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Neurosurg Clin N Am 14 (2003) xiii–xiv

Preface

Surgery for psychiatric disorders

Ali R. Rezai, MD

Steven A. Rasmussen, MD
Guest Editors

Surgery for psychiatric disorders has intrigued
the psychiatric, neurological, and neurosurgical
communities as well as the lay public for the past
70 years. Few other therapies have generated such
controversy, enthusiasm, misconception, and, at
times, indiscriminate use. Recent advances in image
guidance, devices, and stereotactic procedures, as
well as rapid expansion of our knowledge of the
functional neuroanatomy of the major psychiatric
disorders has led to renewed interest in neurosurgical approaches to these conditions. This issue of
the Neurosurgery Clinics of North America was
envisioned with the purpose of compiling the
perspectives of experts on the cutting edge of
research in the neurosurgical treatment of psychiatric disorders.
Currently, the two most common psychiatric
disorders amenable to surgical intervention are
obsessive-compulsive disorder (OCD) and major
depression. OCD affects 4 to 7 million people in
the United States at an annual cost of $8 billion
per year and was among the 10 leading medical
or psychiatric causes of disability in developed
countries (1998 World Health Organization
study). Conservative estimates of the lifetime
prevalence of major depression are from 2.6%
to 5.5% in men and 6.0% to 11.8% in women.
Approximately 50% to 85% of patients with major
depression experience recurrent episodes of illness.
In addition to subjective distress, the disorder can
be a cause of profound disability, with pervasively

Benjamin D. Greenberg, MD, PhD

negative effects on marital, parental, social, vocational, and other life functions.
Advances in the efficacy, safety, and tolerability of treatments for OCD and depression have
been made in the past 20 years. However, a significant number of patients with OCD and major
depression refractory to nonsurgical treatments
remain severely ill. These individuals, who are living lives of hopeless desperation, may ultimately
face the tragic end of suicide. The hope that surgery can offer relief to these patients from agony
and suffering is the fundamental imperative that
demands ongoing research in this area.
It is clear that psychiatric neurosurgery
will undergo a rapid evolution over the next
decade. Today, dedicated multidisciplinary teams
specializing in treating psychiatric patients have
at their disposal the entire spectrum of modern
functional neurosurgical techniques, including
lesioning, radiosurgery, and neurostimulation.
Advances in our understanding of the functional
neuroanatomy and electrophysiology of the relevant circuitry underlying these conditions will
increasingly guide placement of lesions or deep
brain stimulation (DBS) electrodes. To promote
further growth in this field, centers with psychiatric and surgical expertise must design studies
that are prospective and randomized, using reliable and validated diagnostic and evaluation tools
that measure changes in symptoms and quality of
life.

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xiv

A.R. Rezai et al / Neurosurg Clin N Am 14 (2003) xiii–xiv

To critically examine neurosurgery for psychiatric disorders, we must start by carefully examining
the past. Kopell et al provide a historical perspective that reminds us of the complexities of psychosurgery and an enduring caution for the future.
These historical endeavors were limited by a lack
of scientific rationale and other limitations such
as surgical techniques and devices, vague patient
selection, indiscriminate use, and nonstandardized
evaluations. In spite of the decline of surgery for
psychiatric disorders since the 1950s, early studies
of stereotactic lesioning demonstrated significant
improvements in symptoms of patients with major
depression and OCD with few cognitive or neurological side effects. Current stereotactic methods,
using considerably smaller and more precisely
located targets, have much lower morbidity. Neuroimaging research has focused attention on the
relationship between activity in specific neuroanatomical networks and psychiatric symptoms and
on changes after effective treatment. The articles
by Rauch and Greenberg et al provide an overview
of the scientific foundation and the emerging therapeutic strategies being explored today.
The articles by Greenberg, Cosgrove, and
Chang et al consider the evidence for the safety
and efficacy of lesioning procedures. The evidence
has definite limitations but nevertheless sheds light
on critical issues in assessing the long-term effectiveness and morbidity associated with anterior
cingulotomy, anterior capsulotomy, subcaudate
tractotomy, and limbic leucotomy. Jeanmonod
et al describe a novel lesioning approach to neuropsychiatric disorders based on recent evidence
related to thalamocortical dysrhythmias that their
group have shown are present in these conditions.
Nuttin et al present recent data on the use of DBS
technology for the treatment of OCD.
Two additional novel somatic treatments for
refractory depression have also been the subject
of systematic study over the past decade. George
et al review the neurobiologic rationale and summarize treatment outcome data for transcranial
magnetic stimulation, while Carpenter et al review
similar evidence for vagal nerve stimulation.

Given the past history of the field, it is particularly important that research in this area move
forward on a solid scientific and ethical foundation. Collaborative efforts between centers with
dedicated multidisciplinary teams of psychiatrists,
neurosurgeons, and basic scientists are needed to
develop treatments with proven efficacy and safety
before the premature introduction of these procedures into routine clinical use. In this context, we
have included an editorial reprinted from a recent
publication of the OCD-DBS collaborative group
in neurosurgery that focuses on recommendations
for future research efforts in this area. Finally, any
publication focusing on surgery for psychiatric
disorders must include a thoughtful discussion
of the ethical implications of these procedures.
Fins et al offer a careful and considered review
of the ethical issues in this field, including issues
of informed consent.
Together, these articles provide a comprehensive overview of the current state of surgery for
psychiatric disorders and the complex issues surrounding the re-emergence of this field. They
represent a window into what promises to be
an exciting future for the development of novel
neurosurgical approaches to psychiatric disorders
that are based on the neurobiologic basis of these
conditions.
Ali R. Rezai, MD
Section of Stereotactic and
Functional Neurosurgery
Department of Neurosurgery
The Cleveland Clinic Foundation
Cleveland, OH, USA
Steven A. Rasmussen, MD
Butler Hospital
Brown University
Providence, RI, USA
Benjamin D.Greenberg, MD, PhD
Department of Psychiatry and Human Behavior
Brown University
Providence, RI, USA

Neurosurg Clin N Am 14 (2003) xv–xvi

Letter to the editor

Deep brain stimulation for psychiatric disorders
There is increasing interest in the use of deep
brain stimulation (DBS) as a treatment for patients with psychiatric conditions. For example,
the preliminary results from the first trials,
reported by Nuttin et al [1], have shown that
DBS may have beneficial effects in patients with
severe obsessive-compulsive disorder (OCD) that
is refractory to treatment. These preliminary results suggest that DBS may have a role in the
treatment of patients with intractable OCD.
Treatment of psychiatric patients with DBS remains investigational, however, and is not considered standard therapy.
Concern regarding the use of neurosurgery for
the treatment of patients with psychiatric illnesses
is attributable largely to the indiscriminate and
widespread application of extensive, destructive
procedures before the stereotactic era. The tragic
example of frontal lobotomy, which was performed many times before adequate long-term
safety data were available, remains an enduring
caution.
Given this history, it is incumbent on the scientific community to respect the dignity of patients who may be included in studies by ensuring
adequate protection while providing access to
potential therapeutic innovations. We recommend
that all investigators adhere to comprehensive
standards that protect this potentially vulnerable
population while they pursue valuable clinical research. Toward that end, we urge that investigators
who are engaged in this research establish multidisciplinary, multicenter teams to systematically
investigate DBS in OCD. On the basis of our experience, we recommend that studies aimed at investigating the use of DBS to treat patients with
psychiatric illnesses meet the following minimum
requirements.
1. An ethics committee (eg, the Institutional
Review Board in the United States) that will

2.

3.

4.

5.

6.

have ongoing oversight of the project should
approve the investigational protocol.
A patient assessment committee should evaluate each patient as a possible candidate for
inclusion in the protocol. The role of this
committee is to ensure that potential candidates meet certain medical and psychiatric
criteria and are appropriate for inclusion in
the study and to monitor the adequacy of the
consent process. Patient assessment committees should be constituted broadly to achieve
an ethically valid consensus, and they should
have the opportunity to obtain independent
capacity assessments when indicated.
Candidates for DBS surgery should meet
defined criteria for severity, chronicity, disability, and treatment refractoriness.
The use of DBS should be limited solely to
those patients with decision-making capacity
who are able to provide their own informed
consent. Patient consent should be maintained and monitored throughout the process,
and patients should be free to halt their
participation voluntarily.
Patient selection, surgical treatment, device
programming, and comprehensive, regular
psychiatric follow-up should be conducted at
or supervised by a clinical research center.
The investigative team should include specialists from the following disciplines, and they
should work in close collaboration:
a. A functional neurosurgical team with established experience in DBS.
b. A team of psychiatrists with extensive experience in the psychiatric condition under
investigation.
c. Preferably, both of the preceding groups
should have some experience in neurosurgical
treatment for psychiatric disorders. If not,
close consultation with experienced centers is
indicated.

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doi:10.1016/S1042-3680(03)00007-X

OH.N).354:1526. RI 02906. Rezai Erwin Montgomery Don Malone Cleveland. 9.0273. . QUEST program (L1170) for providing the electrical stimulation devices. Gybels J. Cosyns P. embarking on this type of research requires a major commitment of time.xvi The OCD-DBS Collaborative Group / Neurosurg Clin N Am 14 (2003) xv–xvi 7. Demeulemeester H. The procedure should be performed to improve patients’ lives and never for political. Meyerson B. Paul Cosyns Loes Gabriels Antwerp. USA Acknowledgments We acknowledge the Flemish Scientific Foundation (project G. Fins New York. We acknowledge the Medtronic. Bart Nuttin Jan Gybels Leuven. Sweden Steven A. USA References [1] Nuttin B. Inc. NY. The surgery should be performed only to restore normal function and relieve patients’ distress and suffering. DBS has the potential to offer hope for severely ill patients. energy. Electrical stimulation in anterior limbs of internal capsules in patients with obsessivecompulsive disorder [letter].97. and the National Alliance for Research on Schizophrenia and Depression for financial support. 8. Ali R. but investigations in this area should proceed cautiously to maintain the public trust necessary for scientific progress. and resources across disciplines before and after device implantation. Investigators must disclose potential conflicts of interest to regulatory bodies such as ethics committees or institutional review boards and to potential enrollees during the informed consent process. the Research Council of the Katholicke Universiteit Leuven (project OT-98-31). USA In our experience. law enforcement. Rasmussen Benjamin Greenberg Gerhard Friehs Butler Hospital Brown University 345 Blackstone Boulevard Providence. Belgium Joseph J. or social purposes. Lancet 1999. Belgium Bjorn Meyerson Sergej Andreewitch Stockholm.

Cleveland Clinic Foundation. Rezai. a Swiss psychiatrist named Gottlieb Burckhardt (Fig. Department of Neurosurgery. and every path that leads to new victories is lined with the crosses of the dead. This is the tale of a treatment whose promise remains largely unknown and unfulfilled even today. but it was Broca’s work that looked specifically to the brain.’’ pressure from his colleagues led him to abandon his efforts. Although in Burckhardt’s series of six patients. Fulton. such intervention led to virtual worldwide banning of a seemingly promising surgical venue. 1).see front matter Ó 2003. three were considered ‘‘successes’’ and two ‘‘partial successes. The legacy of Moniz.1016/S1042-3680(03)00002-0 . . Leborgne (‘‘Tan’’) in front of the Parisian Anthropological Society meeting in 1861. Cleveland. E-mail address: rezaia@ccf. the impetus to explore the surgical options in psychiatric treatment has once again arisen. Elsevier Inc. of localization that allowed the surgical intervention on neural function.org (A.Neurosurg Clin N Am 14 (2003) 181–197 Psychiatric neurosurgery: a historical perspective Brian Harris Kopell.Every new surgical approach must first seek its special indications and contraindications and methods. Suite 8R.’’ Medical scientists and clinicians soon seized on the idea of localization in the treatment of mental disorders. One stands fast in the old principle: ‘‘primum non nocere’’. he ushered in the age of localization (Fig. New York University Medical Center. MDb. it is this phenomenon that is fundamental to understanding the rise and ultimate fall of psychosurgery in the twentieth century. Yet. however. New York.* a Department of Neurosurgery. 9500 Euclid Avenue. flourishing. I do not 1042-3680/03/$ . USA b Section of Stereotactic and Functional Neurosurgery. Localization married the concepts of behavior and function with a precisely defined anatomic neural substrate. Ali R. drawing from these animal studies. In the late 1800s. Before this. and demise of psychosurgery in the early twentieth century may serve to caution our current endeavor to intervene surgically in psychiatric patients. OH 44195.R. 3) reported the results a series of surgical procedures in which he drilled holes in the heads of six severely agitated psychiatric patients and extracted sections of their frontal lobes [2]. In 1891. almost inconceivable. Rezai). In the hands of the most prominent physicians and Nobel laureates of the age. USA Why intervene surgically to treat psychiatric disorders? Certainly. Franz Joseph Gall’s phrenology (Fig. that such a rapid leap from animal experiments in the laboratory to clinical practice on human beings could take place. 2) tried to localize function based on cranial landmarks. doi:10. Why the descent from mainstream ‘‘miracle’’ to medical anathema? When Paul Broca presented his case of patient M. . It was the first step at unlocking the ‘‘black box. despite the best of intentions. Indeed Burckhardt’s report itself ends with a bold challenge to the fundamental practice of medicine: Doctors are different by nature. It might seem surprising.’’ I belong naturally to the second category. 560 First Avenue. the other states: ‘‘melius anceps remedium quam nullum. Friedrich Goltz performed experiments on dogs in which removal of the temporal lobes resulted in animals that were more tame and calmer than the ones not operated on [1]. past efforts have been marked with ambiguous results at best and have been associated with ignoble circumstances at worst. NY 10016. and Freeman The birth. It was the concept * Corresponding author. All rights reserved. MDa. S-80.

Almeida Lima (Fig. the frontal leukotomy. 4). Paul Broca. [3] ‘‘First. . and a series of 20 patients commenced. . and other higher intellectual faculties. . to undertake the procedure. at the age of 30 years. Kopell.’’ The battle line for psychosurgery in the early twentieth century was drawn. [8]’’ . when altered in a surgical fashion. . objective data are far more difficult to obtain. .html. Carlyle Jacobsen.R. [There simply existed too] great a difference between the psychic life of man and that of animals. . At the Second World Congress of Neurology in London.it is not possible to obtain experimental subjects among animals. In the short run. learning. .’’ [4] This discovery would echo the troubles clinicians would have a decade later as the proliferation of lobotomy raged out of control. Moniz realized that his inspiration from animal data was a tenuous one: ‘‘. Fulton and Jacobsen made the observation that frontal lobe ablation could result in the lessening of ‘‘anxiety states’’ in chimpanzees [6]. Egas Moniz made this observation in 1935: Fig. would result in definitive change of the seemingly ethereal entities of thought and mind itself. memory. I [expect] to be able to transform the psychic reactions and to relieve the patient thereby [7]. it was necessary to cut the connecting pathways in progressively higher neuroanatomic levels of the system. 6 and 7). . in 1935. It is this fundamental struggle between the obligation of the physician to remain cautious and the desire to help those in need that would define the efforts to intervene surgically in the mentally ill. 1. In attendance at that meeting was a Portuguese neurologist by the name of Egas Moniz and an American neuropsychiatrist by the name of Walter Freeman (Figs. Drawing from Fulton and Jacobsen’s data as well as synthesizing case reports of neurosurgeons operating on various frontal lobe lesions at the time. yet he found that ‘‘turning to questions It is necessary to alter these synapse adjustments and change the paths chosen by the impulses in their constant passage so as to modify corresponding ideas and force thoughts into different channels.H. He convinced a young neurosurgeon in Lisbon.182 B. Despite this bold leap into human clinical practice.edu/depts/ mcne/founders/page0013. however. . In 1929. Fulton applied this approach to frontal lobe function in chimpanzees. do no harm ( primum non nocere)’’ versus ‘‘Better an unknown cure than nothing at all (melius anceps remedium quam nullum). Fulton and Jacobsen presented their work showing behavioral changes in chimpanzees after ablation of frontal lobe areas (Fig. 5) [5].uic. John F. His plan was to sever the white matter bundles connecting frontal lobe regions with the rest of the brain. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 involving perception. A. His research interest was an extension of Sherrington’s thought: to reveal the relations among neural systems. Moniz made the critical analytic jump linking the seemingly irrational behaviors and thoughts of psychiatric patients with an anatomically ‘‘normal’’ but disordered neural substrate—a concrete neural substrate which. Then. 8). Fulton became the chairman of Yale University’s Department of Physiology (Fig. another fateful meeting occurred. .) believe that we should allow this to hold us back. By upsetting the existing adjustments and setting in movement in other [connections]. it led Fulton to collaboration with a recently hired psychologist. (Available at: www. The lower level thus becomes disconnected or ‘‘disinhibited’’ and reveals itself through changes in neurologic behavior.

B. too. Why would scientists of such renown as Moniz and of such promise as Freeman be so hasty in applying such a radical and virtually unfounded remedy? Why did melius anceps remedium quam nullum become so much more important and more seductive than primum non nocere? Why did ‘‘do something’’ become more imperative than ‘‘first. hopes. 2. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 183 Fig. a therapy that was untried and possibly dangerous was better than the status quo. For Freeman. prejudices. Science is the realm of theory.wustl. who held that psychiatric illness had a tangible basis in neuropathophysiology. something that an organicist like myself could understand and appreciate’’ [9]. Walter Freeman chanced on Moniz’s initial communications regarding frontal leukotomy in the obscure journal Lisboa Medicina. It deals with the currency of truth and hard fact. Freeman wrote to Moniz in May of 1936. telling him of his inspiration and his intention to apply Moniz’s procedure in the United States. A. Freeman. His contemporaries who treated psychiatric maladies with psychotherapy. useless prattle by his account. Kopell. a neuropsychiatrist of the ‘‘organicist’’ school. do no harm’’? Medicine is an art that is not practiced in the idealized bubble of science.jpg.edu/ mjstrube/psy315/phrenology.R. nevertheless.) In 1936. hypothesis. Phrenology localization scheme.H. Medicine is where science meets all the human foibles. and desires to . (Available at: www. had frustrated Freeman.artsci. here was ‘‘something tangible. recognized that the scientific basis for the procedure was ‘‘naive’’. and the experimental model.

more importantly. equal to the total . (From Feldman RP.’’ ‘‘[Medicine] is more wrapped up in human. with permission. shock therapies were dangerous and difficult to manage. because patients were allowed by default to languish according to the natural history of their disease. Fig. The most important of these ‘‘shock’’ treatments were injections of metrazol (camphor). Neurosurgery 2001. beginning in the 1930s. because these patients required constant vigilance from nurses and medical staff. time-dependent concerns than is generally admitted’’ [10].000 patients. all designed to trigger convulsions and states of unconsciousness in the patient.’’ in these early versions. increase the number of discharges from inpatient facilities. John F. The seizures of metrazol and electroconvulsive therapies. A. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 Fig. there were 480. such as barbiturates. Yet. these unfortunate side effects were tolerated because of the ability of these ‘‘somatic’’ treatments to alter the clinical course of a patient’s mental disease and. often had the byproduct of spinal and long bone fractures. Nowhere was this desire to ‘‘do something’’ stronger than in the field of psychiatry at the dawn of the twentieth century. Although extremely welcomed because of their clinical ‘‘effectiveness.) ‘‘do something. Kopell.br/ cm/n02/istoria/lobotomy. and electroconvulsive therapy. a wave of ‘‘somatic’’ therapies began to ‘‘revolutionize’’ psychiatric practice (Fig. some containing as many as 10. Insulin-therapy was cost.and labor-intensive. (Available at: www.000 psychiatric inpatients. Gottlieb Burckhardt. 3. ‘‘Therapeutic nihilism’’ was the philosophy of treatment among psychiatrists at this time. 9). Indeed.R. The inpatient psychiatric institutions of the early twentieth century had become a vast network of juggernaut institutions. Psychosurgery: a historical overview.H. there was little ground gained in the ability to change the emotional and mental dynamics of psychiatric disease. patients were terrified of entering into the near-death states of insulin coma.org. unmodified by anesthesia or muscle relaxants. Inpatient admissions were climbing at an alarming rate.epub. Then.184 B.48:647–59. Even with the advent of powerful drugs. By 1940. there were no drugs or medical procedures available that were used to treat the specific symptoms of mental illness. insulin-induced hypoglycemic comas. Furthermore. 4. The economic environment of inpatient psychiatric care in the nascent twentieth century is also central to understanding the widespread adoption of such a risky and uncertain treatment as psychosurgery by the medical community. Goodrich JT.htm). Fulton.

H. Evidence mounted that any patient hospitalized for longer than 2 years would stay until death. talked in a low.R.) number of beds in all nonpsychiatric hospitals combined [11]. with permission. the discharge rate decreased. Lisbon. Scientific reports. p. The Moniz procedure. untried. they rapidly proceeded with an increasing number of patients.B. 12 and 13). A. A. Therapeutic nihilism coupled with an overcrowded and economically overwhelmed inpatient psychiatric system was fertile ground for an untested. . 5. This was a middle-aged woman who suffered from ‘‘agitated depression. It was not uncommon for institutions to house twice the number of patients for which they were designed. Kopell. Freeman. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 185 Fig. In a communication that appeared in Psychiatric Quarterly in 1945. one psychiatrist equated inpatient psychiatric admission as being ‘‘identical with doom’’ [13]. natural tone. 146. 1977. 10). Her husband asserts that she is more normal than she has ever been’’ [14].’’ having had a habit of wild outbursts in which ‘‘she exposed herself before the window and urinated upon the floor’’ [15]. abandoning the Moniz leukotome for a dull flat knife known as a bistoury (Fig. Scenes of 100 cots placed side by side in a ward built for 25 leading to elderly patients climbing over one another to use the toilet pervaded the inpatient psychiatric landscape [12]. They also modified the Moniz procedure.showed excellent appreciation of her changed condition. and largely scientifically unsupported ‘‘miracle. They considered their initial patient. As the number of admissions increased. began a series of patients in September of 1936. became the Freeman-Watts technique. 11) and approaching from the side as opposed to the top (Figs. Within a year.H. Emboldened by their success. a resounding success.’’ Freeman brought the miracle of Moniz to the United States in 1936. With the lack of effective therapies. In their initial communication they noted: ‘‘She was well dressed. the prefrontal or standard lobotomy. . Albert Maisel’s pictorial essay in the May 1946 edition of Life magazine described the inpatient mental health system as ‘‘little more than concentration camps on the Belsen pattern. frontal leukotomy. Freeman and Watts were eager to share the results of their successes with the . The mathematics of this situation led to vast overcrowding and inhuman conditions (Fig.. having convinced a young neurosurgeon by the name of James Watts to work with him (himself a former student of Fulton’s).’’ Even the psychiatrists themselves began to lose hope. (From Egas Moniz centenary. the rate of recoveries dropped. Cortical areas ablated in Fulton’s experiments.

but his warnings fell on deaf ears.epub. ‘‘nothing less than miraculous’’ [19]. .H. Kopell. Fulton rose to defend the work of Freeman and Watts. 6. In 1 year.htm. He was in solid support of the medical community proceeding with the operations but predicated this support on the concept of carefully designed clinical trials in elite academic institutions [18]. Using his professional reputation among neurologists and psychiatrists as well as his ties to neurosurgeons (indeed. . 7. Initially. . Walter Freeman. . five of six schizophrenics in his series showed no improvement) [16]. . Although he acknowledged the tenuous scientific link between animal studies and clinical practice. (Available at: www. Other neurosurgeons took notice. James Lyerly. with depressive and obsessional types faring best and schizophrenics faring worst (in fact. br/cm/n02/historia/lobotomy.br/cm/ n02/historia/lobotomy. No one knows. Chief of the Neurosurgical Service at the Hospital of the University of Pennsylvania. The procedure was soon to spread throughout the medical community. He modified the Freeman-Watts procedure that he believed was a ‘‘blind’’ one by using a brain speculum so that the white matter to be cut was exposed to visual inspection. Watts. he echoed the need for a procedure to relieve the overburdening of the national psychiatric hospitals. especially among psychiatrists.htm. Egas Moniz. Francis Grant. began applying the Freeman-Watts technique in Florida. . The initial response from the professional community.R.epub. They believed that the procedure was too radical and too unfounded in its scientific basis. and Moniz procedure.org. Lyerly had operated on 19 patients and presented his results at the meeting of the Florida Medical Association. least of all Moniz’’ [17]. was hostile.org. None had any ‘‘serious complications.) Fig. he was the Harvey Cushing Society’s second president). Rezai / Neurosurg Clin N Am 14 (2003) 181–197 Fig. (Available at: www.’’ Lyerly called the procedure.186 B. Four previously chronically institutionalized patients had already been discharged. Freeman would note that the choosing of patients based on disease type was critical to the procedure’s success. A. None died. . a wellrespected community neurosurgeon and a founding member of the Harvey Cushing Society. Fulton won support for the Freeman.) professional community. he thought that there was rich opportunity for research and significant promise for the procedure. One psychiatrist wrote: ‘‘[It is like] burning down the house to roast a pig . By the end of 1937. What has Moniz accomplished?.

’’ A ‘‘clinical drift’’ effect was evident as the procedure became free from any constraints. With the publication of Freeman and Watts’ Psychosurgery in 1942. J. Psychosurgery and the limits of medicine. with permission. p.G. 8. Using his flair for the dramatic. 159. such as The New York Times. Drilling through the skull was rather peculiar. Almeida Lima. it’s just as if that vague unformed apprehension that has been with me all these years suddenly cleared up [20]. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 Fig. were sensationalizing the successes of the prefrontal lobotomy. the task of rigorously controlled academic institutions and off limits to the community practitioner. Fulton once envisioned the psychosurgery effort as an experimental one. Cambridge: Cambridge University Press. Neurosurgery 2001. 187 Fig. Kopell. Newsweek.) and W. Surgeon: Did you feel anything particularly during the operation? Patient: No. (From Feldman RP.H. Freeman dispensed with the customary scientific format and instead presented what was equivalent to pulp nonfiction: Surgeon: Well. the fervor over the success of the lobotomy spread from the professional community to the lay community. 1998.B. Time. Once both the profession and the public recognized lobotomy as a treatment of vast potential. A. I’m glad it is. Now. Freeman and other fervent supporters of lobotomy warned that the procedure should be used . but it didn’t hurt at all. Initially. Jason Mixter at the Massachusetts General Hospital began performing lobotomies in 1938. or any one person. Goodrich JT. isn’t it? Patient: Yes. with permission. every aspect of the medical community was participating in the psychosurgery ‘‘miracle. and Reader’s Digest.) The lay public was especially taken with Freeman and Watts’ book. Even I can read it and understand what I am reading about’’ [21]. Love of the Mayo Clinic traveled to Florida to learn the procedure from Lyerly so that he could start a series of lobotomies. Life. Last resort. Psychosurgery’s fragile connection to the laboratory and the scientific community would begin to grow weaker and weaker.R. (From Pressman J. I’m glad you did it under local because I wanted to see what it was all about. A patient undergoing insulin shock therapy. this is the most interesting medical book that I have ever seen. 9. there wasn’t any real pain except when the first needle went in. One state hospital superintendent wrote to Freeman that his 17-yearold daughter read it and told him: ‘‘Daddy. lay publications. Psychosurgery: a historical overview. its fate ceased to be in the hands of Fulton.48:647–59. Soon. You know I wasn’t dreading this particularly. Now. the operation is over now anyway. Freeman. By 1939.

1998. 1972. Psychosurgery.jpg. Demonstration of the approach of the Moniz procedure (frontal leukotomy). Laitinen L. 149.gggodwin.) . Vaernet K. Charles C. The Incontinent Ward. A. 12.R. p. Kopell. (Available at: www. Examples of bistoury knives. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 Fig. they were ignored in the desire to ‘‘do something’’ for a group of patients who had no alternative form of therapy available. 10. (From Pressman J. however. with permission.com/17-18m.) Fig. (From Hitchcock E. Last resort.H. Byberry State Hospital.) sparingly in cases of schizophrenia because of its poor clinical effect compared with other psychiatric diseases. 11.188 B. with permission. Fig. Cambridge: Cambridge University Press. Proceedings of the Second International Conference on Psychosurgery. Thomas: Springfield. Psychosurgery and the limits of medicine.

B. Conversely. . the most important question to Freeman was. By 1948. ‘‘Did it work?’’ [27]. ‘‘free’’ from his restrictive association with Watts. Freeman had lobotomized another 2400 patients [24]. (From Freeman W.Why not use a shot gun’’ [26]. traveled across the country to fulfill what he considered was an unanswered need (Fig. Freeman severed psychosurgery’s final ties with its roots. Amarro Fiamberti. . Fulton believed that the most reliable and safe medical knowledge came from a combination of basic animal research coupled to a few rigorously designed and executed clinical trials. 2nd edition. Their conflict exemplified their personal philosophies regarding the leap from laboratory to clinic and the growing chasm between psychiatric neurosurgery and its physiologic roots.’’ he envisioned the procedure being able to be performed by any surgically untrained physician after the most minimal instruction. the neurosurgeon. including those recently institutionalized as well as those not hospitalized. Thus. prefrontal lobotomy was entering its heyday. Although Freeman refined the common house tool into what he called a ‘‘transorbital leucotome. Freeman wished to operate on a ‘‘better grade’’ of patient. In one 12-day period. Kopell. Freeman. those of neurosurgery itself. with an ice pick. Springfield: Charles C Thomas. in fact. being too few in number and too expensive in cost. with ice pick in hand. Drawing from an obscure report of an Italian psychiatrist. a ghastly procedure in which the frontal white matter is cut by a metal spike inserted through the thin bony orbit above the eye [22].) Psychosurgery’s most ardent proponent ironically exemplified this clinical drift. Fulton’s incredulous missive to Freeman seethed. Freeman was frustrated with Watts’ veto power over patients who he believed were not disabled enough by their illness. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 189 Fig. with permission. Freeman thought that the rate-limiting step to psychosurgery’s dissemination was. Freeman and Watts recorded 625 operations between 1936 and 1948. It did not take long for Watts to sever his ties with Freeman. Freeman. Freeman did not relent. At the end of World War II. What counted to Freeman were not intelligence tests but the . 13. 14).H. 15). Freeman’s initial choice to accomplish this procedure was the common ice pick (Fig. he operated on 225 patients. Fulton realized that the complete lack of reliable objective testing methods available to psychiatry at the time made it impossible to track lobotomy’s efficacy from any scientific point of view. claiming that the transorbital procedure was ‘‘much less traumatizing than a shotgun and almost as quick’’ [26]. and there was no surgical backup if a hemorrhage did occur. Watts J. Freeman operated in earnest. Time magazine heralded the age of ‘‘mass lobotomies’’ [25]. with ‘‘every physician his own lobotomist’’ [23]. A.R. he was horrified at the ghastly treatment that the patient received under Freeman’s new procedure. Demonstration of the approach in the Freeman-Watts procedure (prefrontal or standard lobotomy). Patients were not draped in sterile linen. Freeman developed the transorbital lobotomy. Yet. however. was looking to expand the use of his procedure. Gone were the days of ‘‘surgery of last resort’’. By 1957. Psychosurgery: in the treatment of mental disorders and intractable pain. 1950. ‘‘What are these terrible things I hear about you doing lobotomies in your office with an ice pick?. Like other neurosurgeons. Fulton was appalled at Freeman’s new course of action.

it was over. (From Freeman W. They remained unconvinced. were performed in the United States [28]. approximately 20. the U.) successful return of patients to everyday life.190 B. The stereotactic era Indeed. The awarding of the Nobel Prize to Egas Moniz in 1949 typified the simultaneous legitimization of lobotomy amid growing concerns regarding its efficacy and side effects. Freeman would dump shoe boxes crammed with letters from ‘‘grateful’’ lobotomized patients onto the desks of skeptical colleagues. the procedure had become as mainstream a treatment as appendectomy. generally used to fight allergies. A. their mental state changed. Freeman died in 1972 at the age of 76 years [29].H. From 1936 to the mid-1950s. it was a surgeon who helped end the ‘‘golden age’’ of psychosurgery and usher in the pharmacologic age of psychiatry. they were rather indifferent. Yet. Primum non nocere versus Melius anceps remedium quam nullum. The death knell for psychiatric neurosurgery was sounded. as this interest waned. Henri Laborit. No longer did they seem anxious about their upcoming surgery. a surgeon in Paris. Psychosurgery: in the treatment of mental disorders and intractable pain. This procedure started as a rather extensive one and became more refined as the volume of brain in the surgical target became smaller. the frontal leukotomy.R. in Freeman’s case. yet. virtually all frontal lobotomies of some form. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 Fig. it fell on deaf ears. technologic developments. The results were stunning. Patients who had stood in one spot without moving for weeks and patients who had to be restrained because of violent behavior could now make contact with others and be left without supervision. A fellow surgeon passed the word to his brother-in-law.000 psychosurgical procedures. and it took the field of psychiatry by storm. Freeman carried on his one-man war. he noticed that when he gave a strong dose to his patients. He was relentless in his attempt to convince his colleagues to perform more of his procedures. ushered in a second wave of psychiatric neurosurgery. Freeman transorbital (‘‘ice pick’’) procedure. Ironically. a psychiatrist named Pierre Deniker. This trend . the first modern neurosurgical procedure for psychiatric disease.S. Springfield: Charles C Thomas. there was some suggestion that minimizing cortical damage and focusing on the white matter tracts could retain efficacy while minimizing side effects. 14. On occasion. In 1952. Then. 1950. sought to interrupt white matter tracts associated with the frontal lobes. Watts J. in fact. Kopell. As the experience with frontal lobotomy increased. especially in the realm of stereotaxis. even as psychosurgery’s most ardent scientific proponents began to question the widespread use of lobotomy. with permission. Food and Drug Administration approved chlorpromazine. Deniker’s interest was piqued. Yet. 2nd edition. and he ordered some chlorpromazine to try on his most agitated and uncontrollable patients. In 1954. was looking for a way to reduce surgical shock in his patients. Having tried antihistamines.

The lesion is approximately 15 to 18 mm in length and 4 to 5 mm in width (Fig. (From Pressman J. the ideal target lays 17 mm from the midline. are considered at length in the article by Greenberg and his colleagues in this issue. 406. p. The lesion is typically made bilaterally 2 to 2. clergy. and 1 mm above the roof of the ventricles (Fig. and the Hamilton Depression scale for depression (HAM-D). both of which are stereotactic operations. . they do suggest a viable means of treatment for a subset of patients who may have no other options. with permission.H. Kopell. Their safety and efficacy for their main current indications. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 191 bioethicists and neurosurgeons is assembled to make sure the patient in question is both refractory and appropriate. 17) [35. lawyers. 16).5 cm from the tip of the frontal horns. One technique involves the use of radiofrequency. Cingulotomy Surgery on the cingulate gyrus dates back to observations in the 1940s that severing fibers from the cingulate gyrus led to a decrease in anxiety type states [32]. localized by air ventriculography and made using thermocoagulation. the inherent bias of a nonrandomized non-double-blind study and the lack of objective functional imaging techniques. Therapeutic failure is determined by quantitative analysis using the most appropriate and accurate psychiatric batteries of tests available. a patient must fail several rounds of treatment with multiple psychotropic medications combined with appropriate psychotherapy before he/she is considered for surgical treatment.R. The procedure performed today has been refined using the latest in stereotactic equipment and imaging techniques. Last resort. When surgical treatment is ultimately considered. 1998. In 1952. There are two forms of this procedure. Wycis and Spiegel introduced the dorsomedial thalamotomy [30. Capsulotomy Developed in Sweden by Lars Leksell and by Talairach in France. capsulotomy. Stereotactic cingulotomy is the most frequently reported neurosurgical procedure for psychiatric disease in the United States and Canada. Freeman often traveled the country. neuropsychologists. which are all stereotactic interventions. In 1967. Next.36]. a patient must meet Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria for a particular psychiatric disease such as obsessive-compulsive disorder (OCD) or affective disorder. was made bilaterally in the anterior cingulate. a multidisciplinary team consisting of psychiatrists.B. 15. intractable OCD and depression. First. the Clinical Global Impression (CGI). and limbic leukotomy. and 8 mm above the intercommissural line. Cambridge: Cambridge University Press. Ballantine et al [34] introduced the modern stereotactic procedure in which a lesion. neurologists. Fig. The four psychiatric neurosurgical procedures currently in use are cingulotomy. Specifically. 10 mm rostral to the anterior commissure. Psychosurgery and the limits of medicine. the target area is between the anterior third and middle third of the anterior limb of the internal capsule at the approximate level of the foramen of Monro. In 1947. The procedures themselves are described below. performing his transorbital procedure. 7 mm lateral from the midline. These procedures are typically performed on the severe and refractory psychiatric patient. Freeman in a Winnebago. A. Whitty et al [33] reported their cingulectomy. most notably. and the other uses gamma radiation to make the lesion. Although many of the following studies of psychiatric neurosurgery have had significant flaws. the first subcortical stereotactic neurosurgical procedure performed on human beings and the model on which all modern psychiatric neurosurgical procedures are based. The second wave of psychosurgery was born. such as the Yale-Brown obsessive-compulsive scale (Y-BOCS). anterior capsulotomy has been in use for refractory psychiatric illness since 1949. In either case. in which a 4-cm  1-cm section of cingulate gyrus was resected bilaterally.) toward increasingly discrete subcortical lesions culminated in the application of stereotaxis on psychiatric neurosurgical procedures. subcaudate tractotomy.31].

Capsulotomy lesion sites. Proceedings of the Fifth World Congress of Psychiatric Surgery. Elsevier/North-Holland Biomedical Press.) . 1979. Meyerson B. (From Hitchcock E. Kopell.R.H. with permission. Lancaster: MTP. 1973.) Fig. Livingston K. with permission. Surgical approaches in psychiatry. Ballantine H. A. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 Fig. (From Laitinen L. Typical cingulotomy lesions. Modern concepts in psychiatric surgery. 16.192 B. 17. Proceedings of the Third International Congress of Psychosurgery.

Lancaster: MTP. 19). What now? Despite the fact that neurosurgery for psychiatric illness decreased in frequency in the latter half of the twentieth century and that neurosurgical technologic developments like stereotaxis vastly improved the quality of the surgical intervention itself. and obsession symptoms while minimizing postoperative epilepsy and cognitive/personality deficits [37. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 193 Subcaudate tractotomy Another stereotactic procedure geared toward interrupting fibers from the orbitofrontal cortex to the thalamus is subcaudate tractotomy (innominatomy). a region of white matter localized beneath the head of the caudate known as the substantia innominata. a beta-emitter that releases lethal radiation to tissue within 2 mm. Sites of subcaudate (basofrontal) tractotomy lesions. having refined the technique. did not expect to come out in favor of psychosurgery. In the United States. Limbic leukotomy Although the other three aforementioned procedures each target a single anatomic substrate. for one. A.B. as the Chairman reported in his review: ‘‘We looked at the data and so they did not support our prejudices. charges of abuse and allegations of surgery for social control culminated in the establishment of a National Commission in 1977.) continued to grow. These rods have a halflife of 68 hours. The target site.38]. placing two rows of four rods each made the lesion. extending from 6 to 18 mm from the midline and being 20 mm long in an anteroposterior direction (Fig. Kopell. the procedure was developed in England by Desmond Kelly and Alan Richardson in the early 1970s. I. Surgical approaches in psychiatry. Careful emphasis was taken to review the efficacy and safety of these procedures. have created the lesion by radiofrequency thermocoagulation [39]. a fourth procedure is designed to interrupt fibers at two separate areas. with permission. 20). This board examined all the neurosurgical procedures performed in the United States from the freehand frontal lobotomies to the stereotactic lesioning procedures. The lesion itself lays at the anteroposterior level of the planum sphenoidale. the operation was designed to relieve depressive.H. has traditionally been localized by ventriculogram. anxiety. Like the human behavioral example of Newton’s third law of motion. Later studies. one involving a frontothalamic loop and the other involving an area of the Papez circuit (Fig. Developed by Knight in 1965 in London. (From Laitinen L. 18). Proceedings of the Third International Congress of Psychosurgery. the negative bias toward its practice Fig. Initially. after which they become inert.R. 18. But we saw that some very sick people had been helped by it’’ [40]. The National Commission’s findings were surprising. Called limbic leukotomy. The lesion is created by multiple 1-mm  7-mm rods of ytrrium-90. Livingston K. the fervor with which psychosurgery was welcomed in the first half of the twentieth century became an ardent backlash against what was regarded as a reckless and sinister procedure. . A stereotactic apparatus places the rods after bilateral burr holes are made just above the frontal sinus and 15 mm from the midline. 1973. The operation itself consists of three 6-mm thermocoagulative or cryogenic lesions in the lower medial quadrant of each frontal lobe (to interrupt frontothalamic connections) and two 6-mm lesions in each cingulum (Fig.

Papez circuit. Treatment-resistant mental disorders. Livingston K. One of the challenges in treating psychiatric disease during the zenith of lobotomy was the quantitative analysis of patients throughout the course of treatment.42].44]. exemplified by such devices as the gamma knife. Surgical approaches in psychiatry. enables lesions to be made without any upfront risk to the patient. Affective disorder. in any of their forms. 1973. similarly has a treatment-resistant subset of patients [43. There are several reasons to continue to evaluate the role of neurosurgery in the treatment of psychiatric disease. surgery may still be a viable treatment alternative in the psychiatrists’ armamentarium. self-mutilation and suicide can be the final tragic outcome for a significant number of these refractory psychiatric patients.H. which includes major depression and bipolar disorder. The promise of a modern undertaking of psychiatric neurosurgery is that it is no longer equivalent to lobotomy. however. 19.) The National Commission was so impressed by the potential benefit of psychiatric neurosurgery that it recommended a review board be formed to study these procedures in a more scientific manner. there still exists a population of psychiatric patients who are refractory to aggressive conventional treatment with medication and empirically proven psychotherapies. such as the Y-BOCS. We benefit from the technologic leaps that have occurred over the past 50 years. Neurosurgical practice has also grown tremendously since the heyday of frontal lobotomy. Proceedings of the Third International Congress of Psychosurgery.194 B.R. Stereotactic radiosurgery. and HAM-D. Modern psychiatric testing batteries. techniques have been developed that allow the neurosurgeon to modulate neurologic function while minimizing the risk to the patient. By most reviews of current treatment strategies. bolstered by technologic advancements in stereotactic equipment coupled with the advent of intraoperative microelectrode recording. Kopell. can hit physiologic targets with a degree of accuracy never before possible. must be looked on as degenerative and potentially fatal neurologic illnesses. Furthermore. Lancaster: MTP. approximately 10% of all OCD patients show an unrelenting downward course despite all psychotherapeutic and pharmacologic treatments [41. For some of these patients. allow for a more accurate and objective evaluation of patients undergoing psychiatric neurosurgical procedures in ways that were not previously available. A particularly intractable population exists among OCD patients. This review board was never formed. Despite adherence to therapeutic guidelines and conscientious compliance. Today’s neurosurgeon. It should be made clear that the end point for untreated psychiatric disease is dismal. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 Fig. Because it is estimated that 3% of the world’s population suffers from OCD. A. this alone is a substantial patient population. (From Laitinen L. Setting aside the loss of productivity on both a personal and professional level. with permission. CGI. Perhaps the neurosurgical technical development that holds the most significance for psychiatric neuro- .

because of the vast resources implicit in the multidisciplinary approach. with permission. This highlights the difference between the surgical efforts for movement disorders and psychiatric disease: although the experimental animal model has bolstered movement disorder surgery. psychiatric neurosurgery may never enter community practice. we have learned from the example of lobotomy that we must tread carefully. A. the inherent lack of valid animal models in the latter has hindered efforts. of course. with its inherent ability to be turned ‘‘on’’ and ‘‘off.R. As our knowledge of the circuitry underlying psychiatric disease increases. Despite all these improvements and the heeding of past .) surgery is deep brain stimulation (DBS). Today. Livingston K. Proceedings of the Third International Congress of Psychosurgery.’’ might prove particularly useful. Because previous efforts to prove the efficacy of surgical intervention in psychiatric disease have been hampered by the lack of double-blind studies. 20. As we re-explore surgery’s role in psychiatric treatment. (From Laitinen L. allow the clinical investigator a noninvasive method of directly and precisely localizing brain function and anatomy.H. Limbic leukotomy lesion sites.B. such as positron emission tomography (PET). 1973. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 195 Fig. must remain firmly in the realm of a limited number of academic institutions. Surgical approaches in psychiatry. Ultimately. With its ability to modulate neuronal function without the necessity of a permanent lesion. DBS has already become the mainstay of the neurosurgical treatment of movement disorders. Such a link between functional imaging and surgical practice has already been demonstrated in the endeavors in chronic pain and movement disorders. better surgical targets will become apparent. these imaging techniques allow us to evaluate human brain function directly without having the potential misdirection that animal models may entail. Lancaster: MTP. state-of-the art imaging techniques. functional magnetic resonance imaging (fMRI). Kopell. Together. and magnetoencephalography (MEG). This intermediate link between animal physiologic models and clinical practice is a fundamental paradigm shift with respect to the initial efforts with lobotomy. Although experimental. Our initial efforts. DBS. these tools can help to eliminate some of the shortcomings of past studies of psychiatric neurosurgical procedures. Our knowledge of the pathophysiology underlying psychiatric disease has also grown.

340. Last resort. 79. Duffield JE. Psychosurgery and the limits of medicine. Nevertheless. et al. Psychosurgery and the limits of medicine. 97–100. [11] Pressman J. Last resort. p. Psychosurgery and the limits of medicine. 1995. Cambridge: Cambridge University Press. 61–73. Last resort. 83–4. Anterior cingulectomy in the treatment of mental disease.26:797. Science 1947. [4] Pressman J. Lancet 1952. 3rd edition. [31] Spiegel EA. [20] Freeman W. Cambridge: Cambridge University Press. Psychosurgery and the limits of medicine. [32] Freeman W. [15] Pressman J. Psychosurgery: intelligence. 1954. [29] Pressman J. Watts J. Philadelphia: WB Saunders. Psychosurgery and the limits of medicine. 337–40. 345. Psychosurgery and the limits of medicine. Physiological and psychological results of thalamotomy. patients and clinicians alike must always be cognizant of the potential dangers in this task. 1998. Ueber die Verrichtungen des Grosshirns. p. 1998. Psychosurgery and the limits of medicine. 1952. 1998. Psychosurgery and the limits of medicine. past efforts suggest that a real potential to benefit some extremely sick people may exist. Allegemeine Z Psychiatr 1891.R. 1998. Psychosurgery and the limits of medicine. [30] Spigel EA. Washington. p. A. Sweet WH. Psychosurgery and the limits of medicine. p. [2] Burckhardt G. p. 1942. p. [25] Pressman J. In: Abstracts of the Second International Neurological Congress. Arch f d ges Physiol 1991. Proc R Soc Med 1949. Jacobsen CF. p. 1998. Psychosurgery and the limits of medicine. The functions of the frontal lobes: a comparative study in monkeys. [13] Eliasberg W. 110. Last resort. J Neurosurg 1967. [5] Fulton JF. p. 104–5. Operative neurosurgical techniques. [34] Ballantine HT Jr. [21] Pressman J. Watts J. Cambridge: Cambridge University Press. 1998. [12] Pressman J. Proceedings of the Third Research Conference on Psychosurgery. Last resort. 1998. editors. p. Psychosurgery. chimpanzees. p. Psychosurgery and the limits of medicine. 82:1–14. 1998. Jackson TA. 151. Psychosurgery. [18] Pressman J. [27] Pressman J. [28] Kramer M. (also see Time. Tow PM. [35] Mindus P. Flanagan NB. Kopell. 146.1:475–81. Thomas. DC: USPHS Publication 221. 81. 407. [6] Jacobsen CF. Psychosurgery and the limits of medicine. p. [14] Pressman J. Thomas. 1998. Stereotactic anterior cingulotomy for neuropsychiatric illness and intractable pain. Last resort. 1942. Springfield: Charles C. In: Schmidek HH. How I came to perform leucotomy. Last resort. als Beitrag zur operativen Therapie der Psychosen. Cambridge: Cambridge University Press. emotion and social behavior following prefrontal lobotomy for mental disorders. 341. Cambridge: Cambridge University Press. Last resort. Last resort. p. Meyerson BA. Psychosurgery and the limits of medicine. Psychiatr Q 1945. Stereotactic apparatus for operations on the human brain. 77. 342. Last resort. Psychosurgery and the limits of medicine. Thomas. 159–68. [16] Pressman J. p. The 1951 survey of the use of psychosurgery. Last resort. . p. editor. Psychosurgery. Great and desperate cures. p. [19] Pressman J. Last resort. Wycis HT. 86). et al. 1998. In: Overholser W.H. Rass Studi Psichiatr 1937. 26:488–95. Watts J. Cambridge: Cambridge University Press. Last resort. 1443–54. p. Psychosurgery and the limits of medicine.196 B. [10] Pressman J. 1948. Psychosurgery and the limits of medicine. 1998. p. p. Springfield: Charles C. Last resort. p. 1998. Cambridge: Cambridge University Press. 1935. References [1] Goltz F. Psychosurgery and the limits of medicine. 1998. Lisbon.42:89–93. Cambridge: Cambridge University Press. Cambridge: Cambridge University Press. p. Indications. [17] Pressman J. Proposta di una tecnica operatoria modificata e semplificata per gli interventi alla Moniz sui lobi frontali in malati di mente.106:349. Rezai / Neurosurg Clin N Am 14 (2003) 181–197 mistakes. Last resort. 1998. Cambridge: Cambridge University Press. Cambridge: Cambridge University Press. p.47:463–548. Cambridge: Cambridge University Press. [3] Freeman W. [22] Fiamberti A. An experimental analysis of the functions of the frontal association areas in primates. p. 1998. p.19:697–701. [23] Pressman J. 1998. Last resort. Cambridge: Cambridge University Press. Cambridge: Cambridge University Press. methods and results. 1998. [7] Moniz E. J Nerv Ment Dis 1935. Cassidy WL. 198. 152. Springfield: Charles C. [8] Valenstein. Last resort. Wycis HT. It is up to future multidisciplinary endeavors conducted in carefully controlled centers of academic expertise to determine whether this potential is either real or folly. and man. 1942. Last resort. [33] Whitty CWM. Cambridge: Cambridge University Press. [9] Pressman J. Cambridge: Cambridge University Press. Cambridge: Cambridge University Press. 11–4. 70–1. Institutionalizing the obsessive psychopath. Wolfe JB. [24] Pressman J. p. Marks M.26:1–49. 138. 1998.. Uber Rindenexcisionen. Cambridge: Cambridge University Press. 77. September 15. [26] Pressman J.

