations relating to neuroplasticity have led to: • New diagnostic markers. • A better understanding of certain pathogenetic mechanisms. • The proof of activity of certain compounds. We believe that it is important to give a progress report on the concept of neuroplasticity and its influence on the understanding of the mechanisms of depression. We are grateful to Dr David R. Rubinow from the National Institute of Mental Health in Bethesda, Md, for bringing together the most qualified authors in the field to discuss this topic in this issue of Dialogues in Clinical Neuroscience.

Yours sincerely,

Jean-Paul Macher, MD

Marc-Antoine Crocq, MD

113

editors. and publisher cannot be held responsible for errors or for any consequences arising from the use of information contained in this journal.Medical Publishing Division 192 avenue Charles-de-Gaulle 92578 Neuilly-sur-Seine Cedex .Institute for Research in Neuroscience and Neuropsychiatry BP29 . or editorial board. and submission of manuscripts Marc-Antoine CROCQ. editors. recording.com Copyright © 2004 by Les Laboratoires Servier All rights reserved throughout the world and in all languages. and also publishes free contributions in the field of neuroscience as well as other non–topic-related material. All contributions are reviewed by members of the Editorial Board and submitted to expert consultants for peer review. subscriptions.fr Annual subscription rates: Europe €150. biological. Each issue addresses a specific topic. PhD Servier International .France E-mail: mail.dialneuro@fr. and therapeutic aspects. MD FORENAP . NOVACK. MD FORENAP . ISSN 1294-8322 Design: Christophe Caretti / Layout: Graphie 66 Imprimé en France par SIP 1. The authors.Institute for Research in Neuroscience and Neuropsychiatry BP29 .92578 Neuilly-sur-Seine Cedex .novack@fr. EDITORIAL OFFICES Editor in Chief Jean-Paul MACHER. transmitted.68250 Rouffach .com PUBLISHER Les Laboratoires Servier 22 rue Garnier .asso.95310 Saint-Ouen-l’Aumône 114 . rue Saint Simon . Rest of World €170. or through an information storage and retrieval system.68250 Rouffach .France Tel: +33 3 89 78 71 20 (direct) or +33 3 89 78 70 18 (secretariat) Fax: +33 3 89 78 51 24 / E-mail: macrocq@forenap.netgrs. Indexed in EMBASE and Elsevier BIOBASE.Dialogues in Clinical Neuroscience is a quarterly publication that aims to serve as an interface between clinical neuropsychiatry and the neurosciences by providing state-of-the-art information and original insights into relevant clinical. or stored in any form or by any means either mechanical or electronic.France Tel: +33 1 55 72 33 10 / Fax: +33 1 55 72 68 88 E-mail: sarah. Production Editor Sarah A. No part of this publication may be reproduced. without the written permission of the copyright holder. Opinions expressed do not necessarily reflect the views of the publisher.France Tel: + 33 3 89 78 70 18 / Fax: +33 3 89 78 51 24 Secretariat.netgrs. including photocopying.

Zarate Jr. Stockmeier. Marc-Antoine Crocq In this issue David R. RUBINOW 115 . Charney. Gage Regulation of cellular plasticity and resilience by mood stabilizers: the role of AMPA receptor trafficking Jing Du. Manji ISSUE COORDINATED BY: David R. Grazyna Rajkowska Neuroplasticity in mood disorders Wayne C. Quiroz. Gray. Neil A. Gabriele Flügge Clinical research Cellular abnormalities in depression: evidence from postmortem brain tissue Craig A. Rubinow State of the art Structural plasticity of the adult brain: how animal models help us understand brain changes in depression and systemic disorders related to depression Bruce S. Husseini K. Steve T. Manji Pharmacological aspects Neural plasticity: consequences of stress and actions of antidepressant treatment Ronald S. McEwen Basic research Structural plasticity of the adult brain Fred H. Carlos A. George DeJesus.Contents Page 113 117 119 135 143 157 171 185 199 217 Editorial Jean-Paul Macher. Husseini K. Drevets Cellular plasticity and resilience and the pathophysiology of severe mood disorders Dennis S. Szabo. Duman Cellular consequences of stress and depression Eberhard Fuchs. Jorge A.

Nedelec. Jacques Chambron.Contents Page 227 235 243 Free papers Texture analysis of the brain: from animal models to human applications Jean-François J. Schad Texture analysis methodologies for magnetic resonance imaging Andrzej Materka ISSUE COORDINATED BY: David R. Olivier Yu. Jean-Paul Macher Problems in texture analysis with magnetic resonance imaging Lothar R. RUBINOW 116 .

the generation of new neurons. in the last article. as well as the ontogeny of susceptibility to psychiatric illness. and the cAMP-CREB (cyclic adenosine monophosphate [cAMP]–cAMP-response element binding protein) cascade. but this better understanding will also lead to a reconceptualization of how psychiatric illness is acquired. He suggests that the cellular and molecular underpinnings of structural and functional plasticity offer promising clues to the pathophysiology of depression and targets for drug development. a central tenet of our neurobiological training was that the structure of the brain was fixed. Dennis S. This comprehensive review of postmortem studies discusses the possible functional implications of abnormalities of cell morphology and distribution and introduces the circuitry that is described in more detail in the second article by Wayne C.. but also restricted our understanding of a variety of fundamental processes including learning. neurogenesis. commitment. perhaps most importantly. This capacity for self-repair represents one of the therapeutic frontiers in the treatment of neuropsychiatric illness. Drevets (page 199). Craig A. and the transduction of environmental factors to changes in brain function. In the first Clinical research article. as well as new therapeutic targets. and functional integration. They provide a basis for understanding depression as an impairment of synaptic and structural plasticity. For many of us. Jing Du and colleagues (page 143) review the evidence suggesting the role of glutamatergically mediated synaptic plasticity in both the pathophysiology and treatment of affective illness. This belief was not only incorrect. he provides a synthesis of identified neuropathological and imaging abnormalities in affective illness. and pharmacotherapy: the neurotrophin BDNF (brain-derived neurotrophic factor). The compelling models described make apparent the complexity and dynamic nature of adaptation. adaptive responses of the brain—neuroplasticity—and the relevance of neuroplastic changes to the pathophysiology of neuropsychiatric illness. This issue of Dialogues in Clinical Neuroscience describes the flexible. its molecular mediators in altering brain structure. Gage (page 135) reviews an element of neuroplasticity. and describes the multiple steps involved in the process of neurogenesis: differentiation. at a molecular level. these authors provide an excellent introduction to glutamate receptor pharmacology and intracellular signaling as a way of demonstrating both the mechanisms of action of mood stabilizers and targets for subsequent drug development. In the second Basic research article. Elucidation of this circuitry at functional and structural levels will also help illuminate substrates for component processes common to a variety of neuropsychiatric disorders. and. Charney and his colleagues (page 217) suggest that studies of neuroplasticity will result in a new psychiatric nosology. Thus. McEwen (page 119) provides an introduction to allostasis—adaptation to stress—and an overview of the structural and cellular consequences of stress. Indeed. how it is optimally treated (with attention to both structural and functional elements).In this issue. Stockmeier and Grazyna Rajkowska (page 185) describe in detail the neural and glial abnormalities identified in several critical brain regions in affective illness.. with consequent implications for its treatment. Fred H. and resilience. survival. development of susceptibility to disease. the mechanism of action of psychotropic medications. and the kinetics of stress-induced structural remodeling. Rubinow. highlighting those neural circuits strongly implicated as dysfunctional in affective disorder. MD 117 . Duman (page 157) discusses the effects of stress and antidepressants on neuroplasticity. While focusing on neuroimaging studies. ie. adaptation and maladaptation to stress. particularly as these effects relate to depression. not only will the therapeutic armamentarium be expanded as we better understand the mechanics of neuroplasticity. He focuses on two mediating systems that appear to link. In the other Pharmacological aspects article. Bruce S. In the first Basic research article. While focusing on AMPA (α-amino-3-hydroxy-5methyl-4-isoxazolepropionate) and GluR1 (glutamate) receptor trafficking. neuroplasticity. David R. depression. Ronald S. In one of the Pharmacological aspects articles. stress. how resilience is expressed at cellular and organismic levels. as was the number of neurons in the adult brain. In the State of the art article. Eberhard Fuchs and Gabriele Flügge (page 171) describe the pharmacology of the stress response by focusing on changes in monoamines and monoamine receptors in several animal stress models.

German Primate Center. Heidelberg. Md.Contributors Bruce S. PhD Andrzej Materka. MD Author affiliations: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology. NIH NIMH/MIB. The Salk Institute. Jackson. Bethesda. USA Author affiliations: Mood and Anxiety Disorders Program. Calif. Departments of Psychiatry and Pharmacology. Germany Author affiliations: Institute of Electronics. PhD Author affiliations: Division of Molecular Psychiatry. The Rockefeller University. CT. New Haven. Poland Craig A. Drevets. Germany Eberhard Fuchs. Duman. Bethesda. MD Author affiliations: Laboratory of Genetics. USA Author affiliations: National Institute of Mental Health. Lodz. MSEE. NY. Göttingen. PhD Author affiliations: The University of Mississippi Medical Center. Gage. USA Fred H. Rouffach. USA Author affiliations: Department of Biophysics and Medical Radiation Physics. La Jolla. New York. McEwen. Manji. Stockmeier. USA 118 . Md. PhD Wayne C. Nedelec. PhD. Md. DSc Author affiliations: Clinical Neurobiology Laboratory. German Cancer Research Centre. Schad. Bethesda. Charney. Yale University School of Medicine. MD. Miss. National Institute of Mental Health. USA Author affiliations: FORENAP. PhD Author affiliations: Laboratory of Molecular Pathophysiology. FRCPC Jean-François J. PhD Dennis S. Technical University of Lodz. USA Husseini K. PhD Lothar R. Department of Psychiatry and Human Behavior. France Ronald S.

However. For example. The amygdala. and stressful experiences have been reported to be a major risk factor in the occurrence of depressive disorders. in the brain. body. and behavior is a protective one. such as the neurotransmitters. repeated stressful experiences have deleterious effects.dialogues-cns. The hippocampus. Changes in the brain after acute and chronic stressors mirror the pattern seen in the metabolic. McEwen. cytokines. and the physiological and behavioral responses are intended to promote adaptation via a process called “allostasis. the amygdala and hippocampus.edu) Copyright © 2004 LLS SAS. eg. are used to survive and adapt to the challenge. 1230 York Avenue. expresses receptors that enable it to respond to glucocorticoid hormones in the blood.” becomes hyperactive in posttraumatic stress disorder and depressive illness. LLS SAS Dialogues Clin Neurosci. anxiety Author affiliations: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology. It undergoes atrophy in a number of psychiatric disorders. Stressful events are those which are threatening or.1 And. W Keywords: structural plasticity. USA (e-mail: mcewen@rockefeller. a key structure for memories of events and contexts. in part because the very same mechanisms that help protect in the short term are now either mismanaged and/or overused. PhD hen we experience a stressful event. NY 10021. play key roles in interpreting what is stressful and determining appropriate responses. and years. Box 165. stress. unexpected and surprising. which is important for “emotional memories. and cytokines and chemokines from the immune system. depression. that is. 2004. In animal models of stress. All rights reserved 119 www. and reduction in number of neurons in the dentate gyrus. decreased dendritic branching. and other mediators. © 2004. other hormones. Two brain structures. New York. brain. and impaired immune function. it also responds to stressors with changes in excitability. short-term adaptation (allostasis) followed by long-term damage (allostatic load). and immune systems. there is evidence for growth and hypertrophy of nerve cells in the amygdala. allostasis. the parasympathetic and sympathetic nervous systems. over weeks. months.” Chemical mediators of allostasis include cortisol and adrenalin from the adrenal glands. the initial response of the brain. PhD. allostatic load. and hormones. at the very least. and neurotransmitters. USA Address for correspondence: Bruce S. fat deposition obesity. The Rockefeller University. McEwen. Allostatic load of this kind is seen in major depressive illness and may also be expressed in other chronic anxiety and mood disorders. New York.6:119-133. the overactivity of stress hormones in the blood and endogenous excitatory The brain interprets experiences and translates them into behavioral and physiological responses. The Rockefeller University. cardiovascular. atherosclerosis. NY. the dysregulation and overactivity of these systems can promote changes that appear to be deleterious.State of the art Structural plasticity of the adult brain: how animal models help us understand brain changes in depression and systemic disorders related to depression Bruce S.org . bone demineralization.

CRS also increases aggression between animals living in the same cage (Table II).10 which are consistent with the opposite effects of stress on hippocampal and amygdala structure. which regulate excitability and morphological changes (Figure 1). 120 .16 Indeed.State of the art Selected abbreviations and acronyms CGRP CRS DG GR IGF-1 MR NMDA PSA-NCAM tPA calcitonin gene–related peptide chronic restraint stress dentate gyrus glucocorticoid receptor insulin-like growth factor–1 mineralocorticoid receptor N-methyl-D-aspartate polysialated neural cell adhesion molecule tissue plasminogen activator Acute stress induces formation of spine synapses in CA1 region of hippocampus6 and chronic stress also increases spine synapse formation in hippocampus and amygdala. GR. there are reports of hippocampal volume loss and enlargement of the amygdala. as will be discussed below.9 and enhances amygdala-dependent unlearned fear and fear conditioning. mossy fiber.11 Psychosocial stress suppresses neurogenesis and causes dendritic shrinkage. The hippocampus is a target for adrenal steroids. corpus callosum.17. CA1 Sch Perfusion pathway MF Dentate gyrus CA3 Figure 1. MR. Along with many other brain regions.7 The contrasting changes of dendrites in amygdala and hippocampus after chronic restraint stress (CRS) offers an unprecedented opportunity for understanding underlying mechanisms. is considered to be a model of human depressive illness.18 Studies in the tree shrew have shown that treatment with anti- amino acid neurotransmitters in the brain suppress neurogenesis in dentate gyrus (DG) and causes debranching of dendrites in hippocampus and medial prefrontal cortex. CRS for 21 days or longer impairs hippocampal-dependent cognitive function8. CC. which influence function in this structure as well (Table I). glucocorticoid receptor. the amygdala also contains adrenal steroid receptors. MF. Sch.12-15 and one of these stress models. the tree shrew. mineralocorticoid receptor. Schaffer colateral.2-5 The hippocampus contains receptors for adrenal steroids. whereas chronic stress causes neurons in amygdala to show dendritic growth. in major depression and a number of other mood and anxiety disorders.

2 .23 This suggests that the hippocampal role in contextual fear conditioning is enhanced by moderate levels of glucocorticoids.20 Synaptic reorganization is also a likely consequence of these rather drastic structural changes. Moreover. Allostasis and mechanisms for behavioral adaptation The amygdala and hippocampus are both involved in contextual fear conditioning and in passive avoidance learning.26 Glucocorticoids enter the brain. mineralocorticoid receptor.19 Besides reduced neurogenesis in DG.30. in passive avoidance. there is also evidence for reduced size of principal neuron cell bodies in hippocampus.25 Adrenal steroids also play a supporting role in the learning of a spatial navigation task in mice. glucocorticoids enhance learned fear21 and they play an important role in forming the memory of context in contextual fear conditioning. Table I. low levels of MR GR mostly. No. low levels of MR GR mostly. Cumulative effects of restraint stress on behavior.27 This finding illustrates a role for GRs acting upon the genome in a task that is known to depend on the hippocampus. low levels of MR GR mostly. suggesting that there is a mechanism for containing.24 Thus. Glucocorticoids potentiate serotonin inhibition of the processing of excitatory input to the lateral amygdala from the thalamus. such structural changes seem likely to play a major role in the volume loss in the human hippocampus and the related effects on cognitive function and affect. the sensory input that is important for Hippocampus Amygdala Septum Hypothalamus Cerebral cortex Midbrain Brain stem Cerebellum MR and GR GR and some MR GR and some MR GR mostly.22.McEwen Dialogues in Clinical Neuroscience . and mood-stabilizing drugs prevents stress-induced hippocampal structural changes.15. however.Structural plasticity of the adult brain . and glucocorticoid administration restores the normal learning curve. In fear conditioning.32-34 Adaptive structural plasticity One of the ways that stress hormones modulate function within the brain is by changing the structure of neurons. in mice in which the glucocorticoid receptor (GR) is deleted and replaced with a GR that lacks the DNA binding domain. and local implants of exogenous corticosterone into hippocampus. glucocorticoids do not improve task acquisition. adrenal steroids may regulate the nature of the signals that reach the amygdala and allow for greater discrimination of the most salient cues for learning. patches of MR GR mostly fear conditioning. MR. but not of the actual effect of footshock in rats that are already familiar with the context where the shock is administered. 121 . glucocorticoid receptor. Distribution of adrenal steroid receptors in brain regions.28 Other evidence for glucocorticoid actions supports an inverted U-shaped dose–response curve in which low to moderate levels of adrenal steroids enhance acquisition of tasks that involve the hippocampus.22. antiseizure. the input from the entorhinal cortex to the DG is ramified by the connections between • Cognitive impairment. which may underlie their biphasic actions on memory and recall.27 Adrenalectomy impairs the acquisition of the memory of hidden platform location in the Morris water maze. whereas high levels of glucocorticoids disrupt task acquisition. amygdala.26 Catecholamines work outside of the blood–brain barrier and their effects can be blocked by β-adrenergic–blocking agents. and nucleus tractus solitarii are all able to enhance passive avoidance learning. Within the hippocampus. Interestingly. GR. but the fear conditioning is either not so dependent on glucocorticoids or is so strong that glucocorticoid influences are hard to demonstrate.Vol 6 . other actions of glucocorticoids via GRs are known to involve the protein–protein interactions that are not prevented in mice carrying the GR defective in the DNA binding domain.14. which do not cross the blood–brain barrier.25. both catecholamines and glucocorticoids play a role in facilitating learning.29-31 Adrenal steroids have biphasic effects upon excitability of hippocampal neurons. and the animal models cited above provide evidence that synapses can be rapidly formed as a result of stress. which is consistent with reduced size of the dendritic tree.Yet there is evidence for an influence of glucocorticoids on the flow of information within the amygdala.18 This article will review underlying mechanisms and consider their applicability to furthering our understanding of the pathophysiology of mood and anxiety disorders. spatial recognition memory (hippocampus) • Increased anxiety and enhanced fear conditioning (amygdala) • Increased aggression (amygdala) Table II. Taken together. 2004 depressant. or limiting.

52 Rats can be observed from above by a video camera in this apparatus. The new granule neurons appear to be quite excitable and capa- Remodeling of dendrites Another form of structural plasticity is the remodeling of dendrites in the hippocampus. where a substantial number of them will go on to differentiate into granule neurons within as little as 7 days.35 The net result is a 600-fold amplification of excitation as well as a 300-fold amplification of inhibition. certain types of acute stress and many chronic stressors suppress neurogenesis or cell survival in the DG. IGF-1 is the mediator of the ability of exercise to increase cell proliferation in the DG.51 Neurogenesis in the DG There is structural plasticity within the DG-CA3 system. 12 CA3 neurons. dentate gyrus.39 The subgranular layer of the DG contains cells that have properties of astrocytes (eg. Estradiol accelerates cell proliferation in female rats. and many changes in brain chemistry. low testosterone.2 Such dendritic reorganization can also be seen in rats undergoing adaptation of psychosocial stress in the visible burrow system (VBS). One granule neuron innervates. Figure 2.45 It is also increased by a form of classical conditioning that activates the hippocampus (“trace conditioning”) prolongs the survival of newly born DG neurons. expression of glial fibrillary acidic protein) and give rise to granule neurons. and each CA3 neuron innervates.15. In the adult rat.47 On the other hand. on average. 9000 new neurons are born per day and survive with a half-life of 28 days. Why is the CA3 so vulnerable? Feed-forward excitability serves memory functions but increases vulnerability for excitotoxicity. 50 other CA3 neurons via axon collaterals.37 ble of participating in long-term potentiation. as well as 25 inhibitory cells via other axon collaterals (Figure 2). The dominant shows the fewest scars and has the highest level of testosterone.39 CRS causes retraction and simplification of dendrites in the CA3 region of the hippocampus (Figure 4).41 There are many hormonal and neurochemical modulators of neurogenesis and cell survival in the DG. a few subordinate males may die and others (showing scars from bite marks) will show enlarged adrenals. Neurogenesis and/or survival of newly born cells is increased by putting mice in a complex (“enriched”) environment. which provide some degree of control of the system. in that new neurons continue to be produced in the DG throughout adult life38 and CA3 pyramidal cells undergo remodeling of their dendrites. Lack of IGF-1 and insulin in diabetes has the opposite effect and decreases cell proliferation.2.42-44 Neurogenesis in the adult DG is enhanced by the hormone insulin-like growth factor–1 (IGF-1) and by serotonin and a number of antidepressant drugs.State of the art the DG and the CA3 pyramidal neurons.48-50 Chronic stress has even more potent effects on neurogenesis and neuronal survival. The VBS is an apparatus with an open chamber where there is a food and water supply and several tunnels and chambers.46. CRS for 21 days suppressed neurogenesis and CRS for 42 days causes the number of DG neurons to decrease along with total DG volume (Figure 3). male rats housed with several females establish a dominance hierarchy within several days. 122 . As to why this system exists.2 as will be discussed further below.36. and the mediators of these inhibitor effects include excitatory amino acids acting via N-methyl-D-aspartate (NMDA) receptors and endogenous opioids.38. In the VBS. these newly born cells appear as clusters in the inner part of the granule cell layer. Over the course of the next week. but also has somewhat larger adrenal glands than cage control rats. DG. the DG-CA3 system is believed to play a role in the memory of sequences of events. on the average. although long-term storage of memory occurs in other brain regions.40 After administration of bromodeoxyuridine (BrdU) to label DNA of dividing cells.

We refer to the phenomenon as “dendritic remodeling” and we generally find that it is a reversible process.57 This agrees with our finding that MR activation by aldosterone in adrena- 123 .58-60 Recent evidence indicates that presynaptic receptors containing kainate receptor subunits such as GluR6 are important for the feed-forward actions of glutamate on mossy fiber terminals. Excitatory amino acids released by the mossy fiber pathway play a key role in the remodeling of the CA3 region of the hippocampus. which showed reduced branching compared with the cage controls. Below we consider mechanisms involved in structural remodeling.57 In particular. both block CRS.53 What this result emphasizes is that it is not adrenal size or presumed amount of physiological stress per se that determines dendritic remodeling. Nacher J. Glt-1. Regarding changes in brain structure. Repeated restraint stress for 42 days reduces volume of the dentate gyrus (DG) and the number of neurons in the DG. A. Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus.17:879-886. phenytoin. it was the dominant rats that had a more extensive pattern of debranching of the apical dendrites of the CA3 pyramidal neurons in the hippocampus. but a complex set of other factors that modulate neuronal structure. Magarinos. M. Pevet. is elevated by CRS in hippocampus. γ-aminobutyric acid (GABA). P. Control.2 Probably the most important interactions are those with excitatory amino acids such as glutamate. We previously showed that NMDA receptor blockade and the Na/Ca channel blocker. particularly in the CA3 region. and regulation of glutamate release by adrenal steroids may play an important role.McEwen Dialogues in Clinical Neuroscience . McEwen BS. 2004 Figure 3. 2003.Vol 6 . Hof PR. S. The role of adrenal steroids in the structural remodeling described above reflects may interactions with neurochemical systems in the hippocampus. McEwen. and GluR7. providing another indication that elevated gluta- A B Figure 4. Eur J Neurosci. Hippocampal CA3 pyramidal neurons are remodeled by 21-d restraint stress. compared with the subordinate rats. preferential mineralocorticoid receptor (MR) occupancy by low corticosterone (CORT) levels enhanced mRNA levels for KAR2. GluR6. and excitatory amino acids (Figure 5). B. No. 21 days’ chronic restraint stress.61 and one study showed that a number of kainate receptor subunit mRNAs are regulated biphasically by adrenal steroids. Blackwell Publishing. A single restraint stress does not suppress cell proliferation. Copyright © 2003. it occurs in a matter of hours and reverses itself just as quickly when hibernating animals are aroused from torpor (A. B.54-57 We have found that the glutamate transporter. including serotonin.and glucocorticoid-induced remodeling of dendrites in CA3. Repeated restraint stress for 21 days suppresses cell proliferation.Structural plasticity of the adult brain . mate levels are an important component of structural plasticity. In hibernating hamsters. Inc. Reproduced from reference 51 with permission: Pham K. unpublished data). 2 .

Glucocorticoids increase glutamate levels.80 and enhancement of long-term potentiation. Besides glucocorticoids and excitatory amino acids. stratum radiatum. such as increased paired-helical-like phosphorylation of tau66 and reduced tyrosinated tubulin. SO. Brainderived neurotrophic factor (BDNF) plays a major role in activity-dependent synaptic and dendritic remodeling. Blow-up of CA3 region. and 5-HT2 receptors. N-methyl-D-aspartate (NMDA) receptors. stratum pyramidale. McEwen. providing further evidence that CRS-induced structural plasticity and the molecular markers Glt-1 and phosphoCREB are useful in study of psychiatric illnesses. SP. we have found that in medial and central amygdala77: • tPA is released under stress and initiates neural remodeling. E. stratum oriens. However. T.76-78 It has been suggested that tPA may play a role in the processing of proBDNF into active forms. kalirin. neurotrophins and gp130 cytokines are implicated in structural plasticity along with extracellular proteases such as tissue plasminogen activator (tPA) and neuropsin.63. 124 . treatment with the mood stabilizer lithium prevented CRS-induced structural remodeling of the stress-induced elevation of Glt-1 and CREB phosphorylation (G.State of the art lectomized (ADX) rats restored levels of [3H]kainate binding in the mossy fiber region of CA3.GABA. DG. The Rac/Rho guanosine triphosphatases (GTPases) and related proteins such as the guanosine triphosphate (GTP) exchange factor. cytoskeletal changes.56 However. plasminogen (inactive zymogen) leads to plasmin (active serine protease).67. B. guanosine triphosphate–activating protein [GAP-43]). SR. the activation of the CREB (cyclic adenosine monophosphate response element–binding protein) system is a likely candidate mediator. this needs much careful study. CA3 neurons highlighting stratum lucium (SL). and recent evidence indicates that phosphorylation of CREB is chronically activated in rats subjected to CRS. Because excitatory amino acids play a key role along with circulating glucocorticoids.62 It is possible that CREB is involved in activity-dependent synapse formation.68 Except for one relevant study on seizures.69-73 and is implicated in hippocampal-dependent memory formation. S. For example. Overall.74 BDNF also regulates tPA release from neurons75 and tPA is released from nerve terminals in hippocampus and other brain areas such as amygdala. Wood. decrease 5-HT1A receptors. have been shown to play a key regulatory role in cytoskeletal modifications in developing and adult neurons. Nevertheless. C. calcium currents. A. further studies are needed. γ-aminobutyric acid. Cross-section of dorsal hippocampus. and alter subunit expression of GABAA receptors. dentate gyrus. CREB has been linked to regulation of synaptic plasticity and particularly neurogenesis. unpublished data).65 there are no studies thus far of the effects of chronic stress on these pathways or of the modifications of the cytoskeleton itself.65 and new evidence shows that posttranslational modification of tubulin65 and phosphorylation of the microtubule associated protein tau66 take place along with changes in the actin cytoskeleton. Using tPA knockout mice. Structural changes in dendrites and spine synapses are the result of modifications in the microtubule system of the cytoskeleton.81 Activity of tPA is an important mediator of structural plasticity and enhanced fear in the amygdala resulting from acute restraint stress.64 However. 5-hydroxytryptamine (5-HT) turnover.67 under conditions in which reorganization of dendrites and synaptic connections occur. Young. B. which is evident as a result of long-term potentiation.65 are consistent with increased cytoskeletal rigidity. • This release is plasminogen-independent (extracellular signal–regulated kinase [ERK1/2]. where mossy fiber terminals form synaptic contacts . the role of glucocorticoids in activation of the CREB system has not been thoroughly investigated.79 The activity of tPA is associated with structural plasticity and increased fear. • Glutamate levels • NMDA receptors • Ca++ currents • 5-HT turnover • 5-HT2 receptors • 5-HT1A receptors • GABAA receptors ++ ++ ++ ++ ++ -+/- Figure 5. L.77 motor learning.

Permanent damage as a result of stress The remodeling of the hippocampus in response to stress is largely reversible if the CRS is terminated at the end of 3 weeks. The neuroimmune peptide. and newly formed neurons to make connections. CGRP. cytotoxic T cells are able to produce cytotoxic death of neurons. It is well established that glucocorticoids exacerbate damage to the hippocampus caused by ischemia90 and seizures. which are constitutively expressed. No. neurogenesis is reduced in DG and dendrites are shorter and less branched. 2004 • tPA induces termination of its own action via plasminogen-activator inhibitor–1 (PAI-1). Neuropsin is another protease that is induced in hippocampus by NMDA-mediated excitation in seizures and leads to proteolysis of the presynaptic adhesion molecule. Removal of the PSA residue by endoneuraminidase (EndoN)88 is a powerful tool for manipulating this system.85 However. 2 . at least in part. and these changes have disappeared after CRS for 42 days.59.83 Leukemia inhibitory factor (LIF) is particularly interesting because it interferes with neurotrophin signaling84 and causes dendritic retraction in cell culture.51 We do not yet know whether structural changes occurring after 6 weeks of CRS are reversible or whether they can be accelerated by antidepressant or antiepileptic drugs that block the effects of stress and glucocorticoids on remodeling.92 Glucocorticoids exacerbate excitotoxic damage and do so. The ability of neuronal processes to expand or contract. This important neuropeptide has multiple functions including: its actions as a potent vasodilator96 and an immune modulator. but this possibility needs to be kept in mind if it turns out that prior CRS has a protective effect on subsequent responses to excitotoxic challenge. and it is conceivable that increased expression of LIF might play a role in dendritic shortening.McEwen Dialogues in Clinical Neuroscience . the phenomenon of ischemic preconditioning95 reveals that prior stimulation of the hippocampus can induce a protective mechanism that may reduce the damage produced by a full-scale ischemic event. a modulator of hormone release involved in growth and development.10 After 3 weeks of CRS.93 and. since PSA removal abolishes plasticity of suprachiasmatic neurons to environmentally induced phase shifting of the diurnal rhythm. We are presently studying the long-term effects of stress. L1.60 and there is an increase in PSA-NCAM expression in the DG that is consistent with increased mobility of neuronal processes even in the face of reduced DG neuron pro- duction. • tPA activity is required for increased anxiety in the elevated plus maze.51. but may be part of a 125 . which need to be investigated. which is mediated by CRF and an inducer of apoptosis (reviewed in reference 103). The increased expression of CGRP in mossy cells is especially prominent after bilateral ADX under conditions in which there is apoptosis of granule cells. by facilitating trafficking of immune cells to the injury site.Structural plasticity of the adult brain . it has not yet been determined whether acute or chronic stress increases LIF expression.Vol 6 . It is not clear whether the same mechanisms might be operative when stress is applied and whether they might affect the response to excitotoxicity in response to seizures. there.51 This raised questions about the role of PSA-NCAM in adaptive structural plasticity. and the CGRP immunoreactivity is enhanced within the inner third of the molecular layer of the DG. is dependent on the extracellular environment in which polysialated neural cell adhesion molecule (PSA-NCAM) plays an important role. One of the prominent features of excitotoxic damage or removal of adrenal steroids is the robust induction of calcitonin gene–related peptide (CGRP) in terminals and cell bodies in hippocampus and in mossy cells.91.89 We now turn to the important question of whether chronic stress increases or decreases vulnerability of the hippocampus to damage from other insults.94 However.86 PSA-NCAM is associated with regions of the brain that show structural plasticity such as the inner granule cell layer of the DG and the mossy fiber terminals of CA3.82 The gp130 cytokines are expressed in hippocampus under stimulation by seizures. is one of the most diverse and influential immunoregulators of the periphery. along with their receptors. Continuation of CRS for a total of 6 weeks abolishes the upregulation of PSA-NCAM and results in a significant 6% reduction in DG volume and 13% reduction in granule neuron number. and a stimulator of sympathetic outflow. Nor do we know whether the structural changes occurring with CRS increase or decrease the vulnerability of the hippocampus to damage by excitotoxicity. Some of the different functional roles for CGRP may not be independent.87 CRS for 21 days causes increased PSA-NCAM expression in the DG proliferative zone even though cell proliferation is suppressed.97-102 as well as a neural and immune developmental regulator. Protective agents may also involve substances that are upregulated in the brain in response to damage or threat of damage.

Protective and damaging effects of the mediators of adaptation Individual differences in the progression of a number of disorders that accumulate with time can be conceptualized as an accumulation of wear and tear of daily experiences. The brain is the master controller of the three systems noted above and is also a target of these systems.103. subject to both protection and damage. references 133 and 134). the endogenous excitatory amino acid neurotransmitters appear to play a major role in these changes.108 The role of CGRP may then not only protect against immune system damage to neurons. the expression of CGRP within the hippocampus increases in four separate models of CNS injury: ADX. When that does not happen. their effects on target cells are prolonged. there is allostatic load and the brain is at increased risk for damage. lifestyle. we already noted the studies showing that hippocampal volume loss in major depressive illness is related to duration of the depression rather than to age per se of the patients.121-123 Moreover.119 even though they are also an essential part of normal synaptic neurotransmission and plasticity. the same type of elevated and prolonged secretion of glucocorticoids during aging has also been associated with impairment of cognitive function in rodents118-120 and humans. act upon receptors in various tissues and organs to produce effects that are adaptive in the short term. and they produce effects locally to either propagate or inhibit further neural activity.107 other studies have shown that both microglia and astrocytes express CGRP receptors and that exposure to physiological levels of CGRP induces c-fos in microglia and astrocytes and increases plasminogen activators.” meaning “maintaining stability through change. leading to other consequences that may include receptor desensitization and tissue damage. In particular the diurnal rhythm is distorted. but can be damaging if the mediators are not shut off when no longer needed. type 2 diabetes. In each case. but may also participate in plasticity and healing. Allostasis also applies not only to circulating hormones. the reasons for these different results are beyond 126 . glucocorticoids from the adrenal cortex. When release of the mediators is not efficiently terminated.126 and the stress hormone axis in major depression is resistant to suppression by the synthetic glucocorticoid dexamethasone.116 The processes of allostasis and allostatic load have been described and measured for metabolic and cardiovascular changes that are associated with obesity.130-132 Not all studies report such changes (see. and cardiovascular disease. autonomic nervous system. Although the upregulation of CGRP may be associated with neuronal cell survival. Therefore.127 It is also noteworthy that androgen levels are elevated in women with major depression.117 However.115. and cytokines from cells of the immune system. neurotransmitters are released by neuronal activity. which interact with the genetic constitution and predisposing early life experiences. A number of studies have shown that CGRP is expressed following various kinds of trauma and plays an important role in the acute phase response that may be of particular relevance to the outcome of the regional injury response in the central nervous system (CNS). and immune system are mediators of adaptation to the challenges of daily life.104 In recent studies.”112 Physiological mediators.124 Normally low evening levels of cortisol are increased in a subset of depressed patients125. allostatic load refers to the “cost” of adaptation. referred to as “allostasis. Neurotransmitters and hormones are usually released during a discrete period of activation and then are shut off.105 trimethyltin ingestion. and this may reflect elevated growth hormone release as a result of the hypercortisolemia.106 and kainic acid injections. for example.”113. however.129 Each of these patterns of elevation constitutes an “allostatic state.109-111 The neuroendocrine system. This process has been named “allostatic load. such as adrenalin from the adrenal medulla. the expression of this peptide was limited to the specific region of damage and in association with the surviving neuronal population. and the mediators themselves are removed from the intracellular space by reuptake or metabolism in order not to prolong their effects. Regarding the brain. but also to organs and tissues of the body. and major life stressors.105 intrahippocampal colchicine injection. Allostatic states in depressive illness Stress hormones are elevated in major depressive illness.State of the art cascade of events that constitute the healing response to injury. In the nervous system. which undoubtedly reflects adrenal hyperactivity.128 IGF-1 levels are also reported to be elevated in major depression.” and represents a pathway for the development of allostatic load in the brain and in other organs throughout the body.114 which refers to the price the tissue or organ pays for an overactive or inefficiently managed allostatic response.

178 Conclusion Translational studies of brain changes in major psychiatric illnesses such as unipolar and bipolar depression and posttraumatic stress disorder are showing that changes in volume of structures such as hippocampus.Vol 6 .176 On the other hand. but declined rapidly over several years. depression. Such cumulative.149 the elevation of amygdala activity may be a first step that leads to overactivation of systems involved in physiological and behavioral coping.138. Sheline and colleagues described magnetic resonance imaging (MRI) evidence for discontinuities that might represent sites of damage. with an actual enlargement of the amygdala in the first episode of major depression.173-175 Finally. bone mineral loss. The long-term consequences of this may well be a wear and tear on the body that results in a number of pathophysiological consequences. with elevations of excitatory amino acid tone. in a recent study in young depressed subjects. One region is the prefrontal cortex. Depressive illness is associated with a hyperactivation of the amygdala.146 and more recently.162-165 There are parallels between the story for major depression and what is known about psychiatric and somatic features of Cushing’s disease involving melancholia. such as cardiovascular instability. On the one hand. since the amygdala regulates both autonomic nervous system activity and adrenocorticotropic hormone (ACTH) and cortisol production through outputs of its central nucleus. as well as neuronal density in both unipolar and bipolar disorder.140 The key. 2004 the scope of this discussion. It is important to note that other brain regions besides hippocampus are affected in depressive illness and undergo structural changes. prefrontal cortex. particularly when depression lasts a long time. However. as well as gender and age. the combination of long-term allostatic load.147 This is reminiscent of the increased dendritic branching reported in rats after repeated immoblization stress (see above and reference 148). but they may be explained by differences in the duration of depression. there are other changes in the body that reflect dysregulated hypothalamopituitary axis (HPA) and autonomic activity. the possibility that neural damage may ultimately occur in major depression cannot be disregarded. It should be noted that hippocampal size in elderly twins shows only 40% genetic contribution. 127 . and structural imaging141 showed loss of volume in familial pure depressive disorder. together with dysregulation of the autonomic nervous system in major depression. hippocampal volume loss in Cushing’s disease is at least partially reversible over several years after correction of the hypercortisolemia. hippocampal volume was not smaller in first-episode depression. and also sends outputs via the central nucleus for autonomic arousal and via the basal nucleus for more active aspects of coping. and are slow in developing. Besides the brain changes in major depression.McEwen Dialogues in Clinical Neuroscience .151 It is thus possible that initial hypertrophy gives way to atrophy in this important brain structure.139 the duration of the depression and the subtype of depression were not carefully controlled.These constitute allostatic load that produces cumulative pathophysiology.150 It is important to note that there are reports that in recurrent major depression of long duration the amygdala may undergo shrinkage.130 Although some recent postmortem studies on brains from depressed individuals did not show neuron loss in hippocampus.137 In subjects with a long-term history of depression.170-172 Interestingly.158 is associated with increased blood platelet reactivity159-161 and increased risk for cardiovascular disease. long-term effects include bone mineral loss152-154 and abdominal fat deposition. Since the amygdala integrates information related to fear and strong emotions. there is evidence for hippocampal atrophy in Cushing’s disease along with memory impairments.145. whereas autopsy studies142-144 have shown loss of volume and glial cells. much more work needs to be done on this brain region.Thus. abdominal obesity.166-169 In addition.4 However. with the predominant influence being environmental. a largely unexplored area concerns the effects of antidepressant medication on the brain and body changes associated with depressive illness.149. withdrawal from antidpressant treatment may cause imbalances in neurotransmitter systems. certain antidepressants may contribute to some of the associated pathophysiology. unanswered question is whether such changes can be prevented or even reversed. No.155-157 Moreover. There is one animal study showing that chronic glucocorticoid treatment induces loss of dendrites in the rat prefrontal cortex.136 with an association detected with presence of the ApoE4 genotype.177 and contribute to the allostatic load that occurs as the depressive state continues. which may also be reversible if caught in time. Hippocampal atrophy has been found in relation to depression in the elderly.Structural plasticity of the adult brain .131. and increased risk for cardiovascular disease.135 This emphasizes the importance of experimental factors and allostatic load in determining hippocampal volume. 2 .

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Lumbar bone mineral density in patients with major depression: evidence of increased bone loss at follow-up. 1992. Testosterone. 1999. endocrinologically a syndrome of premature aging? Maturitas. 1998. Stress. Rajkowska G. Allostasis. Lucassen PJ. Proc Natl Acad Sci U S A. Abercrombie HC. Mauri M. 1998. 147. 142. Am J Psychiatry. Cizza G. Rao BSS. 127. Starkman MN. 1996. 2002. Heuser I. Hippocampal volume reduction in major depression.51:708-714. Hypercortisolemic depression is associated with increased intra-abdominal fat. McQuoid DR. Strasburger CJ.6:20-29. Sheline YI. 169. Musselman DL. Barch DM. Anderson ER. Byrum CE. Mintun MA. 162. 2001. and hippocampal volume in major depression. Sinforiani E. Neuroreport. 2002. Nemeroff CB.141:215-219. Depression: a major. Heritability of hippocampal size in elderly twin men: equivalent influence from genes and environment. Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease. Vannier MW. Stress. 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2000. Bremner JD.Vol 6 . Colla M. Life Sci. 2003. 177. 180. 1997. 178. 181. Antidepressant treatment and global tests of coagulation and fibrinolysis. Sugden K. Brand L. GABA levels and NMDA receptor binding in rat hippocampus. Harvey BH. Drevets WC. 179.62:130. 133 .McEwen Dialogues in Clinical Neuroscience .Structural plasticity of the adult brain .301:386-389. Jonker LP. Heuser I. Neuroimaging studies of mood disorders.27:539-547.71:43-54. NMDA receptor involvement in imipramine withdrawal-associated effects on swim stress. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Moffitt TE. J Clin Psychiatry. 182. Dempfle CE. 2003. Lederbogen F.45:797805. Caspi A. No. 1999. 2 . 2001. Kendler KS. Dreuschle M. Heenop M. Weber B. McEwen BS. Stein DJ. Biol Psychiatry. Biol Psychiatry. 2002. 2004 176.54:1105-1117.48:813-829. Karkowski-Shuman L. Science. Does stress damage the brain? Biol Psychiatry. Stressful life events and genetic liability to major depression: genetic control of exposure to the environment? Psychol Med. et al. Harvey B. Neurobiology of antidepressant withdrawal: implications for the longitudinal outcome of depression. Stein D.

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works. quite elaborately from the cell body. it is no wonder that the most common model or analogy of how the brain operates is that of a computer. Learning how behavior and environment regulate brain structure and function will lead to strategies to live more effective lives and perhaps protect from. The neurons receive the signals on their antennae. and connections between and among neurons. All rights reserved Adult neural stability One of the main reasons for viewing the brain as a stable machine or computer is because this analogy helps explain how we can remember from one instant to the next. Therefore. neurological disease. like the liver. hose of us who study the nervous system believe that the brain is the organ that controls our behavior.org 135 . heart. are results of the brain’s processing of information and directing our subsequent actions. If the underlying structure was changing all the www.edu) Copyright © 2004 LLS SAS. what we think and what we do. Each neuron can have thousands of these synapses on its dendrites and cell body. The aggregation of this information passing and processing results in thought and behavior. and tissue. T Keywords: neurogenesis. Gage. What is as remarkable is that the changes that occur in the adult brain are influenced by the behaviors an individual engages in. The specific site where the chemical signal from one cell makes contact with another cell is called a synapse. and plays. USA (e-mail: gage@salk. or repair. The brain is an organ. Given this basic assumption. and is made of chemicals. and kidney. adult stem cell. called dendrites. Calif. 10010 North Torrey Pines Road. The synapse is the structural unit that transmits the majority of information between neurons. cells. Communication between brain cells is mediated through neurons with long processes (axons) that connect many cells at once and release small batches of chemical information (neurotransmitters) to a network of other neurons. CA 92037. Laboratory of Genetics. © 2004. Gage. brain structure. LLS SAS Dialogues Clin Neurosci. The real trick for the neuron is to calculate (interpret) the temporal and spatially transmitted information it receives and to send that interpreted message onto the next neurons in a circuit. PhD. which is made up of signaling cells (presynaptic boutons) and receiving cells (postsynaptic spines). depression Author affiliations: Laboratory of Genetics. USA Address for correspondence: Fred H. 2004. The Salk Institute. while obviously influenced by the experience.6:135-141. it is likely wrong or at least very limiting.dialogues-cns. La Jolla. This view is now being challenged with clear evidence that structural changes occur in the brain throughout life. brain damage and brain disease. including the generation of new neurons and other brain cells. PhD The adult brain has long been considered stable and unchanging.Basic research Structural plasticity of the adult brain Fred H. except for the inevitable decline that occurs with aging. The Salk Institute. which protrude. While this analogy may have some heuristic value. as well as the environment in which an individual lives. in many cases. La Jolla.

