Lennart Heimer: Concepts of the Ventral Striatum and Extended Amygdala

Neurosurg Focus 25 (1):E8, 2008

Lennart Heimer: concepts of the ventral striatum and extended amygdala

W. JEFF ELIAS, M.D., DIBYENDU KUMAR RAY, M.D., AND JOHN A. JANE SR., M.D., PH.D. F.R.C.S.(C) Department of Neurosurgery, University of Virginia Health System, Charlottesville, Virginia

Dr. Lennart Heimer, the famous neuroanatomist of Swedish descent, died last year but left a legacy that will impact the neurosciences and potentially psychosurgery for years to come. He developed an anatomical technique for demon- strating the terminal boutons that helped to delineate basal forebrain anatomy. During these studies, he realized the relationship of basal forebrain structures to the limbic system, thus initiating the concept of the ventral striatum and parallel basal ganglia circuitry. Heimer excelled as a teacher as well and honed his brain dissection technique to one of the most effective tools for understanding neuroanatomy. His legendary sessions with neurosurgical residents resulted in his recognition as one of the world’s leading fiber tract dissectors. His gentle, engaging manner has been documented in several media formats. (DOI: 10.3171/FOC/2008/25/7/E8)

KEY WORDS • basal forebrain • extended amygdala • nucleus accumbens • ventral pallidum • ventral striatum • substantia innominata

NE of the world’s great neuroanatomists died last he was the Swedish junior slalom champion and later qual- year, but his legacy will impact neuroscience and ified for the Swedish Olympic team in 1952 (Fig. 2). As a O psychiatry for years to come. Dr. Lennart Heimer native to a city traditionally considered a “Vinterstaden” (Fig. 1), an American scientist of Swedish origin, devel- (winter city), it is said that Lennart was never late in putting oped a fiber tract and terminal bouton tracing technique and on his skis when an opportunity arose, and it was also on utilized it over the course of a long and prolific scientific the ski slopes that he met his Norwegian wife, Hanne- career to delineate the basal forebrain structures. From his Björg, with whom he spent the remainder of his 51 years. early pioneering studies came the concepts of the ventral Had it not been for his wife and his burning interest in med- striatum and the extended amygdala—a neuroanatomical icine, Heimer might have stayed on the ski slopes for the framework of the utmost interest to psychiatrists involved rest of his life. in schizophrenia and addiction and now to neurosurgeons The decision to pursue medical research was not an obvi- as they again enter the field of psychosurgery. ous choice for the grandson of a stationmaster and the son Dr. Heimer shaped the lives of many scientists, both of a “häradsskrivare” (government executive) from central young and old, from his laboratory at the University of Sweden. Heimer initially studied land and water resources Virginia; however, he had an equal passion for teaching. engineering for a career in civil engineering. However, well Scores of medical students, residents, and faculty physi- into his 2nd year at Chalmers University of Technology at cians learned neuroanatomy from his famous brain dissec- Göteborg on the Swedish west coast, he regretted the deci- tions. Retiring from the research laboratory just a few years sion and realized that medicine would be a more interesting ago, he continued to teach, publish, and speak until the last year of his life. With a full national and international lecture and appropriate choice. Because Heimer lacked the neces- schedule planned for the year, Dr. Heimer died of pancre- sary biology classes, he traveled to Freies University in atic cancer on March 12, 2007, at the age of 77 years. He West Berlin to complete his premedical training. It was at was surrounded by his family at his farm in Trevilians, this time that he pursued another talent—art—which he Virginia, where he was working on his last book.27 would utilize throughout his career. In fact, in 1959 as a 1st- year medical student at the University of Göteborg (now Gothenburg), the largest university in Scandinavia, Heimer The Development of a Neuroanatomist wrote and illustrated his first textbook of neuroanatomy Lennart Heimer was born in Östersund City, the capital with a little help from his father, who corrected his mis- of Jämtland county in central Sweden, on March 11, 1930, spellings.16 The ambitious student requested that the leg- to Gösta and Rakel (Karlstedt) Heimer. As a young man, he endary Alf Brodal write a foreword for the book, although had a passion for sports, excelling in soccer and track and this request was refused given Heimer’s youth and inexpe- field. He was most gifted in alpine skiing, however; twice rience.