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Neurosurg Clin N Am 14 (2003) 199–212 Neurosurgery for intractable obsessive-compulsive disorder and depression: critical issues Benjamin D. For this reason. including deep brain stimulation. MDb. including anterior cingulotomy. USA c Department of Psychiatry. This article considers the efficacy and safety of lesion procedures. Carpenter.D. Butler Hospital.1016/S1042-3680(03)00005-6 . USA e Department of Psychiatry. Lawrence H. Rasmussen. USA The effectiveness and tolerability of treatments for obsessive-compulsive disorder (OCD) and depression have seen impressive improvements over past decades. PhDa. collaborating closely with neurosurgeons. Brown Medical School. Scott L. Treatments for OCD and depression have come a long way in recent decades. MA. MDd. Although the historical experience remains an enduring caution. MD. and neuropsychologists in specialized multidisciplinary teams. The evidence has important limitations but sheds light on critical issues in assessing the long-term effectiveness and morbidity associated with existing procedures. Massachusetts General Hospital. Boston. modern neurosurgical procedures remain a therapeutic option. E-mail address: bdg@butler. Donald Malone. doi:10. Gerhard Friehs. subcaudate tractotomy. Psychiatric neurosurgery remains controversial. there has been considerable interest in transcranial magnetic stimulation. The same methodologic issues arise when considering the newer nondestructive techniques that are currently in development for the treatment of intractable psychiatric illness. neurologists. USA d Department of Neurosurgery. OH. and limbic leukotomy. MDe. MDa a Department of Psychiatry and Human Behavior. there has been continuing work aimed at developing what might be termed neuroanatomically-based treatments. MDb. OH. Neuroimaging research has focused attention on the relations between activity in specific neuroanatomic networks and psychiatric symptoms and on changes in such relations after effective treatment. Moreover.org (B.*. Greenberg. largely because indiscriminate use of prefrontal lobotomy in the middle of the twentieth century frequently produced significant deficits in emotional responsiveness and motivation. an increasingly specific neurobiologic rationale for psychiatric neurosurgery is being developed.see front matter Ó 2003. Price. some patients with either disorder have severe chronic illness that the best conventional methods are unable to improve. anterior capsulotomy. Providence. Ali R. RI 02906. Linda L. For them. MDa. some patients with either disorder continue to manifest severe chronic illness that is refractory to treatment. Elsevier Inc. Determining the effectiveness and side effect burden of neurosurgery for intractable psychiatric illness is a task primarily for psychiatrists. Rauch. Rezai. Georg Noren. The Cleveland Clinic Foundation. RI. USA b Department of Clinical Neuroscience. For example. current stereotactic methods using considerably smaller and more precisely located targets have much lower morbidity. Nonetheless. The Cleveland Clinic Foundation. Cleveland. MDa. MDc. Cleveland. surgery may be of benefit to patients who fail to improve with the best available conventional treatment. Providence. All rights reserved. Steven A. Even so. 345 Blackstone Boulevard. Greenberg). Brown Medical School. A small number of prospective studies support the view that neuro- * Corresponding author. a noninvasive method for stimulating the cerebral 1042-3680/03/$ . sometimes with little or no therapeutic benefit.

1 billion in direct costs and $5. modern neurosurgical procedures in use for the last four decades have remained treatments of last resort for patients with otherwise intractable illness. as a treatment for refractory depression (see the article by George et al in this issue). Behavior therapy is effective in 70% to 80% of patients completing a course of treatment. however. Typical and atypical neuroleptics are effective in controlled studies but impose an additional side effect burden. Symptoms. weight gain. vagus nerve stimulation (VNS) has been proposed as a novel surgical approach for refractory depression (see the article by Carpenter et al in this issue).2]. The evidence also suffers from limitations. citalopram and paroxetine. A substantial number of OCD sufferers find that the distress induced as a necessary part of the therapy is intolerable. OCD was among the 10 leading medical or psychiatric causes of disability in developed countries in a 1998 World Health Organization study [6]. Prevalence seems to be similar in other countries and cultures. The anxiety and compulsive urges typically become progressively more transient and less intense as therapy continues. however. is sedating and may induce dependence. It is estimated that they provide substantial benefit to only 50 to 70% of patients seeking treatment [1]. This literature offers a degree of hope to affected individuals and their families. Behavior therapy is particularly useful for OCD and holds a central place in effective treatment regimens. or sedation [7]. neurologists. is a second-line agent. and leaves some important questions unanswered. are usually chronic [3. one study found that more than half of patients who responded to an adequate trial of a serotonin reuptake inhibitor stop taking the medicine within 2 years because of sexual dysfunction. Greenberg et al / Neurosurg Clin N Am 14 (2003) 199–212 cortex. in close collaboration with neurosurgeons. images. Specific treatments for OCD have been developed over the past decades. The article concludes with a discussion of the limitations of the evidence and considers some central unanswered questions. These include sedation. the historical background. or 4 to 7 million people in the United States [1. as with other benzodiazepines. OCD typically begins in childhood or adolescence. Clonazepam also seems to be partially effective as an augmenting agent but. such as fluoxetine. Even as research on those techniques continues. the epidemiology.5 to 3 times higher in individuals with an affected first-degree relative [4]. The discussion then focuses on current views of neurosurgery for intractable OCD and depression among psychiatrists. and current treatment of OCD and depression are briefly considered. especially for typical neuroleptics. and the distress resulting from them. Medication augmentation strategies can benefit patients who fail to respond to SSRI monotherapy [8. Most recently. feelings. The illness is characterized by recurrent thoughts.4]. To begin. are the mainstay of pharmacologic treatment. and either refuse to start or .D. side effects may substantially limit the treatment adherence usually necessary for ongoing symptom relief. After the symptoms and their environmental triggers are characterized in an individual patient. impairment in social and occupational functioning [1]. neuropsychologists. Selective serotonin reuptake inhibitors (SSRIs). We conclude by focusing on those unresolved issues and suggest ways of answering them in systematic prospective research. or behaviors that persist against the patient’s attempts to eliminate them and which are accompanied by marked and often overwhelming anxiety. Psychiatrists will play the central role. For example. both on existing lesion procedures and on the newer nondestructive therapies of deep brain stimulation targeting the same circuitry. extrapyramidal reactions. however. sertraline. the current procedures. and evidence for safety and effectiveness. weight gain. the therapy involves deliberate provocation of increases in anxiety by exposure to those triggers while encouraging resistance to compulsive rituals. Evaluating the benefits and side effect burdens of psychiatric neurosurgery will require the dedicated work of interdisciplinary teams. and. symptoms. and bioethicists. a tricyclic antidepressant and a potent but non-serotonin reuptake inhibitor. Even when effective. The disorder tends to be familial.9 billion in indirect costs related to lost productivity [5]. with the risk 1. significantly improving patients’ lives. affecting from 2% to 3% of the population.9]. a risk of tardive dyskinesia or tardive dystonia over time. including $2. OCD is associated with significant.200 B. Obsessive-compulsive disorder OCD is common. This article considers the evidence for the safety and effectiveness of existing lesion procedures. fluvoxamine. Clomipramine. and often dramatic. Current behavioral and pharmacologic therapies are far from universally effective. Total costs of the disorder in the United States were estimated at $8 billion per year in 1990.

most prominently memory loss. although the proportion of patients accepted for surgery was reduced from 50% to 60% to about 20% during that period. More severe forms of depression are often treated with electroconvulsive therapy (ECT). guilt. Current awareness of psychiatric neurosurgery Neurosurgical treatment for intractable psychiatric illness has gradually become more visible to the general public. Combinations of 201 these various approaches are frequently employed in clinical practice. Even when the best available medication and behavior therapies are applied. hallucinations. in part because of recent attention paid by the media to the therapeutic potential of deep brain stimulation in psychiatry. with increases in both morbidity and mortality often reported. Delusions. on a small number of prospective investigations. Unfortunately. Most psychiatrists. Greenberg et al / Neurosurg Clin N Am 14 (2003) 199–212 fail to complete it. likewise showed widespread awareness of psychiatric neurosurgery and a willingness to consider it for selected patients. ECT can be associated with significant adverse effects. The average age of onset is the late 20s. More than 20 drugs are approved or commonly used to treat depression in the United States [14].8% in women [11]. Eighty-three percent of a random sample . This awareness is based on past retrospective studies and. Available antidepressant drugs can be grouped into four major categories: tricyclics and tetracyclics. with tremendous suffering and overall functional impairment. but depression can also exacerbate the course of other psychiatric and medical conditions. and other drugs acting on biogenic amine systems. a substantial proportion of patients fail to recover from episodes of depression. Approximately 50% to 85% of patients with major depression experience recurrent episodes of illness [12]. and catatonia are sometimes present. more recently. Little et al [18] observed an 18. anhedonia.5% in men and 6.B. SSRIs. impaired concentration. a survey published in 1984 found that 78% of adult psychiatrists in the United Kingdom had referred patients for subcaudate tractotomy. psychomotor abnormalities. A later survey of psychiatrists in the United States. conservative estimates place its prevalence at 2. the disorder can be a cause of profound disability. Depression is quite common. In addition to subjective distress. Using rigorous operational criteria. mainly for refractory depression and OCD [19]. Depression Major depression is characterized by depressed mood. Death from suicide is a major direct complication of the illness. vocational. such optimal therapy is not widely available and is also expensive. which has been in use for this indication for nearly 70 years and is still considered a gold standard of antidepressant treatment. parental. Despite the availability of effective treatments. apathy. Later data indicate that referrals for psychiatric neurosurgery in Britain continued at roughly the same rate from 1979 to 1993. in contrast. and suicidal ideation and behavior [10].D. with pervasively negative effects on marital. have been aware that modern lesion procedures offered a last avenue of hope for patients with intractable OCD and depression for the last several decades. with the risk 1. This group suffers from intractable OCD. monoamine oxidase inhibitors (MAOIs). appetite and weight disturbance. published in 1999 [21]. social. and academic role function [13]. This decline resulted from the institution of high-dose medication trials as a screening criterion. Moreover. The disorder tends to be familial.5 to 3 times higher in individuals with an affected first-degree relative [10]. Fava and Davidson [17] estimated that 29% to 46% of depressed patients fail to respond fully to an antidepressant trial in which adequate dosing and duration have occurred. limiting its application to only a few individuals presenting for treatment. and more patients responded to such trials before surgery [20]. however. in the United States.6% to 5. The recent Global Burden of Disease Study identified depression as the fourth leading cause of disability in the world and the leading cause of disability in adults [6]. For example. fatigue. an estimated 10% of patients remain severely affected. Particularly for seriously ill patients. Less severe forms of the illness can be treated effectively with certain forms of psychotherapy and light therapy [14]. sleep disruption. it seems that the most effective treatment is a combination of expert medication management and intensive behavior therapy offered by experts at specialized treatment centers. punitive. ECT is often viewed by the lay public (and many nonpsychiatric physicians) as primitive. and potentially neurotoxic.9% rate of refractoriness in depressed geriatric patients treated in a university tertiary care setting. particularly in the management of complicated or refractory cases [16].0% to 11. Efficacy for these agents is well established [15]. but it may develop at any age.

74% of psychiatrists in the same survey indicated that they would consider referring appropriate patients. Greenberg et al / Neurosurg Clin N Am 14 (2003) 199–212 of American Psychiatric Association members replied that they knew about neurosurgical treatment for intractable OCD. neurosurgical treatment of patients with OCD.23]. increasingly. and an editorial statement by the OCDDBS Collaborative Group [26] reprinted in this issue. depression (see the article by Rauch in this issue) [24. These issues are discussed in more detail at the end of this article. The powerful social and scientific legacies of the past indiscriminant use of prefrontal lobotomy are considered at length in the article by Koppell and Rezai in this issue.D. a few features of the early experience and literature are briefly mentioned. 1950 [27]. For OCD. overshadowing any benefits that accrued. establishing that definitive medication trials and behavior therapy conducted by clinicians expert in treating refractory illness have failed to provide adequate benefit [22. Greenberg. Importantly. acceptance for surgical treatment by the few centers with specialized teams of psychiatric and neurosurgical experts requires that patients meet rigorous entry criteria. particularly when severe. Patients must be capable of fully informed consent. At a 2002 psychopharmacology review course. is made for patients with intractable depression. a careful reading of that early literature also leads to the conclusion that some patients were helped by these procedures: A woman. patients. A negative perspective persists. Anecdotal experience of one of us found a similar high degree of awareness of neurosurgery for intractable OCD recently. To introduce some key issues here. That article. . focus especially on recommendations for future research in this area.25]. and society at large. and the adequacy of those trials. Prospective data on potential adverse effects on cognition and personality are systematically collected before and for years after the procedures. there remained a recognition that neurosurgery might be appropriate for a small group of patients with otherwise intractable illness. a detailed review of the response to prior treatment trials. Recent US Food and Drug Administration (FDA) approvals of deep brain stimulation for treatment-refractory tremor and Parkinson disease and increasing therapeutic use of these techniques in other countries have also enhanced consideration of the potential of neurosurgery for intractable psychiatric illness. who for some thirty years had suffered from obsessive fear of contamination and who had scrubbed not only the toilet seat but the whole bathroom for an hour or so before using the toilet and then for an hour or more afterward in an effort to spare others from the danger of contamination. is generally a chronic illness. the adverse consequences of psychiatric neurosurgery in the middle of the twentieth century remain in the minds of physicians. psychotherapists. this includes. Similarly. In this unsystematic sample. 85% of an audience of 124 psychiatrists responded that they knew of psychiatric neurosurgery for OCD. There are important absolute and relative contraindications and procedural safeguards. Awareness of current neurosurgical procedures among psychiatrists occurs against a background of advances in our understanding of the neuroanatomic bases of OCD and. for a long period this woman manifested the same tendency toward compulsive cleaning of the bathroom before and after evaluation even though she admitted that she did not feel the same anxiety and fear of contaminating others that had previously been present.202 B. Freeman and Watts. Nevertheless. Some lessons of history Reports of the deleterious sequelae of radical destructive operations have had a lasting impact. and other psychiatric conditions has a long and controversial past. the majority (68%) indicated that they would consider referring patients with intractable illness (B. The compulsive activity gradually disappeared during the ensuing years. Still. unpublished observations). So. In the midst of gradually emerging newer information and cautious optimism about the potential for newer procedures. . This case vignette illustrates several important issues. major affective illness. Following her operation. Irreversible and sometimes devastating adverse effects were common after lobotomy. despite the advances in conventional behavior therapy and medication treatments that had occurred by the end of the twentieth century. One is that OCD. Another point is that the first effect of the operation was a reduction in anxiety. Careful multidisciplinary review is undertaken to establish accuracy of diagnoses and that the illness is treatment refractory. Later in this issue. Fins considers ethical implications emerging from this history in light of present developments. even though compulsive behavior . in part.

For the much more focal lesion procedures used currently. postsurgical behavior therapy. Their primary indications are intractable OCD and major depression. It is because of such adverse effects that lobotomy was permanently abandoned. is within cingulate cortex itself. The development of these techniques was informed at first not by specific empiric evidence but by the general ideas that frontosubcortical (and particularly frontothalamic) connections were important in higher brain function and that limbic networks modulate emotion [22. and adherence to.31–34]. What follows is a relatively brief description of these four procedures. the compulsive cleaning gradually abated over a period of years. by having a patient join his own household. mainly for this reason [30]. the best evidence is also that maximal improvement takes months to years (see the article by Cosgrove et al in this issue) [28]. Freeman and Watts depicted responses to lobotomy like that cited previously in terms of the dominant psychodynamic model of the day: We have compared the emotion to the fixing agent that prevents a photographic image from fading back into obscurity. several groups of neurosurgeons and psychiatrists. during the 1950s and 1960s. In 1947. 1947 [29]. the most widely performed and recognized procedure in the United States. In one patient. with compulsive and hysterical fits. He studied changes in personality and cognition in great detail over time in a series of eight patients. Because the lesioning electrodes were placed in a highly vascular structure without modern imaging guidance. Rylander. She is with me in body but her soul is in some way lost. mainly in Europe. Those deep feelings. were the first to report that dorsomedial thalamotomies improved obsessive-compulsive symptoms. The reader is referred to the article by Cosgrove and colleagues in this issue for recent perspectives based on their experience in Boston with anterior cingulotomy. G. explored the therapeutic effects of selective lesions made under stereotactic guidance. Although not intended by the authors. Later. One of the crucial lessons of this history is that research on psychiatric neurosurgery must systematically assess patients for potential changes in personality. including emotional responsiveness and motivation.B. Rylander [29] gave a compelling glimpse of this and other adverse effects after the Freeman and Watts prefrontal lobotomy procedure. who began stereotactic neurosurgery in patients. Prefrontal lobotomy bleaches the affect attached to the ego. and limbic leucotomy (a combination of subcaudate tractotomy and cingulotomy). a 28-year-old woman suffering from ‘‘anxiety periods. . The aim was to sever connections between subcortical structures and the frontal lobes. The evidence of their safety and efficacy is presented in subsequent sections. Freeman and Watts.’’ the resulting catastrophically diminished emotional capacity after lobotomy is vividly described by her mother: She is my daughter but yet a different person.D. anterior capsulotomy. cingulotomy. 203 Development of modern lesion procedures Speigel and Wycis. each of these techniques would be expected to affect activity within networks suggested by neuroimaging studies to be important in OCD and depression (see the article by Rauch in this issue). are gone. this understanding also hinted at the possibility that emotional blunting after neurosurgery could go well beyond a reduction in distress caused by OCD symptoms. The target of anterior cingulotomy. Although developed before the era of functional and modern structural neuroimaging. All these operations remain in use for a small number of patients with intractable neuropsychiatric disorders. The response to treatment was usually slow. Subcaudate tractotomy and anterior capsulotomy in particular interrupt connections of orbital and medial prefrontal cortex to the thalamus. Greenberg et al / Neurosurg Clin N Am 14 (2003) 199–212 continued. Remove the emotion and the image gradually fades. The reasons for this are poorly understood and likely multifactorial. in some cases. hemorrhages were frequent and 10% of the patients died. despite the radical nature of that operation. Effects of these procedures on a small number of patients with severe non-OCD anxiety disorders have also been reported. 1950 [27]. those tendernesses. The procedures developed most successfully (Fig. especially in severely affected individuals. 1) were subcaudate tractotomy. In this example. Their stereotactic procedure was much less radical than lobotomy but still dangerous. Research on neurosurgical treatments for intractable OCD should take into account that the course of response is likely to be prolonged and may depend on the availability of.

starting in the 1950s. As discussed later in this article. It is the work of Ballantine and his colleagues at the Massachusetts General Hospital in Boston. The particular intent of gamma knife capsulotomy in the United States has been to target connections between dorsomedial thalamus and orbital and medial prefrontal cortex. A total lesion volume of approximately 4 mL resulted. this group demonstrated that anterior cingulotomy had a favorable safety profile. subcaudate tractotomy has also been used for other severe anxiety disorders. Capsulotomy was further developed and used in a large series of patients by Lars Leksell and colleagues at the Karolinska Institute in Sweden. Neurosurgical procedures for intractable obsessive-compulsive disorder and depression. There is a more recent report of a modified technique of subcaudate tractotomy [36]. studying its efficacy for a range of psychiatric indications.38]. Subcaudate tractotomy In this procedure. Rhode Island. The gamma knife procedure has been the focus of ongoing research in Providence. trials of deep brain stimulation at the capsulotomy target site for intractable OCD are underway. In the United States. thermocoagulation lesions were made bilaterally using bipolar electrodes placed in the anterior third of the capsule.D. lesions intended to interrupt orbitofrontal-subcortical connections are made under the head of the caudate nucleus in the substantia innominata [35].204 B. Although therapeutic effects in schizophrenia were considered unsatisfactory. This investigative team has performed approximately 1000 cingulotomies. gamma knife anterior capsulotomy has been used almost exclusively for intractable OCD. Anterior cingulotomy Fig. More than 1300 of these Originally conceived by Fulton as a treatment for psychiatric disorders. After craniotomy. however. Beginning in 1962. The procedure was later applied to psychiatric disorders when mood and anxiety symptoms were found to improve in pain patients. in contrast to the newer technique of gamma knife capsulotomy. Radioactive yttrium-90 seeds were placed at targets under the head of the caudate nucleus. followed by Kullberg [40] and his colleagues. that is responsible for cingulotomy being the best known and most widely used procedure for intractable psychiatric illness in North America. Talairach and co-workers were the first to make selective lesions there. Greenberg et al / Neurosurg Clin N Am 14 (2003) 199–212 operations were performed in the United Kingdom from the period of its first development until the early 1990s. results in patients with severe anxiety were better. Anterior capsulotomy This procedure targets the fiber bundles in the anterior limb of the internal capsule connecting the frontal lobes and thalamus [37. In addition to intractable OCD and depression. 1. cingulotomy’s first use was actually for intractable pain. over the past decade. This approach was developed by Geoffrey Knight in the United Kingdom in 1964 as an attempt to limit adverse effects by restricting lesion size. This procedure is now called open capsulotomy or thermocapsulotomy. Current . Whitty et al [39] first reported the effects of cingulotomy in OCD.

Recent evidence suggests that limbic leucotomy may also be of benefit to patients with severe repetitive self-injurious behaviors occurring in the setting of severe tic disorders [44]. the resulting total lesion volume is in the range of 4 to 6 mL [41]. presumably as a result of symptomatic improvement. and some other severe anxiety disorders.45. cingulotomy. however. or confusion. subcaudate tractotomy. this was replaced by MRI guidance. influenced the length of the hospital stay. About 40% of patients return months later for a lesion-extending second operation to enhance efficacy. thermocoagulation electrodes are used to make lesions on each side through bilateral burr holes. The risk of postoperative epilepsy has been estimated at less than 1%. The rate of seizures was similar to that reported previously. Two or three sets of bilateral lesions are made using radiofrequency electrodes (see the article by Cosgrove and Rauch in this issue). A later review reported on 1300 patients who had subcaudate tractotomy up until 1993 [20]. in a 1975 study of 208 patients who underwent subcaudate tractotomy. mainly for depression but including some OCD patients. which frequently lasted as long as 1 week. which. Again. and weight gain. and limbic leucotomy.5 years. side effects of thermocapsulotomy included one intraoperative hemorrhage . incontinence. Initially. In a later group of 24 patients with OCD followed prospectively. Limbic leucotomy Kelley and colleagues [42] developed this multitarget procedure in the 1970s. a smaller number of patients had the surgery for intractable OCD. the subcaudate tractotomy group showed a markedly lower suicide rate: 1% after surgery compared with 15% in patients with affective illness who were not treated surgically. Safety The adverse effect profiles of the more focal surgical interventions of the past 40 years have been notably more benign than that of lobotomy. Persistent deterioration of intellectual function has been relatively rare in patients with severe OCD and depression who underwent these procedures [23. or somnolence.B. Longer term adverse effects included mild untoward personality change in 6. in essence. Lesions at sites where stimulation induced marked autonomic changes were believed to be the most effective [43]. Because the intent is to produce the smallest effective lesion. Transient disinhibition after surgery was described as common. Subcaudate tractotomy Adverse effects Postoperative side effects were reported to include headache. hemorrhage. depression. As currently practiced. The latter set of lesions may have a more anterior placement than is typical for subcaudate tractotomy. the effects of intraoperative electric stimulation have been used to identify the surgical target for this procedure. Indications for limbic leucotomy have historically been intractable depression. Interestingly. Anterior capsulotomy Adverse effects Adverse effects of open anterior capsulotomy in the initial series of 116 patients described by Leksell and colleagues [47] included postoperative headache. The major operative complications of the open neurosurgical approaches have included infection. Compared with a comparison group of patients with major affective disorders. In 1991. persistent adverse personality changes were not found. Individuals were followed for a mean of 2. Three of the 208 patients died by suicide during the follow-up period. and OCD. Under local anesthesia. seizures. several independent groups of investigators have evaluated the effects of capsulotomy.2%. Greenberg et al / Neurosurg Clin N Am 14 (2003) 199–212 indications for anterior cingulotomy include intractable pain. intractable depression was the most common diagnosis. Using comprehensive batteries of measures collected before surgery and compared with 205 measures taken after surgery. resulting from migration of one of the yttrium seeds.D. in several instances.7% of patients.46]. The risk of changes in cognitive function and personality after these procedures has been carefully studied. One death occurred as a direct complication of surgery. combines the bilateral lesions of cingulotomy with those of subcaudate tractotomy. ventriculography was used to guide lesion placement. typically lasting 1 week at most. improved performance on cognitive measures has been documented. Thermocoagulation or cryoprobes are used. The duration of confusion. Moreover. In contrast. Seizures were reported in 2. the procedure is often done in stages. OCD. confusion. Such side effects have been relatively rare. There were no deaths as a complication of surgery. The targets for this procedure are located in the anterior cingulate cortex (Brodmann areas 24 and 32) adjacent to the underlying fibers of the cingulum bundle.

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without neurologic sequelae and 1 patient who
developed seizures. There were transient episodes
of confusion during the first week in 19 of 22
patients available for follow-up as well as occasional nocturnal incontinence. Fatigue was present in 7 patients (29%), 4 (17%) described poor
memory, and 2 patients (8%) had ‘‘slovenliness.’’
One patient committed suicide in the postoperative phase, and 8 patients suffered from depression severe enough to require treatment. Excessive
fatigue was a complaint in 7 patients, and 4 had
poor memory. Weight gain was common after
open capsulotomy, with an average increase of
about 10% in patients in this sample [38].
In another report, no significant cognitive
dysfunction or adverse personality changes were
found on a psychometric test battery administered
to a sample of 200 capsulotomy patients [46].
In contrast, a small study found perseverative
responses to be more common after thermocapsulotomy in 5 patients with a severe, treatmentrefractory, non-OCD anxiety disorder [48].
Differences in rates of adverse effects across
studies seem due, at least partly, to differences in
the volume of tissue lesioned, although this is not
fully clear in published reports. The same seems
to be true for procedure efficacy; that is, the
effectiveness and the side effect burden of the open
procedure both appeared to increase with greater
lesion volume [41].
Most recently, the Providence group has found
that gamma capsulotomy was generally well
tolerated and effective for patients with otherwise
intractable OCD. The lesions resulting from the
gamma capsulotomy procedure are generally
smaller than those produced by open thermocapsulotomy. Adverse events included transient cerebral edema and headache (in 6 of 31 patients
[20%]), small asymptomatic caudate infarctions
(3 of 31 patients [10%]), and possible exacerbation of preexisting bipolar mania (2 of 31 patients
[6%]). No group decrements were observed on
cognitive or personality testing. Nevertheless, 1 of
31 patients (3%) developed a persistent mild frontal
lobe syndrome, including apathy and amotivation
(S. Ramussen et al, manuscript in preparation).

secondary to intraoperative hemorrhage in the era
before image-guided surgery was estimated to be
0.03%. There has been only one stroke in the era
of MRI-guided cingulotomy. Side effects in the
immediate postoperative period include headache,
nausea, and difficulty with urination, usually resolving within days. Seizure incidence has ranged
from 1% to 5%. This effect was seen particularly
in patients with a prior seizure history.
In the most recent series [28], 9 of 44 patients
(20%) had at least one adverse effect after cingulotomy. In two cases, sequelae were enduring:
seizures responsive to ongoing anticonvulsant
treatment and worsening of preexisting urinary
incontinence as a result of prostate cancer. Another
patient developed edema and hydrocephalus requiring ventriculostomy. In addition, 2 patients
reported worsened memory, and 1 patient described apathy and decreased energy. Those behavioral symptoms resolved within 1 year after
surgery.
Although transient memory problems were
reported by up to 5% of patients overall, an
independent analysis concluded that no significant
cognitive or behavioral impairments occurred in
a series of 34 patients undergoing cingulotomy for
intractable psychiatric illness. A later study of 57
additional patients reached the same conclusion.
[41,49–51]. In fact, in these reports, patients are
noted to exhibit improved cognitive function,
perhaps because symptom reduction after cingulotomy facilitated test performance. One study
[52] described subtle impairment of attention,
however, and another [53] described mild alterations of intention and self-initiated action after
cingulotomy for chronic pain. It has been speculated [28] that cingulotomy may be less likely to
produce cognitive deficits in OCD or major depression because anterior cingulate dysfunction
may already be intrinsic to those disorders.
In that series [28], one patient (2%) committed
suicide approximately 6 years after cingulotomy.
This patient’s OCD symptoms had improved after
surgery. Before cingulotomy, the patient had
a long history of severe depression, with more
than 8 years of nearly continuous suicidal thinking and a prior suicide attempt.

Anterior cingulotomy
Adverse effects
In the Massachusetts General Hospital experience of approximately 1000 anterior cingulotomies, there have been no deaths from the surgical
procedure itself [41]. The incidence of hemiplegia

Limbic leucotomy
Adverse effects
Kelly and his collaborators have described the
effects of limbic leucotomy in several reports.
In an initial prospective study of 66 patients, no

B.D. Greenberg et al / Neurosurg Clin N Am 14 (2003) 199–212

seizures and no deaths resulted from the procedure. Early postoperative side effects included
headache, lethargy, apathy, and incontinence
lasting from days to weeks. Postoperative confusion lasted for days at least; patients frequently
remained hospitalized for more than 1 week for
this reason. Patients were subsequently followed
for an average of 16 months. One patient had
severe memory impairment attributable to improper lesion placement. Twelve percent of patients had persistent lethargy in that series. IQ
testing showed a slight improvement for this
group after limbic leucotomy [54].
A recent report of 21 patients undergoing
limbic leucotomy for OCD or depression at
Massachusetts General Hospital [55] found the
adverse effects noted in previous reports, including apathy, urinary incontinence, and memory
impairment. These side effects were infrequent
and transient.

Effectiveness
Reports on efficacy of current neurosurgical
procedures for intractable psychiatric illness span
a period of more than 40 years. Psychiatric and
neurosurgical methods used have therefore varied
over time. Several limitations result. Illness
definitions were not necessarily consistent across
sites or over time. Outcome measures have also
differed. Furthermore, effective medication and
cognitive-behavioral treatments only appeared
after the earliest reports. Because it was later
required that these be systematically tried before
patients would be eligible for surgery, only the
more recent studies have enrolled patients most
similar to those who would be potential candidates for such procedures today. Furthermore,
earlier reports of the effectiveness of these procedures were retrospective and typically described
relatively small patient samples. More recent investigations of these treatments are prospective,
with generally larger sample sizes.
Direct comparisons of any two procedures
at the same center, for example, the study by
Kullberg [40], are rare, and randomized controlled
trials are nonexistent. One reason for this is that
sham procedures involving craniotomy have
generally been considered unethical. It is important in this regard that the newer procedures of
gamma knife capsulotomy and deep brain stimulation lend themselves more easily to controlled
trials.

207

Subcaudate tractotomy
Effectiveness
Depression has been the most common diagnosis for patients undergoing this procedure. In an
early report, Strom-Olsen and Carlisle [56] described beneficial effects in depressed patients who
underwent stereotactic subcaudate tractotomy.
A subsequent report from this group, in which
structured interviews were used, described a 55%
response rate in a total of 96 depressed patients
operated on through 1973 and followed for 2.5
years on average [35]. More recently, in their
review of the same group’s experience from 1979
to 1991, Hodgkiss et al [57] classified 34% of
depressed patients as ‘‘recovered’’ or ‘‘well’’ and
32% as ‘‘improved’’ of a total 183 such patients
who had undergone the surgery. Malizia [58]
found similar rates of response.
OCD patients also reportedly benefit from
subcaudate tractotomy. Strom-Olsen and Carlisle
[56] reported that of 20 OCD patients, 10 were
either fully recovered or with only slight residual
symptoms 3 months after subcaudate tractotomy.
Four of these patients subsequently relapsed over
a 2-year follow-up period. Goktepe et al [35]
subsequently described a response rate of 50% in
a second sample of OCD patients after subcaudate tractotomy. A response rate of 62.5% in
patients with severe non-OCD anxiety disorders
was also noted in that sample. In contrast, efficacy
was poor for patients diagnosed with schizophrenia, substance abuse, or personality disorders.
The most comprehensive review of responses
to subcaudate tractotomy included 1300 cases.
Published in 1994, it concluded that subcaudate
tractotomy enabled 40% to 60% of patients to
lead normal or near-normal lives [20]. As noted
previously, compared with a suicide rate of 15%
in patients with similar major affective disorders,
1% of patients committed suicide after subcaudate tractotomy. Those investigators suggested
that several clinical features were predictors of
positive response. These included (1) major depression, (2) an onset that is sudden or occurs in
midlife or the peripartum period, (3) a positive
family history, and (4) a prior response to ECT
treatment.
Anterior capsulotomy
Effectiveness
Leksell’s group initially reported that half of
those patients with obsessional neurosis and just
less than half (48%) of depressed patients (of

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a total sample of 116, which also included patients
with schizophrenia and nonobsessional anxiety)
had satisfactory outcomes. Although modern
rating scales were not used, criteria for judging
improvement were strict. Only patients who were
free of symptoms or much improved were judged
to be responders. Herner [47] reported that the
obsessional patients in this series benefited most
after capsulotomy. After follow-up ranging from
2 to 6 years, outcome was ‘‘good’’ or ‘‘fair’’ in 14
of 18 patients (78%) who underwent open capsulotomy in the 1950s. A study by Bingley et al [37]
found that 25 of 35 patients (71%) were either
symptom-free or much improved an average of 35
months after thermocapsulotomy. Twenty-four of
these patients had been unable to work before
surgery because of OCD symptoms; 20 resumed
work after surgery.
Mindus and Jenike [59] retrospectively reviewed all cases of capsulotomy reported by the
early 1990s. They judged that 64% of 213 patients
for whom adequate information was available
could be considered responders. Response could
not be determined in 149 of the total of 362
patients, however, and it is not fully clear if the
patients for whom response could be determined
were representative of the entire sample.
A later prospective study of capsulotomy for
intractable OCD found that 16 of 35 patients
(46%) were judged symptom-free by independent
psychiatrists and that 9 more were much improved, giving a response rate of 70% overall [60].
The effectiveness of lesion enlargement in OCD
patients unresponsive to an initial thermocapsulotomy was addressed by Burzaco [61]. He
reported that in 17 OCD patients of a total of
85 who did not respond to the first procedure, half
were judged to have a satisfactory outcome after
reoperation.
Preliminary findings from an ongoing study of
anterior capsulotomy performed using the gamma
knife also find evidence of efficacy (S.A. Rasmussen
et al, manuscript in preparation). In the first series
of 15 patients, single bilateral lesions in the anterior
capsule lacked therapeutic effects. After placement
of a second set of bilateral lesions, improvement
began to occur in some patients. Using a conservative definition of therapeutic response, 4 of 15
patients had at least a 35% drop on the Yale-Brown
Obsessive-Compulsive Scale (Y-BOCS) plus a minimum 15-point improvement on the Global Assessment Scale on 5-year follow-up.
A subsequent group of 16 patients received two
pairs of bilateral lesions during one session. At the

3-year follow-up, 10 of 16 (62%) met this response
criterion. Anecdotally, after surgery, adherence to
and success of behavioral therapy seemed much
enhanced in responders. Overall, improvement,
judged by conservative criteria, was faster and
occurred in more patients after the one-stage,
double, bilateral gamma capsulotomy procedure.
The therapeutic response, once achieved, was
generally stable.
Anterior cingulotomy
Effectiveness
Whitty and colleagues [39] were the first to
report the effects of cingulotomy in OCD. Four of
the initial sample of five patients showed significant improvement in symptoms and function.
Later, Kullberg [40] reported that 4 of 13 (31%)
OCD patients improved significantly after cingulotomy. In a larger sample, Ballantine and
colleagues [62] reported marked improvement in
17 of 32 (35%) obsessional patients after cingulotomy. Of those, 8 were almost symptom-free
and 9 others had marked symptom reduction.
Including these individuals and other patients
judged to have significant but less marked benefit,
a total of 56% of OCD patients noted significant
improvement an average of 8.6 years after the
procedure [62]. A later study using more current
methods of diagnosis and severity assessment was
reported by Jenike and colleagues [63]. They
retrospectively evaluated 33 patients meeting
criteria for OCD who had undergone cingulotomy
at the Massachusetts General Hospital over a 25year period. Using the Y-BOCS and the Clinical
Global Improvement Scale, the authors estimated
that 25% to 30% of the patients benefited
substantially from the operation. In a subsequent
prospective study of 18 severely ill treatmentrefractory OCD patients, they found that 5 of 18
(28%) met conservative criteria for being much or
very much improved. Three of the 18 patients had
lesser but still notable benefit, giving an overall
rate of significant improvement of 44% [63].
In the most recent prospective study, 44 OCD
patients were studied using current methodologies, including rigorous screening and review.
Empirically validated symptom and quality of life
assessments were used. Thus, the diagnosis was
certain to be intractable OCD (ie, severe OCD
refractory to adequate trials of available treatments). At a mean of 32 months after one or more
cingulotomies, 14 patients (32%) met conservative
criteria for treatment response and 6 others (14%)

the literature does provide important guidance on a number of key points. Bearing these problems in mind. and the patients were less well characterized than in some studies. Neuroimaging studies will play a key role in achieving these aims (see the article by Rauch in this issue). Ballantine et al [62] reported that of 118 depressed patients treated with stereotactic cingulotomy. Thus. Limbic Leucotomy Effectiveness An initial report from Mitchell-Heggs and colleagues [54] described 89% of 27 OCD patients as improved at a postoperative follow-up of 16 months. A recent editorial . Bartlett and Bridges [64] later disputed these results. Using modern diagnostic and symptom assessment procedures. including the group of 27 described in the original report by Mitchell-Heggs et al [54]. The major academic centers conducting this work have since been obtaining systematic prospective data using modern assessment tools. and the need for long-term prospective follow-up and postoperative management. including patient selection. The sample sizes were relatively small. Future research in psychiatric neurosurgery must proceed cautiously. although one has been proposed for gamma knife capsulotomy in intractable OCD [23]. personality disorders. Research is expected to narrow these gaps in a number of ways. Montoya and colleagues [55] found positive responses (conservatively defined) in 36 or 50% of 21 patients who underwent limbic leucotomy for OCD or depression at the Massachusetts General Hospital after a mean follow-up of 26 months. For depression.D. Nevertheless. however. which may have value in predicting response. This limits the ability of researchers to enhance patient selection based on clinical characteristics. constraining statistical power. This is important. 42% were ‘‘recovered’’ or ‘‘well’’ and 24% were ‘‘improved. Nevertheless. and understanding the mechanisms of therapeutic action. Summary Intractable OCD and depression cause tremendous suffering in those affected and in their families. randomized controlled trials of neurosurgical treatment for intractable psychiatric illness have not been reported. Mitchell-Heggs et al [54] also described a 78% response in patients with major depression. which has varied most over time but also across patients enrolled in trials. including approaches to referral. the number of patients who have received any one procedure has been relatively small. The impaired ability to function of those affected imposes a heavy burden on society as a whole. Methodologic limitations of the earlier reports on any of these procedures were described previously in this article. and functional impairments.B.’’ A later review of 34 patients who underwent cingulotomy in the era of MRI guidance found that 60% of patients with unipolar depression had favorable responses. and symptom subtypes. more recent studies confront some remaining issues that have been difficult to overcome fully. So will cross-species translational research on the anatomy and physiology of the pathways implicated in the pathophysiology and response to treatment in these disorders. Existing data suggest that lesion procedures offer benefit to a large proportion (ranging from 209 about 35%–70%) of patients with intractable OCD and depression. Another key factor in response may be postoperative management. In their initial report. chronicity. because patients with intractable OCD and depression referred for neurosurgery have high rates of comorbid Axis I diagnoses. First. even with improved methodologies. The development of deep brain stimulation has also made sham-controlled studies possible and also allows within-patient designs to be considered. Kelly [65] then extended his group’s original findings and reported on 49 patients. As noted previously. may be likewise useful. The literature also suggests that although serious long-term adverse events have occurred. patient selection. optimizing the procedures themselves. He found that 84% of the patients were improved at a mean follow-up of 20 months [65]. Greenberg et al / Neurosurg Clin N Am 14 (2003) 199–212 were partial responders. Other features. these are relatively infrequent overall. 20 patients (45%) were at least partial responders at long-term follow-up after one or more cingulotomies [28]. noting that patients with significant residual symptoms were included in the 89% improvement rate. important gaps in knowledge remain in all these areas. such as age of onset. Price and colleagues [44] recently reported beneficial responses to limbic leucotomy in five patients with otherwise intractable severe repetitive self-mutilation occurring in the setting of ticlike behaviors.

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these tools enable investigators to test hypotheses about pathophysiology. despite a resurgence of interest and accelerated research in this field. USA Contemporary neuroimaging methods have been influential in advancing neurobiologic models of psychiatric disorders. it should be possible to rationally develop new and superior treatments as well as to predict treatment outcomes in a manner that could optimally guide selection among alternative treatments for individual patients in the clinical setting. data from neurosurgical treatment research can provide feedback to inform evolving models of psychiatric disease. Dr Rauch is supported in part by RO1MH60219 and the Massachusetts General Hospital Psychosurgery Fund. however. based on predictors of response. doi:10. All rights reserved.harvard. I present anticipated future directions of research in this field. 1042-3680/03/$ . I describe neurocircuitry models of OCD and MD. Massachusetts General Hospital–East. reciprocally. that would enable patients who are unlikely to have good outcomes forego the risks and costs of neurosurgical treatment.see front matter Ó 2003. Given recent advances in neuroimaging and neurocircuitry models of these disorders. and predictors of treatment response [1]. One goal is to refine neurosurgical treatments for OCD and MD so that they are safer and more effective. 13th Street. focusing on relevant neuroimaging data. whereas the potential E-mail address: rauch@psych. little is known regarding the mechanisms by which neurosurgical treatments for OCD and MD have their beneficial effects. Elsevier Science (USA). clinical reports suggest that the effectiveness of contemporary neurosurgical treatment for these indications is only modest. MD Psychiatric Neuroscience Program. in the current article. and. Thus. a variety of neurosurgical treatments have been developed in an effort to help people suffering from severe and otherwise treatment-refractory psychiatric disorders—principally obsessive-compulsive disorder (OCD) or major depression (MD). I then review the neuroanatomy of psychiatric neurosurgical procedures and related neuroimaging findings. Charlestown. As reviewed in this issue. In general. it is anticipated that neuroimaging research will substantially contribute to the ultimate achievement of a pathophysiology-based diagnostic scheme in psychiatry and also help to elucidate the mechanisms of action by which treatments have their effects. for adverse effects is still considerable. Providing means for measuring indices of human brain structure and function in vivo. the changes associated with treatment. Moreover. To date. Rauch. 149. it would be of great value to find ways to improve outcome. I would propose that there is great opportunity for synergy at this interface: neuroimaging and neurocircuitry models of disease can help to guide practical progress in the domain of neurosurgical treatment. Finally.Neurosurg Clin N Am 14 (2003) 213–223 Neuroimaging and neurocircuitry models pertaining to the neurosurgical treatment of psychiatric disorders Scott L. as the neuroscience of psychiatry evolves. on related topics [2–6]. together with my colleagues. Room 9130.1016/S1042-3680(02)00114-6 .mgh. Toward that end. In fact. the time seems ripe for a fruitful synthesis of psychiatric neuroimaging and neurosurgical data. MA 02129. another goal is to identify selection criteria. Bldg.edu. This article necessarily extends previous reviews that I have written.