8 and later to nonhuman primates and humans in the 1990s. However. liver. with stress and aging decreasing neurogenesis and environmental enrichment and exercise increasing neurogenesis.3 Bjorklund. lung. The previously accepted dogma of adult neural stability is now being called into question. as proposed by Francis Crick. The replacement of dead cells by transplantation of externally derived cells continues both experimentally and clinically and. In the adult center the nerve paths are something fixed and immutable. nothing may be regenerated” (S. It may also provide the underpinning for the adaptability and flexibility. providing L-dopa for Parkinson’s disease [PD]. highly regulated by experience. However. This behavior of adult stem cells that were expanded in culture and transplanted back to the adult brain contrasts with the behavior of fresh tissue derived from the fetal brain that has not been extensively expanded in 136 . kidney. if the brain is the seat of consciousness.” The dominant strategy for repairing a broken. they did differentiate into astrocytes and oligodendrocytes in other areas. because there is no way to fix it. structural plasticity provides the mechanism for the brain to repair itself. A stem cell is an uncommitted cell that. amyotrophic lateral sclerosis. when it divides. the cells survived well and differentiated or matured into authentic neurons in the two areas of the brain where neurogenesis normally occurs.6 A deeper blow to the dogma of adult neural stability has been the recent acceptance of the ability of certain areas of the adult brain to generate new neurons throughout life. known as adult neurogenesis. Ramon y Cajal. optimism for transplantation therapy has been renewed.4 and Aguayo5 and their colleagues in the 1960s and 1970s revealed that damaged axons could grow under some extraordinary circumstances. or “plasticity” as neuroscientists refer to it. Researchers were convinced that “Once development was ended. and most have the capacity to generate new cells to replace damaged ones.2 This dogma even influenced clinical research and the accepted methods for treating brain damage. or spinal cord injury). can give rise to itself (self-renewal) and can also give rise to any or all of the three main cell lineages of the brain: neurons.Basic research time. like fibroblast growth factor (FGF) and epidermal growth factor (EGF). injured. 1928). Using a variety of methods. to induce them to divide indefinitely in culture dishes in the laboratory. In general.1 how would we maintain a self identity if the brain were not stable? Well. the numbers of adult stem cells can be greatly expanded and they can be genetically marked in culture and then transplanted back to the adult nervous system. how could we do that? For that matter. more experimentally. and oligodendrocytes. the fonts of growth and regeneration of the axons and dendrites dried up irrevocably. which works pretty well for a while) or. or damaged brain was to replace the lost neurotransmitters (for example. Pioneering studies by Raisman. astrocytes. the demonstration of “stemness” in vivo in the adult brain is difficult. Interestingly.10 In these studies. Huntington’s disease [HD]. the therapeutic strategy clinicians would suggest could be summed up as “try not to damage your brain. and blood have some level of repair capacity. it is now possible to isolate these stem cells from the adult brain and use specific growth factors. and in some ways even more importantly. but was. to replace the missing or dead neurons (as in neural transplantation for treating PD. All organs of the body have some capacity to repair themselves following minor injury. These studies have led to a recent stampede of very promising work that could lead to the regeneration of cut or damaged axons due to spinal cord injury. Early evidence of this ability was generated by Altman and colleagues in the 1960s and 1970s.9 During this same period. the brain was considered unique in its lack of ability to repair itself once it had matured to adulthood. Most of the studies that have determined that the cells from the brain are stem cells have done so by studying the cells in vitro. at least to a small extent. In addition. the dirty little secret is coming out: the brain is not stable and that is a good thing.7 and was beautifully extended to birds by Goldman and Nottebohm in the 1980s. The structural changes seen in the brain may be required to provide the extra capacity we need for dealing with complexity.Alzheimer’s disease. in fact. Until recently. Stem cells in the adult brain The surprising observation that neurogenesis continues in the adult nervous system has led to the discovery that there are stem cells in the adult brain that generate the new neurons. heart. the hippocampus and the olfactory bulb. with the new hope provided by the availability (albeit limited) of the pluripotent human embryonic stem cells. Skin. it was discovered that adult neurogenesis itself was not stable and predictable. that is required for dealing with the variety of challenges that we face throughout life. the adult stem cells did not readily differentiate into neurons in any other areas.

these fetal stem cells are so immature that. if taken at the appropriate time and from the appropriate location. depending on where they end up and what type of activity is going on in that brain area at that time. in order to find ways whereby we can enhance it.Gage Dialogues in Clinical Neuroscience . Once the cells are committed to becoming a neuron or glial cell. The factors that regulate neurogenesis are being intensely investigated and new factors that modulate different components of neurogenesis are being discovered on a regular basis. survive and differentiate quite readily into the types of neurons and glial cells from which they were obtained. to a limited extent. therefore. direct it. The irony then is that fetal tissue grafts are more mature than adult stem cells that have been isolated and expanded in culture. they will continue toward that cell type and eventually integrate and replace the missing function. a hippocampal neuron. The way to make both fetal and adult stem cells more useful for therapeutic transplantation applications is to determine what the signals are in development that induce the stem cells to become a particular neuronal type. 2004 culture. then why can’t the brain repair itself after injury or disease? The answer seemed to be that the brain is capable of repairing itself and that it already does. the fetal cells have already matured somewhat and have committed themselves to a particular neuronal type. Freshly dissociated cells from the fetal brain. about 50% of these newborn cells never make it and instead die and disappear. No. the concept of neural self-repair emerged. receiving and sending information. and. The question was posed: if the adult brain has pockets of stem cells that can become neurons. astroglial cells (which play a crucial role in generating and maintaining the health of neurons). giving rise to another stem cell (self-renewal) and some progeny that may grow up to be working cells. factors known to be important in development of the nervous system.Thus. like Sonic hedgehog11 (which was first discovered in fly brain and called hedgehog). These properties of fetal tissue make it more amenable to therapeutic applications. outside of the limited number of stem cells. and one that—as I said earlier and will emphasize repeatedly—is highly regulated. the adult cells are too mature and will not withstand the isolation and transplantation procedures. On average. then the cells will either die or become glial cells or merely persist as stem cells. neurogenesis is a process. Let’s first summarize what we know about the process of adult neurogenesis. For example. the birth of new brain cells or neurogenesis is not an all-or-nothing event.Vol 6 . they proceed toward their predetermined fates. Part of the problem with fetal tissue is that there are so few cells available that are at just the right age and in just the right location. Even so. Surprisingly. we may not be too far away from this goal. committed dopamine cells are being taken from fetal substantia nigra for transplantation. Those that do survive may become a neuron or glial cell. other growth factors like brain-derived neurotrophic factor (BDNF)13 and insulin-like growth factor (IGF)14 play important roles in keeping the cells alive and encouraging 137 . it takes over a month from the time the new cell is born until it is functionally integrated in the brain. they have lost the youthfulness to survive and integrate into the adult brain. in HD treatment. The current strategy is. At this juncture of stem cell biology and adult neurogenesis. to try to understand how. BMPs (bone morphogenetic proteins) and Notch12 (which were also first discovered in fly brain) appear to be regulators of whether the newborn cells decide to become glia. The progeny must move away from the influence of the mother stem cell into an area that is permissive for maturation. adult neurogenesis normally occurs. fetal cells are being taken from fetal basal ganglia and transplanted into patients. not an event. in experimental treatments for PD. For example. However. and oligodendrocytes (a third type of cell in the brain that insulates the neuronal axons so that they can transmit their information efficiently). In fact. and molecules associated with the glial cells that surround the stem cells instruct the newborn cells to become neurons. unless the adult brain has all the necessary signals to direct them to a particular neural type.Structural plasticity of the adult brain . and perhaps to what end. The problem with the adult brain is that. and then induce the stem cells toward that lineage in a culture dish just far enough so that. only the primitive fetal stem cells will divide extensively. once placed in culture. What is adult neurogenesis/cell genesis? As it turns out. as was seen with adult stem cells. 2 . and more generally harness the residual elements of neural plasticity that are inherent to neural self-repair as a treatment for brain disorders.The multipotent stem cell divides periodically in the brain. given minimal local environmental signals. ie. which means that either many fetuses must be used for each transplantation or the cells must be put in culture to expand their number. have been shown to regulate the proliferation. once they are subsequently transplanted to a particular part of the brain. but the fate is not guaranteed.

to occur everywhere in the brain and spinal cord. eg. it is not nature or nurture. where the cells differentiate into a variety of different kinds of neurons. but more correctly an interaction or cooperation between the two. the survival of the newly born neurons. the process of generating new neurons. or their integration into the neural circuitry.21. or more precisely the dentate gyrus of the hippocampus. especially in the hippocampus. For example. cell genesis results in the birth of new glial cells that are likely participating in the microrepair process. Understanding how neurogenesis is normally regulated will be the key to developing strategies to counteract the misregulations of neurogenesis. as with most things. experiences. It is the understanding of how these growth factors and cellular environments control neurogenesis in the normal setting that will lead to development of therapies aimed at enhancing and directing neurogenesis in disease states.19 The second brain area—and the only structure where neurogenesis has been confirmed in all adult mammals from mice to man—is the hippocampus. In fact.19 The stem cells of the hippocampus reside in the interior of the densely packed granule cells. Reports that new neurons are born outside of the two well-documented areas of neurogenesis. a brain structure involved in smell.24 In addition to the positive effects of exercise and environmental enrichment. and thus any theory for the functional significance of neurogenesis will likely interpret the value of new neurons in terms of providing flexibility and How does the process of neurogenesis respond in the damaged. there is a clear genetic underpinning to neurogenesis. does not occur spontaneously in every part of the brain. First and foremost. and do not have a clear picture as to what role these new cells may play in the function of this brain structure. the frontal cortex. the role that the new neurons play in behavior has likely less to do with birth of the cells and more to do with the properties of the newly born functioning neuron. Since it takes a month from the time the new cells are born until they are integrated into the functional circuits of the brain. low levels of neurogenesis may be detected in more regions of the adult brain and spinal cord. while cell division or cell genesis appears. as well as the environmental stimuli that regulate neurogenesis. most forms of experimental epilepsy25. we anticipate that we will be able to direct neurogenesis anywhere in the brain. and disease. Certainly. Once the stem cells divide and progeny are born. van Praag discovered that running on a running wheel alone was sufficient to nearly double the number of dividing cells.22 However. though with new and more sensitive methods. resulting in robust increases in new neurons. surprisingly. it only occurs robustly in two areas of the brain. as well as a significant improvement in learning and memory. injured.15. Where does adult neurogenesis/ cell genesis occur? Neurogenesis. In an attempt in my laboratory to tease out the elements of the enriched environment that are critical for the increased neurogenesis.Basic research the young cells to mature and become functional. For example. The hippocampus is critical to the formation of new memories. a striking number of neurological diseases and conditions have been shown to affect neurogenesis.23. the process of neurogenesis is also negatively regulated by events in the environment. One of the most striking aspects of neurogenesis in the hippocampus is the number of events.10 The most robust cell proliferation occurs in the ventricles of the forebrain. have not been substantiated. injury.26 result in a robust 138 . with a correlation in mice showing that those strains of mice with higher rates of neurogenesis learn more quickly. as we learn more about the molecular mechanism that controls neurogenesis.We are just now learning about how the olfactory bulb functions normally. future studies are focusing in part on determining whether the spines and synapses of the newly born neurons have properties that give them advantages over neurons that have been in the circuit for the whole life of an animal. movement of adult and even old mice from a rather sterile simplified cage into a large enriched environment with significant complexity and diversity will result in a significant increase in new neurons by decreasing the number of cells that die.This increase in new neurons correlates with increased functioning of the hippocampus. or diseased brain? In the last 5 years. such as stress. they migrate into the densely packed area and over the next month either die or survive and contribute to the function of the critical brain area.20 Thus. and factors that can regulate either the rate of cell division.16 In most areas of the brain.18. adaptability to the processing of new information. where large numbers of cells migrate forward to the olfactory bulb.17 It is most likely that the complexity of the methods used to prove neurogenesis have led to these anomalous observations.

These incorrectly generated new neurons have been speculated to play a role in the persistence of certain types of abnormal behavior and pathology that result from the epileptiform activity. the strategy may not be to make endogenous cells become neurons. interestingly. there is converging evidence to support this view. as a result of the epileptic state. This is particularly the case for hippocampus-associated behaviors and functions. and with encouraging results. Some of this repair is likely to be behind the often-observed remarkable though quite variable recovery that occurs after many strokes. and stroke. and lithium) augment neurogenesis in the dentate gyrus of experimental animals and. but most of these cells die soon thereafter. which are diseases that involve the hippocampus (a structure where neurogenesis does occur). running and exercise) reverse depression by activating neurogenesis in the dentate gyrus. and repair the brain after small. Importantly. several neural diseases have been associated with changes in neurogenesis. Harnessing the endogenous capacity for self-repair that exists in the adult brain We now know that the brain does indeed have a pool of residual cells that can divide making new cells that can roam around the brain and spinal cord and. and thus offer little hope for repair. migration (getting the cells to places where they are needed). This has led to a hypothesis that depression is in part caused by a decrease in neurogenesis in the dentate gyrus and thus antidepressant therapy and physical therapy (ie. Now the principle strategy is to learn enough about the factors that regulate each of the components of neurogenesis in order to control cell proliferation (making more cells).Vol 6 . the time required to observe therapeutic effects of these drugs corresponds to the time course for neurogenesis. In addition. epilepsy. given the remarkable structural plasticity of these new brain cells. in the case of PD. more recent studies have revealed that. • In diseases like spinal cord injury or multiple sclerosis. the most straightforward strategy would be to induce more neurogenesis or reroute neurogenesis. While this is currently only a working hypothesis. the brain is inducing repair by bringing new cells in from areas of the brain that do have stems cells and directing them to the sites of damage. tianeptine. there is loss of cells in areas of the brain that do not normally give rise to new neurons. but some survive and. in the case of HD. but rather to ensheath oligodendrocytes. prevent. moreover. differentiate into new functioning cells. it is hoped that this aberrant neurogenesis could be blocked or perhaps the aberrantly generated cells could be trained to wire up correctly (even at a later point in time).27. We are also beginning to understand some of the cellular and molecular factors. under special conditions. • In diseases like HD and PD.Gage Dialogues in Clinical Neuroscience . it is likely that this microrepair system is adequate to protect. and dopamine neurons. Cerebral stroke also results in a striking increase in the proliferation of new cells in the hippocampus. stress reduces the process of neurogenesis leading to fewer newborn cells in the dentate gyrus. the task will be to enhance the endogenous capacity. No. this will require more knowledge about which cells are affected in a disease. By understanding how neurogenesis normally occurs to generate healthy neurons. Growth factors like EGF and FGF are now being used to try to enhance the intrinsic repair process.28 Quite remarkably. and chronic stress is believed to be the most important causal factor in depression aside from genetic predisposition. While with severe strokes. As mentioned above. Many of these new cells die. in fact. and differentiation (turning the cells into the type of cell that is needed). the best strategy would be to induce the local dividing cells to proliferate and then differentiate in small spine neurons. in certain types of stroke (like ischemia). 2 . For diseases of the brain and spinal cord. there is a consistent correlation between improved function and increases in neurogenesis.Structural plasticity of the adult brain . 2004 increase in the proliferation of stem cells within the hippocampus. where very specific cell types die to cause the symptoms. these new cells migrate to the wrong place in the hippocampus and appear to differentiate incorrectly. 139 . often-unrecognized strokes. this microrepair is not enough to reverse the damage. selective serotonin reuptake inhibitors. as well as knowing more about the factors that regulate the components of neurogenesis: • For depression. Since the endogenous cells already have the capacity to make these cells at low frequency in the intact spinal cord. which is leading to the examination of other factors that affect adult neurogenesis and the determination of their effects on depression.29 One of the most striking correlations between disease and neurogenesis is in depression. that regulate the process of neurogenesis. as well as environment events.30-32 Antidepressants (tricyclic antidepressants.

Es destacable el hecho que los cambios que ocurren en el cerebro adulto son influenciados por las conductas que el individuo adopta. 12. travaille et agit. Luskin MB. 2000. Pencea V. Degeneration and Regeneration of the Nervous System. Development and growth of axonal sprouts from noradrenaline and 5-hydroxytryptamine neurons in the rat spinal cord. Aberg ND. Plasticité structurale du cerveau adulte Le cerveau adulte a longtemps été considéré comme stable et immuable. 13. Lim DA. Ce point de vue est maintenant remis en question par des arguments manifestes en faveur de changements structuraux apparaissant dans le cerveau au cours de la vie. Raisman G. Crick F. 2000. 2. Gage FH. I imagine a time when selective drugs will be available to stimulate components of neurogenesis. 11. and this treatment will be combined with very specific physical therapy directed at activating specific brain areas to accept and integrate the new cells in that brain area. 4. Regenerating the damaged central nervous system. Stenevi U. Shults CW. trabaja y se desenvuelve. Richardson PM.287:1433-1438. dont la création de nouveaux neurones et autres cellules cérébrales et de connexions parmi les neurones et entre eux. Eriksson PS.14:25-48.80:2390-2394.4:1313-1317. 1994.Basic research Conclusion The task ahead—to realize the goals of these strategies— is not an easy one. excepto por la declinación inevitable que ocurre con el envejecimiento. Apprendre comment le comportement et l’environnement régulent la structure et la fonction cérébrales conduira à adopter des modes de vie plus efficaces et peut-être se prémunir contre des lésions et pathologies cérébrales. Aguya AJ. McGuiness UM. J Neurosci.6: 21-27. Das GD. Mammalian neural stem cells. Altman J. sauf en ce qui concerne l’inévitable déclin survenant avec le vieillissement.31:21-33.20:2896-2903. Kaspar BK. May RM. Nat Med. Neuronal production. Trevejo JM. 6. The adult substantia nigra contains progenitor cells with neurogenic potential. Nature. 1971. 140 . 2001. 3. 9. Ramon y Cajal S. West K. The Astonishing Hypothesis. Goldman S. 14. Bingaman KD. Katzman R. septum. Eriksson PS. NY: Hafner. ou les traiter. Perfilieva E. Willhoite AR. NY: Simon & Schuster. New York. 2002.407:963-970. Nottebohm F. Brain Res. Hedbacker H. como también de conexiones entre las neuronas. ❏ I thank Mary Lynn Gage for her valuable assistance with this manuscript. incluyendo la generación de nuevas neuronas y otras células cerebrales. como también por el ambiente en que vive. Tramontin AD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. Bjork-Eriksson T. Dziewczapolski G. but it is the knowledge that this is a realistic and approachable strategy that heralds a remarkable change in how we even think about brain disease. Gage FH. thalamus.284:264-265. Este punto de vista actualmente se cuestiona debido a claras evidencias acerca de cambios estructurales en el cerebro a lo largo de la vida. Brain Res. 1983. The implication of this knowledge is that we will be able to conduct our lives in such a way as to limit brain disease and enhance the natural repair process. Lai K. El conocer cómo la conducta y el ambiente regulan la estructura y función cerebral conducirá a adoptar modos de vida más efectivos y tal vez ayudará a protegerse de. 5. Gage FH. Bjorklund A.22:6639-6649. 10. 8. Lie DC. Alverez-Buylla A. 1969. J Neurosci. J Comp Neurol. 7. et al. 1998. Neuron. migration and differentiation in a vocal nucleus of the adult female canary brain. Nat Neurosci. Gage FH.124:319-335. New York. Kaspar BK. damage. Plasticidad estructural del cerebro adulto Por largo tiempo el cerebro adulto se ha considerado estable e inmodificable. 1928. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Axons from CNS neurons regenerate into PNS grafts. Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. Le fait remarquable est que les changements apparaissant dans le cerveau adulte sont influencés par les comportements qu’un individu adopte ainsi que par l’environnement dans lequel celui-ci vit. 1997. Wiegand SJ. Proc Natl Acad Sci U S A. Science. and repair. Neuronal plasticity in the septal nuclei of the adult brain. 1980. 1965. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Neurogenesis in the adult human hippocampus. trans. o a tratar daños y enfermedades cerebrales.21:6706-6717. 2000. REFERENCES 1. Oscarsson J. Horner PJ.28:713-726. 15. Nature. Schaffer DV. Herrera DG. Infusion of brainderived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum. 2003. J Neurosci. and hypothalamus. Garcia-Verdugo JM. Aberg MA.

Nature. Brandon EP. T. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. 30. Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord. Yodoi J. 24.17:3727-3738. Kempermann G.6:507-518. 31. 2 . 141 . van Praag H. 1997. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. 19. Duman RS. Nozaki K. 32. Mol Psychiatry. Curr Biol. Sloviter RS. 1998. Cell.12:606-608.32:1890-1896. Schinder AF. 20. Power AE. Petreanu LT. 1998. 1999. J Neurosci. Saxe M. Kuhn HG. Kempermann G. Running enhances neurogenesis. Yagita Y.Structural plasticity of the adult brain . Sejnowski TJ. Gage FH. Ishikawa M. Alvarez-Buylla A. 29. Gross C.5:262-269. 2002. Messing RO. et al. Kempermann G. 27. 2002. Gage FH.8:939-942. et al. Christie BR. 2002.831:283-287. 26. Takahashi J. 2000. Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dantate gyrus. Brismar H. Kuriu. 18. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors.415:1030-1034. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus. Christie BR. Science. Lledo PM.18:7768-7778. Proc Natl Acad Sci U S A. et al. 1997. J Neurosci. learning and long-term potentiation in mice. Frisen J. Jacobs BL. van Praag H.20:2218-2228. Santarelli L. Liu J. 2001.301: 805-809. 25. Horner PJ. No. Palmer TD. Antidepressants and neuroplasticity. Parent JM. 2002. Smith GA. 2004 16. Kitagawa K.2:266-270. Lansford R. Proc Natl Acad Sci U S A. Leibowitz RT. Brain Res. Yu TW. et al. Functional integration of adult-born neurons.4:183-194. Lowenstein DH. Neurogenesis by progenitor cells in the ischemic adult rat hippocampus. Carlen M. Toni N. Takagi Y. Nat Neurosci. 2000. Genetic influence on neurogenesis in the dentate gyrus of adult mice. Sharp FR.Vol 6 . 2003. Gage FH. 17. 21. Gage FH. Science. 2003. Curr Biol. Carleton A. D’Sa C. Cell proliferation without neurogenesis in adult primate neocortex. Solway K.94:10409-10414. Hashimoto N. Bipolar Disord. 22. Cassidy RM. Nat Neurosci. Functional neurogenesis in the adult hippocampus. Proliferation of neuronal precursor cells in the dentate gyrus is accelerated after transient forebrain ischemia in mice. 1999. Rakic P. Kempermann G. Ohtsuki T. 2001. Kornack DR. Nakatomi H. Stroke. Enquist LW. Okabe S. 23.96:13427-13431.110:429-441.294:2127-2130.Gage Dialogues in Clinical Neuroscience . Gage FH. van Praag H. Adult brain neurogenesis and psychiatry: a novel theory of depression. 28. 1999. Geschwind DH. Becoming a new neuron in the adult olfactory bulb. van Praag H. J Neurosci.

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9000 Rockville Pike. Quiroz. phosphorylation Author affiliations: Laboratory of Molecular Pathophysiology.6:143-155. MD 20892.org 143 . National Institute of Mental Health. Neil A. Mood and Anxiety Disorders Program. BS. Szabo. Manji. and prefrontal cortical neuronal circuits thought to support the behavioral and visceral manifestations of mood disorders.The brain systems that have heretofore received the greatest attention in neurobiological studies of mood disorders have been the monoaminergic neurotransmitter systems. antidepressant. Steve T. valproate. FRCPC espite the devastating impact that mood disorders have on the lives of millions worldwide. In this context. Jorge A. USA Copyright © 2004 LLS SAS. glutamate receptor GluR1. Laboratory of Molecular Pathophysiology. Gray. Carlos A. Bethesda. PhD. MD.Basic research Regulation of cellular plasticity and resilience by mood stabilizers: the role of AMPA receptor trafficking Jing Du. and density of glia and neurons in discrete brain areas. Manji. There is increasing evidence from a variety of sources that severe mood disorders are associated with regional reductions in brain volume. size. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated. It is thus noteworthy that recent studies have shown that structurally dissimilar mood stabilizers lithium and valproate regulate GluR1 receptor subunit trafficking and localization at synapses. MD. and raises the possibility that agents more directly affecting synaptic GluR1 represent novel therapies for these devastating illnesses. Husseini K. National Institute of Mental Health.nimh. Building 10. as well as reductions in the number. Unit 3 West. D Keywords: lithium. Md. © 2004. the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. there is still a dearth of knowledge concerning their underlying etiology and pathophysiology. Zarate Jr. All rights reserved Address for correspondence: Husseini K. LLS SAS Dialogues Clin Neurosci.nih. MD.dialogues-cns. Room 3s250. striatal. which are extensively distributed throughout the network of limbic. bipolar disorder. 2004. clinical studies over the past 40 years have attempted to uncover the specific defects in these neurotransmitter systems in mood disorders by utilizing a variety of biochemical and neuroendocrine strategies.1-3 Thus. it is noteworthy that a growing body of data suggests that the glutamatergic system (which is known to play a major role in neuronal plasticity and cellular resilience) may be involved in the pathophysiology and treatment of mood disorders. MD. MD. USA (e-mail: manjih@intra. Glutamate -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) GluR1 receptor trafficking plays a critical role in regulating various forms of neural plasticity.gov) www. Bethesda. PhD.

which can become progressive over time. affective.17 Overall. and cortical volume/thickness in the subgenual PFC. amygdala. Consequently. dorsal anterolateral PFC. recurrent mood disorders. while dysfunction within the monoaminergic neurotransmitter systems is likely to play important roles in mediating some components of the pathophysiology of mood disorders. including the PFC. orbital cortex.3 In this perspectives paper. 144 . which must include an understanding of the underlying basis for the predilection to episodic and often-profound mood disturbance. ventral striatum. and that antidepressants and mood stabilizers exert major effects on the signaling pathways that regulate cellular plasticity and resilience. and hippocampus. and hippocampus suggest that multiple neuronal circuits underlie the neuropathology of mood disorders. the layer-specific cellular changes observed in several distinct brain regions. they do not fully explain all the facets of these complex neuropsychiatric disorders.5 In addition to the acknowledgement that investigations into the pathophysiology of complex mood disorders have been excessively focused on monoaminergic systems.9. and enlargement of third ventricle in mooddisordered patients relative to healthy control samples. and memory. Glutamate is the major excitatory synaptic neurotransmitter regulating numerous physiological functions in the mammalian central nervous system (CNS). they have been of limited value in elucidating the unique biology of mood disorders.3.A recognition of the clear need for better treatments and the lack of significant advances in our ability to develop novel. We follow with a discussion of the emerging data that suggests regulating the balance of glutamatergic throughput via N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors may play an important role in the actions of our most effective thymoleptic agents.Basic research Selected abbreviations and acronyms -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid CAMKII calcium/calmodulin-dependent protein kinase II EAAT excitatory amino acid transporter LTD long-term depression LTP long-term potentiation NMDA N-methyl-D-aspartate MAPK mitogen-activated protein kinase PCP phencyclidine PKA protein kinase A PP1 protein phosphatase 1 WMH white matter hyperintensities While such investigations have been heuristic over the years.1. the potential role of the glutamatergic system in the pathophysiology and treatment AMPA of bipolar disorder has only recently begun to be investigated in earnest. and represent very attractive targets for the development of novel therapeutics for these devastating disorders. learning. and in basal ganglia and dorsal raphe nuclei and hippocampus. What is the evidence for impairments of cellular plasticity and resilience in severe mood disorders? Structural imaging studies have demonstrated reduced gray matter volumes in areas of the orbital and medial prefrontal cortex (PFC). and are reshaping views about the neurobiological underpinnings of these disorders. neuron size/density. and reductions in nonpyramidal neurons (~40% lower) in CA2 of the hippocampal formation in bipolar disorder subjects compared with controls. improved therapeutics for these devastating illnesses has led to the investigation of the putative roles of intracellular signaling cascades and nonaminergic systems in the pathophysiology and treatment of mood disorders. there has been a growing appreciation that progress in developing truly novel and improved medications has consequently also been limited. and represents a major neurotransmitter system in the circuitry thought to subserve many of the symptoms of severe.11-16 Morphometric studies also have reported layer-specific reductions in interneurons in the anterior cingulate cortex (ACC). This is not altogether surprising since the behavioral and physiological manifestations of the illnesses are complex and include cognitive. such as synaptic plasticity. we review the growing body of data that suggests that severe mood disorders are associated with impairments of cellular plasticity and resilience.10 Postmortem neuropathological studies have shown abnormal reductions in glial cell counts/density. recent evidence demonstrating that impairments of neuroplasticity may underlie the pathophysiology of mood disorders. ACC.6-8 Somewhat surprisingly. effects that may arise from perturbations of neurotrophic signaling cascades and the glutamatergic system. These observations have led to the appreciation that.4.2. have generated considerable excitement among the clinical neuroscience community.

22 In fact. but are highest among bipolar patients.14. or the sequelae of recurrent affective episodes per se.Regulation of cellular plasticity and resilience by mood stabilizers . particularly those with late-onset depression (ie. 2004 motoric. Unlike the monoamines. Furthermore. cell number. 2 . several postmortem brain studies are now providing direct evidence for reductions in regional CNS volume. their presence—particularly in the brains of young bipolar patients—suggests importance in the pathophysiology of the disorder. particularly in the frontal lobes. these lesions have been also found to be increased in children with psychiatric disorders. as is discussed extensively in this issue and elsewhere. since—as we discuss in detail below—the glutamatergic system is known to play critical roles in regulating various forms of plasticity.Vol 6 . the right putamen. WMH severity has been suggested to predict poorer response to antidepressant therapy.23 and also early in the course of bipolar illness in adolescent subjects. and are thus undoubtedly mediated by networks of interconnected neurotransmitter systems and neural circuits. when compared with controls. glutamate participates in wide-ranging aspects of both normal and abnormal CNS function. however.The latter is actually synthesized in glia.24 Although the cause of WMH in mood disorders is unknown. and is then transported to neurons where glutaminase is able to convert this precursor to glutamate (Figure 1). are known to play important roles in stress-induced morphometric brain changes. and bilateral pallidum externum in postmortem brain samples obtained from patients with unipolar depression or bipolar depression. via an active process (requiring adenosine triphosphate [ATP]). a small proportion of glutamate is formed directly from glutamine.Du et al Dialogues in Clinical Neuroscience . elderly depressed patients who experience their first depression after age 60).29 Since some clinicians may be less familiar with the intricacies of the regulation of glutamate receptor subtypes. we now present a brief overview of the functioning and regulation of NMDA and AMPA glutamatergic receptors. Silverstone and colleagues21 reported that bipolar patients showed more severe deep WMH on brain MRI than age-matched unipolar and control subjects.26 Together. Elderly adults (>60 years old) with severe WMH are 3 to 5 times more likely to have depressive symptoms as compared with persons with only mild or no white matter lesions. A primer on glutamatergic signaling: critical roles in cellular plasticity and resilience As the principal mediator of excitatory synaptic transmission in the mammalian brain. Understanding these issues will partly depend upon experiments that delineate the onset of such abnormalities within the illness course and determine whether they antedate depressive episodes in individuals at high familial risk for mood disorders. as well as alterations of circadian rhythms and neuroendocrine systems.28. the concentration of glutamate in the extracellular space is highly 145 . and cell body size. these results support the contention that WMH indicate damage to the structure of brain tissue. Baumann and associates18 reported reduced volumes of the left nucleus accumbens.31 The major metabolic pathway in the production of glutamate is derived from glucose and the transamination of α-ketoglutarate. and likely disruption of the neuronal connectivity necessary for normal affective functioning. glutamate and aspartate cannot adequately penetrate into the brain from the periphery and are produced locally by specialized brain machinery.25. these prominent atrophic changes and impairments of plasticity have drawn much attention to the glutamatergic system. mediated by both NMDA and non-NMDA receptors. Recently. No. Following release. The abnormal presence of white matter hyperintensities (WMH) has been reported in multiple magnetic resonance imaging (MRI) studies of geriatric patients with affective disorder. and that late. It is not known whether these structural brain changes seen in patients with severe mood disorders constitute developmental abnormalities that may confer vulnerabil- ity to abnormal mood episodes.30 The metabolic and synthetic enzymes responsible for the formation of these nonessential amino acids are located in glial cells as well as neurons.and early-onset patients had more severe subcortical gray matter hyperintensities (particularly in the putamen) compared with controls. which require transport of amino acids through the blood–brain barrier.30.13 In addition to the accumulating neuroimaging evidence. compensatory changes to other pathogenic processes.19 Tupler and colleagues20 reported that late-onset depressed patients had more severe hyperintensity ratings in deep white matter than early-onset patients and controls. Nevertheless.27 alterations in glutamatergic signaling. We follow with a discussion of the exciting emerging data suggesting that glutamatergic signaling represents a very attractive target for the development of novel therapeutics for severe mood disorders. and neurovegetative symptomatology.

2A. GTn. indeed. a Rho family GTPase. Glutamatergic system. VA: American Psychiatric Publishing Inc. nitric oxide synthetase. PTP1D. NMDA receptor. proline-rich tyrosine kinase-2. The American Psychiatric Publishing Textbook of Psychopharmacology. α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. nNOS. NMDAR. Ras guanosine triphosphatase (GTPase)–activating protein. GTg. PP1. raising the possibility that astrocytic loss (as has been documented in mood disorders) may contribute to deleterious GLU signaling. and Rsk. PKA and PKC. 5-hydroxytryptamine (serotonin) receptor 1A. Copyright © 2003. H-ras. Rap2. receptors. ERK. heat-shock protein 70. but more so by astrocytes. PSD95. PYK2. ribosomal S6 kinases.Basic research Figure 1. Nemeroff CB. but also on astrocytes. myosin V. Manji HK. a small GTPase. NMDA receptor accessory protein. Src. as described in the text. calcium/calmodulin-dependent protein kinase II. Neurotransmitters. Gly. It is now known that there are a number of important intracellular proteins. PP2A. a family of protein tyrosine kinases. glycine. current data suggests that astrocytic glutamate uptake may be more important for clearing excess glutamate. MyoV. 146 . and second messengers in psychiatric disorders. Raf. glutamate transporter (glial). glutamate transporter. Hsp70. signal transduction. and 2B. protein phosphatase 1. SHP2. In astrocytes. Glutamate has its action terminated in the synapse by reuptake mechanisms utilizing distinct GLU transporters (GLUTs). This figure depicts the various regulatory processes involved in glutamatergic neurotransmission. Shank. Shank family of multidomain proteins. American Psychiatric Publishing Inc. In: Schatzberg A. AMPA. and PP2B. 5-HT1A. Glutamate can then be released by a calcium-dependent excitotoxic process. which can also be transported to neurons and participate in glutamate synthesis. protein A kinase anchoring protein. AKAP. Gould TD. eds. extracellular signal–regulated kinase. Glutamate is either metabolized or sequestered and stored into secretory vesicles by vesicular glutamate transporters (VGluT). which are able to alter the function of glutamate receptors. GKAP. a family of dendritic multidomain proteins. guanylate kinase–associated protein. protein kinase A and C. which exist not only on presynaptic nerve terminals. src homology 2 domain–containing tyrosine phosphatase. MEK. Harvey rat sarcoma viral oncogene homologue. Homer. protein-tyrosine phosphatase 1D. SynGAP. 2003:3-52. CAMKII. glutamine can undergo oxidation to yield α-ketoglutarate. postsynaptic density protein 95. Arlington. Rac1. Modified and reproduced with permission from reference 30: Szabo ST. Yotiao.

KA2 Metabotropic receptors Group I • mGlu1a. Receptor subtype units. each of which is composed of a different set of subunits. AMPA. NR2C. mGlu8b. Presynaptic regulation of glutamate release occurs through metabotropic glutamate receptors (mGluR2 or mGluR3). mGlu4d • mGlu6 • mGlu7a. Once released from the presynaptic terminal. N-methyl-Daspartate [NMDA]) and metabotropic receptors. by the activation of AMPA or kainate receptors on the same postsynaptic neuron) is the Mg2+ blockade relieved. Every channel is assembled of (most likely) four subunits associated into a dimer of dimers. Only when the membrane is depolarized (eg.36 By contrast. and EAAT4 mainly localized in cerebellum. hippocampus. though there is evidence that phosphorylation of the transporters by protein kinases may differentially regulate glutamate transporters and therefore glutamate reuptake (discussed in reference 30). with EAAT1 and EAAT2 being found primarily in glial cells. 2 . Glutamate concentrations have been shown to rise to excitotoxic levels within minutes following traumatic or ischemic injury. No. mGlu8c.33. EAAT3 localized in neurons. the AMPA receptor (AMPAR). glutamate is able to bind to numerous excitatory amino acid (EAA) receptors. 2004 regulated and controlled. mGlu7d • mGlu8a. These are the NMDA receptor (NMDAR). The ionotropic glutamate receptor ion channels are assemblies of homooligomeric or hetero-oligomeric subunits integrated into the neuron’s membrane. ferent synthetic ligands. the binding of both glutamate and glycine is still not sufficient for the NMDA receptor channel to open.34 Every subunit consists of an extracellular amino terminal and ligand-binding domain. mGlu7b. NR2B. mGlu8d Table I. NMDA receptors The NMDA receptor is activated by glutamate and requires the presence of a coagonist. mGlu4c. However.35 The subunits associate through interactions between their amino terminal domains forming a dimer that undergoes a second dimerization mediated by interactions between the ligand-binding domains and/or between transmembrane domains. these transporters are differentially expressed in specific cell types. and NMDA glutamate receptor antagonists attenuate stress-induced atrophy of CA3 pyramidal neurons. mGlu1c. In the adult mammalian brain. these receptors are also located on the postsynaptic element. EAAT2 (or GLT-1). mGlu4b. Glutamate receptor subtypes: a focus on NMDA and AMPA receptors The many subtypes of glutamatergic receptors in the CNS can be classified into two major subtypes—the ionotropic and metabotropic receptors (Table I). α-amino-3-hydroxy5-methyl-4-isoxazole propionic acid. microdialysis studies have shown that severe stress increases extracellular levels of glutamate in hippocampus. at resting membrane potential. GluR7 • KA1. and an intracellular carboxyl terminal domain. NR2D • NR3A. However. and the kainate receptor (KAR).Du et al Dialogues in Clinical Neuroscience . 147 .33. GluR4 Kainate • GluR5. including both ionotropic (eg. mGlu1d Group II • mGlu2. Under these conditions.34 Three different subgroups of glutamatergic ion channels have been identified utilizing their pharmacological ability to bind dif- Ionotropic receptors NMDA • NR1 • NR2A. namely glycine or D-serine. The latter two groups are often referred to together as the “non-NMDA” receptors. at early stages of development. striatum. three transmembrane domains and a re-entrant pore loop (located between the first and second transmembrane domains). NMDA and AMPA glutamatergic receptors are colocalized in approximately 70% of the synapses. and there is evidence that the function of the glutamate transporters becomes impaired under these excitotoxic conditions. the NMDA receptor channel will open and permit the entry of both Na+ and Ca2+ (Figure 1).32 Moreover. GluR3. mGlu7c. with EAAT2 being the most predominantly expressed form in the forebrain. GluR2. the NMDA ion channel is blocked by Mg2+ ions. primarily by a sodium-dependent reuptake mechanism involving several transporter proteins. since.The major glutamate transporter proteins found in the CNS include excitatory amino acid transporters (EAATs): EAAT1 (or GLAST-1). as has been observed in crystallographic studies. mGlu1b. septum. NR3B AMPA • GluR1.Vol 6 . but undoubtedly subserve unique functions (Table I). which subserve the function of autoreceptors. The physiological events regulating the activity of the glutamate transporters are not well understood. GluR6. and amygdala. and EAAT3 (or EAAC1).Regulation of cellular plasticity and resilience by mood stabilizers . Additionally. mGlu3 Group III • mGlu4a. synapses are more likely to contain only NMDA receptors. Radioligand binding studies have shown that NMDA and AMPA receptors are found in high density in the cerebral cortex. to be activated.

and the experimental drug dizocilpine (MK-801). including receptor insertion and internalization.Basic research The NMDA receptor channel is composed of combination of NR1. NR2B.37 These latter observations have led to the investigation of NMDA antagonists as putative novel antidepressants. modulate synaptic strength. to become hyperphosphorylated. which is required for receptor function. whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death.37 NMDA receptors play a critical role in regulating synaptic plasticity. In clinical psychiatric studies. calcium entry through nonsynaptic NMDA receptors. An important recent development is the finding that two of the primary molecules involved––Ca2+/ calmodulin-dependent protein kinase II (CAMKII) and the NMDA subtype of glutamate receptor––form a tight complex with each other at the synapse.” which can lead to long-term strengthening of the synapse by multiple mechanisms. Two molecules of glutamate and two of glycine are thought to be necessary to activate the ion channel. NR2A. triggered by glutamate exposure or hypoxic/ischemic conditions. thereby allowing for more rapid dissociation of glutamate and therefore a rapid deactivation of the AMPA receptor (reviewed in reference 41). drugs of this type have been shown to have neuroprotective properties against anoxia and hypoglycemia. In contrast. however. and requires two molecules of glutamate to be activated (Table I). Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF) gene expression as strongly as did stimulation of L-type calcium channels. in turn. thereby permitting its activation. which increases their conductance. In preclinical studies. this binding appears to enhance both the autophosphorylation of the kinase and the ability of the entire holoenzyme. the process is highly regulated with a 148 .29. activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. it is generally believed that it is the activation of the AMPA receptor that results in neuronal depolarization sufficient to liberate the Mg2+ cation from the NMDA receptor.39 Interestingly. The hallucinogenic drug PCP. which has 12 subunits. The AMPA receptor channel is composed of the combination of GluR1. two other sites have been identified called the sigma (σ) site and the phencyclidine (PCP) site. Emerging data suggest that AMPA receptor trafficking. One important mechanism involves direct phosphorylation of the glutamate-activated AMPA receptors.38 Induction of LTP and LTD in the CA1 region of the hippocampus and in many regions of the brain has now clearly been demonstrated to be dependent on NMDA receptor activation. Furthermore.38 The best-studied forms of synaptic plasticity in the CNS are long-term potentiation (LTP) and longterm depression (LTD) of excitatory synaptic transmission. The molecular mechanisms of LTP and LTD have been extensively characterized and have been proposed to represent cellular models of learning and memory. GluR2. It is intriguing that activation of synaptic NMDA receptor versus nonsynaptic receptor has an opposite effect on cell survival via differential regulation of CREB (cyclic adenosine monophosphate [cAMP]–response element binding protein) function. as discussed above. once CAMKII is bound to the NMDA receptor. AMPA receptors have a lower affinity for glutamate than the NMDA receptor. it may organize additional anchoring sites for AMPA receptors at the synapse. ketamine. ketamine has been shown to transiently induce psychotic symptoms in schizophrenic patients. Ca2+ influx through NMDA receptors can activate a wide variety of kinases and/or phosphatases that.40 AMPA receptor trafficking plays critical roles in the regulation of various forms of neural plasticity The AMPA receptor is stimulated by the presence of glutamate and characteristically produces a fast excitatory synaptic signal that is responsible for the initial reaction to glutamate in the synapse. and to produce rapid antidepressant effects in depressed patients. all bind at the latter site and are considered noncompetitive receptor antagonists that inhibit NMDA receptor channel function. these studies await clinical confirmation. and delivery to synaptic sites. provides an elegant mechanism for activity-dependent regulation of synaptic strength. During NMDA-receptor–dependent synaptic plasticity. Synaptic NMDA receptors have antiapoptotic activity. GluR3. NR3A. The binding site for glutamate has been localized to the NR2 subunit and the site for the coagonist glycine has been localized to the NR1 subunit. and GluR4 subunits. Within the ion channel. In fact.39 This hyperphosphorylated state has been postulated to represent a “memory switch. and NR3B subunits (Table I).AMPA receptor subunits undergo constitutive endocytosis and exocytosis. NR2C. NR2D.

50 AMPA receptor trafficking is subunit-specific and regulated by phosphorylation of its C-terminal domain. disk large.Vol 6 . Each subunit is composed of N-terminal extracellular domain. AMPA receptors are multimeric assemblies of the subunits GluR1 to GluR4. protein kinase C (PKC). which is lacking AMPA receptors.53 Phosphorylation of GluR1 at PKA site can be enhanced by synapse-asso- ciated protein 97 (SAP97)/protein A kinase anchoring protein (AKAP79) complex that direct PKA to GluR1 via a PDZ (PSD95. and is possibly involved in interaction with SAP97. membrane-spanning domain.51 Phosphorylation of GluR1 at the PKA site p845 facilitates the insertion of GluR1 onto the membrane and synapses. Regulation of AMPA receptor trafficking by signaling cascades Most vesicle trafficking requires the ordered coating of a donor membrane. and C-terminal intracellular domain. can dephosphorylate the phosphorylation of GluR1 at p831 site by CAMKII. it is widely accepted that AMPA receptor trafficking is the key player in these phenomena. and in regulating learning and memory in rodents.57.55 First. the AMPA single conductance is directly increased by CAMKII at Ser831 of GluR1 subunit. 2004 variety of signal transduction cascades being capable of producing short. CAMKII. and is often associated with LTP. calcineurin and protein phosphatase 1 [PP1]) target GluR1 to recycling endosomes.58 This enhancement of synaptic GluR1 level by activation of CAMKII requires an intact C-terminal domain of GluR1.42-45 These observations have led to an extensive series of studies. these are the very same signaling cascades that mood stabilizers and antidepressants exert major effects on. AMPA receptor trafficking is highly regulated by the protein kinase A (PKA). 149 .52 Dephosphorylation of the GluR1 by protein phosphatases (eg. No. although the mechanisms of LTP and LTD have not been completely elucidated.49. which have clearly demonstrated that AMPA receptor trafficking is highly regulated by antidepressants and mood stabilizers46. Phosphorylation of Ser880 on GluR2 provides a switch from receptor retention at the membrane by binding to ABP (AMPA receptor–binding protein)/GRIP (glutamate receptor–interacting protein). CAMKII is required for the delivery of AMPA receptor to the synapse.56 Second.54 CAMKII pathway Numerous studies have demonstrated that CAMKII is required for the proper formation of LTP in slice preparations. Therefore. where rephosphorylation by PKA may occur and the receptors will be reinserted onto the membrane. transport by passive or active delivery along microtubule. CAMKII translocates to the postsynaptic site. which work as molecular switches. to receptor internalization by binding to PICK 1 (protein interacting with C kinase-1). In contrast.51. and mitogen-activated protein kinase (MAPK) signaling cascades.Du et al Dialogues in Clinical Neuroscience .47 (see below). Rap mediates NMDA-dependent removal of synaptic GluR2/GluR3–containing vesicles via a pathway that involves p38 MAPK. may in turn control the AMPA receptor level at synapses.Regulation of cellular plasticity and resilience by mood stabilizers . budding and fusion to form transport vesicles. where it has two major effects on AMPA receptor activity at the postsynaptic site during the formation of LTP.or long-term changes in synaptic surface expression of AMPA receptor subunits. and subsequent alteration of protein-protein interactions. Most importantly for the present discussion. Ras mediates activity-evoked increase in GluR1/GluR4–containing AMPA receptor surface expression at synapses via a pathway that requires p42/44 MAPK activation. The regulation through Ras and Rap. 2 .59 PP1. preventing constitutive exchange and conferring inducible delivery of the heteromer. PKA pathway The GluR1 subunit appears to govern the trafficking behavior of heteromeric GluR1/GluR2 receptors.60 Extracellular signal–regulated kinase (ERK) MAPK pathway A recent study reported that the small guananine triphosphatases (GTPases) Ras and Rap are involved in AMPA receptor trafficking through a postsynaptic signaling mechanism.55 In response to stimulation. Indeed.48 AMPA receptors adopted this mechanism to be delivered to the neuronal membrane surface. ZO1) domain interaction. which is also known to be a important modulator for learning and memory. and final fusion with the target membrane.61 PKC pathways AMPA GluR2 receptors respond to secondary signals by constitutive receptor recycling.

namely the antidepressant imipramine. and in fact it is unlikely we will ever develop rodent models that display the full range of symptomatology clinically expressed in man.53 However. Lithium. these two agents have been shown to exert robust effects on the very same signaling pathways known to regulate AMPA receptor trafficking (vide supra). we found that an agent that provokes mania. lithium and valproate. Thus. lithium and valproate attenuated surface GluR1 expression after long-term treatment. Specifically.76. Because lithium and valproate both require several weeks to exert their therapeutic effects.or cocaine-induced hyperactivity. • The effects were specific for antimanic agents. interestingly. exert effects on AMPA receptor trafficking. a monovalent cation. AMPA antagonists have been demonstrated to attenuate psychostimulant-induced development or expression of sensitization and hedonic behavior without affecting spontaneous locomotion. the changes in GluR1 were observed only after chronic (and not acute) administration. we investigated whether lithium and valproate regulate synaptic plasticity and AMPA receptor trafficking in the hippocampus. an 8-carbon fatty acid.66 ing. it is widely believed that adaptive changes in intracellular signaling and/or cellular physiology underlie the beneficial effects. are the two most commonly used agents in the treatment of mania. a brain region known to be involved in critical affective neuronal circuits. activation of PKA appears to trigger LTD and endocytosis of AMPA receptors. our laboratory has sought to determine if two structurally highly dissimilar antimanic agents. clathrin/dynamine-dependent endocytosis) always seems to be involved.3 We have found that the structurally highly dissimilar antimanic agents lithium and valproate have a common effect on downregulating AMPA GluR1 synaptic expression in the hippocampus after prolonged treatment with therapeutically relevant concentrations as assessed both in vitro and in vivo.68 and others69 have established several criteria that findings should meet in order to maximize the likelihood of their therapeutic importance: • This effect of mood stabilizers on GluR1 is a common effect of the structurally dissimilar antimanic agents lithium (a monovalent cation) and valproate (which is an 8-carbon branched fatty acid). While it is impossible to determine whether synaptic GluR1 attenuation occurs in patients being treated with lithium or valproate. one current model of mania. has an opposite effect as it upregulates AMPA synaptic strength in the hippocampus. our laboratory8. • This attenuation of synaptic GluR1 by lithium and valproate occurs in the hippocampus.62-65 The mechanism for AMPA receptor trafficking is specific for brain region and neuronal type. as a promanic antidepressant produced opposite effects. a brain region presumed to be involved in the circuitry of mood disorders.47. • Similar to the clinical therapeutic effects. psychostimulants like amphetamine and cocaine are known to induce manic-like symp- AMPA receptor trafficking and mood disorders: implication for development of new medications In view of the critical role of AMPA receptor trafficking in regulating various forms of plasticity. • This effect of lithium and valproate on synaptic GluR1 occurs at therapeutic concentrations both in vivo and in vitro. For example. which has been extensively used and has reasonable heuristic value in the study of mood disorders.Basic research phosphorylation of GluR2 at Ser880 by PKC may release the AMPA receptor from the anchoring proteins and initiate the internalization of receptors. additionally.70-75 The need to use caution in the appropriate application of animal models to complex neuropsychiatric disorders has been well articulated. Further supporting the therapeutic relevance of the find- 150 . involves the use of psychostimulants in appropriate paradigms. and valproic acid (VPA). In cultured hippocampal neurons. in CA1 pyramidal cells.77 However. our experimental conditions attempt to mimic this situation as closely as possible. in midbrain dopamine cells. Further supporting our data are recent studies that show that AMPA receptor antagonists attenuate several “manic-like” behaviors produced by amphetamine administration. Thus. some studies have demonstrated that AMPA receptor antagonists reduce amphetamine. Thus. the endocytosis of AMPA receptors mediating LTD is triggered by very different signaling cascades in different cell types despite the fact that a conserved cell biological mechanism (ie.67 Since chronic administration of mood stabilizers bring about numerous biochemical effects. protein phosphatases seem to be involved in triggering LTD through dephosphorylation of GluR1 and phosphorylation of PKA site on GluR1 is associated with LTP.

the best-established animal models mania utilize the administration of amphetamine or cocaine to produce hyperactivity. The various glutamate receptors and the presumed antiglutamatergic drug sites of action are presented. glutamate. TCA. and trigger frank manic episodes in individuals with bipolar disorder. excitatory amino acid transporter.36:35-83. and a glutamate release inhibitor. Riluzole is a glutamate release inhibitor (acting through blockade of Na+ voltage dependent channels). Thymoleptic agents. which exert major effects on the glutamatergic system. the fact that AMPA receptor antagonists are capable of attenuating psychostimulantinduced sensitization.Du et al Dialogues in Clinical Neuroscience . an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist. NMDAR.Vol 6 .Regulation of cellular plasticity and resilience by mood stabilizers . mGlu group II (or III) receptor. KAR. 2004 toms in healthy volunteers. Quiroz J. Felbamate is a noncompetitive NMDA receptor antagonist (glycine NR1 and glutamate NR2B). and hedonic behav- Glia Glutamine synthetase gln gln glu mG mG EAAT1/2/(3) glu EAAT3 Kainate glu Memantine luR I II luR mGluRI gln glutaminase mGluRI ? Felbamate ? α-Ketoglutarate TCA glu (-) glu glu NMDAR mGluRIII Riluzole ? ? AMPAR mGluRII KAR Second-generation mGlu agonist Presynaptic neuron Postsynaptic neuron Figure 2. 2 . risk-taking behavior. Manji HK. Thus. an mGlu group I receptor (mGluRI) antagonist. these psychostimulantinduced behavioral changes are attenuated by the administration of chronic lithium in a therapeutically relevant time frame. 151 . Modified and reproduced with permission from reference 28: Zarate CA. Moreover. and increased hedonic drive—all very important facets of the human clinical condition of mania. AMPA receptor. gln. The sites for second-generation mGlu group II and III receptor agonists are also depicted. Payne J. 2002. NMDA receptor. No. tricarboxylic acid cycle. hyperactivity. Modulators of the glutamatergic system: implications for the development of improved therapeutics in mood disorders. AMPAR.78 Thus. Memantine is a noncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor. glu. Psychopharmacol Bull. mGluRII (or mGluRIII). and probably an AMPA and kainate (KA) antagonist. glutamine. Copyright © 2002. MedWorks Media LLC. a γ-aminobutyric acid GABAA agonist. KA receptor. EAAT.