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FIG. 2. Photograph of Heimer, a gifted athlete who excelled in numerous sports, although downhill skiing was his passion. In FIG. 1. Photograph of Dr. Lennart Heimer, the American neu- 1952 he qualified for the Swedish Olympic team. roanatomist of Swedish descent, who developed a silver impregnation stain for tracing terminal boutons throughout the brain. He used this technique to delineate the human basal forebrain anato- chology and Brain Science at the Massachusetts Institute of my, and he proposed the concept of the ventral striatum. Technology (Fig. 3). The premier neuroanatomy labs at the time were located in Boston with Nauta, Scandinavia with Brodal, and Hungary with Szentágothai. Heimer had grad- As a medical student in the Department of Anatomy, uated in 1963 with an M.D. degree and never continued Lennart was asked by his professor to research the spinal toward a Ph.D., believing that his publications spoke for column and sitting. His refusal, because of his intense inter- themselves. est in brain anatomy, left him somewhat ostracized within Nauta had distinguished himself as one of the world’s the department. Fortunately, he found success with the behavioral psychologist Knut Larsson, who not only estab- lished him as an avid cigar enthusiast, but also influenced the remainder of his scientific career. Heimer, Larsson, and a skilled laboratory technician constructed a stereotactic apparatus to access all regions of the rodent brain, including its basal surface.22 Through serendipity, two important findings resulted from their early studies: 1) lesions local- ized to the medial preopticoanterior hypothalamic region abolished sexual behavior in rats and 2) extensive lesions at the junction of the mesencephalon and diencephalon were followed by a drastic increase in sexual behavior.31 Later they discovered that the destruction of the main olfactory system eliminated mating in nonexperienced animals for the entire lifespan.23,24 The studies on the sexual behavior of rats seemed limited without more detailed knowledge of the neuronal circuits in the basal forebrain, and Heimer became curious as to whether new axonal tracing techniques utilizing silver impregnation could be used to delineate functional brain anatomy. FIG. 3. Photograph of the young neuroanatomist (far right) and The success of these early studies with Larsson by the his wife, Hanne-Bjorg (second to the right). After medical school, time Heimer was 35 years of age resulted in an offer to Heimer was invited to study with Dr. Walle Nauta (left), one of the work with Dr. Walle J. H. Nauta in the Department of Psy- preeminent neuroanatomists of the era.