Further.214 S. Here. whereas TS and trichotillomania. Thus. and the thalamus resonant with failed striato-thalamic inhibition (ie.9]. I systematically review how these various methods have been employed to develop a cohesive neurobiologic model of OCD. whereas the caudate has been principally implicated in OCD. and body dysmorphic disorder as well as OCD. For instance. rather than segregation. This basic scheme has been extended to provide a comprehensive model for a group of purportedly related disorders called ‘‘obsessive compulsive spectrum disorders. it has been proposed that the CSTC circuits involving orbitofrontal cortex (OFC). in the case of OCD. the OC spectrum disorders characterized by intrusive cognitive and visuospatial symptoms. This model of normal CSTC function suggests a flow of information from motivation to cognition to motor behavior. the caudate nucleus. The ‘‘striatal topography model’’ of OC spectrum disorders suggests that these diseases share the attribute of CSTC dysfunction due to primary striatal pathology and that the clinical picture in each case reflects the topography of pathology within the striatum and hence the constellation of dysfunction across CSTC circuits [6. It is evident that neurobiologic models of OCD and related disorders have evolved in parallel with our understanding of the relevant basic neuroscience as well as with accrual of data from patient studies. filtration) within this same circuitry. pioneering neuroanatomic research by Haber and colleagues [11] has provided a scheme for considering CSTC function that emphasizes a cascading spiral interaction. findings of subtle volumetric abnormalities involving the striatum have predominated [12–14]. Magnetic resonance spectroscopy (MRS) provides a means for measuring the relative concentration of certain endogenous chemical compounds in vivo. In fact. the notion is that OCD and body dysmorphic disorder. In particular.’’ encompassing Tourette syndrome (TS). Moreover. cognitions and motivations to act seem to persist (as obsessions with attendant anxiety. Such morphometric methods have only modest sensitivity. trichotillomania. involve pathology within the putamen and dysfunction of sensorimotor CSTC circuitry. The prevailing theory suggests that a relative imbalance favoring the direct versus indirect pathways within this circuitry lead to overactivity (ie. involve caudate pathology. studies of TS [15. To elaborate.L. In adults with OCD versus healthy comparison subjects. anterior cingulate cortex (ACC). N-acetyl aspartate (NAA) is an MRS-visible compound thought to serve as a marker for healthy neuronal density. respectively) such that motor output fails to reset these thoughts and motivations. Rauch / Neurosurg Clin N Am 14 (2003) 213–223 Neuroimaging and neurocircuitry models of obsessive compulsive disorder Neurocircuitry model of obsessive-compulsive disorder and related disorders Contemporary neurobiologic models of OCD and related disorders have focused on corticostriato-thalamo-cortical (CSTC) circuitry. Neuroimaging studies of obsessivecompulsive disorder There is now an impressive array of different neuroimaging techniques that can be used in a complementary fashion to advance psychiatric neuroscience. Morphometric MRI studies have been performed to test hypotheses regarding regional brain volumes in OCD. it is useful to review the findings of pertinent psychiatric neuroimaging research. amplification) within OFC and ACC. and the caudate nucleus are central to the pathophysiology of OCD [6.16] and trichotillomania [17] have principally implicated the putamen or lenticulate. reduced levels of NAA can be detected as . consistent with the striatal topography model of OC spectrum disorders.8] describing segregated parallel CSTC circuits provided an important framework for subsequent theories of pathophysiology in OCD. there is a convergence of evidence to suggest that some primary pathologic process within the striatum might underlie the CSTC dysfunction in OCD. and some studies have failed to find striatal abnormalities in OCD [19]. principally characterized by intrusive sensorimotor symptoms. across CSTC circuits. This raises the possibility that OCD (as well as other OC spectrum disorders) might not reflect dysfunction within a single segregated CSTC circuit but rather represent a failure in the smooth cascade of information across the various CSTC circuits. the influential reviews by Alexander and colleagues [7. In this regard. Most recently. although an initial study of body dysmorphic disorder has also found a subtle abnormality involving the caudate [18]. hence driving stereotyped motor repetition (compulsions). Specifically.10].

in patients with OCD. Pretreatment neuroimaging data can also be used to test hypotheses regarding predictors of treatment response. several studies have yielded convergent findings that most consistently indicate increases in activity within OFC. and. Similarly. and the caudate nucleus during the OCD symptomatic state versus a control state [31–34]. however. automatic) sequence learning is known to be normally mediated by CSTC circuitry. Functional neuroimaging studies of OCD have likewise produced convergent results implicating OFC. A series of studies have demonstrated a reduction of activity within OFC. Interestingly. such as posttraumatic stress disorder and specific phobias [35. in children. which was neutralized after successful treatment [40]. Symptom provocation methods have been used in conjunction with functional imaging to test hypotheses regarding the brain regions that exhibit changes in activity level in association with OCD patients experiencing obsessions and the urge to perform compulsions. Pre. which indicates that some cases of OCD and related disorders can occur as a consequence of autoimmune-mediated striatal degeneration [23]. To elaborate.24] and reduced volumes of OFC and amygdala [25]. These findings converge well with morphometric MRI results and are also consistent with neuroimmunologic research. Several such studies have been performed to investigate the neural correlates of OCD symptom reduction after treatment with serotonergic reuptake inhibitors as well as behavior therapies. to a lesser extent. Across numerous such studies. There have been several isolated reports of regional volumetric abnormalities beyond the striatum in OCD. these have included abnormal thalamic and putamen volumes [26. Rauch / Neurosurg Clin N Am 14 (2003) 213–223 a possibly more sensitive indication of regional neuronal degeneration or maldevelopment characterized by lower neuronal density or sparse arborization. 215 Moreover. pharmacologic induction of anxiety attacks in healthy subjects has likewise been associated with increased activity within anterior paralimbic regions but not in anterolateral OFC or the caudate nucleus [37]. Further. A series of studies of this type in OCD have indicated that pretreatment activity within OFC predicts subsequent treatment response [41–44]. Given that such studies are confounded by nonspecific anxiety. the caudate nucleus [28–30]. Interestingly. ACC. in contrast. Again.27]. higher levels of OFC hyperactivity were associated with poorer subsequent responses to treatment with serotonergic reuptake inhibitors [41–44]. these have included gross increases in white matter volume [12. These findings are consistent with the idea that serotonergic reuptake inhibitors might have their antiobsessional effects via their action within OFC [45] and that behavioral therapy may have its beneficial antiobsessional effects via extinction mediated by frontoamygdala interactions [6]. an interregional correlation analysis indicated that at the pretreatment time point. higher levels of OFC hyperactivity were associated with better subsequent responses to treatment with behavior therapy [42]. although they exhibited a capacity to learn the sequence information that was comparable to normal subjects. in one of these studies. Implicit (ie. In adults.36].L. they failed to recruit the right striatum in a normal . there was an abnormal positive correlation between right OFC and the right caudate. ACC. and the caudate nucleus after successful treatment of OCD [38–41]. ACC. ACC.S.and posttreatment neuroimaging studies are conducted to test hypotheses regarding changes in brain activity profiles associated with successful reduction in symptoms. nonconscious. In this context. and the caudate. when patients with OCD were studied while performing such a task. Cognitive activation studies have been performed in conjunction with functional neuroimaging methods to test hypotheses regarding the functional integrity of striato-thalamic circuitry in the context of an implicit sequence learning task. whereas the recruitment of the caudate nucleus and anterolateral OFC seems to be somewhat more specific to the symptomatic state in OCD. Neutral state (including nominal resting state) studies have been performed to test hypotheses regarding baseline differences in regional brain activity between patients with OCD and healthy comparison subjects. and this function may be rightlateralized to some extent [46–48]. it has been instructive to contrast the brain activity pattern associated with OCD symptoms with the patterns reported for other anxiety disorders. the most consistent findings in OCD have been relative hyperactivity of OFC. Interestingly. a series of MRS studies of OCD have found reduced striatal NAA [20.21] but normal NAA levels within the lenticulate [22]. symptom provocation studies of other anxiety disorders. a single report of reduced NAA within the ACC in OCD has been published [21]. have frequently found activation of ACC and other anterior paralimbic regions.

This may explain why patients with OCD have intrusions of information into consciousness that might otherwise be processed nonconsciously by individuals without OCD. has reciprocal connections with the amygdala and projects to the hypothalamus to influence the HPA axis as well as other functions that are disturbed in depression. a triad of areas seem to play a critical role in mediating the balance of activity between the ventral and dorsal compartments both in health and disease.62–64]. motor. Of note. neuroimaging studies of OCD support a cohesive model. and neuroendocrinologic as well as affective disturbances. grossly. Of note. Finally. Taken together. Neuroimaging and neurocircuitry models of major depression Neurocircuitry model of major depression Similar to OCD.’’ including anterior. There is hyperactivity at rest within the OFC-caudate CSTC circuit. and hippocampus than patients with OCD alone [53]. These findings in OCD have been replicated and seem to indicate that patients with OCD are deficient at recruiting the striatum in the service of thalamic gating [49. there appears to be hypoactivity within the dorsal compartment and hyperactivity within the ventral compartment. These dorsal and ventral compartments communicate with their striatal counterparts. patients with OCD plus comorbid MD exhibit a profile that differs from that of patients with OCD alone [53]. in addition to its role in cognition. and parietal cortex as well as premotor cortex. because most patients with severe treatment-refractory OCD who receive neurosurgical treatment also suffer from comorbid MD. In addition to the limbic CSTC circuit.55–61]. the dorsal and ventral compartments seem to be reciprocally inhibitory [36. it has been proposed that exposure to stress during early development or chronically could represent a risk factor for the evolution of such a profile [65]. Thus. At the cortical level. Interestingly. The amygdala is positioned to assess the reward and threat value of external stimuli and has the capacity to drive the balance of activity toward the ventral compartment.216 S. A similar profile is present within ACC. in MD. which is exaggerated during symptom provocation and attenuated after successful treatment. map onto a corresponding functional anatomy [57].50. the cognitive and motor deficits of MD may be explained by dysfunction within a ‘‘dorsal compartment. the dorsal compartment is linked to the dorsal (cognitive/motor) striatum. Of clinical relevance. successful treatment of MD (via any of a number of modalities) may . Therefore.L. Rauch / Neurosurg Clin N Am 14 (2003) 213–223 fashion [49. it is useful to consider the clinical characteristics of MD as they relate to different functional domains. OFC. The pregenual ACC has the capacity to facilitate the restoration of dynamic equilibrium between the compartments via its inhibitory influence over both dorsal and ventral elements [36. and anterior insular cortex. Further.62–64]. MRI and MRS studies suggest striatal pathology. prevailing models of MD have focused on other critical elements of the limbic system. The affective symptoms of MD may be related to dysfunction within a paralimbic ‘‘ventral compartment.50]. functional imaging data from before and after treatment with paroxetine suggest that patients with OCD plus MD exhibit increased activity within the striatum after successful treatment. In general. dorsal and lateral prefrontal cortex. namely. thalamus. OCD subjects showed aberrant bilateral medial temporal activation (not seen in normal subjects during implicit sequence learning) in a manner similar to that evidenced when normal subjects are learning information consciously [49–51]. although this seems to be a more nonspecific finding across anxiety states. This is particularly germane to the focus of this review. Moreover. it is proposed that amygdala hyperactivity and hippocampal inefficacy may be central to the pathophysiology of MD. which is consistent with cognitive activation studies that indicate deficits in striatal recruitment and thalamic gating as well as possible compensation via hippocampal activation. Importantly. which. the hippocampus. Resting state neuroimaging data suggest that patients with OCD plus MD have lower metabolism within the caudate.’’ including subgenual ACC. neuroimaging-motivated neurobiologic models of MD have also involved CSTC circuitry. dorsal ACC. activity within OFC predicts subsequent response to treatment with medication or behavior therapy. Further. and the ventral compartment is linked to the ventral (limbic) striatum. in turn. Thus. MD episodes (both in unipolar MD and bipolar disorder) are characterized by cognitive. the amygdala and hippocampus as well as the hypothalamic-pituitary-adrenal (HPA) axis [2. whereas patients with OCD alone exhibit decreased activity within the striatum after treatment [54].52]. such as sleep and appetite.

78] and OFC [79].86]. which have revealed glial cell loss in subgenual cortex [80] as well as reduced glia and smaller neurons within OFC [81] and cell atrophy within dorsolateral prefrontal cortex [82]. Neuroimaging studies of major depression In comparison to OCD. Using this approach in conjunction with functional MRI.73]. and there is some suggestion that this finding might be left-lateralized [86]. the neuroimaging literature on MD is more abundant and more difficult to interpret parsimoniously. Functional imaging studies using pictures of human faces displaying various emotional expressions have provided a means for assessing amygdala responsivity to social cues of varying arousal value and valence [95. The complexity of this area has been exacerbated by clinical heterogeneity. The amygdala has been found to be hyperactive in neutral state studies of patients with MD [86. however. MRI studies have also found reduced volumes in prefrontal cortex [73. These structural imaging findings resonate with postmortem studies of MD. Neutral state functional imaging studies have demonstrated hyperactivity within OFC and anterior insular cortex during MD episodes [83–87].77]. and/or enhanced efficacy of pregenual ACC. the exaggerated response in the left amygdala was attenuated toward normal after successful treatment with antidepressant medication [99].88]. have begun to yield a more cohesive picture of MD pathophysiology and its resolution.L. a subsequent analogous study of patients with MD revealed exaggerated amygdala responses within the left amygdala. stimulation (or protection) of the hippocampus.96]. activity within OFC seems to be inversely correlated with MD symptom severity (as well as with anxiety in some cases). Of note.75]. these same areas seem to exhibit elevated activity during induced states of transient sadness [59. have been found to exhibit reduced activity during MD episodes [91]. Rauch / Neurosurg Clin N Am 14 (2003) 213–223 rely on some combination of deactivation of the ventral compartment. moreover. Interestingly. exhibiting prompt habituation effects. Most recently. whereas the left amygdala seems to exhibit a more temporally stable response that is highly valence dependent . Conversely. and cortical parcellation methods have been applied to discover reduced volume in subgenual cortex [56. Although hyperactivity within this region is attenuated with successful treatment. early disparities in how various neuroanatomic terms were applied contributed to confusion over how apparently discrepant findings could be reconciled.86. MD studies have included mixed cohorts as well as more homogeneous cohorts of patients with unipolar MD and bipolar MD as well as MD in the elderly and in the context of primary neurologic disorders.90]. reduction in activity within the dorsal compartment has been observed during transient induction of sad mood [59]. it has been found that patients with posttraumatic stress disorder exhibit exaggerated responsivity within the right amygdala to threat-related stimuli [98]. Structural neuroimaging studies of MD using morphometric MRI segmentation methods have shown reduced volumes of the hippocampus [60. recent functional imaging studies of healthy subjects seem to suggest that the right amygdala may be more temporally dynamic in its response. suggesting that this region may be recruited in a compensatory fashion [34.55. it has been possible to probe automatic aspects of such amygdala responses relatively dissociated from the top-down influences of frontal cortex [97]. Likewise.S. Although initial studies of MD indicated reduced activity within subgenual cortex [56.88. Importantly. and studies that segmented the hippocampus and amygdala conjointly have often been negative [76]. hypoactivity in these regions returns toward normal after successful antidepressant treatment of patients with MD [59.89] and reduction of hyperactivity in the 217 context of successful antidepressant treatment [59. Further. including those investigating mood states in normal subjects and studies of changes associated with various antidepressant treatments. subsequent correction for reduced volume in that area has revealed relative hyperactivity [56]. Moreover. In addition.94]. Elements of the dorsal compartment.92]. including anterior and dorsolateral prefrontal cortex as well as dorsal ACC. some residual hyperactivity may persist even during extended remission of MD [86].66–71] and the striatum [72. cognitive activation studies have indicated an attenuated capacity for patients with MD to recruit dorsal ACC successfully [93]. Further. findings within the striatum have been less consistent [74. The severity of MD symptoms is correlated with amygdala activity [86]. Of note. inhibition of the amygdala. by presenting such face stimuli beneath the level of conscious awareness. careful neuroanatomic studies along with functional neuroimaging studies.

ablative neurosurgical treatments for OCD and MD include anterior cingulotomy. which. in addition to reducing cortical mass and activity within dorsal ACC. Of note. it is likely that these lesions modify cingulo-striatal projections and disinhibit pregenual ACC. although resting state functional imaging studies of MD have not typically indicated baseline abnormalities in pregenual ACC. Given the prevailing neurocircuitry model of MD. the neuroanatomic ramifications of these ablative procedures remain incompletely understood.102]. Hence. In fact. In OCD. it might be more appealing to consider that lesions of dorsal ACC might produce disinhibition of pregenual ACC. In fact. Alternatively. reducing activity within the ventral compartment. Rather. might render patients more responsive to antidepressant pharmacotherapy after surgery. however.L. the hippocampus.218 S. A single case study of bilateral orbitomedial leukotomy has demonstrated reduced activity within OFC. Anatomy and imaging of neurosurgical treatments for major depression and obsessive-compulsive disorder As outlined in detail throughout this issue. and the exaggerated response and failure to habituate to threat-related stimuli that is characteristic of selected anxiety disorders could be associated with right amygdala dysfunction [101]. For orbitomedial leukotomy. posterior cingulate cortex is well positioned to modulate activity within the OFCcaudate CSTC circuit [107–110]. lesions of the cingulum might interrupt ascending influences of the amygdala on the dorsal compartment. such as directly lesioning subgenual ACC or OFC. Specifically. Such findings are confounded by symptomatic improvement of OCD. and anterior capsulotomy. would be hypothesized to reduce symptoms. the prevailing negative bias that is characteristic of MD could be associated with left amygdala dysfunction. a recent functional neuroimaging study of OCD demonstrated that presurgical activity within posterior cingulate cortex correlated with subsequent response after anterior cingulotomy [111]. during the course of a successful trial of antidepressant medication. This provides a framework for understanding lateralized differences in amygdala function across mood and anxiety disorders. This could also help to explain the high comorbidity that is observed across mood and anxiety disorders. individuals with higher levels of pregenual ACC activity before treatment exhibited a superior antidepressant treatment response. given that various etiologies of amygdala dysfunction might be agnostic to the laterality of pathology. these are all potential sites of therapeutic action. the lesions are placed within dorsal ACC and typically impinge on the cingulum bundle [104]. In the case of limbic leukotomy. including OFC. Thus. Given the prevailing neurocircuitry model of OCD. resting state functional neuroimaging studies have rarely found hypoactivity in this region [53. the lesions might also disrupt amygdalofugal fibers to OFC and subgenual ACC [112].106]. leading to reduced OCD symptoms. Given the composition of the cingulum bundle. Likewise. this multisite operation would presumably combine the benefits (as well as the potential adverse effects) of the two . interruption of reciprocal projections between OFC and the thalamus would theoretically decrease reverberating (amplified) activity in the OFCcaudate CSTC. To elaborate. the lesions are purportedly placed so as to interrupt fibers of passage connecting OFC and subgenual ACC to the thalamus. subcaudate tractotomy. Likewise. which characteristically yields this profile of attenuated hyperactivity throughout the circuit. and the thalamus in a woman with OCD when comparing postsurgical with presurgical regional cerebral metabolism [113]. it is also possible that its disruption in cingulotomy could influence re- ciprocal connections between the ACC and several other structures. pretreatment levels of activity within this area have been found to predict subsequent response to antidepressant medication [103]. in MD. Although studies of MD have repeatedly noted volumetric reductions in the hippocampus. or posterior cingulate cortex [105]. in turn. ACC. Interestingly. the caudate. In the case of subcaudate tractotomy as well as bilateral orbitomedial leukotomy. MD patients seemed to exhibit increased activity within the hippocampus at week 1 and subsequent decreases in hippocampal activity by week 6 [58]. the amygdala. lesions similar to those of anterior cingulotomy and subcaudate tractotomy are combined. In the case of anterior cingulotomy. Rauch / Neurosurg Clin N Am 14 (2003) 213–223 [100]. comparisons of presurgical with postsurgical MRI data indicate that volume may be reduced within the caudate nucleus and posterior cingulate cortex by 6 to 12 months after anterior cingulotomy [104. limbic leukotomy.

1998. Summary and future directions Neuroimaging research has helped to provide a progressively sound basis for constructing neurocircuitry models of OCD and MD. editors. there are now opportunities to more flexibly (and reversibly) modulate activity within neural circuits of interest [117]. 1999. Rauch / Neurosurg Clin N Am 14 (2003) 213–223 aforementioned procedures. Textbook of anxiety disorders. 2001. Baer L. p. Greenberg BD. Similarly. disruption of pathologic CSTC circuitry at the level of OFC-caudate or reciprocal OFCthalamic communications could underlie the therapeutic effects of anterior capsulotomy. [3] Rauch SL. and/or individualized interventions (eg.L. p. p. Minichiello WE. Boston: Mosby. Obsessive-compulsive disorders: practical management. Furthermore. Dougherty DD. lesions of the ventral portion of the anterior limb of the anterior capsule are likewise purported to interrupt OFC/subgenual ACC–thalamic connections. editors. 1998. In: Stein DJ. 2002. It is foreseeable that progress in this area could lead to the identification of superior targets for ablative procedures. Cosgrove GR. Although extrapolation from nonhuman primate data can be informative. Washington. 7th edition. Crutcher MD. Washington. ‘‘prefrontal’’ and . Rauch SL. Harvard Rev Psychiatry 1997. Jenike MA. [7] Alexander GE. deactivation of subgenual ACC or disruption of interconnections among the elements of the ventral compartment is a plausible mode of therapeutic action for anterior capsulotomy. advancing science in this domain is essential to optimizing neurosurgical treatment for psychiatric disorders in the future. obtaining additional data from human subjects is essential to understanding the mechanisms by which psychiatric neuro- 219 surgery has its effects. Furthermore. [2] Dougherty DD. editors. Comprehensive textbook of psychiatry. more effective selection of appropriate surgical candidates. if the lesions themselves impinge on the striatum. Sadock BJ. For MD. editors. Hollander E. p. Controlled treatment trials in this area should include a parallel neuroimaging component to maximize the clinical and scientific benefits derived from these efforts. Baxter LR. In: Kaplan HI. Baer L. Whalen PJ. functional imaging data from a small cohort of patients with severe anxiety disorders undergoing anterior capsulotomy demonstrated reductions in activity within orbitomedial frontal cortex from presurgical to postsurgical scans [116]. This can occur if the lesions interrupt fronto-striatal projections. DeLong MR. Again. Boston: Mosby. DC: American Psychiatric Publishing. A single case study of limbic leukotomy has demonstrated reduced activity within the caudate nuclei in a patient with OCD and TS when comparing postsurgical with presurgical regional cerebral oxygen metabolism [114]. Moreover. 191–206. Basal ganglia-thalamocortical circuits: parallel substrates for motor. Rauch SL. Neurobiological models of obsessive compulsive disorders. Neurosurgical treatments for psychiatric diseases. References [1] Dougherty DD. the patient exhibited improvement in both OCD and TS symptoms after limbic leukotomy. the placement of these lesions may also compromise adjacent territories of the striatum. for OCD. Neuroimaging and neurobiological models of depression. [4] Rauch SL. Cora-Locatelli G. Neuroimaging of OCD and related disorders. In: Jenike MA. 2516–21. Psychiatric neuroimaging research: contemporary strategies. current knowledge regarding the neurobiologic consequences of contemporary psychiatric neurosurgical procedures is quite limited. DC: American Psychiatric Press. Baltimore: Williams & Wilkins. 222–53. [5] Rauch SL. an MRI study of anterior capsulotomy for OCD and other anxiety disorders indicated that appropriate placement of lesions within the right anterior capsule was critical to subsequent therapeutic response [115]. 289–317. Pathogenesis of OCD. Clinically. In the case of anterior capsulotomy. This promises the potential to advance our understanding of OCD and MD pathophysiology while systematically progressing toward improved neurosurgical treatments for the most severe and treatment-refractory forms of these diseases. Still. our understanding of the pathophysiologic underpinnings of these disorders remains only tentative. whereby targets are individually determined for each patient). editors. or if infiltration of edema surrounding the lesions encroaches on the striatum itself or on fronto-striatal projections. With the advent of deep brain stimulation. Interestingly. Obsessive-compulsive disorders: practical management.S. Minichiello WE. In: Jenike MA.5:138–59. oculomotor. [6] Rauch SL.

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Elsevier Science (USA). and ethical reasons. Not all patients respond to these modern treatment methods. MD. the results and complications of cingulotomy are reviewed and compared with those of other common psychosurgical procedures. and 1. Boston. Many different neurosurgical procedures have been performed on a variety of cortical and subcortical targets. we explore the anatomic and physiologic basis for cingulotomy and the indications for surgery. and.harvard. USA Since its introduction in 1936. Finally. by definition. the same year that Moniz [1] reported his initial experience with prefrontal lobotomy. Massachusetts General Hospital and Harvard Medical School.365 standard prefrontal lobotomy operations performed between 1943 and 1954 and confirmed that the rate of ‘‘improvement’’ was approximately 70% but also reported a 6% mortality. FRCS(C)a. E-mail address: cosgrove@helix. MDb a Department of Neurosurgery. Fulton [5] was the first to suggest that the anterior cingulum would be an appropriate target for psychosurgical intervention. Boston. and memory.mgh. Moniz [2] later described his experience with larger numbers of patients after more specific and restricted frontal lobe lesions were created using a leukotome. USA b Department of Psychiatry. Foltz and White [8] reported their experience with stereotactic cingulotomy for intractable pain and noted that the best results were in those patients with concurrent anxiety-depressive states. in some instances. surgery for psychiatric illness has had a long and controversial history for various scientific. and many remain severely disabled. Ballantine and Giriunas [9] subsequently demonstrated the safety and efficacy of cingulotomy in a large number of patients with psychiatric illness. doi:10. Rees Cosgrove. Currently. Guidelines for the appropriate selection of surgical candidates are presented along with details of the operative technique. anxiety. In this article. These complications underscored the need for a less radical and more specific approach to the surgery. the cingulate gyri. Freeman and Watts [3] subsequently described their prefrontal lobotomy.see front matter Ó 2003. Papez [10] postulated that a reverberating circuit in the human brain might be responsible for emotion. 15 Parkman Street. ACC Suite 331. the accepted therapeutic approach to most psychiatric disease involves a combination of well-supervised pharmacologic.edu (G. electroconvulsive therapies. Anatomic and physiologic rationale for cingulotomy In 1937. Tooth and Newton [4] reviewed 10.1016/S1042-3680(02)00115-8 . Cosgrove). All rights reserved. moral. and cingulotomy * Corresponding author. was initially carried out as an open procedure [6.R. Scott L. behavioral. Moniz [1] performed prefrontal leukotomies by injection of absolute alcohol into the frontal lobes and reported ‘‘worthwhile’’ improvement in 14 of 20 patients. Some of these patients might be considered appropriate candidates for surgical intervention if the therapeutic result and overall level of functioning could be improved. Initially. 1% epilepsy rate. Rauch. MA. The components of this rudimentary limbic system included the 1042-3680/03/$ . however.7].*.5% marked disinhibition. These early operations were associated with significant mortality and morbidity. Massachusetts General Hospital and Harvard Medical School. the lesion had to involve the medial frontal lobes and. which was performed with a specially designed calibrated instrument that was inserted blindly to the midline and swept back and forth to interrupt surgically the white matter tracts in the frontal lobes. The authors noted that to achieve the best results. and it has been the surgical procedure of choice in North America over the last 30 years. MA.Neurosurg Clin N Am 14 (2003) 225–235 Stereotactic cingulotomy G.

Two reports have found regional decreases in metabolic activity correlating with a decrease in severity of OCD symptoms as measured by the Yale-Brown Obsessive-Compulsive Scale (YBOCS) after successful pharmacologic or behavioral treatment. Although the exact mechanisms are unknown. Positron emission tomography (PET) studies have provided perhaps the most compelling evidence for implicating orbitofrontal cortex. and basal ganglia dysfunction in OCD. cingulate cortex. and anterior temporal cortices. This may explain how lesions in one anatomic area might affect the integrity and function of other brain regions. septal nuclei. Orbitofrontal and cingulate cortex has also been implicated in OCD. it is likely that certain psychiatric disorders (ie. and dorsomedial thalamic nuclei. Therefore. left thalamus. and cingulate areas in some cases of new-onset OCD [19]. Currently. and complex motor effects. the amygdala. anterior thalamic nuclei. obsessivecompulsive disorder (OCD). The limbic system. another disorder of the basal ganglia characterized by coprolalia and motor tics. cingulate gyri. such as decreased response inhibition.R. may also explain some features of OCD. Detailed morphometric analysis of MRI scans in OCD patients has also suggested focal abnormalities in striatal areas with subtle volumetric abnormalities involving caudate nuclei [20]. It was subsequently expanded by McLean [11] in 1952 to incorporate paralimbic structures. Data from clinical and neuroimaging studies have also converged to implicate the corticostriatothalamic circuits in the pathophysiology of OCD [14–16].L. In a small series of patients with chronic anxiety disorder and severe phobias. and overattention to irrelevant details. orbitofrontal cortex. Electric stimulation of the anterior cingulum and subcaudate region has been shown to alter both autonomic responses and anxiety levels in human beings [12]. 6 patients who failed to respond had significantly higher right anterior cingulate and right orbital metabolism than did 11 drug-responsive patients [24]. The frontal-striatal-pallidothalamic-frontal loop. and other anxiety disorders. and the other reported decreased right orbitofrontal metabolism [21. OCD. Many patients with Tourette’s syndrome (TS).226 G. there is mounting evidence that the limbic system. Stimulation of the hypothalamus in animals produces autonomic. MRI has also demonstrated specific brain lesions in the frontal. other anxiety disorders) may reflect a final common pathway of limbic system dysregulation.25]. have significant OCD symptoms throughout their lives [18]. mamillary bodies. Rauch / Neurosurg Clin N Am 14 (2003) 225–235 hypothalamus. and their interconnections. inflexibility. including the cingulate gyrus and its interconnections. insular. plays a central role in the pathophysiology of major depressive disorder (MDD). are reminiscent of OCD symptoms. which suggests that the hypothalamus integrates and coordinates the behavioral expression of emotional states [13]. rare neurologic movement disorders like Von Economo’s encephalitis and Sydenham’s chorea are known to affect the basal ganglia and have been associated with obsessive and compulsive symptoms [17]. endocrine. Rauch et al [27] reported atrophy in the caudate body in subjects who had undergone one or more cingulotomies approximately 6 months before morphometric MRI studies. leading to symptom improvement. including orbital frontal. From a clinical perspective. Such investigations are beginning to demonstrate the functional connectivity of the cingulate gyri with subcortical nuclei. and right caudate nucleus [26]. Clinical observations suggest that OCD and MDD patients do not improve immediately after psychosurgery but that several weeks to months are required for positive clinical effects to be fully manifest. which has been so well characterized for its control of motor function in Parkinson’s disease. because the cognitive and behavioral features associated with lesions in this area. has direct input to the hypothalamus and seems to be strategically located to mediate and interconnect somatic and visceral stimuli with higher cortical functions. Thus. it is likely that secondary . hippocampi. In one study of clomipramine treatment in childhood-onset OCD. activation PET studies performed as the patients were presented with stimuli to recreate their fears demonstrated consistently increased regional cerebral blood flow (rCBF) in the anterior cingulate cortices. PET 18F-fluorodeoxyglucose studies in children and adults have consistently reported significant elevation of absolute glucose metabolic rates for the cerebral hemispheres and orbital gyri and somewhat less consistent elevation for the caudate nucleus in OCD patients as compared to normal controls [21–23]. Cosgrove. which includes the cingulate gyrus. MDD. temporal. S. Recently. one reported decreased caudate activity. one can only speculate how disruption of different pathways in the limbic system or cingulate gyri might normalize activity.

and treatment-refractory psychiatric illness should be considered for cingulotomy. Chronicity in this context refers to the enduring nature of the illness without extended periods of symptomatic relief and may be less important than the severity of the illness. The major psychiatric diagnostic groups as defined by the Diagnostic and Statistical Manual of Mental Disorders. confirmation of treatment refractoriness usually requires more than 5 years of illness before surgery. revised (DSM-IIIR) that might benefit from surgical intervention include OCD and major affective disorder (ie. The referring psychiatrist must demonstrate an ongoing commitment to the patient and the evaluation process and must also agree to be responsible for postoperative management. If the patient meets these criteria. S. and reason for discontinuation for any suboptimal trial.G. Disability may be reflected. Rauch / Neurosurg Clin N Am 14 (2003) 225–235 neural degeneration or metabolic alterations in brain areas other than the region where the lesions are actually made may be involved in the therapeutic effect. Schizophrenia is not currently considered an indication for surgery. Adequate trials of electroconvulsive therapy or behavioral therapy when clinically appropriate must also be demonstrated. In general. electroconvulsive therapy before considering neurosurgical intervention. Similarly. such as a YBOCS score of greater than 20 for OCD or a Beck Depression Inventory (BDI) score greater than 30. lesions that affect these target areas might be expected to modulate neuropsychiatric dysfunction (the reader is referred to the article by Rauch et al in this issue for a more comprehensive presentation of these issues). Because of the diffuse nature of the monoaminergic projections and their role as neuromodulators. Neurochemical models suggest that the affective and anxiety disorders may be mediated via monoaminergic systems. the potential benefit from such an intervention must be balanced against the risks imposed by surgery. it is clear that the basal ganglia. 3rd edition. these models are not particularly instructive in terms of the functional neuroanatomy relevant to different neurosurgical treatments as they are currently employed. Detailed questionnaires that document the extent and severity of the illness as well as a thorough account of the diagnostic and therapeutic history must be provided by the psychiatrist. and these patients remain candidates for surgery. only adult patients (older than 18 years) who are able to render informed consent and who express a genuine desire and commitment to proceed with surgery are accepted. he or she would undergo a more detailed presurgical screening evaluation by an experienced multidisciplinary group of psychiatrists. Thoughtful assessment of psychosurgical candidacy requires that criteria for severity. unipolar major depression or bipolar disorder) [28]. for instance. chronicity would require at least 1 year of 227 enduring symptoms without significant remission. Cosgrove. Patient selection Only patients with severe. Severity is usually measured using validated clinical research instruments corresponding to specific indicators. substance abuse. As in all medical decisions. OCD. duration. Nevertheless. In many instances. however. and cingulate cortex in particular play a principal role in the pathophysiology of these diseases. A history of personality disorder. disabling. The patient and family must also agree to participate completely in the evaluation process as well as in the postoperative psychiatric treatment program. and treatment refractoriness be operationalized to form guidelines. In particular. The illness must prove to be refractory to systematic trials of pharmacologic. depression. The specifics of pharmacologic trials should include the agents used.R. and. response. at our institution.L. chronicity. all patients must be referred for surgical intervention by their treating psychiatrist. lesions in the cingulate cortex or other targets in the limbic system may ultimately modify these diffuse monoaminergic systems to exert a beneficial effect. To determine that their psychiatric illness is refractory to treatment despite appropriate care. when appropriate. dose. or other significant axis II symptomatology is often a relative contraindication to surgery. chronic. disability. and other anxiety states remain unclear. . although practically speaking. by a Global Assessment of Function (GAF) score of less than 50. psychologic. limbic system. Although the exact neuroanatomic and neurochemical mechanisms underlying depression. patients present with mixed disorders combining symptoms of anxiety. The severity of the patient’s illness must be manifest both in terms of subjective distress and a decrement in psychosocial functioning. In this regard. the serotonergic system has received emphasis with respect to OCD. and OCD.

risks of. Validated clinical research instruments (eg. reoperation and enlargement of the cingulotomy lesion are considered (Fig. Burlington. A thorough review of the medical record is carried out to ensure that the illness is indeed refractory to an exhaustive array of conventional therapies. and 20 to 25 mm posterior to the tip of the frontal horns [29]. a limited bicoronal scalp incision is made. 1-mm interval) are selected in a plane parallel to the proposed trajectory of the thermocoagulation probe and spanning the entire anterior cingulum and frontal horns of the lateral ventricles. Surgical technique Cingulotomy was initially performed using ventriculography for surgical guidance. over the past several years. Results The results of bilateral cingulotomy in 198 patients suffering from a variety of psychiatric disorders were reported retrospectively by Ballantine et al [30] in 1987. The MGH experience suggests that 40% to 50% of patients require repeat surgery and that better long-term outcomes are achieved with repeat surgery and multiple lesions in the cingulate gyrus. 3). On the day after surgery. 7 mm from the midline. Cosgrove. and neurosurgeon in the outpatient setting. Rauch / Neurosurg Clin N Am 14 (2003) 225–235 neurosurgeons. and neurologists (Cingulotomy Assessment Committee). additional lesions can be placed anterior to the initial cingulotomy. The procedure is then carried out in an identical fashion on the opposite side. and independently conducted clinical examinations by a psychiatrist. Intraoperative stimulation is not performed routinely. There must be unanimous agreement that the patient satisfies selection criteria. After dural opening and cauterization of the pia. and burr holes are placed bilaterally just anterior to the coronal suture and 1.5 to 2. BDI.0 cm from the midline. GAF. A family member or close relative must also understand the evaluation process and the indications for. incorporating approximately 2. especially in the lower extremities. The resulting lesion is approximately 15 to 20 mm in height and 10 mm in diameter and should encompass the cingulum from the roof of the ventricle to the cingulate sulcus.0 to 2. this has been replaced by MRI– guided stereotactic techniques. Target coordinates are calculated for a point 2 to 5 mm above the roof of the lateral ventricle. If this operation does not provide satisfactory improvement in the patient’s symptoms. With a mean follow-up of . 2).228 G. and an additional lesion is made superiorly using the same parameters to ensure complete destruction of the cingulum. and alternatives to surgery and must agree to be available to provide emotional support for the patient during the hospitalization. YBOCS. If necessary.5 cm of anterior cingulate cortex (Fig. and using the midsagittal scan as a reference. but over the past decade. Therefore. and that the requirements for informed consent are fulfilled. Using the surgical techniques described previously.L. brain MRI. there is generally a delay to the onset of beneficial effect on depression and OCD. An electrocardiogram and appropriate blood tests are obtained to assess medical risks and to exclude organic etiologies for mental status abnormalities. repetition time [TR]=600 milliseconds). a postoperative MRI scan is obtained to document the placement and extent of the lesions (Fig. The Massachusetts General Hospital (MGH) evaluation also includes an electroencephalogram (EEG). oblique coronal sections (4-mm thick. Minnesota Mutiphasic Personality Inventory [MMPI]) are employed to quantify psychiatric symptom severity and outcomes.R. a standard thermistor-equipped thermocoagulation electrode (Radionics. is incurred. neurologist. The procedure is carried out under mild sedation and local anesthesia. that the surgery is indicated. If there has been no response to the initial cingulotomy after 3 to 6 months. the cingulotomy can be converted to a limbic leukotomy at a later date by placing a lesion in the subcaudate region bilaterally. three separate lesions have been placed at the initial operation. S. After calculation of the stereotactic target coordinates. neuropsychologic testing. the electrode can be withdrawn 5 to 10 mm. but neurologic testing is carried out during lesioning to ensure that no impairment of motor or sensory function. A T1-weighted stereotactic MRI scan is obtained (echo time [TE]=10 milliseconds. MA) with a 10-mm noninsulated tip is introduced to the target and heated to 85°C for 90 seconds. Although the patient may experience an immediate reduction in anxiety. 1). This latency may be as long as 6 to 12 weeks and must be clearly explained to the patient and referring psychiatrist. This allows for more accurate placement of the lesions and direct visualization of individual differences in cingulate and ventricular anatomy.

including the SSRIs. the entire group improved significantly in terms of functional status. because many of the patients were treated before the introduction of modern psychopharmacology. This was the first study to demonstrate in a prospective fashion that cingulotomy is an effective intervention in OCD patients as measured by standardized psychiatric rating scales and independent observers. Concerns remained about the validity of these conclusions. 5 met conservative criteria as treatment responders (>35% improvement in their YBOCS and a Clinical Global Improvement [CGI] outcome of very much improved or much improved) and 2 others were considered to be possible responders (>35% improvement in their YBOCS or a CGI outcome of very much improved or much improved). A retrospective study was therefore devised to evaluate cingulotomy in the treatment of OCD using independent observers and strict outcome criteria. It was thought that many of these patients might have responded positively to the SSRIs and thus were not truly refractory to treatment. The acute hemorrhagic lesion undergoes a dramatic reduction in size as the edema resolves. S. in patients with OCD. Of 18 OCD patients in this study who underwent cingulotomy at the MGH after failing all modern pharmacotherapies. Recently. 1.6 years. Average duration of follow-up was longer than 2 years. 8.G. specifically the selective serotonergic reuptake inhibitors (SSRIs). and no serious adverse effects were found. Valid criticism of these results included the concern that many of these patients might not have met modern DSM-IV-R criteria for their psychiatric disorder and that the assessment of outcome was performed by biased observers. another prospective study with long-term followup by the same group of investigators reported . In addition. Midsagittal (A) and axial (B) T1-weighted MRI scans obtained 48 hours after a single anterior cingulotomy lesion. 33 met modern DSM-IV-R criteria for OCD. Overall. at least 25% to 30% of patients demonstrated substantial benefit from the procedure as defined by a 50% improvement in their YBOCS [31]. for an overall response rate of 28% to 40% [32]. approximately 56% were found to have undergone worthwhile improvement. Rauch / Neurosurg Clin N Am 14 (2003) 225–235 229 Fig. 50% were found to be functionally well and 29% were found to have shown marked improvement. using subjective rating scales. A prospective study was therefore undertaken using independent observers and clinically validated outcome rating scales.R. Of the 35 patients who were operated on for refractory OCD. namely. Cosgrove. 62% of patients with severe affective disorder were found to have had worthwhile improvement. Similarly.L. the referring psychiatrists. In 14 patients suffering from nonobsessive anxiety disorders.

Midsagittal (A) and axial (B) T1-weighted MRI scans obtained 48 hours after three anterior cingulotomy lesions ablating approximately 2. 2. In more than 800 cingulotomies performed at the MGH since 1962. One patient suffered a delayed intracerebral hematoma after a fall 4 weeks after surgery but suffered no long-term neurologic deficits. with a mean followup of almost 3 years. there have been no deaths and only two infections.R.L. Between 32% and 45% of patients were judged to be responders. Cosgrove. This improvement was greatest in Fig. Note the original lesion placed 12 months earlier and the acute lesion anteriorly. A subsequent evaluation of 57 patients before and after cingulotomy found no evidence of lasting neurologic or behavioral deficits after surgery. similar findings in 44 treatment-refractory OCD patients [33]. Two acute subdural hematomas occurred early on in the series secondary to laceration of a cortical artery at the time of introduction of ventricular needles. 3. An independent analysis of 34 patients who underwent cingulotomy demonstrated no significant behavioral or intellectual deficits as a result of the cingulate lesions themselves [34]. Axial T1-weighted MRI scans obtained 48 hours after repeat anterior cingulotomy. but only 1 patient suffered permanent neurologic impairment. S. Rauch / Neurosurg Clin N Am 14 (2003) 225–235 Fig. .5 cm of cingulate cortex. A comparison of preoperative and postoperative Weschler IQ scores demonstrated significant gains after surgery.230 G.

R. or anterior capsulotomy. it appears that cingulotomy is a useful intervention in many patients with severe treatment-refractory major depression or OCD. Using a five-point global scale and rating scales for depression and anxiety. The original surgical procedure was performed using stereotactically implanted radioactive yttrium 90 seeds. The best review of the surgical results for subcaudate tractotomy was presented by Goktepe et al [38] in 1975. although patients with concomitant psychotic disorders and depression might still be helped with surgery and should not be excluded. Surgical indications included major depressive illness. or alcohol abuse did poorly. There is general agreement among centers that patients with major affective disorder. such as subcaudate tractotomy. with good results seen in about half of these individuals. Appropriate selection of patients for surgery remains the major responsibility of the psychiatrist. they reviewed 208 patients with a mean follow-up of 2. Discussion Although any patient with a severe psychiatric illness was once considered a candidate for surgical intervention. Although this response rate may appear low at first glance. Rauch / Neurosurg Clin N Am 14 (2003) 225–235 patients with chronic pain and depression but negligible in those with the diagnosis of schizophrenia [35]. good results were seen in 68% of patients suffering from depression. limbic leukotomy. smaller lesions in are created by thermocoagulation with MRI stereotactic guidance. Currently. Cingulotomy has been the preferred surgical intervention in our experience because it provides substantial relief to a significant number of patients and is associated with a low incidence of complications or adverse events [29].L. Using subjective rating scales. Patients with schizophrenia. personality disorder. one must remember that all patients were completely refractory to every available treatment and that any measurable improvement might thus be considered salutary. Many other centers believe that alternative surgical interventions. In patients with depression and OCD. 62. approximately 60% to 70% of patients show significant improvement. Stereotactic techniques have certainly minimized side effects. 3 had committed suicide. and preliminary PET studies of patients with OCD indicate that presurgical cerebral metabolic rates within a territory of posterior cingulate cortex predict subsequent outcome after cingulotomy [36]. and 50% of patients with obsessive neurosis. Cosgrove. it is now clear that the prudent indications for psychosurgery are more restrictive. Of the 134 patients available for structured interview. S.5 years. guided by the informed and expert opinions of the other members of the psychosurgical team. Of the 25 patients who had died at the time of review. drug abuse. approximately 30% to 45% of patients who undergo cingulotomy are considered to be responders.7%. OCD. total improvement or improvement with minimal symptoms was clinically observed in two thirds of the patients. One patient died from . Some patients who had only temporary benefit from the initial lesion had second lesions created lateral to the first.5% of patents with anxiety states. Personality disorders and psychoactive substance use disorder are also significant relative contraindications to surgery. The aim was to interrupt white matter tracts between orbital cortex and subcortical structures by placing a lesion in the region of the substantia innominata just below the head of the caudate nucleus. overall success rates could be greatly improved. The incidence of complications was small but included postoperative seizures in 2. 231 but the issue of case selection remains a major consideration.2% of patients and undesirable personality traits in 6. Overall. and anxiety states as well as a variety of other psychiatric diagnoses. If preoperative evaluation could select those patients with a better chance of responding favorably to cingulotomy. When more objective clinically validated rating scales are used to assess outcome. chronic anxiety states. and OCD are the best candidates for surgery. Advanced neuroimaging data may ultimately aid in optimal patient selection. which yielded large lesional volumes of approximately 2000 mm2. It can be safely concluded that schizophrenia is not an indication for psychosurgery. Much of the controversy surrounding the use of psychosurgery may be attributed to the indiscriminate application and high morbidity seen with the early surgical procedures. Transient disinhibition was common.G. can provide better results in a similar patient population. Subcaudate tractotomy was introduced by Knight [37] in Great Britain in 1964 as one of the first attempts to restrict the size of the surgical lesion and therefore minimize the side effects seen with standard prefrontal lobotomy.

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G.R. Cosgrove, S.L. Rauch / Neurosurg Clin N Am 14 (2003) 225–235

inadvertent destruction of the hypothalamus
when a yttrium seed migrated off target.
Limbic leukotomy was introduced by Kelly
et al [39] in 1973 and combines subcaudate tractotomy with anterior cingulotomy. This procedure
was designed to disconnect orbital-frontal-thalamic pathways with the former lesion and to
interrupt an important portion of Papez’s circuit
with the latter. Kelly et al [39] reasoned that these
two lesions might lead to a better result for the
symptoms of OCD than either lesion alone.
Indications for surgical intervention included
obsessional neurosis, anxiety states, depression,
and a variety of other psychiatric diagnoses. This
stereotactic procedure placed three small (6-mm
diameter) lesions in the lower medial quadrant of
each frontal lobe and two lesions in each cingulate
gyrus.
Using the same five-point scale described in the
study of Goktepe [38], 66 patients were assessed
before and after surgery (mean follow-up of 16
months). In patients with obsessional neurosis,
89% were clinically improved; in chronic anxiety,
66% were improved; in depression, 78% were improved; and in a small number of schizophrenics,
more than 80% were improved [40]. Kelly et al
[41] later reported in 49 patients with OCD that
84% were improved 20 months after surgery.
They too noted that postoperative symptom improvement was not immediate, with a fluctuating
but progressive reduction of symptoms over the
first postoperative year. Although many patients
complained of lethargy, confusion, and lack
of sphincter control in the early postoperative
period, persistent complications were rare. No patients developed seizures after surgery, 1 patient
suffered severe memory loss because of improper
lesion placement, and 12% of patients complained
of persistent lethargy. Measurements of IQ showed
slight improvement after surgery.
Recently, the results of a more modern series
of MRI-guided stereotactic limbic leukotomy
were reported in 21 patients [42]. Mean follow-up
was longer than 2 years, and 35% to 50% of patients were considered to be treatment responders
using clinically validated rating scales. Transient
side effects were more common than after either
cingulotomy or subcaudate tractotomy alone, with
permanent minor memory loss or urinary difficulties observed in approximately 10% of patients.
Although Talairach et al [43] were the first to
describe anterior capsulotomy, Leksell popularized the procedure for patients with a variety
of psychiatric disorders [44]. The aim was to

interrupt presumed frontothalamic connections in
the anterior limb of the internal capsule, where
they pass between the head of the caudate nucleus
and the putamen. Clinical indications initially
included schizophrenia, depression, chronic anxiety states, and obsessional neurosis but are
currently almost entirely limited to OCD.
The target coordinates as described by Leksell
are in the anterior one third of the anterior limb of
the internal capsule 5 mm behind the tip of the
frontal horns and 20 mm lateral to the midline
at the level of the intercomissural plane. Lesions
were created by thermocoagulation using a bipolar
electrode system and were typically approximately
15 mm in height and 4 to 5 mm in diameter.
In the first 116 patients operated on by Leksell,
50% of patients with obsessional neurosis and
48% of depressed patients had a satisfactory
response [44]. Only 20% of patients with anxiety
neurosis and 14% of patients with schizophrenia
were improved. In this classification system, only
patients who were free of symptoms or markedly
improved were judged as having a satisfactory
response. Of the patients who were rated as worse
after capsulotomy, 9 were schizophrenics, 4 were
depressives, and 3 were obsessives. In another
series of 35 patients with OCD who underwent
capsulotomy and were followed prospectively by
independent psychiatrists, 16 were rated as free of
symptoms and 9 were much improved, for an
overall satisfactory result of 70% [45]. In a review
of all cases of capsulotomy previously reported in
the literature, Mindus et al [46] found sufficient
data to categorize outcome in 213 of 362 patients.
Of these, 137 [64%] were deemed to have a
satisfactory result.
More recently, Mindus et al [47] followed 24
patients prospectively with standardized rating
scales. Complications of the surgery included
transient episodes of confusion during the first
week in 19 of 22 patients available for follow-up,
with occasional nocturnal incontinence. One
patient was noted to have an intracranial hemorrhage without neurologic sequelae, and 1 patient
suffered seizures. One patient committed suicide
in the postoperative phase, and 8 patients suffered
from depression requiring treatment. Excessive
fatigue was a complaint in 7 patients, and 4 had
poor memory. Two patients showed slovenliness.
Weight gain is common after capsulotomy, with
an overall mean weight gain of about 10% in all
patients. No evidence of cognitive dysfunction has
been reported in 200 capsulotomy patients studied
using a variety of psychometric tests. Reoperation

G.R. Cosgrove, S.L. Rauch / Neurosurg Clin N Am 14 (2003) 225–235

was required in 2 patients who did not achieve
a satisfactory result, with only 1 improving after
the second operation. Burzaco [48] subjected 17
of his 85 patients to a second procedure during
which the lesions were enlarged, and half of these
reoperations yielded satisfactory results.
In 1977, Kullberg [49] attempted to compare
cingulotomy and capsulotomy in the treatment of
26 patients in a randomized fashion. Six of 13
capsulotomy patients and 3 of 13 cingulotomy
patients were better, but transient deterioration
in mental status was much more marked after
capsulotomy than after cingulotomy.
With currently available data, it is impossible
to determine whether there is one optimal surgical
technique or strategy. The obstacles that prevent
a direct comparison of results across centers
include diagnostic inaccuracies, nonstandardized
presurgical evaluation tools, center bias, and
varied outcome assessment scales. In virtually all
published reports, however, some modification of
the Pippard Postoperative Rating Scale, CGI
scale, or equivalent has been used to determine
clinical outcome [50]. The Pippard scale rates
outcome in five categories as follows: A=very
much improved, B=much improved, C=slightly
improved, D=unchanged, and E=worse. The
CGI expands the scale and rates outcome as
follows: 1=very much improved, 2=much improved, 3=slightly improved, 4=unchanged,
5=slightly worse, 6=much worse, and 7=very
much worse.
Although comparisons are imperfect and the
rating of outcome is subjective, these scales do
seem to have some clinical validity. If a Pippard
outcome of A and B or a CGI outcome of 1 or 2
is considered satisfactory, cingulotomy was effective in 56% of patients with OCD, subcaudate
tractotomy in 50%, limbic leukotomy in 61%,
and capsulotomy in 67%. In patients with major
affective disorder, cingulotomy was effective in
65%, subcaudate tractotomy in 68%, limbic
leukotomy in 78%, and capsulotomy in 55% [51].
The difficulty with these results is that they
were obtained many years ago before the availability of modern psychopharmacologic treatments. Patients who undergo surgery today have
a much wider range of drug therapies and tend to
be much more resistant to treatment. Comparing
current outcomes with historical results can
therefore be misleading. Direct comparisons of
the relative efficacy of the various modern surgical
options will only be possible when centers report
their experience using validated objective rating

233

scales (eg, YBOCS, BDI). Based on current methods of comparison, the clinical superiority of
any one procedure is not convincing. Although
many centers claim advantages for their specific
surgical intervention, we are unable to determine
whether one of the four major psychosurgical
procedures is superior to the others at this point.
Cingulotomy is more commonly performed in the
United States, whereas in Europe, capsulotomy
and limbic leukotomy are more prevalent. They
all seem to be roughly equivalent from a therapeutic point of view, but in terms of unwanted
side effects, cingulotomy seems to be the safest of
all procedures currently performed.
Regardless of the choice of procedure, surgical
failures should be investigated, and if the lesion
size or location is suboptimal, consideration
should be given to another procedure. At least
45% of patients undergoing cingulotomy require
repeat operation, with good results being salvaged
in half [29]. Because of this high rate of reoperation in cingulotomy, we now recommend placement of three lesions in each cingulate gyrus at
the first operation to ablate approximately 2.5 cm
of the gyrus. The exact size or volume of tissue
required for an effective outcome at each of the
target sites has yet to be determined.
Although controversy exists regarding the exact
choice of surgical procedure to be employed, there
is unanimous agreement that the presurgical evaluation be performed by committed multidisciplinary teams with expertise and experience in the
surgical treatment of psychiatric illness. Diagnosis
based on the DSM-III-R or DSM-N-R classification scheme is encouraged, and although it is impossible to mandate uniformly across all centers,
prospective trials employing standardized clinical
instruments with long-term follow-up are needed.
Comparisons of preoperative and postoperative
functional status remain an important parameter
in addition to targeting psychiatric symptoms in
characterizing outcome. All centers with experience
emphasize the importance of rehabilitation after
surgery and the need for ongoing psychiatric
follow-up. The operation is not a panacea and
should be considered as only one aspect in the
overall management of these patients.