The mechanisms by which glutamate receptors are actively recruited to synapses have long intrigued the neuroscience community.79. 6. Manji HK. 2000. cocaine. Antidepressants and neuroplasticity.83 They showed that surface GluR1 labeling on processes of medium spiny neurons and interneurons was increased by brief incubation with a dopamine D1 agonist. The development of new modulators of AMPA receptor signaling for the treatment of mood disorders may lead to improved therapeutics for these devastating disorders. Drevets WC. 2002. DiLeone RJ. the information reviewed here suggests that they may also play important roles in the pathophysiology and treatment of complex neuropsychiatric disorders. chronic exposure to the psychostimulants amphetamine and cocaine caused an increase in GluR1 level in the ventral tegmental area (VTA). It remains unclear whether these impairments correlate with the magnitude or duration of the biochemical perturbations in mood disorders. Lenox RH. Timing is everything: does the robust upregulation of noradrenergically regulated plasticity genes underlie the rapid antidepressant effects of sleep deprivation? Biol Psychiatry. J Psychiatry Neurosci. Nevertheless. Manji HK. Bipolar Disord. Gold SJ. Lenox RH. Concluding remarks Regionally selective impairments of structural plasticity and cellular resiliency.4:183-194. Quiroz JA. locomotor hyperactivity. reduced sleep. the biochemical and behavioral studies investigating the effects of antimanic (lithium and valproate) and promanic (antidepressants. Zarate CA Jr.83 Although these studies were designed to investigate the role of GluR1 in mediating the effects of drugs of abuse. 2000. J Clin Psychiatry. 4. Signaling: cellular insights into the pathophysiology of bipolar disorder. 2002. may also exist in mood disorders. reflect an enhanced vulnerability to the deleterious effects of these perturbations (eg.80 Furthermore.82 An elegant series of studies has recently provided insights into how dopamine receptors. it is noteworthy that many of the symptoms of mania resemble the effects of psychostimulants (eg. Monteggia LM. Curr Opin Neurobiol. Drevets WC. Payne JL.7:541-547. in striking contrast to the effects seen with the antimanic agents lithium and valproate. 2002. Barrot M. 2001. and psychosis). The cellular neurobiology of depression. Over the last few years. 7. racing thoughts. which have been postulated to contribute to the development of classical neurodegenerative disorders.Very recent studies from other laboratories have also demonstrated that chronic administration of antidepressants enhances membrane expression of GluR1 as well as phosphorylation of GluR1 at the PKA site (p845) and the CAMKII/PKC site (p831). which are activated during psychostimulant administration. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Neuron. Nat Med. The findings that mood stabilizers—in therapeutically meaningful paradigms—regulate AMPA receptors at synapses opens new potential avenues for new drug development in regards to regulating glutamatergic synaptic strength in critical neuronal circuits (Figure 2). The neurobiology of treatment response to antidepressants and mood-stabilizing medications. 8. Bakish D.11:240-249. due to genetic factors and/or early life events).48:518-530. Charney DS. Taken together. an impressive amount of information has been gathered regarding the mechanisms underlying the regulation of AMPA receptor localization at synapses. might influence glutamatedependent forms of synaptic plasticity. 5. Beaulieu S. or indeed represent the fundamental etiological process in mood disorders.27:260-265. Manji HK. 2001. Neurobiology of depression. which are being increasingly recognized as important to drug addiction.52:921-926. 152 . 2002. 3. D'Sa C. we found that the chronic administration of the antidepressant imipramine—which is capable of triggering manic episodes in susceptible individuals78—increased hippocampal synaptic expression of GluR1. Manji HK. Eisch AJ.Basic research ior70-75 provides compelling behavioral support for our contention that AMPA receptors play important roles in regulating affective behavior. and amphetamine) agents on GluR1 strongly suggest that AMPA receptor trafficking is an important target in the pathogenesis and treatment of certain facets of bipolar disorder. ❏ REFERENCES 1. Nestler EJ. Young LT. As mentioned already. it is noteworthy that there is growing evidence from preclinical and clinical research that the glutamatergic system is involved in the pathophysiology and treatment of mood disorders. Biol Psychiatry. Duman RS.81 Additionally. it is noteworthy that AMPA potentiating agents reportedly have efficacy in preclinical models of depression.34:13-25. The nature of bipolar disorder. 2. and these effects have been postulated to represent a trigger for sensitization to drug abuse.61(suppl 13):42-57.

Kerwin R. 2003. Mackay D. 11. Biol Psychiatry. 1998.35:5-49.4:89-104. 16. Ces études suggèrent que la régulation de la plasticité synaptique médiée par le glutamate peut jouer un rôle dans le traitement des troubles de l’humeur et évoquent la possibilité pour ces maladies invalidantes d’un nouveau traitement par l’intermédiaire de molécules affectant plus directement le GluR1 synaptique. Biol Psychiatry. Todtenkopf MS. Benes FM. Le trafic neuronal de la sous-unité GluR1 du récepteur AMPA (acide glutamate α-amino-3-hydroxy-5méthyl-4-isoxazole propionique) et les changements morphologiques qui en résultent jouent un rôle crucial dans la régulation des différentes formes de plasticité neuronale. Cotter D. Beyer JL. Estos estudios sugieren que la regulación de la plasticidad sináptica mediada por el sistema glutamatérgico puede jugar un papel en el tratamiento de los trastornos del ánimo y se aumenta la posibilidad que agentes que afecten más directamente la subunidad GluR1 sináptica se transformen en nuevas terapias para estas devastadoras enfermedades.45:1085-1098. 17. et al. Psychopharmacol Bull. ainsi qu’avec des réductions en nombre. 13. 2004 Regulación de la plasticidad celular y de la resiliencia mediante estabilizadores del ánimo: el papel del tráfico del receptor AMPA Diversas fuentes aportan una evidencia creciente acerca de la asociación entre los trastornos del ánimo severos y reducciones regionales del volumen cerebral. No. 15. 2 . Everall I. como el litio y el valproato regulan el tráfico de la subunidad GluR1 y su localización en las sinapsis.58:545-553. Miguel-Hidalgo JJ. 10. Quiroz JA. Adler CM. Volumetric brain imaging findings in mood disorders. 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En este contexto es destacable que una información creciente sugiere que el sistema glutamatérgico (que se sabe que juega un papel importante en la plasticidad neuronal y en la resiliencia celular) puede estar involucrado en la fisiopatología y en el tratamiento de los trastornos del ánimo. Manji HK.9:273-284. Manji HK. 9.Vol 6 . Es de destacar que estudios recientes han mostrado que estabilizadores del ánimo. los datos sugieren que los trastornos del ánimo severos están asociados con un deterioro en la plasticidad estructural y en la resiliencia celular. A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives.

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New Haven.Pharmacological aspects Neural plasticity: consequences of stress and actions of antidepressant treatment Ronald S. it could be argued that neural plasticity is one of the most essential and important processes that the brain performs as it relates to many types of central nervous system functions. gene expression. and could contribute to stress-related mood disorders. This article reviews the literature demonstrating altered plasticity in response to stress. 34 Park Street. Continued elucidation of the mechanisms underlying neural plasticity will lead to novel drug targets that could prove to be effective and rapidly acting therapeutic interventions. many different stimuli can activate neural plasticity processes in different brain structures. 2004. including environmental. and also structural alterations of neuronal spines and processes. PhD Neural plasticity is emerging as a fundamental and critical mechanism of neuronal function. behavioral. and even the birth of new neurons in the adult brain. exposure to inappropriate or prolonged stress has been reported to alter molecular and cellular markers of neural plasticity. eural plasticity is a fundamental process that allows the brain to receive information and form appropriate adaptive responses to the same or similar stimuli. and abnormal or inappropriate stimuli. and even induce neural plasticity-like responses. Duman. Elucidation of the molecular and cellular mechanisms underlying neural plasticity is a major goal of neuroscience research. disrupted or abnormal plasticity could lead to maladaptive neuronal responses and abnormal behavior. and evidence that chronic antidepressant treatment can reverse or block the effects. USA (e-mail: ronald. LLS SAS Dialogues Clin Neurosci. N General mechanisms of neural plasticity Neural plasticity encompasses many different types of molecular and cellular responses that occur when cells in the brain are induced to respond to inputs from other Address for correspondence: Ronald S. and clinical evidence indicating that altered plasticity occurs in depressed patients. Duman. and pharmacological stimuli. The second part of the review will present evidence that antidepressant treatment blocks the effects of stress or produces plasticity-like responses. This could occur in response to genetic abnormalities of the cellular machinery required for plasticity. The molecular and cellular adaptations underlying learning and memory are the best-characterized and moststudied examples of neural plasticity.dialogues-cns. USA Copyright © 2004 LLS SAS. New Haven. Yale University School of Medicine. For example.org . and significant advances have been made in recent years.6:157-169. which allows the brain to receive information and make the appropriate adaptive responses to subsequent related stimuli. CT 06508. PhD. All rights reserved 157 www. neurotrophic factor. These mechanisms include regulation of signal transduction and gene expression. Departments of Psychiatry and Pharmacology.duman@yale. Thus. This review will discuss the literature demonstrating altered neural plasticity in response to stress. In fact. CT.edu) Keywords: signal transduction. social. Altered plasticity could thereby contribute to psychiatric and neurological disorders. However. © 2004. neurogenesis. neuronal atrophy Author affiliations: Division of Molecular Psychiatry.

4. Some examples of stress responses are discussed in this section. Emotional arousal can enhance learning and memory via synaptic plasticity of amygdala-dependent pathways. a consistent suppression of neural plasticity is observed after exposure to stress or adrenal glucocorticoids. In studies of LTP. and intensity of the stressor.2 Changes in the shape and even number of spines can occur very rapidly (minutes to hours) after glutamate stimulation. Ca2+ is a major intracellular signaling molecule that activates a signaling cascade. Spines mark the location of glutamate synapses and have been the subject of intensive investigation for understanding synaptic plasticity. This leads to the subsequent activation of N-methyl-D-aspartate (NMDA) receptors and the resulting influx of Ca2+. a process that requires gene expression and protein synthesis.7 In one of these studies.5 However. the suppression of LTP was observed after exposure to an uncontrollable stressor and correlated with behavioral performance in a learning and memory task.6. in slices of brain and rodent models of behavior. and CREB. including activation of Ca2+/ calmodulin-dependent protein kinase. including long-term potentiation (LTP). as well as cAMP signaling. activation of glutamate and Ca2+-dependent pathways can result in structural alterations at the level of dendritic spines. and this is thought to be the basis for intense. long-term memories of traumatic events and posttraumatic stress disorder. are the neurotrophic factors. stress can also impair subsequent learning and memory and can even lead to amnesia.Pharmacological aspects Selected abbreviations and acronyms BDNF cAMP CaRE CREB FGF-2 5-HT LTP NMDA PDE4 PKA SSRI brain-derived neurotrophic factor cyclic adenosine monophosphate cAMP response element cAMP response element binding protein fibroblast growth factor–2 5-hydroxytryptamine (serotonin) long-term potentiation N-methyl-D-aspartate phosphodiesterase type IV protein kinase selective serotonin reuptake inhibitor Mechanisms of long-term plasticity: gene expression and protein synthesis The Ca2+/cyclic adenosine monophosphate (cAMP) response element (CaRE) binding protein (CREB) is one of the major transcription factors that mediate the actions of Ca2+. the length of stimulation. see reference 1). Gene targets that have been implicated in learning and memory. The systems that have been most extensively studied are cellular and behavioral models of learning and memory.3 There are a number of gene targets that are influenced by Ca2+. the stress could be terminated) did not lead to reduced LTP or decreased learning and 158 . The mechanisms identified for learning and memory most likely also subserve plasticity occurring in other regions and for other adaptive functions of the brain. and are relevant to the effects of stress and antidepressant treatment. These alterations are made permanent or long-term when they are stabilized or consolidated. CREB has been reported to play a role in both cellular and behavioral models of learning and memory. cAMP. as well as the magnitude of stimulation. cells or circulating factors. Glutamate causes neuronal depolarization via activation of postsynaptic ionotropic receptors that increase intracellular Na+.6 The influence of stress on hippocampal-dependent learning is complex and dependent on the type of learning task. Mechanisms of acute neural plasticity: synaptic transmission and protein kinases The effects underlying the rapid responses to neuronal activation are mediated by activation of the excitatory neurotransmitter glutamate and regulation of intracellular signaling cascades (for a review of acute mechanisms underlying LTP. Stress alters learning and memory Stress is known to significantly influence learning and memory. duration. and the pattern of gene regulation is dependent on the cell type. Altered neural plasticity in response to stress Recent reports have demonstrated altered molecular and cellular responses to stress and have contributed to the hypothesis that altered neural plasticity contributes to stress-related psychiatric illnesses. one of the most abundant neurotrophic factors in the brain. Within minutes to hours. and the effects are dependent on the type. Giving the animals control over the stress (ie. This section will briefly discuss some general mechanisms and concepts of plasticity. Of particular interest is brain-derived neurotrophic factor (BDNF).

decreasing the number and length of apical dendrites. Stress causes atrophy of hippocampal neurons One of the best-characterized examples of altered structural plasticity in response to stress is the atrophy of hip- pocampal neurons. and glucocorticoid administration mimics this effect.Vol 6 . Stress results in at least two major actions in two different subfields of the hippocampus. or viral infections) Figure 1. Administration of glucocorticoids causes a similar effect. No. see the reviews in references 4 to 7. partly because of the high levels of glucocorticoid receptors expressed in this brain region. 2 . mf. Chronic antidepressant administration can reverse the atrophy of CA3 neurons and block the downregulation of neurogenesis in the dentate gyrus. and decreased expression of brain-derived neurotrophic factor (BDNF) could contribute to pyramidal cell atrophy.10 They found that repeated restraint stress results in atrophy of the dendrites of CA3 pyramidal neurons in the hippocampus.9 For additional references and discussion of the effects of stress on learning and memory. hypoxia. Model of hippocampal plasticity showing structural alterations in response to stress: atropy of CA3 pyramidal neurons and decreased neurogenesis of dentate gyrus granule cells. which was first described by McEwen and colleagues (Figure 1).Duman Dialogues in Clinical Neuroscience . 2004 memory.Neural plasticity and depression . Stress results in powerful effects on the hippocampus. hypoglycemia. measured as a decrease in the number and length of apical dendrites. sc. 159 . Schaffer colaterals. Repeated stress causes atrophy or remodeling of CA3 pyramidal neurons. The atrophy Hippocampal plasticity CA1 sc CA3 mf pathway Granule cell Dentate gyrus Stress Glucocorticoid BDNF Antidepressant NE and 5-HT Stress Glucocorticoid BDNF Antidepressant NE and 5-HT BDNF BDNF Atrophy or death Increased neurogenesis Increased survival and growth Decreased neurogenesis Increased vulnerability resulting from genetic and environmental factors (eg. mossy fiber. Stress also decreases the proliferation of newborn granule cells in the dentate gyrus. The effects of antidepressant treatment occur via acute regulation of serotonin (5-hydroxytryptamine [5-HT]) and norepinephrine (NE) and the regulation of intracellular signaling and gene expression.11 The reduction in dendritic arborization was found to be dependent on long-term.8 A role for BDNF in the actions of stress on LTP has also been suggested. repeated exposure to restraint stress (3 weeks) and to be reversible when the animals are removed from stress.

selective serotonin reuptake inhibitor.16 (Figures 1 and 2). the active form in rodent. but decreased dendrite length and branching in the CA3 pyramidal neurons of the hippocampus. ECS. The hallmark of the stress response is activation of the hypothalamic-pituitary-adrenal (HPA) axis. including anxiety. the process of neurogenesis is highly regulated by a variety of stimuli and can be considered a form of neural plasticity. These progenitor cells give rise to newborn neurons that migrate into the granule cell layer and mature into adult neurons.15.12 The actions of stress and glucocorticoids are blocked by administration of an NMDA receptor antagonist. Hypertrophy of the amygdala could underlie increased learning and memory as a result of stressinduced emotional arousal. and learning increase neurogenesis. the reduction in neurogenesis and the behavioral despair is reversed by antidepressant treatment. stress also results in a dramatic downregulation of neurogenesis in the hippocampus. Neural progenitor cells are restricted to the subgranular zone (SGZ) that is located between the granule cell layer (GCL) and hilus.Pharmacological aspects of CA3 pyramidal cells appears to result from the elevation of adrenal glucocorticoids that occurs during stress because chronic administration of corticosterone. NE.18 Exposure to just a single stressor is sufficient to significantly decrease neurogenesis in the adult hippocampus. and depression. exposure to inescapable stress in the learned helplessness model of depression decreases adult neurogenesis and this effect correlates with behavioral despair in this model.18 In addition to these factors.11-13 In contrast to the atrophy of hippocampus. Neurogenesis is influenced by a number of different stimuli in either a positive or a negative manner as indicated. Regulation of CREB and decreased expression of BDNF in response to stress Stress results in a wide range of effects that influence many different neurotransmitter and neuropeptide systems. electroconvulsive seizures. In the hippocampus.17 Interestingly. mfp. between the granule cell layer and the hilus. posttraumatic stress.21 and footshock. monoamine oxidase inhibitor. neural progenitor cells are found in the subgranular zone. MAOI.10. while aging and exposure to drugs of abuse decrease neurogenesis. and has been observed in rodents and tree shrews. stress influences the number of newborn neurons or neurogenesis in the adult hippocampus15. including subordination stress. exercise.14 This study found chronic immobilization stress increased the dendritic arborization of pyramidal neurons in the basolateral amygdala. SSRI. results in a similar decrease in number and length of dendrites.22 In addition. Stress decreases neurogenesis in the adult hippocampus In addition to regulation of the morphology of neurons in the hippocampus. and altered gene expression. Adult neurogenesis is decreased by different types of stress. The hippocampus is one of two brain regions where neurogenesis continues to occur in adult organism (the other region is in the subventricular zone).20 maternal separation.19 predator odor. noradrenaline.10 Atrophy of CA3 pyramidal neurons occurs after 2 to 3 weeks of exposure to restraint stress or more long-term social stress. indicating that this glutamate receptor is required for atrophy of CA3 neurons. recent studies demonstrate that chronic stress causes hypertrophy of neurons in the amygdala. 160 . These cells give rise to newborn cells that migrate into the granule cell layer and mature into neurons with the morphological and physiological characteristics of adult granule cells. signal transduction pathways.16. enriched environment.22 Moreover. and may be relevant to the pathophysiology of stress-related disorders. Increased Neurogenesis in adult hippocampus arborization of neurons in the amygdala could thereby enhance emotional states or disrupt normal processing of emotional responses. Model demonstrating the regulation of adult neurogenesis in the hippocampus. The proliferation and survival of newborn neurons is subject to change and can be considered a form of neural plasticity. mossy fiber pathway. which includes increased circulating levels of GCL SGZ Decreased by: • Intruder stress • Predator odor • Footshock stress • Maternal separation • Learned helplessness • Glucocorticoids Increased by: • SSRI • NE reuptake inhibitor • MAOI • ECS • Exercise mfp Figure 2. For example.

27-29 The role of other factors that could underlie the actions of stress on adult neurogenesis is a subject of interest and could lead to novel targets for drug development.34 In addition to hippocampus. No. and gene expression is discussed in the second half of this review.30.35 Evidence from postmortem studies Atrophy of hippocampus or other brain regions could result from loss of cells (neurons or glia) or decreased size of the cell body or neuronal processes.40 Levels of BDNF are also decreased in prefrontal cortex and hippocampus of depressed patients. the effects of antidepressant treatment oppose or reverse the effects of stress. Postmortem analysis of CREB and BDNF has also provided evidence consistent with a loss of neural plasticity in depression. direct evidence to support this hypothesis has been provided by brain imaging and postmortem studies of depressed patients. Indeed. antidepressant treatment results in molecular and cellular responses that demonstrate an increase in neural plasticity. Evidence from brain imaging studies Magnetic resonance imaging studies have demonstrated that the size of certain brain structures is decreased in mood disorder patients. Moreover. these studies demonstrate that the volume of the hippocampus is decreased in patients with depression. The evidence for regulation of neural plasticity at the level of neurogenesis.33. chronic stress leads to decreased levels of phosphoCREB in many limbic brain regions.10 In addition. 2004 adrenal glucocorticoids.24 In contrast.31 Reduced hip- Antidepressant treatment increases neural plasticity In contrast to the effects of stress. As mentioned above. these studies have paved the way for additional studies that demonstrate that antidepressant treatment results in structural remodeling. The regulation of phospho-CREB is complex and is dependent on the brain region and whether the stress is acute or chronic. In many cases.36-38 There is much less known about the hippocampus and additional studies will be required to determine what accounts for the atrophy of hippocampus observed in depressed patients. Levels of CREB are decreased in the cerebral cortex of depressed patients or suicide victims. which could lead to decreased plasticity and function. In particular. Levels of BDNF expression in hippocampus are dramatically downregulated by both acute and chronic stress.Duman Dialogues in Clinical Neuroscience . 2 . pocampal volume is also observed in patients with posttraumatic stress disorder (PTSD).26 Stress has profound effects on the expression of BDNF in the hippocampus.32 The reduction in hippocampal volume is directly related to the length of illness. as well as the pathophysiology of mood disorders. and this effect could contribute to the atrophy and decreased neurogenesis caused by stress (Figure 1). and anxiety—has also been reported in patients with depression or bipolar disorder. Taken together. studies by McEwen and colleagues have demonstrated that glucocorticoids contribute to the atrophy and decreased neurogenesis of hippocampal neurons resulting from exposure to stress.41 Reduced levels of CREB and BDNF. The hippocampus contains very high levels of glucocorticoid receptors and is therefore significantly impacted by stress.Vol 6 . The transcriptional activity of CREB is regulated by phosphorylation and levels of phospho-CREB are used as an indirect measure of CREB activation and function (Figure 3). 161 . stress is reported to influence CREB and BDNF in the hippocampus and other brain regions. these findings provide additional support for the hypothesis that neural plasticity plays a significant role in the treatment.23-26 Acute stress increases levels of phospho-CREB in many limbic regions associated with mood disorders and this may represent a normal or appropriate adaptive responsiveness. indicate that the ability of limbic brain structures to mount adaptive responses is compromised in depressed patients.Neural plasticity and depression . mood. two molecular markers of neural plasticity. Atrophy of limbic brain structures in depressed patients Evidence from basic research studies provide strong support for the hypothesis that stress-related illnesses such as depression could include alterations in brain structure and neural plasticity. atrophy of prefrontal cortex and amygdala—brain regions that control cognition. signal transduction.39. The most extensive studies have been conducted on prefrontal and cingulate cortex and demonstrate that the neuronal body size and number of glia is decreased in depressed patients.

48 The influence of antidepressant treatment on the atrophy of CA3 pyramidal neurons resulting from chronic exposure to stress has been examined. and that the behavioral effects of SSRI treatment were similarly blocked. and electroconvulsive seizures are reported to increase adult neurogenesis. Analysis of dendrite branch number and length is tedious and labor intensive. These results are the first evidence that increased neurogenesis is necessary for an antidepressant response in behavioral models. tianeptine. These studies demonstrate that chronic antidepressant treatment can block or reverse the downregulation of neurogenesis that results from exposure to stress. including an atypical antidepressant. Antidepressant treatment blocks the downregulation of neurogenesis caused by stress The influence of antidepressant treatment in the context of stress has also been examined.43 In addition.22. different classes of antidepressants. although novelty-suppressed feeding is responsive to chronic antidepressant treatment—and this is why it was chosen— this paradigm is a better model of anxiety than depression. There are a few limitations to this study. This is consistent with another report demonstrating that decreased neurogenesis is not correlated with behavior in the learned helplessness model of depression.47 and a neurokinin-1 receptor antagonist.Pharmacological aspects Antidepressant treatment increases adult neurogenesis Neurogenesis is increased by chronic antidepressant administration One of the most surprising discoveries of recent times in the field of depression is that antidepressant treatment regulates neurogenesis in the adult hippocampus (Figures 1 and 2).42 a selective serotonin reuptake inhibitor (SSRI). A recent study has addressed this question by using a combination of irradiation and mutant mouse approaches. chronic antidepressant treatment increases the number of newborn neurons in the adult hippocampus of rodents or tree shrews. Second. They found that upregulation of neurogenesis by chronic administration of an SSRI was completely blocked in 5-HT1A null mutant mice. although the effects of antidepressant treatment were blocked. A functional role for neurogenesis in the action of antidepressant treatment A major issue in the field of adult neurogenesis is how to test the function of newborn neurons. consistent with the time course for the therapeutic action of antidepressants. One 162 . it is possible that intact neurons are sufficient to sustain baseline response and that more long-term inhibition of neurogenesis would be required to influence activity. In contrast to the actions of stress. the rate of cell proliferation (ie. different types of antidepressants have been tested. a subtype that has been implicated in the actions of antidepressant treatment.42. These studies demonstrate that chronic administration of tianeptine blocks the atrophy of CA3 apical dendrites that is caused by stress. but additional studies of other antidepressants are necessary to determine the relevance of this effect in the actions of antidepressant treatment. including blockade of intruder stress.42 maternal separation. the number of newborn neurons) and the survival of newborn neurons. novelty suppressed feeding and chronic mild stress.43-45 Antidepressant treatment influences two important aspects of neurogenesis.49 This study demonstrates that focused irradiation of hippocampus in the mouse completely blocks neurogenesis and there was a corresponding blockade of the behavioral actions of antidepressant treatment in two behavioral models. However. In addition.22 In addition.12 Chronic administration of an SSRI antidepressant did not block the atrophy of CA3 neurons in this study. Santarelli et al49 studied the effects of antidepressants in mice with a null mutation of the 5-HT1A receptor. in the absence of antidepressant administration. First.43 The upregulation of neurogenesis is dependent on chronic antidepressant treatment. The cAMP-CREB cascade and depression Neural plasticity upon antidepressant treatment is likely to involve adaptations of multiple intracellular signaling cascades and even interactions of these pathways.47 and learned helplessness.50 Together these studies indicate that neurogenesis is not required for baseline response.46 An increase in the number of newborn neurons could contribute to the reversal of hippocampal atrophy observed in depressed patients. irradiation and 5-HT1A null mutation alone. Several different types of stress have been tested. did not produce a depressive phenotype. including serotonin (5-hydroxytryptamine [5-HT]) and noradrenaline reuptake inhibitors.

2004 of the pathways that is regulated by antidepressant treatment and has been demonstrated to contribute to the actions of chronic antidepressant responses is the cAMP-CREB cascade. neuronal survival P P P P RNA BDNF gene ??? CaRE Figure 3. including β-adrenergic (βAR). neurogenesis. α1-adrenergic (α1AR).53. the subject of this section. and increased function and expression of CREB.Vol 6 . For reviews covering other signal transduction pathways. In this way. 2 . antidepressant treatment upregulates the cAMP-CREB cascade in limbic regions of the brain including the hippocampus and cerebral cortex. 5-HT7. increased levels of cAMP-dependent protein kinase (PKA).54 This work demonstrates that chronic antidepressant treatment upregulates the cAMP second-messenger cascade at several different levels. Model demonstrating the upregulation of the cyclic adenosine monophosphate (cAMP)–cAMP response element binding protein (CREB) cascade and expression of brain-derived neurotrophic factor (BDNF) by antidepressant treatment. it is likely that other signaling pathways are also regulated by—and play a role in—the actions of antidepressants. This includes Antidepressant treatment 5-HT/NE 5-HT/NE βAR 5-HT7 Gs Adenylyl cyclase Gi/o α1-AR 5-HT1A Rolipram cAMP Ca2+-dependent or MAP kinase cascades PKA BDNF/trophic effects: synaptic plasticity. The BDNF promoter has at least one Ca2+/cAMP response element (CaRE) that is regulated by phosphorylation (P) of CREB.Neural plasticity and depression . 163 . and 5-HT1A receptor subtypes. Chronic. CREB could serve as a common target for different types of serotonin (5-hydroxytryptamine [5-HT]) and norepinephrine (NE) receptors. This includes increased coupling of stimulatory G protein (Gs) to adenylyl cyclase. including Ca2+/calmodulin-dependent kinase and mitogen-activated protein (MAP) kinase. Antidepressant treatment upregulates the cAMPCREB cascade Several studies have investigated the influence of antidepressant treatment on the cAMP-CREB pathway (Figure 3).Duman Dialogues in Clinical Neuroscience . No. see reference 51 and 52. but not acute. CREB can also be phosphorylated and activated by other kinases. One downstream target of CREB that has been shown to have antidepressant effects is BDNF. However.

trkB.53. prodynorphin).46. and rolipram was one of the first selective PDE4 inhibitors. BDNF) versus the nucleus accumbens (ie.61 The different behavioral effects of CREB can be explained by different target genes in the hippocampus (ie. First. CREB can serve as a target for multiple signal transduction pathways and neurotransmitter receptors that activate these cascades. upregulation of the cAMP-CREB cascade is observed in response to chronic administration of different classes of antidepressants. Microinfusions of BDNF into the hippocampus produce an antidepressant-like response in the learned helplessness and forced swim models of depression.58 Second. while expression of a dominant negative mutant of CREB results in an antidepressant response in the forced swim test.28. In this way. it is now clear that these factors are expressed in the adult brain. consistent with the time course for the therapeutic action of antidepressants. and are critical for the survival and function of adult neurons. such as Ca2+/calmodulin-dependent protein kinase. viral expression of CREB in the hippocampus of rat produces an antidepressant response in the forced swim and learned helplessness models of depression. and is observed with different classes of antidepressants. In addition. Transgenic overexpression of a dominant negative mutant of the BDNF receptor. Studies to identify additional gene targets and gene profiles using gene microarray analysis are currently being conducted. increased levels of cAMP-dependent protein kinase (PKA). further studies demonstrated that the effects of CREB are dependent on the brain region where it is expressed.59 However. and is relatively long-lasting (up to 10 days after infusion). in the hippocampus and other forebrain 164 . antidepressant treatment results in significant upregulation of BDNF in the hippocampus and cerebral cortex of rodents.55-57 Upregulation of these components of the cAMP-CREB signaling pathway is dependent on chronic antidepressant treatment. In addition. it is clear why decreased expression of BDNF could have serious consequences for the function of limbic brain structures that control mood and cognition. expression of CREB in the nucleus accumbens produces a prodepressant effect. viral vector. However. but not other psychotropic drugs. or other types of neuronal insult. The induction of BDNF would be expected to protect neurons from damage resulting from stress.51. we have found that chronic rolipram administration increases neurogenesis in adult hippocampus. In addition to phosphorylation by PKA.62 The antidepressant effect of BDNF is observed after a single infusion. indicating that this is a common target of antidepressant treatment.Pharmacological aspects increased coupling of the stimulatory G protein to adenylyl cyclase. Regulation of neurotrophic factors and depression The regulation of CREB by antidepressant treatment indicates that regulation of gene expression also plays a role in the actions of antidepressants. In contrast. CREB is also phosphorylated by Ca2+-dependent kinases. are dynamically regulated by neuronal activity. drugs that block the breakdown of cAMP produce an antidepressant response in behavioral models of depression.54 The primary target for inhibition of cAMP breakdown is cAMP-specific phosphodiesterase type IV (PDE4). and mutant mouse approaches. Activation of the cAMP-CREB cascade produces an antidepressant response Direct evidence for cAMP-CREB signaling in the action of antidepressant treatment has been tested by pharmacological. and by mitogen-activated protein kinase pathways (Figure 3).52 but BDNF is one that has gained attention and is relevant to neural plasticity responses to antidepressant medications. There have been many gene targets identified for antidepressants. On the basis of these considerations. elevated glucocorticoids.54 Increased expression of BDNF is dependent on chronic treatment. For example. Antidepressant treatment upregulates BDNF Neurotrophic factors were originally identified and studied for their role in development and neuronal survival. compared with repeated administration of a chemical antidepressant. and increased levels of CREB as well as phospho-CREB.60 Transgenic expression of dominant negative CREB in the nucleus accumbens is consistent with this effect. BDNF has antidepressant effects in behavioral models of depression The possibility that BDNF contributes to the actions of antidepressant treatment is supported by behavioral studies of recombinant BDNF and transgenic mouse models.

Additional brain imaging and postmortem studies. a midbrain region where 5-HT cell bodies are localized. these studies indicate that BDNF could contribute to antidepressant responses in both forebrain and brain stem structures by affecting different populations of neurons. as with any fundamentally important mechanism. as well as basic research approaches will be required to further test this hypothesis.64 Together.59 Although these effects must be replicated and extended (for example. increasing levels of BDNF. No.Duman Dialogues in Clinical Neuroscience . Brain imaging studies have been conducted to examine the influence of antidepressants on the volume of limbic brain regions. to the regulation of neurogenesis) in additional banks of postmortem tissue. One study demonstrates that hippocampal atrophy is inversely proportional to the length of time a patient receives antidepressant medication. gene expression. 2 . antidepressant treatment opposes these effects of stress and depression. it is possible that microinfusions of BDNF into the hippocampus influence 5-HT neuronal function by acting at presynaptic sites. the studies to date provide compelling evidence that neural plasticity is a critical factor in the pathophysiology and treatment of depression. 2004 structures is also reported to block the effect of antidepressant treatment. and VGF. reduces neurogenesis.67 A longitudinal study of PTSD patients before and after antidepressant treatment has found that there is a partial reversal of hippocampal atrophy in patients receiving medication. care must be taken that the drugs developed for such targets do not interfere with the nor- 165 . including the hippocampus. Studies are under way to examine the role of FGF-2 in antidepressant regulation of neurogenesis and regulation of behavior in models of depression. Clinical evidence of relevance of neural plasticity to antidepressant treatment Basic research studies clearly demonstrate that antidepressant treatment regulates signal transduction. and causes atrophy or CA3 pyramidal neurons. demonstrating that BDNF signaling is necessary for an antidepressant response. Several other growth factors have been identified by microarray analysis and gene expression profiling. and amygdala.53. In contrast. also produces an antidepressant response in the learned helplessness model.Neural plasticity and depression . This issue is more difficult to address in clinical studies. In any case. Alternatively. and could contribute to antide- pressant regulation of neurogenesis. including vascular endothelial growth factor.54 This hypothesis is based in part on studies demonstrating that stress decreases BDNF. but evidence is slowly accumulating. Antidepressants influence other neurotrophic factor systems Because of the preclinical and clinical evidence implicating neurotrophic factors in the pathophysiology and treatment of depression. levels of BDNF are increased in patients taking an antidepressant at the time of death.66 Studies are currently under way to determine the functional significance of these growth factors in models of depression. Levels of CREB immunoreactivity are increased in patients receiving antidepressant treatment at the time of death relative to unmedicated patients.63 Microinfusions of BDNF into the dorsal raphe. Evidence at the molecular level is also provided by postmortem studies. and could therefore enhance 5-HT signaling as observed after brain stem infusions of BDNF. One of the most robust effects identified to date is that antidepressant treatment increases the expression of fibroblast growth factor–2 (FGF-2). and the cellular responses that represent neural plasticity. the results are consistent with the hypothesis that neural plasticity is upregulated in patients receiving antidepressant medication.Vol 6 . Brain imaging and postmortem studies provide additional support.64 A neurotrophic hypothesis of depression Basic research and clinical studies of BDNF have resulted in a neurotrophic hypothesis of depression and antidepressant action. demonstrating atrophy and cell loss of limbic structures. increasing neurogenesis. neuritin. studies have been conducted to examine other neurotrophic factor systems. prefrontal cortex. Novel targets for the treatment of depression The hypothesis that antidepressant treatment increases neural plasticity provides a number of novel targets for drug development. However.39 In addition. and reversing or blocking the atrophy and cell loss caused by stress and depression.68 The latter study demonstrated a corresponding increase in verbal declarative memory in response to antidepressant treatment.65 FGF-2 is known to have a potent influence on neurogenesis during development and in the adult brain.

Conclusions Studies of the molecular and cellular mechanisms underlying neural plasticity responses in learning and memory. cognition.74 Riluzole.75 Specific 5-HT and norepinephrine receptor subtypes that activate cAMP (eg. First. and drug abuse to name but a few. β-adrenergic. a sodium channel blocker. One of the promising aspects of neural plasticity is that it implies that the alterations that occur are 166 . Characterization of the antidepressant actions of these compounds will be needed.56 Small molecular agonists for neurotransmitter receptors have also exhibited some promise. and side effects have hampered these efforts. the clinical use of rolipram has been limited by its side effects. it may be possible to stimulate the expression of endogenous BDNF expression by stimulating signaling pathways known to regulate this neurotrophic factor. as well as neurogenesis in adult hippocampus. BDNF as a target for drug development The use of BDNF and other neurotrophic factors for the treatment of neurological disorders has been a subject of interest for several years.71 Studies of mutant mice demonstrate that null mutation of PDE4D produces an antidepressant-like phenotype indicating a role for this isozyme. memory.18 Because antidepressant treatment increases the expression of both BDNF and FGF-2. Targets for antidepressant regulation of neurogenesis Identification of the signal transduction and gene expression pathways that are responsible for the actions of antidepressant regulation of neurogenesis is a subject of intense investigation. and insulin-like growth factor–1. these two factors are currently being investigated. Progress in our understanding of neural plasticity has profound implications for the treatment of a number of psychiatric and neurodegenerative disorders. 5-HT7).46. regulation of neural plasticity is an exciting area of research for design of new drugs for a variety of indications. Studies are currently under way to characterize the regional distribution and function of the three PDE4 isozymes expressed in brain (PDE4A. depression. Ca2+. To more directly replicate the in vivo situation. 5-HT1A) pathways could also be targets for development. Gene targets of CREB. Activation of ionotropic glutamate receptors increases BDNF expression and could be targeted for the treatment of depression.73 One drug that modulates glutamate transmission and increases BDNF expression is memantine. and PDE4D) and the role of these isozymes in the actions of antidepressant treatment.72 and similar studies are currently under way for PDE4A and PDE4B. as well as other neurotrophic/growth factors that have been shown to regulate adult neurogenesis. Rolipram is a PDE4-selective inhibitor that has been demonstrated to have antidepressant efficacy in early clinical trials and behavioral models of depression. Targets for regulation of the cAMP-CREB cascade There are several different sites within the cAMP pathway that could be targeted for drug development. while another mediates its side effects. Nevertheless. including learning.69. and neurodegenerative disorders. although problems with delivery. anxiety. This is just a partial listing of the signal transduction cascades and factors that could contribute to antidepressant regulation of adult neurogenesis. efficacy.Pharmacological aspects mal function of the brain. The identification of four different PDE4 isozymes that are equally inhibited by rolipram raises the possibility that one of the isozymes underlies the antidepressant actions of rolipram. include BDNF. primarily nausea. as well as identification of additional neurotransmitter and signal transduction systems that regulate BDNF. or mitogen-activated protein kinase (α1-adrenergic. activation of the cAMP-CREB cascade by inhibition of PDE4 increases the expression of BDNF. One that has already proven to be effective for antidepressant treatment is blockade of PDE4 and the breakdown of cAMP. also increases BDNF expression. are some of the most exciting and rapidly advancing areas of research in neuroscience. mood.70 However. FGF-2. as well as fear. This section discusses a few of these targets in the context of the pathways regulated by antidepressants and stress.Activation of the cAMP-CREB signaling cascade using either pharmacological or transgenic approaches is reported to increase both proliferation and survival of newborn neurons in the hippocampus. to name but a few. and for enhancing performance in what are considered normal subjects. PDE4B.58 supporting the possibility that antidepressants increase neurogenesis via regulation of this intracellular pathway.

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Biochim Biophys Acta.908:187-196.411:67-70. J Neurosci. 1996. Makino S.35:5-49. 43. 2001. Ter Horst GJ. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews.15:1048-1060. Eur J Neurosci. Gado MH. Bruijnzeel A. Randall P. Rizavi HS. Glial reduction in the subgenual prefrontal cortex in mood disorders. Nestler EJ. Gould E. Monteggia LM. Czeh B. et al. et al. Wiegant VM. Schlinder AF. et al. Nature. Manev R. 2001. Bengzon J. 42. et al.7:933-941. Malberg J. Anderson ER. 19. Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness. 40. 54. Cloning and charactization of additional members of the G protein–coupled receptor family. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. et al.531:225-231. Kuipers SD. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Tanapat P. 1997. Mol Psychiatry. Nakagawa S. van der Hart M. Substance P receptor antagonist and clomipramine prevent stress-induced alterations in cerebral metabolites. Science. 1995. Manji H. C D’Sa. McEwen BS. Vyas A. 29. Daniels DC.352:1754-1755. Lee H. 21. 18. 1990. Price JL. J Neurosci. Gold SJ. Watanabe Y.45:1085-1098. J Neurosci. Biol Psychiatry. Duman R. Stress and hippocampal plasticity.2:260-265. Duman RS. Olivier JD. Chattarji S. Nestler E. Landau S. Trentani A. Shors TJ. 2000. J Neurochem. Duman R. The cellular neurobiology of depression.99:11435-11440.