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FIG. 4. Photomicrograph of terminal boutons surrounding a neuron, as demonstrated by the Fink-Heimer stain. This modification of prior tract tracing techniques enabled scientists to visualize terminal boutons instead of degenerating axons. It became the primary tract-tracing method of the time. eminent neuroanatomists with his silver technique for trac- 35,36 FIG. 5. Heimer used electron microscopy in addition to tract- ing degenerating axons. The Nauta stain revolutionized tracing methods in his studies of neural connectivity. He was able the study of brain anatomy so that projection fibers and tar- to demonstrate neuronal function with ultrastructural analysis of gets of deep nuclei could be traced and identified. Nauta’s axonal boutons. laboratory attracted brilliant young scientists like Heimer, and the atmosphere surrounding these pioneering studies was energetic and exciting. It was during this time with the science center at the University of Aarhus, Denmark, but he gifted technician Robert Fink that Heimer developed meth- returned to a joint appointment in the Departments of Neu- ods for selective silver staining of degenerating axonal bou- rosurgery and Otolaryngology—Head and Neck Surgery at tons.9 Although considered a modification of Nauta’s the University of Virginia, the position that he would main- method for staining degenerating axons, the Fink-Heimer tain for the rest of his career. stain had the advantage of tracing degenerating nerve fibers In the 1970s funding for research in neuroanatomy and and visualizing their terminal boutons (Fig. 4). Initial connectivity waned as molecular biology assumed the ma- doubts centered on whether the Fink-Heimer method actu- jor interest of neuroscientists to understand brain function; ally identified axonal projections, but electron microscopy however, Heimer persevered with his tract-tracing tech- studies of the terminal boutons with Alan Peters soon vali- niques and electron microscopy studies. He preached the dated the technique.25 In fact, Heimer also demonstrated concept that anatomy is critical to understanding brain or- that electron microscopy could reveal the function of ter- ganization, which in turn reveals brain function. Indeed he minal boutons: symmetric, flat boutons were inhibitory and demonstrated this principle as he used neuroanatomy to asymmetric, round boutons were excitatory. By the age of understand the anatomical associations and chemical rela- 40 years, Heimer had accomplished much and was recog- tionships of the limbic brain. nized in Scientific American as a pioneering neuroana- 20 tomist. The Fink-Heimer stain represented the primary Teaching by Brain Dissection tool for tracing central nervous system pathways such as the fine neural connections of the basal forebrain. While uncovering the basic anatomical structures in his After 7 years at the Massachusetts Institute of Tech- laboratory in Cobb Hall at the University of Virginia, Dr. nology, the young Heimer was recruited to the University Heimer developed an equal passion for teaching. He uti- of Virginia by Dr. Jan Langman, chairman of the Depart- lized brain dissection much like he used fiber-tracing tech- ment of Anatomy, and by Drs. John Jane and Sven Eb- niques in research—to elucidate the basic concepts of neu- besson of the Department of Neurosurgery to develop a roanatomy to medical students, residents, and any strong neuroscience research program. An older, distin- enthusiast of the neurosciences. These legendary brain dis- guished neuroanatomist was passed over for the position as sections grew from Saturday neurosurgery conferences to Heimer demonstrated youth, vigor, and expertise with the other departments of the medical school and then to other new electron microscopy and fiber-tracing techniques (Fig. universities. Soon Heimer was recognized not only for his 5). In essence, he was viewed as the future of neuroanato- many accomplishments in the lab but also as an expert my—which eventually proved true. His texts on experi- teacher and dissector of the brain. He believed brain dis- mental neuroanatomical techniques became basic refer- section to be fundamental to any student of neuroscience as ences for neuroscientists.26,29 There was a single year in “no book, plastic model, or high-tech computer simulation 1979-1980 when Dr. Heimer helped to establish a neuro- can replace gross dissections as a vehicle for the study of

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FIG. 6. Drawings showing the ventral striatum of the human basal forebrain. A. Coronal schematic at the level of the nucleus accumbens. B. The ventral pallidum (VP) extends downward into the region recognized as the substantia innominata. C. The sublenticular portion of the substantia innominata is associated with the extended amygdala. In this concept of the substantia innominata, the basal nucleus of Meynert (B) is a relatively small third component. D. Central (Ce) and medial (Me) nuclei of the amygdala are apparent with their corresponding projections along the stria terminalis and the superior component of the bed nucleus of the stria terminalis. ac = anterior commissure; BL = basolateral nucleus of amygdala; BM = basomedial nucleus of amygdala; BSTL = bed nucleus of stria terminalis, lateral division; BSTM = BST, medial division; BSTS = BST, superior division; Cd = caudate; Cl = claustrum; EGP = external segment of the globus pallidum; Ent = entorhinal cortex; f = fornix; HDB = diagonal band; Hy = hypothalamus; IGP = internal segment of GP; La = lateral nucleus of the amygdala; opt = optic track; ox = optic chiasm; Pir = piriform cortex; Pu = putamen; SLEA = sublenticular component of extended amygdala; st = stria terminalis; Th = thalamus; VDB = diagonal band; VS = ventral striatum. This figure was published in Handbook of Chemical Neuroanatomy, Vol 15, Heimer L, de Olmos J, Alheid G, et al, p 58, Copyright Elsevier, 1999. the human brain.”15 Only a few basic instruments and sim- ences for hours and effectively imparted his vast knowl- ple tissue fixation were required to provide lasting knowledge of brain structure with a gentle and concise manner. edge of the body’s most complex organ. Armed with only In 1983 he organized his teaching thoughts into the clas- a brain knife and a formalin-fixed brain, he captivated audi- sic medical school text, The Human Brain and Spinal