Summary
Cingulotomy can be helpful in certain patients
with severe, disabling, and treatment-refractory
major affective disorders, OCD, and chronic

234

G.R. Cosgrove, S.L. Rauch / Neurosurg Clin N Am 14 (2003) 225–235

anxiety states. This form of psychosurgical
treatment should only be carried out by an expert
multidisciplinary team with experience in these
disorders. Cingulotomy should be considered as
one part of an entire treatment plan and must be
followed by an appropriate psychiatric rehabilitation program. Many patients are greatly improved after cingulotomy, and the complications
or side effects are few. Cingulotomy remains an
important therapeutic option for disabling psychiatric disease and is probably underutilized.
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the anterior cingulate gyrus. Department of Diagnostic Radiology. Korea Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder involving intrinsic and repetitive thoughts as well as ritualistic and irrational behavior that causes marked distress [1. In particular. and in this system. Recently. and elements of the basal ganglia and thalamus [10. Jong Doo Lee.W. Seoul.9% and 1. The resultant SPM data are more accurate than conventional semiquantitative measurements [13]. single photon emission tomography (SPECT). Chang). Seoul.kr (J.6%. we evaluate the role of SPECT in OCD diagnosis by comparing the brain SPECT images of drug-free OCD patients with those of normal controls and drug-naive schizophrenia patients. Kodala et al [3] have reported the lifetime and 6-month prevalence rates to be 2. Korea c Division of Nuclear Medicine. Elsevier Inc.yonsei. many functional neuroimaging studies have been performed with PET. Compared with the consistent metabolic alteration recorded on PET. Chan Hyung Kim. doi:10. the neurobiologic basis of OCD has received much attention. 120-752. These defined regions in the pathogenesis of OCD were predominantly determined based on PET studies.c.1016/S1042-3680(03)00006-8 .see front matter Ó 2003. low spatial scanner resolution. few SPECT data have been reported. voxel-based analysis using statistical parametric mapping (SPM) has become available. the published data on blood flow studies with SPECT have been inconsistent and variable in determining cortical and subcortical structures with abnormal perfusion patterns. Yonsei University College of Medicine. the ROI method is subjective to operator bias in that large ROIs may dilute small activation sites but small ROIs may not differentiate activation sites from noise. Korea d Department of Neurosurgery. Some of the most important information has resulted from functional neuroimaging studies using functional MRI (fMRI). Yonsei University College of Medicine.2]. semiquantitative measurements of the radioactivity within regions of interest (ROIs) after normalization to the cerebellar uptake are currently used as an analytic method.d.Neurosurg Clin N Am 14 (2003) 237–250 Single photon emission computed tomography imaging in obsessive-compulsive disorder and for stereotactic bilateral anterior cingulotomy Jin Woo Chang. and positron emission tomography (PET) [4–10]. respectively. Recently. Sang Sup Chung. and intraindividual variation because of the presence or absence of OCD symptoms at the time of injection.11]. CPO BOX 8044.*. MD. There * Corresponding author. Seoul. Using this sophisticated analysis method. subject variation. including inconsistency of SPECT data analysis. different scanning techniques. MDa. MDb. Yonsei University College of Medicine. may be a number of reasons for this. We then explore the role of SPECT in surgical outcome after bilateral anterior cingulotomy 1042-3680/03/$ . an activated region is compared with a control area by statistical processes after assigning some threshold values and a probability value [12]. Yonsei University College of Medicine. MDa. however. Korea b Department of Psychiatry. Neuroimaging studies provide evidence for a role in OCD of the specific frontal-subcortical brain circuit connecting the orbitofrontal cortex. with many modalities of evidence suggesting a neurologic basis for OCD. All rights reserved.ac. In this report. however. E-mail address: jchang@yumc. Seoul. PhDd a BK21 Project for Medical Science.

ordering. The duration of illness exceeds 3 years. The severity of OCD behavior was quantified by the Yale-Brown Obsessive-Compulsive Scale (YBOCS) [14]. The mean age (SD) was 25. revealing results of 13. These healthy subjects had no psychiatric or neurologic illnesses. H. a complicating current axis II Table 1 Clinical findings of obsessive-compulsive disorder patients for study I Case Case Case Case Case Case Case 1 2 3 4 5 6 7 Sex/age (years) Onset age (years) Symptom duration (years) Y-BOCS HAM-D HAM-A Main symptoms M/24 M/22 F/29 M/29 M/20 M/33 M/21 15 20 27 24 15 16 18 10 2 2 5 5 17 3 27 28 35 25 30 27 30 19 20 26 18 17 25 15 10 15 10 9 10 14 15 H. C W.23. 6. or substance abuse. is considered poor. O. 9. No patients had any psychotropic medications in the 4 weeks before SPECT study. checking.9  3. C C.3  5. Current and up-to-date treatment options have been tried systemically for at least 3 years without appreciable effect on the symptoms or have had to be discontinued because of intolerable side effects. Yale-Brown Obsessive-Compulsive Scale. male. R C. Thirteen patients in this group were followed up for more than a year (mean follow-up of 22. obsession. revealing an overall total score of 28. 5. 7. The mean age of the schizophrenia group was 28.4  8. The patient fulfills current diagnostic criteria for OCD. Also excluded from consideration for surgery were patients younger than 18 years of age or older than 60 years of age. manifest abuse of alcohol. Single photon emission computed tomography for obsessive-compulsive disorder diagnosis Seven patients with severe primary OCD (six men and one woman) were studied.8 years.4  4. Their mean onset age of symptoms was 19. Nine drug-naive cases of schizophrenia (three undifferentiated and six paranoid types) were also included for comparison purposes. HAM-D. The disorder is causing substantial suffering as evidenced by ratings. delusional disorder.238 J. The control group consisted of seven normal volunteers (four men and three women) with a mean age of 30.16].4 months) (Table 2). a complicating axis I diagnosis (eg. Single photon emission computed tomography and surgical outcome Fifteen refractory OCD patients underwent bilateral stereotactic anterior cingulotomy using MRI guidance. HAM-A. The main compulsive symptoms were washing. Criteria for surgical candidacy included the following: 1. and hoarding. female. without neurosurgical intervention. C W. All patients met the Diagnostic and Statistical Manual for Mental Disorder. R O. hoarding. W. washing.5 years (range: 2–27 years).W. The depression and anxiety scales were also evaluated using the Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A) [15.8  2. checking. Hamilton Anxiety Scale. Exclusion criteria included histories of central neurologic disorders. C W. Chang et al / Neurosurg Clin N Am 14 (2003) 237–250 by comparing pre. Y-BOCS. organic brain syndrome. 3. tics. Hamilton Depression Scale. F.7 years. The patient gives informed consent. or illicit drugs).7 years.6  6.6  4. sedatives. 4.2 years.6. this disorder must also have been thoroughly addressed with appropriate trials of first-line treatments. 1994) criteria for OCD as evaluated by two independent psychiatrists and a neurosurgeon who is experienced in psychosurgery. If a comorbid psychiatric condition is present.and postoperative brain SPECT imaging. (American Psychiatric Association. and the duration of symptoms was 6. C. 8. The patient agrees to participate in the preoperative evaluation program and postoperative rehabilitation program.3  4. respectively (Table 1). C Abbreviations: M.1 and 12. The disorder is causing substantial reduction in the patient’s psychosocial functioning as evidenced by ratings. 4th Edition (DSM-IV). R. . The prognosis. 2.

hoarding. obsession.8-mm electrode with a 10-mm bare tip (Radionics. O. W S.J.7  10. The average symptom onset age was 24. 2 demonstrates the resolved perilesional edema along the radiofrequency lesions 3 months after cingulotomy. No patients had taken any psychotropic medications in the 4 weeks before SPECT study (before and after surgery). Stereotactic localization of the targets was achieved using the MRI-compatible Leksell stereotactic frame (Elekta Instruments. The electrode was then withdrawn 8 mm to produce the second lesion. 10).2 years. Surgical procedure Patients were placed under local anesthesia. however. 1 and 2). and 7 mm lateral to the midline. 2 mm above the roof of the ventricle. Fig. checking. atrophy. Burlington. C C.8  9. diagnosis from clusters A (eg. W. male. and 6 mm in lateral dimension (Figs. The SPECT study was acquired in a 128  128 matrix with 3 of angular increment for 20 minutes. highresolution.9 years.5-T unit (Milwaukee. CGI-S. W C. 2 mm above the roof of the ventricle. Y-BOCS. Radionics). Attenuation correction was performed by Chang’s method. A 1. Hamilton Depression Scale. and a complicating current axis III diagnosis with brain pathologic findings (eg. HAM-A. Yale-Brown Obsessive-Compulsive Scale.W. S. sin. The first lesion was made 15 mm posterior to the frontal horn of the lateral vehicle. . MA) was inserted into the target to create radiofrequency thermocoagulation lesions at 85 C for 90 seconds using a lesion generator (RFG-3C. HAM-D. Hamilton Anxiety Scale. R C. Transaxial images were obtained by the filtered-back projection method using a Butterworth filter (cutoff frequency of 1. C C. order no. GA) on a General Electric Signa 1. and coronal and sagittal images were calculated. antisocial or histrionic personality disorder). The mean age of the patients (nine men and four women) was 35. Fig.5  5. WI). F. washing. and symptom duration was 10. and bilateral burr holes were made in front of the coronal suture 20 mm laterally from the midline. Chang et al / Neurosurg Clin N Am 14 (2003) 237–250 239 Table 2 Clinical findings of obsessive-compulsive disorder patients for study II Case Case Case Case Case Case Case Case Case Case Case Case Case 1 2 3 4 5 6 7 8 9 10 11 12 13 Sex/Age (years) Onset age (years) Symptom duration (years) Y-BOCS CGI-S HAM-D HAM-A Main symptoms M/25 M/34 F/53 M/41 M/45 M/26 M/40 F/36 F/31 M/18 F/38 M/48 M/30 15 16 44 36 39 15 18 20 24 14 27 33 20 10 17 8 4 5 10 21 15 7 4 11 15 10 29 36 40 34 37 38 38 39 35 28 38 30 32 7 7 7 7 7 7 7 7 7 7 7 6 7 19 25 50 47 30 21 21 41 20 13 15 22 29 10 13 32 25 24 8 8 17 10 7 9 20 22 H. Digital Scintigraphic Incorporation.3 years. W W C W C S Abbreviations: M. Brain images were obtained using a braindedicated annular crystal gamma camera (RASPECT. MA) equipped with low-energy. 1 demonstrates the diffuse perilesional edema along the radiofrequency lesions immediately after cingulotomy. H. Atlanta. Four lesions along two tracks were created on either side of the anterior cingulate gyrus. 13 mm in anteroposterior (AP) dimension. paranoid personality disorder) or B (eg. W C. C. tumors). This edema resolved gradually. female. Lesions were confined to the anterior cingulate gyrus. Imaging procedures The SPECT procedure was performed for patients and controls after an intravenous injection of 740 MBq of Tc 99m ethyl cysteinate (ECD). The electrode was then withdrawn 8 mm to produce the fourth lesion. (Waltham. The result was an elliptocylindrically shaped lesion approximately 18 mm high. R. W C. and 7 mm lateral to the midline.1 cycle per centimeter. The third lesion was made 22 mm posterior to the frontal horn of the lateral ventricle. parallel-hole collimators. Clinical Global Improvement of Severity Scale. ordering.

the reconstructed SPECT data were reformatted into Analyze (Mayo Foundation. Baltimore. 3. UK) software [18].W. Lon- don. (A) The axial image. Silicon Valley. T1. Institute of Neurology. (B) T1weighted axial image. (B) The coronal image. Chang et al / Neurosurg Clin N Am 14 (2003) 237–250 Fig. 1.67 mm of x and y pixel size. The SPECT images of the Fig.34 mm of slice thickness. (C) The coronal image. and 2 bytes of signed integer of pixel values. CA) using automatic image registration (AIR) [17] and SPM (SPM96.240 J.and T2-weighted MRI 3 months after cingulotomy demonstrated the resolved perilesional edema along the radiofrequency lesions. Lesions were confined in the anterior cingulate gyrus. 1. University College of London. (A) T2-weighted axial image. After attenuation and scatter correction. . 2. Statistical parametric mapping Analysis of data was performed on a SUN UltraSpare 10 workstation (Sun Microsystems. MD) header format consisting of 4096 bytes of header. T2-weighted MRI 3 days after cingulotomy demonstrated the diffuse perilesional edema along the radiofrequency lesions.

was seen in the OCD group (Fig. All patients were evaluated at or as near to 6-month intervals as possible after surgery in our hospital.09 and a corrected extent threshold probability value of 0.18. the thalamus. All patients were followed up with a personal interview conducted by the psychiatrists. including immediate and delayed memory.W. SPM{t}. linear algorithm. Montreal. including immediate and delayed memory. executive control. Clinical assessment and follow-up Results of single photon emission computed tomography for obsessive-compulsive disorder diagnosis Clinical findings. which was adapted from a six-item Orientation-MemoryConcentration Test [22]. 12 affine parameter model for controlling the number of degrees of freedom used in registration.05. 5000 pixel value for thresholds to be used for organ of interest in both the standard and the reslice images. A probability of less than 0. visual integration. diffusely decreased perfusion within the bilateral cerebral and cerebellar cortices. increased perfusion was seen within the anterior cingulate gyrus in five patients and the frontal lobe in two. The resulting t statistic. including the inferior frontal gyrus. sections were displayed as transverse. 5). and coronal slices with hot color maps. The differences in these scales between the preoperative state and postoperative state (6 months. however. and the front lobe (Fig. The optimal cutoff point to differentiate patients with dementia from control subjects was 10/11 on the SBT-K. verbal memory. and general intellectual function. 241 Neuropsychologic evaluation Patients were evaluated using a battery of neurocognitive/neuropsychologic evaluation methods designed to measure the functional domains of language. we evaluated all patients on postoperative day 14 with the Korean version of the Short Blessed Test (SBT-K) [21]. by Hopkins Verbal Learning Test (HVLT). Chang et al / Neurosurg Clin N Am 14 (2003) 237–250 normal and patient groups were separately coregistered to remove variations resulting from differences in the size and shape of individual brains. Increased perfusion within the basal ganglia. the left basal ganglia. 12 months) were assessed using a Wilcoxon signed rank test. and trilinear interpolation. . The data were then normalized to a PET template (MNI template. For graphic presentation of the results. complications.58. showed increased perfusion within the anterior cingulate gyrus.001. attention and executive functions by the Wisconsin Card Sorting Test (WCST) and Stroop test.09 or 1. The mean image of the OCD group at a threshold probability value of 0. The neurocognitive battery of tests to assess each domain consisted of the following standardized tests with well-established reliability and validity: intellectual functioning by the Korean Wechsler Adult Intelligence Scale (K-WAIS). and patient progress were prospectively recorded. In addition to this battery of standard neurocognitive tests. by the Rey-Osterrieth Complex Figure Test (RCFT). and the orbitofrontal cortex was seen in only one patient (Fig.05 and a corrected extent threshold probability value of 0. Evaluation by the neurocognitive battery and by postoperative SPECT was performed between 6 and 12 months after surgery. Individual OCD images were also compared with the normal group by shifting the SPM parameters to a probability value of 0.01 was considered significant. motor control. The surgical outcome was also assessed/evaluated by the results of Clinical Global Improvement Scale (CGI) as well as the HAM-D and the HAM-A tests [15. The statistical analysis was performed to compare the mean SPECT images of the OCD group with those of the schizophrenia and normal control groups and the postoperative images with preoperative images in the surgical group.005 and a Z value of 2. and verbal fluency by Controlled Oral Word Association Test (COWA). Hyperperfusion within the orbitofrontal cortex or the caudate nucleus was not evident.16. visuospatial construction and memory. The parameters for co-registration were: intra-modality. attention. sagittal. Statistical analyses were conducted to examine the effects of cingulotomy.64. 3).J. The severity of OCD behaviors was quantified by the Y-BOCS [14]. learning and memory.20]. The statistical results were displayed by rendering on the reference three-dimensional MRI images with a probability value of 0. Montreal Neurological Institute. Quebec.19] and smoothed with 8-mm Full Width Half Maximum (FWHM) before SPM statistical analysis. Canada) [2.001 or 0. When individual SPECT images of the OCD patients were compared with the mean images of the normal control group. was transformed to SPM{Z} with a threshold of 3.05 for SPM{Z}. with a Z value of 3. 4).

1  7.0 before surgery.6 and 10.9  2.8 and 4. The mean HAM-D score was also reduced significantly from 27.01). The mean CGI-Severity score was also reduced significantly from 6. Most patients experienced an immediate reduction in depression and anxiety after cingulotomy. respectively (P < 0. except hoarding behavior.2  10. The mean postoperative SBT-K score was 6. and within the orbitofrontal cortex in three (Table 3). respectively (P < 0. and the temporo-occipital areas compared with the schizophrenia group (Fig.242 J.3  5.9 before surgery to 4. hyperperfusion was seen within the anterior cingulate gyrus in all patients.6. All OCD symptoms seemed to respond to surgery. When the SPM parameters were shifted to the threshold probability value of 0. The patients tolerated the procedure well. Chang et al / Neurosurg Clin N Am 14 (2003) 237–250 Fig. and none experienced serious permanent complications related to the procedure. whereas those at 6 and 12 months after cingulotomy were reduced significantly to 24. 6).0  6. within the thalamus in five.4 and 21.9  4.01).1. The mean Y-BOCS score was 34.5  11.4 at 6 and 12 months after cingulotomy.01). respectively (P < 0. 3.005.1 and 6. All patients scored below the optimal cutoff point for differentiation of dementia (10/11) on the SBT-K.58 and a corrected extent threshold probability value of 0.01).2 at 6 and 12 months. within the basal ganglia in four.001.8 before surgery to 16. within the caudate nucleus in three. The OCD group showed increased perfusion within the anterior cingulate gyrus. respectively (P < 0. (A) Statistical parametric mapping (SPM) results showing areas of hyperperfusion in OCD patients. (B) SPM results rendered on the reference three-dimensional MRI revealed significantly increased perfusion of the anterior cingulate cortex on the reference three-dimensional MRI.3  7. the bilateral frontal.2  7. Also reduced significantly was the mean HAM-A score from 16. The mean CGI score at 12 months was 2.05.W. Outcome of anterior bilateral cingulotomy All patients demonstrated improvement in their Y-BOCS score after cingulotomy (Table 4).5  6. Three patients .1. with a Z value of 2.8 before surgery to 9.0 at 6 and 12 months after cingulotomy. Group comparison of obsessive-compulsive disorder (OCD) patients with healthy control subjects at the threshold of P < 0.

One case of wound dehiscence occurred from scratching of the wound as a result of compulsive behavior. Chang et al / Neurosurg Clin N Am 14 (2003) 237–250 243 Fig. postoperative [Ed-corrected] IQ ¼ 105). these patients recovered from their minor problems within the first operative month. and cerebellar areas. (A) Statistical parametric mapping (SPM) results showing areas of decreased perfusion in OCD patients (increased perfusion in healthy control subjects). Several patients experienced minor interference with verbal fluency and minor personality changes. the wound healed well after reclosure. Group comparison of healthy control subjects with obsessive-compulsive disorder (OCD) patients at the threshold of P<0.J. although it was not statistically significant (mean preoperative IQ ¼ 99. visuospatial skills. 4. the OCD patients demonstrated reduced perfusion . Single photon emission computed tomography and anterior bilateral cingulotomy We performed postoperative SPECT in eight patients after cingulotomy. however. language. and frontal execu- tive function. the other five patients refused for various reasons.001. (B) SPM results rendered on the reference three-dimensional MRI showing decreased perfusion within bilateral parieto-occipital.W. inferior frontal. we observed an improvement of intellectual function after cingulotomy in several patients. On the contrary. showed transient disorientation during the postoperative period. After surgery. however. The neuropsychologic testing demonstrated that cingulotomy did not cause any significant cognitive problems in areas like intelligence.

244 J. In our series. Discussion Outcome of bilateral anterior cingulotomy for obsessive-compulsive disorder There was an overall significant improvement in the Y-BOCS and HAM-D scores. bilateral anterior cingulotomy is regarded as an important therapeutic option for intractable OCD [23. and this delayed process may suggest that effects are related not only to . (A) Statistical parametric mapping (SPM) results rendered on the reference three-dimensional MRI. In general. all patients showed gradual improvement after surgery. A single case analysis of an obsessive-compulsive disorder patient (case 6) at the threshold of P < 0. 7).24]. As reported previously [23. (B) SPM results rendered on the sagittal single photon emission computed tomography image.01) (Fig. 5. and the thalamus.24].W. Chang et al / Neurosurg Clin N Am 14 (2003) 237–250 Fig.005 revealed hyperperfusion within the anterior cingulate cortex. a bilateral lentiform nucleus. within the anterior cingulate gyrus and the right orbitofrontal cortex in the summated and subtracted postoperative SPECT images compared with the preoperative SPECT images (P < 0. the left head of the caudate nucleus. Studies on the effects of cingulotomy for OCD during the last decade have demonstrated that about one third of patients were improved after cingulotomy [25]. with no significant change in neuropsychologic testing after stereotactic bilateral anterior cingulotomy. there was a general delay in the onset of improvements of symptoms.

005 P < 0.005  P < 0. minor interference with verbal fluency. however. right. and no significant adverse effects were encountered after cingulotomy.01). and the head of the caudate nucleus.001  Lt P < 0. These areas are interconnected anatomically and are among the regions implicated in the pathophysiology of OCD. and minor personality changes.001   P < 0. Our entire group improved significantly in terms of functional status (P < 0. it becomes important to have the proper target location and the optimal lesion volume in the anterior cingulate gyrus. visuospatial skills. Bilat. subtle personality and functional changes could remain. Prior reports have claimed that only 39% of patients were considered responders or possible responders on the basis of demonstrating an improvement on the Y-BOCS of more than 35% or a CGI score of 1 or 2 [24]. the anterior cingulate gyrus.001  + P < 0. Rt. The responder and possible responder ratios were 30. lack of spontaneity.24]. We did experience minor and transient mental deterioration (subsided within 1 week).005 P < 0. described as a nonresponsive/flat affect. orbitofrontal cortex. language. on the basis of an improvement on the Y-BOCS of more than 35% or a CGI score of 1 or 2. bilateral. respectively. We believe that these minor neurobehavioral sequelae do not hinder the performance of cingulotomy as a treatment method for a certain portion of intractable OCD patients so as to improve their quality of life. Our neurocognitive/ neuropsychologic battery of tests in these patients demonstrated that cingulotomy did not cause any significant cognitive problems in areas like intelligence. As Cohen et al [26] reported.W.001  P < 0.8% and 30. Single photon emission computed tomography and obsessive-compulsive disorder A number of neuroimaging studies using PET have determined abnormal activity in the orbitofrontal cortex. Lt.001  Lt P < 0. 1. One possible explanation for this is that our lesion is larger than those used in other studies. Chang et al / Neurosurg Clin N Am 14 (2003) 237–250 245 interruption but to reorganization of neural pathways after surgery.     Rt  Bilat   Lt   + +   4 5 6 7 Case Case Case Case + + + +            Bilat   Lt  + Case 3 + Bilat + Case 2 +   Bilat Lt Lt Lt Lt Frontal (Rt) Frontal Occipital Temporal Frontal Temporal Temporal Occipital Temporal Temporal  Occipital Bilat P < 0. We are not recommending that our positive results justify general adoption of the procedure as a routine treatment for OCD.005 P < 0. This transient postoperative complication seemed to occur as a result of temporary perilesional brain edema around the lesions. as evident in Fig.005 P < 0. left.7%. For patients undergoing stereotactic bilateral anterior cingulotomies. .005 J. and frontal executive function.001 + Thalamus OFC Basal ganglia Caudate Anterior cingulate Table 3 Statistical parametric mapping data of obsessive-compulsive disorder versus healthy control group Case 1 Other areas P < 0.Frontal (Bilat)    Rt Lt Lt          Abbreviations: OFC. Our study featured more possible responders than those of previous reports [20.

comparative studies of the OCD patients before and after Table 4 Surgical outcome after cingulotomy for study II Evaluation method Preoperative Postoperative 6-month Postoperative 12-month Y-BOCS (mean  SD) CGI-S (mean) CGI HAM-D (mean  SD) HAM-A (mean  SD) 34.4 16.3  5. (A) Statistical parametric mapping (SPM) results showing areas of hyperperfusion in OCD patients.0  5. Clinical Global Improvement.24* 2.5  11. Hamilton Depression Scale.246 J.3  7. in particular. Clinical Global Improvement of Severity Scale.612* 4. and. Our brain perfusion study of OCD patients using high-resolution SPECT showed consistently increased perfusion within the anterior cingulate gyrus compared with that of normal controls and other psychiatric patients (drug-naive schizophrenia).621* 9.83* 2. Our results have shown outcomes using SPECT for the first time and have correlated it to clinical improvements as determined by standard- ized tests.01 (Wilcoxon signed rank test).982* 6.W. Hamilton Anxiety Scale. * P < 0.001.2  7. HAM-D. (B) SPM results rendered on the reference three-dimensional MRI showing hyperperfusion within a bilateral anterior cingulate cortex and the frontal and parieto-occipital areas.123* 21. SPECT results demonstrated reduced perfusion within the anterior cingulate gyrus and the right orbitofrontal cortex after surgery. Hyperperfusion within the caudate nucleus or the orbitofrontal cortex was less frequently observed.2  10. the thalamus.5  6.9  4.9 24. HAM-A. CGI.01 6.75 16.1 10.88 Abbreviations: Y-BOCS.1  7. Functional imaging of OCD with 18F-fluorodeoxyglucose (18F-FDG) PET at resting state demonstrated the hyperactivity of various anatomic structures. CGI-S. . the orbitofrontal cortex. 6. such as the basal ganglia. In addition to resting PET.431* 4. Group comparison of obsessive-compulsive disorder (OCD) patients with drug-naive schizophrenia at the threshold of P < 0.414* 27. Yale-Brown Obsessive-Compulsive Scale. Chang et al / Neurosurg Clin N Am 14 (2003) 237–250 Fig.

because the orbitofrontal cortex and caudate nucleus are relatively smaller and thinner than the anterior cingulate gyrus. the orbitofrontal cortex [4. the emotional state and presenting symptoms at the time of injection are important determinants in brain perfusion SPECT but are less critical in PET. regional cerebral blood flow measured during symptom provocation using oxygen-15–labeled carbon dioxide PET showed increased blood flow within the caudate nucleus. however. the PET studies were conducted using 18F-FDG. treatment have shown a decrease in cerebral glucose metabolism within the caudate nucleus. First. a SPECT study performed during symptom provocation would be better than resting SPECT to evaluate the pathophysiologic mechanism of OCD.11]. This decrease in metabolism was correlated with a significant improvement in OCD symptoms. Mindus and Jenike [31] found that orbital and caudate glucose metabolic rates decreased significantly 1 year after bilateral anterior capsulotomy compared with those before surgery. Nordahl et al [30] found no difference in activity within the caudate nucleus. Group comparison of preoperative images with postoperative images at the threshold of P < 0. especially on transaxial images. there are several inconsistencies in the published data.35]. is rapidly taken up by the neurons in the brain within a few minutes. which requires 40 to 60 minutes between injection and imaging. The difference between PET and SPECT may stem from several factors. however.29] showed increased metabolic rates within the orbitofrontal cortex and the anterior cingulate gyrus. the anterior cingulate gyrus. The spatial resolution of current cameras used may be another important factor. Perani et al [27] described hypermetabolism within the anterior cingulate gyrus. small activation sites within these small .5. Therefore. Therefore. 7.J. thalamus. and the orbitofrontal cortex [33]. Therefore. 99m Tc EDC for brain SPECT. proportional to the cerebral blood flow [32]. such as decreased perfusion in the orbitofrontal cortex [34] and the caudate nucleus [8.10. Chang et al / Neurosurg Clin N Am 14 (2003) 237–250 247 Fig.5] found increased metabolism in the whole brain. it is apparent that studies of pretreatment and posttreatment OCD have most consistently shown findings of decreased orbitofrontal cortex and caudate activity after treatment. In fact. although resting brain SPECT has demonstrated contradictory findings. and basal ganglia but not in the orbitofrontal cortex. (B) SPM results rendered on the sagittal single photon emission computed tomography image.W. Swedo et al [28. whereas Baxter et al [4. (A) Statistical parametric mapping (SPM) results showing decreased perfusion at the anterior cingulate gyrus and the right orbitofrontal cortex. Regardless of the specific treatment or type of imaging modality used.05. Despite these findings. especially in the orbitofrontal cortex and the caudate nucleus but not in the anterior cingulate gyrus. For example. and the anterior cingulate gyrus [27].

including the orbitofrontal cortex.09 and 0.W.001 or P < 0. a review of the OCD functional brain imaging literature reveals a remarkable amount of data suggesting the presence of abnormalities in the orbitofrontal cortex. Neuroanatomic studies have also shown that the striatum contains a complex system—neurochemically specialized zones called striosomes dispersed within a larger compartment called the matrix [7. all of which are structures linked by well-described neuroanatomic circuits [10]. In addition. analysis may be inconsistent and conflicting in cases with slightly increased radioactivity within an activation site. data were analyzed using an SPM method in which relative activity distribution between the subject and control groups was compared and transformed to the unit of normal distribution in terms of z values and then displayed in coronal. The SPECT data may correctly demonstrate the major changes of perfusion after cingulotomy. the anterior cingulate gyrus. The caudate nucleus and the orbitofrontal cortex are relatively smaller and thinner than the anterior cingulate gyrus. and the thalamus. In this study. and the thalamus (n ¼ 5) was frequently observed.58 and P < 0. there are many reports concerning the role of the orbitofrontal cortex in the genesis of OCD and many PET studies demonstrating a decrease in cerebral glucose metabolism in the orbitofrontal cortex after OCD treatment [4. allowing the possibility for small activation sites within these small areas to be obscured and diluted by the surrounding normal cells or background activity as a result of poor spatial resolution. in SPECT or even PET studies without SPM. including poor spatial resolution. The only equivalent observation was in the anterior cingulate gyrus. The observation that obsessive-compulsive behaviors can be controlled by lesioning at several targets. and anterior cingulate gyrus. in terms of secondary change of perfusion according to cingulotomy has not been fully elucidated. Right-sided orbitofrontal metabolic reduction was noted in the same reports. Although not all studies agree. although five of the seven patients showed hyperperfusion within the anterior cingulate cortex on higher z and probability values (3. The analytic method of measuring radioactivity in terms of ROI or calculation of hemispheric ratio may contribute to false-negative results as well as false-positive results as previously described.39]. supports the hypothesis that these structures are closely related and involved with the neuronal circuitry of OCD. In our study. there was no observation of any hyperperfusion in the orbitofrontal cortex before the treatment. as previously discussed. Thus.001. hyperperfusion within the caudate nucleus (n ¼ 3). the caudate. and the improvement of OCD symptoms may be related to change of the orbitofrontal cortex. SPECT has many weaknesses. 2 and 3). Of special note was the observed decrease of perfusion in the right side of the orbitofrontal cortex. First. Chang et al / Neurosurg Clin N Am 14 (2003) 237–250 areas might be obscured and diluted by the surrounding normal cells or background activity as a result of the poor spatial resolution of SPECT cameras.11. We assumed that the perfusion in the anterior cingulate gyrus was caused by the cingulotomy itself.248 J. Several studies comparing therapy-related regional cerebral metabolic effects in patients with OCD have demonstrated orbitofrontal hypermetabolism on the right side before treatment [28. Second. all patients showed anterior cingulate hyperperfusion on lower thresholds (z value of 2. Therefore. The SPM analysis is known to be more accurate and reliable than semiquantitative measurement [13]. the orbitofrontal cortex (n ¼ 3). the disparity between various studies. We suggest two potential explanations for this divergence of results. the reduction of perfusion in the right orbitofrontal cortex was an interesting result. Those reports also showed an increased glucose metabolism in the caudate nucleus and the orbitofrontal cortex before the treatment.005.36]. respectively). In the literature. The striosomes of the caudate nucleus receive inputs from the orbitofrontal cortex and the anterior cingulate gyrus. however. and sagittal views showing only those voxels that reach a statistical significance of P < 0.005). In this study. In our study. Lippitz et al [38] also suggested the crucial role of the right hemisphere in OCD. however. including PET and SPECT images. A more interesting finding was the observation of postoperative hypoperfusion in the anterior cingulate gyrus and the right orbitofrontal cortex in the OCD patients. and the caudate processes the cortical information in . especially on transaxial images.37].29. internal capsule. axial. the anterior cingulate gyrus may be the key center for the genesis of OCD. the OCD patients exhibited increased perfusion in the anterior cingulate gyrus compared with both the healthy controls and the schizophrenic patients (see Figs.

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Contemporary psychosurgery and a look to the future. et al. [36] Saxena S. et al. [18F] FDG PET study in obsessive-compulsive disorder.2:23–8. et al. Thomas EK.48:548–55. Flaherty AW. Mindus P. Arch Gen Psychiatry 1991. Neuropsychiatry and SPECT in an acute obsessive compulsive syndrome patient. New York: McGraw-Hill. 51:62–70. Grady CL. In: Gildenberg PL. [35] Lucey JV. J Neurosurg 2001. dosimetry. Br J Psychiatry 1995. Bressi S. et al.250 J. et al. [20] Jenike MA. [22] Katzman R. Caudate regional cerebral blood flow in obsessive-compulsive disorder. Cerebral glucose metabolic rates in obsessive compulsive disorder. Baer L. Pietrini P. Psychiatry Res Neuroimaging 1997. Cerebral glucose metabolism in childhood-onset obsessive compulsive disorder: revisualization during pharmacotherapy. The basal ganglia and adaptive motor control. Treatment of psychiatric illness by stereotactic cingulotomy. Liddle PF. Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography. . Neuropsychopharmacology 1989. Lee KU. Colombo C. et al. 1998.44:452–60. Meyerson BA. Am J Psychiatry 1983. J Comput Assist Tomogr 1991.166:244–50. A long-term follow-up of 33 patients. Ballantine T. et al. Neurosurgical treatment of malignant obsessive-compulsive disorder. Arch Gen Psychiatry 1989. Alpert NM. 173(Suppl 35):26–37. et al. Lesion topography and outcome after thermocapsulotomy or Gamma Knife capsulotomy for obsessive-compulsive disorder: relevance of the right hemisphere. Biodistribution. Chang et al / Neurosurg Clin N Am 14 (2003) 237–250 [19] Friston KJ. et al. [38] Lippitz BE. Moser DJ. Brody AL. Hellman RS.15:921–38. Costa DC. [27] Perani D. et al.38:1365–75. Cingulotomy in psychosurgery. Aosaki T. Br J Psychiatry 1995. 46:518–23. Psychiatr Clin North Am 1992. [26] Cohen RA. Frith CD. Fuld P. and neurotransmitterspecific projection system. Paya B.30:1018–24. Plastic transformation of PET images. Schapiro MB. [32] Holman BL. Neurology 1999. Regional cerebral blood flow in obsessive-compulsive patients with and without a chronic tic disorder. Reliability and validity of the Korean version of Short Blessed Test (SBT-K) as a dementia screening instrument. Leonard HL. Eur Arch Psychiatry Clin Neurosci 1999. et al. A SPECT study. Alterman RL. Cerebral glucose metabolism in childhood-onset obsessivecompulsive disorder. A clinical/metabolic correlation study after treatment.249:156–61. [31] Mindus P.W. p. Arch Gen Psychiatry 1994. Science 1994. Biol Psychiatry 1987. Schizophr Bull 1997. [24] Cosgrove GR. Validation of a short orientation-memory-concentration test of cognitive impairment.166:390–2. Schwartz JM.23: 403–21. [28] Swedo SE. [37] Simpson S. Cabranes JA. Ballantine HT.53:819–24. Bouckoms AJ. Brown T. [34] Crespo-Facorro B. thalamus. [21] Lee DY.49:690–4. Yoon JC. [33] Rauch SL. editors. Busatto G. [40] Heckers S. Br J Psychiatry 1998. [30] Nordahl TE. [23] Ballantine HT. Benkelfat C. Impairments of attention after cingulotomy.74:25–33.22:807–19. 1965–70. [29] Swedo SE. J Korean Neuropsychiatr Assoc 1999. and clinical evaluation of technetium-99m-ethyl cysteinate dimer in normal subjects and in patients with chronic cerebral infarction. panic disorder and healthy controls on single photon emission computerized tomography. Tasker RR. [25] Feldman RP. Arch Gen Psychiatry 1992. et al. J Nucl Med 1989. et al. Semple WE. [39] Graybiel AM.140: 734–9.15:634–9. Neuropathology of schizophrenia: cortex. Neurosurgery 1999. Jenike MA. Goldsmith SJ.265:1826–31. Kaplan RF.95:944–56. Jenike MA. Cingulotomy for refractory obsessive-compulsive disorder. et al. Goodrich JT. Lopez-Ibor AMI. basal ganglia. et al. et al. Neuroimaging and fronto-subcortical circuitry in obsessive-compulsive disorder. et al. Baldwin B. Textbook of stereotactic and functional neurosurgery.

Neurosurg Clin N Am 14 (2003) 251–265 Neuropsychiatric thalamocortical dysrhythmia: surgical implications D. Switzerland b Department of Physiology and Neuroscience.and postsurgical magnetoencephalographic (MEG) studies. U. Considering the central role of recurrent oscillatory thalamocortical properties in the generation of normal hemispheric functions. Zurich. R. 31-47238. Swiss National Science Foundation (grants 31-36330. MD. R. Such past errors have raised important philosophic and ethical issues that remain with us for good reasons. USA d Psychiatry Center Hard. New York University School of Medicine. Llinas). M. 2(2). PhDa. All rights reserved. This condition. University Hospital. E. Switzerland Neuropsychiatric surgery has had a long and complex history with examples of less than optimal surgical procedures implemented in wrong settings.GCRC NIH NCRR M01RR00096).see front matter Ó 2003. * Corresponding author. Elsevier Science (USA). Jeanmonod. NIH/NINDS 1 F31 NS42973-01. NY 10016. including clinical follow-ups and pre. A. the existence of enormous suffering as a result of chronic therapy-resistant disabling neuropsychiatric disorders compels a search for alternative surgical approaches based on a sound understanding of the underlying physiopathologic mechanisms. Ramirez. M. This work was supported by the University of Zurich. Reprinted from: Thalamus and Related Systems 2003. This result is attained via reduction of both thalamic overinhibition and low-frequency oversynchronization. New York University School of Medicine. affective. and the New York University Medical Center General Clinical Research Center (NYU. strategically placed. We present here our experience with 11 patients. PhDb. Laboratory for Functional Neurosurgery.96. where most cells have been shown to be locked in low-frequency production and to have lost their normal activation patterns. M.* a Neurosurgical Clinic. Lanz. Sternwartstrasse 6. Schulman. Cancro. 8091 Zurich. MDa. We bring evidence from single cell physiology and magnetoencephalography for the existence of a set of neuropsychiatric disorders characterized by localized and protracted low-frequency spontaneous recurrent activation of the thalamocortical system. NY. MDa. MDd. The medial thalamic lesion is localized in the posterior part of the central lateral nucleus (CLN). and anxiety disorders as well as obsessive-compulsive disorder (OCD) and impulse control disorder (ICD). we propose a surgical approach that provides reestablishment of normal thalamocortical oscillations without reduction of cortical tissue and its specific thalamic connectivity. MSB-442. The evidence speaks for a benign and efficient surgical approach and for the relevance of the patient’s presurgical cognitive and social settings.1016/S1042-3680(02)00116-X . New York.med.edu (R. labeled thalamocortical dysrhythmia (TCD). USA c Department of Psychiatry. underlies certain chronic psychotic. J. PhDa. Magnin. 550 First Avenue. Nevertheless. Dana Foundation. Ribary. and 3154179.nyu.MDc. Morel. E-mail address: llinar01@endeavor. PhDb. BSb. Thalamic disinhibition is obtained by a lesion in the anterior medial paralimbic pallidum. Siegemund. PhDb. Llinas. R.92. 1042-3680/03/$ . Kronberg. New York. BSb. Charles A.98). University Hospital of Zurich. pallidal and medial thalamic lesions that serve to make subcritical the increased low-frequency thalamocortical recurrent network activity. making them more or less prone to postoperative psychoreactive manifestations on rekindling of personal goals and social re-entry. doi:10. It consists of small.

This gave rise to the three main stereotactic operations still in use today in view of their efficiency and limited side effects: (1) the anterior cingulotomy [4]. electroencephalographic (EEG) [8–12]. (2) resistance to pharmacologic and other conservative therapies. In this context. Jeanmonod et al / Neurosurg Clin N Am 14 (2003) 251–265 After the questionable and inordinately wide application of the prefrontal lobotomy [1. The target is reached using an anteroposterior angle of 60 and a mediolateral angle of 5 to 10 .16]. Postoperative relief percentages were given by the patients themselves. the central lateral thalamotomy (CLT) and the anterior medial pallidotomy (AMP). The patients. The goal of this article is to describe this approach at the surgical. and its stereotactic coordinates are located anteroposteriorly 2 mm posterior to the posterior commissure. in the generation of the neuropsychiatric disorders. (3) major (or endogenous) depression (7 patients) or bipolar mood disorder (2 patients). however. mediolaterally 12 mm lateral to the ventricular border. positron emission tomographic (PET) [13. and dorsoventrally 2 mm ventral to the intercommissural plane. and its stereotactic coordinates are located anteroposteriorly 4 mm posterior to the anterior commissure. and the third had a vagal nerve stimulator. The CLT lesion measures 4 mm in diameter over 12 to 14 mm in length. Spiegel and Wycis [7] explored the possibilities of stereotactic interventions in the mediodorsal nucleus of the thalamus and described positive results in psychotic patients. and (3) the anterior capsulotomy [6]. with a mean of 15 years. and electroconvulsive therapy (ECT) was applied in four patients before they were referred to us. histologic [15.19] and magnetoencephalography [20–23] and characterized by increased low-frequency generation. seven men and four women. as its name implies.252 D. clinical. In addition. Such surgical approaches have been efficient against major depression and OCD but not against psychosis. the second had a gamma knife thalamotomy. and often several. many groups realized the necessity of confining surgical interventions to the paralimbic (or mesocortical) domain [3]. the mediodorsal nucleus.14]. of the following clinical manifestations: (1) psychotic hallucinatory/delusional disorder (4 patients). increased low frequencies. We believe that the presence of a high percentage of complex atypical neuropsychiatric syndromes is a result of the fact that these patients exhibited particularly resistant disease forms related to widespread and strong TCD mechanisms and were thus at the forefront in terms of surgical indication. The CLT targets the posterior part of the CLN. (4) anxiety disorder (7 patients). These three procedures entail an interruption of the thalamocortical paralimbic frontal network. Surgical strategy We have applied the following criteria for surgical indication: (1) a protracted evolution of the disease (many years). and (3) a major impact of the symptoms on the patient’s quality of life. ranged in age between 21 and 59 years (with a mean age of 35 years) at the time of the first surgery. and dorsoventrally at the level of the intercommissural plane. One of them had a gamma knife capsulotomy. targets the paralimbic anterior and medial pallidum. and MEG levels. mediolaterally 6 mm lateral to the border of the third ventricle.2] in the first half of the twentieth century. and (5) ICD (4 patients). and radiologic [16] studies indicate spiking activities. we elected to normalize low-frequency production without affecting the anatomic integrity of the functional cognitive thalamocortical network. It is reached using an anteroposterior angle of 55 and a mediolateral . (2) OCD (8 patients). Our surgical approach is based on two premises: the central role of the oscillatory thalamocortical properties in the generation of normal hemispheric functions [17] and the existence as a physiopathologic basis to neuropsychiatric disorders of a TCD as evidenced by thalamic single cell recordings [18. Methods Patient group All patients (n=11) suffered from chronic therapy-resistant neuropsychiatric disorders. (2) the subcaudate tractotomy [5]. three patients came to us after prior unsuccessful interventions. including at least one. There are both older and more recent data demonstrating the physiopathologic and histologic involvement of paralimbic cortical areas and their corresponding specific thalamic partner. and hypometabolism as well as histopathologic and MRI changes in these domains. Indeed. The AMP. The duration of the disease before the first surgery ranged between 6 and 21 years. Available drug treatments were used without success in all of them. Two surgical targets have been developed. Early on.

3 Hz.21] as well as magnetic source imaging. We report on five patients with such full surgical treatment. two patients operated on only on one side on the basis of the discovery of a unilateral thalamic causal lesion (and. Two of these bursts are shown using a faster time scale. and two parkinsonian patients displaying endogenous neuropsychiatric manifestations (anxiodepressive episodes and ICD plus depression) and treated by a unilateral AMP.D. considered fully treated). Example of a unit activity recorded in the posterior part of the central lateral nucleus of the thalamus. All these properties indicate that these bursts are the consequence of the deinactivation of calcium T-channels as a result of cell membrane hyperpolarization. 1. Physiologic confirmation of target localizations within given geometric confines is provided by microelectrode recording (Fig. The AMP lesion measures 4 mm in diameter over 6 mm in length. Note that (1) the interspike interval (ISI) within a burst increases with each successive interval and that (2) the shorter the first ISI is in a burst. Fig. two patients partly operated on (the first with a left CLT/AMP and the other with a bilateral CLT). These features are quantified in the two lower histograms. Upper row: the discharge is composed of a series of recurring bursts of action potentials at a frequency of 3. Jeanmonod et al / Neurosurg Clin N Am 14 (2003) 251–265 angle of 20 . Figure 2 displays the CLT and AMP lesions as seen on our stereotactic atlas [24] and MRI. in the absence of evidence to the 253 contrary. On the right. the duration of the first ISI in a burst shows a tight inverse relation to the number of following spikes within this burst (fitting with a logarithmic function). The general surgical goal was a bilateral coupling of CLT and AMP. Analyses included power spectra and coherence studies [20. plotting of the duration of ISIs as a function of their position within the burst illustrates the progressive lengthening of successive intervals within bursts composed of an increasing number of action potentials. the larger is the number of spikes within this burst. the so-called low-threshold calcium spike bursts. 1) as well as by macrostimulation. Magnetoencephalography Pre.and postoperative MEG recordings were performed in three patients. On the left. revealing their intrinsic characteristics. .