Jin SJC. Russell RS. Antidepressant-like actions of an AMPA receptor potentiator (LY392098). Chen AC. Nakagawa S.23:349-357. Curr Ther Res. Griffey K. Chen J. Biol Psychiatry. Biol Psychiatry.40:1028-1033. Kim JE. 2 . Lindsay R. Huang Y. et al. 72. Chronic antidepressant administration increases the expression of cAMP phosphodiesterase 4A and 4B isoforms. Untreated depression and hippocampal volume loss.160:1-3. Neuropharmacology. 1997. Shi B.38:23-29.22:3251-3261. Expression of the cAMP response element binding protein (CREB) in hippocampus produces antidepressant effect. The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain. Duman RS. Neuropharmacology. FASEB J. Sastre-Y-Hernandez M. Duman RS.61:1017-1024. 2003. J Neurosci. Nestler EJ. Mezes PS.24:10883-10890. Vythilingam M.22:267-272. Neve RL. Duman RS. 71. Li X. Lane S. 2002. et al. Marvanova M. Conti M. Clay M. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. Southwick SM. Charney DS. Nakagawa S. Thome J. No. 60. Neve RL. Lee R. 2002. Neuropsychopharmacology. Siuciak JA. 2004 58. 2001. Sheline Y. Takahashi M. Lindstron T.Vol 6 . Katoh-Semba R. Zhang H-T. et al. Ueda H. Asano T. Saarelainen T. Clinical effects of the neurotrophic selective cAMP phosphodiesterase inhibitor rolipram in depressed patients: global evaluation of the preliminary reports. Konradi C. 67. Gado MH. 2003. Adams D.18:247258. 1983. Castren E. 2003. 61. Wiegand SJ. 63. Pharmacol Biochem Behav. 66. 1999.49:753-762. Wallace TL. Malberg J. 2001. 73. Hunsberger J. Collier E. Activation of the trkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects.23:10841-10851. Horowski R. Duman RS. 2001. Shin KH. Kraemer HC.21:7397-7403. Pirhonen J. Mallei A. Shirayama Y.56:131-137. J Neurosci.5’-monophosphate phosphodiesterase inhibitors. Hendolin P. Vermetten E. 62. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Am J Psychiatry. Carlezon WA. Wong G. 169 . J Neurosci. Terwilliger R. Riluzole enhances expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus. 2001. 59.27:587-595. Newton S. Bremner JD. 2003. Newton S. Lucas G. Fujioka T. J Neurosci. Carlson RR. Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus.22:9868-9876. 68. 74. Lakso M. 2001. 2002. 65. Pliakas A. J Neurosci.19:610-618. Chen A-H. Lewis DR. Wachtel H. et al.Duman Dialogues in Clinical Neuroscience . 2002. Potential antidepressant activity of rolipram and other selective cyclic adenosine 3’. 70. Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated CREB expression in the nucleus accumbens. 1985. 2002. J Neurosci. Shirayama Y. Antidepressant treatments induce the expression of basic fibroblast growth factor in cortical and hippocampal neurons. Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect.Neural plasticity and depression . Tizzano JP. Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Mol Cell Neurosci. Mocchetti I. 64. 69. Skolnick P. Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. 75. Nawa H. Salvanayagam E.54:693-702. J Neurosci.16:1328-1330. Gene profile of electroconvulsive seizures: induction of neurogenic and angiogenic factors.

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6:171-183. dopamine transporter. 37077 Göttingen. Germany Address for correspondence: Eberhard Fuchs. Since social stress in animals evokes symptoms that resemble those found in depressed patients.Pharmacological aspects Cellular consequences of stress and depression Eberhard Fuchs. Gabriele Flügge. and emotional processes. chronic social stress can serve as an experimental paradigm to investigate the neuronal processes that may also occur during depressive disease in humans. adrenaline. Kellnerweg 4. Germany (e-mail: efuchs@gwdg. Clinical Neurobiology Laboratory.dialogues-cns. histamine. German Primate Center. which is known to be accompanied by hyperactivity in central nervous neurotransmitter systems. Antidepressants are presently believed to exert their primary biochemical effects by readjusting aberrant intrasynaptic concentrations of neurotransmitters. Research over past years has led to considerable advances in the understanding of the neural causes of depression and the cellular mechanisms that underlie the beneficial effects of currently available antidepressants. More importantly. including alterations in neuronal structures. chronic psychosocial stress serves as an experimental model to evaluate the cellular and molecular alterations associated with the consequences of major depression. Here. PhD. 2-adrenoceptor.1 and to secrete glucocorticoids from the adrenal gland.2 These corticosteroids have been identified as prominent factors that modify metabolic processes in both the body and the brain during stress as well as depression. such research forms the basis for the future development of more effective antidepressant drugs. German Primate Center. suggesting that imbalances within the monoaminergic systems contribute to the disorder (monoaminergic hypothesis of depression). All rights reserved 171 .3 However. such as serotonin or noradrenaline. we review the results that comprise our understanding of stressful experience on cellular processes. such as the hypothalamo-pituitary-adrenal (HPA) axis. PhD Stress is known to activate distinct neuronal circuits in the brain and induce multiple changes on the cellular level. This causes mood alterations in the affected individual and has the potential to reverse the psychopathological processes. motor. The brain responds to stress experiences in a complex manner related to the activation and inhibition of neurons that are involved in sensory. dopamine. S Stress changes the activity of noradrenergic and adrenergic neurons Stress is known to activate neurohormonal systems. neuronal remodeling. induces cellular changes that can be regarded as a form of plasticity. 2004. cognitive.de) Copyright © 2004 LLS SAS. serotonin. www. noradrenaline. adrenaline. with particular focus on the monoaminergic systems and structural changes within brain target areas of monoaminergic neurons. 5-HT1A receptor. the other group of essential substances in basic and accelerated metabolism includes the monoamines. LLS SAS Dialogues Clin Neurosci. to release the central nervous “stress peptide” corticotropin-releasing factor.org Keywords: noradrenaline. © 2004. tressful life events are among the most potent factors that trigger or induce depressive episodes in humans. thus alleviating the symptoms of depression. Chronic stress. tree shrew Author affiliations: Clinical Neurobiology Laboratory. Göttingen. On the basis of clinical observations that stress often precipitates a depressive disease. autonomic. PhD.

and histamine. B. The beststudied group of noradrenergic neurons. phospholipase. low concentrations of noradrenaline induce adrenoceptor upregulation. cAMP. where they form groups of cells that project axons to many parts of the brain. α2A-AR is also expressed in neurons that release the excitatory neurotransmitter glutamate. regulates noradrenaline release via a negative feedback loop. These membrane-bound proteins convey signals from the extracellular to the intracellular compartment of a cell (Figure 2). which itself regulates many cellular functions including gene transcription. alter α2-AR numbers in distinct brain 172 .14.17 Brain α2-AR changes have been observed in depressed patients (see below).18 Expression of this autoreceptor is reduced soon after the onset of stress (see below).7-10 Acute stress induces only a transient rise in noradrenaline levels. second messengers (eg. The α2A-AR autoreceptor in LC noradrenergic neurons. GPCR signaling requires several steps for transmission of the signal.22. The noradrenergic and adrenergic neurons are located in the brain stem.19 In general. resulting in anxiety-like behavior in rats and monkeys. Noradrenaline and adrenaline bind to the same types of adrenergic receptors.23 Different forms of stress. α2-AR stimulation leads to a transient inhibition of neuronal firing through hyperpolarization that is related to the modulation of calcium and potassium channels. The present survey focuses on processes related to stress-mediated activation of monoaminergic neurons in the brain.13 Because of their widespread distribution in the brain.11 On the other hand. are the α2-adrenoceptors (α2ARs).Pharmacological aspects Selected abbreviations and acronyms 2-AR -AR DAT GPCR 5-HT LC 2-adrenoceptor -adrenoceptor dopamine transporter G protein–coupled receptor 5-hydroxytryptamine (serotonin) locus ceruleus dopamine. lasting from milliseconds to many minutes. and arachidonic acid). A long-term effect occurring minutes after binding GPCR is the regulation of gene transcription and subsequent protein synthesis (Figure 2). located in the pontine locus ceruleus (LC). The limbic system is a collection of regions that appear to regulate emotional processes (Figure 1). kinases. which modulate the electrical activity of the neuron. innervate several brain regions including the neocortex and the limbic system.15 The involvement of α2-ARs in the regulation of attention is suggested by the finding that methylphenidate (the nonamphetamine stimulant used to treat children with attention-deficit hyperactivity disorder) affects neuronal activity in the LC. and C). When stimulated through stressful challenge.12 Changes in α2-ARs alter the activity of neurons The most studied adrenergic receptors. α2ARs are diversely involved in mediating the analgesic and sedative effects of agonists such as dexmedetomidine14 and in modulating the baroreceptor reflex. noradrenergic and adrenergic neurons release more noradrenaline and adrenaline. with respect to regulation in chronic stress. As a consequence.20.5 There are different types of adrenergic receptors in the brain whose activation either stimulates or inhibits the respective target neurons. In addition. cyclic adenosine monophosphate [cAMP]. as well as ion channels. and that the turnover of these neurotransmitters is accelerated so that their concentrations and/or amounts of their metabolites fluctuate in relation to the intensity and duration of the stressor. The binding of a natural agonist such as noradrenaline or adrenaline to the receptor initiates a cascade of intracellular events that drive the activity of the cell and involve effectors such as enzymes (eg.21 There is reduced intracellular formation of the second messenger.16 Administration of the antagonist yohimbine (a sympatholytic drug that is used to treat impotence) increases firing of the LC neurons. leading to a reduction in adrenoceptor numbers (receptor downregulation). calcium ions. for example. and phosphatases). noradrenaline is released from the nerve terminals in the target brain region and is bound to adrenergic receptors belonging to the group of G protein–coupled receptors (GPCRs). of which three subtypes are known (A. such as immobilization or a cold environment. but chronic stress with recurrent environmental challenges can lead to repetitive increases in concentration. The noradrenergic LC neurons play an important role in the regulation of mood and emotions as well as of attention span. respectively. adenylyl cyclase. cyclic guanosine monophosphate [cGMP]. serotonin (5-hydroxytryptamine [5-HT]). although with slightly different affinities. adrenoceptors on the surface of the target neurons are bombarded with noradrenaline.6 Various experiments have shown that during stress.

2004 A. Currently available antidepressants are thought to adjust the balance between the different neurotransmitter systems. Monoaminergic neurons innervate almost all brain areas. The noradrenergic neurons of cell groups A1. Serotonin D. The dopaminergic neurons of the substantia nigra and the adjacent ventral tegmental area (VTA) project to the striatum and to regions in the neocortex. and to the thalamus. They are important in the initiation of movements and for emotional processes. A2. and A7 project to more restricted regions. A. cerebellum. Modulation of neuronal activity by these monoamines is an important factor of well-balanced central nervous activity.Cellular consequences of stress and depression . They play an important role in the regulation of mood and attention. Noradrenaline B. A5. The noradrenergic neurons of the locus ceruleus project to the limbic and cortical regions. Furthermore. No. B. 2 . Dopamine C.Fuchs and Flügge Dialogues in Clinical Neuroscience . 173 . D. Histamine Figure 1.Vol 6 . Serotonin. Stress leads to hyperactivity of the monoamine neurons and thus to a dysregulation of neuronal activity. Noradrenaline. Dopamine. C. Histamine. and spinal cord. The serotonergic neurons located in the raphe nuclei project to almost all parts of the brain and are involved in many functions including the regulation of emotional processes. there is a dopaminergic cell group in the hypothalamus that regulates neuroendocrine processes. They project to all parts of the brain and are important for arousal (the excited brain state).4 They are important for autonomic function. Histaminergic neurons are located in the tuberomammillary complex of the hypothalamus.

This leads to phosphorylation and/or dephosphorylation of many intracellular proteins as well as ion channels that are located in the plasma membrane of the cell.28 During a stress period lasting several weeks. Transcripts (mRNA) are later translated into protein. Phosphorylation/dephosphorylation induces opening and closing of these channels and this modulates the electrical activity of the neuron. Calcium ions released from intracellular stores and other second messengers activate protein kinases and phosphatases. such as cyclic adenosine monophosphate (cAMP) and diacylglycerol. serves as the machinery that transduces the extracellular signal to various effectors at the intracellular side of the plasma membrane. adrenergic regulation changes. β. diacylglycerol.24.Pharmacological aspects regions. Neurotransmission via a G protein–coupled receptor (GPCR): binding of the neurotransmitter to the receptor initiates a cascade of intracellular events that drive the activity of the neuron or cell.27 This receptor downregulation is most probaNeurotransmitter bly related to the stress-mediated rise in noradrenaline concentrations. phosphatases) DNA mRNA Protein synthesis Figure 2. Regulation of noradrenaline release is impaired soon after the onset of the stress period. These dynamic cellular processes are accelerated during stress when neurotransmitter concentrations are elevated. These enzymes catalyze the synthesis of second messengers. as revealed by reduced expression of the α2A-AR in the LC. and γ. Ca2+ Cytoplasm Ion channel Nucleus Gene transcription Activation of downstream enzymes (protein kinases. The G-protein complex. giving an initially high level and γ β G-protein complex Neuronal membrane GPCR α Membrane-bound enzyme α cAMP.26 Our experiments showed that chronic psychosocial stress reduces α2-AR expression in brain regions that regulate autonomic functions and emotional behavior. to the enzymes adenylyl cyclase or phospholipase. which regulate gene transcription in the nucleus. consisting of subunits α. 174 .25 We investigated the consequences of chronic psychosocial stress using a stress paradigm in male tree shrews.

and (iii) the effects differ in different brain regions.52 A polymorphism in the promoter region of the 5-HT transporter (5-HTT) gene is thought to contribute to anxiety in humans. studies on postmortem material from brains of depressed human patients also revealed the upregulation of α2-ARs in several brain regions. 2004 then finally a low level of noradrenaline. since normal receptor numbers are restored through the reinsertion of 175 .Cellular consequences of stress and depression . probably due to a gradually acquired deficit in transmitter synthesis. thereby restoring the normal receptor pattern in the membrane. analgesia. transport. This is the case in the prefrontal cortex.11.54 Rhesus monkeys with the short-sequence allele have low concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid in their cerebrospinal fluid. No.and β2-ARs are differentially regulated. and they innervate almost every area of the brain.39 The number of β1-ARs in the temporal and frontal cortex of suicide victims has been found to be significantly lower than in matched controls.56 although the serotonergic neurons of the dorsal raphe nucleus do not change their discharge rate during stress.42 On the other hand. sleep. Stress and 5-HT neurons It is generally assumed that changes in serotonergic neurons underlie depressive diseases because the most widely used antidepressants are SSRIs. indicating increased turnover rates of the neurotransmitter.43 Stress downregulates β-ARs in the brain.8. Finally.34 Antidepressants that interact with α2-ARs such as mirtazapine probably counteract this deficit. β-ARs also change during stress GPCR β-adrenoceptors (β-ARs) increase cAMP synthesis. noradrenaline concentrations are obviously low throughout the whole brain. (ii) β1.41 However.36 They are present in neurons and glial cells.46 The serotonergic neurons of the dorsal raphe nucleus that project to the forebrain are autoactive and discharge in a stereotyped pattern that changes during the sleep–wake–arousal cycle.Fuchs and Flügge Dialogues in Clinical Neuroscience .46 Nevertheless.37 When stimulated by agonists (adrenaline or noradrenaline).35 intracellularly sequestered receptor molecules into the plasma membrane. they undergo intracellular sequestration with subsequent reinsertion into the plasma membrane. and motor output.49-51 5-HT definitely regulates mood. since its transporters and receptors are targets for several psychotropic drugs. nociception. However.” which assumes there is a reduced noradrenaline concentration in the brains of depressed patients. which raise extracellular levels of 5-HT.44 Our data from the tree shrew chronic stress model reveal that (i) the effects are dependent on the duration of a stressful event. humans with a genotype conferring high levels of expression of monoamine oxidase A (MAOA.54 Stress elevates the concentrations of 5-HT and its metabolites in several brain regions. the majority of 5-HT-producing neurons are located in the brain stem. Several experimental results have confirmed the “5-HT deficit hypothesis” of depression. Therefore. and/or release from the noradrenergic neurons. high levels of endogenous agonists quickly reduce numbers of β-AR molecules in the plasma membrane of target cells. after 4 weeks of psychosocial stress. most of them on or near the midline. the treatment of rats with the selective serotonin reuptake inhibitors (SSRIs) citalopram and fluoxetine increased β1-AR radioligand binding in the frontal cortex and striatum.31-33 These data therefore support the “noradrenaline deficit hypothesis. a brain area important for the regulation of mood and behavior. β-ARs are rapidly internalized into the cells.45 Some of the stress-induced changes are only transient.38 β-ARs are first internalized into the cell.29 Following a chronic stress period. and β-AR blockers have been used to treat depression and anxiety. In mammals. inducing desensitization. the psychotropic role of β-AR downregulation is still under discussion since the antidepressant desmethylimipramine also downregulates brain β-ARs.55 This finding agrees with the view that low brain 5-HT levels (“decreased serotonergic activity”) have negative effects on emotionality. β-AR dysfunction is thought to play a role in psychiatric disorders. it has been suggested that the 5-HT system is involved in almost every brain function.47. regulation of cardiovascular and respiratory activity. 5-HT concentration per se is probably not the only trigger for mood changes. the enzyme that degrades 5-HT) are less likely to develop antisocial problems than individuals with lower MAOA expression. 2 .48 Due to its wide distribution.40. the number of β1-ARs was decreased in cells of the hippocampus and parietal cortex.53 and an epidemiological study provides evidence that an allele encoding a short DNA sequence in this promoter region increases the risk of developing a depressive disorder.30 Interestingly. such as the regulation of neuroendocrine secretion.Vol 6 .

81 The mesocortical dopaminergic system is obviously more stress-sensitive than the mesolimbic and the nigrostriatal systems. and it modulates potassium and calcium channels. they affect the activity of pyramidal neurons in the hippocampus. but also to low testosterone.76 The stress-induced downregulation of postsynaptic 5-HT1A receptors in distinct cortical areas and the hippocampal formation.62-64 The 5-HT1A receptor has been implicated in many functions. in genetically intact animals. whereas they were reduced in the lateral septum. 5-HT1A receptor binding sites were increased in the ventral prefrontal cortex. and other regions.67. a brain region normally devoid of these receptors. depending on the type of neuron where it is expressed. the persistent stress-induced activation demonstrated in the noradrenergic system has not been demonstrated in the dopaminergic system. Groups of dopaminergic neurons are located in the midbrain.83 In the tree shrew model. which initiates motor responses. and their life history. A variant of the 5HT1A receptor gene was found in Tourette’s patients and. hypothalamus. Dopaminergic cells of the substantia nigra and the adjacent midbrain tegmentum project to the telencephalon including the striatum. in schizophrenics. which arise from the ventral tegmental area. suggesting that repeated exposure to the same stressor results in inhibition rather than activation of dopaminergic neurons. the best characterized 5-HT receptor.60. The agonists buspirone and gepirone act as anxiolytics and display antidepressantlike effects in clinical trials.58 Many receptors (>14) are known to mediate the effects of 5-HT. which showed that stress reduces 5-HT1A autoreceptor functioning.64 This agrees with electrophysiological data from the rat brain stem.74 Restraint stress downregulated 5-HT1A receptors in the hippocampus of rats.71-73 Schizophrenics also displayed some 5-HT1A receptor binding in the cerebellum. forming the nigrostriatal pathway. Social stress in male animals lowers testosterone levels.82. the adrenal hormones that regulate the transcription of many genes. 4 weeks of psychosocial stress downregulated DAT in the striatum. Postsynaptic 5-HT1A receptors regulate the activity of neurons in cortical. and other regions. Like other 5-HT receptors.64 However. and normal 5-HT1A receptor numbers can be restored by a testosterone substitution (Figure 3).Pharmacological aspects stress induces alterations in those brain regions that are targets of the serotonergic neurons. could also be attributed to high levels of glucocorticoids. an initial increase in mesolimbic dopamine release was later followed by a decline. with only their affinity being reduced. there are conflicting data on this issue. For example.78 Stress affects dopaminergic neurons Responses of the dopamine system to stress received particular attention because of the potential involvement of this catecholamine in human psychopathologies that are known to be exacerbated by stress. it is interesting to note in relation to postsynaptic 5-HT1A receptor downregulation that the effect is not exclusively due to high glucocorticoid levels. We also found a 176 . limbic. so that repeated exposure of rats to forced swimming increased 5-HT concentrations in the striatum.57 Chronic restraint stress in rats accelerated 5-HT turnover in the hippocampus and produced low amounts of the monoamine. in tree shrews. such as schizophrenia. This GPCR inhibits neuronal activity by reducing cAMP formation or phosphoinositide hydrolysis.75. it is involved in the regulation of mood and emotional behavior.77 It is interesting that the number of somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus did not change during chronic stress in male tree shrews.59 The present survey focuses on the 5-HT1A receptor.69.65 and there is evidence that 5-HT1A receptor dysfunction is involved in depressive disorders. the genetic background of the animals.80 Other data suggest that the effects depend on the severity and controllability of the stressor.61 The somatodendritic 5-HT1A autoreceptors located on the serotonergic neurons in the raphe nuclei regulate 5-HT release. whereas another report showed no difference between suicides and controls.70 Furthermore. other psychiatric diseases—as well as depression—might cause changes in 5-HT1A receptors of the central nervous system.4 The mesocortical and mesolimbic dopamine pathways. and this effect was attributed to a stress-induced rise in plasma glucocorticoids. have been implicated in emotional and memory processes.68 However. Under restraint stress.66 Human brain studies showed that 5-HT1A receptor binding in depressed patients is lower than in healthy subjects. Dopamine transporter (DAT) knockout mice with high extracellular dopamine levels were easily aroused by the mild stress of novelty.79 However. Brains of nonviolent suicides had increased 5-HT1A receptor binding in the frontal cortex in one report.

upper left) in the hippocampal formation release the neurotransmitter serotonin (gray balls). Colors indicate numbers of receptors in the different regions of the hippocampal formation: orange. 2004 positive correlation between locomotor activity. D3. moderate numbers.86 However. social defeat in male rats also decreased DAT binding sites in the striatum. but that the normal receptor number is restored following testosterone treatment. the serotonin-1A (5-HT1A) receptors (orange). there are indications that D1 and D5 receptors are located postsynaptically. 2 . high receptor numbers. no receptors. No. yellow. The three pseudo-color pictures demonstrate receptor binding in normal male tree shrews (left). 177 . purple.Cellular consequences of stress and depression . in tree shrews that were submitted to chronic psychosocial stress (middle).36 Experiments with various knockouts could not determine where on the neurons these receptor subtypes are located (presynaptic versus postsynaptic location). which binds to its receptors. Five distinct dopamine receptors have now been cloned. Note that after chronic social stress receptor numbers are decreased. which is reduced in stressed animals. and in stressed tree shrews that had received testosterone as a treatment (right). and the total number of DAT binding sites.84 Low levels of DAT may indicate low extracellular dopamine concentrations. D1 and D2. these exert opposing effects on the adenylate cyclase system. and D4 receptors are located presynaptically and postsynapti- Serotonin receptor Terminal of serotonergic neuron Release of serotonin Stress and testosterone Stress Normal Figure 3. green. Serotonergic nerve endings (schematic drawing.Vol 6 .85 Dopamine was initially considered to convey its cellular actions via two receptor subtypes. whereas D2. In agreement with these findings. low numbers.Fuchs and Flügge Dialogues in Clinical Neuroscience .

98 In the CA3 pyramidal neurons of the hippocampus.91 H1 and H2 receptors modulate release of the “stress hormones” corticotropin-releasing factor and vasopressin from hypothalamic neurons. conformational changes in receptors. unpublished observations). ion channels via stimulation of GPCRs). past research has shown that this is indeed the case. H1 and H2 receptors are mainly postsynaptically located with high densities in limbic brain regions.90 The electrophysiological properties of these cells are similar to those of the other aminergic neurons. which may lead to either increased or decreased synthesis of a given protein (Figure 2).91 The central histamine system is involved in many functions. antagonists and H3 receptor agonists decrease anxiety.88 In the tree shrew model.36 Histamine modulates glutamatergic neurotransmission. whereas during chronic stress histamine turnover in the striatum and nucleus accumbens is affected.91.93 while various stressors such as dehydration or hypoglycemia stimulate histamine release. dendritic retraction could be prevented by the antidepressant tianeptine. with slow spontaneous firing. histaminergic neurons are found exclusively in the posterior ventral hypothalamus. • Internalization of receptors and intracellular trafficking as described for β-ARs. where glucocorticoids also induce alterations in the arborization of dendrites. broad action potentials. Stress-induced neuronal remodeling and plasticity The stress-induced processes described above include changes in different compartments of cells: • Alterations in membrane-bound proteins that occur within seconds after the stressful stimulus (eg. with reduced thresholds and higher amplitudes.100 In addition.92 Histamine activates three types of receptors whose expression varies between brain regions. these changes in receptors and DAT indicate impaired dopamine release after stress. • Changes in large enzyme complexes involved in the intracellular signaling cascade. • Changes in gene transcription. Activity in histaminergic neurons correlates closely with the sleep–wake cycle. the arborization Histaminergic neurons under stress The central nervous histamine system has been less extensively studied with respect to stress. and because of the existence of antidepressants that block the H1 receptor (eg.99 Also. but not by the SSRIs fluoxetine and fluvoxamine. and pronounced afterhyperpolarization. Antidepressants that block the D2 receptor (eg. In mammalian brains. Neurons with many or highly arborized dendrites potentially have large receptive fields (Figure 4). and electrophysiological measurements revealed that this phenomenon was accompanied by a facilitation of action potentials. Histaminergic neurons are also active in alarm situations and/or during activation of the peripheral sympathetic nervous system. clomipramine and fluvoxamine) might contribute to an improvement in motivation. although it definitely plays an important role in the stress response. but send their fibers to all brain regions. while H3 is a somatodendritic autoreceptor that regulates release of the bioamine. Dendrites are the major regions of neuronal synaptic contact with other neurons.Pharmacological aspects cally.36.89 Taken together.95 A relationship between histaminergic neurotransmission and emotional processes is suggested by the fact that H1 receptor 178 . It is possible that these dynamic processes may even lead to morphological changes in the cells. with the presynaptic receptors acting as inhibitory autoreceptors. being highest when awake and lowest during rapid-eye movement sleep. The first proof that chronic stress induces a remodeling of brain cells came from morphological studies on dendrites of pyramidal neurons in area CA3 of the hippocampus. Such a deficit in dopamine release might also account for a lack of motivation in depression.96. In contrast to chronic daily social defeat. single experiences of social defeat on two consecutive days induced similar changes in the apical dendrites.87.94 Acute restraint stress stimulates histamine turnover throughout the diencephalon. with a reliable increase in the prefrontal cortex. The retraction of the dendrites of these neurons was observed after chronic social stress and this effect was attributed to the stress-induced rise in glucocorticoids. D1 receptors were slightly increased in the striatum after 4 weeks of psychosocial stress (Mijnster et al.97 Similar phenomena occur in pyramidal neurons in the prefrontal cortex. doxepin and amitriptyline). enzymes. Even handling of rats raised histamine release in the prefrontal cortex of rats. chronic social defeat in male rats induced a shrinkage of the apical dendrites of the CA3 pyramidal neurons. while D2 receptors were upregulated in the hippocampus. with these changes persisting over 3 weeks.

Stress was also shown to prevent long-term potentiation (LTP. Schematic drawing of a CA3 pyramidal neuron plus its dendrites. in contrast. Synapses are sites of signal transmission between neurons. the cytoskeletal fibers.114 Furthermore. Recent tree shrew studies showed that chronic psychosocial stress reduced the expression of certain genes that are related to the shape of neurons and other brain cells.Vol 6 .104 Activation of the NMDA receptor initiates changes in the actin cytoskeleton that stabilize the synaptic structure. No. expression of genes associated with excitatory neurotransmission and mechanisms of neurotransmitter release were significantly altered. 2004 of the dendrites at the basal pole of the pyramidal neurons was increased after the double defeat paradigm. thus reducing the surface area of the neuron with the consequence that the neuron receives less information from other neurons (see text for details). but one may speculate that they are accompanied by alterations in gene transcription.112 The physiological role of these changes is unknown. a large group of genes in the hippocampus has been shown to be differentially expressed after glucocorticoid treatment. whereas.108 However. although other factors such as sex hormones may also have an effect on their formation. such as handling the experimental animals daily. Note the small soma in comparison to the highly arborized apical and basal dendrites.103 Spines may form rapidly under the influence of synaptic activity. a mechanism of synaptic plasticity that is thought to be related to memory formation) of CA neurons in the hippocampus. recent studies using the optical dissector technique.Cellular consequences of stress and depression .106 In response to an acute stress.Fuchs and Flügge Dialogues in Clinical Neuroscience . experiments using an in situ end-labeling technique to identify apoptotic (dying) cells showed a significant decrease in the number of apoptotic cells when all hippocampal areas were analyzed.76 Apical dentrites Spine Synapse Soma Basal dentrites Axon Figure 4. The shape of a spine is related to the arrangement of the actin-containing microfilaments. 2 . Inset: dendritic shafts can build up protrusions (spines) that form synapses with axons or dendrites from other neurons. one of the most prominent receptors for the excitatory neurotransmitter glutamate. Chronic psychosocial stress reduces the arborization of the apical dendrites.109 Moreover. 179 .Their nuclear ultrastructure changes as shown in the significant intensification in Nissl staining.110 Although stress-induced death of principal neurons in the hippocampus is questionable. This inhibition of LTP was observed in male rats after only two exposures to social defeat. female rats showed reduced spine density.102 Synapses are often located at the tips of the spine protrusions on the dendritic shafts of neurons (Figure 4). showed that stress does not affect neuron numbers in the CA1 and CA3 areas of the hippocampus. a reliable method for quantification of neurons within an entire brain region. Formation and disappearance of spines are regulated by many factors such as gonadal hormones.113 In the brains of adult rats that had been prenatally stressed through the stressful treatment of the pregnant dams.100.101 Therefore.105 Spine formation in the neurons of the prefrontal cortex can be induced by even minor stimuli. it is clear that stress profoundly affects these neurons. Chronic stress and neuronal death? There have been reports that social stress leads to cell death in the hippocampal formation.101 The antidepressant tianeptine increases the amplitude of excitatory postsynaptic potentials and this mechanism appears to be related to alterations in the phosphorylation of the N-methyl-D-aspartate (NMDA) receptor.107 It therefore appears that spine morphology is modulated by stress.111 An electron microscopic analysis indicated that this effect is due to increased heterochromatin formation in the neuronal nuclei. spine density was enhanced in the hippocampus of male rats. two severely stressful experiences had longlasting consequences on the morphology of neurons that differed from those induced by daily chronic stress.

Actualmente se cree que los antidepresivos ejercen sus efectos bioquímicos primarios mediante un reajuste de las concentraciones intrasinápticas aberrantes de neurotransmisores. The work summarized here was in part supported by the German Science Foundation. A partir de las observaciones clínicas. Consecuencias celulares del estrés y la depresión Se sabe que el estrés activa distintos circuitos neuronales en el cerebro e induce múltiples cambios a nivel celular incluyendo alteraciones en las estructuras neuronales. avec une attention particulière sur les systèmes monoaminergiques et les changements structurels des régions cérébrales cibles des neurones monoaminergiques. telles la sérotonine et la noradrénaline. such as major depression. such as the time delay for a full therapeutic response. Selon les conceptions actuelles. Sur la base d’observations cliniques ayant montré que le stress déclenchait souvent une maladie dépressive. Cet article passe en revue les résultats qui contribuent à notre compréhension des conséquences du stress sur les processus cellulaires. el estrés psicosocial crónico sirve como modelo experimental para evaluar las alteraciones celulares y moleculares asociadas con las consecuencias de la depresión mayor. and the EC. ❏ The contributions of former and current members of the Clinical Neurobiology Laboratory at the German Primate Center are gratefully acknowledged. y compris des altérations des structures neuronales. le stress psychosocial chronique peut être pris comme modèle expérimental pour évaluer les altérations moléculaires et cellulaires associées aux conséquences d’une dépression majeure. the substantial number of nonresponders. con particular atención a los sistemas monoaminérgicos y los cambios estructurales de las áreas cerebrales blanco de las neuronas monoaminérgicas. Ceci suggère que les déséquilibres des systèmes monoaminergiques sont impliqués dans la genèse de la dépression (hypothèse monoaminergique). the DAAD. que indican que a menudo el estrés precipita una enfermedad depresiva. the limitations of current antidepressant medications. Recent preclinical and clinical studies suggest that major depressive disorders are associated with cellular resilience and an impairment of synaptic and structural plasticity. Although this concept is still in its infancy. and bothersome side effects merit a full exploration of all plausible agents with novel antidepressant mechanisms of action. les antidépresseurs exercent leur effet biochimique primaire en réajustant les concentrations intrasynaptiques aberrantes des neurotransmetteurs. the exact neurobiological processes leading to depression and the mechanisms responsible for the therapeutic effects of antidepressant drugs are still not completely understood. lo que sugiere que el desbalance dentro del sistema monoaminérgico contribuye al trastorno (hipótesis monoaminérgica de la depresión). Aquí se revisan los resultados que contribuyen a nuestra comprensión acerca de las consecuencias del estrés sobre los procesos celulares.Pharmacological aspects Conclusions and further directions Despite extensive preclinical and clinical investigations. and that antidepressant medications may act by correcting this dysfunction. Conséquences cellulaires du stress et dépression Il est reconnu que le stress met en jeu des circuits neuronaux distincts dans le cerveau et induit de nombreux changements au niveau cellulaire. Antidepressants are presently believed to exert their primary biochemical effects by readjusting aberrant intrasynaptic concentrations of neuromodulators such as 5-HT. como la serotonina y la noradrenalina. However. it has increasingly attracted research efforts that may result in new treatment strategies for the etiopathophysiology of psychiatric disorders. 180 .

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2004. Chua C. 2 . 1995. Brain Res. 183 . 2000. 2003.16:807-816. 2001. Swan L. Toni N. 109. Krey LC. Homeostatic maintenance in tree shrew hippocampal CA3 neuron excitability after chronic stress. Fuchs E. Czeh B. Falduto J. 2004 99. 100. Eur J Neurosci. In: Elsner N. Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress. Spine changes associated with long-term potentiation. Kinnunen AK. 2003. Neurosci Lett. Mol Cell Biol. 106. Eur J Neurosci. Eysel U. Seib LM. Lucassen PJ. How to use the optical fractionator: an example based on the estimation of neurons in the hippocampal CA1 and CA3 regions of tree shrews. Terry-Lorenzo RT. Daily injections alter spine density in rat medial prefrontal cortex. Fuchs E.21:6292-6297. Buchs PA. Eur J Pharmacol.14:161-166.86:736-748. Frasch ACC.6:1194-1200. Koenig JI. Hippocampus. 2001. Germany: Georg Thieme Verlag. Oliver CJ.10:596-604.Vol 6 . In press. McEwen BS. The Netherlands. Endocr Rev. Deslandes A.Fuchs and Flügge Dialogues in Clinical Neuroscience . Ackermann M. Alfonso J. Chronic psychosocial stress differentially affects apoptosis in hippocampal subregions and cortex of the adult tree shrew. Fuchs E. van der Hart MG. 101. Identification of genes regulated by chronic psychosocial stress and antidepressant treatment in the hippocampus. Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampus.Cellular consequences of stress and depression . 2004. Magarinos AM. 111. Fuchs E. 108. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis.19:659666. eds. Flügge G. Gleisberg M. Kole MHP. Fuchs E. 2001. Vollmann-Honsdorf GK. No. Pollevick GD. Chronic psychosocial stress induces morphological alterations in hippocampal pyramidal neurons of the tree shrew.and postsynaptic gene expression in the rat frontal pole. Fuchs E. Muller D. Brain Res Protocols. Cortisol treatment and psychosocial stress differentially alter the nuclear ultrastructure of hippocampal pyramidal neurons.22:4690-4701.673:275-282. Eur J Neurosci.337:29-32. Göttingen Neurobiology Report 1999. Vollmann-Honsdorf GK. 2003. University of Groningen. Elliott E.7:284301. 107. Matus A. Stuttgart.7:211-221. The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats. Hippocampus. 113. Keuker J. Sapolsky RM. 1999:524. PhD Thesis. Uno H. 2002. 112. 1999. 2002. Nat Neurosci. Kole MHP. CA3 pyramidal neuron correlates of the stress response analyses of form and function. 105. Czéh B. Activity-induced targeting of profilin and stabilization of dendritic spine morphology. J Neurosci.371:113-122. Vollmann-Honsdorf GK. 1986. Fuchs E. 102. Kole MH. Repeated variable prenatal stress alters pre. De Kloet ER. Shors TJ. 114. McEwen BS. et al Targeting protein phosphatase 1 (PP1) to the actin cytoskeleton: the neurabin I/PP1 complex regulates cell morphology. 2003. 103. Flügge G. J Neurochem. 104. 110. Bilbe G. Flügge G. Wellman CL.

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and the amygdala and hippocampus. These studies in postmortem brain tissue confirm and extend structural and functional neuroimaging studies that reveal volumetric and metabolic changes in the same frontolimbic brain regions in the same disorders. 2500 N State St. In parallel and often intersecting ways. in vivo neuroimaging studies have permitted significant insights into the general location of dysfunctional brain regions in depression. novel studies at the microscopic level support the contention that mood disorders are associated with abnormalities in cell morphology and distribution. and molecular features of depression are being unlocked by studies in postmortem brain tissue. including dorsolateral prefrontal. LLS SAS Dialogues Clin Neurosci. neuropathology Copyright © 2004 LLS SAS. Convergence of cellular changes at the microscopic level with neuroimaging changes detected in vivo provides a compelling integration of clinical and basic research for disentangling the pathophysiology of depression. Convergence of cellular changes at the microscopic level with neuroimaging changes detected in vivo provides a compelling integration of clinical and basic research for disentangling the pathophysiology of depression. Major depressive disorder (MDD) and bipolar disorder (BPD) have been examined in postmortem brain tissue by several laboratories in the past 6 years. postmortem brain. pharmacological. MS 39216.Clinical research Cellular abnormalities in depression: evidence from postmortem brain tissue Craig A. All rights reserved 185 . orbitofrontal. © 2004. and anterior cingulate cortex. PhD. Jackson. Novel studies at the microscopic level are establishing that the mood disorders are associated with abnormalities in cell morphology and distribution. anatomical substrates associated with the neuropathology of mood disorders have been revealed through both in vivo neuroimaging studies and morphological and neurochemical studies on postmortem brain tissue.umsmed. While neuroimaging studies have given significant insight into the gross morphological location of dysfunctional brain regions in depression. Miss. neuroanatomical. Regionally localized and cell type–specific changes in neuronal and glial cytoarchitecture recently identified in Author affiliations: The University of Mississippi Medical Center. PhD. Cell-counting studies report changes in the density and size of both neurons and glia in a number of frontolimbic brain regions. Stockmeier. uring the past two decades. cellular. Department of Psychiatry and Human Behavior. In addition to long-recognized neurochemical abnormalities in depression. Grazyna Rajkowska.dialogues-cns. In the past 6 years. orbitofrontal. including dorsolateral prefrontal. glia. bipolar disorder. USA (e-mail: cstockmeier@psychiatry. PhD During the past two decades. in addition to the long-recognized neurochemical abnormalities. and the amygdala and hippocampus. University of Mississippi Medical Center. USA Address for correspondence: Craig Stockmeier. and biochemical studies of postmortem brain tissue are permitting new insights into the pathophysiology of depression. and anterior cingulate cortex.org D Keywords: major depression. Box 127. The ultimate integration of these two research approaches will occur with premortem longitudinal clinical studies on well-characterized patients linked to postmortem studies of the same subjects. 2004. cell-counting studies have identified changes in the density and size of both neurons and glia in a number of frontolimbic brain regions. the neurochemical.edu) www. Department of Psychiatry and Human Behavior. neuron. Jackson.6:185-197.

but not in the primary sensory cortical regions such as somatosensory1 or visual cortex. Elsevier. reductions in neuronal density and size in some populations of cortical neurons have been independently reported. While MDD and BPD are clearly not neurodegenerative disorders. For both subjects. Note that neuronal sizes are smaller in layers II and III in the depressed subject than in the control subject. The concomitant decrease in the density of large neuronal cell bodies and increase in the density of small neuronal cell bodies suggests that neuronal shrinkage/enlargement or perhaps altered neuronal development. Note especially dramatic increases in the density of small neurons in layer II associated with significant reductions in the density of the largest neurons of this layer. For example. Neuronal abnormalities in mood disorders are not immediately evident. Photomicrograph depicting cell composition across the six cortical layers in rostral orbitofrontal cortex (upper left). marked reductions in neuron density are found in both MDD and BPD. 1999. Copyright © 1999. Changes in neuronal size and size-dependent density in layer II of rostral orbitofrontal cortex in a 73-year-old female with MDD as compared to a 71-year-old psychiatrically normal female control subject.4 However. Biol Psychiatry. Expanded printouts of cortical layers with neuronal cell bodies represented by equivalent diameter circles with the area measured for the individual neuron in its equatorial plane (right panel). Miguel-Hidalgo JJ. impaired neuroplasticity is associated with these mood disorders. rather than outright neuronal loss.1. It is not clear how factors such as genetic risk factors. and γ-aminobutyric acid (GABA) neurotransmitter systems in these disorders.5 These reductions in density of large-sized neuronal cell bodies are accompanied by increases in the density of neurons with smaller-sized cell bodies (Figure 1). Reprinted from reference 5: Rajkowska G.1-12 These abnormalities have been described in association cortices such as dorsolateral prefrontal. neurodevelopmental abnormalities. It remains to be determined whether the chronic administration of clinically effective therapeutic medications can reverse or even staunch histopathological changes in the mood disorders. and anterior cingulate cortex.Clinical research Selected abbreviations and acronyms AVP BDNF BPD CRH GABA GFAP HPA MDD NAA NMDA arginine-vasopressin brain-derived neurotrophic factor bipolar disorder corticotropin-releasing hormone -aminobutyric acid glial fibrillary acidic protein hypothalamic-pituitary-adrenal (axis) major depressive disorder N-acetylaspartate N-methyl-D-aspartate across all cortical laminae. is responsible for neuronal abnormalities in mood disorders. 186 .45:1085-1098. the progression of the disease. neuronal abnormalities at the microscopic level in mood disorders appear to be specific to frontolimbic cortical regions— observations in postmortem tissue that are consistent with in vivo neuroimaging studies of volumetric and metabolic alterations in the same frontocortical regions. The etiology of histopathological changes observed in postmortem brain tissue is unknown. the postmortem delay was less than 17 hours and fixation time was less than 10 months.3. or exposure to antidepressant or mood-stabilizing medications contribute to the abnormal neuronal and glial observations in mood disorders. et al. Control 200 I Depressed III IV V II 500 VI Alterations in neurons and glia in cerebral cortex In MDD and BPD. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. inasmuch as there is no significant reduction in the density of Nissl-stained neurons measured White matter Pia (µm) III Figure 1. glutamatergic.2 Thus. orbitofrontal. when neurons are assessed within individual cortical layers or in subgroups determined by size or immunohistochemistry. the density of large-sized neuronal cell bodies is reduced in cortical layers II to VI in the dorsolateral prefrontal and rostral orbitofrontal cortex in MDD. Wei J. Orbitofrontal cortex Cortical layers Pia I II II mood disorders complement and expand hypotheses of dysfunction within the monoaminergic.

are reported in specific cortical layers of the anterior cingulate and prefrontal cortices in four other studies.2.12 but not by all investigators. however.8 layers III and V of the dorsolateral prefrontal cortex3-5 and in layers III. In three of these investigations. visualization of neuronal dendritic trees in cerebral cortex using the Golgi silver impregnation method has not yet been conducted in subjects with mood disorders. dorsolateral prefrontal cortex. Our recent measurements of the density and size of calbindin-immunoreactive neurons in layer II and the upper part of layer III of the dorsolateral prefrontal cortex revealed a 43% reduction in the density of these neurons in MDD as compared to controls. the nuclei of these glial cells might enlarge in size and change in shape. in addition to density.15 Significant increases in glial size are observed in the dorsolateral prefrontal cortex in BPD4 and to a smaller degree in MDD. Studies looking at synaptic proteins in the anterior prefrontal13 and anterior cingulate cortex14 describe reductions14 or no changes13 in synaptic proteins in mood disorders. glial size is reported as increased. changes in the shape of glial nuclei to a less rounded conformation are detected in the dorsolateral prefrontal cortex in BPD. Glial reductions have been reported consistently by independent laboratories in the anterior cingulate cortex. As a consequence of increased metabolic demand.4. and orbitofrontal cortex in MDD and/or BPD subjects.12 In addition. may be closely related to in vivo clinical evidence suggesting that MDD is associated with decreased levels of GABA in cerebral cortex. glial cells that survive and are not damaged might be forced to play a larger role in supporting the metabolic needs of the surrounding neurons. in BPD. when data from familial and nonfamilial subgroups of patients were combined.10 The depression-related decrease in calbindin immunoreactive neurons.Postmortem abnormalities in depression . For example. Reductions in glial cell density.The estimation of glial cell number in this study is combined across all six cortical layers. However. suggest that some compensatory mechanisms may take place in mood disorders.The size of glial cell bodies (corresponding to glial cell nuclei in Nissl-stained material) has been estimated in several studies. as compared to control subjects.12 Two other studies. reductions in neuronal soma size have been observed in BPD by some. 2004 In BPD. a decrease in density of pyramidal neurons in cortical layers III and V4 and nonpyramidal neurons in layer II6 has been observed in the same cortical regions.7 but not by all studies. paralleled by an increase in the size of glial nuclei. a 24% to 41% reduction in the number of a general population of Nissl-stained glial cells is reported in the subgenual region of the anterior cingulate cortex (ventral part of Brodmann’s area 24) in a small subgroup of patients with familial MDD and familial BPD.1. a minor increase in the size of small nonpyramidal neurons was noted in the anterior cingulate cortex in BPD subjects. as compared to normal controls.Vol 6 .5 comparing these cohorts to psychiatrically normal control subjects.6. did not report significant changes in neuronal size in the anterior cingulate cortex. similar increases in glial size are noted in the anterior cingulate cortex in MDD.11 Another manifestation of neuronal pathology in cerebral cortex in mood disorders is the reduced size of neuronal cell bodies.Stockmeier and Rajkowska Dialogues in Clinical Neuroscience . It can be speculated that a decrease in the density of glial cells is indicative of a decrease in the number of normally functioning glial cells. appears to be affected in mood disorders. V.2 In a manner more subtle than in MDD.8 In another study.2. Calbindin immunoreactive neurons are known to colocalize GABA. in the anterior cingulate cortex7 and dorsolateral prefrontal cortex9 in BPD.8. 2 .5 orbitofrontal cortex. IV. No.8 Moreover. Systematic studies of dendritic trees and synaptic contacts in prefrontal and cingulate areas are warranted to shed light on the possible etiology of smaller neuronal cell bodies in mood disorders. The most consistent cell abnormality described in mood disorders has unexpected finding of prominent reductions in the density and number of glial cells. More recently.6 Factors leading to a reduction in the size of neuronal soma are not known. 187 . Smaller soma size may be related to smaller dendritic trees and/or abnormal morphology of synaptic contacts.4 Reductions in glial density.1. calbindin.1 However.1. and no information is provided on laminar specificity of glial loss. Glial cell size and shape.5 in mood disorder patients. the reductions are not found.3.3-5 whereas two other studies find glial size to be unchanged in MDD or BPD. and VI of the caudal orbitofrontal cortex. These glial reductions are observed in layer VI of the supragenual anterior cingulate cortex. in the dorsolateral prefrontal cortex. This last observation coincides with reports on reductions in the density of layer II nonpyramidal neurons that are identified with an antibody against the calciumbinding protein. At the same time.5 and anterior cingulate cortex. however. decreases in laminar neuronal densities have also been reported in the dorsolateral prefrontal cortex4 and anterior cingulate cortex. which colocalize GABA. Smaller soma sizes have been reported in subjects with MDD.1.