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FIG. 8. Photograph of Dr. Heimer and his long-time friend and collaborator José de Olmos of Argentina. The two worked together to pioneer the concepts of the ventral striatum and extended amygdala. Sadly, de Olmos died the year following Heimer’s death.

ventral striatum projects to limbic regions (Fig. 6). This notion was first demonstrated in rodents by using cytoar- chitectural, histochemical, and tract tracing experiments.18 The discovery of new fiber tract tracing methods in the 1960s allowed the discovery of new forebrain circuitry, namely, the ventral striatum and extended amygdala. At the FIG. 7. Drawing illustrating the extended amygdala. The central forefront of these techniques were the Fink-Heimer modi- division of the amygdala (Ce) is associated with projections via the fication of the Nauta-Gygax method9 and the cupric-silver stria terminalis to the lateral hypothalamus, and the medial division method of de Olmos.6 Both silver impregnations allowed (Me) projects to the medial hypothalamus. Notice that the later- the study of these long, circuitous fiber tracts in the human obasal nuclei of the amygdala are not included in the extended basal forebrain. amygdala. The supracapsular component of the extended amyg- In some early rodent experiments utilizing his modified dala is depicted in Fig. 6B, whereas the sublenticular component is silver staining technique, Dr. Heimer lesioned the pre- most visible in Fig. 6C. Amg = amygdala; Co = cortical amyg- piriform cortex and olfactory tubercle to demonstrate that daloid nuclei. This figure was published in Handbook of Chemical Neuroanatomy, Vol 15, Heimer L, de Olmos J, Alheid G, et al, p subsequent degeneration occurred in the mediobasal fore- 59, Copyright Elsevier, 1999. brain—the substantia innominata. This observation con- tradicted the commonly accepted belief that the olfactory cortex projects substantially to hypothalamic regions.18 He Cord: Functional Neuroanatomy and Dissection Guide,13 remarked, “that the olfactory tubercle represents a striatal which has since been republished in its current second edi- structure rather than a cortical olfactory structure could tion.14 Because of the high demand for his live dissections, hardly be dismissed.” The fact that there are no reciprocal Heimer produced a digital video disc sponsored by the Am- projections between the two, as would normally be expect- erican Association of Neurological Surgeons that captures ed with association cortex, further supported this notion. his method, lilting accent, and gentle mannerisms in a time- Lesions in the nucleus accumbens and olfactory tubercle less work.12 These dissections are also available on the in- resulted in neuronal degeneration along the continuum of ternet from the online journal Neurosurgical Focus of June the ventral globus pallidum,29 and thus the terms “ventral 2005.15 Fortunately, his technique for brain dissection has striatum” and “ventral pallidum” were introduced to des- been recorded in several formats for all to enjoy and to cribe this apparent extension of the basal ganglia. ascertain a sense of the man so dedicated to his students and Just as the dorsal basal ganglia projects through the thal- his subject. amus or more specifically through ventral anterior and ven- trolateral nuclei as part of its cortical circuit, it was later suggested that the ventral striatal-pallidal system projected Concepts of the Ventral Striatum through the medial dorsal nucleus of the thalamus, herald- and Extended Amygdala ing the idea of parallel corticostriatalthalamic circuits from dorsal and ventral basal ganglia.19 The fundamental concept of the ventral striatopallidal In this concept of the basal forebrain, which contains system is that the allocortex (olfactory cortex and hip- ventral striatum and extended amygdala, the substantia pocampus) is related to the basal ganglia in a manner sim- innominata no longer represents an independent structure ilar to the neocortex with its corticostriatopallidal circuit. in the region but instead is divided into its 3 component Thus, parallel circuits exist in the basal ganglia whereby the parts. The anterior portion represents the subcommissural