MA) on a Linux (Red Hat. and the sample rate was 508 Hz. The electrocardiogram was simultaneously recorded digitally for off-line heartbeat artifact rejection. Spontaneous brain activity was continuously recorded for 5 minutes while the patient reclined and was asked to stay alert with eyes closed or eyes open. VA=ventral anterior nucleus. The coordinates of atlas sections are 7. Artifacts emanating from cardiac and other distant sources were removed by the software in a channel-specific manner. Pf=parafascicular nucleus. NC) cluster computer system. A . parvocellular division. A whole-head. VLp(d. Cd=caudate nucleus. ZI=zona incerta. Jeanmonod et al / Neurosurg Clin N Am 14 (2003) 251–265 Fig. dorsal and ventral divisions. San Diego.e=internal and external pallidum. MDpc=mediodorsal nucleus. parvocellular division. CM=centre me´dian nucleus. CA) was used for all patients. the Fouriertransformed signals obtained with the multitaper method were expanded with the singular value decomposition for frequencies of interest.1 to 100 Hz. AV=anteroventral nucleus. In both series. Sagittal atlas projections (left column) and 2-day postoperative T1-weighted MRI images (right column) of central lateral thalamotomy (A) and anterior medial pallidotomy (B) lesions. PuT=putamen.2 mm (A) and 12 mm (B) lateral to the ventricular border. LD=lateral dorsal nucleus. Natick. VM=ventral medial nucleus. Vamc=magnocellular division of VA. The bandpass was 0. 2. Spectral analysis of 5-second windows using the multitaper technique and cross-correlation between spectral amplitudes at different frequencies was performed with in-house software and commercial Matlab 6 (Mathworks. MEG system (4D Neuroimaging. As for magnetic source imaging. and the crosses indicate the position of the posterior (A) and anterior (B) commissures. Scale bars: 2 mm in atlas and 10 mm in MRI. A complex space mode for each frequency was composed using the first five singular vectors. Vla=ventral lateral anterior nucleus. The lesions represented in atlas sections do not include the edematous area seen on MRI. Li=limitans nucleus.254 D. Stippled areas in the central lateral nucleus represent densocellular clusters. CL=central lateral nucleus. PuM=medial pulvinar. Raleigh. 148-channel. VPMpc=ventral posterior medial nucleus. GPi. ac=anterior commissure.v)=ventral lateral posterior nucleus. R=reticular nucleus. STh=subthalamic nucleus. sections are oriented with posterior to the left and the intercommissural plane (represented by an interrupted line in the left panels) horizontal.

caused by the concurrence of multiple acute mental stressors. he presents with 100% relief of the schizoaffective. and affective bipolar manifestations with a few ICD elements. after surgery. Patient 5. anxiety. The facts . only recently. suffered from a 21-year OCD coupled with major depression. Patient 4. from which he fully recovered over a few weeks. Figures 3 and 4 display the patient’s MEG findings before and 3 months after surgery. suffered from a 14year syndrome characterized by the coupling of an OCD with major depression in addition to anxiety and psychotic elements. He underwent surgery on the left side only on the basis of the discovery of a small. smoothed solutions were linearly interpolated onto the tessellated cortical surfaces of a sealed MRI previously segmented using Free Surfer [27]. he presented with two 255 episodes of agitation. The current density solutions were smoothed with a three-dimensional gaussian kernel. OCD. Noise reduction was performed with Tikhonov regularization using the generalized cross-validation criterion. Medication is being tapered slowly in view of its 20-year use. Patient 2. born in 1956. sweating. with activation of powerful guilt and feelings of self-insufficiency. Jeanmonod et al / Neurosurg Clin N Am 14 (2003) 251–265 volumetric source space was constructed using the averaged MRI MNI-152 [25] provided in SPM99. The lead field operator was computed using a spherically symmetric volume conductor model. One and a half year later. She still experiences moderate to strong episodes of reactive depression based on marked insufficiency feelings. and unfulfilled personal wishes. At a follow-up 2 years after the bilateral CLT/AMP. the patient is currently in a withdrawal process from benzodiazepine dependence marked by anxiety. Patient 6. she described complete relief of her obsessive manifestations and was shaken by the emptiness left by their disappearance. probably developmental. anxiety. Independence level and daily activities have increased significantly. Voxels with a gray matter probability higher than 0. had a 20-year history of a schizoaffective disorder characterized by delusional. the patient presents with complete relief of the OCD. which is still present 2 years after surgery. she complains about obsessive ideas that she has great difficulty in describing. born in 1980. including schizoaffective (delusions and bipolar disorder) and anxiety disorders as well as ICD and OCD. Anxiety and impulse control problems are centered on year-long difficulties in social and familial interactions. born in 1970. hallucinatory. he experienced progressive and then complete symptom relief. suffered from an OCD associated with outspoken vegetative manifestations (ie. Over a few weeks after the second CLT/AMP. confusion. This probabilistic source space was transformed onto a head-centered coordinate system and scaled. he enjoys complete relief of his OCD symptoms. She shows signs of an anxiodepressive state and. inactive abnormality in his left mediodorsal thalamic nucleus. there is relief of the psychotic elements. In the context of a preexistent substance use disorder. For visualization. His drug intake could be markedly reduced. Although the patient could never conduct social interaction for more than a few minutes before surgery. he can have hour-long discussions with members of the team. Inverse source imaging of the space modes at frequencies of interest were computed using a recursively weighted minimum-norm algorithm [26]. and psychotic manifestations and has redeveloped a social and professional life to a degree inconceivable before surgery. born in 1971. At the follow-up 6 months after the bilateral CLT/AMP and with a significant drug reduction. daily vomiting) and anxiety for 6 years before surgery. born in 1973. and only moderate improvement of the anxiety and ICD. Six years after the bilateral CLT/AMP. experienced a 10-year history of a complex neuropsychiatric syndrome. At a followup of 1 year after the left-sided CLT/AMP.4 were selected. vascular. major depressive. and depression resulting from personal and social stressors. His clinical improvements correlate with the MEG recordings shown in Figure 3 before and 1 year after surgery. Immediately after the second CLT/AMP. and ICD symptomatology but with only 50% relief of his anxiety and hyperactivity.D. Results Patient descriptions Patient 1. He experienced only one reactive depressive episode in the postoperative phase. was affected for 14 years by a complex syndrome with OCD and ICD as well as anxiety and psychotic disorders. His global improvement estimation is 60%. at least a 50% reduction of the OCD. Patient 3. motivation for psychotherapeutic treatment. frustrating/disappointing confrontations. born in 1957. In the interim period.

Jeanmonod et al / Neurosurg Clin N Am 14 (2003) 251–265 Fig. The postoperative power spectra of Patient 7 (middle left) and Patient 1 (middle right) are mainly characterized by a reduction in theta and beta power. Coherence was analyzed applying a cross-correlation analysis of the variation along time of the spectral power for frequencies between 0 and 40 Hz. and the right panel shows coherence for the same patient after surgery. (See also Color Plate 1. Power spectra (four top panels) and coherence plots (three bottom panels) are displayed. The top right panel presents the power spectrum of Patient 2. A peak shift into the theta domain and power increase in the theta and beta bands are demonstrated for TCD patients in comparison to controls. Magnetoencephalographic data from three patients in this series. and tinnitus patients. The bottom left panel shows such coherence for controls. The top left panel shows the power spectra from controls (blue) and thalamocortical dysrhythmia (TCD) patients. the middle panel shows coherence for Patient 2 before surgery. neurogenic pain. including neuropsychiatric as well as parkinsonian. with a postoperative (blue) curve demonstrating the reappearance of the alpha peak and the power decrease in the theta and beta bands.) .256 D. allowing reappearance (Patient 7) or better visualization (Patient 1) of the alpha peak. 3.

and (2) the mismatch between what is/has been and what should be. There have been variable but overall 257 significant improvements in daily activities and independence. As for the previous patient. associated with marked feelings of self-insufficiency. an activity that would have been impossible before surgery without his parents). For 5 years after a right-sided AMP coupled to a subthalamotomy to alleviate his motor syndrome. suffered in the context of a parkinsonian disease from a 16-year neuropsychiatric depressive disorder and ICD. the patient describes an at least 50% improvement of his OCD. resulting in a state of massive anxiety as a result of the emptiness after suppression of the constant obsessive ideas. A conceptual rigidity with lack of adaptation to the new situation was seen in two patients. as for Patient 1) was performed. One year and a half later. with strong improvement of one OCD element (obsessive social component) but lack of improvement of another (obsessive cleanliness). 70% relief of depression and pain. disease progression at both motor and neuropsychiatric levels poses the question of surgical restabilization of the other hemisphere. a differentiated result is observed.D. born in 1970. The global improvement rate is 70%. suffered from an 18year OCD associated with an anxiety disorder and depression. suffered from a 13-year OCD associated with major depressive episodes. vascular anomaly in the left mediodorsal nucleus. born in 1937. 80% relief of dyskinesias. There were no postoperative major depressive episodes. Patient 9. and (4) frustration and depression (1 patient). He presented 80% to100% relief of this disorder during a year and a half after a left-sided CLT/AMP coupled to a pallidothalamic tractotomy [19]. 90% relief of anxiety. pain. all patients demonstrated significant to complete relief from their neuropsychiatric ailments. suffered from a 20-year neuropsychiatric syndrome characterized by obsessive. . ranging between 50% and 100% improvement. born in 1970. Patient 7. This psychodynamic context was complicated by the presence of an excess in self-demands so as to comply with a strict and perfectionist picture of herself. born in 1944. born in 1971. tinnitus. We observed the following postoperative reactive manifestations: (1) anxiety (1 patient). There is a clear-cut increase of independence and 60% improvement of daily activities (the patient traveled two times on his own from the Midwest to New York City and found the office of one of the authors. The acute postoperative evolution was characterized by total control of the OCD symptomatology. and a vagal nerve stimulator brought no relief but only an increase in anxiety. During the 2 years after the bilateral CLT. A second CLT/AMP is being considered. Multiple ECT sessions were applied without results. probably old. Patient 10. (3) anxiety and nonacceptance/frustration (3 patients). Summarizing (Table 1). Recently. MRI examinations showed the presence of an inactive. a drug reduction has not yet been possible. Jeanmonod et al / Neurosurg Clin N Am 14 (2003) 251–265 that she has no memories. the patient presented with complete relief of both motor and neuropsychiatric symptoms. 20% relief of tinnitus. there have been fluctuating degrees of response of the OCD symptoms. but only a slight (30%) improvement of anger. anxiety. of obsession-free moments and that several firstdegree relatives also suffer from neuropsychiatric disorders provide a formidable barrier to adjustment of her perspective toward a disease-free existence. we await complementary evidence to ascertain better the necessity of a bilateral AMP. and dyskinetic elements. disease progression at both motor and neuropsychiatric levels raises the possibility of a right-sided intervention. At a follow-up of 9 months after the first left-sided CLT/AMP. At the moment. Given this context. The patient’s spontaneous interpretation concerning the fluctuating reappearance of obsessions was that her anxiety was so severe that she herself reactivated some of them to relieve her inner tension. and depressive disorders associated with anger. (2) anxiodepressive state (3 patients). which was submitted to gamma knife surgery with no change in symptomatology. even as a child. Repeated ECT and a gamma knife bilateral capsulotomy did not improve the symptomatology and may have triggered anxiodepressive manifestations. Patient 11. He is presently on one antidepressant drug at a low dose only and is undergoing psychotherapy. His MEG recordings before and a year and a half after surgery correlate well with these clinical results and are shown in Figure 3. suffered in the context of a parkinsonian disease from a 13-year major depressive disorder characterized by unmotivated abrupt anxiodepressive episodes. A unilateral left-sided CLT/AMP (considered in principle to be sufficient. The patient’s evolution is colored by (1) the fear that something still may progress in his brain and jeopardize his improvements and future. Patient 8.

PSY.31 43 36 21 28 27 30 31 29 59 50 Patient 1 2 3 4 5 6 7 8 9 10 11 10 20 14 14 6 21 20 18 13 16 13 Disease duration (years) + + + + ECT + + GK + VNS L Thal/MD L Thal/MD Causal lesion PSY/BIP/ANX/OCD/ICD PSY/BIP/ICD OCD/DEP/ANX/PSY OCD/ICD/ANX/PSY OCD/ANX OCD/DEP OCD/ANX/DEP OCD/ANX/DEP OCD/DEP DEP/ICD ANX/DEP Symptoms L CLT/AMP Bilateral CLT/AMP Bilateral CLT/AMP Bilateral CLT/AMP Bilateral CLT/AMP Bilateral CLT/AMP L CLT/AMP L CLT/AMP Bilateral CLT R AMP L CLT/AMP Operation Relief (%) 100 100 100 100 100 100 90 100 70 100 100 100 100 90 90 100 <50 <50 0 100 50 100 0 >50 <50 75 50 100 100 100 PSY DEP/BIP OCD ICD ANX Abbreviations: ECT. obsessive-compulsive disorder. MD. electroconvulsive theraphy. central lateral thalamotomy and anterior medial pallidotomy. CLT/AMP. vagal nerve stimulator. Thal. Jeanmonod et al / Neurosurg Clin N Am 14 (2003) 251–265 . Age (years) Table 1 Overview of patient data 258 D. mediodorsal nucleus of the thalamus. psychotic disorder. thalamus. frustration. left. anxiety disorder. right. ANX. DEP. VNS. R. L. GK. gamma knife. major depression. OCD. F. impulse control disorder. ICD. Percentages correspond to relief estimation by the patients. bipolar affective disorder. BIP.

Fig. 4.21] support the proposition of such an edge effect.12] and may be directly correlated with cortical [14] and thalamic [13] hypometabolism in PET studies. 5): 1. as demonstrated in psychotic patients [8. 3.30]. as evidenced by an increased multifrequency coherence between theta and beta domains. there was an increase of beta power and of the coherence between the theta domain and the alpha and beta (9–13 Hz and 13–30 Hz) ranges. The final step in the description of this syndrome is the proposed existence of activation of high-frequency (beta and gamma) cortical domains as the result of an asymmetric corticocortical GABA-ergic collateral inhibition [20. causing the production of low-threshold calcium spike (LTS) bursts by thalamic (see Fig.29. an ‘‘edge effect’’ as observed in the retina as a result of lateral inhibition. would result from the asymmetric inhibition between a low-frequency cortical area and neighboring high-frequency domains. Surgical control of the thalamocortical dysrhythmia Considering the central role of resonant oscillatory thalamocortical properties in the generation of normal hemispheric functions. 3) indeed demonstrate increased theta power. Our coherence studies [20. this paralimbic theta focus disappeared. such a source anomaly may be found in the paralimbic cortical domain or in the paralimbic striatum [16. The Rolandic mu rhythm. and emotional instability [28]. The proposed mechanism. anterior parahippocampal. orbitofrontal. There was also a reduction of beta power. emotional. This hyperpolarized state is the source of calcium T-channel deinactivation [31]. was also described in individuals with mild to moderate anxiety. Hyperpolarization through disfacilitation and/or overinhibition of thalamic relay and/ or reticular cells by the disease source. 3). providing a ring of reduced inhibition onto. which is considered a normal EEG component. This activation of high-frequency areas might express itself through abnormal EEG spiking activity. Its existence has also been revealed by EEG studies [9. slow rhythmicity. In psychotic disorders. This TCD is characterized by the following sequential set of events (Fig. 1) and/or reticular neurones. After surgery. namely. with the presence of a variable number of identifiable peaks (see Fig. 2. and thus activation of.D. Recurrent divergent corticothalamic and reticulothalamic projections back to the thalamus provide the necessary coherent diffusion of these frequencies to various related cortical areas. Discussion The neuropsychiatric thalamocortical dysrhythmia Evidence is presented both at the single cell and MEG levels that a TCD.21]. which is an event seen with much less prominence in the normal brain. being locked in the theta lowfrequency domain by their ionic properties. psychotic and affective disorders as well as ICD and ICD. we propose a surgical approach that does not imply a reduction of functional thalamocortical loops and is based on regulation toward normality of . There was maintenance of well-defined bilateral mu Rolandic activity as well as discrete temporal and occipital. Neurones in such a state impose a slow rhythmicity to the thalamocortical loops they are part of. In terms of source localization. After surgery. and basal medial prefrontal cortices. The possibility of the alternative triggering of a neuropsychiatric disorder by a chronic dysfunction of the cognitive 259 network (comprising conceptual. with the cortical anomaly providing corticothalamic disfacilitation and the striatal anomaly providing pallidothalamic overinhibition. the cortex surrounding this low-frequency area. Interfrequency coherence came down close to that of controls. we observed a clear-cut decrease in theta power down to values comparable with those of controls and the reappearance of a normal alpha peak at or above 10 Hz. probably normal. Our MEG recordings (see Fig. underlies certain of the main neuropsychiatric disorders. In addition. mnestic. 4 displays in Patient 2 the presence of a domain of increased theta activity (selected according to his power spectrum between 4 and 10 Hz) in the right-sided medial and lateral temporopolar.11]. Jeanmonod et al / Neurosurg Clin N Am 14 (2003) 251–265 Magnetoencephalographic data Preoperative MEG recordings demonstrated a marked increase of power in the theta domain (4–8 Hz). irritability. as previously defined [18–23]. and attentional functions) is discussed later in this article.

Jeanmonod et al / Neurosurg Clin N Am 14 (2003) 251–265 .260 D.

each with its specific (yellow) and nonspecific (green) thalamic relay cell projecting to the cortex and reticular nucleus. At the cortical level. Magnetoencephalographic source localization for Patient 2. thus resulting in low-frequency thalamocortical oscillation. (See also Color Plate 3. For this purpose. Either thalamic cell disfacilitation or overinhibition (central module) hyperpolarizes thalamic cell membranes. Schematic diagram of the thalamocortical circuits that support the thalamocortical dysrhythmia mechanisms. and basal medial prefrontal areas. The rationale and general results of this operation are in full accordance with long-standing electrophysiologic studies [33] demonstrating the progressive spread of the b Fig. one (blue) pyramidal cell with its corticothalamic and corticoreticular output. A similar if less welldefined procedure has been known as medial thalamotomy since the dawn of stereotactic neurosurgery [32]. (See also Color Plate 2. The thalamocortical dysrhythmia of this patient is localized in the right-sided paralimbic domain comprising the temporopolar. Three thalamocorticothalamic loops are thus displayed. results in high-frequency coherent activation of the neighboring (right) cortical module (edge effect).D.to 10-Hz activity onto the patient’s MRI examination before (eight top images) and after (eight bottom images) surgery. low-frequency activation of corticocortical inhibitory interneurones (red).) dysrhythmic thalamocortical oscillations as documented by our MEG data. the goal of which is to make subcritical the increased low-frequency thalamocortical generation. orbitofrontal. we use small pallidal and medial thalamic lesions. 4. This allows the deinactivation of calcium Tchannels and the generation of low-threshold calcium spike bursts. Divergent corticothalamic and reticulothalamic projections (from central module to left module) provide the substrate for low-frequency coherent discharge of an increasing number of thalamocortical modules. with their feed-forward thalamocortical activation and their respective recurrent feedback corticothalamic and corticoreticulothalamic activation inhibition. This low-frequency focus disappears after surgery. Three thalamocortical modules are shown. The conjunction of the specific and nonspecific loops is proposed to generate increased cortical activation through temporal coincidence. anterior parahippocampal. Projection of 4. by reducing lateral inhibitory drive.) . which can be accomplished by a carefully placed and restricted lesion in the medial thalamus. and two reticular cells (red) with their projections back to thalamic relay cells. Jeanmonod et al / Neurosurg Clin N Am 14 (2003) 251–265 261 Fig. to move the dynamic properties of the system away from the increased low-frequency coherent activity. The CLT has as a goal a reduction of low-frequency overamplification and oversynchronization. in other words. 5.

The second target. The results presented here for 11 patients unequivocally demonstrate that this surgical approach has significant therapeutic value against symptoms pertaining to psychotic. however. mnestic. we did not observe permanent classical postoperative prefrontal deficits. depression. orbitofrontal. however. and attentional functions. Accumulating evidence from EEG and MEG studies underscores the fact that conceptual and mnestic [10. where more than 95% of the cells produced spontaneous LTS bursts (see Fig. a clear-cut limit concerning reactive. There is. which. This is a reasonable conjecture given the fact that patients experience no obvious reduction in sensory. emotional. we restrict the lesion to the affected site and spare the other medial thalamic subnuclei. we mean conceptual. such as capsulotomies. major depressive. which may cause long-term deleterious effects (eg. As expected given the nature of the lesions. Postoperative reactive decompensations are understandable by the fact that the disinhibitory approach presented here may result in a momentary hyperactive phase during the acute postoperative period.37–39] as well as emotional [40] activation in human beings increases low-frequency theta activity. If this is confirmed. 1) and/or were unresponsive to stimuli [18]. consequently. including prefrontal and perceptual functions. This process serves to reinforce the TCD. however. A future systematic study will address this issue concerning the coupling of CLT and AMP lesions. posterior parietal. We have taken advantage of physiopathologic data to focus our medial thalamotomy target on the posterior part of the CLN. in which the goal is a reduction of cortical activity through thalamocortical disconnection. Thalamocortical slow burn Evidence of progressive cortical [36] and thalamic [16] atrophy has been documented in patients suffering from neuropsychiatric disorders. the AMP. One likely mechanism for such morbidity is a persistent increase in calcium entry into the thalamic cells generating LTS bursts. The observed patient histories already dispel the possibility of adverse postoperative prefrontal abulic manifestations or personality changes. This phenomenon leads to thalamocortical self-destruction. Furthermore. seem to have taken over the function originally fulfilled by the CLT. a sort of ‘‘slow burn’’ with loss of neuronal substrate. By doing so. The neuropsychologic-sparing quality of CLT has been documented in a large group of patients suffering from other TCDs (manuscript in preparation). to more LTS burst generation and more low-frequency production. A low-frequency increase may thus arise either on the basis of a disease-related or endogenous abnormal input to the thalamus (as the result of a micro. and bipolar disorders as well as OCD and ICD. this reduction in inhibition (or disinhibition) is attained by targeting the paralimbic anterior internal pallidum [30]. over time. cingulotomies. In the case of neuropsychiatric disorders. motor. as opposed to endogenous. The cognitive factor By cognitive. the system may fall into a self-reduction mode. via calcium-triggered apoptosis). Jeanmonod et al / Neurosurg Clin N Am 14 (2003) 251–265 cortical recruiting response during low-frequency stimulation of the medial thalamus. or cognitive abilities after CLT. and frustration. and neither patients nor families complained about a personality reduction or alteration. cingulate. as the level of thalamocortical and corticothalamic activation decreases and exposes thalamic cells to more disfacilitation and. which were fully compatible with her anxiodepressive postoperative reactive profile [35] and happened in the context of a maintained general cognitive performance and improved general IQ. the surgical treatment of a TCD would not only provide symptom relief and disease control but would additionally acquire a protective role. Under these conditions. addresses the issue of reducing thalamic excess inhibition. symptoms in the domains of anxiety. and medial temporal areas. the thalamic nonspecific system has been shown to serve as a temporal coincidence activator when summed with the thalamic specific input to the same cortical site [34]. Patient 6 presented with neuropsychologic impairments in the executive and memory domains. insular. and subcaudate tractotomies. which are supported by the activation of the widespread paralimbic (or mesocortical) and association networks [3] located in dorsolateral and medial prefrontal. Patient 3 presented with clear-cut neuropsychologic improvements in a large number of domains.262 D. the continuous high-frequency cortical activation caused by the edge effect provides a framework for the development of excitotoxicity of cortical cells. In addition. This condition serves to emphasize the fundamental difference between the procedure described here and the other available surgical approaches.or macroscopic brain anomaly) or via .

Such postoperative reactive manifestations are represented by anxious or anxiodepressive states and are also characterized by nonacceptance/ frustration postures possibly leading to depression or by lack of adaptation to the new situation. that the evidence for benign and efficient surgical intervention against the neuropsychiatric TCD syndrome is already compelling. and 7). and (4) symptoms fitting well with the personal internal and situational profile (eg. with the latter providing support for the integration of the new situation as well as the resolution of old unresolved issues. 31:1–29. they may be regarded as mirroring an uninterrupted continuum of uncontrollable and thus disturbing low-frequency distortions of the cognitive network. One possibility is that these manifestations may be responsive to surgery in the measure in which they are endogenous. and V. In this sense. and frustration is even self-entertained. 6. Along this line. Nonacceptance of a given situation recedes only when the person has decided that it should indeed recede.D. Psychotic and affective (bipolar and major depressive) disorders described are viewed here as having an endogenous origin and are well controlled by the CLT/AMP. Transorbital leucotomy. and frustration may even increase for a time after surgery. Patient 6). postoperative anxiety reactions may be initially strong but amenable to external and internal relieving factors and may thus subside relatively quickly and easily (Patients 1 and 2). Jeanmonod et al / Neurosurg Clin N Am 14 (2003) 251–265 a ‘‘top-down’’ mechanism driven by mental activity and generating low frequencies on a reactive basis. and 7). (2) the genesis of chronic reactive psychiatric disorders with a long-term unsolved mental conflict at their source. more clinical experience must be amassed to define in detail the possibilities of this surgical approach in disabling neuropsychiatric disorders. The potential appearance of strong postoperative reactive manifestations requires a close association between surgery and psychotherapy. the question may be raised as to their origin and their resistance to surgery in view of the fact that anxious and depressive symptoms on the other side may respond to surgery. however. As for the postoperative anxiodepressive and frustration- 263 related manifestations. We propose. Dodd for instrumentation. Fear. despair. Lancet 1948. Patient 9). C. 2. This finding provides a substratum for (1) the appearance of reactive phenomena in the postoperative period. 4. Encephale 1936. 6. (3) difficulties in describing the symptoms (eg. Indeed. Summary Clearly. Patients 1. Patients 4. and 7). Our experience has shown that this situation provides a new chance to approach and solve long-standing resistant emotional conflicts by psychotherapy. Distinctive characteristics indicating a reactive basis to these observations are (1) symptomatology not present before surgery in relation to the new postoperative situation (eg. J. References [1] Freeman W. however. Les premie`res tentatives ope´ratoires dans le traitement de certaines psychoses. . This mental profile may thus represent a stronger challenge for the relevant network and correlate with more difficult and protracted postoperative evolutions (Patients 3. but the issue of the endogenous or reactive origin of these disease entities remains as yet unresolved. Streit for histologic work. 6. representing a powerful cognitive source for increased lowfrequency activity necessitating intensive psychotherapeutic support. OCD and ICD manifestations also receded after surgery. To the contrary. Lebzelter for psychotherapeutic support to the patients. thus presenting the observed resistance to surgery. Bu¨gler for secretarial help. Another way of viewing this is that whereas all anxiodepressive and frustration-related disorders are of reactive origin. 4. (2) large variations across time and according to situations (eg. Our clinical observations show that surgery can provide marked reduction or even suppression of the disease-related TCD but does not address the cognitive reactive manifestations of the patient to her/his new postoperative situation. [2] Moniz E. 3. expectations. frustration/anger and conceptual rigidity do not cause direct suffering. and (3) the grouping of many if not all neuropsychiatric disorders into a dynamic realm of thalamocortical dysfunction. the loss of control that may occur in any healthy human brain during strong stimulus-bound transitory emotional reactions may be viewed as a short-lived and in this sense not unhealthy (although sometimes quite undesirable) TCD phenomenon. some of them may be self-entertained. Acknowledgments The authors thank V. whether their triggering mechanism is endogenous or reactive. 2:371–3.

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and several other relevant parameters using validated psychiatric and neuropsychologic scales. and P. PhDa. an ethical review board. Although psychiatrists and psychologists blindly evaluated obsessions. Antwerp. The authors acknowledge the FWO (project G. MScEngb.N.) is also filing a patent together with Medtronic. MD. anxiety.kuleuven.C. Using strict selection criteria. Belgium Electric stimulation of the anterior limbs of the internal capsule was introduced as a treatment for patients with severe incapacitating and treatmentresistant obsessive-compulsive disorder (OCD) by two groups that collaborated closely: the Belgian group. the patients were screened by a committee for neurosurgery for psychiatric disorders. which consisted of a psychiatric branch at the University of Antwerp and a neurosurgical branch at the Katholieke Universiteit Leuven. All rights reserved.3]. and an expert committee [3]. two quadripolar electrodes (Model 3887 [4-mm contact spacing. The electrodes were placed 3 mm anterior to the anterior border of the anterior commissure and entered the brain via precoronal burr holes. Pisces Quad Compact. doi:10.nuttin@uz. UZA. The investigational treatment was approved by the Leuven and Antwerp local hospital ethical standards committees on human experimentation and was in accordance with the declaration of Helsinki of 1975 (1983 revision and subsequent revisions). The stimulation targets were similar to those aimed for in the anterior capsulotomy [1.be (B. Belgium d Department of Psychiatry. Belgium c Department of Neurosciences and Psychiatry.0273. UZA. Katholieke Universiteit Leuven and University Hospitals Leuven. and the Swedish group at the Karolinska Institute in Stockholm [1. MD. The authors (B. compulsions.see front matter Ó 2003.) have been previously involved in research and/or education that was in part sponsored by Medtronic. Nuttin).Neurosurg Clin N Am 14 (2003) 267–274 Electrical stimulation of the anterior limbs of the internal capsules in patients with severe obsessive-compulsive disorder: anecdotal reports Bart J. Minneapolis. The three most ventral stimulating contacts were placed in the internal capsule. Katholieke Universiteit Leuven.N) and Research Council of the Katholieke Universiteit Leuven (project OT-98-31 and VIS-project ZKB1159) for financial support.ac.N. L.).*. Leuven. * Corresponding author. Antwerp. Elsevier Science (USA). some unpublished psychiatric and neurosurgical clinical observations may enlighten and document certain effects of this kind of brain modulation..1016/S1042-3680(02)00117-1 . Herestraat 49. Materials and methods In six patients with severe incapacitating and treatment-resistant OCD. Medtronic) (Medtronic Inc.N. Nuttin.G. and the fourth one was sited dorsal to the internal capsule. 3-mm contact length]. B-3000..97. Paul Cosyns. MN) were implanted into the anterior limbs of the internal capsules by one of the authors (B. depression. Loes Gabriels.. MD. Although it was clearly shown that anterior capsular stimulation induces beneficial effects in patients with severe OCD. PhDd a Department of Neurosurgery. Belgium b Department of Psychiatry. One author (B. Drsc. Kris van Kuyck. Leuven. and the Medtronic QUEST program (L1170) for providing the stimulating devices. E-mail address: bart. Patients gave written and witnessed informed consent.J.2]. we only report here on some observations that interested the authors 1042-3680/03/$ .

He could not take a bus.) changed the stimulation parameters (amplitude varying between 0 and 10. We never started chronic stimulation if these effects were interpreted as side effects and if they persisted longer than 1 minute.C. and the compelling urge to touch. or drowning. these authors as well as the patients and their families were blinded for stimulation condition. Nuttin et al / Neurosurg Clin N Am 14 (2003) 267–274 and on responses to stimulation subjectively reported by the patients. During all evaluation sessions. Her parents always had to stay within eyesight or. Subjects The first patient (Patient 1) was a 35-year-old man who suffered from many different obsessions and compulsions. washing. If the patients received a programming device. the patients still did not know when the stimulator was automatically switched on or off. She also hoarded old magazines and empty cigarette packs. one author (B. a 52-year-old woman. stabbing. He also had a fear of writing compromising things. and pulse width varying between 60 and 450 microseconds) and the stimulation contacts of the quadripolar electrodes. a 40-year-old woman. objects. and a nurse came daily to help her with this routine. He had an excessive fear of hair growth and detested aging.’’ He avoided being in a quiet environment and listened to loud beat music whenever he could. because his habit of always checking in the back mirror made driving dangerous. strangling. She had excessive and intrusive sexual thoughts about masturbating. had to talk to her continuously to reassure her. He had excessive checking compulsions and cognitive escapes (rationalizing) to counter these aggressive thoughts. and she developed a whole range of compulsions to prove their existence and reality. Washing herself had become impossible. Effects that appeared immediately after starting anterior capsular stimulation are presented in the following list. Unless otherwise defined in the text. He had strong ideas that a road accident or drowning could have happened to someone and that he would not have given the necessary assistance or would not have alerted the emergency services. including washing. and things might not be real preoccupied her. Observations and subjective reports Acute changes with stimulation in the early postoperative period Bilateral square wave pulse stimulation was started immediately after surgery. and when in a car. Patient 2.5 V. and a compelling urge to ask questions were omnipresent. hypersomnolence. germs. His ‘‘major’’ current obsession was ‘‘the sound of silence. He contacted his sister (or the police) several times a day to check that no accidents had taken place where he had passed. the patients may have guessed that the stimulator was on because of the simulation-induced effects. A comorbid undifferentiated somatoform disorder was present with persistent complaints of vertigo. buying compulsions.N. Compulsive hand washing. and P. Two other authors (L. Patient 6 was a 37-year-old man who suffered from mostly aggressive obsessions. or any harmful household product. checking. and household items (white-spirit). counting.J. he laid on the back seat with his eyes closed and a towel covering his face. however. Going to the toilet took an hour (two or three times per day) and required assistance from her mother both day and night. they were not blinded. Subjective feelings reported by the patient  Anxiety: the patient may be tense or may be so anxious that he/she experiences an impression of death .) evaluated the patients. tar. frequency varying between 5 and 130 Hz. In some conditions. and counting rituals. He had continuous intrusive thoughts and flashing images of harming others by poisoning. He could not drive a car anymore. Patient 4 was a 35-year-old man who had strong fears of harming others by not being careful enough and obsessions about poisoning others by contamination with nicotine. Patient 3 was a 38-year-old woman who had excessive toilet. She had an urgent need to ask for reassurance and to repeat sentences and statements for herself. In that condition. He avoided having pens and paper in the same room and could only read the newspaper when no ballpoint pen was near. when this was not possible. and loss of energy. suffered from excessive concerns with urine and feces and obsessive thoughts about harming others after having touched herbs and plants. The thought that persons.268 B. and rereading-rewriting-recalculating rituals as well as concerns with dirt. Patient 5. had severe contamination obsessions and was overly concerned with bodily waste and secretions.G.

B. patient feels that the stimulator is working like a compact disk that is turning. the therapeutic effects were not at all pronounced in either Patient 1 or Patient 2. although some of these effects remained during continuous stimulation. patient has an impression of being in a tunnel. as if he was going to pass out. Patient 5. Gradually. depression.5 V. Patient 1 reported paresthesias in his face. The same stimulation parameters were used in Patient 4. patient has a black visual field on the left side and a white one on the right side. Clear improvements in obsession. He once reported seeing a beautiful woman exactly at the moment the stimulator was switched on.J. he felt uncomfortable. and/or legs) Tingling sensation (in the face or chest) Feels something in the throat Difficulty in swallowing Headache Sleepiness Peculiar thoughts (eg. there were also occasions when the patient did not report anything when being stimulated at 10. patient thinks about tennis) Visual symptoms and visual hallucinations (eg. the wall seems to come closer. Nuttin et al / Neurosurg Clin N Am 14 (2003) 267–274                      Relief of anxiety Feeling of happiness Sadness Nausea General unpleasant feeling Strange feeling Feeling of fainting Feels something in the head Sensation of warmth (in the face. patient sees a certain person he/she has heard about but has never seen sitting beside her/him. the amplitude necessary to induce those beneficial effects rose to 6.5 V. although he could state no reason for this cheerfulness. Apart from the feelings and signs mentioned here. Patient 4 and Patient 6 uttered verbal perseverations for about 10 to 15 seconds (perhaps the equivalent of recurrent obsessive thoughts and repetitive compulsive acts). The patient himself did not feel any improvements in his obsessive thoughts during this first stimulation episode. At first. everything becomes darker. . but a friend and his mother both remarked that he seemed less tense. patient wants french fries. compulsion. patient has an impression that the ceiling is dirty) Feels difficulty in breathing Becomes nervous and has the impression that time passes quickly Feeling of heavy legs Frontal pain One patient reported vaginal contractions on three occasions Objective signs noted by the observer            Patient makes a deep sigh Skin of the face turns red Sweating in the face and hands Patient says meaningless words during 20 seconds Patient repeats words or sentences continuously Repetitive movements with the hands Laughing or crying Yawning Patient speaks louder Orofacial or total body dyskinesias Dysarthria 269 The list includes subjective feelings and objective signs that appeared immediately after starting anterior capsular stimulation and may have disappeared within 10 to 30 seconds. Similar high voltages applied in Patient 1 and Patient 2 also induced more pronounced beneficial effects in those patients. patient has an impression that the room moves. and Patient 6 with similar beneficial effects as in Patient 2 and Patient 3. She was stimulated with either the three most ventral contacts programmed as cathodes and the uppermost contact as an anode or with all four contacts programmed as cathodes and the stimulator as an anode at 4 V using pulses of 210 microseconds at a frequency of 100 Hz. and anxiety were noted. feet. Patient 4 reported feeling happy and inclined to laugh. and 100 Hz or that the reaction was unclear. 200 microseconds. These effects were sometimes reproducible with similar amplitudes and sometimes not reproducible. When the stimulator was switched off for 3 days. Patient 1 started to comment on his noise obsession and felt worse. Immediately after stimulation with these parameters. It was only in Patient 3 that the authors saw marked acute changes as have been described elsewhere [1]. At higher amplitudes. chest. patient sees fog. everything becomes smaller. throat. patient sees black pieces of dust everywhere. An improvement in mood was induced by using the three most ventral contacts as cathodes and the uppermost contact as an anode with an amplitude of 3 V and with the pulse lasting for 210 microseconds at a frequency of 100 Hz.

talked.N. he said it was only a brief flash in his mind that had immediately disappeared. Respective follow-up times are 50 months (Patient 1). As an example. and 3 months (Patient 6). 47 months (Patient 3).5 and 10. She told us that if she programmed the amplitude to 9 V. To reduce battery consumption. 9 months (Patient 5). Patient 6 heaved several deep sighs before starting his perseverative sentences.5 V when she visited someone. a condition that she disliked. He talked a lot more and faster than before. When stimulation was first turned on. the stimulator was programmed so that it was automatically switched off at night and switched on at 6:00 AM in Patient 2 and Patient 3. On days with stimulation. Patients 2 through 6 reported spontaneously that several symptoms had improved during the period that stimulation actually took place. a feeling she described ‘‘as if she loses something. and were trapped in obsessional thoughts and mental compulsions (constructing and repeating sentences or counting to decrease restlessness) as severe as before surgery. but were tired as a result of the loss of sleep at night. when battery power resumed. they felt better.5 V for the sake of saving battery time made her a bit more anxious and worried. Stimulation at 100 Hz or 130 Hz and stimulation at higher pulse widths (210 microseconds up to 450 microseconds) induced better symptom reduction than stimulation at 5 Hz or at a pulse width of 60 microseconds. 7. To decrease battery consumption even more. she would start dancing on the table. Conversely. During the day. were anxious. He felt casual but not indifferent. Programming the stimulators for 1 minute on and for 1 minute off induced a happy face for 1 minute with a smile and a sad face during the following minute. using the three most ventral contacts as cathodes and the uppermost contact as an anode. symptoms were comparable to the prestimulation level. Patient 2 never wanted to use the programming device. could not continue sleeping. as with the continuous stimulation regimen. The patients did not like this kind of stimulation algorithm because they never felt continued relief of anxiety and the sudden mood switches made them feel completely unnatural.270 B. and this was tested for 30 minutes in two patients.5 V when she was at home.J. the symptoms were reduced in Patient 1 and Patient 3. Patient 3 used 6. tense and depressed. They were allowed to change amplitude and pulse width. a programming device was given to Patient 2 and Patient 3 as one of the strategies. Nuttin et al / Neurosurg Clin N Am 14 (2003) 267–274 When prompted to elaborate on this. They both asked to get another stimulation paradigm after some days.5 V when she was in a crowd. programming the three most caudal contacts as anodes and the uppermost contact as a cathode. The upper amplitude and pulse width thresholds were determined by one of the authors (B. They could only continue sleeping after 6:00 AM. but both his friend and the . and 8. he felt his heart beating. doing the opposite in the same patients.’’ She chose 330 microseconds as the optimal pulse width and has been using this pulse width for more than 3 years now. Unilateral right-sided stimulation for 2 weeks with the stimulator on during 1 minute and off during the following minute did not improve symptoms as compared to the preoperative condition. had more energy. Many contact combinations were tried out. she noted that Patient 5 was in the best of spirits. 49 months (Patient 2). ‘‘No change’’ was noted during visits when stimulators were turned off. Patient 1 stated that he experienced only marginal or temporal benefit. The patients themselves were given the capacity to use high amplitudes and pulse widths only when they felt they needed it. Effects of continuous stimulation We evaluated the six patients on a regular basis and asked peers and family about each patient’s condition. He felt more light-hearted and stated that he did not see a reason why he would make his life so difficult. This higher amplitude immediately induced palpitations and an excessive need for sleep. She demanded much less reassurance than usual.) after ensuring that these parameters did not cause side effects in an acute setting. Both patients awoke at night about 1 minute after the stimulator was switched off. and laughed a lot. Decreasing the amplitude to 6. and he had difficulty in falling asleep. he felt restless and worked up. Patient 5’s sister kept a diary during the patient’s postsurgical hospitalization. again without the patient knowing. 28 months (Patient 4).5 V in all six patients 3 to 5 months after the intervention. With higher amplitudes. Manipulation of stimulation parameters The amplitudes necessary to induce symptom reduction rose to between 6. whereas frequency was kept constant at 100 Hz.

B. Patient 2 asked fewer questions and started to do part of the housekeeping (cleaning. He had been taking care of his wife and children for so long that he felt he deserved some relief and the right to engage in activities he had had to give up because of her disorder. She was a lot more dynamic. ironing. that his obsessions and compulsions were only products of his mind. Patient 6. She used clothes she had not dared to wear for many years. laundry. Validated tests using strict research paradigms have been submitted for publication elsewhere. She started to go to school and wanted to live on her own. She actually started to read the books she formerly collected and stored in the cellophane packing in which they came.J. she was expected to take up part of the responsibilities and regain some independence. A disequilibrium in the systemic environment of the patient in reaction to the changes attributable to stimulation has to be taken into account. He joined his family in a barbeque party without fear of burning others. She found it difficult to develop interests of her own and longed for the continuous closeness of her husband. She accompanied her mother to the cemetery on All Souls’ Day. She could re-enter her former bedroom. She continued to live with her parents because this was comfortable. and controlled less. She was in a better mood. but she took more initiative. She was living on disability benefits and controlled her own finances. was happier. where he had formerly dreaded the thought of having strangled or hurt one of the other children. His friend also noted that he seemed more peaceful and less preoccupied by his obsessions. she complained loudly each time someone switched the television on. She still felt the urge to ask for reassurance but could control it most of the time. After some weeks of stimulation. and regained her interest in art history. He certainly talked less about them and was less self-centered. attended cultural events. as if the noise obsession was still there but had become less intrusive. This was unthinkable before. He realized that he could resist the urge to control for accidents. He could postpone checking the parking lot and make short walks. Patient 5 was less anxious and less tense. She realized that living in her own apartment was financially unacceptable for the . which was previously impossible. She experienced overall a 50% reduction in contamination fears and washing compulsions. Conversely. the nurse who came to wash her before surgery only paid short reassuring visits but did not need to assist her anymore. had taken care of her for many years. and cooking) again. Going to the toilet was less time-consuming. and she also dared to touch a cleaning towel. He again 271 enjoyed going with his children to a playground or amusement park. After stimulation. together with her two sisters. Patient 3 became more independent and started traveling alone and abroad. Patient 5 felt much more self-confident and assertive during stimulation. Nuttin et al / Neurosurg Clin N Am 14 (2003) 267–274 authors observed a slight but definite improvement in mood. however. She stopped hiding for family meetings. Patient 3 reported a 90% decrease in obsessions and compulsions. and was not depressed. She continued to ask many questions. whereas before stimulation. and she did not insist on her mother’s assistance during the night anymore. because she would have become trapped in ideas of nonexistence. felt a lot more relaxed with stimulation. She had been subdued and lived with her parents. in whom follow-up is only 3 months. Patient 4 reported being more relaxed. she was not symptom-free and thus claimed that she could not accept full responsibility for herself and still needed help. felt much happier. read newspapers. She started listening to music again and enjoyed watching television. she wanted to decide for herself at what time she would come home at night. She could again enter rooms at home where she did not dare to go before surgery. but she sometimes wondered if she wanted to care for them when they became older and in need of help. It is clear that anterior capsular stimulation may improve some of the symptoms of OCD patients. Always being amid older people. was much less anxious. she also had trouble in building meaningful relationships with people of her own age. She also could not stand the fact that her sisters were sharing their deepest feelings with each other and wanted to take part in this. and that there was no real need to act on them. He readily finished his ‘‘to do’’ list of chores that he had always postponed before surgery and felt the need for new interests. She was also sad because she realized that she had missed a large part of her young life as a result of the continuous severity of her OCD. who. which had been impossible previously because she became obsessed with thoughts of death and mortality. When Patient 2 became able to do some of the housekeeping again. and watched television more frequently. She no longer accepted any authoritarian behavior from her father or dominance by her sisters.

it was almost always clearly noticeable that the effects of bilateral stimulation were more pronounced than those of unilateral stimulation. whether it was right-sided or left-sided stimulation. who are electrically stimulated in either subthalamic nuclei or ventral intermediate nuclei. medication was completely changed 2 years after surgery by the treating psychiatrist. This caused numerous discussions within the family. Stimulation was always performed with a symmetric voltage supply. All patients immediately contacted one of the authors (B. Patient 5 started adult education classes and devotes serious energy to her studies. Similarly. He also started some volunteer work at a library (part-time). in observing acute reactions (minutes) when changing stimulation parameters. The patients’ urge to ask for renewal of the stimulators was comparable to that of some parkinsonian patients. beyond that. Patient 4 went through a divorce at the time of surgery. Patients 2 through 5 were unemployed at the time of surgery and did not start to work afterward. exposure and response prevention [ERP]) was given during this period. but because impedances differed somewhat between the left and right sides. and art connoisseurs stated that he painted better and more balanced than before implantation of the electrodes. OCD patients need follow-up with their psychiatrist.J.N. he dared to try out new ways of painting. Patients were asked to remain under the care of their treating psychiatrist for treatment ‘‘as usual’’ and to come to our centers only as part of the research evaluation.272 B. His success placed social demands on him. although he never thought about this before surgery. He received critical acclaim. which made him produce many paintings per day. although only two of them had a programmer by which they could really check whether the battery had run low. straightaway after the stimulators . the follow-up of electrically stimulated OCD patients is comparable to the follow-up of electrically stimulated parkinsonian patients. After he started being stimulated. he felt lots of energy. and he tended to experience more fear of failure and an extreme need for endorsement. Nuttin et al / Neurosurg Clin N Am 14 (2003) 267–274 moment. medication was tapered off to a minimum before surgical intervention and kept stable throughout the first year of stimulation. Usually. Patient 1 is still taking the same medication. After 1 year of stimulation. family relationships. Patient 1 was more successful in his work. and social life. and counseling In the opinion of the authors. but the dose of benzodiazepine (BZD) could be slightly reduced for Patient 2 and Patient 3. Patient 2 became more active in housekeeping tasks. to request this when their battery runs low. It seems likely. A similar form of increased independence as a result of stimulation could be noted in Patient 1. Replacement of batteries When batteries wore out. the battery of one stimulator was usually empty earlier than that of the other. although not yet studied in detail.) when they thought the battery was empty. Their condition changed dramatically after stimulator renewal. physical and psychologic well-being is low. He has recently started to go out again on Saturday nights and is meeting new people. No additional psychotherapy specifically aimed at improving OCD (eg. For Patient 4. Patient 3 was much less dependent on her parents. Severe OCD interferes with the ability to work and to do the housekeeping and with education. patients started to feel worse again and OCD symptoms resumed at their former intensity over the course of a few days. During stimulation. As parkinsonian patients are still followed by a neurologist. He painted more of his own ideas and developed a style of his own. all six patients remain defective in several domains of healthrelated QoL. implying that unilateral stimulation is less effective than bilateral stimulation. only one of the stimulators (either right or left side) had run low when patients requested a check on battery status for sudden worsening. Until now and for the sake of scientific methodology. whereas she had been hospitalized almost continuously for several years before surgery. None of the patients engage in ERP treatment. Only the first four patients have completed their first year of stimulation to date. but they avoid less and seem to involve themselves more in everyday life. He was a successful artist. and her family relationships improved tremendously. additional treatment. even on the operating table. Impact of stimulation on quality of life Quality of life (QoL) in patients considering neurosurgery for treatment-refractory OCD is low. Medication. that the stimulated patients respond better to drug treatment and behavioral therapy than when not stimulated.