In addition. as compared with normal control subjects. and normal control subjects. there is a significant decrease in the mean soma size of pyramidal neurons in depressed subjects. In most of the depressives. On the basis of covariate analyses.19-26 but not in other studies. CA1 and CA4. Glial pathology in depression appears to extend beyond the frontal cortex to the hippocampus. Studies using MRI demonstrate reduced volume of the hippocampus in subjects with MDD or a history of MDD.25. Glial cell pathology in mood disorders does not appear to be universally noted throughout the cerebral cortex.26 Few studies have structurally examined the postmortem human hippocampus in depression. or suicide. cell density is significantly increased in MDD.27-29 It appears that hippocampal atrophy is preferentially seen in older. recurrently depressed subjects or subjects who are refractory to antidepressant medications.1 Recent reports suggest a lack of marked glial pathology in the supragenual part of the anterior cingulate cortex.17 studies report no significant cell loss in any hippocampal region in any of the subject groups. smoking. Cellular integrity and apoptosis have been examined in the hippocampus in subjects with depression.30 Decreases in astrocytic immunoreactivity for cellular GFAP and the neuron-specific phosphoprotein B50 (or GAP-45) were detected in CA1 and CA2 in depression.31 The authors suggest that apoptosis may only be a minor contributor to volume changes in the hippocampus in depression.12 the entorhinal cortex in BPD and MDD. Other reports of hippocampal changes in mood disorders identify a significant decrease in the density of nonpyramidal neurons in the CA2 region and a reduction in reelin-positive cell density in the hilus in subjects with BPD.5 Glial pathology in mood disorders has yet to be systematically studied in subcortical structures. there was evidence for a slight increase in fragmented DNA associated with apoptosis and necrotic neuron death detected in the dentate gyrus. antidepressant drug prescription in the last month of life. tissue pH.17 or the most rostral part of the orbitofrontal cortex in MDD (corresponding to the transitional cortex between Brodmann areas 10 and 47).32. A recent study of the hippocampus in a large number of subjects with MDD Alterations in neurons and glia in the hippocampus Preclinical and neuroimaging studies have implicated the hippocampal formation in the pathophysiology of MDD.16 may be another factor in the etiology of enlarged glial cells in depression. In the granule cell layer of the dentate gyrus. these 188 . brain weight.18 Evidence for an interaction between the hippocampus and depression comes from magnetic resonance imaging (MRI) studies examining the volume of the hippocampus. Changes in glial cell density or number are not found in the sensorimotor cortex in either MDD or BPD. However.30. while patterns of reactive astrogliosis and synaptic reorganization proteins are significantly altered in only some hippocampal regions in depression.36 Representative photomicrographs are presented in Figure 2. Recently.The substantial increases noted in neuronal packing density and decrease in neuronal soma size detected in postmortem tissue may be related to the decrease in hippocampal volume noted by some in MDD.Clinical research Glutamate-induced swelling of astroglia. steroid-treated subjects.31 Using semiquantitative methods. postmortem interval. Prominent abnormalities in the CA regions and dentate gyrus are found in subjects with MDD. age. In addition. as compared with normal control subjects. reported in animal cell cultures. plasticity within the hippocampal formation may be involved in neurobiological responses to stress and to antidepressant drug action.35 Neuronal and glial cell packing density and soma size were estimated recently in Nissl-stained sections including the hippocampal subfields in 16 subjects with MDD and 16 age-matched normal control subjects.34. Only one report suggests that glial pathology extends to limbic subcortical regions. the main findings of increased neuronal density and decreased neuron soma size in depression are not significantly altered when taking into consideration such factors as gender.There is a significant increase in the mean density of pyramidal neurons in depressed subjects. hippocampal volume is generally considered to be significantly decreased only in older depressed subjects with multiple episodes of depression. hippocampal volume and function was assessed over the course of illness in younger patients with MDD.26 Recollection memory is diminished in subjects with either a first episode or multiple episodes of depression.33 Two other studies conducted on the postmortem hippocampal formation in a small sample of subjects with BPD reveal a decrease in the density and size of nonpyramidal neurons in the CA2 region and some disorganization in neuronal clusters in layers II and III of the entorhinal cortex. with a significant reduction in glial number noted in the amygdala in subjects with MDD and unmedicated subjects with BPD.

In an immunohistochemical study of subjects with MDD and others with BPD or schizophrenia. Cresyl violet–stained coronal section from a 54-year-old male (23-h postmortem interval). Neuropil consists of the lattice of glial cells and their processes. dendritic spine complexity. No. Note the intensely stained granule cell layer of the dentate gyrus (DGgr) in A and B.Stockmeier and Rajkowska Dialogues in Clinical Neuroscience . 2 . Neurons and glial nuclei of the granule cell layer of the dentate gyrus are depicted in D by the large black arrows and black arrowheads. The hypothesis of neuropil reduction in the hippocampus in MDD is supported by other postmortem studies revealing a decrease in dendritic spine density on neurons and diminished arborization of apical dendrites in the subiculum in a small group of mixed subjects with bipolar disorder or depression37 and decreased levels of synaptic proteins found in CA4 in BPD. The scale bars in A and C are 750 µm and 25 µm. Figure 2. Dwivedi et al40 observed a significant reduction in mRNA and protein levels of BDNF in hippocampus as well as dorsolateral prefrontal cortex in suicide victims with either MDD or other psychiatric disorders. Alterations in neurons and glia in subcortical structures The search for morphological abnormalities in subjects with mood disorders has been less intense in subcortical structures than in cerebral cortical regions. In a recent study.Postmortem abnormalities in depression . and glial processes.39 Chen et al39 provide the first evidence beyond rodent studies that chronic antidepressant drugs upregulate the expression of BDNF in the human hippocampus. locus ceruleus. the decrease in expression of BDNF occurred regardless of antidepressant treatment. Brightfield photomicrographs of coronal sections of the postmortem human hippocampal formation. respectively. dendrites. dorsal raphe nucleus.36 In MDD.41-43 Successful clinical treatment (or even the use of placebo) in depression was associated with an increase in metabolism in prefrontal cortex and a decrease in metabolism in hippocampus. the diminished volume of the hippocampus noted by some in depression may be critically determined by a loss in neuropil including dendritic branching. the immunoreactivity of BDNF.38 Thus. and alterations in these factors might be related to changes in cell density and volume in depression. An adjacent coronal section processed by Timm staining. The different pattern of neuronal pathology in the frontal cortex (decrease in density) and hippocampus (increase in density) suggests unique involvement of these brain regions in the neuropathology of depression. It remains to be determined whether alterations in BDNF are related to increases in the packing density of neurons in the hippocampal formation or prefrontal cortex. and may be related to decreases in hippocampal volume noted by neuroimaging studies in MDD (see above). The different pattern of density change noted in depression in the hippocampus in contrast to frontal cortical areas may be related to a unique reduction in neuropil in the hippocampus in depression. and proximal axons surrounding neuron cell bodies. Pyramidal neurons and glial nuclei of CA3 are highlighted in C by the large white arrows and white arrowheads. Other evidence of dissimilarities between prefrontal cortex and hippocampus has been reported in MDD. B. respectively. as measured by optical density. increases in the packing density of glial cells detected in postmortem tissue suggests a potential reduction in surrounding neuropil (see above). A. There is preliminary evidence that BDNF in the human hippocampus may be regulated by chronic treatment with antidepressant medications. The expression of brain-derived neurotrophic factor (BDNF) has been measured in the hippocampus of subjects with depression. 2004 and aged-matched normal control subjects reports a significant increase in the density of glial cells in all hippocampal CA subfields and the granule cell layer of the dentate gyrus.Vol 6 . is upregulated in the dentate gyrus and hilus only in subjects taking antidepressant medications (regardless of psychiatric diagnosis). Only a few studies in postmortem brain tissue on a relatively small number of subjects have attempted to estimate the number of neurons in such subcortical structures as hypothalamus. In the Dwivedi et al40 study. and the clear demarcation in B between hippocampal subfields CA2 and CA3 afforded by the Timm staining. respectively. and amyg- 189 .

56 These cortical regions also exhibit abnormal cell density and size in cell-counting studies of postmortem tissue. Some of the cellular abnormalities detected postmortem in cortical and subcortical structures in MDD and BPD may be related to disruption of monoaminergic transmission in depression. the neurons of which give rise to the frontal circuits critical for higher cognitive and limbic functioning. compared to normal controls. orbitofrontal cortex.49 Subtle structural abnormalities have been reported in mood disorders in the monoaminergic brain stem nuclei. increases in CRH mRNA.58 Expression of another component of serotonin neurotransmission. Another study in a larger number of subjects found no differences in the number of pigmented neurons in the locus ceruleus between subjects with MDD (most were suicides) and control subjects. CRH immunoreactivity is increased in the locus ceruleus and pontine dorsal and median raphe nuclei. Arango et al51 report fewer pigmented neurons within the rostral locus ceruleus. Moreover.44-52 Results of these subcortical histopathological studies are somewhat inconsistent. In fact. decreased number and density of nitric oxide synthase–containing neurons in the paraventricular hypothalamic nucleus are described in a small group of subjects with either MDD or BPD.46. as compared to normal controls. insula and dorsolateral prefrontal cortex. the serotonin transporter.47 These findings of increases in specific immunoreactive neurons are consistent with the evidence of activation of the hypothalamicpituitary-adrenal (HPA) axis in some subsets of depressed patients. For example.59 The serotonin-transporter deficit may be related to the pathology of layer VI neurons reported in the same cortical layer by postmortem cell-counting studies in depression. Increases.48 On the other hand. alterations in neuronal density and size have been found in the dorsolateral prefrontal. An increased number and density of tryptophan hydroxylase immunoreactive neurons is observed in the dorsal raphe nucleus of suicide victims with MDD compared with controls. subtle neuronal abnormalities reported by some studies in the monoaminergic brain stem nuclei 190 .44. or no change in the cell number or density are reported in the hypothalamus and brain stem nuclei in depressed subjects.59. Stereological investigation of specific types of hypothalamic neurons reveals an increase in the numbers of arginine-vasopressin (AVP)–immunoreactive neurons. and somatic symptoms exhibited by subjects with MDD or BPD. and in the number of CRH neurons colocalizing AVP are also found in depressed patients. cognitive. anterior cingulate cortex. including medial temporal cortex. However. the major sources of serotonin (dorsal raphe nucleus) and norepinephrine (locus ceruleus) projections to the cerebral cortex. decreases. and anterior cingulate cortex. further evidence of dysfunction in limbic circuits in depression.45 Moreover.53. the authors find that radioligand binding to serotonin-1A receptors is decreased in medication-free subjects with MDD in several cortical regions.55 Subtle neuronal alterations are also reported in the hypothalamus and hippocampus. is also decreased in the dorsolateral prefrontal and ventral/orbitofrontal cortex in postmortem brains from depressed suicide victims.57 In a neuroimaging study. and corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus in subjects with BPD or MDD.17 These postmortem findings suggest that some changes in the morphology of hypothalamic neurons and brain stem neurons may take place in mood disorders. orbitofrontal.50 In suicide victims. oxytocin-expressing neurons. cellular changes found in superficial layers of the prefrontal cortex in depressed subjects may be related to alterations in serotonin-1A receptors in superficial layers of cortex in suicide victims.54 No changes in neuronal densities were detected in amygdala in subjects with either MDD or BPD.Clinical research dala. the temporal pole.52 Although the number of neurons in the locus ceruleus does not appear altered in MDD. Functional implications of pathological changes in neural circuits Morphological abnormalities detected postmortem in mood disorders are most likely related to dysfunction of neural circuits regulating emotional. Studies in postmortem brain tissue identify alterations in serotonin and norepinephrine receptors and transporters in the dorsolateral prefrontal cortex and ventrolateral/orbitofrontal cortex in brains from suicide victims with or without clinical depression. future studies employing stereological techniques and a larger number of subjects are required to determine the exact pathology in these regions in depression.60 Detailed laminar analysis of the density of serotonin transporter–immunoreactive axons reveals that this deficit in depression is localized in cortical layer VI of the dorsolateral prefrontal cortex.

Neuronal pathology detected in cortical layers III. microglia. Nissl staining only reveals morphological features of glial cell bodies and not glial cell processes. In contrast. the density of pyramidal neurons is selectively reduced in the dorsolateral prefrontal cortex in subjects with BPD. and VI and give rise to long projections to other cortical associational regions (layer III). myelin formation (oligodendrocytes). The crucial role of glial cell types in brain function is currently being reevaluated. glutamate. as well as levels of tyrosine hydroxylase in the locus ceruleus. as well as reductions in the density of nonpyramidal neurons in layer II of the anterior cingulate cortex suggest deficient GABAergic neurotransmission.64 The layer-specific changes in neuronal density and size identified in mood disorders implies that both inhibitory local circuit neurons and excitatory projection types of cortical neurons may be involved in the neuropathology of mood disorders. Nonpyramidal inhibitory neurons using GABA are localized mainly in cortical layer II and establish local cortico–cortical connections within or between adjacent functional columns of cortical cells. and astrocytes. pyramidal glutamatergic excitatory neurons reside predominantly in cortical layers III. One study of suicide victims. V. 2 . drugs that reduce glutamatergic activity or glutamate receptor–related signal transduction may also have antimanic effects. and the formation of synapses and neurotransmission. and dopaminergic neurons that project axons to prefrontal and anterior cingulate cortex. and GABA neurotransmitter systems are involved in the pathophysiology of these disorders.66 Reductions in size and density of layer II neurons in the orbitofrontal and dorsolateral prefrontal cortex. in the dorsolateral prefrontal cortex implicates astrocytes in the overall glial pathology in MDD.Vol 6 . depression.63 and dopaminergic receptors and transporters in the amygdala. These findings in postmortem brain tissue coincide with an in vivo proton magnetic resonance spectroscopy study in the anterior cingulate cortex revealing a reduction in glutamate levels in depression. Glial cells are composed of distinct populations of oligodendrocytes. In addition to their traditional roles in neuronal migration (radial glia).68 Although no significant group dif- 191 . Most nonpyramidal neurons in cortical layer II colocalize GABA and recent clinical evidence suggests that MDD is associated with decreased levels of cortical GABA. the localization of morphological abnormalities in the mood disorders occurs in prefrontolimbic circuits that are likely to regulate emotional.11 In summary.66 Depression-related decreases in glutamate levels or the density of glutamatergic pyramidal neurons may alter in cortex and elsewhere the glutamatergic recognition site and its coupling to the NMDA receptor complex.Postmortem abnormalities in depression . Moreover.67 Interestingly. some of whom were diagnosed with MDD. and somatic symptoms in depression. V.52.15 The three distinct glial cell types cannot be identified in the previously mentioned studies as those tissues were stained for Nissl substance and such staining does not distinguish reliably between types of glial cells. The observation in the mood disorders of neuronal pathology in specific cortical layers gives support to the hypotheses that the monoamine. It remains to be determined whether the cellular pathology is the reason for. and thalamus (layer VI).65 There is increasing preclinical and clinical evidence that antidepressant drugs directly or indirectly reduce the function of N-methyl-D-aspartate (NMDA) glutamate receptors.4 further confirming the pathology of glutamatergic neurons in mood disorders. recent immunohistochemical examination of glial fibrillary acidic protein (GFAP). reveals changes in the glutamatergic recognition site and its coupling to the NMDA receptor complex in the anterior prefrontal cortex. serotonergic. Functional implications of glial abnormalities in depression The glial cells analyzed in the above studies do not represent a homogeneous population of cells. Postmortem neurochemical studies in MDD report alterations in noradrenergic α2-adrenergic receptors and the norepinephrine transporter.62 serotonin-1A receptors in the midbrain dorsal raphe nucleus. On the other hand. cognitive. striatum (layer V).Stockmeier and Rajkowska Dialogues in Clinical Neuroscience . and inflammatory processes (astrocytes and microglia). and VI of the dorsolateral prefrontal cortex and anterior cingulate cortex in MDD may be associated with the pathology of excitatory pyramidal neurons within these laminae that use glutamate as their neurotransmitter. 2004 suggest dysfunction of monoaminergic projections originating from the brain stem neurons and terminating in frontolimbic cortical regions. a marker of reactive astroglia. neuronal metabolism. or the consequence of.61. No. glia (predominantly astrocytes) are now thought to provide trophic support to neurons. It is likely that the functions and morphology of cortical neurons are affected by alterations in the functional state of noradrenergic.

there is a significant correlation between age and GFAP immunoreactivity among subjects with MDD.75 Moreover. unpublished observation) indicate that the levels of GFAP protein in the same area of the dorsolateral prefrontal cortex are also reduced in these young (D) but not old (C) subjects with major depression as compared to age-matched control subjects. For example. Elsevier. 2000. 192 . as compared to young control subjects and older (46 to 86 years old) subjects with MDD (Figures 3A and 3B). Reproduced (A and B) from reference 68: Miguel-Hidalgo JJ.73 Oligodendrocytes may also be involved in the cellular pathology of depression. Clinical evidence confirms that late-onset depression (first depressive episode when older than 50 years) differs from early-onset depression by its etiology. the involvement of GFAP expression in early. phenomenology. and that GFAP levels are positively correlated with age at the time of death and with the age of onset of depression.74. another protein in brain.69 Thus. and GFAP immunohistochemistry A 100 GFAP protein level C B 100 r=0. further immunohistochemical and molecular studies are needed to definitively determine which specific glial cell types are compromised in BPD and whether the same or different types of glial cells are involved in the pathology reported in MDD. there are ultrastructural changes in oligodendrocytes and there is a reduction in the density and immunoreactivity of these cells. Note that the level of actin. Baucom C.0005 Area fraction (%) Area fraction (%) 80 80 60 60 Controls (70) Depressed (73) 40 40 D GFAP 20 20 0 0 20 Actin 30 40 50 60 70 80 90 Controls Depressed Depressed age (years) Controls (27) Depressed (34) Figure 3. This subgroup of younger adults with MDD also had a shorter duration of depression and most of these subjects were suicide victims. in addition to changes in size and shape. when the entire group of MDD (young and old) is compared with normal controls.890 P<0. and cerebrovascular pathology. Dilley G.versus late-life depression differs because the underlying pathophysiology in early-life depression is different from that in late-life depression.68 Reductions in the glial fibrillary acidic protein (GFAP) immunoreactive astroglia are found in a subgroup of young adults with major depression as compared to aged-matched control subjects and older subjects with major depression (A) and these reductions are correlated with the age of the subjects at the time of death (B). In both the dorsolateral prefrontal and anterior frontal cortex in subjects with BPD or MDD. Recent preliminary observations (Si et al. might be related to the dysfunction of monoamine and glutamate systems reported extensively in depression. et al. Reductions in glial number and density. key oligodendrocyte-related and myelin-related gene expression is reduced in the dorsolateral prefrontal cortex in BPD. An illustration of the pathology of glial cells found in the dorsolateral prefrontal cortex in MDD. Copyright © 2000. Biol Psychiatry. ion channels.5.48:861-873.70-72 Alterations in GFAP in both BPD and MDD are also suggested by a proteomic study in which different forms of GFAP proteins displayed disease-specific abnormalities. Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder. is unchanged in a depressed subject as compared to the control.76 While these results are intriguing.Clinical research ferences in the packing density of GFAP-reactive astrocytes are present in this study. A significant reduction in the population of reactive astroglia is found in a small subgroup of young (30 to 45 years old) subjects with MDD. astrocytes express virtually all of the receptor systems. Recent observations from our laboratory confirm that the levels of GFAP protein are also reduced in these young adults with MDD as compared to age-matched control subjects (Figures 3C and 3D).

In two of our studies. Unfortunately. To measure the entire volume. has yet to be established. In one study where the total cell number was estimated in the subgenual cortex.56 Some of the critical issues to be considered when interpreting the studies of postmortem brain tissue include the psychiatric status of the subject at the time of death and the underlying psychiatric disorder. There have been no systematic studies on the effect of antidepressant and mood-stabilizing medications 193 .80 and the neural lobe of the pituitary.15 Thus. with consequences that may be detected by functional neuroimaging. a precise link between cell loss and atrophy. Other frequent drawbacks to studies of postmortem brain tissue include low numbers of subjects per cohort. however. evolving criteria used to establish psychiatric diagnoses. have prevented the estimation of a total tissue volume and. the results obtained with this cohort must be cautiously interpreted since the majority of living individuals with depression do not attempt or commit suicide.77.Vol 6 . The question of whether cell abnormalities can be attributed to the effect of therapeutic medications is open to debate.Postmortem abnormalities in depression .Stockmeier and Rajkowska Dialogues in Clinical Neuroscience . observed in the animal brain. A mounting body of data suggests that treatment with antidepressant or mood-stabilizing medications regulates neuronal survival and also influences neurogenesis.83 so that sampling is confined to the region within these borders. or the time of fixation of the tissue.While suicide makes tissues available for most postmortem studies of depression. Statistical analyses conducted in all of the above morphometric studies yielded no significant correlation between cell density or size and any of these confounding variables. longitudinal clinical studies on wellcharacterized patients should be linked to subsequent postmortem studies of the same subjects.84 There are unquestionable limitations to the use of postmortem brain tissue in studying the mood disorders. the cause of death of the subjects (suicide or by other means).82. total cell number. postmortem delay. norepinephrine. No. Pharmacologically induced increases in neurogenesis in adult rodent brain have been reported in two independent studies. the regional and hemispheric localization of the brain regions being studied. Furthermore. Astroglia regulate the levels of extracellular glutamate and thereby protect neurons in vitro from cell death and provide energy for neurons. Ideally. that some of the cellular alterations in mood disorders are related to prior treatment with antidepressants and lithium (for further discussion see reference 85). consequently. and the mechanisms underlying the regulation of neurogenesis and glial proliferation have to be further investigated. in most studies of mood disorders in postmortem tissue. or inadequate expertise in cytoarchitectonic delineation of individual brain regions. limited availability of the complete tissue region.5. Moreover. and the presence and duration of treatment with a psychotropic medication. a loss of glial but not neuronal cells has been demon- strated in familial mood disorders. the exact borders of the studied region have to be established. or dopamine neurotransmission. observed in the postmortem human brain. whether these increases represent a protective or compensatory effect of these medications. Astrocytic pathology in MDD may indirectly promote glutamate-mediated neuronal excitotoxicity. there is evidence that treatment with lithium induces an increase in the astrocytic protein GFAP in rodent hippocampus79. It cannot be ruled out. the possible inclusion of subjects with concurrent psychoactive substance use disorders.1 Glial reductions reported in this study may in fact reflect a true loss of glial cells since the neuroimaging studies in the same cortical region show a reduction in the volume of gray matter.81 However. In the mood disorders. the postsynaptic monoaminergic receptors distributed on glial cell bodies and processes may play a role in serotonin.36 enough depressed nonsuicide subjects were available to tentatively determine that the main findings of these studies appear to persist regardless of whether the depressed subjects died by suicide or natural causes.78 Moreover. 2 . 2004 transporters found in neurons. For the estimation of a total number of neurons or glia in a particular brain region. as well as limitations in reliably distinguishing cytoarchitectonic borders of a studied region. it is essential that the total volume of a studied area be calculated. the alterations in cell density and size are likely to be related to the disorder itself and not to the age of subjects at the time of death. and medication-induced production of new cells. Limitations in postmortem pathology studies in mood disorders Postmortem studies cannot yet clearly define whether a true loss of cells underlies prominent reductions in cell density and size detected in mood disorders. It is important to seek to control for the potential effects of suicide on postmortem biological observations in depression. astroglia are the primary sites of glutamate uptake by glial transporters and are important in regulating NMDA receptor activity. whether “control” subjects were psychiatrically normal.

These NAA measures reflect neuronal integrity and metabolism whereas changes in glutamate-glutamine-GABA metabolites may reflect changes in membrane structure. recent magnetic resonance spectroscopic studies of nonhuman primates exposed to early life stressors or repeated stressors also reveal a significant decrease in NAA. The precise region. colocalization of cellular changes detected in postmortem tissues with in vivo neuroimaging findings proves that postmortem studies provide an important interface between clinical and basic research in unraveling the neuroanatomical substrates of depression. and size observed in postmortem tissues at the microscopic level. which may be related to alterations in cell number.91 Such increases in NAA are found in a number of regions including frontal cortex. anterior cingulate cortex. Postmortem studies in depression also indicate that while MDD and BPD are clearly not neurodegenerative disorders. Interestingly. or the results of treatment with therapeutic medications. density. metabolic. and Public Health Service Grants MH60451. most likely due to an insufficient number of treated versus untreated subjects. the above data suggest that structural and metabolic alterations observed in vivo may be related to alterations in cell viability. and glutamate content. glial functions. hippocampus. may be related to alterations in cell number. preliminary microarray studies of gene expression in postmortem brain tissues from subjects with mood disorders confirm that the dorsolateral prefrontal and anterior cingulate cortex are sites of pathology in mood disorders. cell density. and related volumetric changes.Clinical research on cell number and morphology in the postmortem human brain.and layer-specific alterations in neuronal and glial architecture observed in mood disorders are consistent with the hypotheses of specific dysfunction in monoamine. Abnormal regulation of glucose metabolism. MH61578. For the first time. but not all. and amygdala. neuroimaging studies reveal volumetric. MH67996. Together. and P20 RR17701. and GABA neurotransmitter systems in these disorders. in glutamate-glutamine-GABA metabolites in the adult anterior cingulate cortex of these animals were also observed 10 years after the stressors. Conclusion Cellular abnormalities in mood disorders are observed in the dorsolateral prefrontal cortex. and high-energy phosphate metabolism are observed in the prefrontal and temporal cortex. high-resolution magnetic resonance spectroscopy in unmedicated subjects with BPD report decreased N-acetylaspartate (NAA) levels bilaterally in the hippocampus89 and in the dorsolateral prefrontal cortex. regional cerebral blood flow. It remains to be fully elucidated to what extent these findings represent neurodevelopmental abnormalities.88 Neuroimaging studies that examine neurochemical changes in the living brain provide further support for the hypothesis that mood disorders are associated with changes in cell viability and function. NAA is regarded as a measure of neuronal viability and function. postmortem cell-counting studies in mood disorders have established that MDD and BPD are brain diseases with unique pathological alterations in neuronal and glial cells. In these same brain regions. Structural neuroimaging studies in mood disorders provide evidence of modest but intriguing volumetric changes that suggest cell loss and/or atrophy.86 Some studies. The studies reviewed above undeniably prove the usefulness of postmortem tissue in unraveling the microscopic anatomical substrate of depression. report enlargement of the lateral and third ventricles in mood disorders87 that may be indicative of atrophy of surrounding cortical and subcortical regions. itself. basal ganglia. and size. therapeutic doses of lithium increase levels of NAA in the brain of subjects with BPD. It is unknown whether the cellular changes observed postmortem in mood disorders can be reversed by antidepressant and mood-stabilizing medications. In contrast. Although molecular and genetic mechanisms associated with depression are yet to be unraveled. progression of the disorder. glutamate.92 Increases 194 .90 as compared to healthy controls. and therefore the changes in NAA levels seen in BPD strongly implicate alterations in neuronal viability.94 ❏ The authors acknowledge the support of the National Alliance for Research on Schizophrenia and Depression. biochemical changes (in glucocorticoid or trophic factors levels) accompanying repeated disease episodes. which. orbitofrontal cortex. and are localized almost exclusively in the gray matter. Functional neuroimaging studies in MDD and BPD lend further support to physiological abnormalities in cortical and subcortical frontolimbic regions. The NAA decrease in the animals exposed to repeated stressors was normalized by chronic treatment with the antidepressant tianeptine. For example.93. MH63187. and neurochemical alterations in subjects with mood disorders. and amygdala in mood disorders. Moreover. these disorders are associated with impaired cellular neuroplasticity and resilience.

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J Neurochem. 2000.63:617-624. Chronic administration of lithium chloride increases immunodetectable glial fibrillary acidic protein in the rat hippocampus. Accessed 5 May 2004. 2 . et al. et al. Society for Neuroscience. Miguel-Hidalgo JJ. GFAP expression is reduced in the dorsolateral prefrontal cortex in depression. 2002:363. Mann JJ. Evans S. Clinical and phenomenological comparisons of late-onset and early-onset depression. Available at http://sfn. Boston.57:729-738. Achaval M. 58.47:305-313. 2000. 65. Brain Res. Blumberg H. Callicott JH. Schenck JE.46. 70. Du F. 2000. Rajkowska G. Rajkowska G. Heun R. Klimek V. Putz B. Vawter M. Widdowson PS.8. A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. J Neurochem. 60. 2002. 80. J Neurosci. Program No.52:735-746. 2001. et al. Relationship of age. Rajkowska G. December 8-12. Uranova N. Subgenual prefrontal cortex abnormalities in mood disorders. et al. Tate DL. Biol Psychiatry. oculomotor. 1990. The importance of a human 3D database and atlas for studies of prefrontal and thalamic functions. 2003.20:91049110. 79. Austin MC.1275-1286. Santos P. and cell proliferation are prevented by antidepressant treatment with tianeptine. Biol Psychiatry. Online. et al. et al. New Orleans.8:324-332. et al. de Vos K. Bissette G. Nature. Am J Psychiatry. 66. The Postmortem Brain in Psychiatric Research.18:7394-7401. 2003. Dilley GE. 640. Simpson JR Jr. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Dilley G. Tupler L. Sachs N. Nestler EJ. Program No. “prefrontal” and “limbic” functions. Auer DP.and late-onset depression in the elderly by their lifetime symptomatology. et al. et al. et al.16:361-372. Hays J. Wise A. et al.Postmortem abnormalities in depression . 63. et al. Watanabe T. Saltzman A. Ordway G. Soares J. 1997. et al. Prog Brain Res. Ordway GA. Basal ganglia-thalamocortical circuits: parallel substrates for motor. Klimek V.57:174180. Belmaker RH.85:119-146. Stockmeier CA.48:813-829. Lithium treatment causes gliosis and modifies the morphology of hippocampal astrocytes in rats. et al. Variability in locations of areas 9 and 46. Price J. Huang YY. 2002. La. Scientific Abstract 36. 78. et al. 2000. 74. Biol Psychiatry. Neuropsychopharmacology. 64. 2000. Nowak G. 2000. et al. Goldman-Rakic PS. Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men.675:157-164. 1995. Prog Brain Res. Cytoarchitectonic definition of prefrontal areas in the normal human cortex: II. 84. Mol Psychiatry. 89. 72. Whitehead R. Neuronal pathology in the hippocampal area of patients with bipolar disorder. Tomita H. The Stanley Neuropathology Consortium. bipolar affective disorder and major depression. 2003. Arch Gen Psychiatry. 1995.48:1-8. Society for Neuroscience. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. 90. 33rd Annual Meeting.19. Proliferation of glial cells in vivo induced in the neural lobe of the rat pituitary by lithium. Crutcher MD. 92. Levine S.com/itin2003/. Underwoood MD. Biol Psychiatry. Monoamine receptors in postmortem brain: do postmortem brain studies cloud or clarify our understanding of the affective disorders. Distinction of early. 56. 88. Neuroimaging studies of mood disorders. Sargent PA. et al. et al. Orlovskaya D. Arch Gen Psychiatry. et al.98:12796-12801. 67. Kraft E. Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims. Dilley GE.48:861-873. 93. 91. 2000. Janosky JE. Glutamate and GABA systems as targets for novel antidepressant and mood. Biol Psychiatry.28:1328-1335. Disease-specific alterations in frontal cortex brain proteins in schizophrenia. Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Lesser IM. 152:785-788. 2000. Meta-analyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders. Gubbi AV. Rocha E. Decreased numerical density of oligodendroglial cells in postmortem prefrontal cortex in schizophrenia.386:824-827. 2000.126:357-368.

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Many of the regions affected by these structural abnormalities show increased glucose metabolism during depressive episodes. reductions in neurons in MDD and BD. physiological. Postmortem histopathological studies of these regions have shown abnormal reductions of synaptic markers and glial cells. neuroimaging abnormalities. hippocampus. © 2004. and emotional experiential responses to stressors. Some of the subject samples in which these metabolic abnormalities have been demonstrated were also shown to manifest abnormally elevated stressed plasma cortisol levels. bipolar disorder. which depends upon interactions between elevated glucocorticoid secretion and N-methyl-D-aspartate (NMDA)–glutamate receptor stimulation. striatum. 15K North Dr. because the regions affected by structural abnormalities in mood disorders are known to play major roles in modulating the endocrine. T Keywords: major depressive disorder. Mood and Anxiety Disorders Program.nih. NIH NIMH/MIB. these data support other evidence that excitatory amino acid transmission is elevated in limbic-cortical-striatal-pallidal-thalamic circuits during depression. and. and preliminary evidence suggests they may in some cases arise prior to the onset of depressive episodes in subjects at high familial risk for MDD. behavioral. 2004. 15K North Dr. These structural imaging abnormalities persist across illness episodes. Some mood-stabilizing and antidepressant drugs that exert neurotrophic effects in rodents appear to reverse or attenuate the gray matter volume abnormalities in humans with mood disorders. Md. These neurotrophic effects may be integrally related to the therapeutic effects of such agents. The co-occurrence of increased glutamatergic transmission and cortisol hypersecretion raises the possibility that the gray matter volumetric reductions in these depressed subjects are partly accounted for by processes homologous to the dendritic atrophy induced by chronic stress in adult rodents. All rights reserved Address for correspondence: Wayne C. amygdala.dialogues-cns. Drevets. USA Copyright © 2004 LLS SAS.gov) 199 www. In other cases. parahippocampal gyrus. Drevets. recurrent mood episodes. USA (e-mail: drevetsw@intra. Bethesda.nimh. NIH NIMH/MIB. and receptor pharmacological correlates of mood disorders have enabled significant advances toward delineating the neurobiological correlates of mood disorders. Drevets. Because the glucose metabolic signal is dominated by glutamatergic transmission. MD. LLS SAS Dialogues Clin Neurosci. the availability of tools allowing noninvasive assessment of the human brain proved critical to illuminating the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD).6:199-216. Mood and Anxiety Disorders Program. in rare cases.Clinical research Neuroplasticity in mood disorders Wayne C. autonomic. MSC 2670. the magnitude of abnormality is reportedly correlated with time spent depressed. MD. MD 20892-2670. The results of studies applying imaging technologies and postmortem studies have Neuroimaging and neuropathological studies of major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of brain structure in areas of the prefrontal cortex. postmortem studies Author affiliations: Wayne C.org . Bethesda. neuroplasticity. MD he recent development of neuroimaging technologies that permit in vivo characterization of the anatomical. Because these conditions were not associated with gross brain pathology or with clear animal models for spontaneous. and raphe nucleus.

6-10 Abnormalities of gray matter volume and histology have now been identified in several brain structures using volumetric MRI and postmortem neuropathological assessments. For example. elderly MDD subjects with a late age at depression onset have an elevated prevalence of MRI signal hyperintensities (in T2-weighted MRI scans. Thus. Many limitations in the sensitivity in reproducing findings across studies appear to be accounted for simply by technical issues of image acquisition and/or analysis. in some cases.1 In other cases.5 For example. in cases where they are evident in otherwise healthy individuals at high familial risk for developing mood disorders). as putative correlates of cerebrovascular disease) in the deep and periventricular white matter.Clinical research Selected abbreviations and acronyms ACC BD FPDD 5-HT MDD NMDA PFC VTA anterior cingulate cortex bipolar disorder familial pure depressive disease 5-hydroxytryptamine (serotonin) major depressive disorder N-methyl-D-aspartate prefrontal cortex ventral tegmental area cation of functional imaging approaches. or abnormalities in cellular viability or proliferation. because the conditions encompassed by the diagnostic criteria for MDD appear to be heterogeneous with respect to pathophysiology and etiology. the structural abnormalities in these regions may prove relevant to the emotional dysregulation that is clinically manifest in mood disorders. changes in neuronal arborization or synapse formation. lesion analysis. and functional neuroimaging studies in experimental animals and healthy humans. guided clinical neuroscience toward models in which both functional and structural brain pathology play roles in the pathogenesis of mood disorders. It is noteworthy that neuroimaging laboratories selecting depressed subjects according to MDD criteria alone have rarely been able to replicate their own previous findings in independent subject samples. which. however. Instead. These reversible abnormalities presumably reflect areas where metabolic activity increases or decreases to mediate or respond to emotional and cognitive manifestations of the depressive syndrome. The regions affected by these abnormalities have been shown to play major roles in modulating emotional behavior by electrophysiological. disagreements within the literature appear to reflect differences in subject selection criteria applied across studies. Longitudinal positron emission tomography (PET) imaging studies of MDD and BD identified abnormalities of regional cerebral glucose metabolism and cerebral blood flow (CBF). and in other cases appeared mood statedependent (reviewed in reference 1.2-4 In contrast. persisted beyond symptom remission. neuroimaging abnormalities appear to be specific to subsets of MDD subjects. abnormalities that persist independently of the mood state may instead reflect neuropathological sequelae of recurrent illness or neurodevelopmental abnormalities that may confer vulnerability to MDD (eg. Figure 1). requiring that subjects have familial aggregation of illness and an early age at illness onset improved sensitivity for identifying subject samples with reproducible neuroimaging abnormalities. which is not the case for elderly depressives with an early age at depression onset. the psychiatric imaging literature is in disagreement regarding the specific location and direction of some abnormalities. Moreover.1 For example. areas where CBF and metabolism appeared irreversibly decreased in depressives relative to controls in PET studies of MDD and BD were subsequently associated with focal tissue reductions in magnetic resonance imaging (MRI)–based morphometric and postmortem histopathological studies of MDD and BD. Such abnormalities in CBF and metabolism may reflect pathological changes in synaptic transmission associated with altered neurotransmitter receptor function. Clinical differences related to the capacity for developing mania or psychosis or having a late age at illness onset have also been shown to influence neuroimaging data. because local glucose metabolism and CBF (which is tightly coupled to glucose metabolism) reflect summations of the energy utilization associated with terminal field synaptic transmission during neural activity. elderly MDD cases with a late-life onset and delusional MDD cases have been shown to have lateral ventricular enlargement—a feature which is generally not present in MDD cases who are elderly but have an 200 . cerebrovascular disease. which in many cases were guided by initial appli- Sensitivity for detecting neuroimaging abnormalities in depression The neuroimaging abnormalities discovered to date have not had effect sizes sufficient to permit sensitive or specific classification of individual cases. Similarly.

Because only the medial wall of the cortex is shown. the location of the lateral orbital/ventrolateral prefrontal cortex (PFC)/anterior insular region is better illustrated in Figure 2B.19 and postmortem studies of MDD and BD reported abnormal reductions in the size of neurons and/or the density of glia. A major technical issue that influences the sensitivity for detecting neuroimaging abnormalities across studies is the low spatial resolution of imaging technology relative to the size of brain structures of primary interest. MRI studies involving images of this resolution have been able to reproducibly show regionally specific reductions in mean gray matter volume across groups of clinically similar depres- sives versus controls. The regions where neurophysiological imaging abnormalities have been consistently reported in unmedicated MDD samples are listed and approximately shown on this midsagittal brain diagram in which subcortical structures are highlighted onto the medial surface. 2004 early age of MDD onset.14 In the posterior orbital.1 compatible with evidence that chronic administration of these mood stabilizers increases expression of the neurotrophic factors in rodents. they have lacked sensitivity to detect the relatively subtle tissue reductions extant in mood disorders in individual subjects.5 mm3) have commonly been negative because of the substantial partial volume effects that arise when attempting to segment regions of only 3. Moreover.6 although the PFC appeared significantly larger in BD subjects chronically medicated with lithium or divalproex than BD subjects who were either unmedicated or medicated with other agents. In some cases. These findings were confirmed by postmortem studies of clinically similar samples (see below). 2 . In addition. Effective treatment with selective serotonin (5-hydroxytryptamine [5-HT]) reuptake inhibitors did not alter the subgenual PFC volume in MDD.to 4-mm cortex thickness in such low-resolution MRI images. volumetric abnormalities have been identified in specific prefrontal cortical (PFC). The most prominent reductions in the cortex have been identified in the anterior cingulate gyrus ventral to the genu of the corpus callosum. The red arrows have indicate histopathological and/or gray matter volumetric abnormalities in postmortem studies of primary mood disorders. studies attempting to replicate such findings using data acquired at lower spatial resolutions (ie. However. voxel sizes ≥1. depressed MDD samples relative to healthy control samples. where gray matter volume has been abnormally decreased 20% to 40% in depressed subjects with familial pure depressive disease (FPDD).16 and in postmortem neuropathological studies of MDD. 201 . No.11-13 relative to healthy controls or mood-disordered subjects with no first-degree relatives with mood disorders. Summary of neuroimaging abnormalities in early-onset.Drevets Dialogues in Clinical Neuroscience . major depressive disorder (MDD). the volumetric resolution of state-of-the-art image data has recently been about 1 mm3. The “ventral anterior cingulate” region refers to both pregenual and subgenual portions (see text and Figure 2). compared with the cortex thickness of only 3 to 4 mm.Vol 6 .17. With respect to morphometric assessments of gray matter volume.18. The arrows in front of each region name indicate the direction of resting state abnormalities in glucose metabolism in unmedicated.20. cortex. and ventrolateral PFC. Volumetric MRI imaging abnormalities in mood disorders Frontal lobe structures Volumes of the whole brain and entire frontal lobe generally have not differed between depressed and healthy control samples. mesiotemporal. volume has also been shown to be reduced in in vivo volumetric MRI studies15.Neuroplasticity in mood disorders . treatment responsive vs nonresponsive. In contrast.18 Reductions in gray matter volume were also found in the dorsomedial/dorsal anterolateral PFC in MDD subjects versus controls. or in midlife depressives who are not delusional. but not in MDD. familial BD. abnormalities in both directions have been reported which may depend either on the specific region involved or on the clinical state (eg. enlargement of the third ventricle has been consistently reported in BD. and psychotic depression6. primary.21 Dorsal anterior cingulate Dorsal caudate Posterior cingulate Dorsal medial/ anterolateral PFC Ventral anterior cingulate Medial thalamus Ventrolateral PFC Anterior insula Lateral orbital cortex Ventral striatum Amygdala Medial cerebellum Hippocampus or Areas where neuropathological/morphometric changes reported Indicates direction of metabolic abnormality relative to control Figure 1. see text). and basal ganglia structures in mood disorders.

50 or not different38 relative to healthy controls. These findings were consistent with the postmortem study of Baumann et al.39. in BD. but not the remainder of the hippocampus. In postmortem studies of BD. it appears more likely that MRI images acquired at ≤1. amygdala volume was reported to be increased. reductions in hippocampal volume were identified by Noga et al37 and Swayze et al38 relative to healthy controls. in unipolar depressives relative to healthy controls. Although mean amygdala volumes did not differ between BD and control samples.44 increased. the literature is in disagreement. Nevertheless. Dupont et al56 and Lenze et al57 failed to find significant differences in caudate or lentiform nucleus (putamen plus globus pallidus) volumes between younger MDD subjects and controls. but not in women who had depression without early-life trauma.43. and Krishnan et al53 found a smaller caudate nucleus volume in depressives (mean age 48) than controls.27 Two studies reported abnormalities of the hippocampal T1 MRI signal in MDD. they were smaller in BD subjects who had not been recently medicated with mood stabilizers than in BD subjects who had been taking such agents. Although the extent to which disagreements in the results across studies are accounted for by confounding factors (such as medication effects) remains unclear. A recent study employing this technique established that mean amygdala volumes are decreased bilaterally (P<0. abnormal reductions in the mRNA concentrations of synaptic proteins40 and in apical dendritic spines of pyramidal cells41 were specifically observed in the subicular and ventral CA1 subregions of the hippocampus. In BD. Krishnan et al42 observed that the T1 relaxation time was reduced in the hippocampus. with magnitudes of difference ranging from 8% to 19% with respect to healthy controls.001) in MDD relative to healthy control samples.55 which found that caudate and accumbens area volumes were markedly decreased in both MDD and BD samples relative to control samples. and Sheline et al23 observed that elderly subjects with MDD have a higher number of areas with a low MRI signal than age-matched controls in T1-weighted images. Husain et al52 reported that the putamen was smaller in depressives (mean age 55) than controls. The significance of such abnormalities remains unclear. In the amygdala. Similarly.49.Clinical research Temporal lobe structures Morphometric MRI studies of specific temporal lobe structures reported significant reductions in the hippocampal volume in MDD. in contrast. A recent study using high-resolution MRI scans found that the volume of the subiculum. permit valid and reliable volumetric measures of the human amygdala. consistent with evidence that some mood stabilizers exert neurotrophic effects. Other groups found no significant differences between MDD and control samples.5 tesla lack the spatial and tissue contrast resolution needed to measure amygdala volumes with sufficient validity and reliability. Vythilingam et al36 reported that the hippocampal volume was abnormally decreased in depressed women who also had suffered early-life trauma. For example. The amygdala’s small size and proximity to other gray matter structures seriously limits the specificity (accuracy) for delimiting amygdala boundaries in images acquired using MRI scanners of ≤1.5-tesla field strength. although Pearlson et al39 and Nugent et al27 found no differences between BD and control samples. Abnormalities of corpus callosal volume in mood disorders The genual subsection of the corpus callosum was reduced in volume in both depressed women with MDD and their high-risk. was decreased in BD relative to control samples.22-28 Sheline et al23 and MacQueen et al28 reported that the hippocampal volume was negatively correlated with the total time spent depressed or with the number of depressive episodes in MDD.29-35 The inconsistency in the results of MDD studies may reflect pathophysiological heterogeneity within the MDD samples studied. female offspring (insufficient num- 202 . High-resolution MRI images acquired at 3-tesla magnetic field strength.51 Amygdala volumes were decreased both in currently depressed and currently remitted MDD subsamples. Krishnan et al54 also reported smaller putamen and caudate volumes relative to controls.46-48 decreased. The factors accounting for the discrepant results across studies remain unclear.14 Basal ganglia Volumes of some basal ganglia structures have also been reported to be abnormally decreased in mood disorders. Studies of MDD have reported that amygdala volume is decreased. In a sample limited to elderly depressives. but not in the entire temporal lobe.45 or not different26 in depressives relative to healthy controls.