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Unauthenticated | Downloaded 10/04/21 12:39 AM UTC W.J. Elias, D. Kumar, and J. A. Jane Sr. substantia innominata, which is the ventral extension of the Note, however, that the exact targets for deep brain stim- pallidum. The posterior portion involves the sublenticular ulation electrodes in the ventral striatum regions remain un- substantia innominata and is associated with the extended clear.3 amygdala. “This two part division of the substantia innominata is one of the corner stones of [the] conceptualization of the basal forebrain.”33 For completeness, it should be The Ultimate Tribute mentioned that the third component of the substantia in- Very few people earn during their lifetime a level of sta- nominata is the cholinergic basal nucleus of Meynert, tus and respect that garners recognition from colleagues which occupies a relatively small volume compared with and peers from around the world. Lennart Heimer was one the anterior and posterior divisions (Fig. 6). such man. In October 1998, neuroscientists from across the In the 1920s Johnston30 suggested an association be- globe convened in Charlottesville for a 3-day symposium tween the bed nucleus of stria terminalis and the centrome- addressing the ventral striatum and honoring in particular dial amygdaloid nuclei because he observed a continuum the man who conceived of it. Conference organizer, Jac- of these structures during human and nonhuman vertebrate queline McGinty, described the event: “To hear such out- embryonic development. Decades later a similar rela- standing presentations and passionate discussion intermin- tionship was noted in mammals when de Olmos,5 a close gled with overwhelming camaraderie and admiration for friend of and collaborator with Heimer, observed columns Lennart Heimer was a rare and unique opportunity.”33 The of gray matter in the sublenticular substantia innominata quality of scientific work presented was superb and was (Figs. 7 and 8). Using his cupric-silver technique, de Olmos catalogued by the New York Academy of Sciences as the demonstrated a continuum of central amygdala around the text Advancing from the Ventral Striatum to the Extended internal capsule to the lateral bed nucleus of the stria ter- Amygdala.33 No one was more deserving of such a high- minalis, and he later corroborated this circuit as well as its quality conference than Heimer, and Dr. John Jane Sr. very association connections by performing retrograde fluores- appropriately summarized this acknowledgment with an cent tracer studies. evening toast from the poet W. H. Auden: “Let us honor if A similar, medial circuit was later identified when retro- we can the vertical man, though we value none but the hor- grade fluorescent tracers were injected into the rodent izontal one.” accessory olfactory bulb and labeled cells in a continuous Lennart Heimer’s influence on neuroanatomy is pro- column were observed from the medial amygdala to the found and permanent. In a similar way, his colleagues and posterior ventral region of the sublenticular region to the coworkers influenced him and in turn were changed by the medial bed nucleus of the stria terminalis.7 Thus, the cen- relationship. José de Olmos, George Alheid, Robert Switz- tral division of the extended amygdala is associated with er, Scott Zahm, and Laszlo Zaborszky are devoted basic projections to the lateral hypothalamus, whereas the medi- scientists and friends who carry forward the concepts and al division projects to the medial hypothalamus. teachings of Lennart Heimer. His clinical colleagues in the Department of Neurosurgery at the University of Virginia Implications for Psychosurgery Health System are forever grateful and have dedicated their new library to him. The ventral striatopallidal system and the extended Dr. Heimer is survived by his wife, Hanne-Bjorg; sons, amygdala are thus major components of the limbic system Hakon, Mikael, Gösta, and Knut; 4 grandchildren; and sis- and have been implicated in schizophrenia, addiction, de- 17 ters Gudrun Strandberg and Bodil Karlén of Sweden. He pression, and obsessive–compulsive disorders. It has been left an enormous legacy of students and colleagues in all proposed that the development of schizophrenia is related 38 fields of neuroscience and psychiatry. His ideas and scien- to excessive inhibition in these pathways, and morpho- tific contributions will last for generations. metric studies have revealed volume loss in the amygdala and/or hippocampus in 54% of patients with schizophrenia.4 Findings of Kluver and Bucy, as well as more recent Acknowledgments evidence from intracranial limbic electrodes8 and patients undergoing temporal lobectomy, have indicated that the We thank the Heimer family for kindly allowing us to prepare 39 this article. We also thank Drs. Robert Switzer, Alan Peters, Laszlo amygdala is associated with aggression and emotion. In Zaborszky, and Scott Zahm for providing information. Mrs. Cindy fact, bilateral stereotactic amygdalotomy has been per- Roberson assisted with manuscript preparation. formed for severe aggressive behavior34 and self-mutilation 10 disorders. Perhaps extended amygdala structures will be References targeted for future psychiatric interventions.27 Neurosurgeons have long been interested in treating psy- 1. Abelson JL, Curtis GC, Sagher O, Albucher RC, Harrigan M, chiatric disease by targeting the limbic system. Early Taylor SF, et al: Deep brain stimulation for refractory obsessive- lesioning procedures included capsulotomy and subcaudate compulsive disorder. Biol Psychiatry 57:510–516, 2005 tractotomy—targets remarkably close to ventral striatal 2. Anderson D, Ahmed A: Treatment of patients with intractable structures. More contemporary neurosurgical interest in obsessive-compulsive disorder with anterior capsular stimulation. Case report. J Neurosurg 98:1104–1108, 2003 psychiatric disease has been focused on these regions in the 3. Aouizerate B, Cuny E, Martin-Guehl C, Guehl C, Amieva H, context of deep brain stimulation, including the subgenual 25 Benazzouz A, et al: Deep brain stimulation of the ventral caudate cingulate and Brodmann area for treatment-resistant nucleus in the treatment of obsessive-compulsive disorder and major depression32 and obsessive-compulsive disorder major depression. Case report. J Neurosurg 101:682–686, 2004 treatments targeting the anterior capsule1,2,11,37 and nucleus 4. Bogerts B, Meertz E, Schönfeldt-Bausch R: Basal ganglia and lim- accumbens shell. bic system pathology in schizophrenia. A morphometric study of