Apart from severe OCD. He also made some sexual insinuations and passes directed at some acquaintances. Nuttin et al / Neurosurg Clin N Am 14 (2003) 267–274 were switched on. Side effects Possible side effects were a major concern when starting this new kind of therapy. These sudden changes required adaptations in their relationship that were not easy to attain. Also. she showed more energy during the daytime and took much more initiative than before surgery. he wanted to continue the stimulation. and he felt uneasy about it. she chose to continue stimulation because she appreciated the fact that the benefits of the stimulation were so much greater than the disadvantage of the fatigue. Although Patient 3 once reported that one of the authors resembled her previous lover. he remembered the hyperactive state but not the showing off and swaggering behavior. the degree of this change fluctuated. rechargeable batteries) or to reduce battery consumption. Fatigue lasting for several months was a major complaint of Patient 3. Patient 3 complained of a worsening of . Patient 4 twice experienced a brief hypomanic state (2–3 days) after placement of new batteries. For those reasons. although there was a more than usual swelling of the face in Patient 5 during the first 4 days after surgery. He tried to impress others and even threatened violence if others did not accept him as ‘‘the man who could do it all. During most of the time. which was prophylactically treated with antibiotics for 1 week even though cultures of aspirated subcutaneous fluid remained sterile. Patient 1 felt the leads and the stimulator and wanted to take the system out.’’ He felt good about himself and regretted that his brother (who also had severe OCD and had committed suicide several years before) could not have benefited from stimulation. His family reported that he was overactive and could not sleep at all for 36 hours. or infections. He found the advantages of the capsular stimulation not comparable to the disadvantage of needing to have the stimulators replaced every 8 months. Complications Technical problems and hardware failures The most important inconvenience was definitely the high current amplitude needed to maintain acceptable results in the years after the surgery. Stimulators had to be replaced every 5 to 12 months in all patients. There were no intracranial hemorrhages. but one can think of strategies either to improve battery technology (eg. he also suffered from undifferentiated somatoform disorder. epileptic fits. Severe weight loss as a result of severe pyelonephritis in Patient 2 caused the left stimulator.B. On some days. it was difficult to accept this and to put it into perspective. The electrode was replaced. they knew that these bad feelings were caused by technical reasons. no frontal signs were noted during subsequent neuropsychologic testing. Paradoxically. but clear beneficial effects on OCD symptoms were still seen. He explained that during an argument years earlier. In Patient 5. All patients reported better sleep at night. When she was given the option of decreasing the amplitude to get immediate relief of her fatigue. his former wife had told him he could never be sure that he was his son’s father and that this had come into his mind and obsessed him for a few days. and he suddenly demanded a paternity test for his 8-yearold son. we could only stimulate with three of the four contacts on the left side. the impedance of the uppermost contact increased to more than 4000 shortly after implantation. but the husband once said that we had suddenly altered his wife into a lovely young flower. and although after a few battery replacements. Therefore. This makes the therapy difficult to use as standard therapy. They felt bad again. to migrate more caudally. When questioned about these episodes in a psychiatric interview some time later. He was not used to this appeal. In Patient 2.J. however. his electrodes were removed. and the patient improved again. This traction led to fracture of the left electrode and worsening of the OCD symptoms 44 months after surgery. which was implanted in the left hemiabdo- 273 men. All patients reacted strongly when the batteries ran down. which induced traction on the extension cable and thus on the electrode. and he underwent a bilateral anterior capsulotomy. The beneficial effects were sometimes only seen after several days. no permanent pathologic frontal signs were observed in the other patients. which suggests a broken contact. The stimulators could be replaced under local anesthesia and in an ambulatory setting. Other patients complained less about the presence of the stimulators. He did not persist in demanding the paternity test.

[3] Cosyns P. Patient 2 was treated for pyelonephritis. et al. The authors still want to stress that anterior capsular stimulation remains investigational and needs optimization. Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder.5:35–9. Patient 2 lost weight. . same technique. not all stimulation-induced effects can be explained. and Friehs in Providence and the group of Drs Rezai. Demeulemeester H. At this stage. Cosyns P. The effects are a valuable source for further neurophysiologic and neuroanatomic research. which was interpreted as being unrelated to the stimulation. It was reassuring that when the group of Drs Rasmussen. Greenberg. and Patients 3 through 5 gained weight to different degrees. but neuropsychologic tests before and 1 year after surgery could not document any difference.274 B. Caemaert J. References Summary Anterior capsular stimulation induces some improvement in severe treatment-resistant OCD patients.354:1526. Functional stereotactic neurosurgery for psychiatric disorders: an experience in Belgium and The Netherlands. especially to try to solve the problem of the short battery life of the stimulators. Adv Tech Stand Neurosurg 1994. [2] Nuttin B. Nuttin et al / Neurosurg Clin N Am 14 (2003) 267–274 memory. et al. similar effects were seen in the patients. Cosyns P. Electrical stimulation of the brain for psychiatric disorders.21: 239–279. CNS Spectrums 2000. Lancet 1999. Gabriels L. Haaijman W. et al. and Malone in Cleveland started to operate on OCD patients using exactly the [1] Nuttin B.J. Montgomery.

and without the benefit of controlled data to establish its efficacy. Houston.Neurosurg Clin N Am 14 (2003) 275–282 Cervical vagus nerve stimulation for treatment-resistant depression Linda L. Through sensory afferent connections in the nucleus tractus solitarius (NTS). Further evidence of VNS effects on the basal limbic structures. the vagus has extensive projections to brain regions that are thought to modulate activity in the limbic system and higher cortex [2–4]. doi:10. MDa. orbitofrontal cortex. which reach the amygdala. That VNS has come to be regarded as one of the most promising new forms of therapeutic brain stimulation reflects a tremendous need for better long-term treatments of disabling depression as well as great expectations for the application of new technologies in treating mental illness. A synthesis of this preclinical literature led Zabara [6. The history of its development and practical considerations for its application in psychiatric disorders are reviewed in this article. Carpenter). E-mail address: Linda_Carpenter_MD@Brown. * Corresponding author. Anatomy of the vagus nerve The vagus nerve. Slow-wave response in the anterior rhinal sulcus and amygdala to VNS was noted in awake cats with high cervical spinal section [3]. RI 02906. and cingulate was generated by a study in monkeys [4]. Carpenter.edu (L. thorax. Zabara observed VNS-induced cortical electroencephalographic (EEG) changes and seizure cessation in dogs. Approximately 80% of the vagus is sensory afferent fibers. MDb. Friehs. USA b Department of Clinical Neurosciences and Neurosurgery. MDa a Department of Psychiatry. All rights reserved. RI 02906. thalamus. Lawrence H. the VNS Therapy system (Cyberonics. such as autonomic control and regulation of heart and gut viscera. Providence. TX) for delivery of cervical vagus nerve stimulation (VNS) had become an approved treatment for medication-resistant or -intolerant depression or bipolar disorder in Europe and Canada. Elsevier Science (USA). carrying information to the brain from the head. 100 Butler Drive. Brown University Medical School. Pathways connecting the NTS with the parabrachial nucleus and the locus ceruleus (LC) carry afferent vagal input to norepinephrine-containing neurons. neck.*. best known for its parasympathetic efferent functions. The authors have received grant/research support from Cyberonics. insula. Only 4 years later. and abdomen [1]. when Bailey and Bremner [2] described synchronized activity of the orbital cortex produced by VNS in cats. 345 Blackstone Boulevard.see front matter Ó 2003. Preclinical investigations of vagus nerve stimulation The first published report suggesting that VNS directly affected central function appeared in 1938.’’ Latin for ‘‘wandering’’) via a surgically implanted programmable prosthesis was approved by the US Food and Drug Administration (FDA) for medically refractory partial-onset seizures in 1997. leading him to postulate 1042-3680/03/$ . and other limbic structures [5]. Price. Gerhard M. 7] to hypothesize and further investigate in dogs the notion that VNS would have anticonvulsant action.L. thalamus.1016/S1042-3680(02)00121-3 . Providence. Brown University Medical School and Butler Hospital.b. USA Intermittent electric stimulation of cranial nerve X (called the ‘‘vagus. hypothalamus. is actually a mixed sensory and motor nerve.

the first multicenter pivotal VNS trial was being conducted in the United States and Fig. for therapeutic left cervical vagus nerve stimulation. By 1990. access to the vagus was achieved through an abdominal or diaphragmatic approach. the epilepsy studies demonstrated that cervical VNS was well tolerated. Carpenter et al / Neurosurg Clin N Am 14 (2003) 275–282 that the antiepileptic mechanisms of action of VNS would involve direct termination of an ongoing seizure as well as seizure prevention [8]. Perhaps more important to the future development of clinical VNS applications.1%).7%). paresthesia. The VNS Therapy system commercially manufactured by Cyberonics includes a pocket watch-sized generator that is implanted subcutaneously in the left chest wall in a fashion similar to placement of a cardiac pacemaker [10]. voice alteration or hoarseness. a patient can completely abort a stimulation-induced AE by holding or taping a small magnet over the pulse generator. Inc. and favorable practice and reimbursement economics have all contributed to the success of VNS in the treatment of patients with severe epilepsy. data from these studies supported the use of cervical VNS as a safe and effective adjunct treatment for difficult-to-treat epilepsy [15]. Perkins.000 epilepsy patients worldwide have received cervical VNS (S. 1). .7%) [17]. and the treatment has been judged by the American Academy of Neurology’s Technology and Therapeutics Committee as having ‘‘sufficient evidence . the categorical response rate (defined as a 50% or greater reduction in seizure frequency) reached 43% and was maintained at the 3-year mark [13]. Although few epilepsy patients receiving VNS have achieved full remission and become free of anticonvulsant medications.276 L.14]. Results from three open trials and two double-blind studies [11. . personal communication 2003). hoarseness or temporary vocal cord paralysis (0. the first human implants were performed for a pilot study of cervical VNS in patients with medication-resistant epilepsy who were not candidates for neurosurgery [9]. and hypesthesia or lower left facial paresis (0. A telemetric wand connected to a portable computer is held to the chest (over the patient’s clothing) to assess and control the stimulation parameters in a noninvasive office procedure.’’ Stimulation-related AEs could be diminished by reprogramming the device to deliver a lower level of output current. cough. Bipolar electrode coils are wrapped around the left vagus nerve near the carotid artery in a separate neck incision (Fig. The leads are subsequently tunneled under the skin for connection with the programmable generator. based on a preponderance of Class I evidence’’ [15]. Clinical trials of vagus nerve stimulation for epilepsy In 1988. with adverse events (AEs) rarely leading to discontinuation of VNS therapy [16]. At the time of this publication.12] indicated a 25% to 30% mean decline in seizure frequency and suggested a tendency for anticonvulsant benefits to be sustained or improved over time with continuing VNS [13. to rank VNS for epilepsy as effective and safe. High continuation rates (72% at 3 years). infection with subsequent explantation (1. Pooled data from epilepsy clinical studies (n=454) show minimal surgical complications associated with implantation: infection without explantation of the device (1. Side effects related to the intermittent stimulation itself (ie. dyspepsia) were judged to be mild or moderate most of the time and were noted to decrease over time with ongoing VNS at the same ‘‘dosage. Collective data from the epilepsy trials showed that after 2 years of continuous VNS.L. In preclinical investigations. Europe to investigate its role in medically refractory epilepsy [11]. Alternatively. . 1. Schematic representation of placement of the NeuroCybernetic Prosthesis manufactured by Cyberonics. Cyberonics. lack of compliance issues or druginteractions. more than 20.8%).

a theoretic VNS-induced increase in NTS concentration of c-aminobutyric acid (GABA) and/or a decrease in NTS glutamate level could explain the antiseizure activity of VNS [20]. The similarities between VNS and electroconvulsive therapy (ECT). 5-hydroxyindoleacetic acid (5-HIAA). during follow-up visits at the study site. Wilder was that the VNS patients seemed to be in better spirits as time passed. or recurrent treatment-resistant depression was first studied in an open-label fashion in 30 patients at four academic sites in the United States [26]. considered to be the most effective available antidepressant treatment. After a 2-week single-blind period for recovery from surgery. and hypothalamus [18]. These considerations. chronic. Further support for a role of noradrenergic neurotransmission comes from a report of suppression of the antiseizure effects of VNS in animals after lesions of the LC [19]. Studies in rats during VNS reveal increases in cellular activity as measured through the oncogene C-fos in the amygdala. lamotrigine) that have demonstrated beneficial effects in mood-disordered patients. LC. thalamus. Bilateral decreases were seen in the hippocampus. a study of lumbar cerebrospinal fluid (CSF) components in epilepsy patients sampled before and after 3 months of VNS showed significant increases in CSF concentrations of GABA and trend-level decreases in glutamate [21]. also supported the hypothesis that VNS may have primary antidepressant properties. Both retrospective data analysis [23] and prospective 277 assessments during epilepsy trials [24] suggested that VNS was associated with a reduction in depressive symptoms. and cingulate gyrus. and the major metabolite of serotonin. Florida. Carpenter et al / Neurosurg Clin N Am 14 (2003) 275–282 Anticonvulsant mechanism of action research Ascending projections from the NTS to the midline raphe and LC are hypothesized to be the pathways through which VNS exerts antiseizure and neuropsychiatric effects. a possible role for VNS in the treatment of depression seemed worthy of investigation. homovanillic acid (HVA). In light of the growing number of modern anticonvulsant agents (eg. patients frequently stayed in the same hotel in Gainesville. cingulate. Patients enrolled in the study. Anecdotal reports of mood improvements apparently unrelated to reduction in seizure frequency further inspired the VNS investigators to systematically assess mood and anxiety symptoms [11. insula. Vagus nerve stimulation as a potential treatment for depression During the early epilepsy trials of VNS. together with the known anatomic projections of the vagus to regions of the brain involved in mood regulation and the preclinical and human CSF data suggesting that VNS altered major neurotransmitter systems implicated in depression. Blood flow increases were seen in the rostral medulla. Consistent with this hypothesis. hypothalamus.’’ had either bipolar or unipolar forms of affective illness and continued to be severely symptomatic despite exposure to an average of 16 different clinically administered treatments (including an average of five strictly defined adequate antidepressant trials) for the current major depressive episode. A positron emission tomography (PET) study in epilepsy patients demonstrated significant VNS-induced modulation of blood flow in key brain structures thought to be involved in seizures and emotion regulation [22].J. called ‘‘D-01. all with greater activation on the right side. Open-label study of vagus nerve stimulation for treatment-resistant depression (D-01) The safety and efficacy of VNS for nonpsychotic. The majority (66%) had undergone a course of ECT for the index depressive episode before enrolling in the VNS study and undergoing surgical implantation of the VNS Therapy system. Incidental findings of psychiatric improvements during clinical trials of anticonvulsant therapies have provided the rationale for further investigation into the potential utility of other drugs like carbamazepine in the management of bipolar disorder [25]. carbamazepine.L. Although the basic mechanisms of action are unknown. amygdala. the patients began active VNS with an initial 2-week period of stimulation adjustment (consistently programmed to take place in cycles of 30 seconds ‘‘on’’ and 5 minutes ‘‘off ’’ but variable in intensity of output current) and a subsequent 8-week . Other provocative findings from the CSF study were trends toward VNS-induced increases in levels of the major metabolite of dopamine. An astute observation made by a hotel clerk and reported to VNS investigator B. even in the absence of improvement in seizures. valproic acid.L.12]. and postcentral gyrus. provided a rationale for studying VNS in a new population of subjects.

A large-scale pivotal study was thus designed to be almost identical to the open-label study that preceded it. A second cohort of 30 patients with treatment-resistant depression meeting similar inclusion and exclusion criteria was added to the open-label study. It is worth noting that changes in dose or type of psychotropic medication and VNS stimulation parameters were not controlled after exit from the acutephase study. and mental health domains even among patients who were considered VNS acutephase nonresponders [27].’’ were released to the press in early 2002. was still much higher than what might be expected in such a severely ill and treatment-resistant population.5% for the combined cohorts (n=60). there continued to be evidence of sustained or even enhanced response to VNS (13/24 responders [54%]) [29]. which failed to confirm the short-term antidepressant efficacy of the adjunct therapy statistically [30]. because they did not appear to benefit from VNS in the open-label study. however. Safety data from the D-01 open-label depression study mirrored that of the epilepsy trials. The overall acute response of 30. introducing the possibility that the observed improvements were not entirely attributable to the ongoing VNS. The only identifiable predictor of response was degree of treatment resistance as measured by the number of failed antidepressant trials in the index depressive episode. placebo-controlled study of vagus nerve stimulation for depression (D-02) Encouraging results from the open-label studies clearly indicated a need for a placebo-controlled investigation of the antidepressant efficacy of VNS. Neuropsychologic tests indicated neurocognitive improvements after VNS relative to baseline. social function. as most side effects were experienced only during stimulation and were considered mild. No dose-response relationship was detected when final output current data were examined. the association of adjunct VNS with sustained depressive symptom reduction and improved functional status after 2 years is suggestive of antidepressant efficacy in a naturalistic setting. Additionally. Carpenter et al / Neurosurg Clin N Am 14 (2003) 275–282 period of fixed-dose VNS. A somewhat less robust response rate of 21% was seen at the end of the ‘‘acute phase’’ (10 weeks of active VNS) for this second cohort. but only 15% responded to active VNS. For those who had reached the 2-year mark. After 1 year of VNS. All patients continued on stable psychotropic medication regimens. The categoric response rate (50% or greater decrease in total score on the 28-item Hamilton Rating Scale for Depression [HRSD]) after 10 weeks of adjunctive VNS was 40% for the first 30 patients. After completing the 12-week acute study. Quality of life assessments suggested that VNS was associated with improvements in vitality. Two hundred twenty-five patients received VNS (2 weeks of VNS stimulation parameter adjustments and 8 weeks of fixed-dose VNS) in an ‘‘add-on’’ study design. especially in those who experienced decreased depressive symptoms [27]. Nevertheless. Longer term follow-up results: open-label study of vagus nerve stimulation for depression (D-01) Although the short-term results were considered encouraging. patients in the sham condition who continued depressed would cross over to active stimulation. 91% (10/11) of the first cohort of acute-phase study responders had maintained their response and 18% (3/17) of the initial nonresponders had achieved a reduction of depressive symptoms sufficient to meet ‘‘responder’’ criteria [28]. and longterm data would be collected on all patients. Speculation about why the D-02 treatment group response was inconsistent with the openlabel study results included hypotheses about inadequate dosing of VNS stimulation.278 L. with the exception of double-blind randomization to either active VNS or a sham condition. the protocol exclusion criteria were revised to exclude those with the highest levels of treatment resistance (six or more failed adequate trials in the index depressive episode).L. When the entire sample (n=59) participating in the open-label (D-01) study was followed to the 1year mark. The placebo (sham) response rate was low at 10%. A preliminary comparison of the output current . Substantial functional improvement was also seen. called ‘‘D-02. Acute safety and tolerability of VNS were demonstrated. the response rate was 45% and the remission rate was 27%. Pivotal. suggesting acute antidepressant efficacy in a difficult-to-treat depressed population. with 15% meeting criteria for full remission of the depressive episode. More severely refractory patients experienced poorer responses to the 10-week VNS therapy. the longer term data generated even more enthusiasm for VNS in treatmentresistant depression. Results of the randomized controlled study.

In summary. such data seem to provide converging lines of evidence that VNS exerts measurable effects in brain regions and neurotransmitter systems implicated in mood disorders. it is not appropriate to interpret dynamic brain imaging results and other biologic correlates of VNS in depressed patients as evidence of its mechanism of antidepressant action. That qualification notwithstanding. The 10week trial of VNS seemed to produce resolution of classic rCBF abnormalities in depressed patients. Carpenter et al / Neurosurg Clin N Am 14 (2003) 275–282 delivered in the D-02 depression study with that used in the initial open-label depression study and in epilepsy studies suggests that stimulation set at 1. Although this finding raises the provocative possibility that VNS simply takes longer (ie. with larger sample sizes and over longer periods of exposure to VNS. and perisylvian temporal structures. it seems premature to conclude either that 279 more placebo-controlled trials of VNS will be needed or that the present data set will be adequate to demonstrate an adequate level of antidepressant efficacy. tolerable. This newly developed fMRI technique was also used to examine whether BOLD signal changes depend on the frequency of VNS [33]. especially among those showing a favorable clinical response. there has been considerable interest in the clinical course and longer term outcomes experienced by the depressed patients who continue to receive VNS after finishing the acute-phase trial. and left amygdala. such as hearing a tone. anterolateral temporal. will eventually be available. particularly in light of the pressing need for safe. hypothalamus.L. More extensive evaluation of follow-up data. the response rate at the 1-year mark was 44%. ‘‘Mechanisms of action’’ research in depression One of the most compelling aspects of the VNS development ‘‘story’’ is the growing body of clinical neurobiologic research findings that speak to its direct actions on the brain and central nervous system. After 10 weeks of VNS. In depressed patients. At present. a BOLD fMRI response to VNS was shown in areas regulated by the vagus nerve: orbitofrontal and parieto-occipital cortex bilaterally. systematic efforts are underway to ‘‘ramp up’’ or increase the dose of VNS in pivotal study patients who have not yet remitted in hopes of generating data that will better address the possibility of a dose-response relationship for VNS in depression. Interestingly. It is possible that changes in antidepressant therapies or VNS stimulation parameters account for the growing percentage of patients meeting categorical criteria for antidepressant response over time. Results confirmed that acute immediate regional brain activity changes vary with the frequency or total dose of stimulation. Stimulation parameters were at lower settings in the D-02 study compared with those used in the initial open-label D-01 depression studies and epilepsy trials. longer than the 10 weeks of acute-phase therapy) to exert its antidepressant effects. including the posterior insula. patients had reduced regional cerebral blood flow (rCBF) to left dorsolateral prefrontal. A method for synchronized blood oxygenation level-dependent (BOLD) functional MRI (fMRI) was developed to detect signal from the implanted device and link it to fMRI image acquisition [32]. recent device regulatory precedents suggest that statistically significant longterm longitudinal results may be appropriate to support FDA approval. if not impossible. Additionally. A single-photon emission computerized tomography (SPECT) imaging study conducted in six depressed patients receiving VNS in the openlabel study found that compared with normal controls. the longer term data do not reflect response under continued controlled conditions. and effective maintenance treatments for patients with severe chronic and/or recurrent depressions. . Longer term results in the pivotal study (D-02) In light of the apparent gradual accumulation of more VNS responders over time in the D-01 open-label study.L.0 mA or higher is associated with higher rates of clinical response. these depressed patients showed increased rCBF in the superior frontal gyrus and right mesial (posterior hippocampus) and lateral temporal cortex. it will remain difficult. at baseline [31]. left temporal cortex. which is consistent with 1-year outcomes measured from subjects in the open-label study. Nevertheless. to parse out the effects of antidepressant medications or spontaneous remissions in this large cohort and to demonstrate antidepressant effects that can be clearly attributed to adjunct VNS. results suggested that VNS exerts a dose-dependent modulatory effect on other brain activities. Because antidepressant action of VNS has yet to be empirically established. In a preliminary look at data from the first 36 patients to have completed a full year of VNS in the D-02 pivotal study [30].

Unlike the CSF results obtained during the epilepsy trials. but regional or local anesthesia has been used in some centers. Several other types of biologic measures of VNS are currently being investigated to evaluate the effects of VNS in treatment-resistant depression. Because of the potential for heating of the electric leads. eating disorders/obesity. anxiety disorders. A second incision similar in size is made in the chest wall (or alternatively in the axillary region for a superior cosmetic result) for insertion of the pacemakerlike pulse generator. General anesthesia is used in most cases. Special ‘‘send-receive coils’’ have been used to concentrate magnetic fields away from the neck area when MRI of the brain is necessary. posttraumatic stress disorder (PTSD). As is still the case with most available pharmacotherapies. in the pivotal study (D-02) [35]. including evoked response potential (ERP) recordings and provocative neuroendocrine challenge responses. The battery life of the currently available pulse generator model is approximately 8 to 12 years. a number of potential new indications for VNS are being explored. This norepinephrine finding is of interest in light of known anatomic connections and animal studies demonstrating that VNS exerts effects on higher brain regions via actions at the LC. the direct mechanism of therapeutic action of VNS is still not known. which coil around the vagus nerve (see Fig. migraine headache. has patents for ‘‘application of pulsed electrical signal’’ in the treatment of movement disorders. Other potential clinical applications of vagus nerve stimulation In addition to the use of VNS for treating medication-refractory epilepsy and depression. and rapidcycling bipolar disorder are also underway. The biologic data thus far suggest that VNS has acute and chronic effects on various key indices of brain activity and neurotransmitter regulation that have also been implicated in mood regulation. including an open-label study of bilateral diaphragmatic VNS (using higher output currents than used in cervical VNS applications) for morbid obesity. A tunneling tool subcutaneously passes the electrodes to the site connection with the pulse generator. without subsequent admission to the hospital for routine postsurgical recovery or monitoring. After 10 weeks of VNS. Inc. 1). Carpenter et al / Neurosurg Clin N Am 14 (2003) 275–282 Sleep EEG studies have also measured apparent VNS-induced improvement in indices of sleep macro.280 L. obsessive-compulsive disorder (OCD). however. however. the data suggested that an increase in CSF level of norepinephrine during VNS was correlated with better clinical outcome. no changes in CSF GABA were detected. the major dopamine metabolite. A device ‘‘programmer’’ who is knowledgeable about the operation of the VNS Therapy system must be present but not sterile in the operating room to perform lead testing before surgical incisions are closed. and patients manifested significantly less awake time and ‘‘light sleep’’ and significantly more stage 2 (deep) sleep. Multicenter trials of cervical VNS for panic disorder. results from preclinical and clinical mechanisms of action research. whole-body MRI is contraindicated in patients who have the VNS pulse generator implanted. Based on clinical observations from epilepsy and depression studies. Patients with the VNS Therapy system are asked . and cardiac disease. dementia and Alzheimer’s disease. the depressed group showed a significant VNS-associated increase in CSF concentrations of HVA.L. Consistent with CSF findings reported for a group of seizure patients receiving 3 months of VNS.and microarchitecture in patients with treatment-resistant depression [34]. neuroanatomic knowledge. The surgery typically takes from 30 minutes to 1 hour in the operating room and is usually performed on an outpatient or day surgery basis. A single surgical incision is needed in the chest wall to replace the entire pulse generator once the battery has expired. Cyberonics. the major noradrenergic nucleus in the brain. and market opportunities. chronic pain.to 5-cm incision is made in the neck for placement of the two stimulating electrodes. Practical considerations in the use of vagus nerve stimulation for psychiatric disorders Surgical implantation of the VNS Therapy system is considered a procedure of low technical complexity for a surgeon with experience in the head and neck area. Several of these areas are under current clinical investigation. Lumbar CSF samples were collected in 18 patients both before and after VNS therapy. the amplitude of sleep EEG rhythms was restored to near-normal levels. Although categorical clinical response rates were low. A 4.

Future applications of VNS may include combining it with brain imaging techniques to evaluate immediate dynamic effects and. Epilepsia 1990. [8] Zabara J. Peripheral control of hypersynchronous discharge in epilepsy. An institutional experience with cervical vagus nerve . Projections ‘‘secondaries’’ mesencephaliques. it is useful to consider the relation of VNS to other somatic methods of therapeutic brain stimulation. Early success in establishing adequate terms of coverage and reimbursement by thirdparty payers has contributed to the wide-scale availability of VNS for patients with epilepsy in the United States.000. If the generator battery life is 10 years.26:518. offlabel use of VNS is discouraged at this time. The cost of the VNS Therapy system and surgical implantation for cervical VNS is approximately $20. and transcranial magnetic stimulation (TMS). 31(Suppl 2):S40–3. it can be offered only at academic centers conducting approved research protocols. Heck CN. Dubois F.6(Suppl):S162. 1990. who are at heightened risk for acting impulsively and selfdestructively on feelings of disappointment and hopelessness. providing a rationale for its possible role in the treatment of psychiatric disorders. VNS as a treatment for depression remains investigational in the United States. J Comp Neurol 1937. I: the ratio of sensory and motor studies. Short-term (10 weeks) treatment with VNS failed to demonstrate statistical superiority over sham treatment in a recently completed double-blind study. Because there is much yet to be learned about the effects of various stimulation ‘‘doses’’ and patterns of electric pulse delivery. Anatomic basis for differential regulation of the rostrolateral peri-locus coeruleus region by limbic afferents. VNS might be ranked in the middle [36].33:1005–12. gamma knife neurosurgery. New York: Plenum Press. so antidepressant efficacy has not yet been established. [10] Amar AP. ECT. Carpenter et al / Neurosurg Clin N Am 14 (2003) 275–282 to carry identification cards and are educated about risks related to being in close proximity to strong magnetic fields. [7] Zabara J. Open-label studies in patients with treatment-resistant depression have produced promising results. A sensory cortical representation of the vagus nerve. diencephaliques et amygdaliennes des afferences viscerales vagales. Quantitative studies of the vagus nerve in the cat. with ablative surgery at one end and TMS at the other. Time course of seizure control to brief. Patients’ expectations for dramatic symptom recovery or even cure from severe psychiatric illness may be fueled by the introduction of new technology and the highly interventional nature of the device implantation surgery. deep brain stimulation (DBS). MR spectroscopy (MRS). With those caveats in mind. Dean JC. [5] Van Bockstaele EJ.67:49–67. Biol Psychiatry 1999.1: 405–12. Triune brain in evolution: role in paleocerebral functions. [9] Penry JK. J Neurophysiol 1938. 281 Summary Therapeutic brain stimulation through left cervical VNS now has established safety and efficacy as a long-term adjunct treatment for medicationresistant epilepsy. such as ablative neurosurgery. et al. [6] Zabara J.6:1352–63. making it to roughly comparable to the cost of a course of ECT for depression in an inpatient setting. [3] Dell P. possibly.L. to influence regional focus through adjustment of the stimulation parameters [36].L. Inhibition of experimental seizures in canines by repetitive vagal stimulation. Although it is tempting to imagine that VNS may replace psychotropic medications and the many undesirable side effects that accompany them. Electroencephalogr Clin Neurophysiol 1985a. [2] Bailey P. VNS costs can be calculated at about $2000 per year. Olson R. Data regarding the optimal stimulation parameters for antidepressant effects are extremely limited. especially when response rates at longer term (1 year and 2 years) follow-up time points are considered. Bremer F. Levy ML. At present. Longer term data on VNS in depressed patients as well as further information regarding the possible dose-response relation will help to determine the place of VNS in the armament of therapeutic modalities available for major depression. Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results. Management of such expectations should be undertaken with great care. repetitive stimuli [abstract]. [4] MacLean PD. Valentino RJ. C R Soc Biol 1951. it is important to bear in mind that VNS has been investigated as an adjunct therapy rather than as a monotherapy in most cases to date. Epilepsia 1992. 145:1088–91. as such. References [1] Foley JO. On a spectrum of relative invasiveness of the procedure. Peoples J. Epilepsia 1985. particularly in depressed patients. There is considerable evidence from both animal and human studies that the vagus nerve carries afferent signals to limbic and higher cortical brain regions.

Kling M. Rush AJ. Bohning DE. Neurosurgery 1998. et al. Biological Psychiatry 2002. 39:709–14. et al.51:48–55. technique and outcome. Moreno F. et al.35:616–26. . American Psychiatric Association. Vagus nerve stimulation: a new tool for brain research and therapy.51:(8)152S. et al. Epilepsia 1998. Epilepsia 1998. Vagus nerve stimulation (VNS) for major depressive episodes: One year outcomes. Rush AJ. Epilepsy Res 1995. The effects of VNS on CSF components in depressed subjects [abstract]. Fisher RS.282 [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] L. Vagus nerve stimulation for treatment of partialonset seizures: a randomized active-control trial. et al. Washington DC:2002.36:470–9. 263. Hoppe C. The effects of VNS on regional cerebral blood flow in depressed subjects. Hoffman R. Hamberger A. J Clin Neurophysiol 2001. Krahl SE. The effects of VNS on sleep in depression [abstract]. Salinsky MC. Biol Psychiatry 2002. et al. et al. Vagus nerve stimulation: clinical experience in a large [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] patient series. In: APA 2002 Annual Meeting New Research Program. Washington DC:2002. et al. Neurology 1998.25: 713–28. and predictors of outcome. Ristanovic R. George MS. Ballenger JC. Vagus nerve stimulation for the treatment of medically intractable seizures: results of a 1-year open-extension trial. Pulver MC. et al. Neurology 1999. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy. Vagus nerve stimulation (VNS) for treatment-resistant depression: a multicenter study. et al. Bakay RAE. Carpenter et al / Neurosurg Clin N Am 14 (2003) 275–282 trunk stimulation for medically refractory epilepsy: rationale. E01–E05 VNSSG: longterm treatment with vagus nerve stimulation in patients with refractory epilepsy. Vagus nerve stimulation for treatment of partial seizures. Effect of vagus nerve stimulation on mood in adult epilepsy patients [abstract]. Nahas Z. Schachter SC. I: a controlled study of effect on seizures.18: 408–14. Devous MD. Votaw JR. et al. Naritoku DK. Neurology 1999. Carbamazepine (Tegretol) in manic-depressive illness: a new treatment. Denslow S. side effects. 39(Suppl 6):92–3.47:287–95.53: 1731–5.52(Suppl):A238– P03122. Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Handforth A. Uthman BM. Epilepsia 1998. Schachter SC. Nikolov B. Morris GL. Locus coeruleus lesions suppress the seizure attenuating effects of vagus nerve stimulation. Biol Psychiatry 2000. Rush AJ. Invest Radiol 2001. et al. Neurology 1999. Regulation of limbic motor seizures by GABA and glutamate transmission in nucleus tractus solitarius. Lomarev MP. Rush AJ. Hedner T. Am J Psychiatry 1980. George MS.51(8):152S. Epilepsia 1994. Husain M. Harden CL. Gale K. American Psychiatric Association. Vagus nerve stimulation shows benefits in treatmentresistant depression for up to two years [abstract NR21]. Sackeim HA. Terry WJ.137:782–90.39: 677–86. et al. Clark KB.43:1265–80. George MS. Synchronized BOLD fMRI [abstract]. Walker BR. Kral T. Does vagus nerve stimulation change the long term course of mood disorders [abstract 16E]? In: APA 2002 Annual Meeting Syllabus and Proceedings Summary. Saper CB. Ristanovic RK. et al.53:666–9. Ben-Menacham E. Biol Psychiatry 2002.53:1176–80. Manon-Espaillat R. et al. p.20:221–7. Surgical complications.22:53–62. Scherrmann J. Neuropsychopharmacology 2001. Biological Psychiatry 2002. Arch Neurol 1996. Husain R. Carpenter LL. Marangell LB. Helfert RH. Epilepsy Res 1995. Biol Psychiatry 2000. 6. Henry TR. Ben-Menacham E. 47:276–86. Epilepsia 1999. Biological Psychiatry 2002. Sackeim HA. Harris TS. Handforth A. et al. Mueller WM.51(8)152–3S.51: 280–7. p. Rush AJ. Reassessment: vagus nerve stimulation for epilepsy: a report of the Therapeutics and Technology Assessment Subcommittee for the American Academy of Neurology.39:983–90. Post RM. Smith DC. Martinez JM. Feasibility of vagus nerve stimulation-synchronized blood oxygenation level-dependent functional MRI. Marangell LB. Sackeim HA. DeGiorgio CM. George MS. George MS. Armitage R. Denslow S.L. Vagus nerve stimulation (progress in epilepsy research). Easton A. Lomarev MP. Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures. et al.40:1051–7. Brain blood flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: acute effects at high and low levels of stimulation.51(8)152S. Bruce DA. Epilepsia 1998.

information gleaned from TMS studies will likely inform us about the mechanisms of action of classic neurosurgical techniques like deep brain stimulation (DBS).2].see front matter Ó 2003. Medical University of South Carolina. there is still inadequate understanding of the exact mechanisms by which TMS affects the brain and 1042-3680/03/$ . however. University Hospital. TMS produces noninvasive direct cortical brain stimulation by creating a powerful transient magnetic field [3. PhDi a Department of Psychiatry. Despite TMS’s promise and widespread use. All rights reserved. Andrew Kozela. Thomas Schlaepfer. USA The ability to stimulate the brain in awake alert adults without the need for anesthesia or open craniotomy is a significant advance that has long been a dream of clinicians and neuroscientists. Brown University.Neurosurg Clin N Am 14 (2003) 283–301 Transcranial magnetic stimulation Mark S. Benjamin D. New York State Psychiatric Institute. Transcranial magnetic stimulation (TMS) is the answer to this dream of noninvasive stimulation in awake individuals. MD.1016/S1042-3680(02)00120-1 . Although TMS is not limited to use by neurosurgeons and does not involve surgery. Charleston. The pioneering work of the neurosurgeons Penfield and Perot demonstrated the behavioral results of direct electric stimulation of epilepsy patients during open craniotomy. the Stanley Foundation. the Borderline Personality Disorders Research Foundation (BPDRF). 67 President Street. NINDS grant RO1-AG40956. doi:10.S. Charleston. 345 Blackstone Boulevard. Greenberg. standing of the brain [1. Ziad Nahas. This work demonstrated how powerful and important direct brain electric stimulation might be for advancing under* Corresponding author. MDg. Medical University of South Carolina. Their results were confined to epilepsy patients. NY. USA c Department of Neurology. TMS has considerable promise as a research tool to understand brainbehavior relations. USA i Department of Psychiatry and Human Behavior.h. MDa–e.*. 1051 Riverside Drive. it is important for neurosurgeons to be familiar with this most powerful new tool for causing ‘‘electrodeless electric stimulation. and Kozel’s work with transcranial magnetic stimulation (TMS) has been supported in part by research grants from National Alliance for Research on Schizophrenia and Depression (NARSAD). Drs George. USA g Department of Psychiatry and Mental Hygiene. MDa. Charleston. RI 02906. MD. George). USA f Department of Psychiatry. Because of its noninvasiveness. These are not in the area of TMS therapeutics but are for new TMS machine designs as well as combining TMS with MRI. MDf.d. which then induces electric currents in the brain. SC. SC. Charleston.’’ Advances made with TMS promise to set the stage for other brain stimulation advances in neurosurgery. Charleston. Nahas. and the testing was done during open craniotomy. Moreover. Elsevier Science (USA). Medical University of South Carolina. USA b Department of Radiology. Nahas. Baltimore. Drs George. New York.edu (M. E-mail address: georgem@musc. Institute of Psychiatry. Providence. USA e Center for Advanced Imaging Research. Medical University of South Carolina. F. 3010 Berne.e. 502 North. Switzerland h Johns Hopkins University.d. University of Berne. Sarah H. and Kozel hold several TMSrelated patents either alone or in combination. Columbia University.e. Unit 126. SC. SC. and the Defense Advanced Projects Agency (DARPA). Lisanby. USA d Brain Stimulation Laboratory.4]. George. Department of Psychiatry. Medical University of South Carolina. SC.

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how these effects change as a function of different TMS use parameters, such as intensity
and frequency. Progress in this area is occurring
by performing TMS in animal models and by
combining TMS with functional neuroimaging.
There has been much interest in using repeated
daily administration of TMS as a potential treatment in a variety of neuropsychiatric disorders.
The largest body of work has been done in the
treatment of major depression. Although several
meta-analyses of these antidepressant studies show
that TMS has statistically significant effects greater
than those of placebo, larger sample studies are
still needed to clarify its clinical role. Additionally,
TMS as a treatment for depression has not yet
been approved by the US Food and Drug Administration (FDA), although pivotal trials geared for
eventual FDA approval are currently underway.
This article succinctly summarizes basic TMS
physics and mechanisms and then critically reviews the potential clinical uses of TMS, particularly in the treatment of depression and other
neuropsychiatric conditions.
Description of transcranial magnetic stimulation
and mechanisms of action
TMS uses a powerful handheld magnet to
create a time-varying magnetic field, where
a localized pulsed magnetic field over the surface
of the head depolarizes underlying superficial
neurons [3–5]. High-intensity current is rapidly
turned on and off in the electromagnetic coil
through the discharge of capacitors (Fig. 1). It is

important to realize that TMS, which produces
powerful but brief magnetic fields that, in turn,
induce electric currents in the brain, radically
differs from the currently popular use of low-level
static magnetic fields as alternative therapies.
Constant exposure to static magnetic fields can
have biologic effects [6]. TMS does not produce
magnetic fields for long (microseconds), however,
and they are relatively weak, except directly under
the TMS coil. It is thus assumed that TMS produces its behavioral effects solely through the
production of electric currents in the cortex of the
brain. This assumption has not been proved,
however. If TMS pulses are delivered repetitively
and rhythmically, the process is called repetitive
TMS (rTMS) [7]. rTMS can be modified by the
term fast if the frequency is greater than 1 Hz [8].
Fast rTMS is currently limited to brief runs of
approximately 25 to 30 Hz. Stimulation frequencies faster than this have an increased seizure risk,
and most modern capacitors cannot keep delivering the needed energy before depleting. Thus,
fast TMS is performed at frequencies that would
be considered slow for DBS, where stimulation
frequencies sometimes exceed 150 Hz.
The magnetic field induced by TMS declines
rapidly with distance away from the coil. Thus,
with current technology, TMS coils are directly and
electrically only able to stimulate the superficial
cortex and are not able to produce direct electric
stimulation deep in the brain [9]. Although this
limited depth of penetration is a limitation of the
present technology, deeper brain structures can be
influenced by cortical TMS because of the cortex’s

Fig. 1. Diagram of events leading to transcranial magnetic stimulation excitation. (From George MS, Belmaker RH.
Transcranial magnetic stimulation in neuropsychiatry. Washington (DC): American Psychiatric Press; 2000; with
permission).

M.S. George et al / Neurosurg Clin N Am 14 (2003) 283–301

massive interconnections and redundant corticalsubcortical loops [10]. Moreover, there are several
groups working on novel TMS coil designs that
might be able to reach deeper into the brain without
overwhelming superficial cortical structures.
The amount of electricity needed to cause
changes in the cortex varies from person to person
and also from one brain region to the next [11].
One commonly used method for standardizing
and adjusting the amount of electricity delivered
and induced by TMS across different individuals
is to determine each person’s motor threshold
(MT). The MT is commonly defined as the minimum amount of electricity needed to produce
movement in the contralateral thumb when the
coil is placed optimally over the primary motor
cortex. MT can be determined either by using
electromyographic (EMG) recordings [12] or, with
less precision, by using visible movement [13].
TMS has been shown to produce immediate
effects (within seconds), such as the movement
of the thumb or direct inhibition of another TMS
pulse followed shortly in time. These immediate
effects are thought to result from direct excitation
of inhibitory or excitatory neurons. There is some
evidence to suggest that TMS at different intensities, frequencies, and coil angles excites different
elements (eg, cell bodies, axons) of different neuronal groups (eg, interneurons, neurons projecting
to other parts of the cortex, U fibers) [8,14–17].
This is further complicated by the complex sixlayer arrangement of human neocortex along with
the varying gyral folds, which places some aspects
of the brain close to the surface and others far
away in sulcal folds.
Another example of immediate TMS effects is
called paired-pulse TMS. This technique involves
delivering two TMS pulses to the same region
with varying interpulse intervals (usually milliseconds long) and intensities [12]. Depending on
the relative strength of the first pulse to the second
and the interpulse interval, the first pulse can either
inhibit or enhance the second pulse. Paired-pulse
TMS over the motor area can be used to assess
natural brain inhibitory and excitatory systems at
rest in individuals with different disorders [18,19]
as well as after the administration of different
centrally active compounds or other treatments
[20]. The different TMS use parameters (eg, frequency, intensity, length of stimulation, intertrain
interval) are most certainly all biologically relevant
and likely important. Particular attention has been
focused on whether and to what degree different
frequencies of TMS might have divergent biologic

285

effects. For example, repeated stimulation of a
single neuron at low frequency in culture produces
long-lasting inhibition of cell-cell communications
(called long-term depression [LTD]) [21–24].
Conversely, repeated high-frequency stimulation
can improve cell-cell communication (called longterm potentiation [LTP]) [25]. With these cellular
data on LTD and LTP as a background, there has
been much interest in whether TMS, exciting
hundreds or thousands of neurons in a pulse, can
produce sustained inhibitory or excitatory effects
[26,27]. Several studies have now shown that
chronic low-frequency stimulation of the motor
cortex can produce inhibitory intermediate-term
effects (lasting for several minutes) after stimulation [28,29]. There is also some evidence that
high-frequency stimulation can produce intermediate-term excitatory effects [30]. One of the most
easily demonstrated immediate effects of TMS is
speech arrest, where high-frequency TMS placed
precisely over the Broca’s area can immediately
and transiently block fluent speech [31]. TMS used
in studies like this can produce what are sometimes
referred to as ‘‘virtual lesions.’’ Importantly, none
of these temporary lesion effects were demonstrated to persist beyond the time of active TMS
administration. Thus, the lesions are truly virtual
and temporary. This contrasts with observations
that a train of repeated high-frequency stimulation
can excite the brain so much that it results in
seizure activity [32]. With knowledge of the appropriate limits of stimulation, seizures can be
avoided safely.
Safety issues
Although there is minimal risk of a seizure when
TMS is performed within the published safety
guidelines, the most well-known critical safety
concern with TMS is inadvertently causing a seizure
[7]. It is important to realize that this TMS safety
table was developed in a small subject sample
using a surrogate end point for a seizure—
spread of TMS-induced motor-evoked potentials
(MEPs) beyond the target area of stimulation.
Thus, the safety table exists only for stimulation of
motor cortex and cannot readily be applied to using
TMS over other brain regions. Finally, although
the intensity and frequency of stimulation were
examined, the intertrain interval was not. One of
the inadvertent seizures was induced with stimulation trains that were within the safety guidelines but
that were administered with an excessively short
intertrain interval [33]. A general rule of thumb is

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that one should have an intertrain interval at least
as long as the period of stimulation. A known
seizure disorder, history of epilepsy, or intracranial
abnormality, such as a prior stroke, can all increase
the risk of a TMS-induced seizure [34]. Although an
inadvertent seizure is the main safety hazard
associated with TMS, there have been only 12
reported cases since 1985 when cranial TMS began.
It is, in fact, not easy to intentionally use TMS to
produce a seizure, even in patients with epilepsy
[35]. For example, an attempt to use TMS to
produce a seizure intentionally in a patient with
a focal epilepsy was not successful [35]. In addition,
in a study exploring rTMS as a method to induce
therapeutic seizures, stimulation parameters far
above the published safety thresholds had to be
used to reliably induce seizures [36].
A muscle tension type headache and discomfort at the site of stimulation are less serious
but relatively common side effects of TMS. In
contrast to electroconvulsive therapy (ECT), no
deleterious cognitive effects of 2 weeks of slow or
fast rTMS have been found [37,38]. This is not
surprising, because ECT induces a generalized
seizure, whereas rTMS is being used at subconvulsive levels. Like MRI, TMS could cause the
movement of paramagnetic objects in or around
the head. For this reason, subjects with paramagnetic metal objects in the head or eye are
generally excluded from TMS studies. TMS can
cause heating of metallic implants and the inactivation of a pacemaker, medication pumps, or
cochlear devices. In the United States, rTMS is an
experimental procedure that requires an investigational device exemption (IDE) from the FDA
for research. It should be kept in mind that
modern TMS did not begin until 1985 [39] and
that the total number of subjects or patients to
receive TMS is likely still less than 10,000.
Nevertheless, substantial experience to date suggests that at least in the short term (<10 years),
TMS at moderate intensity has no other evident
lasting adverse effects in adults.
Overview of research uses relevant
to neurosurgery
As a research tool, TMS has been used to
influence many brain functions, including movement [40], visual perception [41,42], memory
[43,44], attention, speech [31,45], and mood [46–
48]. A full review is beyond the scope of this article
[49,50]. We discuss below the TMS uses germane
to neurosurgery.