Drevets Dialogues in Clinical Neuroscience .61 while a third did not.59 These white matter regions contain the transcallosal fibers connecting the orbital cortex. with the greatest effects in layers III.18.20 the dorsal anterolateral PFC (BA9). the mean size of neurons was reduced in the dorsal anterolateral PFC (BA9) in MDD subjects relative to controls. different areas would be expected to show greater or lesser deficits.65 Abnormal reductions in glial cell counts and density. abnormal development.1 which would putatively result from chronically elevated stimulation of the adrenal cortex by adrenocorticotropic hormone (ACTH). the concentration of white matter within the vicinity of the amygdala27 and the white matter volume of the genual and splenial portions of the corpus callosum are abnormally reduced in MDD and BD. The size of these plexuses varies across cortical areas. Reductions in gray matter volume.55 The histopathological correlates of these abnormalities included reductions in glial cells with no equivalent loss of neurons.7.Neuroplasticity in mood disorders .9. Notably. Dupont et al56 reported that the thalamic volume was decreased in unipolar depressives relative to controls.1 Oligodendroglia are best characterized for their role in myelination. Other cerebral structures Morphometric studies of other brain structures in depression have produced less consistent results. suggesting that the reduction in white matter in MDD reflects a developmental defect that exists prior to the onset of depressive episodes.60. and VI. enlargement of the pituitary and adrenal glands has been reported in MDD.71 The intracortical plexuses of myelinated fibers known as “bands of Baillarger” are generally concentrated in layers III and V. the myelin basic protein concentration was found to be decreased in the frontal polar cortex (BA10) in MDD subjects. V. and/or glia-to-neuron ratios have also been found in MDD in Brodmann area (BA) 24 cortex of the pregenual ACC. Further evidence supporting this hypothesis comes from several reports that deficits in glia in the cerebral cortex depend upon laminar analysis.67 In the amygdala and the dorsal anterolateral PFC (BA9). so if the oligodendrocytes related to these plexuses were affected.69 Compatible with these data. 2004 bers of males were studied to determine whether the abnormality extends to males). posterolateral orbital cortex. or atrophy in the number of myelinated axons.68 In several of these studies.66 and the amygdala. the decreases were largely accounted for by differences in the left hemisphere.21. Of MRI studies of the thalamus. Krishnan et al63 showed that MRI-based measures of cross-sectional area and volume of the pituitary were increased (by 34% and 41%. astrocyte and microglial cell counts did not differ significantly between MDD or BD samples and healthy control samples in the amygdala. The volumes of the splenial subregion of the corpus callosum was also decreased in mood-disordered versus control samples. two reported that the vermal volume is reduced in depressives relative to controls.18. and ventral striatum in MDD and/or BD subjects relative to controls.9. the glial type that specifically differed between MDD and control samples was the oligodendrocytes.58 All of these observations support the hypothesis that the glial cell loss in mood disorders is accounted for by a reduction in myelinating oligodendrocytes.64. No. respectively) in depressives (n=19) versus controls (n=19). Postmortem neuropathological assessments of mood disorders Most of the regions where MRI studies demonstrated volumetric abnormalities in mood disorders were also shown to contain histopathological changes or gray matter volumetric reductions in postmortem studies of MDD and BD. Layer VI in particular has a relatively large component of 203 . Of MRI studies of the cerebellum. This observation is consistent with evidence that the adrenal gland is also abnormally enlarged in MDD.20.70. Two studies of thalamic volume in BD also have reported conflicting results. in comparison to age-matched controls.58. either through demyelination.18 and the density of neurons was decreased in the ACC in BD. anterior cingulate cortex (ACC).20. and medial PFC with their homologous cortices in the contralateral hemisphere.18.17. and the reduction in oligodendrocytes may conceivably arise secondary to an effect on myelin. elevations in neuronal density.Vol 6 . which contains transcallosal fibers from the posterior cingulate cortex.1.40. In contrast.62 Consistent with evidence that the hypothalamic-pituitary-adrenal (HPA) axis function is elevated in some mood-disordered subgroups.58. thickness.59 These regions of the corpus callosum were also smaller in child and adolescent offspring of women with MDD who had not yet experienced a major depressive episode.1.54 found no differences between depressives and controls.7. 2 . and reductions in neuronal size. or wet weight have been reported in the subgenual ACC. reductions in synapses or synaptic proteins.67 Finally.9. but Krishnan et al42.17.

suggesting that they function like astrocytes and take up synaptically released glutamate for conversion to glutamine and cycling back into neurons.84 These dendritic reshaping processes depend upon interactions between N-methyl-D-aspartate (NMDA) glutamatergic receptor stimulation and glucocorticoid secretion associated with repeated stress. and cingulate cortex regions that show reductions in gray matter volume and cellular elements.78 Moreover.77 and elevated glucocorticoid levels decrease the proliferation of oligodendrocyte precursors. oligodendrocytes express α-amino-3-hydroxy5-methyl-4-isoxazolepropionate (AMPA) and kainatetype glutamate receptors. including indications of both apoptotic and necrotic degeneration. depressives with FPDD or BD are more likely to show abnormal suppression of cortisol secretion by dexamethasone and blunted hypoglycemic response to insulin8 and to release excessive amounts of cortisol during stress. In the frontal cortex.80 although no data exist to establish a similar role in mood disorders.85 Subjects with FPDD or familial BD also show elevations of glucose metabolism. reductions in astroglia have been reported by postmortem studies of mood disorders. and so the findings that gray matter reductions appear to occur specifically in regions that show hypermetabolism during depression raise the possi- 204 . Glucocorticoids affect glia as well as neurons. Satellite oligodendrocytes may play a role in maintaining the extracellular environment for the surrounding neurons. amygdala.79. In the medial PFC and parts of the hippocampus and amygdala of adult rodents.Clinical research myelinated fibers running between the gray and white matter. and MDD or BD cases.83. Other studies also did not find differences in GFAP between mood disorder cases and controls. ventral striatum.81 Elevations of glutamate transmission and cortisol secretion in mood disorders may also contribute to reductions in gray matter volume and synaptic markers by inducing dendritic atrophy in some brain structures. Finally. Johnston-Wilson et al75 found that four forms of the astrocytic product glial fibrillary acidic protein (GFAP) were decreased in mood-disordered subjects relative to controls. but do not appear to have a role in myelination under normal conditions.72 An electron microscopic study of the PFC in BD revealed decreased nuclear size. clumping of chromatin.1 These vulnerabilities putatively contribute to oligodendrocyte degeneration in ischemic brain injury and demyelinating diseases. Using immunohistochemical staining for GFAP.73 Fewer signs of degeneration were seen in myelin-related oligodendrocytes in white matter. chronic unpredictable stress produces dendritic atrophy in the basolateral amygdala.66 Factors that may conceivably contribute to a loss of oligodendroglia in mood disorders include the elevated glucocorticoid secretion and glutamatergic transmission evident during depression and mania. which resembles the functions mediated by astrocytes. in the medial and orbital PFC.82 The effects of stress on dendritic arborization depend both upon the type of stress applied and anatomical location. and the two glial types may share several functions. and are sensitive to excitotoxic damage from excess glutamate as well as to oxidative stress. and other types of damage to satellite oligodendrocytes. Association between structural and metabolic abnormalities The glucose metabolic signal is dominated by changes in glutamate transmission. but did not affect dendritic arborization in the central nucleus of the amygdala. The targeted nature of the reductions in gray matter volume and glial cells to specific areas of the limbic-cortical circuits that show increased glucose metabolism during depressive episodes is noteworthy given the evidence reviewed below that the glucose metabolic signal is dominated by glutamatergic transmission.82 The depressives with BD and FPDD who show regional reductions in gray matter volume also show evidence of having increased cortisol secretion and glutamate transmission. which largely reflects glutamate transmission. whereas chronic immobilization stress increased dendritic branching in pyramidal and stellate neurons within the basolateral amygdala.These oligodendrocytes are immunohistochemically reactive for glutamine synthetase. For example. The hypothesis that glutamate transmission is elevated in these areas in depression was also supported by a postmortem study in depressed suicide victims. a population of satellite oligodendrocytes exists next to neuronal cell bodies that have largely unknown functions. In other brain regions. although it remained unclear whether this decrement reflected a reduction in the astrocyte density or in GFAP expression. Webster et al76 did not find significant differences in cortical astrocytes between controls. the dendritic arbors undergo atrophy or debranching in response to specific types of repeated or chronic stress. Specifically.74 Many studies of glial function have not distinguished astrocytes from oligodendrocytes.8.

19. areas of reduced CBF and metabolism in depressives relative to controls were found in the ACC ventral to the genu of the corpus callosum (ie. Parkinson’s disease.99 Implications for the pathogenesis of emotion dysregulation The circuits described above have also been implicated in the depressive syndromes arising secondary to lesions or degenerative illnesses.Vol 6 .104-107 Primary and secondary depressive syndromes may thus involve the same neural network.1 During effective antidepressant drug or electroconvulsive therapy. ventral striatum. inhibitory fibers to the mediodorsal nucleus.92 Yet even in these regions.95 The first of these circuits can be conceptualized as an excitatory triangular circuit. Parkinson’s disease or Huntington’s disease) are associated with higher rates of depression than other similarly debilitating conditions and result in dysfunction at distinct points within these circuits and affect synaptic transmission in diverse ways.8 compatible with evidence that these treatments result in desensitization of NMDA glutamatergic receptors in the frontal cortex.The abnormally increased CBF and metabolism in the ventrolateral and orbital PFC. because the idiopathic neuropathological changes evident in the orbital and medial PFC and ventral striatum in primary mood disorders (see above) and those found in neurodegenerative conditions all appear to be capable of inducing depressive syndromes (eg. Huntington’s disease. A common substrate in these cases may be dysfunction of the PFC-striatal modulation of limbic and visceral functions.101 This part of the striatum sends an inhibitory projection to the ventral pallidum.91. the mediodorsal nucleus of the thalamus and the orbital and medial PFC. Lesions involving the PFC (eg. 205 . ACC anterior to the genu of the corpus callosum (“pregenual” ACC).Neuroplasticity in mood disorders . reductions in cortex volume and/or histopathological changes have been found in in vivo MRI studies and/or postmortem studies of MDD and/or BD. γ-aminobutyric acid).86-89 In the depressed phase of familial MDD and BD.96-100 This means that increased metabolic activity in these structures would presumably reflect increased synaptic transmission through the limbic-thalamo-cortical circuit.102 which in turn sends GABAergic (GABA. and medial cerebellum. and cerebrovascular disease). metabolic activity increases during the depressive relapse induced by tryptophan depletion (a dietary challenge that depletes central 5-HT transmission). 2 . regional cerebral metabolism and CBF are abnormally increased in the amygdala.90 In addition to these areas of increased metabolic activity. medial thalamus.At least 85% to 90% of the glucose metabolic measure is accounted for by glutamate transmission from afferent projections originating within the same structure or from distal structures.Drevets Dialogues in Clinical Neuroscience . No. in contrast to the findings of increased CBF or metabolism in parts of the orbital cortex in primary depressives. ventral ACC. Huntington’s disease. In all of these regions where glucose metabolism is increased in the depressed phase relative to the remitted phase. posterior cingulate cortex. The hypothesis that the elevations in glucose metabolism seen in these circuits reflect elevations in glutamatergic transmission is supported by evidence that the anatomical projections between affected areas are excitatory in nature. “subgenual” ACC7) and the dorsomedial/ dorsal anterolateral PFC. tumors or infarctions) and the diseases of the basal ganglia (eg. ventral striatum. and medial thalamus evident in depression (Figure 2) implicate a limbic-thalamo-cortical circuit involving the amygdala. metabolic activity decreases in all of these regions.1. amygdala. and a limbicstriatal-pallidal-thalamic circuit involving related parts of the striatum and the ventral pallidum along with the components of the other circuit. or basal ganglia infarction relative to nondepressed subjects with the same illnesses. although the direction of the physiological abnormalities within individual structures may differ across conditions. The amygdala and the PFC send excitatory projections to overlapping parts of the ventromedial striatum. orbital cortex flow is reportedly decreased or not significantly different in subjects with depressive syndromes arising secondary to Parkinson’s disease. 2004 bility that excitatory amino acid transmission plays a role in the neuropathology of mood disorders.The limbic-striatal-pallidal-thalamic circuit constitutes a disinhibitory side loop between the amygdala or PFC and the mediodorsal nucleus. imaging studies of depressive syndromes arising secondary to neurological disorders have generally shown results that differ from those reported for primary mood disorders. lateral orbital/ventrolateral PFC.4. For example. whereby the basolateral nucleus of the amygdala and the orbital and medial prefrontal regions are interconnected by excitatory (especially glutamatergic) projections with each other and with the mediodorsal nucleus.93 and metabolism is increased in the subgenual ACC in the unmedicated-depressed phase relative to the unmedicated-remitted phase.103 Consistent with this hypothesis.

dorsomedial/dorsal anterolateral PFC. A. glucose metabolic values for the left subgenual ACC measured using magnetic resonance imaging (MRI)–based region-of-interest analysis. lead to functional inhibition in the projected field of the amygdala (for PFC-amygdalar projections) or the medial PFC and ventrolateral PFC. which. Mean. Price JL.113 This hypothesis appears to be compatible with the observations that effective antidepressant pharmacotherapy results in a decrease in meta- A x=-3 y=31 Subgenual PFC c. computer simulations that correct the PET data acquired from this region for the partial volume effect of the reduction in gray matter volume measured in MRI scans of the same subject conclude the “actual” metabolic activity in the remaining subgenual PFC tissue is increased in depressives relative to controls.7 This image localized an abnormality in the subgenual portion of the anterior cingulate cortex (subgenual ACC7). Negative voxel t values where glucose metabolism is decreased in depressives relative to controls in coronal (31 mm anterior to the anterior commissure. †P<0. metabolism. Copyright © 1997. subgenual PFC) in mood disorders. or x=-3) planes of a statistical parametric image comparing depressives relative to controls. lateral orbital cortex. amygdala.) (ie. the volumetric and/or histopathological changes evident in the subgenual and pregenual ACC. and medial thalamus (not shown in A.5 -2. -5. B. Elsevier. initially demonstrated by MRI-based morphometric measures6.108-110 The function of the PFC in modulating the amygdala appears to be impaired in mood disorders. Figure 2.025 controls versus depressed. Curr Opin Neurobiol. in turn.05 controls versus manic.1 1 *† 0. Although none of these subjects were involved in the study that generated the images shown in Figure 3. Metabolism is decreased in depressed subjects with either bipolar disorder (BD) or major depressive disorder (MDD) relative to healthy controls. lateral orbital cortex.” respectively. as discussed below.112 and later by postmortem neuropathological studies of familial BD and MDD. Figure 2A reproduced with permission from reference 6: Drevets WC.12-16. Anterior (or left) is to the left of the image. ‡P<0. hippocampal subiculum. Figure 2B reproduced with permission from reference 94: Drevets WC. subjects scanned in the manic phase of BD (“bipolar manic”) have higher metabolism than either depressed or control subjects in this region. ventrolateral PFC. Ventral ACC The ACC ventral and anterior to the genu of the corpus callosum (“subgenual” and “pregenual. Altered metabolism in the prefrontal cortex (PFC) ventral to the genu of the corpus callosum (c.01 depressed versus manic. Although the reciprocal PFC-amygdalar projections are excitatory in nature. Copyright © 2001. Figure 2) shows complex relationships between CBF. et al. 2001.Clinical research PFC-amygdalar projections may also play a role in the pathogenesis of depressive and anxiety symptoms in mood disorders. which was subsequently shown to be accounted for by a corresponding reduction in cortex volume on the left side (see text).8 Control BD MDD Bipolar manic 206 . which only illustrates negative t values corresponding to hypometabolic areas in the depressives). In contrast.9 Thus. and ventral striatum may interfere with the modulation of emotional behavior.c. the mean glucose metabolism in this independent sample of depressives and controls also confirmed the areas of abnormally increased activity in the depressives in the amygdala. Nature.96.8 t value 0 B Mean regional/global metabolism 1. according to functional MRI data showing that abnormally sustained amygdala activity in response to aversive words or sad faces in MDD is associated with blunted activation of PFC areas.108. Subgenual prefrontal cortex abnormalities in mood disorders. and decreases to normative levels during effective treatment.c. 1997. which appear to be accounted for by a left-lateralized reduction in the corresponding cortex.386:824-827.111 Thus. or y=31) and sagittal (3 mm left of midline.2 *‡ †‡ 1. *P<0.11:240-249. normalized. these connections ultimately appear to activate inhibitory interneurons. and illness state. Neuroimaging and neuropathological studies of depression: Implications for the cognitive emotional manifestations of mood disorders. Simpson JR. Nature Publishing Group.9 *† 0.

namely the infralimbic.Drevets Dialogues in Clinical Neuroscience . electrical or glutamatergic stimulation of medial PFC areas that include prelimbic cortex elicits burst firing patterns from dopamine (DA) cells in the VTA and increases DA release in the accumbens. Mayberg et al122 reported that.64. or a sense of foreboding in humans. have extensive reciprocal connections with areas implicated in the expression of behavioral. panic. and nucleus tractus solitarius. behavioral.127 Lesions of these cortices consequently result in exaggerated plasma ACTH and CORT responses to restraint stress.7. Finally.8. and gastric stress pathology during restraint stress or exposure to fear-conditioned stimuli. and neuroendocrine responses to stress and fear-conditioned stimuli. 2 . bilateral or right-lateralized lesions of the ACC and prelimbic and infralimbic cortex attenuate sympathetic autonomic responses. lateral hypothalamus. compared with subjects showing the poorer response. and receive dense dopaminergic innervation from VTA. and ventral ACCs. or reward/nonreward. raphe.130 It is thus noteworthy that the gray matter reduction in this region in MDD and BD was lateralized to the left side.The prelimbic and infralimbic cortices contain abundant concentrations of glucocorticoid receptors.130 These data suggest that the right subgenual PFC facilitates expression of visceral responses during emotional processing.127 In rats.8.12 The gray matter deficit may nevertheless worsen or initially become apparent following illness onset based upon preliminary evidence in twins discordant for MDD that the affected twin has a smaller volume than their unaffected cotwin. periaqueductal grey (PAG).126 Similarly.114. metabolism was decreased in depressives who later had poor treatment response. subiculum. amygdala. reduce stress-related HPA activity. These areas send efferent projections to the VTA and substantia nigra.113 These phasic.118 The reduction in volume in this region exists early in the illness in familial MDD11 and BD.1 The finding that this region contains histopathological changes in MDD and BD20.117. Wu et al121 reported that depressed subjects whose mood improved during sleep deprivation showed elevated metabolism in the pregenual ACC and amygdala in their pretreatment scans. such as the orbital cortex. left-sided lesions of this area increase sympathetic autonomic arousal and CORT responses to restraint stress. Drevets et al95 initially found increased CBF in MDD. locus ceruleus.131. and endocrine responses to threat.Neuroplasticity in mood disorders . while metabolism in the pregenual ACC was abnormally increased in depressives who subsequently responded to antidepressant drugs. 207 . rats with experimental lesions of prelimbic cortex demonstrate altered autonomic.114 that during depressive episodes metabolism shows a positive relationship with depression severity.125 Electrical stimulation of the ACC elicits fear. 2004 bolic activity in this region in MDD. ventral tegmental area (VTA). accumbens.119 Kimbrell et al120 reported that the subgenual ACC metabolism correlated inversely with the number of lifetime depressive episodes. and subsequent studies extended this observation by demonstrating complex relationships between pregenual ACC activity and subsequent antidepressant treatment outcome.124 Humans with lesions that include these ventromedial PFC structures show abnormal autonomic responses to emotionally provocative stimuli and an inability to experience emotion related to concepts that ordinarily evoke emotion.115.116 and that flow increases in this region in healthy. In rodents and nonhuman primates. suggesting that it may contribute to disinhibition of neuroendocrine and autonomic function in depression.124 In rats. stressinduced CORT secretion. the regions that appear homologous to human subgenual and pregenual ACC. while the left subgenual PFC inhibits or modulates such responses. most PET studies have shown that pregenual ACC flow and metabolism decrease in posttreatment scans relative to pretreatment scans. autonomic.132 The ventral ACC also appears to participate in processing of behavioral incentive and motivated behavior. in a tomographic electroencephalographic (EEG) analysis. which.68 suggests the hypothesis that the abnormal reduction in metabolism in treatment-nonresponsive cases reflects more severe reductions in cortex. burst firing patterns of DA neurons appear to encode information regarding stimuli that predict reward and deviations between such predictions and actual occurrence of reward. In the pregenual ACC.133 Ventral ACC dysfunction may thus conceivably contribute to disturbances of motivated behavior and hedonic perception in mood disorders. and vocalization in experimental animals.Vol 6 . when stimulated by corticosterone (CORT).10.128-130 In contrast. stress. prelimbic. During effective antidepressant treatment. No.127. compatible with the possibility that the reduction in metabolism in this region measured via PET reflects a partial volume effect of a gray matter reduction that worsens with repeated illness. Pizzagalli et al123 reported that depressives who ultimately showed the best response to nortriptyline showed hyperactivity (higher theta activity) in the pregenual ACC at baseline. nondepressed humans during sadness induced via contemplation of sad thoughts or memories.

and stimulation of these sites attenuate defensive behavior and cardiovascular responses evoked by amygdala stimulation.18. suggesting that this region functions to attenuate emotional expression. Instead.124. Flow normally increases in the vicinity of this dorsomedial/dorsal anterolateral PFC in healthy humans as they perform tasks that elicit emotional responses or require emotional evaluations. respectively. direct inhibition of pathological limbic activity in areas such as the amygdala and ventral ACC may attenuate the mediation of depressive symptoms.143. Consistent with this hypothesis.135 Moreover. These data appear to be consistent with electrophysiological and lesion analysis data showing that parts of the orbital cortex participate in modulating behavioral and visceral responses associated with defensive.1 In healthy humans.81.91 Postmortem studies of MDD and BD found abnormal reductions in the size of neurons and/or the density of glia in this portion of BA9.8.8 The orbital cortex neurons may thus “relax. Lateral orbital/ventrolateral PFC In the lateral orbital cortex.124.128 although the homologue to these areas in primates has not been clearly established. the BA9 cortex sends efferent projections to the lateral PAG and the dorsal hypothalamus through which it may modulate cardiovascular responses associated with emotional behavior. and reward-directed behavior as reinforcement contingencies change.144 The orbital cortex and amygdala send overlapping projections to each of these structures and to each other through which they appear to modulate each other’s neural transmission. CBF increases in this region during anxious anticipation of an electrical shock to an extent that correlates inversely with changes in anxiety ratings and heart rate.116.146 These observations also suggest that the reduction of CBF and metabolism in the orbital cortex and ventrolateral PFC during antidepressant drug treatment may not be a primary mechanism through which such agents ameliorate depressive symptoms.8.1 The elevated activity in these areas in MDD appears to be mood-state dependent.143.145 Activation of the orbital cortex during depression may thus reflect compensatory attempts to attenuate emotional expression or interrupt unreinforced aversive thought and emotion. In primates. Posterior orbital cortex flow also increases in subjects with obsessive-compulsive disorder or simple animal phobias during exposure to phobic stimuli and in healthy subjects during induced sadness. the resting CBF and metabolism have been abnormally increased in unmedicated subjects with primary MDD (Figure 3).20. while metabolic activity is abnormally increased in these areas in treatment-responsive unipolar and bipolar depressives. ventrolateral PFC.95.124 It is thus conceivable that dysfunction of the dorsomedial/dorsal anterolateral PFC may contribute to impairments in the ability to modulate emotional responses in mood disorders. and anterior insula. currently remitted MDD subjects who experience depressive relapse during tryptophan depletion show increased metabolic activity within these areas in the depressed versus the remitted conditions.19. more severely ill or treatment-refractory samples show CBF and metabolic values lower than or not different from those of controls. lesions of the dorsomedial PFC result in exaggerated heart rate responses to fear-conditioned stimuli. While CBF and metabolism increase in these areas in the depressed phase relative to the remitted phase of MDD.95 and.” as reflected by the return of metabolism to normal lev- 208 . during treatment with somatic antidepressant therapies. flow and metabolism decreases in these regions.93 similar to other structures where histopathological and gray matter volume changes exist in MDD.1 The relationship between depression severity and physiological activity in the lateral orbital cortex/ventrolateral PFC is complex. and sadness. emotional. anxiety. cerebrovascular lesions of the orbital cortex are associated with an increased risk for depression.139 This inverse relationship between orbital cortex/ventrolateral PFC activity and ratings of depression severity extends to some other emotional states as well. the magnitude of these measures is inversely correlated with ratings of depressive ideation and severity. In rats.Clinical research Dorsomedial/dorsal anterolateral PFC Metabolism and CBF are abnormally decreased in the dorsolateral and dorsomedial PFC in MDD.1 The dorsomedial PFC region includes the dorsal ACC92 and an area rostral to the dorsal ACC involving cortex on the medial and lateral surface of the superior frontal gyrus (approximately corresponding to BA9 and BA32). and for the failure of antidepressant drug treatment to correct metabolism in these areas.140-142 with the change in posterior orbital CBF correlating inversely with changes in obsessive thinking.19 Nevertheless.134 which may account for the reduction in metabolism in this region in MDD.

In the left amygdala.135. Figure 3A reproduced with permission from reference 126: Price JL. Regional cerebral blood flow changes during anticipatory anxiety.Neuroplasticity in mood disorders .137 or in MDD samples meeting Diagnostic and Statistical Manual of Mental Health Disorders (DSM) criteria.149 or for those who are responsive to sleep deprivation. The PET images in A and B from which the t image was generated have been stereotaxically transformed to the coordinate system of Talairach and Tournoux.20:368.94 consistent with the elevation of basal CBF and metabolism in the left amygdala in such cases (physiologically activated tissue is expected to show an attenuation of further rises in the hemodynamic/metabolic signal in response to tasks that normally engage the same tissue). 1994. 2004 els.8. The duration of the amygdala response to emotionally valenced stimuli is also abnormally prolonged in response to sad stimuli in depression.25 t value 4. Drevets WC. B. although the initial amygdala CBF response to sad faces was similar in depressives and controls. The image sections shown are from an image of t values. Elsevier. as antidepressant drug therapy attenuates the pathological limbic activity to which these neurons putatively respond.95 The positive t values shown correspond to areas where flow is increased in the depressives relative to the controls.150-152 although the interpretation of the latter results was confounded by technical problems that reduced sensitivity for measuring amygdala activity.Vol 6 .145 The amygdala In the amygdala. Networks related to the orbital and medial prefrontal cortex: a substrate for emotional behavior? Prog Brain Res. 2 .136 During antidepressant treatment that both attenuates depressive symptoms and prevents relapse. Areas of abnormally increased blood flow in subjects with major depressive disorder (MDD). MacLeod AK. Soc Neurosci Abstr.0 209 . produced by a voxel-by-voxel computation of the unpaired t statistic to compare regional CBF between a depressed sample selected according to criteria for familial pure depressive disease (FPDD) (n=13) and a healthy control sample (n=33).8 Functional imaging data acquired as subjects view emotionally valenced stimuli that normally activate the amygdala also demonstrate altered physiological responses in MDD. Copyright © 1996. the hemodynamic response to viewing fearful faces was blunted in depressed children153 and depressed adults.136 for MDD melancholic subtype.8. Raichle ME.0 t value 4. Area of increased flow extended through the lateral orbital cortex to the ventrolateral prefrontal cortex (VLPFC) and anterior insula.107:523-536.148 type II or nonpsychotic type I BD.136 A. Society for Neuroscience.Drevets Dialogues in Clinical Neuroscience . 1996. The abnormal activity in these regions was replicated using glucose metabolism imaging in independent subject samples. No. Orbital cortex x=-17 0 2. neurophysiological activity is altered both at rest and during exposure to emotionally valenced stimuli in some depressive subgroups. Figure 3B reproduced with permission from reference 138: Drevets WC.5 B Anterior insula VLPFC x=-41 0 2. amygdala metabolism decreases toward normative levels. The basal CBF and metabolism are elevated in mood-disordered subgroups who meet criteria for FPDD (Figure 3). Snyder AZ. Carmichael ST.95.136. Videen TO. Drevets et al94 observed that.137 from which the corresponding atlas outline is shown.136. metabolism has not been abnormal in unipolar depressives meeting criteria for depression spectrum disease.95 The x coordinate locates sagittal sections in millimeters to the left of midline. Anterior is left. Sagittal section at 17 mm left of midline illustrating areas of increased CBF in depression in the amygdala and orbital cortex.8.135. this response habituated during repeated A Amygdala Figure 3. Copyright © 1994.121 In contrast.

anterior.167. stimulation of astrocyte and radial glial cell-based 5-HT1A receptors results in release of the trophic factor S100β. depressed phase of MDD. it is conceivable that arborization of the 5-HT neurons may be attenuated.168.156.116. but.17. orbital/ventrolateral PFC) 5-HT1A binding is abnormally decreased in MDD and panic disorder (irrespective of the current presence of comorbid depression). Abnormalities in anatomically related limbic and subcortical structures In the medial thalamus and ventral striatum. which may reflect the effect of either amygdala activity on CRH secretion or cortisol or CRH on amygdala function.154. during fetal development and subsequently during 5-HT neuronal injury.157 Several groups also reported abnormally increased CBF in the posterior cingulate cortex in the unmedicated.169 If glial function is reduced during 5-HT system development in BD and MDD.165 and depressed suicide victims.163. and postsynaptic 5-HT1A receptor binding is also decreased in BD. and posterior cingulate cortices.159 The posterior cingulate cortex sends major anatomical projections to the pregenual ACC. The amygdala plays major roles in organizing other behavioral. the amygdala facilitates stress-related corticotropin-releasing hormone (CRH) release154 and electrical stimulation of the amygdala in humans increases cortisol secretion. CBF and metabolism are abnormally elevated in the depressed phase of MDD and BD. while the hemodynamic response rapidly fell to baseline in the controls.112.136.158 Bench et al158 specifically reported that the elevation of posterior cingulate flow in depressives relative to controls correlated positively with anxiety ratings.Clinical research exposure to the same stimuli in the controls.166. which promotes 5-HT neuronal arborization.1 then the volumetric changes observed during treatment may contribute to their therapeutic effects in mood disorders. In PET studies of MDD and BD. neuroendocrine.85.168 In addition. and autonomic aspects of emotional and stress responses to experiential stimuli.8.166 It is conceivable that the persistently increased anxiety behaviors and the exaggerated fear and behavioral despair responses shown by 5-HT1A receptor knockout mice at least partly reflect effects of deficient 5-HT1A receptor function on neuroplasticity during neurodevel- 210 .95.134. Exposure to aversive stimuli of various types results in increased physiological activity in the posterior cingulate cortex.136 If the reduction in amygdala volume is associated with reductions in synaptic contacts formed by afferent projections from regions known to modulate amygdala function. and decrease during antidepressant pharmacotherapy.161-165 The magnitudes of these differences have been similar to those found by postmortem studies of primary mood-disordered samples17.155 suggesting a mechanism via which excessive amygdala activity may participate in inducing the CRH and cortisol hypersecretion that is evident in MDD. parietooccipital cortex. The above reports that amygdala blood flow and metabolism are abnormally elevated and hemodynamic responses to emotional stimuli are abnormally persistent in MDD support this hypothesis. potentially reflected by the widespread reductions of 5-HT transporter and postsynaptic 5-HT1A receptor expression seen in MDD. Siegle et al44 reported that hemodynamic activity increased in the amygdala during exposure to negatively valenced words to a similar extent in depressives and controls. For example. it remained elevated in the depressives. then amygdala neuronal activity may become disinhibited.85. Similarly. which would appear to hold major implications for alterations in neuroplasticity in these conditions.170 Such a hypoplastic process may also underlie the finding that the area expressing 5-HT1A receptors in the dorsal raphe nucleus is abnormally decreased in depressed suicides.166 These data are also compatible with results of studies showing that MDD and panic disorder subjects show blunted thermic and adrenocorticotropin/cortisol responses to 5-HT1A receptor agonist challenge.160 Neuroreceptor imaging abnormalities in mood disorders Neuroreceptor imaging studies of mood disorders have demonstrated reductions in 5-HT1A receptor binding in mood disorders.85. but not in the depressives over the imaging period. Siegle et al44 reported that the abnormally prolonged hemodynamic responses of the amygdala to sad words occurred particularly in the MDD subjects who had reduced amygdala volumes.116. CBF and metabolism in the left amygdala correlates positively with stressed plasma cortisol secretion.8.162 The 5-HT1A receptor plays major roles in the neuroplasticity involving serotonergic and other neurons. If the neurotrophic effects of mood-stabilizing drugs restore and protect modulatory connections formed between the amygdala and cortex. Both presynaptic (in the raphe) and postsynaptic (insula. Notably.

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Clinical research
Cellular plasticity and resilience and the pathophysiology of severe mood disorders
Dennis S. Charney, MD; Georgette DeJesus, MD; Husseini K. Manji, MD

Recent advances in the identification of the neural circuits, neurochemicals, and signal transduction mechanisms involved in the pathophysiology and treatment of mood disorders have led to much progress toward understanding the roles of genetic factors and psychosocial stressors. The monoaminergic neurotransmitter systems have received the most attention, partly because of the observation that effective antidepressant drugs exert their primary biochemical effects by regulating intrasynaptic concentrations of serotonin and norepinephrine. Furthermore, the monoaminergic systems are extensively distributed throughout the network of limbic, striatal, and prefrontal cortical neuronal circuits thought to support the behavioral and visceral manifestations of mood disorders. Increasing numbers of neuroimaging, neuropathological, and biochemical studies indicate impairments in cellular plasticity and resilience in patients who suffer from severe, recurrent mood disorders. In this paper, we describe studies identifying possible structural, functional, and cellular abnormalities associated with depressive disorders, which are potentially the cellular underpinnings of these diseases. We suggest that drugs designed to enhance cellular plasticity and resilience, and attenuate the activity of maladaptive stress-responsive systems, may be useful for the treatment of severe mood disorders.
© 2004, LLS SAS Dialogues Clin Neurosci. 2004;6:217-225.

epression is a common, chronic, and often disabling psychiatric illness, which is estimated to affect 5% to 10% of the population. It frequently appears in early life, has a chronic course, and is considered a risk factor for other medical illnesses, such as coronary vascular disease, diabetes, and osteoporosis. This is not altogether surprising given the extensive bidirectional “mind-body” interactions mediated via the autonomic nervous system, immune system, and a host of neuroendocrine factors. According to the World Health Organization (WHO), depression is the leading global cause of years of life lived with disability and the fourth leading cause of disabilityadjusted life-years. Disability-adjusted life-years is defined as the reduction in an individual’s productive life, and takes into account premature mortality.1,2 Considering the high morbidity and mortality associated with depression, it is unfortunate that the psychological and neurobiological underpinnings of depression have not been specifically defined. Although major depression is currently diagnosed by means of a diagnostic system (Diagnostic and Statistical Manual of Mental Health Disorders, Fourth Edition [DSM-IV]) based upon phenomenology, this disorder most likely embodies a heterogeneous set of disorders with multiple causes. Therefore, one of the major goals of current and future research on depression is the development of a diagnostic system based on etiology.3 This goal is becoming increasingly closer to reality due to recent progress in the identification of neural circuits, neurochemicals, and signal transduction mechanisms
Keywords: mood disorder; depression; neuroplasticity; stress; resilience; brain morphology Author affiliations: National Institute of Mental Health, Bethesda, Md, USA Address for correspondence: Prof Dennis S. Charney, National Institute of Mental Health, 15K North Drive, Room 101, Bethesda, MD 20892-2670, USA (e-mail: charneyd@nih.gov)

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Clinical research
Selected abbreviations and acronyms
BDNF CREB ERK HPA LTP MAP PFC brain-derived neurotrophic factor cyclic adenosine monophosphate (cAMP) response element binding protein extracellular response kinase hypothalamo-pituitary-adrenal (axis) long-term potentiation mitogen-activated protein prefrontal cortex there should be an appreciation of the episodic and often intense mood disturbance, which can become progressive over the time. Furthermore, the phenotypic expression of the disease involves not only episodic and often profound mood disturbances, but also a constellation of cognitive, motor, autonomic, endocrine, and sleep/wake abnormalities. Additionally, while most antidepressants exert their initial effects by increasing the levels of serotonin and/or norepinephrine in the synapse, clinical antidepressant effects exclusively result after chronic administration (days to weeks). This suggests that a cascade of downstream effects is ultimately responsible for the clinical antidepressant effects of these medications. These observations have led to the recognition that, although monoaminergic neurotransmitter system dysfunction undoubtedly plays an important role in mediating some facets of the pathophysiology of depressive disorders, additional fundamental alterations in cellular plasticity cascades are most likely involved.13-15 The functional impairments during mood episodes have long been recognized; however, there is increasing evidence of significant interepisode impairment as well. The devastation of these disorders is further complicated by the fact that the medications currently used for their treatment are associated with variable rates of efficacy and not intolerable side effects.An appreciation for both the need for more efficacious treatment for mood disorders and the absence of significant advances in the development of truly innovative therapeutics has led to the investigation of intracellular signaling cascades and their role in the pathophysiology and treatment of mood disorders. Thus, while traditionally viewed exclusively as neurochemical disorders, recent evidence suggests the presence of impairments of cellular plasticity cascades, which produce not only functional, but also morphological impairments; this evidence has generated considerable excitement among the clinical neuroscience community and is reshaping views about the neurobiological underpinnings of these disorders. Thus, as we discuss in detail below, increasing neuroimaging, neuropathological, and biochemical studies suggest impairments in cellular plasticity and resilience in patients who suffer from severe, recurrent mood disorders. The term “neuroplasticity” encompasses diverse essential processes by which the brain perceives, adapts to, and responds to a variety of internal and external stimuli. Manifestations of neuroplasticity in the adult central nervous system (CNS) include alterations of dendritic function, synaptic remodeling, long-term potentiation (LTP),

underlying the pathophysiology and treatment of depressive illness.4,5 Advances toward specifying the contribution of genetic factors,6 psychosocial stressors,7,8 and gene–environment interactions to susceptibility to depression are also taking place.9,10 It is anticipated that, in the next few years, combined use of genomic and proteomic strategies to refine complex psychiatric diseases into mechanism-based subcategories may ultimately facilitate the matching of specific target-based therapies to particular markers in certain patient subgroups.11 Of all brain systems, the monoaminergic neurotransmitter systems have received the greatest attention in neurobiological studies of depressive disorders. The implication of these systems in depression is based on several observations: (i) effective antidepressant drugs exert their primary biochemical effects by regulating intrasynaptic concentrations of serotonin and norepinephrine; and (ii) antihypertensives that deplete these monoamines sometimes precipitate depressive episodes in susceptible individuals. Furthermore, the monoaminergic systems are extensively distributed throughout the network of limbic, striatal, and prefrontal cortical (PFC) neuronal circuits implicated in the behavioral and visceral manifestations of mood disorders.12 Over the past 40 years, clinical studies have aimed to uncover specific flaws in these neurotransmitter systems in mood disorders by using various biochemical and neuroendocrine approaches. In fact, assessment of cerebrospinal fluid (CSF) chemistry, neuroendocrine responses to pharmacological challenge, and neuroreceptor and transporter binding have demonstrated a number of abnormalities of the serotonergic, noradrenergic, and other neurotransmitter and neuropeptide systems in mood disorders. Although such studies have been useful in the past, they have proved to be of limited value in clarifying the particular pathophysiology of depressive disorders. In order to clarify the biological underpinnings of these disorders,

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axonal sprouting, neurite extension, synaptogenesis, and neurogenesis. In this perspective paper, we describe studies identifying possible structural, functional, and cellular abnormalities associated with depressive disorders—the potential cellular underpinnings of these micro- and macromorphological brain changes.We suggest that therapeutics designed to enhance cellular plasticity and resilience, and to attenuate the activity of maladaptive stress-responsive systems may have considerable utility for the treatment of severe mood disorders.

Brain imaging studies in depressed patients
Positron emission tomography (PET) imaging studies have unveiled various abnormalities of glucose metabolism and regional cerebral blood flow (CBF) in limbic and PFC structures in patients with mood disorders.Although some disagreement exists regarding the specific locations and the direction of some of these abnormalities, unmedicated subjects with familial major depression show a consistent increase in regional CBF and metabolism in the amygdala, orbital cortex, and medial thalamus, and decreased metabolism and CBF in the dorsomedial/dorsal anterolateral PFC and anterior cingulate cortex ventral to the genu of the corpus callosum (ie, subgenual PFC) relative to healthy controls.16,17 These abnormalities suggest that limbic-thalamic-cortical and limbic-cortical-striatalpallidal-thalamic circuits, involving the amygdala, orbital and medial PFC, and anatomically related parts of the striatum and thalamus are involved in pathophysiology of depression. Additionally, these circuits have been implicated more generally in emotional behavior by electrophysiological, lesion analysis and brain mapping studies of humans and experimental animals.12,15 Some of these abnormalities reverse during symptom remission, suggesting that there are areas where neurophysiological activity may increase or decrease in order to mediate or respond to the emotional and cognitive manifestations of depression. However, CBF and metabolism do not completely normalize during effective antidepressant treatment in many of these areas. Morphometric magnetic resonance imaging (MRI) and postmortem investigations have also demonstrated alterations in cerebral structure that persist regardless of mood state and may contribute to the corresponding abnormalities of metabolic activity.16,17 Structural imaging studies have shown reduction in gray matter volumes in areas of the orbital and medial PFC, ventral striatum and

hippocampus, and enlargement of third ventricles in mood-disordered patients when compared to healthy controls. Complementary postmortem studies have demonstrated abnormal decreases in cortex volume, glial cell counts, and/or neuron size in the subgenual PFC, orbital cortex, dorsal anterolateral PFC, and amygdala.12,14,15-17 It remains unclear whether these alterations in brain structure represent developmental abnormalities that may increase an individual’s susceptibility to abnormal mood episodes, compensatory changes to other pathogenic processes, or the sequelae of recurrent affective episodes per se.The clarification of these issues will in part depend on investigations that outline the onset of such abnormalities within the illness course, as well as determine whether they precede depressive episodes in individuals with a high familial risk for mood disorders. The lack of complete reproducibility among neuroimaging or postmortem studies is not altogether surprising, and the disparities likely represent variations in experimental design and in patient populations. Further research is needed in order to understand whether more specifically defined subtypes of depression or mood disorders are associated with any specific abnormality.18 The marked reduction in glial cells in these regions has been especially interesting, given the tremendous recent progress in our understanding of the critical roles of glial cells in regulating neuronal function. Thus, there is now compelling evidence that radial glial cells have the potential not only to guide newly born neurons, but also to self-renew and to generate both neurons and astrocytes. Furthermore, recent data have shown that astrocytes increase the number of mature, functional synapses on CNS neurons sevenfold, demonstrating that CNS synapse number can be profoundly regulated by glia. Glial cells are also known to play critical roles in regulating synaptic glutamate levels, CNS energy homeostasis, and the liberation of trophic factors, which in turn participate in the development and maintenance of synaptic networks formed by neuronal and glial processes.16,17,19-22 Glial function abnormalities could thus prove essential to structural plasticity impairments and overall pathophysiology of mood disorders.

Stress and brain morphology
The majority of studies of adaptive neuronal plasticity in response to stress, as well as hypothalamo-pituitaryadrenal (HPA) axis hormones, have focused on the hip-

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Clinical research pocampus.30 HPA axis hyperactivity in mood disorder patients has been demonstrated by a variety of techniques/measures. It has been hypothesized that the depressive subtypes most frequently associated with HPA activation are also the most likely to be associated with reductions in hippocampal volume. and the CA1 and CA3 pyramidal cell layers.31. Moreover. some patients with Cushing’s disease also show reduced hippocampal volumes.32 The results of recent longitudinal studies investigating the effects of early life stress and inherited variation in monkey hippocampal volumes underscore the need for caution when interpreting the clinical neuroimaging studies described above. blunted ACTH response to corticotropin-releasing hormone (CRH) challenge.25 Profound alterations in mossy fiber terminal morphology and significant synapse loss have also been described. It is noteworthy that glucocorticoids may exert deleterious effects on neural plasticity and morphology. These studies suggest that small hippocampal volume also reflects an inherited trait. LTP).23 Many patients with Cushing’s disease.This stress-induced atrophy of CA3 neurons results after 2 to 3 weeks of exposure to restraint stress or more long-term social stress. These cell layers and their connections (mossy fiber pathway and Schaffer collateral) have long been used as cellular models of learning and memory (ie.The hippocampus has a very high concentration of glutamate and expresses both glucocorticoid (GR) and mineralcorticoid (MR) corticosteroid receptors.23. including increased cortisol levels in plasma (especially at the circadian nadir). Paternal half-siblings with small adult hippocampal volumes showed an initial larger relative increase in cortisol level following removal of all mothers after weaning. In this study. he demonstrated a significant rearrangement of apical dendrites in corticosterone-treated animals. MR activation in the hippocampus (CA1) is associated with reduced calcium currents. vide infra) that have not yet been studied in the same detail as the hippocampus. Corrective surgical treatment results in an enlargement of hippocampal volume in proportion to the treatment-associated decrease in urinary free cortisol concentrations. However. since a significant percentage of mood disorder patients show some form of HPA axis activation. Dendritic remodeling of hippocampal neurons is one of the best-characterized effects of stress on cellular morphology. slight structural changes are also found in the CA1 and dentate gyrus following a 1-month multiple stress paradigm. while GR activation leads to increased N-methyl-D-asparate (NMDA) receptor throughput and increased calcium currents that could predispose to neurotoxicity. These longitudinal studies in monkeys randomized paternal half-siblings (monkeys raised apart from one another by different mothers in the absence of fathers) to one of three postnatal conditions that interfered with various facets of early maternal care. 220 . enlarged pituitary and adrenal glands. Histopathological changes in rat PFC after corticosterone administration have recently been described although this area has not been as comprehensively studied as the hippocampus. in which pituitary gland adenomas cause cortisol hypersecretion. though these may be relatively scarce in the hippocampus of primates.23. correlating inversely with plasma cortisol concentrations. and emphasize the need for caution in the simple attribution of causality in the cross-sectional morphometric studies of the hippocampus in humans. increased cortisol response to adrenocorticotropic hormone (ACTH).29. as well as hippocampal atrophy. reduced corticosteroid receptor feedback has been implicated in this process by challenge studies with dexamethasone and dexamethasone plus CRF. plasma cortisol levels 3 and 7 days later did correlate with hippocampal size. including the dentate gyrus granule cell layer. This suggests that stress may result in a significant reorganization of the apical dendritic arbor in medial PFC in rats. This is partly due to early studies on neuronal populations of the limbic brain regions. urine. quantifying dendritic morphology in three dimensions. Wellman28 examined pyramidal neurons in layers II and III of the medial PFC.24 Although the effects of chronic stress in the CA3 layer tend to be most pronounced.27 and more prevalent in cortical regions. In fact.33 However. it is clear that stress and glucocorticoids also influence the survival and plasticity of neurons in other brain regions (such as PFC. and CSF.26. with an increase in the dendritic material proximal to the soma and a decrease in distal dendritic material. and reduced CRH receptor density in the brain (presumably reflecting a compensatory downregulation to sustained CRH elevations) at postmortem examination. Using a Golgi-Cox procedure. increasing evidence implicates glutamatergic neurotransmission in stress-induced hippocampal atrophy and death.24 Dendritic remodeling is deeply observed in the CA3 pyramidal neurons as atrophy-decreased number and length of the apical dendritic branches. In both unipolar and bipolar patients. and has been observed in rodents and tree shrews. also show marked depressive symptoms.

stressed mice expressed approximately 70% less Bcl-2 mRNA than unstressed mice following stroke.39 Phosphorylation of Bad takes place via activation of a downstream target of the MAP kinase cascade.38. mediates neurotrophic factor signaling. including PI-3K. Recent studies have shown that MAP kinase cascade activation can inhibit apoptosis by inducing the phosphorylation of Bad (a major proapoptotic protein) and increasing the expression of Bcl-2 (a major antiapoptotic protein).40-43 Recently.45 In this study. A growing body of evidence indicates that not only is Bcl-2 neuroprotective. No. while BDNF binds to TrkB. but not in transgenic mice overexpressing Bcl-2. while phosphoCREB was reduced in the frontal cortex and other cortical regions. High corticosterone concentrations were significantly correlated with a greater stroke size in wild-type mice. In this context. leading to induction of Bcl-2 gene expression. this reduction indicates that chronic stress could downregulate CREB phosphorylation indirectly. Rsk can phosphorylate CREB.46-48 Depressed individuals may also have genetic abnormalities in CREB and BDNF. and glial-derived neurotrophic factor (GDNF). it is likely that the dynamics of the impairments of cellular plasticity and resilience are determined by intrinsic properties of the affected regions. it is now clear that stressors may exert major effects on cellular plasticity and resilience by regulating the expression and function of growth factor cascades. and axonal regeneration. neurite outgrowth. Therefore. There is emerging evidence—mainly from postmortem studies—supporting a role for abnormalities in neurotrophic signaling pathways in depression. enhanced Bcl-2 expression seems to offset the potentially harmful consequences of stress-induced neuronal endangerment.Vol 6 . Additionally. nerve growth factor [NGF] and brain-derived neurotrophic factor [BDNF]).44 Since CREB is phosphorylated and activated by phospho-ERK1/2 directly. but also that it exerts neurotrophic effects and promotes neurite sprouting. the differential survival is likely modulated not only by region-specific expression of protective factors. as well as protein coupling leading to of the MAP kinase cascade activation. 2004 Stress effects on cellular plasticity and resilience In addition to the cellular mechanisms described above. Mitogen-activated protein (MAP) kinase cascade. The resulting receptor activation results in phosphorylation and activation of effectors. but not in transgenic mice that express increased neuronal Bcl-2. In addition. and the TrkB receptor have been described in suicide victims. This increased Bcl-2 expression likely involves a protein known as the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). BDNF.35. but also by the network properties of vulnerable structures. insulin-like growth factor–1 (IGF-1). Therefore. the phosphatidylinositol-3 kinase (PI-3K)/Akt pathway. including regulation of Bcl-2 family members.37 The family of receptors known as Trks. as well as cytokines. rather than by inducing cell survival pathways.36 These factors promote cell survival through the suppression of intrinsic.Charney Dialogues in Clinical Neuroscience . 221 . 2 .33. Decreased levels of CREB. and subsequently downregulate the transcription of some genes such as Bcl-2 and BDNF. Nerve growth factor binds to the TrkA receptor.34 Neurotrophic factors (eg. it has been demonstrated that chronic stress (21 days’ foot-shock) induces a marked and persistent hyperphosphorylation of an extracellular response kinase (ERK) in higher PFC layer dendrites. Rsk activation mediates the actions of the MAP kinase cascade and neurotrophic factors on the expression of Bc1-2. increase cell survival. stress greatly exacerbated stroke in control mice. This phosphorylation by Rsk promotes the inactivation of Bad. and suggests that pharmacologically induced upregulation of Bcl-2 may be useful in the treatment of a various disorders that have been linked to endogenous or acquired impairments of cellular resilience. cellular apoptotic machinery. It is now clear that the neurotrophic factor–ERK1/2–MAPK–Bcl-2 signaling cascade has a critical role in cell survival in the CNS and that a fine balance exists between the levels and activities of cell survival and cell death factors. distal dendrites.Cellular plasticity and resilience and severe mood disorders . ribosomal S-6 kinase (Rsk). BDNF–ERK1/2–CREB–Bcl-2 cascade dysregulation may be a key mechanism via which prolonged stress induces atrophy of select vulnerable neuronal subpopulations. Although dysregulation of this cascade most likely results in decreased neuronal survival. This occurs via binding of these factors to membrane receptors and regulation of intracellular signal transduction pathways that can control apoptosis. or both. which contain an intrinsic tyrosine kinase domain. and the PI-3K cascade are currently thought to be responsible for mediating many of the effects of neurotrophic factors. it is worth mentioning that a recent study revealed that severe stress exacerbates stroke outcome by suppressing Bcl-2 expression.