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brain volume and shrinkage. Arch Gen Psychiatry 42:784–791, 23. Heimer L, Larsson K: Mating behavior of male rats after olfacto- 1985 ry bulb lesions. Physiol Behav 2:207–209, 1967 5. de Olmos J: The amygdaloid projection field in the rat as studied 24. Heimer L, Larsson K: Mating behavior in male rats after destruc- with the cupric silver method, in Eleftherious BE (ed): The tion of the mamillary bodies. Acta Neurol Scand 40:353–360, Neurobiology of the Amygdala. New York: Plenum Press, 1972, 1964 pp 145–204 25. Heimer L, Peters A: An electron microscope study of a silver stain 6. de Olmos JS: A cupric-silver method for impregnation of terminal for degenerating boutons. Brain Res 8:337–346, 1968 axon degeneration and its further use in staining granular argy- 26. Heimer L, Robards MJ: Neuroanatomical Tract-Tracing rophilic neurons. Brain Behav Evol 2:213–237, 1969 Methods. New York: Plenum Press, 1981 7. de Olmos JS, Alheid GF, Beltramino CA: Amygdala, in Paxinos 27. Heimer L, Trimble M, Van Hoesen GW, Zahm DS: Anatomy of G (ed): The Rat Nervous System. Sydney: Academic Press, Neuropsychiatry: the New Anatomy of the Basal Forebrain 1985, pp 223–334 and its Implications for Neuropsychiatric Illness. Burlington, 8. Fenwick P: Aggression and epilepsy, in Trimble MR, Bolwig TG MA: Academic Press, 2007 (eds): Aspects of Epilepsy in Psychiatry. Chichester, UK: J 28. Heimer L, Wilson RD: The subcortical projections of allocortex: Wiley & Sons, 1986, pp 31–60 similarities in the neuronal associations of the hippocampus, the 9. Fink RP, Heimer L: Two methods for selective silver impregna- piriform cortex and the neocortex, in Santini M (ed): Golgi tion of degenerating axons and their synaptic endings in the cen- Centennial Symposium Proceedings. New York: Raven Press, tral nervous system. Brain Res 4:369–374, 1967 1975, pp 177–193 10. Fountas KN, Smith JR, Lee GP: Bilateral stereotactic amygdalo- 29. Heimer L, Zaborszky L: Neuroanatomical Tract-tracing tomy for self-mutilation disorder. Case report and review of the Methods 2: Recent Progress. New York: Plenum Press, 1989 literature. Stereotact Funct Neurosurg 85:121–128, 2007 30. Johnston JB: Further contribution to the study of the evolution of 11. Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, the forebrain. J Comp Neurol 35:337–481, 1923 Malloy PF, et al: Three-year outcomes in deep brain stimulation 31. Larsson K, Heimer L: Mating behavior of male rats after lesions in for highly resistant obsessive-compulsive disorder. the preoptic area. Nature 202:413–414, 1964 Neuropsychopharmacology 31:2384–2393, 2006 32. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz 12. Heimer L: Dissection of the Human Brain (DVD). Charlottesville, D, Hamani C, et al: Deep brain stimulation for treatment-resistant VA: Departments of Neurosurgery and Neuroscience, University depression. Neuron 45:651–660, 2005 of Virginia, 2006 33. McGinty JF (ed): Advancing from the Ventral Striatum to the 13. Heimer L: Human Brain and Spinal Cord: Functional Neu- Extended Amygdala. New York: New York Academy of roanatomy and Dissection Guide. New York: Springer-Verlag, Sciences, 1999 1983, p 402 34. Narabayashi H, Nagao T, Saito Y, Yoshida M, Nagahata M: Ste- 14. Heimer L: Human Brain and Spinal Cord: Functional Neu- reotaxic amydalotomy for behavior disorders. Arch Neurol 9: roanatomy and Dissection Guide, ed 2. New York: Springer- 1–16, 1963 Verlag, 1995, p 520 35. Nauta WJ, Gygax PA: Silver impregnation of degenerating axon 15. Heimer L: Instructional video. Dissection of the human brain. terminals in the central nervous system: (1) Technic. (2) Chemical Neurosurg Focus 18(6B): E4, 2005 notes. Stain Technol 26:5–11, 1951 16. Heimer L: Manniskans hjarna och ryggmarg; dissektionshandled- 36. Nauta WJ, Gygax PA: Silver impregnation of degenerating axons ning samt oversikt over centrala nervsystemets funktionella anato- in the central nervous system: a modified technic. Stain Technol mi. Goteborg, Sweden: Akademiforlaget, 1961 pp 1–86, 29:91–93, 1954 17. Heimer L: A new anatomical framework for neuropsychiatric dis- 37. Nuttin BJ, Gabriëls LA, Cosyns PR, Meyerson BA, Andréewitch orders and drug abuse. Am J Psychiatry 160:1726–1739, 2003 S, Sunaert SG, et al: Long-term electrical capsular stimulation in 18. Heimer L: The olfactory connections of the diencephalon in the patients with obsessive-compulsive disorder. Neurosurgery rat. An experimental light-and electron-microscopic study with 52:1263–1274, 2003 special emphasis on the problem of terminal degeneration. Brain 38. Stevens JR: Epilepsy, schizophrenia, and the extended amygdala. Behav Evol 6:484–523, 1972 Ann N Y Acad Sci 877:548–561, 1999 19. Heimer L: The olfactory cortex and the ventral striatum, in 39. Trimble MR, Van Elst LT: On some clinical implications of the Livingston KE, Hornykiewicz O (eds): Limbic Mechanisms. ventral striatum and the extended amygdala: investigations of The Continuing Evolution of the Limbic System Concept. aggression. Ann N Y Acad Sci 877:638–644, 1999 New York: Plenum Press, 1978 pp 95–187 20. Heimer L: Pathways in the brain. Scientific American 225: 48–60, 1971 21. Heimer L, de Olmos JS, Alheid GF, Pearson J, Sakamoto N: The Manuscript submitted March 15, 2008. human basal forebrain, part II, in Bloom FE, Björklund A, Hökflet Accepted April 22, 2008. T (eds): Handbook of Chemical Neuroanatomy. Amsterdam: Sources of support: none reported. Elsevier, 1999, pp 57–226 Address correspondence to: W. Jeffrey Elias, M.D., Department 22. Heimer L, Kuikka V, Larsson K, Nordstrom E: A headholder for of Neurosurgery, University of Virginia Health System, Box stereotaxic operations of small laboratory animals. Physiol Behav 800212, Charlottesville, Virginia 22908. email: wje4r@virginia. 7:263–264, 1971 edu.

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