Interestingly, in light of the initial pioneering
results of Penfield, stimulation with TMS has
never evoked the type of complex behavioral symptoms reported with direct electric stimulation in
human beings. TMS has never been reported to
provoke a memory, smell, or song as reported by
Penfield [1,2,51]. There may be several explanations for this difference between TMS and direct
cortical stimulation. First, most TMS studies are
in healthy subjects, whereas the Penfield results
were from patients with refractory epilepsy
requiring surgery. Complex behaviors have not
been provoked by TMS, even when it has been
used in epilepsy patients [35,52]. This area has
not been systematically explored, however.
Second, Penfield and Perot used high-intensity
electric stimulation that even caused seizures in
some instances. In other words, the initial
electric stimulation likely spread to other regions
through pathologically kindled neuronal circuits.
Stimulation of these circuits led to the expression of auras. Thus, most importantly, all the
complex behaviors reported by Penfield and
Perot were actually auras commonly experienced
by the patients. This fact is underappreciated
but was recently confirmed by Perot (P. Perot,
personal communication, 2002). Thus, it is likely
that TMS does not produce complex behaviors
like historic accounts of direct cortical electric
stimulation because TMS has not been delivered
in intensities high enough to cause spreading of
a seizure discharge and elicitation of auras.
Use of transcranial magnetic stimulation
and speech arrest to determine eloquent cortex
TMS delivered over the motor speech area can
produce transient speech arrest. There was initial
interest in whether TMS might be used to determine
eloquent cortex. This information could be useful in patients about to undergo surgical resection
of tumors or seizure foci. Initial reports found
that TMS needed to be delivered at frequencies
around 20 Hz, which was painful and might induce a seizure in a patient with a focal lesion or
epilepsy [52–54]. A later study showed that TMS
could be performed at lower frequencies, sometimes as low as 4 Hz [31]. There has not been a
formal comparison of TMS speech arrest with the
Wada test or functional MRI (fMRI) presurgical
mapping. Some studies have found that the TMSindicated region for motor cortex correlates well
with fMRI-predicted motor cortex and later direct neurosurgical stimulation [55]. Further work

determined both by the frequency of stimulation and the baseline state of the patient [79. personal communication 2002) and Australia [80] . Such work has yielded information about TMS neurophysiologic effects. its full and proper uses as a research tool and clinical treatment are still hampered by incomplete knowledge of the neurobiologic cascade of events triggered by TMS at different settings.69]. two studies have now found divergent effects of TMS on regional activity in depressed patients. rTMS enhances apomorphineinduced stereotypy and reduces immobility in the Porsolt swim test [68. with the opposite happening as well. Pope and Keck [73] have completed a series of studies using more focal TMS in rat models. Numerous animal studies have been important in trying to bridge this knowledge gap and improve our understanding of the modes of action of TMS. however. b-adrenergic receptor binding. high-frequency prefrontal stimulation has been found to increase brain activity over time. They have largely replicated earlier TMS animal studies using less focal coils. Combining transcranial magnetic stimulation with functional imaging A critically important area that will ultimately guide clinical parameters is to combine TMS with functional imaging to monitor TMS effects on the brain directly and to thus understand the varying 287 effects of different TMS use parameters on brain function. and immediate early gene induction [69–71]. In contrast to imaging studies with ECT. aspects of motor control.M. George et al / Neurosurg Clin N Am 14 (2003) 283–301 using TMS to help with presurgical planning for motor or speech areas is warranted [56]. such as the observation that TMS-evoked motor responses result from direct excitation of corticospinal neurons at or close to the axon hillock [67]. These two small sample studies have numerous flaws. which have found that ECT shuts off global and regional activity [75]. and Paus et al [87] used the same modality to show that prefrontal cortex TMS has reciprocal activity with the anterior cingulate gyrus. several studies combining TMS with other neurophysiologic and neuroimaging techniques have helped to elucidate how TMS achieves its effects. where the net effect of the ECT is to decrease prefrontal and global activity [75]. for patients with global or focal hypometabolism. Work with this technology has shown that prefrontal TMS at 80% MT produces much less local and remote blood flow changes than does 120% MT TMS [85].S.72]. Our group at the MUSC [76. patients with focal hyperactivity have been shown to have reduced activity over time after chronic daily low-frequency stimulation. Even with the attempt at focal rat stimulation. Strafella et al [86] used positron emission tomography (PET) to show that prefrontal cortex TMS causes dopamine release in the caudate nucleus. most studies using serial scans in depressed patients undergoing TMS have found increased activity in the cingulate and other limbic regions [76–78]. The effects of rTMS on seizure threshold are variable and may depend on the parameters and chronicity of stimulation [26. replicating some of the earlier MUSC work [84]. They simultaneously show the potential and the complexity surrounding the issue of how to use TMS to change activity in defined circuits. rTMS has been reported to induce electroconvulsive shock (ECS)–like changes in rodent brain monoamines.88] as well as investigators in Scotland (K. In particular. Conversely. The Medical University of South Carolina (MUSC) group has pioneered and perfected the technique of interleaving TMS with blood oxygen level–dependent (BOLD) fMRI. However.80].77. Corticospinal tract development. 2). TMS studies with intracranial electrodes in rhesus monkeys have provided information about the nature and spatial extent of the rTMS-induced electric field [57. Another group in Germany has now succeeded in interleaving TMS and fMRI in this manner. Rodent rTMS studies have reported antidepressant-like behavioral and neurochemical effects. allowing for direct imaging of TMS effects with high spatial (1–2 mm) and temporal (2–3 seconds) resolution [81–83] (Fig. combining TMS with functional brain imaging will better delineate not only the behavioral neuropsychology of various psychiatric syndromes but some of the pathophysiologic circuits in the brain. and medication effects on corticospinal excitability have been studied fairly extensively in nonhuman primates using single-pulse TMS [59–67]. the effects involve an entire hemisphere and cannot readily be extrapolated to what is happening in human TMS using focal coils [74].58]. Ebmeier. In other words. Use parameter effects in animal models Although TMS has been used quite effectively as a tool to investigate normal and pathologic brain function. They also point out an obvious difference from ECT. Over the past year. Because it seems that TMS at different frequencies has divergent effects on brain activity. Within the past year.

cortical excitability. TMS/fMRI images showed that lamotrigine markedly reduced the secondary effects of TMS in other cortical regions. particularly those with inhibitory mechanisms.001. (From Nahas Z. Image of blood oxygen level–dependent (BOLD) functional MRI (fMRI) data from healthy adults. cortical-subcortical connections cause changes in deeper limbic regions (8 individuals. their TMS MT was elevated by 15% compared with the day they received placebo. The initial TMS effect on cortex and the secondary synaptic changes in other regions likely differ as a function of mood state. First. factors like medications and probably diseases like depression modify the TMS-induced limbic effects. Roberts DR. we recently designed and completed a study in 12 healthy young men. where transcranial magnetic stimulation (TMS) has been applied at 120% motor threshold over the prefrontal cortex. and other factors that would change resting brain activity. where we measured the TMS MT as well as performed TMS/fMRI on 2 separate days [89]. This proof of concept study highlights several key points in understanding TMS brain effects. subjects received one single oral dose of 325 mg of lamotrigine or placebo. Biol Psychiatry 2001. 2. and mood-stabilizing effects. On the other day 1 week later. It is thus clear that TMS delivered over the prefrontal cortex has immediate effects in important subcortical limbic regions. Note that although TMS initially affects only superficial cortex. Unilateral left prefrontal transcranial magnetic stimulation (TMS) produces intensity-dependent bilateral effects as measured by interleaved BOLD fMRI. The MUSC group thus wondered whether these TMS-induced limbic effects might be modified by medications that are known to treat or stabilize mood. they received whatever they did not receive during the first session. have all shown that lateral prefrontal TMS can cause changes in the anterior cingulate gyrus and other limbic regions in depressed patients. Uses of transcranial magnetic stimulation as therapy Depression Although the functional anatomy of mood regulation is not nearly as well understood as the . extent P < 0. with permission). Most importantly. little is known about how lamotrigine works within brain circuits to achieve its clinical effects. lamotrigine increased the TMS-induced effects in limbic regions. Lomarev M. This demonstrates that lamotrigine has an inhibitory effect on motor cortex. in a randomized fashion. these TMS effects are easily seen with the interleaved TMS/fMRI and other imaging techniques. P < 0. however.288 M.50:712–720. it is abundantly clear that prefrontal TMS has direct modulating effects on limbic structures. On the day that subjects received lamotrigine. particularly its mood-stabilizing and antidepressant effects. et al. Further studies are needed to determine if this technique is useful in new compound development or in monitoring or predicting clinical efficacy. In direct contrast.05 for display on Talairach normalized MRI template). George et al / Neurosurg Clin N Am 14 (2003) 283–301 Fig. Second. Would a medication that inhibits cortical spreading of electric stimulation change the TMSinduced limbic effects? To answer this. antidepressant.S. Lamotrigine is a use-dependent sodium channel inhibitor with broad-spectrum anticonvulsant. On the first day. As with many central nervous system (CNS) active compounds in which much is known about the pharmacology. The interleaved TMS/fMRI technique shows promise as a useful new method for understanding the regional brain effects of CNS active compounds.

however [107]. most of approximately 20 studies have found modest antidepressant effects that take several weeks to build.S. and other regions commonly referred to as limbic (ie. limbic thalamus. The authors suggested that perhaps TMS works best in patients who are also clinical candidates for ECT. most scientists agree that certain brain regions are consistently affected in depression and. prefrontal TMS was superior to sham and that . Holtzheimer et al [110] analyzed both published and some unpublished sham-controlled studies and concluded that. insula) and paralimbic (ie. mania. it generated much interest in the field. Their different approaches are summarized in Table 1. orbitofrontal cortex). These include the medial and dorsolateral prefrontal cortex. and many early TMS trials were designed using this study to determine the sample size and treatment algorithms.) performed the first open trial of prefrontal TMS as an antidepressant in 1995 [104]. Meta-analyses of transcranial magnetic stimulation antidepressant effect There have now been five independent metaanalyses of the published or public TMS antidepressant literature (Table 1). indicating a moderate to large antidepressant effect. The design of this trial was unorthodox for studying depression. In general. followed immediately by a cross-over double-blind study [105]. The theory behind this work was that chronic. there were two open studies in Europe in the early 1990s using nonfocal round coils centered over the vertex to deliver TMS to broad frontal and parietal regions in an attempt to treat depression [101. 289 An initial study from Spain from a group not involving a psychiatrist and without prior treatment trial experience in depression found profound antidepressant effects in psychotically depressed patients with only 1 week of left prefrontal treatment [106]. modern TMS was specifically designed as a focal. there has been continued high interest in TMS as an antidepressant. TMS was conceived of and launched to serve as a bridge from functional neuroimaging advances in circuit knowledge to the bedside as a focal noninvasive treatment. hippocampus. The samples sizes in these antidepressant trials are thus small (in all. Since the initial studies. hypothalamus.M. beginning with these prefrontal studies. Reasoning that prefrontal and limbic regions were more important for mood regulation than the brain regions near the vertex and that theories of ECT action emphasize the role of prefrontal cortex effects [103]. one of us (M. nonconvulsive. and the funding for these trials has largely come from foundations and governments. A subanalysis was done on those studies directly comparing TMS with ECT. In a different metaanalysis. An initial meta-analysis by McNamara et al [108] of 5 shamcontrolled studies found that TMS was statistically significantly superior to sham TMS and that this difference was robust. overall. parahippocampus.G. leading to small underpowered studies using an inadequate stimulation intensity (80% of MT). perhaps reflecting subject selection bias. Each of these meta-analyses has used different methods of selecting studies as well as different methods of performing the statistical analysis of the literature. frequent. Although there is controversy and much more work is needed. when a patent was filed in Vienna in 1902 [100]. circuit-based approach to therapy. there is not a large industry sponsoring or promoting TMS as an antidepressant (or therapy for other disorders). septum. In more modern times. amygdala. to a lesser extent. George et al / Neurosurg Clin N Am 14 (2003) 283–301 circuitry of the visual or motor systems. The effect size for TMS in these studies was greater than in the studies comparing TMS with sham.S. the cingulate gyrus. certain regions have consistently been implicated in the pathogenesis of depression and mood regulation [90–99]. The notion of using something like TMS as an antidepressant dates back at least to the turn of the century. subconvulsive stimulation of the prefrontal cortex over several weeks might initiate a therapeutic cascade of events in the prefrontal cortex as well as in connected limbic regions. less than 100 subjects per trial) compared with industry-sponsored pharmaceutic trials of antidepressants.67. Multiple trials have been conducted by researchers around the world. The findings of rapid response after only 1 week have not been replicated despite numerous attempts. Since then. A thorough review of all of these trials is beyond the scope of this article.102]. anterior temporal pole. Their results are the same: daily prefrontal TMS delivered over several weeks has antidepressant effects greater than sham treatment. Nevertheless. Thus. involving 1 week of therapy per month repeated over 6 months. Burt et al [109] examined 23 published comparisons for controlled TMS prefrontal antidepressant trials and found that TMS had a combined effect size of 0. Not all TMS antidepressant treatment studies have been positive.

22 studies with Orwin’s method). L. The authors used a funnel plot technique to assess whether there was a publication bias in the literature to date and whether this bias might affect the results of the meta-analysis. right. 2002 DB. ECT. left. The fail-safe results indicated that there would have to be 56 nonsignificant unpublished studies of approximately the same average sample size as the published studies to change the cumulative meta-analysis effect to a nonsignificant result (56 studies with Rosenthal’s method. 2001 Martin et al. R. TMS WMD6.37 432 Cohen’s D=0. WMD. published and 16 unpublished Compare with ECT. 2001 Holtzheimer et al. subjects TMS effect size 5 81 12 210 Open published and 9 unpublished DB. 25–50 negative studies needed to change results 14 overall 9 Right PFCX 1 Compare ECT 1 197 40 2 weeks. which are scientifically important but are of lesser value in establishing clinical significance.7 greater than TMS Abbreviations: TMS.9.S. with the total number of subjects studied being 230. The method is not well suited to look at small effects. As the sample size of studies increases. double-blind. right=0. Cohen’s D=0. Cohen’s D=0.7 Burt et al. 2001 R and L PFCX. transcranial magnetic stimulation. left-sided treatment had a nonsignificantly greater effect size. the effect sizes should begin to converge. electroconvulsive therapy. studies No. The funnel plot (Fig.67 112 Cohen’s D=0. published and unpublished Left PFCX 230 Funnel plot shows publication bias. there is a large chance of both erroneous positive and negative results. TMS WMDDoes not allow for 0.97). DB.35 greater than sham adjustment for difference 2 weeks. Cochrane study . prefrontal cortex. In addition. These authors then used techniques to determine how large this publication bias would have to be to change the results of the metaanalysis. PFCX. George et al / Neurosurg Clin N Am 14 (2003) 283–301 Table 1 Meta-analysis of transcranial magnetic stimulation antidepressant literature Study Selection method McNamara et al. The most critical meta-analysis of the TMS antidepressant field was recently conducted using the guidelines put forth in the Cochrane Library [112]. Yet another meta-analysis was recently conducted by Kozel and George [111].21 favoring ECT Hedge’s D=0. Left PFCX. Cochrane reviews typically try to establish the clinical value of a given therapy using stringent guidelines.31–0. This study cannot be compared directly with the other meta-analyses because it looks at the field from a completely different angle.0 greater than sham 2 weeks. 3) indicates that a publication bias is likely and that there are more positive small sample studies in the TMS antidepressant literature than should occur by chance.81 Left.290 M. DB. This technique assumes that with small sample studies. 3 published Kozel and George. This analysis was confined to published double-blind studies with individual data using TMS over the left prefrontal cortex. weighted mean difference. DB. ECT WMD 1. resembling a funnel. published and unpublished Remarks Active 43% greater than sham Overall. The summary analysis using all 10 studies that met criteria revealed a cumulative effect size of 0. data 12 2002 available 248 Cohen’s D=1. DB No.53 (Cohen’s D) (range: 0.53 R and L PFCX.

with respect to whether or not TMS has clinical significance. can introduce significant bias into the results and conclusions. and also for right dorsolateral prefrontal cortex and low frequency. Janicak and colleagues [116] reported a similar small series finding near equivalence between TMS and ECT. Importantly. ECT was superior to TMS in patients with psychotic depression. Recently. Note that there are insufficient small sample negative studies (shaded oval in B). 2001). these investigators found ‘‘No difference. 3.40) are common in randomized controlled trials of novel antidepressants [113. Even this stringent meta-analysis included 14 trials suitable for analysis. which would be predicted by chance.31–0. This indicates there is likely a publication bias in the current TMS antidepressant literature. with effect sizes (A) and funnel plot (B).S. Moreover. small to medium effect sizes (0. especially in small studies. Although there is general consensus that TMS has statistically significant antidepressant effects. Grunhaus et al [115] compared 40 patients who presented for ECT treatment and were randomized to receive either ECT or TMS. groups try to include unpublished negative data to correct.65. personal communication. for publication bias. however [112]. In an initial study. .114]. . unequal initial distribution of illness severity. Thus. Thus. George et al / Neurosurg Clin N Am 14 (2003) 283–301 291 Fig. which is a moderate effect in the same range as the effects of antidepressant medications. all five metaanalyses of the TMS published literature concur that repeated daily prefrontal TMS for 2 weeks has antidepressant effects greater than those of sham. the Cochrane method does not allow for within-study adjustments for between-group differences in illness baseline and instead uses raw illness variables.between rTMS and sham TMS using the Beck Depression Inventory or the Hamilton Depression Rating Scale. but the two treatments were not statistically different in patients without psychotic depression. This same group recently replicated this finding in a larger and independent cohort with an improved design (L. a more important question is whether these effects are clinically significant. In summary. at least in part. This question has been addressed in a series of studies in which ECT referrals were randomized to receive either ECT or rTMS. Summary of transcranial magnetic stimulation (TMS) sham-controlled antidepressant studies. For example. an important clinical issue is whether TMS would be clinically effective in patients referred for ECT. both in favor of rTMS and both using the Hamilton scale’’ [112].M. Grunhaus. The major differences between these studies and the rest of the controlled studies of TMS efficacy are the . The meta-analyses dis- cussed previously concur on an effect size of Cohen’s D of 0. except for one time period (after 2 weeks of treatment) for left dorsolateral prefrontal cortex and high frequency.

There is now increasing recognition that higher intensities of stimulation might be needed to reach the prefrontal cortex. It is still not known whether TMS over one hemisphere is better than that over another hemisphere or whether there are better methods for placing the coil. especially in elderly patients. Most but not all [119] studies have used focal coils positioned over the left prefrontal cortex. whereas ECT has several.126] reported on an interesting study using either right or left prefrontal TMS in bipolar affective disorder (BPAD) manic patients admitted to their hospital for mania. TMS was performed 1 day per week over the left prefrontal cortex at 110% MT and 5 Hz for 8 seconds for 40 trains. Additionally. Current state of transcranial magnetic stimulation clinical practice for depression In summary. For the most part. however. 2001). although. personal communication. the group receiving right-sided TMS was significantly more improved than the group that had received left-sided TMS.104– 106]. lack of blinding. detailed neuropsychologic testing was not performed. four subjects dropped out of the maintenance study and were labeled nonresponders (average of 25 weeks of treatment). In a similar but slightly modified design. During this follow-up period. TMS was given daily in addition to the standard treatment for mania. TMS is potentially attractive as a maintenance treatment. Pridmore [117] recently reported on a study comparing the antidepressant effects of standard ECT (three times per week) and ECT given one time per week followed by TMS on the other 4 weekdays. Transcranial magnetic stimulation to treat mania Grisaru and his colleagues in Israel [125. which lasted only 1 to 2 weeks. he found that both regimens produced similar antidepressant effects. but one would assume that the TMS and ECT group had less cognitive side effects than the pure ECT group. This same group has attempted to replicate these findings but has not found similar results (N. which was adopted in the early studies [46. At 3 weeks. Its antimanic properties remain to be explored. were likely too brief to generate maximum clinical antidepressant effects. This method was shown to be imprecise in the particular prefrontal regions stimulated directly underneath the coil. These data suggest that TMS might eventually be used as a maintenance tool in depression and that one treatment per week might be a good first attempt at a maintenance schedule. it is unclear how best to deliver TMS. many issues are not resolved. It likely can also induce mania or hypomania in BPAD patients or susceptible patients. the left-sided group was more ill than the right-sided group on several measures. Although the literature suggests that prefrontal TMS has an antidepressant effect greater than that of sham and that the magnitude of this effect is at least as large as that of other antidepressants. TMS is a promising tool for treating depression acutely. some form of maintenance therapy is recommended. an Israeli group recently published their finding that relapse rates in the 6 months after ECT or rTMS were similar [118]. At MUSC recently. Consequently. Unfortunately. Three subjects completed 1 full year of weekly TMS without a depression relapse. After 2 weeks. Maintenance transcranial magnetic stimulation to prevent depression relapse after recovery Because of its noninvasiveness and positive safety and cognitive profile. it is still considered investigational in the United States by the FDA. where prefrontal atrophy may outpace that of motor cortex. For both treatments to maintain maximal benefit. and lack of a sham control. TMS has no measurable cognitive side effects. depending largely on the subject’s head size [120].292 M. The authors concluded that TMS might be useful as an antimanic agent. Much more work is needed. There are also emerging data that TMS therapeutic effects likely take several weeks to build. Additionally. seven treatment-resistant bipolar depressed patients who had responded to an acute TMS trial were offered admission into a 1-year maintenance therapy of weekly TMS [124]. although subjects were assigned to the two groups at random. none of the studies explicitly measured differences in cognitive side effects. Further work is needed. In sum. TMS clinical antidepressant effects are in the range of those of other antidepressants and persist as long as the clinical effects after ECT. most studies have stimulated with the intensity needed to cause movement in the thumb (MT). length of treatment (3–4 weeks). Much work remains to understand the optimum . George et al / Neurosurg Clin N Am 14 (2003) 283–301 patient selection (suitable for ECT). Grisaru. where MTs are measured [121–123]. Unfortunately. For example. presumably. Although it is approved in Canada and Israel as a treatment. the coil has been positioned using a rulebased algorithm to find the prefrontal cortex. Finally.S. many of the initial trials.

as well as a study from Japan using TMS over the prefrontal cortex at low frequencies and doses [134. this tool has clearly opened up new possibilities for clinical exploration and treatment of depression.19]. Many parameters. TMS has been used to examine cortical excitability and inhibition in Tourette’s syndrome. Thus.141]. It will perhaps always be easier to see a clinician occasionally and take daily medication rather than traveling to a treatment facility for TMS on a daily basis. scalp location. however. Schizophrenia TMS has also been investigated as a possible treatment for a variety of neuropsychiatric disorders. Another study at MUSC also found positive effects on tics and obsessive-compulsive disorder (OCD) symptoms [137]. brain regions. which were compounded by medication issues [140. pulse width. one of these early results could not be replicated [129]. 293 Three other recent studies [131–133]. but there was no effect on anxiety or obsessions. interval between sessions. a form of focal dystonia [136]. Further studies are needed. Movement disorders Anxiety disorders Some initial studies found positive effects in Parkinson’s disease [128]. however. Several studies have used TMS to investigate schizophrenia without consistent replication of early findings.M.135] report that TMS may improve effects in Parkinson’s disease. Trimble. therefore. Ebmeier. personal communication 2002). there is one report of potential beneficial effects of slow rTMS in action myoclonus [139]. intertrain interval. Moreover. coil type. coil shape. there are questions about how it might be used in treatment algorithms. the published literature on these conditions is much less extensive than for TMS as an antidepressant. and time of day. Although there are suggestions of antidepressant effects of TMS. and OCD [18. There are two small positive studies showing that TMS can benefit writer’s cramp. Reduced intracortical inhibition has been reported in all three illnesses. One study found modest and transient beneficial effects on tics when applied over prefrontal cortex (M. Greenberg et al [145] found that a single session of right prefrontal rTMS decreased compulsive urges for 8 hours. Despite these major unanswered questions.144] have used low-frequency TMS over the temporal lobes to treat hallucinations in patients with schizophrenia. The TMS MT is reduced in patients with untreated epilepsy [138].S. In a randomized trial of left and right prefrontal and midoccipital 20-Hz stimulation in 12 patients with OCD. frequency. A 1-day prefrontal TMS challenge study by Nahas and colleagues [142] at MUSC failed to find significant effects on negative symptoms. a recent study found that TMS delivered over the supplementary motor area (SMA) actually worsened Parkinson’s disease symptoms [130]. duration. frequency. It is unlikely that the initial combinations of intensity. the Other conditions . In general. After publication of a positive small abstract. those who would otherwise receive ECT. two groups have used TMS to investigate and possibly treat Gilles de la Tourette syndrome [137]. such as intensity. another group has tried to replicate this effect without success (K. or dosing strategy (daily. Some US and European psychiatrists are using TMS in clinical practice to treat depression under their general license to practice. twice daily) are the most effective for treating depression. numbers of sessions. Additionally. It should be remembered that only a small portion of the combinations of use parameters. or in patients who are unable to tolerate systemic therapy because of pregnancy [127] or a medical condition. Therapeutically. the ultimate clinical role of TMS in treating depression may be in medication-refractory cases. hinting at widespread problems in cortical excitability. number of stimuli. Further work is needed in this promising area. and some of the methods described were actually not credible. location. Using TMS probes. personal communication 2002). since the first use of prefrontal TMS as an antidepressant in 1995. Mood was also transiently improved. conclusions about the clinical significance of effects must remain tentative until large sample studies are conducted. if any. dystonia. Important unanswered clinical questions It is not clear which. Hoffman and colleagues [143. George et al / Neurosurg Clin N Am 14 (2003) 283–301 dosing strategy for the antidepressant effect of TMS. remain to be systematically explored. and dosing schedules have been tried. medications work well with TMS or interfere with its therapeutic effects. Although they have replicated their earlier study.

This radical notion was not easily accepted by the field as recently as 8 years ago. in fact. Only two other studies have examined possible therapeutic effects of rTMS in OCD. it is possible to use MST to examine the roles of the location of seizure onset and patterns of seizure spread in the antidepressant effects and cognitive side effects more precisely than one could do with ECT. Because MST offers a focal means of inducing seizures. In contrast. Recent research in ECT and new work in TMS have challenged both aspects of that theory with respect to the antidepressant potential of brain stimulation. A potential new way of using transcranial magnetic stimulation–magnetic seizure therapy as an antidepressant The discussion throughout this article has focused on using TMS to change brain function without inadvertently causing a seizure. thus. a seizure cannot be sufficient [154. who were randomly assigned to right or left prefrontal fast rTMS. because it challenged the then widely held dogma that a seizure was needed for ECT.155]. What we have learned about the features that distinguish effective from ineffective seizures has guided the development of MST as a more targeted way of producing an effective treatment that should be less contaminated by the consequences of generalization to regions of the brain linked to cognitive side effects (medial temporal structures). Additionally. As mentioned previously. Although ECT is the most effective antidepressant. TMS at high frequencies and intensities can cause seizures. This is possible with TMS. A double-blind study using right prefrontal slow (1 Hz) rTMS and a less focal coil failed to find statistically significant effects greater than those of sham [148]. personal communication. Grisaru et al [151] similarly stimulated 10 PTSD patients over motor cortex and found decreased anxiety. Grisaru and colleagues also reported a positive TMS study in PTSD patients (N. further work is warranted testing TMS as a potential treatment for OCD. an anticonvulsant treatment method). it still requires repeated episodes of general anesthesia. After a proof of concept demonstration in primates [152]. whereas the direct application of electricity to the scalp with ECT loses focality and power as a result of the impedance of the overlying tissue.294 M. Further work is needed. personal communication 2002). First. of the scalp and skull. The long-held dogma in the field of convulsive therapy was that a seizure was necessary and sufficient to constitute an effective treatment for depression. because magnetic fields pass through the scalp and skull unimpeded. and by extension. it has cognitive side effects and does not work in up to half of treatment-resistant patients. An initial safety study found that MST seizures were briefer in duration than ECT seizures. one might be able to focus the point of origin of the seizure and thus spare some brain regions from unnecessary exposure to electric currents and to seizure spread.161] add weight to the notion that somatic treatments can improve mood without causing a seizure (VNS does not cause seizures and is. under anesthesia. the recent reports of mood effects with DBS also underline the point that nonconvulsive . which was unrelated to intracortical inhibition and seems to replicate (E. In addition to not being sufficient. ECT produces a seizure through direct electric stimulation.S. George et al / Neurosurg Clin N Am 14 (2003) 283–301 same group reported decreased intracortical inhibition in patients with OCD [146]. any form of transcranial stimulation to be effective in treating depression.M. Somewhat surprisingly. it was demonstrated that it was possible to generate seizures with ECT that lacked efficacy. which has also been noted in patients with Tourette’s syndrome [19]. 2001). and that their acute cognitive side effects were much less with MST [153]. a recent open study in a group of 12 OCD patients refractory to standard treatments. Further clinical and preclinical work with this exciting technique called magnetic seizure therapy (MST) has proceeded. Wassermann. found that clinically significant and sustained improvement was observed in one third of patients [149]. recent work with TMS has challenged the theory that a seizure is necessary at all [156]. Clearly. that patients awoke from anesthesia much faster with MST. If one used TMS to induce an ECT-like seizure. Further work is underway to determine whether this technique has antidepressant effects. The recent suggestions of antidepressant effects of vagus nerve stimulation (VNS) in treatmentresistant depressed patients [157–159] as well as in comorbid epilepsy and depression patients [160. Because MST induces a seizure. Grisaru. Lisanby et al [36] used an enhanced device with four times the usual number of charging modules to induce seizures in depressed patients referred for ECT. OCD patients had a lowered MEP threshold in one study [147]. McCann et al [150] reported that 2 patients with posttraumatic stress disorder (PTSD) improved during open treatment with 1 Hz of rTMS over the right frontal cortex.

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[160] Elger G.25:713. Pollak P. Labar DR. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy. Biol Psychiatry 2000. Ravdin LD. Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy. Wassermann EM. Vagus nerve stimulation (VNS) for major depressive episodes: longer-term outcome. et al.339:1105. Rush AJ. Rush AJ. Pulver MC. Conv Ther 1994. Prudic J. et al.47:276.1:93. Epilepsy Res 2000. Krack P. [161] Harden CL. side effects and predictors of outcome. George et al / Neurosurg Clin N Am 14 (2003) 283–301 [155] Sackeim HA. Biol Psychiatry 2002. N Engl J Med 1998. Vagus nerve stimulation is associated with mood improvements in epilepsy patients. et al. George MS. George MS. Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1993.M. Elger CE. A pilot study of mood in epilepsy patients treated with vagus nerve stimulation. [157] Rush AJ. Nikolov B. 301 [159] Marangell LB.328:839.42:203. . [156] George MS.10:251. Neuropsychopharmacology 2001. Rapid-rate transcranial magnetic stimulation (rTMS) and ECT.S. Rush AJ. Halper JP. Hoppe C. Vagus nerve stimulation (VNS) for treatment-resistant depressions: A multicenter study. Devanand DP. et al. et al. Falkai P. Epilepsy Behav 2000. Sackeim HA. [158] Sackeim HA. [162] Limousin P. George MS. 51:280.

for example. doi:10. ever beset with the common and fatal facility of reaching conclusions from superficial observations. Can today’s investigators avoid the moral blindness of their predecessors? Will society tolerate this new foray into somatic therapy and seek to regulate it as legitimate science. congressional calls for a ban [3]. Elsevier Inc. All rights reserved. Editorialists like William Safire have raised questions about the world of ‘‘neuroethics’’ [11]. our enthusiasm is immediately tempered by history.Neurosurg Clin N Am 14 (2003) 303–319 From psychosurgery to neuromodulation and palliation: history’s lessons for the ethical conduct and regulation of neuropsychiatric research Joseph J. psychiatric. Just a generation ago. asserted that these new developments in neurobiology pose a ‘‘greater threat to human dignity’’ than the debate over cloning [10]. or will a lingering memory of psychosurgery be so overwhelming as to make this impossible? Lay journalists covering the most exciting developments associated with deep brain stimulation often ask these questions [9]. F-173. Weill Medical College of Cornell University. Now. We expect that.5] and the modulation of consciousness in traumatic brain injury [6–8]. USA We are certain that these experiments shall stir up keen discussions in the medical. 1903 Optimism tempered by history As we contemplate the emerging era of neuromodulation and imagine the utility of deep brain stimulation for disease entities in neurology and psychiatry. but hope at the same time that this discussion shall promote the progress of science and above all the benefit of mental patients [1]. such as obsessive-compulsive disorder (OCD) [4. philosophical.edu ment of Parkinson’s disease and contemplating their use for severe psychiatric illnesses. Egas Moniz. Departments of Medicine and Public Health. the doctors. but they only tell part of the story. William Osler. New York–Weill Cornell Medical Center. other confident investigators were heralding invasive somatic therapies like prefrontal lobotomy to treat psychiatric illness. just 30 years later. 525 East 68th Street. the link between psychosurgery and present efforts in neuromodulation is clear. New York. In the lay press. Historical analogies are important. Fins. social and other fields.We. From a scientific 1042-3680/03/$ . neurosurgeons. neurologists. 1936 .see front matter Ó 2003. A recent editorial in The Economist. That era of psychosurgery ended with widespread condemnation. and psychiatrists are implanting deep brain stimulators for the treat- E-mail address: jjfins@med. or cognitive function. NY.cornell. Any student of medical history would have to ask if these developments are ethically appropriate and whether the promise of neuromodulation will be able to transcend the potential peril associated with the manipulation of motor. and the message has been cautionary [13]. and a vow that history should never repeat itself. and constantly misled by the ease with which our minds fall into the rut of one or two experiences [2].1016/S1042-3680(02)00118-3 . and The Washington Post Magazine featured a story on the lobotomist Walter Freeman in response to the excitement over deep brain stimulators [12]. . . are so fallible. psychiatric. MD Division of Medical Ethics. psychological.

efficacy. They have a more benign side effect profile and demonstrate evidence of efficacy for some refractory neuropsychiatric conditions [16]. As we shall see. such as the decline of physician paternalism and the emergence of civil and patient rights [20] reflected in the establishment of bioethics think-tanks like the Hastings Center and the regulatory efforts of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Although these scientific differences are significant. Current psychosurgical procedures utilize modern neuroimaging techniques and are more precise and procedurally diverse. although still a nascent area of investigation. psychosurgery destroyed vital brain tissue through lesioning. These lesions were also permanent. The emergence of neuromodulation as credible science with real and potential clinical applications. far exceeds what was known to psychosurgeons at midcentury [17]. In addition. many of the regulatory recommendations made by the National Commission. Ironically. This lacuna in the law necessitated the Clinton era 1998 National Bioethics Advisory Commission’s ‘‘Report on Research Involving Persons With Mental Disorders That May Affect Decisionmaking Capacity’’ [21]. such as the proposed National Psychosurgery Advisory Board or recommendations on research involving the institutionalized mentally infirmed.19]. There was no mechanism to collect these arguments and regulate these activities. today. deep brain stimulation seeks to modulate brain function through the insertion of electrodes. a more salient distinction is the respective historical and cultural contexts of psychosurgery and neuromodulation. whereas the presently known effects of neuromodulation are reversible. clinical investigators are supported by an extensive platform of structural and functional neuroimaging and detailed anatomic and electrophysiologic studies that allow for more precise hypotheses concerning neural systems underlying disease states.15]. Historically.304 J. In the treatment of Parkinson’s disease. however. By reviewing the history of the psychosurgery movement. although often cogent and well informed. Earlier critiques. In contrast. Although both are somatic therapies. It would take broader societal changes. is emerging both against the historical backdrop of psychosurgery and within an ethical and regulatory context that should be far more attentive to human subject protections. never went into law. As we shall see. Today. Neuromodulation. the permanent cognitive impairment seen with psychosurgical ablation does not occur with deep brain stimulation. Sadly. Deep brain stimulation procedures for movement disorders are covered in the United States by Medicare and have become the standard of care for refractory disease. Modern neuromodulation’s knowledge base. individuals who criticized their colleagues’ practice of psychosurgery in the literature or at national meetings were powerless to ensure that their concerns were heard at the psychosurgeon’s home institution. Psychosurgical operations of the past were crude and their rationale was based on a mix of anecdotal experience and supposition [14. makes it essential that we revisit these earlier ethical and clinical debates so that the hard-won wisdom and scholarship of earlier eras . and lack of therapeutic response. Fins / Neurosurg Clin N Am 14 (2003) 303–319 standpoint. much of this history has already been forgotten or deemed irrelevant. I will maintain that this was possible because there was no mechanism to regulate the conduct of these practices until the advent of modern bioethics in the late 1960s and early 1970s as a scholarly discipline able to influence clinical practice and public policy. In an oddly analogous way. these advances have coalesced so that neuromodulation is now a mature and established therapy for refractory disease [18. there are critically important differences between psychosurgery and neuromodulation. before broader regulations governing clinical research were put into place.J. These improvements have led to greater procedural precision and better diagnostic capacity to identify mechanisms of action. psychosurgery developed before the rise of modern bioethics. There are also important differences between Freeman’s prefrontal lobotomy and psychosurgical procedures performed today. this is yet another set of recommendations that have yet to be ensconced in Federal regulations. were unable to influence clinical or research practice because they were made in a practice environment that had yet to overcome the prerogative of the physician to direct care without additional oversight. I will demonstrate that this work continued in an unregulated and ethically disproportionate fashion despite well-articulated and early criticism. the debate over lobotomy and psychosurgery has gone the way of a Tommy Dorsey long-playing record or a Led Zeppelin eight-track tape.

This implies a thorough understanding of the physiological and psychobiological functions which may have a bearing on the proposed treatment. Oskar Diethelm.J. neurologists. the New York psychiatrist urged professional humility. All was not sanguine in professional circles. that is lay people. He warned of the vulnerability of lay people to the latest scientific trend and the powerlessness of patients. In 1949. He cautioned investigators to have some humility in their speculations and an awareness of the investment that they have in their own theoretic speculations. the citation on his medal read simply.23]. The pleasure of being an inventor and pathfinder is alluring but leads to all the dangers of adventure [30]. It was viewed as a therapy of last resort and positively portrayed in the American media. ‘‘For his discovery of the therapeutic value of prefrontal leucotomy in certain psychoses’’ [27].it is important in medicine to recognize fully the responsibility with regard to those who follow voluntarily that is the physicians. In the era before the introduction of antipsychotics. to those who follow blindly. prefrontal lobotomy offered a potential therapy for the severely and persistently mentally ill who otherwise would require institutionalization. ‘‘who are forced to follow’’: . As early as 1938. In the same address. It should be an inflexible duty to become thoroughly familiar with the drug or procedure to be employed. Diethelm anticipates the Nuremberg Code with its emphasis on the scientific basis of human experimentation and the centrality of informed consent and voluntariness [31]. at least in the early years after its introduction [29]. No one has the right to invent theories to suit his desires without having given full consideration to what has been established or found plausible [30]. When psychosurgery was therapy It is one of those strange paradoxes in history that 2 years after the articulation of the Nuremberg Code and the development of the sterotactic technique. ne´e psychosurgery. The understatement in this inscription fails to capture the lack of effective therapy for severe mental illness and the desperation of patients and the frustration of their families and caregivers. . His comments were more generic and directed toward the growing place of somatic therapy in psychiatry. A young psychiatrist attending the same meeting tells us that. to OCD. he observed: In any scientific treatment which is not fully understood there is the serious danger of not being able to predict possible damage. a contemporary of Freeman and Watts in the United States. In an address at the Annual Meeting of the American 305 Psychiatric Association in San Francisco. . In these comments. Fins / Neurosurg Clin N Am 14 (2003) 303–319 can help to navigate what will be demonstrated as recurrent ethical challenges. a subdiscipline of the field of which psychosurgery would become a part. and neurosurgeons who are destined to face challenges that their forbears could only have imagined. just 3 years after the initiation of the Tuskegee Syphilis Study [25]. and personhood are now resurfacing in the debate over applying neuromodulation techniques. He began his work in 1935 [24]. his work was hailed as being at the vanguard of therapeutics for severe mental illness [28]. Many familiar questions about consent. he urged investigators to assume as ‘‘an inflexible duty’’ to gain knowledge of the mechanism of any proposed therapy [30]. the Nobel Prize celebrated Moniz’s work in medicine and physiology. When Moniz was given the prize. that is the patients. . however. Both the Tuskegee Syphilis Study and psychosurgery would be criticized decades later as an abrogation of patient rights invoking the same ethical principles articulated in the Nuremberg Code. there was no mention of Moniz’s work at the conference and that Diethelm did not mention lobotomy specifically in his address [32]. Egas Moniz won the Nobel Prize for the development of the prefrontal leukotomy [22. To mitigate against these excesses.J. as yet. It is my hope that a reconsideration of this rich history in light of these promising scientific developments will deepen the insight of a new generation of psychiatrists. Specifically. Diethelm’s warnings would be applicable to the leading proponents of psychosurgery as illustrated by the hubris of both Freeman and Moniz. coercion. the first of many psychiatric entities to which this modality may be applied. poignantly warned about the emerging somatic therapies in psychiatry [30]. Diethelm implicitly commented on issues that would later inform the literature on informed consent. and to those who are forced to follow. Although some have maintained that the Nobel Prize was really meant for Moniz’s more enduring discovery of cerebral angiography [26]. however.

. . he suggested that more attention needed to be paid to cognitive impairment and the late effects of scarring. There have been some private cases. of what actual. ‘‘There must be developed a technique of measuring very carefully both the existing function and the defect in the individuals before and after the operation’’ [35]. it is difficult to imagine that the patients who come from state hospital populations are getting the benefit of that type of treatment [35]. are based on conflict. Weinberger was a second-year fellow in neurologic surgery at the University of Pennsylvania and had traveled to the Delaware State Hospital to meet Freeman and to learn how to perform the novel procedure. Grinker was Chief of the Division of Neuropsychiatry at Michael Reese Hospital in Chicago.’’ Ultimately.’’ He was particularly aware of the vulnerability of most of the patients who came from state facilities and whose preoperative assessment was suspect: .J. He also noted the vague way in which cognitive defects were described noting. . he met Freeman in the spring of 1938. thoroughgoing psychologic study and treatment means. Freeman’s method of patient selection and his ‘‘purely observational’’ technique of determining who might be a suitable candidate for surgery mortified Weinberger. he demonstrated the traits that Diethelm believed were so dangerous in a clinical investigator. Weinberger recalls that as a young physician.’’ Given the irreversibility of the procedure. He expressed his ‘‘surprise’’ that patients were lobotomized after only a few months of mental illness before a spontaneous remission might occur and in young patients in their 30s. .mutilating operation that destroys brain tissue. I cannot believe that the recoveries can be explained upon simple coincidence. . Weinberger reported being ‘‘squelched’’ and saying no more [34]. it is true. . there is no return. he summarily dismissed any discussion of the risks and benefits of his prefrontal leukotomy. which might lead to the development of seizure disorders. It is sometimes very tedious and very costly. The recoveries have been maintained. Grinker also observed that a technologic solution to psychic problems was not always in order. the things which one wants to relieve. always safe. At that time. but if it were more possible we would not hesitate to ask for more psychologic work in state hospitals rather than more operating rooms [35]. too. He would later become a training analyst and Editor-inChief of the Archives of General Psychiatry [36]. . This can not always be done. Grinker questioned Freeman’s methodology because ‘‘. although the alternatives were often more time-consuming and taxing: It is obvious that if the anxiety and suffering. but when one thinks of what conservative treatment means. Roy Grinker publicly questioned Walter Freeman at a panel discussion before the Section on Nervous and Mental Diseases at the annual session of the American Medical Association held in Cleveland in 1941 [35]. Just months before the American Psychiatric Association meeting. Concerns were not limited to junior trainees.was answered with a prolonged silent stare and finally one word: ÔExperience!Õ’’ [34]. In an early summary article originally published in the American Journal of Psychiatry in 1937. . which may prove to be an effective surgical treatment in certain cases of mental disorder [33]. he voiced concern about how patients were selected for the procedure and the vagueness of entry criteria that required the patient to have failed ‘‘conservative measures. Freeman.We are dealing with a large number of patients who have been chosen from state hospital populations. Fins / Neurosurg Clin N Am 14 (2003) 303–319 Moniz himself was smug and overly optimistic about his work and methods. was overly confident.a great deal of preconception and emotional bias. . about which he acknowledged ‘‘. Grinker sought to moderate attitudes toward lobotomy. Lawrence M. He asked Freeman about his selection criteria and ‘‘. He also questioned the application of the procedure to a wide range of diagnoses and was concerned about the postoperative defects and the means to assess their impact on intelligence.306 J. . He simply concluded by asserting: Following this exposition I do not wish to make any comment since the facts speak for themselves.’’ He acknowledged that there was controversy between those who believed that the psychoses had an organic basis and might be amenable to ‘‘physical therapy in psychiatry’’ and those opposed to a ‘‘. Prefrontal leucotomy is a simple operation. the rational basis of treatment is a psychological therapy. These were hospital patients who were well studied and well followed.once one cuts. Addressing the risks of the procedure. .