57-59 Chronic antidepressant treatment also increases the neurogenesis of dentate gyrus granule cells. learning. a serotonin selective reuptake inhibitor.14 Antidepressant mechanisms and neurotrophic signaling cascades An increasing amount of evidence suggests that antidepressants regulate neurotrophic signaling cascades. CREB overexpression in the dentate gyrus or BDNF injection leads to an antidepressant-like effect in the learned-helplessness paradigm and the forced swim test model of antidepressant efficacy. thus corresponding to the onset clinical antidepressant effects with these therapies. In this study. and NMDA antagonists that enhance plasticity and cell survival. much more research is required in order to adequately link changes in adult hippocampal neurogenesis to the pathophysiology and treatment of depression.52 Therefore. Santarelli and associates64 utilized both genetic and radiological methods to show that disruption of antidepressantinduced neurogenesis blocked behavioral responses to antidepressants.6 A coding variant of BDNF may be associated with the personality trait of neuroticism. This suggests that neurogenesis is positively regulated by. In mice. an opportunity exists to study the interaction of life stress. and susceptibility to depression.56 In rats. X-irradiation of the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. This polymorphism is associated with alterations in BDNF trafficking and secretion in vitro.Clinical research Sequence variations in the CREB1 gene have been observed in depressed women. as well as electroconvulsive treatment (ECT). Agents capable of reversing the hypothesized impairments of cellular resilience. αamino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) potentiators that increase BDNF expression. exercise). and might be reliant on. New molecular targets might include phosphodiesterase inhibitors that increase CREB phosphorylation.53 Various classes of chronic antidepressant treatments.54. neuroimaging abnormalities consistent with deficient structural plasticity.51 suggest that a polymorphism in the proBDNF molecule is associated with bipolar disorder (a condition in which depressive episodes are accompanied by manic episodes). as well as with alterations in hippocampal working memory in humans. In order to assess whether antidepressant-induced hippocampal neurogenesis is functionally relevant. upregulate CREB and BDNF expression. enriched environment. it is likely that the clinical symptoms of depression are related to changes in hippocampal neurogenesis. Since stress and antidepressants have opposite effects on hippocampal neurogenesis.Additionally. and cell death or atrophy in depression have the potential of becoming new therapeutic classes of antidepressant drugs. The enhancement of hippocampal neurogenesis following chronic antidepressant use highlights the level to which these efficacious treatments can regulate long-term neuroplastic processes in the brain. MAP kinase phosphatase inhibitors that increase expression of the antiapoptotic protein bcl-2.49 Furthermore. as Kempermann65 clearly articulated. Antidepressant treatment increases CREB phosphorylation and CREB-mediated gene expression in mice limbic brain regions. These studies show that chronic administration of different classes of antidepressants and ECT lead to an increase in the proliferation and survival of new neurons. suggesting that the CREB cascade and BDNF are common post-receptor targets of antidepressants. there is a growing appreciation that new medications that 222 . an effective antidepressant potentiating agent. two recent studies50. also increases neurogenesis in the dentate gyrus.15 been reported to occur with conditions that stimulate neuronal activity (eg. neuronal plasticity. Increases in neurogenesis have Concluding comments A substantial body of evidence suggests that impairments in neuroplasticity and cellular resilience play a central role in the underlying biology of mood disorders. Additional evidence that relates upregulation of these pathways and antidepressant treatment comes from antidepressant-like performance in behavioral models. reductions in brain volume. serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine. However. presynaptic glutamate receptor subtypes that attenuate glutamate release. increases in neurogenesis do not occur with chronic administration of nonantidepressant psychotropic medications. Lithium.55 This increase is exclusively seen after chronic use. Together. the above findings suggest that some of the behavioral effects observed with chronic antidepressant use may be mediated by the stimulation of neurogenesis in the hippocampus.63 It is noteworthy that in contrast to the findings seen with chronic antidepressant use. which is a risk factor for depression. signal transduction–related genes.60-62 This effect has not been observed with acute antidepressant treatment.

Science. 223 . Drevets WC. it remains unclear whether the volumetric and cellular changes observed in other brain areas are related to affective episodes. Causal relationship between stressful life events and the onset of major depression.We are optimistic that a new generation of research will clarify the relation among environmental and genetic risk factors to quantify the risk for the development of depression more precisely. Thornton LM. Marazita ML. Sugden K. et al. may be of limited benefit to those patients with refractory depression. Psycopharmacol Bull. In: Kupfer DJ. In fact. 12. Mol Psychiatry. 2002.158:587-593. The evidence discussed here indicates that. 1999. 2004 simply imitate “traditional” drugs. Karkowski-Shuman L. These data suggest that. Barrot M. Prescott CA. Sequence variations in CREB1 cosegregate with depressive disorders in women. The aim of the trophic support would be to enhance and maintain normal synaptic connectivity. Prescott CA. Those strategies assume that the target circuits are functionally intact and that changes in synaptic activity will alter the postsynaptic throughput of the system. Gold SJ. In press. Geneva. 5. Charney DS.301:386389. Kendler KS. prompt and sustained treatment may be necessary to prevent many of the injurious long-term sequelae associated with mood disorders.As a consequence. DiLeone RJ. J Clin Psychiatry. et al. and clinical research techniques are now capable of defining neurobiological phenotypes. 2003. 8. 4. Duman RS.54:177-180. and optimal long-term treatment of severe mood disorders. Biol Psychiatry.156:837-841. Kendler KS.11:240-249. preliminary studies suggest that regional structural changes in the brains of patients with mood disorders may be related with not only severity and duration of the illness. 3. No. those aiming to directly or indirectly alter monoaminergic throughput. there is a growing appreciation that optimal long-term treatment will most likely be achieved by attempting to prevent the underlying disease progression and its attendant cellular dysfunction. World Health Organization. Eisch AJ. 1997. results from transcriptomic and proteomic studies which identified neurotrophic signaling as targets for the longterm actions of antidepressants and mood stabilizers have played a role (along with neuroimaging and postmortem brain studies) in a reconceptualization about the pathophysiology.34:13-25. many patients suffering from mood disorders also have marked structural alterations in crucial neuronal circuits. somewhat similar to the treatment of other chronic medical conditions. Nestler EJ. Therefore. 10. in addition to neurochemical changes. 2. 2004. they are in fact associated with impairments of cellular plasticity and resilience.12. Manji HK. Washington. Prescott. 2001. eds. Stressful life events and genetic liability to major depression: genetic control of exposure to the environment. A Research Agenda for DSM-V. First MB. Monteggia LM. Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. 2003. Charney DS. Mental Health: New Understanding. In fact. Gould TG. therefore permitting the chemical signal to restore maximum functioning of vital circuits essential for normal affective functioning. 2003. some studies have described reduced gray matter volumes and increased ventricle size in patients with mood disorders at the time of their first episode and in early onset of the disease. rather than exclusively focusing on the treatment of signs and symptoms. Karkowski LM.Charney Dialogues in Clinical Neuroscience . DC: American Psychiatric Association. but also with altered treatment response to pharmacotherapy and ECT. 6. Gender differences in the rates of exposure to stressful life events and sensitivity to their depressogenic effects. Maher BS.Vol 6 . Stiffler HBH. Mood disorders and medical illness: a major public health problem. 9. Neurobiology of depression. The molecular medicine revolution and psychiatry: bridging the gap between basic neuroscience research and clinical psychiatry. Am J Psychiatry 2001. 2002:31-83. such as hypertension and diabetes. Although the evidence hints at an association between hippocampal atrophy and illness duration in depressed patients.Cellular plasticity and resilience and severe mood disorders . Neuron. while mood disorders are clearly not classical neurodegenerative diseases. 2 . in order to obtain an optimal treatment response. These advances will result in a dramatically different diagnostic system based upon etiology. 11. Caspi A. Brechbiel A. Manji HK.35:5-49. 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Biol Psychiatry. 2002. Nous suggérons que les médicaments conçus pour augmenter la plasticité cellulaire et la résilience et atténuer l’activité des systèmes inadaptés de réponse aux stress pourraient être utiles au traitement des troubles de l’humeur sévères.45:1085-1098. Zarate C. que se piensa son los responables de las manifestaciones conductuales y viscerales de los trastornos afectivos. funcionales y celulares que se asocian con los trastornos depresivos. Arch Gen Psychiatry. Nestler EJ. Payne J. 2000. En este artículo se describen estudios que identifican posibles anormalidades estructurales. 224 .2:185-193.57:90-93. Haydon PG. Science STKE. Drevets WC. Schwarcz R. 23.Clinical research Plasticidad celular. Manji HK. Les systèmes de neurotransmetteurs monoaminergiques ont retenu le plus d’attention. Los sistemas de neurotransmisión monoaminérgica han concitado la mayor atención. Am J Med Genet. los sistemas monoaminérgicos se distribuyen extensamente a través de la red de circuitos neuronales límbicos. De plus en plus d’études de neuro-imagerie. Manji HK. 13. eds. los que constituyen potencialmente los fundamentos celulares de estas enfermedades. et al. Lenox RH. Mind glue: implications of glial cell biology for psychiatry. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Charney DS. Glial reduction in the subgenual prefrontal cortex in mood disorders.48:766-777. les systèmes monoaminergiques sont largement distribués dans le réseau des circuits neuronaux limbiques. los mecanismos neuroquímicos y de transducción de señales que participan en la fisiopatología y el tratamiento de los trastornos afectivos han conducido hacia un significativo progreso en la comprensión de los papeles de los factores genéticos y de los estresores psicosociales. Manji HK. Un número creciente de estudios de neuroimágenes.57:925-935. De plus. Ullian EM. Endophenotypes in bipolar disorder.114:391-406. New York. 2000. debido a la observación que los antidepresivos eficaces ejercen sus efectos bioquímicos primarios a través de la regulación de las concentraciones intrasinápticas de serotonina y noradrenalina. 2001. Neurobiology of Mental Illness. Se sugiere que los fármacos diseñados para incrementar la plasticidad celular y la resiliencia. 14. en partie parce que l’on a remarqué que les principaux effets biochimiques des antidépresseurs efficaces s’exercent en régulant les concentrations intrasynaptiques de sérotonine et noradrénaline. Biol Psychiatry. The cellular neurobiology of depression. estriatales y corticales prefrontales. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Rajkowska G. The cellular neurobiology of bipolar disorder. Dans cet article. Arch Gen Psychiatry. 20.291:657-661. 2004:397-420. Miguel-Hidalgo JJ. Manji H. 2001. en parte. and depression: multiple pathways lead to increased risk and new opportunities for intervention. 16. Sapolsky RM. Proc Natl Acad Sci U S A. striataux et du cortex préfrontal supposés déterminer les manifestations comportementales et organiques des troubles de l’humeur. Ongur D. 1999. 2001. In: Charney DS. Charney DS. Science. 2004. Glia: listening and talking to the synapse. NY: Oxford University Press. Nat Rev Neurosci. Life stress.225:1-11.95:1329013295. Coyle JT.7:541-547. Quiroz J. nous décrivons des études identifiant de possibles anomalies structurelles. Wei J. genes. resiliencia y fisiopatología de los trastornos afectivos graves Los avances recientes en la identificación de los circuitos neurales. Gould T. Drevets WC. Nat Med. neuropathologie et biochimie soulignent l’altération de la plasticité cellulaire et de la résilience chez les patients souffrant de troubles de l’humeur sévères et récurrents. Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. 17. 19. pueden ser útiles para el tratamiento de los trastornos afectivos graves. fonctionnelles et cellulaires associées aux troubles dépressifs. 2000. Plasticité cellulaire. Control of synapse number by glia. y atenuar la actividad de los sistemas que determinan una mala adaptación al estrés. résilience et physiopathologie des troubles de l’humeur sévères Les progrès récents concernant l’identification des substances chimiques et circuits neuronaux et des mécanismes de transduction du signal impliqués dans la physiopathologie et le traitement des troubles de l’humeur ont amélioré la compréhension des rôles des facteurs génétiques et des facteurs psychosociaux de stress. 22. Christopherson KS. 1998. 15. qui constituent les bases cellulaires potentielles de ces pathologies. 21. Rajkowska G. neuropatológicos y bioquímicos revelan deterioros en la plasticidad celular y la resiliencia en pacientes que padecen trastornos afectivos graves y recurrentes. Barres BA. Además. Sapperstein SK. 18. Price JL. Gould TD.

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we performed a texture analysis4 of MRI images combined with a discriminant analysis. (ii) patients with Alzheimer’s disease. size. rat. coarseness. roughness. as well as in the search for further pharmacological applications in humans.1 Neuronal damage is mainly detected in hippocampus. gray-level dependence histogram. The properties of the local subpattern give rise to the perceived lightness. he epilepsy induced in the rat by lithium pilocarpine (Li-Pilo) constitutes an animal model of human mesial temporal lobe epilepsy. Vol 4. Jean-Paul Macher. At present. between October 1 and 5. Nedelec. MD. slope. 2004. MRI. The purpose here is to illustrate how texture analysis can be used in animal models and in human clinical applications. using the lipocarpine epileptic rat model as an animal model. Jean-Paul Macher.nedelec@forenap. PhD.Free paper Texture analysis of the brain: from animal models to human applications Jean-François J. France (Jean-François J. PhD. uniformity. and (iii) patients with schizophrenia. Materials and methods MRI protocol MRI images were recording using an MRI scanner operating at 4. FORENAP. schizophrenia Copyright © 2004 LLS SAS. Strasbourg. piriform cortex. color. www.6:227-233. on the theme of “Drug Development.3 In order to improve the predictive value of MRI images. fineness. textures are complex visual patterns composed of entities. Thus. epilepsy. Thus. Faculté de Médecine. It may be possible to use an alternative approach. and neocortex. France (e-mail: jeanfrancois. Olivier Yu. PhD. phase. we used MRI to explore the morphological changes resulting from an injection of Li-Pilo that leads to epilepsy. randomness. Alzheimer’s disease. and granulation. which does not rely on the absolute measurement of relaxation times. or subpatterns. France (Olivier Yu. that have characteristic brightness. A large part of the value of MRI is due to the fact that soft tissue contrast is enhanced by the substantial variation in the T1 and T2 relaxation times between tissues. Nedelec. France. Rouffach. etc.” Other articles from this meeting can be found in Dialogues in Clinical Neuroscience (2002. but the examination is often restricted to the detection of hyperintensities.The rats were anaesthetized for MRI by an intramuscular injection of 37 mg/kg ketaAuthor affiliations: FORENAP. entorhinal cortex.org T Keywords: texture analysis. frequency. Nedelec. UK).asso. All rights reserved 227 .7 tesla (SMIS. PhD. directionality.fr) This article is published following the 14th Biological Interface Conference held in Rouffach. PhD. linearity. MD. No 4). Jacques Chambron) Address for correspondence: Jean-François J. texture can be regarded as a similarity grouping in an image. smoothness. Institut de Physique Biologique. Institute for Research in Neuroscience and Neuropsychiatry. MD). thalamus. 2002. brain. BP29. MD Animal model Magnetic resonance imaging (MRI) is widely used to image brain in vivo both in studies in animal models and for human diagnosis. regularity. Jacques Chambron. magnetic resonance imaging (MRI) is the most sensitive imaging method for the study of mesial temporal lobe epilepsy. The results presented here indicate that this procedure can detect defects that cannot be visualized by classic examination and permits a more correct classification of the images. density. In previous studies. LLS SAS Dialogues Clin Neurosci. Generally speaking. 68250 Rouffach. © 2004.dialogues-cns.2. this article summarzes three different MRI studies in (i) rats.

Another possibility is the run-length matrix. obtained after the Li-Pilo protocol. a 256×256 pixel matrix. which is the matrix of the run-length frequency occurring in the image for a certain angle of sight (lines of the same pixel level).After 18 h. Animals and Li-Pilo protocol Eleven 21-day-old. which describes the spatial gray level dependencies.A T2-weighted spin-echo fastimaging method sequence (repetition time [TR]=3800 ms and echo time [TE]=80 ms) was used with 4-cm field of view. MRI images obtained before Li-Pilo treatment were considered as control group images (Figure 1) (64 ROIs were used for the texture analysis). This method has been fully described by Haralick. Retrospectively. The search for hidden defects could then be undertaken in the nonmodified images.Free paper Selected abbreviations and acronyms AD GLDH Li-Pilo MMSE ROI SE Alzheimer’s disease gray-level dependence histogram lithium-pilocarpine Mini-Mental State Examination region of interest status epilepticus ity of the texture). the rats received a subcutaneous injection of pilocarpine (30 mg/kg) and 30 min later 1 mg/kg methylscopolamine intraperitoneally. ie. Images of all the rats were performed 24 h after onset of SE. in order to reduce the peripheral consequences of pilocarpine administration. the rats received 2 mg/kg diazepam by deep intramuscular injection in order to improve their survival. The images of the 11 rats obtained before the injection of Li-Pilo served as control.5 mg/kg xylazine. correlation (relationship between two pixels). and 135°) and for each distance between two pixels forming a pair. Results In all 21-day-old rats (n=20). Discriminant analysis was used for multigroup classification. If the discrimination is successful on the basis of the set of selected parameters. 45°.2±24. Among the 20 rats followed for 4 months. presence or absence of lesions in piriform or entorhinal cortices. homogeneity (uniformity of the gray levels). Using stepwise analysis. and entropy (coarse-grained qual- 228 . mostly based on first-order and secondorder histograms derived from the co-occurrence matrix. 16 exhibited seizures.5 Statistical analysis The statistical analysis was carried out using software from Statistica. For each orientation (0°. As a preliminary step. 1-mm thickness. upon coronal slices of the whole brain. we determined the most important parameters that best discriminated the “lesion” ROIs from the “safe” ROIs observed before the Li-Pilo protocol. we checked the ability of each texture parameter to discriminate between two groups of ROIs. Two hours after onset of status epilepticus (SE). in terms of into which group they are most likely to be classified. three groups of rats could be characterized according to type of images and the possibility of late epilepsy: • Group A: 6 rats with obvious lesions characterized by a hypersignal on T2-weighted images in the piriform or entorhinal cortices 24 h after the SE (Figure 1. • Group B: 4 rats with control-like images (without any hypersignals). 44 ROIs were used for texture analysis). Statsoft Inc. 90°.6 days (mean±SD). pilocarpine injections led to SE within about 50 min. Sprague-Dawley rats were used for the experiments. However. whereas 4 did not. in order to discriminate between lesion and safe ROIs. The question to be answered here is whether the two groups are well distinguished on the basis of the set of texture parameters. which did not present late epilepsy (34 ROIs were used for texture analysis). as shown in Figure 1. it makes sense to classify particular piriform or entorhinal cortices in terms of group membership. a number of co-occurrence matrix parameters may be calculated: contrast (an uneven texture provides large/high contrast values). The software MaZda was used to analyze the texture of the digitized images within all regions of interest (ROI) and yielded 300 parameters.4 The co-occurrence matrix is based on the probability that pairs of pixels with a given level will appear. but which subse- mine and 5. only 80% of rats were still epileptic after a mean delay of 70. • Group C: 10 rats with control-like images (without any hypersignals). All the rats first received lithium chloride (3 mEq/kg) intraperitoneally. Texture analysis Conventional texture analysis was performed using statistical methods. male. as shown Figure 1. ie. all these rats exhibited late epileptic seizures.

predicting the late chronic epilepsy in 10 rats.Texture analysis of the brain . Therefore. but subsequently became epileptic. Groups and classification of rats. Group A exhibited late epileptic seizures. During the 4 months’ clinical follow-up. The resulting classification gave 84 control ROIs and 30 lesion ROIs. Group C had control-like images. Each Group Rats (n) Number of ROIs used in texture analysis Hyperintensity of piriform and entorhinal cortices Texture and discriminant analysis classification of ROIs Prediction of disease Effective chronic epilepsy Human applications in AD The method of gray-level dependence histograms (GLDH) as defined by Chetverikov for 2D7 and generalized to 3D by Kovalev and Petrou8-10 leads to derived features of texture anisotropy from MRI data. The aim A 6 44 Yes 42 lesions 2 control 6 epilepsy Yes B 4 34 No 8 lesions 26 control 2 safe 2 epilepsy No C 10 80 No 22 lesions 58 control 10 epilepsy Yes Table I. but subsequently became epileptic.Vol 6 .6 Group B Group C Figure 1. among which 2 had been incorrectly classified as epileptic (Table I). according to the highest classification score. region of interest.Nedelec et al Dialogues in Clinical Neuroscience . both in the modified images of 6 rats and in the images of 4 rats with apparently nonmodified images. 229 . The above classification process was then used as a basis for prediction for the 114 apparently normal ROIs from the 57 brain slices of the rats in groups B and C. 2 . the conventional MRI study could not predict the fate of the 10 rats in group C. About 50% of the lesion ROIs of the other 12 rats were distributed bilaterally (10 rats in group C and 2 rats in group B). For a given ROI. Group A exhibited late epileptic seizures.This missed latent disease in 3 rats. quently became spontaneously epileptic (80 ROIs were used for texture analysis). Preliminary discriminant analysis yielded a classification function corresponding to the control group or group A. 2004 Control Group A ROI was then classified into one group or the other. The combined texture and discriminant analyses that were based on pixel pattern abnormalities selected 3 texture parameters that characterized structural abnormalities relevant to the hypersignal. Group B presented no late epilepsy. No.The classification based on early texture abnormalities in the piriform and entorhinal cortices improved the results of the regular MRI study. only 2 rats had control ROIs and were safe (group B). The results of the texture analysis yielded 200 texture parameters in each ROI. Each function was a linear combination of the features (or texture parameters) that yielded the best discrimination. Magnetic resonance imaging (MRI) scans in rats before treatment (Control) and after treatments with lithium pilocarpine (Lipilo). 10 rats became epileptic and 4 rats remained nonepileptic. Group C had control-like images. a classification score was calculated from the classification functions. ROI. described by the texture parameters. Discussion and conclusion The MRI study that was based only on the presence of hyperintensity signals in the piriform and entorhinal cortices predicted 6 late chronic epilepsy and 5 safe rats. but subsequently became epileptic. Group B presented no late epilepsy. which did not display visible lesions in their brain images 24 h after SE. Indeed.

at a time when there may have been ongoing structural brain changes. and scores below 10 indicate severe dementia. Each data set had 180×180×124 pixels and the voxel size was 0. The coefficients of such an expansion can characterize any 3D closed surface: coefficient A0. a normalization set is used in order to have the same relative gray level values for different scans: the smallest gray-level value is assigned to 1 and the highest to 255 for the segmented scan. The isotropic features of the histogram are related to brain pathology.0 is the mean radius of the indicatrix. While many features correlate well with the MMSE scores. gray matter.d). five different distances d were used: 0. etc). We can then calculate the quantity h (φ.9375. the relative gray values of the voxels are extremely important. Projections of the orientation histograms can be obtained as illustrated in Figure 2 for a control subject and an AD patient.Two of the scores do not match the clinical diagnosis: AD3 and CO2.9375×1. Thus.9375×0. Projections of the orientation histogram on the z=0 plane obtained from MRI T1 images: from an Alzheimer’s disease patient (left) and a healthy volunteer (right). the function h must be independent of direction and therefore a 3D representation is a sphere. as well as the border between the two types of tissues. 2. and 3 mm. Figure 3 illustrates the best correlation (-0.12 The brains were further segmented to isolate the white and gray matter.5 mm. and the border between gray and white matter. Subject AD3 is interesting because this patient was imaged before the onset of the first clinical symptoms. One component of h is the number of pairs of voxels that are at distance d from each other. The pair of values φ. The scores obtained in the AD patients (named AD1 to AD13) and the control volunteers (named CO1 to CO12) are displayed in Table II. Figure 2.Free paper was to evaluate Alzheimer’s disease (AD) patients for a correlation between the anisotropic features and their score on the Mini-Mental State Examination (MMSE). The maximum score is 30 (typically above 29 for healthy volunteers).11 Methods Two groups of subjects were investigated and analyzed in this study: 12 control volunteers and 13 AD patients. which is routinely used to help diagnose AD. and the local mean curvature.The mean age (range) at time of investigation was 56. Any deviation from this shape indicates anisotropy in the data. 0 is assigned to the voxels that do not belong to the ROI. any other nonzero coefficient represents different types of anisotropy. 2. Because the texture analysis technique effectively counts the number of pairs of voxels that appear in the same relative position and have certain fixed gray values. bones.5. MRI T1-weighted images with coronal orientation were recorded for each subject. MMSE score and correlation with the isotropy coefficient The MMSE score is used to detect dementia. 3D texture representation: isotropy or anisotropy A coordinate system is defined as a cube of data cube in which the x and y axes form the plane of each slice. Another set of features can be extracted by expanding the indicatrix in terms of spherical harmonics. white matter. The control group was matched with the AD group in terms of age and gender.876) with the MMSE score. In every single region. The 3D representation for a fixed distance is a closed digital surface. Scores between 10 and 24 are considered to indicate mildto-moderate dementia cases. along the direction φ .9375 mm.z with one member of the pair having a gray value k and the other l.5. 230 .z defines a unique orientation in 3D space.1 in gray matter for a distance of 0. The azimuthal angle φ is measured on the x.y plane away from the direction of the x axis. The scans were segmented to isolate the brain from external structures (eyes. and the z axis is perpendicular to each slice. Anisotropic features were extracted from four brain regions: the whole brain. the integral anisotropy measure or standard deviation.z. which is called an indicatrix. ventricles. 1.77 (39-72) years for the AD patients and 58. If the data are isotropic. Feature extraction Three features are used to analyze the shape of the 3D indicatrix9: the anisotropy coefficient. which was obtained for the feature A1.33 (47-72) years for the control volunteers.

The co-occurrence matrix is a generalized histogram. the AD brains presented greater anisotropy in their gray matter texture than the control brains. G control volunteers (CO1. Both 2D features and 3D features correlate with the MMSE score. Usually the main characteristic used is the gray value of the image. For the texture analysis. AD2. 231 . which records the frequency with which a certain combination of characteristics appear in the relevant position.856-mm spatial resolution with interslice distance of 3 mm. The features computed reflected the microtextural properties of the brain. CO2. Copyright © 2001 IEEE. etc). Texture features that correlate with the Mini Mental State Examination (MMSE) Score. Moreover. Each data set consisted of slices with a 0. Petrou M. which can then be used for classification. The anisotropic sampling of the data along the z axis (interslice direction) is handled by an appropriate scaling factor of 3. they correlate better with the condition of the subject rather than with age.9375 mm versus the score on the Mini-Mental State Examination (MMSE). In general.856) for all data sets. 3D MRI T2-weighted images were collected for each subject. co-occurrence matrices offer AD13 10 Alzheimer’s disease Patient MMSE score AD1 25 AD2 8 AD3 30 AD4 25 AD5 23 AD6 25 AD7 28 AD8 22 AD9 19 AD10 AD11 14 AD12 24 AD13 12 Controls Subject MMSE score CO1 30 CO2 28 CO3 30 CO4 29 CO5 30 CO6 30 CO7 29 CO8 30 CO9 30 CO10 30 CO11 30 CO12 30 AD2 8 6 A 1.Nedelec et al Dialogues in Clinical Neuroscience . AD3. and social class.13 Methods Two groups of subjects were investigated and analyzed in this study: 19 control subjects and 21 patients with schizophrenia.14 3D texture analysis Human applications in schizophrenia Texture analysis can also provide feature parameters for different classes. 2001:910-913.5 (3/0. reproducibility and comparability are ensured.1 AD11 AD9 AD8 AD4 AD1 AD12 CO5 CO4 CO10 CO6 CO11 CO1 CO12 CO3 CO6 CO9 30 4 2 AD6 0 10 15 20 MMSE AD5 25 AD3 CO7 AD7 CO2 Figure 3. The images were segmented such that only the brain component was extracted for further analysis. 2004 Discussion and conclusion The GLDH method can be used to produce many features that strongly correlated with the MMSE scores when applied to the gray matter components of the MRI T1 scans. indicating that the information is already available in each individual layer. The controls were matched for age. and the requirements that are of interest have to be specified from the outset. The ROI approach has a number of potential problems: inter. etc) and controls (CO1. EMBS Proc. AD3. Mini-Mental State Examination (MMSE) score for subjects with Alzheimer’s disease (AD1. AD2. This approach does not need prior hypotheses and. rather than the shape of each ROI. CO3. difficulties detecting neuroanatomic boundaries.Texture analysis of the brain .Vol 6 . such as gradient magnitude or relative orientation of the gradient vectors. Because they are independent of rotation and translation of the data.and intraoperator reproducibility. CO3. Crum W. ie. Reproduced from reference 13: Segovia-Martinez M. we use generalized co-occurrence matrices. the texture anisotropy at scales of the order of 1 mm. because it is automated. gender. 2 . etc). No. Table II. G Alzheimer’s disease patient (AD1. etc). but other features can be used. 1| in gray matter for d=0. CO2. Generalized 4D co-occurrence matrices have been used to analyze the 3D MRI T2-weighted brain images from controls and patients with schizophrenia. Feature |A1.

15 In each experiment. Strzelecki M. where w is the frequency of the occurrence of a voxel pair i. 5. Lodz. as illustrated in Figure 4. REFERENCES 1.j).5 and so only the features with t>5. 1989. Leroy C. 232 . This was handled inside the EEC COST-B 11 Action entitled “Quantitative magnetic resonance imaging texture.5 were used.The division of the brain was performed by identifying the slices that are anatomically most similar to slices 12 and 24 of the anatomical atlas of Talairach and Tournoux. IEEE Proc.5.” led by Dr R. extension to potential applications for humans can be considered. When the bottom quarter of the brain was used. Finally. a(i.5 were retained and only 2 subjects were misclassified. 1979. In fact. 2002. Haralick RM. Bortolotto ZA. and 14 subjects was misclassified. an angle a(i. Roch C. Namer. from the three series of analysis performed. and V. The feature were selected by thresholding the t values using various limits. Turski L. there were too many features with t>4. Using the bottom half of the brain. g(j). Once the pharmacological aspect in the rat model is clearly demonstrated. Drug effects could also be investigated in order to evaluate whether brain anisotropy or asymmetry varies during drug therapy. 2001. and a distance d(i.j) from each other. Results Three series of experiments were conducted: one considering the whole brain. Epilepsia. Kociołek M. The calculated co-occurrence matrix was w[g(i). with gradient magnitude g(i) and g(j) respectively.Free paper descriptors that include these properties.j) between their gradient vectors. Kovalev. the features were so good that only features with t>7.67:786-804.j. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Namer IJ. Nehlig A. Nehlig A.3:154-171. Magnetic resonance imaging in the study of the lithium-pilocarpine model of temporal lobe epilepsy in adult rats. one considering the bottom half of the brain. 2. Materka A.42(suppl 7):233. 18-21 September 2001. 2D scattergram produced by projecting the high-dimensional feature space onto a 2D feature space and preserving the euclidean distances between the points. and schizophrenia. it was demonstrated that the co-occurrence matrices could characterize the two classes of subjects with 90% accuracy using 3D T2-weighted MRI. and one considering the bottom quarter of the brain. 2001:255-261. Cavalheiro EA. and only 7 subjects were misclassified. For the whole brain. J. d(i. Proceedings of the International Conference on Signals and Electronic Systems. Epilepsia. each element of the co-occurrence matrix was tested as a class discriminator according to the t test. 3. Namer IJ. Dr M. Lerki. The classification was then performed using Statistica software. Turski WA. Roch C. dementia. Computer program for image texture analysis. Petrou.j)]]. Finally. Leroy C. Conclusions The most significant conclusion is that the brains of patients with schizophrenia show structural differences from the brains of the control subject. Cholinergic mechanisms and epileptogenesis. Figure 4. Moreover. A. Poland. such an analysis could be correlated with neurocognitive tests to measure improvements in subjects’ performance. Statistical and structural approaches to texture.43:325-335. 4. Perspectives 8 6 4 2 0 -2 -4 -6 -20 Control subject Schizophrenic patient -15 -10 -5 0 5 10 15 20 Texture analysis is a new approach for image analysis. it appears that these differences are located in the bottom quarter of the brain. Ikonomidou C. who allowed their original data to be included in this overview. brain plasticity could be assessed with such a technique in brain diseases such as epilepsy. Predictive value of cortical injury on the development temporal lobe epilepsy in immature rats: a magnetic resonance imaging (MRI) approach using the lithium-pilocarpine model. Szczypiński P. the best results were obtained by retaining the features with t>4. ❏ The authors thank Dr I. Synapse.

IEEE Trans Med Imaging. orientación. Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. l’une menée dans un modèle animal de rat rendu épileptique par la pilocarpine. Segovia-Martinez M. d’inégalité.Vol 6 . Le présent article se propose d’illustrer comment l’analyse de la texture peut être utilisée dans des modèles animaux et dans des applications cliniques humaines. densidad. fineza. 2004 6. 11. ángulo.20:771-775.Texture analysis of the brain . IEEE Trans Med Imaging. de régularité. Análisis de la textura del cerebro: desde los modelos animales a las aplicaciones en el hombre Las imágenes de resonancia magnética (IRM) se utilizan ampliamente para estudiar cerebros in vivo. 2002. Les propriétés d’un sous-motif local sont à l’origine de ce qui est perçu en termes de luminosité. tersura y granulaciones.20:424-433. 2 . un angle. d’aspect lisse et de granulation. la seconde chez des patients atteints de maladie d’Alzheimer et la troisième chez des schizophrènes. utilizando el modelo de rata epiléptica por lipocarpina. De façon générale. grosor. de densité. Fox N. 233 . Kovalev VA. qui ne s’appuie pas sur la mesure absolue des temps de relaxation. aspereza. una textura puede considerarse una agrupación de unidades semejantes en una imagen. 1994:1071-1073. 7. etc. Crum W. En general. alineación. Kruggel F. Magn Reson Imaging. les textures résultent de motifs visuels complexes composés d’entités et de sousmotifs ayant une brillance. Kovalev VA. Texture anisotropy in 3D images. Israel. de direction.58:187-197. Talairach J. une taille. 1999.8:346-360. uniformidad. Jerusalem. MR image texture analysis applied to the diagnosis and tracking of Alzheimer’s disease. fase. ainsi que dans la recherche d’applications pharmacologiques futures chez l’homme. De esta forma. Graph Models Image Processing. Texture features that correlate with the Mini-Mental state Examination (MMSE) Score. 14. tant sur le plan expérimental dans les modèles animaux que dans une visée diagnostique chez l’homme. de phase. al igual que en la investigación de futuras aplicaciones farmacológicas en el hombre. d’aspect aléatoire. 9. característicos. frecuencia. etc. 2001:910-913. aspecto aleatorio. 8. Detection of late epilepsy by texture analysis of MR brain images in the lithium pilocarpine model. 1998. Namer IJ. IEEE Trans Image Processing. Bondar YS. de finesse. J Psychiatr Res. 1999. Fosltein M. Texture anisotropy in 3D images. Las propiedades de la subconfiguración local determinan la percepción de luminosidad. Se presentan tres estudios diferentes de IRM: (1) en animales. de linéarité. El presente artículo se propone ilustrar cómo se puede aplicar el análisis de la textura en modelos animales y en clínica humana. GLDH-based analysis of texture anisotoropy and symmetry: an experimental study. de fréquence.. Trois études IRM y sont présentées.l8:346-360. NY: Thieme. McHugh P. las texturas son patrones visuales complejos compuestos de entidades o subconfiguraciones que tienen brillo. Folstein S. regularidad. 1996. 1975. 2001. Kovalev V.Nedelec et al Dialogues in Clinical Neuroscience . Gran parte del valor de las IRM se relaciona con el hecho que el contraste del tejido blando se acentúa por la variación importante de los tiempos de relajación T1 y T2 entre los tejidos. Une texture donnée peut donc être considérée comme un groupement de similitudes au sein d’une image. caractéristiques. New York. Yu O. une couleur. Gertz HJ. Il est peut-être possible d’utiliser une autre approche. tamaño. EMBS Proc. Chetverikov D. tanto a nivel experimental en modelos animales como para orientaciones diagnósticas en el hombre. Roch C. IEEE Trans Image Processing. d’uniformité. No. Multidimensional co-occurrence matrices for object recognition and matching. In: Proceedings 12th IPCR. Kovalev VA. (2) en pacientes con enfermedad de Alzheimer y (3) en pacientes con esquizofrenia. Puede ser posible el empleo de una aproximación alternativa que no se basa en la medición absoluta de los tiempos de relajación. de grossièreté. Petrou M. von Cramon DY.12:189-198. 1988. 12.17:475-479. Tournoux P. 10. Freeborough P. Coplanar Stereotaxic Atlas of the Human Brain. Three-dimensional texture analysis of MRI brain datasets. Une grande partie de la valeur de l’IRM est liée au fait que le contraste du tissu mou est accentué par la variation importante des temps de relaxation T1 et T2 dans les divers tissus. Analyse de la texture du cerveau : des modèles animaux aux applications humaines L’imagerie par résonance magnétique (IRM) est largement utilisée dans les études du cerveau in vivo. Chambron J. Petrou M. color. Petrou M. 15. 13. Petrou M. Mauss Y.

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The main problem in texture analysis with MRI is to avoid this artificial texture and minimize its influence. No 4). A fundamental part of the work involves careful study of the optimal MRI data collection strategies for texture analysis. which can be dramatically varied during imaging. Germany Address for correspondence: Department of Biophysics and Medical Radiation Physics. Careful investigation of the dependence of all these variables using texture phantoms (test objects) will help understand how MRI image texture is formed from tissue structures. since different centers may vary their measuring sequences and acquisition protocols for their clinical investigations. Long-term stability is also vital. parameters. magnetic resonance imaging (MRI) has become recognized as a powerful in vivo diagnostic tool. it is essential to design and test reliable and accurate test objects for a detailed assessment of texture analysis methods in MRI. aimed at the development of quantitative methods for MRI texture analysis. The objective of this article is to discuss developments in quantitative MRI—and particularly texture analysis—that maximize diagnostic information. This is critical. M Copyright © 2004 LLS SAS. on the theme of “Drug Development. The main feature of these test objects is their ability to simulate tissue-like textures with tissue-like MR relaxation properties. German Cancer Research Centre. 2002. D-69009 Heidelberg. see the article by Materka in this volume2 or references 3 to 7.6:235-242. © 2004. Vol 4. agnetic resonance imaging (MRI) is one of the most exciting imaging technologies for texture analysis: it offers the best soft tissue contrast.org . and different measuring parameters produce totally different patterns in texture.Free paper Problems in texture analysis with magnetic resonance imaging Lothar R. Im Neuenheimer Feld 280. different techniques and imaging parameters produce totally different patterns in the texture parameters of the same tissues in clinical examinations with different sensitivity to artificial texture overlaid by the scanner. PhD Since its introduction in the 1980s. Therefore.Schad@DKFZ-Heidelberg. and software. and may be reluctant to vary these for texture investigation.” Other articles from this meeting can be found in Dialogues in Clinical Neuroscience (2002. The basic problem in quantitative MRI texture analysis is the large number of different measuring techniques and imaging parameters. brain.This is critical. 2004. Careful study of the dependence of texture parameters on MRI data collection strategy is essential for texture analysis in order to avoid artificial texture from the scanner. The presented work was performed in the framework of a European research project COST (Cooperation in the Field of Scientific and Technical Research) B11 between 1998 and 2002 by institutions from 13 European countries. German Cancer Research Centre. All rights reserved 235 www. as is uniformity of the overall texture. gradient echo.dialogues-cns. LLS SAS Dialogues Clin Neurosci. Another aspect is to examine the test objects under a whole range of MRI measuring sequences and imaging conditions using different scanners to determine their stability and utility. France. because different centers may vary their measuring sequences and acquisition protocols for clinical reasons. Keywords: texture analysis.1 For further detail of texture analysis. Heidelberg. Different measuring techniques. which can be easily changed during a clinical examination. Germany (e-mail: L. between October 1 and 5. magnetic resonance imaging. trabecular bone Author affiliations: Department of Biophysics and Medical Radiation Physics. Thus. and echo planar.de) This article is published following the 14th Biological Interface Conference held in Rouffach. such as spin echo. Schad.

Free paper
Selected abbreviations and acronyms
EPI FLASH FOV MA RF ROI SNR TE TH TR echo planar imaging fast low angle shot field of view matrix size radio frequency region of interest signal-to-noise ratio spin echo time slice thickness repetition time (T2), which are most responsible for tissue contrast and texture.According to the theoretical equation for the spin echo signal9: S ≈ ρ ⋅ (1−e-TR/T1) ⋅ e-TE/T2 [1]

Material and methods
The complexity of this problem can be demonstrated by considering a typical measuring spin echo sequence as measured by a commercial whole-body imager. Various parameters can be easily changed during clinical investigation: image contrast is mainly defined by repetition time (TR) and spin echo time (TE); image resolution is defined by slice thickness (TH), field of view (FOV), and matrix size (MA), which also influence texture analysis.The parameters of k-space acquisition and reconstruction are very important: k-space is the artificial space in which the raw MRI data are collected, and the image contrast and texture is very sensitive to k-space strategies. Other parameters like coil setup and number of active coil segments are also responsible for signal and flip angle (α) variations in the image. Careful investigation of the dependence of all these variables will help understand how MRI image texture is formed in tissue structures. In our studies, MRI acquisition was performed in the standard head coil of a 1.5-T scanner (Siemens Vision, Erlangen, Germany). Spin echo technique One of the most important measuring techniques in clinical diagnosis is the spin echo sequence, in which 90° and 180° radio frequency (RF) pulses produce the spin echo signal. In addition, gradients are used in x, y, and z directions to localize the signal.8 The advantages of this technique are reduced artifacts, clearly defined contrast, and common availability. The disadvantages are the contrast dependency on RF pulse quality, and slice cross-talking, which is typical of a two-dimensional (2D) technique. This imaging technique allows measurement of the three relevant MRI tissue parameters: spin density (ρ), spin-lattice relaxation time (T1), and spin-spin relaxation time

in which S is the spin echo signal, the contrast ρ can be created by a long TR and short TE, resulting in a flat image contrast and texture at high signal intensity (Figure 1a).T1 contrast can be created by short TR and short TE in spin echo imaging (Figure 1b). On the other hand, T2 contrast is created by long TR and long TE, mainly reflecting the water content of the tissue (Figure 1c). These three physical tissue parameters are described in reference 1.The real physical properties of tissues may be obscured by artificial contrast and texture from the scanner. Slice profile Slice profile is defined by the slice gradient and the shape of the RF pulse. Ideally, we would like to measure a rectangular slice, but due to technical reasons the real slice profile is Gaussian shaped. The consequence is that we have signal contributions from neighboring slices that influence the tissue texture. To minimize this effect, an interleaved slicing scheme is used in multislice 2D imaging. k-space Another aspect of artificial texture is connected to the kspace, which describes the strategy for raw data collection. The k-space contains the measured signal frequencies kx and ky, the so-called hologram from which the real MRI image can be calculated by a Fourier transform

A

B

C

Figure 1. Spin echo images of a patient with meningioma. A. ρ-image (TR/TE = 2000 ms/10 ms). B. T1 image (TR/TE = 600 ms/10 ms). C. T2 image (TR/TE 2000 ms/100 ms). TR, repetition time; TE, spin echo time.

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Dialogues in Clinical Neuroscience - Vol 6 . No. 2 . 2004

(Figure 2). Some imaging techniques measure only every second line in the k-space to speed up the imaging sequence, which results in a reduction in the signal-tonoise ratio (SNR) by 1/√2 and aliasing artifacts, with consequences for image texture. Restriction to the center of the k-space with zero filling of the outer part results in the same SNR effect without aliasing. RF excitation Another important variable is the RF characteristic and sensitivity of the transmitting and/or receiving coil, which can produce a lot of artificial texture from the scanner. This is demonstrated in Figure 3 using hard image scaling, which shows a clear signal inhomogeneity due to nonideal RF pulses at the outer range of the phantom (ie, coil). Another coil effect on image texture is produced with coil arrays, where the summarized image is a result of the combination of single coils, each of which contributes its own coil characteristics (eg, SNR, sensitivity, and RF excitation profile) to the summarized image. This means that image texture could slightly differ between the object center and the object boundary, where protons are close or far away from the center of the coil. Gradient echo techniques Significant effects on image contrast and texture are introduced by the imaging sequence itself, since the imaging signal can have a very complex dependence on the physical properties of the underlying tissue. One example is the so-

called gradient echo technique like FLASH (fast low angle shot),10 where the 90° and 180° RF pulses are replaced by a low-angle RF pulse with a bipolar gradient scheme resulting in a gradient echo signal. This measuring technique can be used as fast imaging 2D technique or as a real 3D imaging technique because of the compact timing of the sequence. On the other hand, the FLASH signal has a complex dependence on T1, the local spin-spin relaxation time (T2*), and the flip angle α, according to: S ≈ A ⋅ e-TE/T2* with A = ρ ⋅ sin ⋅ 1− e-TR/T1 1− cos ⋅ e-TR/T1 [2]

A

B
y

C

Fourier transformation

x ky

D

E

k-space kx

Figure 2. The effect of k-space filling on image contrast and texture. The example demonstrates the strong dependence of image texture on the k-space filling factor as used in so-called “keyhole” techniques.

Figure 3. Effect of radio frequency (RF) profile of the head coil on image contrast and texture. A. Phantom measurement demonstrating the signal inhomogeneity due to nonideal RF pulses at the outer range of the image (ie, coil). B to E. Result of a measurement using coil arrays, where the summarized image is a result of the combination of the single coils, which contribute with their own coil characteristic (signal-to-noise ratio, sensitivity, and RF excitation profile) to the contrast and texture of the image.

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Thus, the different flip angle distributions produced by the coil characteristics result in different signals, and as a consequence in different image texture patterns as demonstrated in Figure 4. A very complex signal and texture situation is present in so-called single shot imaging techniques like echo planar imaging (EPI),11 where k-space is filled in one shot with multiple gradient echoes. This is achieved by a gradient scheme in which the upper corner of the k-space is reached by a single gradient pulse followed by a series of blips resulting in a rectangular movement through the kspace. This technique is very sensitive to local susceptibility artifacts, resulting in image distortions and strong T2* contrast dependence. Some special imaging techniques like spiral imaging can produce a very complex pattern in the image texture, since this single shot technique moves on a spiral through the k-space, which can be achieved by oscillating gradients with a phase shift of 90° in the x and y directions. This technique requires data interpolation in k-space to bring the measured data onto a Cartesian coordinate system before Fourier transform. This interpolation can produce spurious artifacts with the consequence that the image texture is dependent on k-space interpolation and image reconstruction. In addition, the problem of texture dependence on measuring technique is more complicated due to the large number of imaging sequences available on modern scanners, as illustrated in Figure 5.

Results and discussion
SNR dependence Figures 6a and 6b show the results of a FLASH experiment in a normal volunteer for SNR dependence measurement of texture parameters. The measuring parameters of the FLASH experiment were: TR/TE/α = 2 ms/ 9 ms/30°; bandwidth (BW) = 195 Hz/pixel; MA = 512×512; FOV = 280 mm; TH = 2 mm; and acquisitions (AQ) = 1 to 324 resulting in an SNR = 1 to 18. Texture parameters (SNR, entropy 5×5, correlation 5×5) of white matter, gray matter, and noise are shown as a function of the number of acquisitions (=SNR2). Figure 6c demonstrates that no texture can be measured in white matter using standard image resolution (0.5×0.5×2 mm3) as described above, since the SNR of white matter has the same characteristics as noise. In contrast, the SNR of gray matter reaches a nearly constant value at about 16 acquisitions and no further improvement can be reached due to the true underlying texture of the tissue. The same observation holds for a typical parameter of microtexture, like entropy 5×5 (Figure 6d), while no dependence

A

B

Figure 4. Example of a 3D FLASH (fast low angle shot) dataset of a normal volunteer measured by the conventional head coil. A. Excellent T1 contrast in the original transversal images. B. A strong signal inhomogeneity is obvious in the reconstructed sagittal images as seen in the homogeneous phantom and corresponding anatomical structures, like upper part of the brain and cerebellum. This artifact is due to the radio frequency excitation profile of the head coil, which produces different T1 weightings and signal amplitudes as a function of the flip angle according to the FLASH formula (Equation 2).

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One milliliter of 0. Sketch of the family of imaging techniques available on modern scanners. RARE. SPGR. magnetization prepared gradient echo imaging. There are many strategies of mixing spin echoes with gradient echoes to speed up imaging time with the consequence of very complex image contrast and texture.25 to 2 mm. half-Fourier acquisition single-shot turbo SE.1% NaN3 was added per liter of agar for microbiological stability. TFLAIR. Berlin) solution at a concentration of 1:4000. Phantom tubes containing foams with coarse. fast spin echo. T2-FFE. T1-weighted fast field echo. Fourier-acquired steady state. GRASS. MPRAGE. and so a careful preparation of the foam phantoms is necessary. 2004 on SNR can be detected for a typical parameter of macrotexture. 1. spoiled gradient recalled acquisition into steady state. 239 . FAST. fast low angle shot.2 to 3. No. echo planar imaging. fast spoiled gradient recalled acquisition into steady state. TFLAIR HASTE MPRAGE turboFLASH snapshotFLASH FSPGR PSLF trueFISP CISS DESS PSIF CE-FAST FISP GRASS FAST T2-FFE FLASH SPGR T1-FFE spoiled FAST FLASH TSE.Schad Dialogues in Clinical Neuroscience . middle. FSE. SE. EPI.15 mm. or mechanically separated spheres of diameter 0.15 mm.8 to 1. dual echo steady state. T2weighted fast field echo.5 and 2. TSE.13 Normalization A texture test object (PSAG) was developed on the basis of polystyrene (PS) and agar solution (AG) to mimic texture properties artificially. With this setup several 3D data sets with different imaging parameters were MPR EPI TGSE GSE GRASE TIR TIR. Two types of spheres were used for the phantom construction: randomly distributed spheres of diameter 0. FISP.Problems in texture analysis with MRI . TIRM. gradient recalled acquisition into steady state. GRASE. TIRM. TGSE.CISS. FSE RARE TSE IR CSE SE Fourier-coding K-space GRE Figure 5. 2 . Copyright © Siemens.8 cm were filled with spheres and by EPI TGSE a hot solution of 4% agar (free and doped with DyCl3). PS spheres are available from the technological process of PS production. turbo fluid attenuated IR. conventional SE. gradient and spin echo. FSPGR. inversion recovery.Vol 6 . and fine density were constructed and filled with a Magnevist® (Schering. DESS. spin echo. constructive interference in the steady state. Polyethylene tubes of diameter 1. or 2 to 3.14 A second texture test object containing foam at different densities in Gd-DTPA solution was used to describe microtexture properties. a sufficient SNR>4 is necessary to measure the real textural behavior of the human brain. which create susceptibility artifacts in the images. FLASH.25 mm. Both types of phantoms were placed next to the head of a volunteer and a position for the imaging slab was chosen such that all vials and part of the volunteer’s brain were contained in the 3D slab. fast imaging with steady precession. HASTE. like correlation 5×5 (Figure 6e).12. turbo SE. Based on this observation. turbo GSE. gradient SE. IR. turbo IR magnitidue. rapid acquisition with relaxation enhancement. T1-FFE. GSE. CSE. Problems with the foam phantoms are air bubbles. turbo IR. TIR.

C to E.15 White matter A C 60 50 B SNR (mean/SD) 40 30 20 10 0 1 4 9 16 25 36 49 64 Noise A Gray matter 81 100 121 144 169 196 225 256 289 324 Number of acquisitions D 1.3 0. indicating that a normalization of texture parameters using test objects is possible (Figure 7).3 White matter 0.3 1.1 -0. Three-dimensional FLASH (fast low angle shot) image of a patient with glioblastoma with texture test objects located beside the head for testing texture normalization.1 0.7 0. texture parameters such as mean gradient show the same behavior in phantoms as in white matter for different patients.1 Phantom spheres 0.4 0.5 0.3 0.25 E 0.0 1 Entropy 5x5 Gray matter White matter Noise 4 9 16 25 36 49 64 81 100 121 144 169 196 225 256 289 324 Number of acquisitions B 0.5 Correlation 5x5 Mean gradient 0.10 -0. and noise are shown as a function of the number of acquisitions (=SNR2). as well as the dependence of the texture parameters on different imaging parameters (eg.05 -0. Figure 7. Texture parameters such as mean gradient show the same behavior in the phantom as in white matter for different patients. In a pilot study. Texture parameters (SNR.5 1 4 9 16 25 36 49 64 81 100 121 144 169 196 225 256 289 324 733 735 737 807 Number of acquisitions Patient number Figure 6.6 0.Free paper acquired to demonstrate the influence of resolution and SNR.TE). entropy 5×5.TR.5 1. 240 . SD. B. texture normalization is necessary. correlation 5×5) of white matter. standard deviation.9 0.1 1.2 0.4 1. FLASH (fast low angle shot) images of a normal volunteer for measuring signal-to-noise (SNR) dependence of texture parameters at (A) SNR =1 (1 acquisition) and (B) SNR =18 (324 acquisitions).20 0. gray matter. However. α.15 0.2 1.8 0. indicating that normalization of texture parameters using test objects is possible. A.0 0. but it is not possible to mimic all texture features by phantoms.

67:258-266. Schad LR. Lundervold A. Germany.eletel. A C 1780 Run length nonuniformity B 1740 ≈ 6% 1700 1660 Direction Horizontal Vertical 45° 135° 1620 Figure 8. Norway). UK. 2004 Clinical application The aim of this pilot study was to assess the possibility of quantitative description of texture directivity in trabecular bone with an attempt to quantitative description of trabecular bone structural anisotropy using texture analysis of 3D FLASH MRI. Noise removal with tissue boundary preservation using fourth-order partial differential equations. Lundervold A. Materka A. 11.Vol 6 . with the voxel size of 0. Texture analysis methodologies for magnetic resonance imaging.Problems in texture analysis with MRI . Mansfield P. were measured on a standard 1.11:889-896. Zuna I. Merboldt KD.4×0. ed.13:577-587. Strzelecki M. Poland). Haralick R. MR tissue characterization of intracranial tumors by means of texture analysis. Hahn EL. COST B11. Statistical and structural approaches to texture. Straughan K. 13. 3. Lysaker M. Quantitation of Magnetic Resonance Image Texture. Accessed 3 December 2003. Applied Mathematics in our Changing World. Lorenz WJ. Tai XC. Paris. Schad L. circular regions of interest (ROI) were marked on corresponding bone cross-sections and effort has been made to maintain a large-size ROI for better statistical significance of texture parameters. REFERENCES 1. European Society for Magnetic Resonance in Medicine and Biology. 1993. Czech Republic). Dialogues Clin Neurosci. 2000.uib. 5. Scotland). 2 . Bock M. Hájek M. Haase A. Feature evaluation of texture test objects for magnetic resonance imaging. Quantitative analysis of this directivity is important to medical diagnosis.10:L55-L58. France. FLASH imaging. Tai XC. Herynek V. Singapore: World Scientific. Matthaei D. eg. Hänicke W. 6. Arvid Lundervold (University Bergen. Noise removal with tissue boundary preservation. Milan Hajek (University Prague.lodz. 2. Textural features for image classification. No. 1993.67:786-804. Multi-planar image formation using NMR spin echoes. Magn Reson Imaging. Schad L.Schad Dialogues in Clinical Neuroscience .11:343. eg.9:126. 17th Annual Meeting. Mag Reson Imaging. Quantitative analysis of this directivity is important to medical diagnosis. Lerski R.3:610-621. 1986. MAGMA. 10. Dinstein I. Blüml S. Semmler W. 2001. 2004.11:873-887.4 mm3. Brix G. 14. Blüml S. Materka A. 1979. Schad LR. Department of Physiology.80:580-594. in early detection of osteoporosis. The images in Figure 8 represent trabecular bone cross-sections in the sagittal and reconstructed transversal direction. as the directivity may vary according to the development of the disease. In: Pietikainen M. Germany) for their help during the COST B11 action in many aspects of texture measurements and analysis. The texture of the bone image shows apparent directivity. Haralick R. 14 to 17 September 2000. Schad LR. Zuna I. Shanmugam K. Norway. A series of 3D FLASH images. as the directivity may vary according to the development of the disease. J Phys Chem Solid State Phys.4×0. Erlangen. ❏ The author like to thank Michael Bock (DKFZ Heidelberg. Materka A. 12.no/costb11/. J Magn Reson. Richard Lerski (University Dundee. 241 . Yan Rolland (University Rennes. Germany). J Comput Assist Tomogr. Boyce D. Frahm J. Multiexponential proton spin-spin relaxation in MR imaging of human brain tumors. Schad LR. 1989. all of 256×256 pixels. Rapid NMR imaging using low flip-angle pulses. Abstracts 2001 (ISSN 1524-6965). 2000. Germany) using a small flex coil. 9. 8. Series in Machine Perception and Artificial Intelligence. MaZda User’s Manual. Jirák D. Zuna I. 1973. which reflects anisotropy of its physical structure according to the direction of gravity (Figure 8c). In: Proceedings of the International Society for Magnetic Resonance in Medicine (ISMRM). Lysaker M.5-T scanner (Siemens Vision. 7. 1950. in early detection of osteoporosis. (C) Texture parameters like run length nonuniformity show a clear dependence on direction of gravity. 1977. Lubomir Pousek (Technical University Prague. Berlin. and Ivan Zuna (DKFZ Heidelberg. Texture Analysis in Machine Vision. MR image texture analysis—an approach to tissue characterization. Bock M. Available at http://www.pl/ cost/ Accessed 3 December 2003. Andrzej Materka (University Lodz. Spin echoes. Phys Rev. Lerski RA. Example of a trabecular bone 3D FLASH (fast low angle shot) measurement of a normal volunteer in sagittal (A) and reconstructed transversal direction (B) for testing texture directivity.p. 4. Härle W. Vol 40. 2000:197-206. 2 to 6 September 2001.6:243-250. University of Bergen. Proc IEEE. Collection of Abstracts First SIAM-EMS Conference. IEEE Trans Syst Man Cybern. New type of phantom for texture analysis based on polystyrene and agar gel. For bone image texture analysis. 15. Czech Republic). Available at http://www. Glasgow. France).

l’imagerie par résonance magnétique (IRM) est devenue un puissant outil de diagnostic in vivo. el eco de gradiente y el eco planar y distintos parámetros de medición producen patrones de textura totalmente diferentes. qui optimisent l’information diagnostique. Cet article sera en grande partie consacré à l’étude minutieuse des meilleures stratégies de recueil de données d’IRM pour les analyses de texture. que dans les paramètres mesurés retentissent sur la texture en entraînant l’apparition de motifs totalement différents. il est essentiel de développer et d’expérimenter des objets de test exacts et fiables pour une évaluation détaillée des méthodes utilisées en IRM pour les analyses de texture.. Otro aspecto consiste en examinar la estabilidad y utilidad de los objetos de prueba mediante diversas secuencias de medición y condiciones en que se realicen las IRM empleando distintos resonadores. Diversas técnicas de medición como el eco de spin. l’écho de gradient. Un autre objectif est d’examiner la stabilité et l’utilité de ces objets de test en les soumettant à toute une gamme de séquences de mesures et de conditions d’imagerie par IRM et de les étudier avec divers types d’appareils d’IRM. Ceci est essentiel. como también la uniformidad global de la textura. La principale caractéristique de ces modèles réside dans leur capacité à imiter des textures semblables à celles produites par les tissus et ayant des propriétés de relaxation RM identiques. Par conséquent. etc. notamment en ce qui concerne les analyses de texture. resulta esencial diseñar y ensayar objetos de prueba exactos y confiables que permitan una evaluación detallada de los métodos de análisis de la textura de las IRM. qu’il s’agisse de l’écho de spin. dans la mesure où les séquences de mesures et les protocoles de saisie cliniques peuvent varier selon les centres et que ces derniers peuvent être réticents à les modifier pour les analyses de texture. Por lo tanto.Free paper Problemas en el análisis de la textura con imágenes de resonancia magnética Las imágenes de resonancia magnética (IRM) se han reconocido como una poderosa herramienta para el diagnóstico in vivo desde su introducción en la década de 1980. 242 . La estabilidad a largo plazo de estos modelos es de gran importancia. l’écho planaire. tout comme l’uniformité globale des textures qui en résultent. Des différences aussi bien dans les techniques de mesure utilisées. pueden variar la secuencia de medición y los protocolos de adquisición de datos y por lo tanto pueden ser reacios a modificar éstos para la investigación de la textura. Este aspecto es central ya que diferentes centros. La característica principal de estos objetos de prueba es su capacidad para simular texturas parecidas a los tejidos y con propiedades semejantes a estos últimos. por razones clínicas. El objetivo de este artículo es discutir el desarrollo de las IRM de tipo cuantitativo y en particular el análisis de la textura. La stabilité à long terme de ces modèles revêt également une grande importance. Una investigación cuidadosa de la influencia de todas estas variables mediante el empleo de texturas fantasma (objetos de prueba) ayudará a comprender cómo se forman las texturas de las IRM a partir de las estructuras de los tejidos. lo que permite maximizar la información para el diagnóstico. Problèmes posés par les analyses de texture au cours de l’imagerie par résonance magnétique Depuis son introduction au milieu des années quatre-vingt. L’évaluation précise de l’influence de ces variables en utilisant des images étalon (« fantômes ») de texture (ou objets de test) facilitera une meilleure compréhension du mode de constitution des textures des structures tissulaires en IRM. Una parte fundamental de este trabajo incluye un cuidadoso estudio de las mejores estrategias de recolección de datos de las IRM para el análisis de la textura. L’objectif de cet article est d’évaluer les avancées de l’IRM quantitative.

ul Wolczanska 223. 2002. selection of most informative parameters. The MaZda software has been designed and implemented as a package of two MS Windows®. One of the unique outcomes of this project is MaZda. eg.org M 243 . MSEE.” Other articles from this meeting can be found in Dialogues in Clinical Neuroscience (2002.exe. and others.dialogues-cns.1. Numerical values of texture parameters can be used for classification of different regions in the image. such as brain tumors. France. eg. multiple sclerosis. Texture quantitation. A European research project COST (Cooperation in the Field of Scientific and Technical Research) B11 was performed between 1998 and 2002 by institutions from 13 European countries.6:243-250. and computer science) to seek MRI acquisition and processing techniques that would make medical diagnoses more precise and repetitive. PhD. and applies to the investigawww. magnetic resonance imaging Author affiliations: Institute of Electronics. on the theme of “Drug Development. 90-924 Lodz. a computer program for quantitative texture analysis developed within the framework of the European COST (Cooperation in the Field of Scientific and Technical Research) B11 program. All rights reserved agnetic resonance imaging (MRI) is a unique and powerful tool for medical diagnosis. Changes of properly selected texture parameters in time can quantitatively reflect changes in tissue physical structure. Copyright © 2004 LLS SAS.exe and B11. computation of a variety of texture parameters for each ROI. Poland Address for correspondence: Technical University of Lodz. it is not sufficient to analyze image properties on the basis of point-wise brightness only. representing either tissues of different origin or normal and abnormal tissues of a given kind. aimed at development of quantitative methods of MRI texture analysis. Poland (e-mail: materka@p. exploratory analysis of the texture data obtained.4 a package of computer programs that allows interactive definition of regions of interest (ROIs) in images. Technical University of Lodz. The diagnostic information is often included in the image texture.Free paper Texture analysis methodologies for magnetic resonance imaging Andrzej Materka. Vol 4. are introduced. LLS SAS Dialogues Clin Neurosci. in that it is a noninvasive technique that allows visualization of soft tissues. © 2004.3 It gathered experts of complementary fields (physics. The functions of MaZda.4 Its functionality extends beyond the needs of analysis of MRI. There is an increasingly growing interest in using MRI for early detection of many diseases. No 4). ie. PC applications: MaZda. Lodz.lodz. higher-order statistics of the image must be taken into account. between October 1 and 5. its description by precisely defined parameters (features) is then needed to extract information about tissue properties. to monitor progress in healing.pl) This article is published following the 14th Biological Interface Conference held in Rouffach.2 In such cases. DSc Methods for the analysis of digital-image texture are reviewed. medicine. Keywords: quantitative texture analysis. and automatic classification of ROIs on the basis of their texture. 2004. Institute of Electronics. Examples of texture analysis in magnetic resonance images are discussed.

A B Figure 1. uniformity. the response of the classifier to a feature vector computed for texture class B is “class B. The results obtained from this stage are used for texture discrimination. Depending on definition of these statistics. kidney-shape bright object in the upper-right quadrant of the image is needed to be numerically characterized. for a population of K images. the calculated parameters can be arranged to form a feature vector [p1. it is easily perceived by humans and is believed to be a rich source of visual information about the internal structure and three-dimensional (3D) shape of physical objects. and applied to the input of the classifier. or object shape determination. In an ideal case. Comparison of vectors computed for images measured for different patients indicates whether the texture covered by ROI represents normal or abnormal tissue. and is marked in red in Figure 1b. these parameters are called texture features. illustrated by examples of its application to selected MRI texture analysis. Feature extraction is the first stage of image texture analysis. Consider a population of K images. color.6 A large collection of examples of natural textures is contained in the album by Brodatz. different properties of the ROI texture can be highlighted.The left and right halves of the image in Figure 2a have different textures. This object is our ROI in this example. textures are complex visual patterns composed of entities or subpatterns that have characteristic brightness. Any of these could be applied to the input of the classifier. in such cases.) The concept of textured image segmentation is illustrated in Figure 2. texture classification. the subimage covered by ROI is a random variable. linearity. granulation. p2. “seeing” a vector drawn from texture of class A. or it is unable to make a choice between assumed texture classes. The essential properties of the MaZda package is described in this report. where information is carried in texture.7 There are four major issues in texture analysis: • Feature extraction: To compute a characteristic of a digital image that can numerically describe its texture properties. one can compute a number. of statistical parameters based on image points contained in the ROI. of the texture as a whole. randomness. In the process of image seg- tion of digital images of any kind. pN]. regularity. Thus. directionality. frequency. • Shape from texture: To reconstruct 3D surface geometry from texture information. slope. it wrongly recognizes a texture class different from the one represented at the input. texture can be regarded as a similarity grouping in an image. Generally speaking. On the basis of its input.Free paper Selected abbreviations and acronyms ANN LDA NDA PCA ROI artificial neural network linear discriminant analysis nonlinear discriminant analysis principal component analysis region of interest • Texture classification: To determine to which of a finite number of physically defined classes a homogeneous texture region belongs (eg. say N. For a population of images. K feature vectors can be computed. each showing a different instance of texture A. the classifier takes the decision as to which predefined texture classes its input represents. phase. A cross-section of human skull (A). each corresponding to a perceptually homogeneous texture (leading to image segmentation). In the example illustrated. Similarly. Feature vectors can be applied to the input of a device called a classifier. size. density. • Texture discrimination: To partition a textured image into regions. …. etc. Such a vector is a compact description of the image texture. coarseness. A feature vector is computed for each image. In an ideal case. roughness.5 The local subpattern properties give rise to the perceived lightness. Consider an MRI cross-section of human skull (Figure 1a) in which an elongated. smoothness.” (Sometimes a classifier cannot make a correct decision. with the region of interest (ROI) marked in red (B). 244 . etc. Texture analysis methods Although there is no strict definition of the image texture. fineness. Assuming that texture is homogeneous within the ROI and that the area of the ROI is sufficiently large. normal or abnormal tissue). the classifier responds with the information “class A” at its output.

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mentation, the two regions are automatically identified and marked in different colors, eg, orange and blue in Figure 2b. (Some parts of the image are wrongly recognized as regions of yet other texture types, though.) There are two main techniques of image segmentation: supervised, where texture classes are known in advance; and unsupervised, where they are unknown, and so the segmenting device has to identify not only the texture classes, but also their number. There exist a variety of different texture segmentation methods, such as region growing, maximum likelihood, split-and-merge algorithms, Bayesian classification, probabilistic relaxation, clustering, and neural networks.2 All of these are based on feature extraction, which is the initial step and is necessary to describe (measure and analyze) the texture properties. This paper is confined mainly to feature extraction and texture classification techniques, which are typically the basic steps performed to support medical diagnosis. Approaches to texture analysis are usually categorized into structural, statistical, model-based, and transform methods. Structural approaches Structural approaches6,8 represent texture by well-defined primitives (microtexture) and a hierarchy of spatial
A

arrangements (macrotexture) of those primitives. To describe the texture, one must define the primitives and the placement rules. The choice of a primitive (from a set of primitives) and the probability of the chosen primitive to be placed at a particular location can be a function of location or the primitives near the location. The advantage of the structural approach is that it provides a good symbolic description of the image; however, this property is more useful for texture synthesis than analysis tasks. The abstract descriptions can be ill defined for natural textures because of the variability of both micro- and macrostructure and no clear distinction between them. A powerful tool for structural texture analysis is provided by mathematical morphology.9,10 This may prove to be useful for bone image analysis, eg, for the detection of changes in bone microstructure. Statistical approaches In contrast to structural methods, statistical approaches do not attempt to explicitly understand the hierarchical structure of the texture. Instead, they represent the texture indirectly by the nondeterministic properties that govern the distributions and relationships between the gray levels of an image. Methods based on second-order statistics (ie, statistics given by pairs of pixels) have been shown to achieve higher discrimination rates than the power spectrum (transform-based) and structural methods.11 Human texture discrimination in terms of the statistical properties of texture is investigated in reference 12.Accordingly, the textures in gray-level images are discriminated spontaneously only if they differ in second-order moments. Equal secondorder moments, but different third-order moments, require deliberate cognitive effort.This may be an indication that, for automatic processing, statistics up to the second order may be the most important.13 The most popular secondorder statistical features for texture analysis are derived from the so-called co-occurrence matrix.8 These have been demonstrated to feature a potential for effective texture discrimination in biomedical images.1,14 Model-based approaches Model-based texture analysis15-20 using fractal and stochastic models attempts to interpret an image texture by use of a generative image model and a stochastic model, respectively. The parameters of the model are estimated and then used for image analysis. In practice, the com-

B

Figure 2. Textured image segmentation.

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putational complexity arising in the estimation of stochastic model parameters is the primary problem. The fractal model has been shown to be useful for modeling some natural textures. It can be used also for texture analysis and discrimination16,21-23; however, it lacks orientation selectivity and is not suitable for describing local image structures. Transform methods Transform methods of texture analysis, such as Fourier24-26 and wavelet27-29 transforms, produce an image in a space whose coordinate system has an interpretation that is closely related to the characteristics of a texture (such as frequency or size). Methods based on the Fourier transform perform poorly in practice, due to lack of spatial localization. Gabor filters provide means for better spatial localization; however, their usefulness is limited in practice because there is usually no single filter resolution at which one can localize a spatial structure in natural textures. Compared with the Gabor transform, the wavelet transform have several advantages: • Varying the spatial resolution allows it to represent textures at the most appropriate scale. • There is a wide range of choices for the wavelet function, and so the best-suited wavelets for texture analysis can be chosen a specific application. Wavelet transform is thus attractive for texture segmentation. The problem with wavelet transform is that it is not translation-invariant.30,31 Regardless of their definition and underlying approach to texture analysis, texture features should allow good discrimination between texture classes, show weak mutual correlation, preferably allow linear class separability, and demonstrate good correlation with physical structure properties. For a more detailed review of basic techniques of quantitative texture analysis, the reader is referred to reference 2. In this paper, we will discuss practical implementation of these techniques, in the form of MaZda computer program. gram. (The name “MaZda” is an acronym derived from “Macierz Zdarzen,” which is Polish for “co-occurrence matrix.”Thus, MaZda has no connection with the Japanese car manufacturer.) Up to 16 ROIs can be defined for an image; they may overlap each other. Once ROIs are established, MaZda allows calculation of texture parameters available from a list of about 300 different definitions that cover most of the features proposed in the known literature. The parameters can be stored in text files. One can demonstrate using properly designed test images that some of the higher-order texture parameters, especially those derived from the co-occurrence matrix, show correlation to first-order parameters, such as the image mean or variance. To avoid this unwanted phenomenon, prior to feature extraction, image normalization is preferably performed. Typically, the features computed by MaZda are mutually correlated. Morover, not all of them are equally useful for classification of given texture classes or to measure properties of the underlying physical object structure. Thus,

Image acquisition

MR scanner

ROI selection

Image normalization MaZda program Feature extraction

Feature selection

MaZda: a software package for quantitative texture analysis
The main steps of the intended image texture analysis are illustrated in Figure 3. First, the image is acquired by means of a suitable scanner. The ROIs are defined using the interactive graphics user interface of the MaZda pro-

Data preprocessing B11 program Texture classification
Figure 3. Main steps of digital image texture analysis.

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there is a need for feature selection.To do that, a subset of the computed parameters can be selected manually. MaZda also offers the possibility of selecting the best 10 features automatically following two different selection criteria. One criterion maximizes the ratio of between-class to within-class variance, which resembles the Fisher coefficient.32,33 The second minimizes a combined measure of probability of classification error and correlation between features.33 The selected best 10 parameters can be used for texture classification. Still, it is too difficult for a human operator to imagine and understand relationships between parameter vectors in the 10-dimensional data space. The B11 program of the MaZda package allows further data processing to transform them to a new, lower-dimension data space. The data preprocessing employs linear transforms, such as principal component analysis (PCA)34 and linear discriminant analysis (LDA),32 as well as nonlinear operations leading to artificial neural network (ANN)–based nonlinear discriminant analysis (NDA).35 The B11 program displays both input and transformed data in a form of a scatter-plot graph. B11 allows also raw and transformed data vectors classification, and evaluation of the usefulness of texture features calculated using MaZda to classification of different texture classes present in image regions. For data classification, the nearest-neighbor classifier (k-NN)36 and ANN classifiers33,37,38 are implemented. Neural networks of the architecture defined during training can be tested using data sets composed of feature vectors calculated for images not used for the training. At the time of writing this paper, MaZda version 3.20 was available. It implements procedures which allow4: • Loading image files in most popular MRI scanner standards (such as Siemens, Picker, Brucker, and others). MaZda can also load images in the form of Windows Bitmap files, DICOM files, and unformatted gray-scale image files (raw images) with pixel intensity encoded with 8 or 16 bits. Additionally, details of image acquisition protocol can be extracted from the image information header. • Image normalization. There are three options: default (analysis is made for original image); ±3σ (image mean m value and standard deviation σ is computed, then analysis is performed for gray scale range between m-3σ and m+3σ); or 1%-99% (gray-scale range between 1% and 99% of cumulated image histogram is taken into consideration during analysis).

• Definition of ROIs. The analysis is performed within these regions. Up to 16 regions of any shape can be defined; they can be also edited, loaded, and saved as disk files. A histogram of defined ROIs may be visualized and stored. • Image analysis, which is computation of texture feature values within defined ROIs. The feature set (almost 300 parameters) is divided into following groups: histogram, co-occurrence matrix, run-length matrix, gradient, autoregressive model, and Haar wavelet–derived features. Detailed description of feature definitions can be found in reference 33. • Computation of feature maps that represent distribution of a given feature over an analyzed image. It is possible to save or load feature maps into a special floating-point file format or into Windows Bitmap file. • Display of image analysis reports, saving, and loading reports into disk files. • Feature reduction and selection, in order to find a small subset of features that allows minimum error classification of analyzed image textures. This is performed by means of two criteria, as explained above. Selected features can be transferred to B11 program for further processing and/or classification. • Image analysis automation by means of text scripts containing MaZda language commands. Scripts allow loading analyzed images and their ROI files, running the analysis, and saving report files on disk. The number of features computed by MaZda is still increasing. New feature groups are added according to suggestions of the project members and other MaZda users.Also, new procedures for data processing are being appended.

MaZda module
MaZda generates windows and selected window elements when the program main functions are invoked. The report window contains list of numerical values of all parameters computed by MaZda for defined ROIs. The selection of texture parameters that are actually computed is made using appropriate options window. Once computed, the reports can be stored as text files. There is a possibility of manual and automatic feature selection that gives lists of 10 parameters maximizing selection criteria. These lists can be stored as text files. Texture parameters can also be computed by MaZda in a rectangular ROI moved automatically around the analyzed image. Parameter values calculated for each ROI

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The raw data were transformed to lower-dimensional spaces. Each circular region in Figure 4a represents a cross-section through a tube filled with polystyrene spheres of different diameters. on some selected texture parameters computed using the MaZda software. Figure 5. This can be explained by the fact that PCA is optimized for representation of data variability. Options of feature maps calculations (ROI size and step size of ROI movement) can be selected using appropriate window tools. it eliminates the classification errors. Magnetic resonance image cross-section of four test objects of different texture. The content of this file is displayed in the left panel of B11 window. ps1. the input to B11 was made of eighty-eight 10-dimensional data vectors. which were test objects manufactured in the Institute of Clinical and Experimental Medicine in Prague. There were 22 images showing different cross-sections of the test objects. Nonlinear transforms and classifiers implemented in B11 employ feedforward ANNs.Thus. with 22 vectors for each texture class.Free paper position can be arranged to form a new image. In each case. the Fisher coefficient F was calculated for the obtained data vectors. leading to 22 examples of texture of each class. and tested using a leave-one-out technique. Although the LDA gives lower value of the Fisher coefficient F.33 The clusters formed in the transform data spaces can be visualized in the form of 2D or 3D scatter plots. A list of 10 best features was then automatically generated based on Fisher coefficient criterion (maximization of the ratio F of between-class to within-class variance). A scatter plot of the input data in the 3D data space was made of first three best texture features. a so-called feature map. A. Magnetic resonance image with eight regions of interest (ROIs) marked with different colors.36 The PCA projection to a lower-dimensionality data space does not improve the classification accuracy. foam 2. Numerical values of about 300 texture statistical parameters were computed using MaZda module. foam 1. ps3. and NDA projections. B. LDA.The best parameters were then passed to the B11 module. and foam 3 are test objects. and its respective ROIs are illustrated in Figure 4b. using the PCA. The example experiment described here was made to verify whether texture classes represented in the image in Figure 4a could be classified based A B ps3 foam 1 foam 2 ps2 ps1 foam 3 Figure 4. which are generated by B11 program and discussed in the next section. They were also classified using a 1-NN classifier. which is not the same as data suitability for class discrimination (which is the case of LDA). The input data preprocessing and classification options can be selected in the options window. 248 . Four regions of interest (four texture classes) defined for the image in A. B11 module This program can either be called from the MaZda windows or run as a separate MS Windows application. Input to this program is a file containing data vectors corresponding to selected texture parameters. Thus. noise Application example 1 Figure 4a shows an MRI image that contains regions of different texture. The results of data transformation and classification are shown in the right panel of the window. Training techniques of these networks are described in the User’s Manual of MaZda. ps2. This step produced eighty-eight 300-dimensional data vectors.

The results collected (Table I) indicate that one cannot specify in advance which particular texture features will be useful for discrimination of texture classes. First.exe and B11. gradient.Texture analysis methodologies for MRI . 2 .Vol 6 . linear discriminant analysis. and wavelet-based features only). Within the framework of a European COST B11 action. ❏ 249 . One can notice that even if histogram data do not represent texture. The numerical experiment carried out on seven images of the described category aimed to verify whether one can find features able to separate mixed. POE. The results are “As computed” data Standardized data Raw PCA LDA Raw PCA LDA Best higher-order features (histogram and wavelet-based features excluded) Fisher 22 31 19 22 31 19 POE+ACC 26 28 3 6 4 4 Best higher-order features (wavelet-based features excluded) Fisher 1 1 1 9 9 1 POE+ACC 24 24 0 4 3 2 Best higher-order features (wavelet-based features only) Fisher 3 4 0 0 0 0 POE+ACC 3 6 0 0 0 0 Table I.41 The MaZda package is available on the Internet. one should verify (using a separate test dataset) whether the ANN does not suffer from the overtraining problem.The modules are seamlessly integrated. higherorder features were considered only.The package has already been used for quantitative analysis of MRI images of different kinds. one can compute a large variety of different texture features and use them for classification of regions in the image.39 such as images of human liver40 and computed tomography images for early detection of osteoporosis.33 So far more than 300 researchers from all over the world have downloaded it onto their computers. however. consequently. MaZda allows generation of feature map images that can be used for visual analysis of image content in a new feature space. Summary Texture analysis applied to MRI (and other modalities) is one of the methods that provide quantitative information about internal structure of physical objects (eg. along with cross-section of six artificial test objects (phantoms designed and manufactured to generate standard texture patterns). highlighting some image properties.This information can be used to enhance medical diagnosis by making it more accurate and objective.38 An overtrained network does not generalize the training data well and. In the second part of the experiment. the two sets of best features were transformed (PCA and LDA) and the transform data were used as new features for classification (by means of a 1-NN classifier tested using the “leave-one-out” technique). PCA. average correlation coefficient. shown in Table I. Number of classification errors (out of 56 samples) for best higherorder features (histogram and wavelet-based features excluded.Those were co-occurrence matrix.Materka Dialogues in Clinical Neuroscience . Using the package. wavelet-based features excluded. Table I shows significance of these parameters in region discrimination. with no possibility of perfect classification. The experiment was performed in three parts. each marked with a different color. histogram-based features were added to the higher-order ones used in the first part. and that raw-data texture features usually do not allow perfect discrimination—some pre-processing is necessary. run-length matrix. that lowest error figure (3/56) was obtained for the LDA data. Table I shows that perfect ROI discrimination is possible even in the raw data space. and autoregressive model–derived parameters.23 The program appears to be a useful research tool in a PhD student laboratory. artificial. and each of the modules can be run as a separate application. it may wrongly classify unseen data points. Perfect classification was achieved for LDA-transformed data. a unique package of computer programs has been developed for texture quantitative analysis in digital images. Moreover. human body tissue) visualized in images. In the third part. wavelet-based features only were used. Extremely large F can be obtained using NDA. ACC.This family of features seems to describe texture for classification purposes extremely well. which indicates. and natural textures.The package consists of two modules: MaZda. Application example 2 Figure 5 shows an MRI image that contains cross-section of human scull. The best of these were automatically selected by MaZda. three on each side of the scull. eg. they are significant to ROI classification. No. Using the B11 program.exe. There are altogether eight ROIs defined for this image. principal component analysis. LDA. by means of linear or nonlinear discriminant transforms. probability of classification error. 2004 the lower F coefficient does not necessarily indicate worse classification.

Kolobrzeg. In: Pietikainen M. Chaudhuri B. Digital Pattern Recognition. Reading. Available at http://www. 10. San Diego. Chen Y. Chellappa R. IEEE Trans Patt Anal Mach Int. Giesler W. Materka A. ed. 1980:135-166. NY: Wiley. IEEE Trans Patt Anal Mach Int. ICSES 2001. 1995.12:55-73. 250 . 1990. Poland. et al. 1989. et al. 36. 1985. Technical University of Lodz. New York. Proceedings of the 20th National Conference Circuit Theory Electronic Networks 1997. 1993. Kak A. Artificial neural networks for feature extraction and multivariate data projection. J Opt Soc Am.Free paper Delivery of MRI images by Dr Richard Lerski of Dundee University and Hospital (Figure 2a). and Dr Michal Strzelecki (Figure 2) is very much appreciated. Uncertainty relation for resolution in space. Singapore: World Scientific. un logiciel développé dans le cadre du programme européen COST (Cooperation in the Field of Scientific and Technical Research) B11 pour l’analyse quantitative de la texture. UK: Academic Press. Texture Analysis in Machine Vision.15:1186-1191. Metodologías de análisis de la textura para imágenes de resonancia magnética Se revisan los métodos de análisis de la textura de imágenes digitales. 13. 1981. 23. 1982. Texture analysis of X-ray images for detection of changes in bone mass and structure. COST B11. Deya C.pl/cost/publications.uib. Texture segmentation using fractal dimension. Feature evaluation of texture test objects for magnetic resonance imaging. Norway. Rosenfeld A. Introduction to Statistical Pattern Recognition. Daugman J. Brodatz P. Patt Recog. Germany: Springer-Verlag. 30. 12. Berlin. Chung P. NY: Academic Press. Series in Machine Perception and Artificial Intelligence. Available at http://www. Lu C. 14. Berlin. Calif: Addison-Wesley.p. 2. Los Alamitos. 33. 1995. New York. UK: Oxford University Press.33:2713-2722.no/costb11/. Clark M.eletel. Vol 40.17:1043-1056. 2000:197-206. Medical Electronic Division. Prof Lothar Schad of German Cancer Research Centre in Heidelberg (Figures 1 and 5). 29. Ahuja N. Chatterjee S. 5. COST B11 Technical Report.5:25-39.lodz. Dezortova M. Neural Networks—Algorithms. 1997. 32. eds. 27. Grey-scale morphological granulometric texture classification. Magn Reson Imaging. 31. Chellappa R. Mass: Addison-Wesley. Poland. 6. 39. Fractal-based description of natural scenes. Shad L. 15.2:1160-1169. 1966. In: Pietikainen M. Freeman J. 41. Les fonctions de MaZda. 1997:493-498. Weszka J. Vol 40. 1991. Principles of Multivariable Data Analysis. Sci Am. Neurocomputing. Materka A. Texture analysis methods—A review. 7. Germany: Springer-Verlag.13:478-482. IEEE Trans Acous Speech Sig Proc. Mao J. Experiments in the visual perception of texture. MaZda Software. Feature selection for texture segmentation. Advances in Image Understanding. 26. Series in Machine Perception and Artificial Intelligence.11:873-887. Serra J. Manjunath B. IEEE Trans Patt Anal Mach Int. Strzelecki M. 8. Image Analysis and Mathematical Morphology. Multichannel texture analysis using localised spatial filters. 19.9:39-55. Fan J. 1995. Materka A. Digital Picture Processing. desarrollado dentro del marco del Programa Europeo de Cooperación en el Campo de la Investigación Científica y Técnica (COST) B11. Segmentation of Textured Biomedical Images Using Neural Networks [in Polish]. 4. Department of Physiology. Accessed 3 December 2003. Dougherty E. Lodz. Available at http://www. Duda R. A comparative study of texture measures for terrain classification. Rosenfeld A. 1984. Unsupervised texture segmentation via wavelet transform. 3. New York. IEEE Trans Neural Networks. Lerski R. Prof Milan Hajek of the Institute of Clinical and Experimental Medicine in Prague (Figure 4). Accessed 3 December 2003. 1994. Texture analysis of human liver.6:661-674. Statistical and structural approaches to texture.67:786-804. J Magn Reson Imaging. Quantitation of Magnetic Resonance Image Texture. Se presentan las funciones del MaZda. Patt Rec. Multifrequency channel decomposition of images and wavelet models.15:68-74.pl/cost/software. 1987. Niemann H. Levine M. 1985. Strzelecki M. 35. Xie Z. Texture Analysis in Machine Vision. IEEE Trans Patt Anal Mach Int. 1988. Mallat S. 28. 16. Cross G. Lodz. IEEE Trans Acous Speech Sig Proc. Poland. 1982. Computer program for image texture analysis in PhD student laboratory. IEEE Trans Patt Anal Mach Int. Lodz-Brussels: Technical University of Lodz. Méthodologies d’analyse de la texture pour l’IRM Les méthodes d’analyse de la texture de l’image numérisée sont ici passées en revue.lodz. 21.lodz.232:34-43. Proc IEEE. IEEE Trans Syst Man Cybern. Calif: Academic Press. Rosenfeld A. Des exemples d’analyse de la texture sur des images par résonance magnétique sont discutés. IEEE Trans Patt Anal Mach Int. 2000:189-195.p. Classification of textures using Gaussian Markov random fields. Singapore: World Scientific. 1985. 34. Pattern Analysis. 1979. Skapura D. Oxford. Brady M. Jirak D. 9. Hecht-Nielsen R. IEEE Trans Patt Anal Mach Int. Unsupervised texture segmentation using Markov random fields. 37. Applications and Programming Techniques. Accessed 3 December 2003. Calif: IEEE Computer Society Press.html. Derin H. Straughan K. 1983. 1973. Strzelecki. Krzanowski W. MR image texture analysis—an approach to tissue characterisation. Jain A. Hart P. Materka A. Sarkar N. 1995. IEEE Trans Patt Anal Mach Int. Weszka J. Cichy P. 1998. 18. Elliot H. 17. University of Bergen. Haralick R.37:2091-2110. et al. et al. ed.30:729-742. 40. Chen C. MaZda User’s Manual. Lerski R. 24. Texture roughness analysis and synthesis via extended self-similar (ESS) model.eletel. Laine A.6:296-316. 1991. Available at http://www.30:729-742. Textures—A Photographic Album for Artists and Designers. Chung P.6:269-285. 1991. Texture classification by wavelet packet signatures. 1993. 22. New York. Julesz B. Technical University of Lodz. Chen C.pl/ cost/ Accessed 3 December 2003. 2001:255-261.p. Tuliszkiewicz J. Markov random field texture models. Lu C. Szczypinski P.17:72-77. ed. 38. 11. spatial frequency and orientation optimised by two-dimensional visual cortical filters. In: Fu K. Fukunaga K. 25. Materka A.html. In: Bowyer K. Redwood City. NY: McGraw-Hill. un programa computacional para el análisis cuantitativo de la textura. Se discuten ejemplos de análisis de la textura en imágenes de resonancia magnética. Kaplan L Kuo C. Opt Eng. Jain A. 1989. Picture recognition. 2002. Pentland A. PhD Thesis. Strzelecki M. 1975. 1996. 20. NY: Dover. Bovik A. Materka A. sont présentées.33:959-963. Markov random fields as models of textured biomedical images.eletel. Vision in Man and Machine. 1997. REFERENCES 1. Taimy P. London. Kociolek M. Pattern Classification and Scene Analysis. Unsupervised texture segmentation via wavelet transform. 1976. Modeling and segmentation of noisy and textured images using Gibbs random fields.

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