. During this meeting. such as hospital discharge. although lobotomy was being used as a therapy in the community. In spite of growing professional uncertainty about the effectiveness of the procedure and its safety. his well-considered concerns about methodology. . . patient selection. .J.I do not think this is the time to disseminate it widely to the profession or to the public.000 Americans were lobotomized. . Diethelm noted that the operative procedures under consideration had ‘‘undergone considerable modification’’ [43]. he asserted that: I do not believe that the surgeon can assume the responsibility of being the operator at the behest of his neurologic and psychiatric friends and say ‘‘I did it because they told me to. ‘‘although we seem well warranted to continue the procedure. .44] and concerns about the side effects of the procedure [45]. 19. it was that a majority of assembled experts urged the adoption of a ‘‘. public sentiment was positive enough to compel the Veterans Administration and state hospitals to introduce the procedure after the war [38]. he cautioned that ‘‘.’’ Unfortunately. it is not even clear that psychosurgery. Instead. . Grinker’s pointed-and balanced-criticism of the lobotomy in 1941 had little impact. methodologic issues remained a concern. ‘‘. Although articulated at conferences or in journals. could be a result of the patient’s family situation [42]. It is estimated that nearly 3000 returning veterans underwent psychosurgery [39]. as I am not iconoclastic about the operation. as performed now. he saw it not as a therapy but ‘‘still an experiment. Fins / Neurosurg Clin N Am 14 (2003) 303–319 Building on a therapeutic approach that was broader than the merely surgical. Indeed. Experts were unable to reach a consensus except to conclude that ‘‘.’’ Until those limitations became better understood.000 to 20. Although he urged restraint and viewed lobotomy as experimental. with patients individualized by diagnosis or other category. . Efforts to introduce quantitative analysis were complicated. these concerns did not decrease the incidence or popularity of the procedure. with many of those subjected to the procedure being returning veterans [37]. because markers of improvement. Without equivocation. It was against this imprecision that experts agreed that there was a need for a comprehensive means of engaging in outcome measures to discern whether the procedure was efficacious and on which subjects. Eleven years after Weinberger personally questioned Freeman about his method of selecting patients and evaluating outcomes. Grinker’s criticisms are all the more credible because he did not categorically condemn the procedure. Although Grinker’s early criticism did little to stem the tide of lobotomy.J. It is estimated that by 1951. however.an enormous amount of further research is an imperative need in nearly every aspect of the field’’ [40]. In the second edition of his comprehensive textbook on psychiatric treatment. Despite growing controversy about the safety and efficacy of psychosurgery at subsequent national conferences [40.universally accepted rating scale.[to] provide an effective method for both case-selection and evaluation of operative results’’ [40]. . and the morbidity associated with the procedure would be revisited by the First Research Conference on Psychosurgery convened by the National Institute of Mental Health in 1949 307 [40]. the editor observed that. outcome data. is more beneficial than harmful’’ [40].’’ He must assume the responsibility of insisting that before such operations are done all conservative means—and by ‘‘conservative means’’ I mean thorough going psychological treatment-have been employed [35]. .’’ Amid proponents and critics of psychosurgery. .perhaps might disappoint some. . these criticisms had little impact on the incidence of psychosurgery in the . He viewed these modifications as evidence of what he described as ‘‘therapeutic insecurity which should exert a strong critical hesitancy on the part of the clinician who is considering surgical procedure’’ [43]. the procedure was widely disseminated as therapy over the next 10 years.’’ He believed that the operation had a ‘‘usefulness’’ but that ‘‘the delimitations of its usefulness have not been clarified. Among these needs was greater clarity about whom the procedure was being performed on and how patients fared. Grinker also outlined the professional responsibilities of the surgeon and his obligation to ensure that adequate assessment occurred before any procedure was performed. he confessed that his point of view. One thoughtful commentator on that era has maintained that the patient’s diagnosis was less relevant than the severity of the patient’s symptoms in determining whether or not he or she would be a surgical candidate [41]. if any consensus was achieved at the First Research Conference on Psychosurgery.

some 6000 patients were operated on in the United States alone [46]. . The authors of this study. Most critically. The popularity of the procedure needs to be contextualized against the dismal condition of state mental hospitals and the absolute lack of effective treatment for the persistently and chronically mentally ill.While there are many limitations and failures with this treatment.Lobotomy is not a cure-all but it can well be regarded as an encouraging therapeutic weapon for a very malignant disease [48]. Indeed. The comments we have heard occasionally to the effect that postlobotomy patients lack judgment. . Rosemary Kennedy. Between 1936 and 1946. maintained that psychosurgical procedures like cingulotomy retained a role in conjunction with standard psychiatric care for refractory patients. It was the social uses of psychosurgery for what was called behavior control that. destructive. Possibly only those who have served in a state hospital can appreciate fully these problems. Nolan Lewis. However. The question was not whether lobotomy altered the status of the patient’s symptoms but whether the cognitive side effects were justified [49].000 procedures had been performed in the United States. Thomas Ballantine. they are overshadowed by the generally satisfactory and not infrequently brilliant results. that caused a furor during that era. for example. As distinct from its earlier iteration as a means to address a patient’s depression or schizophrenia. Fins / Neurosurg Clin N Am 14 (2003) 303–319 United States. with some 4000 estimated by Freeman to have been done or directed by him in 30 hospitals in 15 states nationwide [47]. and cannot.. was among those operated on. such as the Harvard neurosurgeon H. he condemned the use of psychosurgery for political or social purposes. Director of the New York Psychiatric Institute. plan a meal or play a good game of bridge seem to lack satisfactory perspective when one regards the level from which these individuals were plucked. It is still difficult to assess the extent to which technical difficulties or inherent resistance of the disease process contribute to operative failures. which mostly involved patients with schizophrenia. who would also make psychiatric follow-up available. untidy. sociobiologists began to suggest that psychosurgery might have a role in addressing problems like violence or civil unrest. Decisions to operate were to be made in conjunction with a psychiatrist. . such as chlorpromazine in 1954. the lack of an effective alternative would have been sufficient to keep the procedure in ‘‘common use’’ [51]. maintained that: and not on the important issue of efficacy.. criticism of lobotomy hinged on the question of side effects Psychosurgery and the body politic . By the late 1950s. 40. He articulated guidelines to regulate the judicious use of the procedure for the relief of the patient’s suffering and improvement of functioning in society.308 J. One representative report from a state hospital during that era describes lobotomy as a ‘‘fruitful method in the treatment of chronic mental illness. and patients and family were to be informed of potential risks and benefits.000 to 50.J. Amid the social turmoil of that era.4% of patients being able to be discharged from hospital after the procedure [48]. which Ballantine and others condemned. It is perhaps hard to Although studies like this one failed to take into account a potential placebo effect or the possibility of spontaneous remission. and combative to the point of requiring half a dozen attendants to carry out the basic necessities of personal care-become a quiet cooperative individual. it is truly gratifying to observe a patient who was previously a tremendous problem in managementsecluded. this more modern dimension of psychosurgery sought to modify behavior. assisting with various ward tasks. Not even chlorpromazine was enough of an advance to remove psychosurgery entirely from therapeutic consideration in the 1960s and early 1970s. asked whether ‘‘the quieting of a patient’’ was indeed a ‘‘cure’’ and worried about the number of ‘‘zombies’’ and ‘‘mental invalids’’ produced as a consequence of the procedure [50]. The decline of psychosurgery was not prompted by ethical concerns but rather by the advent of modern psychopharmacology and effective therapy for psychoses with the major tranquilizers. Some physicians.’’ with 37. two commentators have opined that even with the growing backlash against psychosurgery in the early 1950s. taking pride in her personal appearance. articulating instead a solely patient-centered rationale for the procedure [52]. and finally returning to her own home. aggressive. Procedures were to be reserved for patients who failed all other methods of treatment. Jr. the sister of President Kennedy.

future man with greater personal freedom and originality. and better balanced than present man’’ [54]. Coupling psychosurgery with burgeoning efforts in computer technology and solid state electronics. they were able to demonstrate a left temporal horn lesion by means of a pneumoencephalogram in a young woman with TLE in whom violent outbursts were inducible using implantable electrodes and telemetric equipment supplied ‘‘through the courtesy and assistance of Dr Delgado’’ [65]. It adds to. social. Much of their work hinged on seeking to demonstrate the relation between organic brain disorders. Mark. Delgado. he did foreshadow developments in psychiatry. moving that field from being dominated by psychoanalysis and ‘‘political psychiatrists’’ toward those having an interest in the organic basis of disease [67]. A physician and physiologist working in the Department of Psychiatry at Yale University. and the Department of the Air Force [60. Delgado came to international attention in 1965 when he returned to his native Spain for a now famous publicity stunt in which he demonstrated the potential of his work by stopping a charging bull in Cordoba’s bullring using a ‘‘stimociever’’ he had developed [55]. Echoing Delgado’s notion of ‘‘greater personal freedom. and does not diminish. and even philosophical implications. noting that ‘‘We are certainly facing ethical. Using notions of self-dominion. but this danger is quite improbable and is outweighed by the expected clinical and scientific usefulness of the method’’ [63]. his human qualities’’ [66]. less destructive.’’ Nonetheless. which had explosive political consequences when first introduced. but they were quite real. and mental disorders’’ [62]. intractable pain. and practical problems not exempt from risks. Delgado studied aggression in primates and then manipulated their response through the use of implantable electrodes. and violent or aggressive behavior. . psychosurgery for social control is highly unlikely. his dignity. such as temporal lobe epilepsy (TLE). Although many of Mark’s aspirations for psychosurgery seem overly optimistic. some of whose work was funded by the United States Public Health Service.J. control over his own behavior. and Vernon H. but we should also expect important medical application of the new methods to epilepsy. philosophic. One news report in the Medical News column in the Journal of the American Medical Association sought to reassure the wary reader that ‘‘Logistically.58]. Delgado. simply because there are not enough neurosurgeons’’ [53]. Delgado’s work raised concerns about the possibilities of mind control. who together coauthored Violence and the Brain [64].R.J. and does not detract from. Fins / Neurosurg Clin N Am 14 (2003) 303–319 imagine today that there could be serious concerns about such futuristic attempts at social control. He acknowledged concerns about the ethical implications of his work and urged ‘‘intelligent collaboration of the best minds’’ to address the field’s ‘‘fundamental medical. In one early case. His position might be best summed up by his observation that ‘‘Fears have been expressed that this new technology brings with it the threat of possible unwanted and ethical remote control of the cerebral activities of man by other men. involuntary movements. argued that society was on the cusp of a new era in which the human mind could influence its own evolution through the use of technology. a member of a psychocivilized society. a psychiatrist at the Neuropsychiatric Institute at the University of California at Los Angeles. This second period in the history of psychosurgery could be said to have begun through the work of Jose M. thus resurfacing the question of mind control. It enhances. he urged continued scientific progress. He wrote about the ‘‘absurd split’’ and the: . Recent reports in the lay press describing a remotely controlled ‘‘cyborg’’ rat with a brain implant [56] alluded to Delgado’s work [57. arguing that ‘‘a better understanding of the neurophysiological mechanisms responsible for aggressive and destructive reactions may provide man with greater capacity to educate and direct his own behavior’’ [59]. 309 Delgado analogized cerebral pacemaking to the growing role of cardiac pacemakers as a means to suggest the utility of brain pacemaking in the future. ultimately leading to a ‘‘. . and his legacy remains a lingering question for the current era of neuromodulation.’’ Mark maintained that ‘‘I believe the correction of that organic condition gives the patient more rather than less. the Office of Naval Research.61]. Leading proponents of psychosurgery for the control of violence were Frank R. Delgado advanced the idea of ‘‘psychocivilizing society’’ using an implantable brain implant that could be operated by remote control [54]. a Harvard neurosurgeon. happier. Ervin. he envisioned an escape from the blind chance of normal evolution to one where man and technology would alter human history.

Breggin sought to characterize psychotherapy and on a continuum of a totalitarian-libertarian axis in which a ‘‘high degree of autonomy and personal freedom characterizes more libertarian therapies’’ [74]. physicians tend to categorize a few abnormal behaviors. Fins / Neurosurg Clin N Am 14 (2003) 303–319 . Breggin’s accusations seem more suited to the clinical work of Freeman than to the positions taken by Mark. political and spiritual crime. If America ever falls to totalitarianism. ‘‘Does the theory that some violence is caused by brain disease lead us to expect it is a characteristic mainly of black people? Certainly not. In retrospect. living conditions. claret is the predominant color [of violence]. ‘‘It creates for themselves an elitist power over the human mind and spirit. In Congressional hearings before the Subcommittee on Health of the Senate Committee on Labor and Public Welfare. these views seemed to have engendered a backlash from the more purely socially oriented practitioners who saw psychiatry in political or sociologic terms [69]. As much as his work in psychosurgery. In a talk delivered at the Hastings Center’s Institute of Society. He was deeply suspicious of how psychosurgeons sought to regulate their activities through review committees that relied on ‘‘professional ethics and medical control’’ to maintain physician control of the situation. Citing the prevalence of domestic violence across all demographics. . Many of them view these behaviors as nothing but the reflections of particular environments. public psychiatric hospitals and psychosurgery were seen as vectors of social control and described as ‘‘custodial concentration camps’’ and ‘‘powerful totalitarian technologies. . Breggin charged that psychosurgeons were unethical because of how they obtained consent for the procedures they performed. Reacting to a brief letter he wrote with colleagues to the Journal of the American Medical Association in 1967 on the potential relation between brain disease and urban riots [71]. and suspicion. where he was Director of Neurosurgery. In this context.historical dichotomy between Ôpurely organic’ and Ôpurely social’ abnormalities. Breggin said. And by the way. Mark’s attempt to address organic illness with due attention to the patient’s voluntary consent comes across as moderate during immoderate times prone to hyperbole. overreaction. At the same time.’’ respectively. At Boston City Hospital. Ultimately. There was a prevailing sense of alarm that psychosurgery was being broadly applied in law enforcement. a Washington social psychiatrist. This schism made Mark the target of what he described as an ‘‘anti-psychiatry campaign’’ [70]. he asserted that ‘‘From this perspective. . Contemporary accounts of that era observed that one of the ‘‘appeals’’ of psychosurgery was viewed as the willingness of law enforcement agencies to embrace this technology for the purpose of addressing seemingly intractable problems. he sought to refute the charge of racism lodged against the neurosurgical treatment of violent epileptics [76]. certain other abnormalities. he sought to overcome the dichotomous practices of his neurologic and psychiatric colleagues and to develop a ‘‘holistic’’ therapy in which ‘‘. On the other hand the theory that personal violence is caused exclusively by social conditions might very well lead us to look at the black ghettos. . Ethics and Life Science’s Working Group on Behavior Control. Indeed.J. Specifically. such as paralysis. such as depression and aggression. He would consistently maintain that violence was colorblind in both domestic and international contexts [77].Lobotomy and psychosurgery is an ethical. It is very important. blindness and dementia as neurological problems. lobotomy is still with us. job and role in society. One international . This assault on psychosurgery was led by Peter Roger Breggin. both rich and poor as well as black and white. A self-described political conservative and civil libertarian [73]. therefore. sociologists and criminologists. . . have found a hard niche within the domain of the psychiatrists. They tend to believe that brain function or dysfunction is not an important determinant of abnormal behavior [68]. to imbed a neurological diagnosis of problems of violence into a larger integrated approach to human behavior. he also advocated a ‘‘committee of some sort’’ that would oversee consent while not accepting patients who do not want therapy.310 J. Mark was accused of racism by proponents of social psychiatry [72]. not black or white’’ [76]. who was opposed to any social application of his work. the dictator will be a behavioral scientist and the secret police will be armed with lobotomy and psychosurgery. He asked.treatment of a patient should involve not only his brain but his family. It should be made illegal’’ [75]. The environmental cues to personal violence may very well cluster around racially differentiated areas’’ [76].’’ Along these lines of comprehensive care. he was one of the first to advocate an ‘‘integrated approach’’ to psychosurgical care.

Virginia. This prevalence data concerning psychosurgery for nonmedical purposes was corroborated by a study conducted by the American Psychiatric Association Task Force on Psychosurgery and by the work of the National Commission.’’ He added that ‘‘When it was considered we were reluctant to face the opposition and destroy our image in the black community.J. fears of psychosurgery transcended the internecine battles of psychiatric subdisciplines. not all were in opposition. Dr Jesse Barber. If behavior modification was done at all. ‘‘I personally feel guilty about not developing a program (of psychosurgery) at Howard University. the issue of behavior control dominated the deliberations of advocates of all stripes whether they were physicians.is due not to discrimination on the part of surgeons but to the economic realities and public policy’’ [81]. she notes that ‘‘In dealing with prisons. Two black neurosurgeons speaking at the 1976 National Minority Conference on Human Experimentation in Reston. In contrast to the media’s favorable—and distorted—depiction of psychosurgery in the early years of lobotomy [84]. only six Hispanics and one black patient were identified. Works like Crichton’s The Terminal Man depicted the ‘‘treatment’’ of a violent criminal with implantation of electrodes. observed. such as group therapy or token economy systems. The Justice Department and several state departments of correction (notably California’s) have shown great interest both in establishing that black rioters and aggressive inmates are suffering from brain dysfunction and in curing them through psychosurgery. philosophers. A 1974 study conducted by the Behavioral Control Research Group of the Hastings Institute surveyed the Commissioners of Corrections for all 50 states to ascertain the prevalence of behavior control in the nation’s prisons [79]. there was.’’ Although these data would suggest that things were better than feared. In a review of 600 psychosurgery procedures performed in 1974. the data suggest that it was otherwise. the least coercive treatments. . the popular culture of the 1970s heightened fears of abuse. None of the respondents used psychosurgery as a treatment procedure. it seemed. ‘‘Both reports concluded that there is no reliable evidence that psychosurgery has been used for political purposes. Forty-seven states and the District of Columbia responded. the author of the report cautioned the reader to be wary of the results. Chief of Neurosurgery at Howard University. In the political climate of that era. who observed that: There is something promising about the notion that the effort to cure sick individuals may result in considerable social . borrowed the name of Ervin’s own institution [85]. Although this citation would suggest widespread use of psychosurgery for social control. attorneys. were employed. Fins / Neurosurg Clin N Am 14 (2003) 303–319 perspective from a New Zealander behavioral scientist observed that: Still another cultural aspect which adds to the appeal of psychosurgery is the readiness of the American government to seek solutions to its domestic problems which hide the causes of the problems. not so coincidentally. The National Commission report would later confirm this finding. Perhaps reflecting the distrust prevalent during the end of the Nixon administration and the Watergate scandal. a fine line between scientific fact and science fiction [83]. urged limited use of psychosurgery with appropriate oversight and review boards [82]. ‘‘not at this time. The Commission noted that ‘‘The fact that so few patients from minority groups have undergone psychosurgery. Psychosurgery can be one such solution if used to ‘‘cure’’ the nation’s social problems. although minority communities were indeed fearful of these procedures. The setting for the procedure was a fictitious neuropsychiatric institute located in Los Angeles. a professor of law at Case Western Reserve University. the publicly announced programs may be only a small percentage of what is actually occurring’’ [79]. Three leading proponents of psychosurgery have advanced the view that many of those involved in ghetto rebellions acted violently because of brain dysfunction. Furthermore. As the American Psychiatric Association report put it.’’ Although there was little evidence for the use of psychosurgery for law enforcement purposes. The accumulated results of racism and poverty were discounted as causal factors since not everyone rioted [78]. however. as exemplified by Breggin’s less than restrained ideologic attacks. In this broader cultural context. or nascent bioethicists. although one added.J. which. More balanced criticism came from individuals like Edward Mearns. . social control or as an instru- 311 ment for racist repression’’ [80].

pointed out that the prisoner himself illustrated the coercive nature of incarceration when his confinement was declared unconstitutional and he had the opportunity to revisit his decision after initially consenting to psychosurgery.how does one know whether the sick are being cured or whether medicine is being used as yet another tool in society’s ever present effort to secure comfort through conformity’’ [88]. But there is something disturbing about the conscious effort to use medicine and medical men institutions to cure a ‘‘sick’’ society. Fins / Neurosurg Clin N Am 14 (2003) 303–319 benefit as well. They issued a number of reports in addition to the one on the ethics of psychosurgery. ‘‘. For it is one thing to use medicine as an instrument of healing and quite another to use it as an instrument for social control [86]. As such. by Senator J. given the public origins of the report. Much of the resistance to psychosurgery—and the broader issue of behavior control—was closely related to emerging concerns about the use of the procedure on prisoners. and minority groups opposed to psychosurgery proved to be much more effective politically than the earlier opposition to psychosurgery from within the medical profession had been’’ [95]. public sentiment. he asked. Department of Mental Health. and their work was prolific.a concept which is heavily influenced by social norms. . in which a three-judge panel in Michigan sought to determine whether a confined prisoner could voluntarily consent to an experimental procedure that might temper his aggressive and criminal behavior [91]. the National . It is somewhat ironic. commenting on this period. echoed this sentiment.312 J. who directed the Hastings Center Working Group on Psychosurgery. Indeed. although they were specifically mandated to address this issue by Congress. that it failed to reach the conclusion that most of the public wanted. Valenstein. warned of the dangers of psychosurgery during 1973 Senate hearings [98]. More critically. led the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to issue a report on psychosurgery in 1977 [81].93]. . Regulatory bioethics: the National Commission’s report on psychosurgery Elliot S. and a label which is often imposed in a particular case because people engage in ÔstrangeÕ behavior of one sort or another’’ [88]. Burt. it becomes more complex when the focus of the intervention is mental illness which is ‘‘. most prominently. Professor Robert A. Hal Edgar of Columbia Law School pointed out that although procedures on the brain are justifiable if they result in a cure of a physical illness like Parkinson’s disease without undue side effects. Instead of adopting the more politically correct position. Some of this was related to a fear of somehow legitimizing a deeply flawed penal system through an affiliation with medicine [90]. Echoing the sentiments of the times about questioning authority. the court went on to cite the entirety of the Nuremberg Code to argue that reasoned and voluntary consent in prison was so greatly impaired as to make lawful consent in that setting impossible [92. observed that ‘‘The coalition of civilrights. President of the Hastings Center. catalyzed in part by an organized and growing scholarly bioethics movement. who might be coerced or unable to give appropriate consent to experimental procedures [89]. Indeed. Concerns about psychosurgery were prominent in testimony leading up to the passage of the act. one of his attorneys.J. the report was a political compromise in lieu of a moratorium or an outright ban as proposed. so there is a danger of having the appearance of therapy. The court opined that there was no scientific basis to suggest that psychosurgery would be therapeutic in the absence of a discernible disorder like epilepsy and that the risk-benefit ratio was disproportionate given the current state of knowledge and the known risks of the procedure. The National Commission was created by the National Research Act of 1974 [97] in the wake of revelations about the Tuskegee Syphilis Study and other research ethics abuses. but much of it was a central concern about the ability of inmates to give voluntary and informed consent. The philosopher Robert Neville. Willard Gaylin. When these new developments allowed him to imagine being set free. he suspended his consent to reconsider surgery given his new circumstances [94]. The National Commission was constituted and staffed by a number of prominent bioethicists. when the real purpose is punishment’’ [87]. to invoke a more modern phrase. anti-psychiatry. . . Neville asserted that ‘‘The ethics of good medicine isn’t easily transferred to good social control. a Republican from Maryland [96]. This issue came to national prominence in the 1973 case of Kaimowitz v. Glenn Beall.

. For the purposes of the report. . the inconsistency of characterizing psychosurgery as therapy at the time it is performed and as experimentation at the time of publication seems to escape 313 them. and the risks of coercion for the voluntarily institutionalized psychiatric inpatient. the National Commission recommended the establishment of a National Psychosurgery Advisory Board that would determine whether the ‘‘specific psychosurgical procedure has demonstrated benefit for the treatment of the psychiatric symptom or disorder of the patient. . It is clearly both [86]. . . . J. The operation shouldn’t be banned [96]. .’’ The IRB was charged with assessing the competence of the surgeon.’’ If the procedure was part of a research study. the National Commission recommended that the IRB ensure adequate pre. the appropriateness of the procedure for a selected patient. change. It is interesting to note that brain surgery for the treatment of movement disorders like Parkinson’s disease or for epilepsy and pain management was excluded from this definition.’’ This addressed a lingering question since the 1940s. They were able to work. neurosurgery. by the endorsement of stringent regulatory guidelines and procedural safeguards that would prohibit psychosurgery for anything other than a patientcentered application: The Commission affirms that the use of psychosurgery for any purpose other than to provide treatment to individual patients would be inappropriate and should be prohibited. .Moreover. did not expect to come out in favor of psychosurgery. Somehow. psychosurgeons do not submit research protocols to review committees for another reason. the National Commission recommended strict oversight by specially constituted institutional review boards (IRBs) with a subcommittee of Department of Health. As Chairman of the National Commission. . The National Commission’s view of psychosurgery was tempered. psychology. This need for treatment suggests speed or at least the avoidance of cumbersome review procedures. I. although the National Commission decided not to recommend a ban of psychosurgery. harkening back to historical concerns about the evaluation of procedural efficacy. the Commission is recommending safeguards that should prevent the performance of psychosurgery for purposes of social or institutional control or other such misuse [81].’’ [81]. informed consent. Furthermore. Psychosurgery is generally viewed as investigational.is to control. Their marriages were intact. . But we saw that some very sick people had been helped by it. and that it did not destroy their intelligence or rob them of their feelings. . destruction or direct stimulation of the brain by any means. . . and the adequacy of the patient’s informed consent. Fins / Neurosurg Clin N Am 14 (2003) 303–319 Commission found sufficient evidence of efficacy of the modern procedures like cingulotomy and not the prefrontal leukotomies of Freeman’s day to endorse continued experimental work in psychosurgery as long as strict regulatory guidelines and limitations were in place.The inconsistency results from characterizing psychosurgery at either point in time as solely therapy or solely experimentation. Addressing concerns about regulatory oversight. . The ambiguity over psychosurgery’s status as experimental or therapy is also implicit in the report. posed most eloquently by Professor Mearns of Case Western Reserve Law School in 1975: .J. and psychiatry to review the technical aspects of the surgery. Education. They simply do not perceive their operations to be experiments. Given the investigational nature of psychosurgery. They view them as therapy. Accordingly. although the National Commission does acknowledge that some patients had been helped by these interventions.J. the advisory board would determine whether enrollment was in compliance with the National Commission’s . IRB review was recommended until the ‘‘safety and efficacy of any psychosurgical procedure have been demonstrated. In addition. for one.They see the patient as ill with a condition that requires specific treatment geared to his particular illness. however. or affect any behavioral or emotional disturbance. it was careful to note that it did not recognize psychosurgery as ‘‘accepted practice. psychosurgery was defined as surgery whose ‘‘primary object of the performance.’’ and included both classic psychosurgeries like ablation as well as its more modern iteration of electric stimulation: ‘‘Psychosurgery includes the implantation of electrodes.and postoperative evaluations. Kenneth Ryan of Harvard Medical School told a Science correspondent: We looked at the data and saw they did not support our prejudices. and Welfare (DHEW)-sanctioned experts or consultants in neurology.

had a legal guardian. In addition to this data. provided that the psychosurgery is performed in accordance with these recommendations’’ [81]. Three years after the report was issued. Califano’s successor. This fundamental issue remained an open question given the small sample of cases reviewed by National Commission consultants. Not all the National Commission’s recommendations were accepted by DHEW Secretary Joseph Califano in his determination [100].by its right name: making holes in people’s heads and slicing their brains in a hitor-miss attempt to make them behave themselves’’ [101]. overly optimistic that the National Commission’s recommendations would eventually be accepted. it is a reasonable response to a highly complex problem.’’ This was a position he later reversed. He criticized Califano’s about-face on the National Psychosurgery Advisory Board and urged the ‘‘immediate cessation of butchery-inthe name of medicine. the National Commission actually encouraged (their word) the Secretary of the DHEW ‘‘. To engage in some rudimentary health services research. that the proposed National Psychosurgery Advisory Board determine whether the specified psychosurgical procedure had a demonstrable benefit for the patient’s condition and if the operation were to be performed as an element of a research protocol. . children. the National Commission also suggested the establishment of a national data collection registry to assess the safety and efficacy of these procedures. among other strictures. psychiatric.’’ He concluded by suggesting that someone take Califano to see ‘‘One Flew Over the Cuckoo’s Nest’’ [101]. he determined to ban psychosurgery for prisoners. he said that he wished the Commission had called psychosurgery ‘‘. still had failed to make a determination over proposed regulations [103]. as submitted to the Secretary.99]. we still have failed to reach a national consensus on research on subjects whose medical. In addition. the National Commission recommended to Congress the imposition of strict sanctions and the threat of Federal defunding if these recommendations were violated and the exclusion of Federal agencies from psychosurgery funding ‘‘unless such agencies or components are primarily concerned with health care or the conduct of biomedical and behavioral research’’ [81]. In an Op-Ed written after Califano’s determination. he and the report were still criticized liberally. ‘‘to establish mechanisms for the voluntary regulation and reporting of psychosurgical procedures. Health and Human Services (HHS) Secretary Patricia Harris. the involuntarily confined mentally ill. One of the more strident columns was by William Raspberry of The Washington Post. . Despite this response. nonetheless. whether these efforts would be in compliance with the recommendations on research involving the institutionalized mentally infirmed [81]. The report set even more stringent guidelines for prisoners and those who were involuntarily committed. as balanced. progressive commentators like George Annas viewed the report. Furthermore. and its basic approach is likely to gain general acceptance’’ [102].314 J. Attempting to balance ‘‘access to potentially beneficial therapy’’ against the coercion or a breach of voluntariness.to conduct and support studies to evaluate the safety of specific psychosurgical procedures and the efficacy of such procedures in relieving specific psychiatric symptoms and disorders. Today. Fins / Neurosurg Clin N Am 14 (2003) 303–319 recommendations on research involving the institutionalized mentally infirmed [81.J. but it too remains in . he endorsed the establishment of a joint committee on psychosurgery. with one abstention. Finally. He was. He observed that ‘‘Certain provisions are unlikely to please either avid promoters of psychosurgery or those favoring a complete ban. . or neurologic conditions make it impossible for them to provide voluntary consent. or were believed to be unable to give informed consent because of impaired decision-making capacity. He decided to promulgate regulations that would limit psychosurgery to those individuals who could provide informed and voluntary consent. however. Despite Califano’s narrowing of the National Commission’s broader recommendations regarding whom psychosurgery might be performed on. Professor Annas was right to appreciate the complexity of these issues and the report’s balanced approach to them. the National Commission recommended that this registry note the indications for procedures and the demographics of those who underwent psychosurgery. and those who were decisionally or legally incompetent and unable to provide consent. composed of leading professional organizations. the National Commission outlined a complex regulatory approach requiring. The 1998 National Bioethics Advisory Commission report on ‘‘Research Involving Persons With Mental Disorders That May Affect Decisionmaking Capacity’’ attempted to address aspects of this question. . Thus.

Increasingly. or are both neuromodulation? This overlap phenomenon is especially confusing if the mechanisms of Parkinson’s disease are compared with those of severe OCD. In France. In the case of Parkinson’s disease. justifying treatment for one disorder but proscribing another. which provides oversight for therapeutic interventions for patients who are able to provide consent themselves [106]. This categorization should be disconcerting to those who embrace equity in the treatment of mental and physical disease as a value. we need to create regulatory mechanisms that will balance human subject protections for individuals with intractable neurologic and psychiatric disorders against scientific progress and access to potentially beneficial interventions. Professional groups are also evolving to articulate ethical principles for the conduct of neuromodulation research as in the case of the Obsessive-Compulsive Disorder Working Group [107]. palliation. we will immediately realize that the distinction between somatic and psychiatric interventions is no longer as neatly sequestered as in the report. Summary: fairness. . Because this body never came into being. Fins / Neurosurg Clin N Am 14 (2003) 303–319 bureaucratic limbo [21. we have been left without both a regulatory framework and a national locus for a debate about the ethical implications of neuromodulation. In OCD. This fiduciary obligation of practitioners. the neurosurgeon Alim Benabid voluntarily sought the approval of the French National Bioethics Commission for approval of a clinical trial of deep brain stimulation in refractory OCD. and psychosurgery Moving forward. In the United States. the line between mind and brain—and neurology and psychiatry—has become blurred. we now know that treatment of the movement disorders of Parkinson’s disease with deep brain stimulation can affect the patient’s emotions. If we begin with definitional issues. the first of many psychiatric maladies for which neuromodulation is likely to be investigated [108. The proposed Psychosurgery National Advisory Board would have been empowered to adjudicate these morally complex decisions in the context of psychosurgery or neuromodulation. The most evolved forums for such deliberations are local bodies like the Cingulotomy Committee at the Massachusetts General Hospital.105].J. The pathophysiology and neural circuits of both diseases share corticobasal gangliothalamic interactions [18] and both could be construed as tremors. Recent history suggests that there remains a need for such a dialogue as well as a national body empowered to review the science behind proposed clinical trials to ensure that our ethical sensibilities are not offended. most notably the cingulotomy as currently performed by Cosgrove’s group [110] and the closed radioablation techniques employing the gamma knife as studied by Greenberg et al [111]. it is reminiscent of Vernon Mark’s prescient anticipation of a time when the mind-brain dichotomy would be less tenable as an ethical demarcation.J. OCD has already been the object of sophisticated psychosurgical interventions. French investigators have demonstrated that deep brain stimulation has the unrecognized potential to alter a mood state and induce a reversible but acute depression [112]. In the spirit of this evolution. Benabid’s actions suggests a continued need for extramural oversight of these still contentious interventions along the lines of the proposed National Psychosurgery Advisory Body. I would like to anticipate some of this analytic work in the 315 context of OCD. and it becomes increasingly problematic to treat one brain condition differently than another. there is no such body to provide this oversight or catalyze this discussion. clinical investigators. This report should serve as a foundation on which additional analysis could be built. Although this analogy is not airtight. it is a limbic-thought tremor. and public policy makers can be facilitated by building on the yet uncompleted efforts of the 1977 National Commission Report on Psychosurgery. especially when the distinction is predicated on a Cartesian dualism unsubstantiated by modern neuroscience. What is the boundary between modulating a movement disorder and potentially altering emotions? Is one intervention a neurologic procedure and the other psychosurgery.104. This regard for fairness becomes even more troubling if we recall Surgeon General David Satcher’s call for parity in the treatment of physical and mental illness [113]. it is a motor tremor. They share mechanistic similarities and are characterized by hypersynchronous activity. although the National Commission distinguished treatment of Parkinson’s disease from psychosurgery. For example.109]. As was described in the New England Journal of Medicine.

J Hist Neurosci 2000. These affective changes may unsettle some observers. These affective changes can range from euthymia to varying degrees of blunting or hypomania. Diane Richardson of the Oskar Diethelm Library of the Payne Whitney Clinic and Chris McKee of the Hastings Center Library for their archival assistance. Rees Cosgrove. Justification for surrogate authorization may have been linked to an implicit view of psychosurgery as palliation when it was being applied to intractable psychiatric suffering. It is only essential that we protect ourselves here. This precedent for joint patient and physician control has important implications for deep brain stimulators given the history of ‘‘behavior control. p. will be to move beyond viewing psychosurgery or neuromodulation as either research or therapy and consider it instead as a form of palliative care. In this regard. in January and June 2002. This will allow for a sharing of power and help ameliorate fears of co-optation of personhood. These interventions are not directed toward cure but rather at the masking of intractable symptoms [114] and the alleviation of suffering. France. If history’s lessons are heard.225(9):1044–6. The analogy to palliative care may also be helpful in fostering a collaborative and patientcentered model of care. from arrogance and insensitivity. especially the blunting end of the spectrum. [Cited in: Tierney AJ.] [2] Osler W. the patient is given the ability to determine the frequency of dosing of pain medication to address his/her perception of pain and level of suffering within preset and safe limits. because investigators have begun to recognize that subjects with OCD have affective changes depending on the setting of their stimulator. Viewing the relief of suffering as an ethical mandate. Ehrlich for their helpful insights. References [1] Moniz E. [3] Medical News. we will appreciate that a more fruitful response is articulating an ethic of responsibility that palliates the suffering of those with intractable psychiatric illness. This is more than a hypothetic issue. Teacher and student. p. 15–21. Franklin G. The ethos of pain and symptom management articulated in the palliative care community is applicable to this work. which is reminiscent of Nolan Lewis’s concerns about the ‘‘the quieting of a patient’’ after the primitive lobotomy [50]. G. London: HK Lewis. 1949. a strategy consistent with palliative care [115]. Rezai and Alim Benabid for the opportunity to present earlier versions of this paper to the neuromodulation meetings held in Aix-Les-Bain. . in my view. as everywhere. Aequanimitas and other addresses. This is not entirely unexpected because of the downstream effects of the stimulation target. JAMA 1973. In PCA. which is a site often ablated in the classic prefrontal leukotomy of Moniz and Freeman. 1904. the frontal lobe’s cingulum gyrus. Whether notions of palliation entered into the National Commission’s balancing and specification of ethical principles is a question that merits additional study. Lisbon. and Amy B. If the past is a prologue. Greenberg. I offer an analogy to patient-controlled analgesia (PCA).316 J.9(1):22–36. How I came to perform prefrontal leucotomy. the National Commission may have been willing to allow surrogates to provide authorization even when the intervention was yet unproven to be therapeutic. Fins / Neurosurg Clin N Am 14 (2003) 303–319 A second analytic issue. ‘‘To be afraid of our technology is to be afraid of ourselves. In: Proceedings of the First International Congress of Psychosurgery. The answer is not to prohibit technology but to insist that it always be subservient to the transcending values of human worth and human dignity’’ [116].’’ The still present fear of mind control by the modern equivalent of Delgado’s stimoceiver makes it critical that patients have an appropriate opportunity to adjust the frequencies of their stimulators within safe and monitored parameters. As Willard Gaylin told us a quarter of a century ago. Benjamin D. we might expect new charges of mind control and a call for the prohibition of this new technology. Either extreme should be avoided. Miller. Egas Moniz and the origins of psychosurgery: a review commemorating the 50th anniversary of Moniz’s Nobel Prize. Acknowledgments The author thanks Nicholas D. the National Commission’s thinking might suggest an alternative analytic framework than that offered by the more restrictive National Bioethics Advisory Commission report [106]. and Ali R. however. Although the recommendation regarding surrogate consent was reversed by Secretary Califano. Congress weighs 2 measures. Schiff. I believe the National Commission may have anticipated the relationship between psychosurgery and neuromodulation and palliation in its willingness to endorse surrogate consent.J. 21–43.

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Color Plates .

The top right panel presents the power spectrum of Patient 2. including neuropsychiatric as well as parkinsonian.) . with a postoperative (blue) curve demonstrating the reappearance of the alpha peak and the power decrease in the theta and beta bands. The top left panel shows the power spectra from controls (blue) and thalamocortical dysrhythmia (TCD) patients. The bottom left panel shows such coherence for controls. A peak shift into the theta domain and power increase in the theta and beta bands are demonstrated for TCD patients in comparison to controls.Plate 1. Magnetoencephalographic data from three patients in this series. Power spectra (four top panels) and coherence plots (three bottom panels) are displayed. and the right panel shows coherence for the same patient after surgery. (See also Fig. Coherence was analyzed applying a cross-correlation analysis of the variation along time of the spectral power for frequencies between 0 and 40 Hz. the middle panel shows coherence for Patient 2 before surgery. neurogenic pain. The postoperative power spectra of Patient 7 (middle left) and Patient 1 (middle right) are mainly characterized by a reduction in the theta and beta power. and tinnitus patients. 3 in article by Jeanmonod et al. allowing reappearance (Patient 7) or better visualization (Patient 1) of the alpha peak.

.Plate 1.

to 10-Hz activity onto the patient’s MRI examination before (eight top images) surgery.Plate 2. Projection of 4. Magnetoencephalographic source localization for Patient 2. This low-frequency focus disappears after surgery. The thalamocortical dysrhythmia of this patient is localized in the right-sided paralimbic domain comprising the temporopolar. (See also Fig. anterior parahippocampal.) . orbitofrontal. and basal medial prefrontal areas. 4 in article by Jeanmonod et al.

Plate 2. .

results in high-frequency coherent activation of the neighboring (right) cortical module (edge effect). 5 in article by Jeanmonod et al. (See also Fig. and two reticular cells (red) with their projections back to thalamic relay cells. Schematic diagram of the thalamocortical circuits that support the thalamocortical dysrhythmia mechanisms. Either thalamic cell disfacilitation or overinhibition (central module) hyperpolarizes thalamic cell membranes. This allows the deinactivation of calcium Tchannels and the generation of low-threshold calcium spike bursts. with their feed-forward thalamocortical activation and their respective recurrent feedback is proposed to generate increased cortical activation through temporal coincidence. by reducing lateral inhibitory drive.) . Three thalamocortical modules are shown. low-frequency activation of corticocortical inhibitory interneurones (red). one (blue) pyramidal cell with its corticothalamic and corticoreticular output. thus resulting in low-frequency thalamocortical substrate for low-frequency coherent discharge of an increasing number of thalamocortical modules. each with its specific (yellow) and nonspecific (green) thalamic relay cell projecting to the cortex and reticular nucleus. At the cortical level.Plate 3. Three thalamocorticothalamic loops are thus displayed.

.Plate 3.

Neurosurg Clin N Am 14 (2003) 321–325

Index
Note: Page numbers of article titles are in bold face type.

A
N-Acetyl aspartate, in magnetic resonance
spectroscopy, in obsessive-compulsive
disorder, 214–215
Amygdala, connections to, in depression,
216–218
Annas, George, on psychiatric neurosurgery
regulations, 314
Anticonvulsant action, of vagus nerve
stimulation, 276–277, 279–280
Antidepressants, for depression, 201. See also
Transcranial magnetic stimulation.
Anxiety disorders, transcranial magnetic
stimulation for, 293–294

B
Ballantine, H. Thomas, Jr., on psychiatric
neurosurgery, 308
Barber, Jesse, on psychiatric neurosurgery, 311
Behavioral therapy, for obsessive-compulsive
disorder, 200–201
Benabid, Alim, deep brain stimulation studies
of, 315
Bipolar mood disorder, thalamocortical
dysrhythmia in. See Thalamocortical
dysrhythmia.
Body dysmorphic disorder, neuroimaging and
neurocircuitry in, 214
Broca, Paul, localization philosophy of, 181
Burckhardt, Gottlieb, frontal lobotomy
procedure of, 181–182

Capsulotomy, for psychiatric disorders
depression, 219, 232–233
history of, 191–192
obsessive-compulsive disorder, 204–208, 219,
232–233
Caudate nucleus, connections to
in depression, 216–219
in obsessive-compulsive disorder, 214,
218–219
Cerebrospinal fluid analysis, in depression, in
vagus nerve stimulation, 280
Chlorpromazine, for psychiatric disorders, history
of, 190
Cingulate cortex, anterior, connections to
in depression, 216–219
in obsessive-compulsive disorder, 214,
218–219
Cingulotomy, for psychiatric disorders, 191–192,
225–235
anatomic considerations in, 225–227
complications of, 230
depression, 204–206, 208–209, 218, 225–228
history of, 225
obsessive-compulsive disorder, 204–206,
208–209, 216, 225–231
SPECT in, 238–249
patient selection for, 227–228, 231
physiologic considerations in, 225–227
results of, 228–231, 241–243
technique for, 228, 239
versus alternative surgical methods, 231–233
Corticostriatothalamocortical circuitry
in depression, 216–219
in obsessive-compulsive disorder, 214, 218–219

C
Califano, Joseph, psychiatric neurosurgery
regulations approved by, 314
Capsule, internal, anterior limbs of, electrical
stimulation of, in obsessive-compulsive
disorder, 267–274

D
Delgado, Jose M.R., on psychiatric neurosurgery,
309
Deniker, Pierre, psychoactive drug therapy
discovery by, 190

1042-3680/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved.
doi:10.1016/S1042-3680(03)00032-9

322

Index / Neurosurg Clin N Am 14 (2003) 321–325

Depression, 199–212
clinical features of, 201
epidemiology of, 201
medical treatment of, 201
neurocircuitry models for, 216–219
neuroimaging in, 216–219
neurosurgery for
capsulotomy, 219, 232–233
cingulotomy, 204–206, 208–209, 225–228
current awareness of, 201–202
effectiveness of, 207–209
history of, 202–203
limbic leukotomy, 205–207, 209, 232
modern procedures for, 203–205
neuroimaging and neurocircuitry related
to, 218–219
safety of, 205–207
subcaudate tractotomy, 204–205, 207,
218, 231
thalamocortical dysrhythmia in. See
Thalamocortical dysrhythmia.
transcranial magnetic stimulation for,
288–293
maintenance, 292
meta-analysis of, 289–292
with intentional seizure generation,
294–295
vagus nerve stimulation for, 275–282

Ethical issues, in neuropsychiatric surgery,
303–319
historical aspects of, 303–308
regulatory aspects of, 312–315
sociopolitical aspects of, 308–312

Diethelm, Oskar, on ethics of neuropsychiatric
surgery, 305–307

Grant, Francis, lobotomies by, 186

E
Electrical stimulation
of internal capsule anterior limbs, for
obsessive-compulsive disorder, 267–274
of vagus nerve, for depression, 275–282
Electroconvulsive therapy, for psychiatric
disorders, 184, 201
versus transcranial magnetic stimulation,
287–289, 291–292, 294
Electroencephalography, in depression, in vagus
nerve stimulation, 280
Eloquent cortex, localization of, transcranial
magnetic stimulation for, 287

F
Fiamberti, Amarro, transorbital lobotomy
procedure of, 189
Freeman, Walter, psychiatric neurosurgical
procedures of, 182–183, 185–190, 303–306
Frontal lobotomy, history of, 182–190, 203,
303–308
Fulton, John F., neurophysiologic studies of,
182, 185–187
Functional neuroimaging, in obsessivecompulsive disorder, 215

G
Gall, Franz Joseph, on phrenology, 181
Gamma knife capsulotomy, for psychiatric
disorders, 204–208
Goltz, Friedrich, temporal lobotomy procedure
of, 181

Grinker, Roy, on ethics of neuropsychiatric
surgery, 306–307

H
Hallucinations, thalamocortical dysrhythmia in.
See Thalamocortical dysrhythmia.
Hippocampus, connections to, in depression,
216–218
Hypothalamic-pituitary-adrenal axis, connections
to, in depression, 216

I
Impulse control disorder, thalamocortical
dysrhythmia in. See Thalamocortical
dysrhythmia.

Epilepsy
transcranial magnetic stimulation for,
286–287, 293
vagus nerve stimulation for, 276–277

Institutional review boards, for psychiatric
neurosurgery research, 313

Ervin, Frank R., on psychiatric neurosurgery,
309

Jacobsen, Carlyle, neurophysiologic studies of,
182

J

Index / Neurosurg Clin N Am 14 (2003) 321–325

K
Kelly, Desmond, limbic leukotomy procedure
of, 193

323

Magnetoencephalography, in thalamocortical
dysrhythmia, 253–256, 260

Knight subcaudate tractotomy, 193

Mania, transcranial magnetic stimulation for,
292

L

Mark, Vernon H., on psychiatric neurosurgery,
309–310, 315

Laborit, Henri, psychoactive drug therapy
discovery by, 190

Mearns, Edward, on psychiatric neurosurgery,
311–313

Leksell, Lars, capsulotomy procedure of, 191

Mixter, W. Jason, lobotomies by, 187

Leukotomy
limbic, for psychiatric disorders, 193
depression, 205–207, 209, 232
obsessive-compulsive disorders, 205–207,
209, 218–219, 232
versus cingulotomy, 232
orbitomedial, for obsessive-compulsive
disorder, 218

Moniz, Egas, psychiatric neurosurgical
procedures of, 182–183, 185–186, 190, 305–306

Lima, Almeida, early frontal lobotomies by, 182
Limbic leukotomy, for psychiatric disorders, 193
depression, 205–207, 209, 232
obsessive-compulsive disorders, 205–207, 209,
218–219, 232
Limbic system, in psychiatric disorders
dysfunction of, 226
pathway disruption in. See Cingulotomy;
Limbic leukotomy.
Lobotomy
frontal, history of, 182–190, 203, 303–308
prefrontal, history of, 182–190
transorbital, 189
Lyerly, James, psychiatric neurosurgical
procedures of, 186–187

Movement disorders, transcranial magnetic
stimulation for, 293

N
National Commission for the Protection of
Human Subjects of Biomedical and Behavioral
Research, psychiatric neurosurgery and,
312–314, 316
National Psychosurgery Advisory Board,
313–315
Neurocircuitry models, for psychiatric disorders,
213–223
depression, 216–219
obsessive-compulsive disorder, 214–216,
218–219
Neuroimaging. See also specific techniques.
for psychiatric disorders, 213–223
depression, 216–219
obsessive-compulsive disorder, 214–216,
218–219
Neville, Robert, on psychiatric neurosurgery, 312

M
Magnetic resonance imaging
blood oxygenation level-dependent
in depression, in vagus nerve stimulation,
279
in transcranial magnetic stimulation studies, 288
in stereotactic cingulotomy, 228, 238
morphometric
in depression, 217
in obsessive-compulsive disorder, 214
Magnetic resonance spectroscopy, in obsessivecompulsive disorder, 214–215
Magnetic stimulation, transcranial. See
Transcranial magnetic stimulation.

O
Obsessive-compulsive disorder, 199–212
behavioral therapy for, 200–201
clinical features of, 200
diagnosis of, SPECT in, 238, 241–242
epidemiology of, 200
medical treatment of, 200
neurocircuitry models for, 214–216, 218–219
neuroimaging in, 214–216, 218–219
neurosurgery for
capsule anterior limb electrical stimulation,
267–274
capsulotomy, 204–208, 219, 232–233
cingulotomy, 204–206, 208–209, 216,
225–231, 238–249

205–207 subcaudate tractotomy. 203–205 neuroimaging and neurocircuitry related to. on psychiatric neurosurgery. Alan. 207 Orbitomedial leukotomy. 245–249 thalamocortical dysrhythmia in. 252 results of. 193 neuroimaging and neurocircuitry models for.. 316 Pallidotomy. 315 transcranial magnetic stimulation for. 251–265 historical perspective of. in obsessivecompulsive disorder. 260 patient selection for. 226. 184 Single-photon emission computed tomography in depression. 181–190 ethical aspects of. 204–205. 213–223 palliative.324 Index / Neurosurg Clin N Am 14 (2003) 321–325 for depression. 202–203 limbic leukotomy. 193 Ryan. neurosurgery in. See Thalamocortical dysrhythmia. 232 modern procedures for. 193. 253–256. 308–312 transcranial magnetic stimulation. for thalamocortical dysrhythmia. 202–203 capsulotomy. Cingulotomy. 259 Parkinson’s disease deep brain stimulation for. 191–192 cingulotomy. R Raspberry. neurosurgery for. in transcranial magnetic stimulation. 190–193 subcaudate tractotomy. 193 stereotactic methods. e. 293 Phrenology. 201–202 effectiveness of. limbic leukotomy procedure of. 237–250 . for obsessive-compulsive disorder. in vagus nerve stimulation. 252–263 magnetoencephalography with. 314 Regulation. 207–209 history of. 226. 238. for obsessivecompulsive disorder. of neuropsychiatric surgery research. 312–315 single-photon emission computed tomography in. 237–250 diagnostic. 241–242 postoperative. 293–294 OCD. 293 Seizures. 259–263 strategy for. 303–308 future techniques derived from. transcranial magnetic stimulation for. 181–197. 204–205. See Depression. 193–196 limbic leukotomy. for obsessive-compulsive disorder. 191–192 early years. 200 Shock therapies. 308 transcranial magnetic stimulation for. 182 Positron emission tomography. 218–219 safety of. 238–241. 246–248 SPECT in. See Obsessive-compulsive disorder. 218. 294–295 Selective serotonin reuptake inhibitors. J. 209. anterior medial. William. Orbitofrontal-subcortical connections in depression. 226 positron emission tomography in. 216–219 in obsessive-compulsive disorder. 316 research on ethical considerations in. See also specific procedures. Kenneth. on psychiatric neurosurgery regulations. for psychiatric disorders. 312–315 Richardson. 303–319 regulation of. 313 S Schizophrenia lobotomy for.g. 182–190 Psychiatric neurosurgery. 246–248 Prefrontal lobotomy. See Obsessive-compulsive disorder. 237–250 sociopolitical aspects of. for psychiatric disorders. 205–207. 218 P Palliative care. history of. 255. for thalamocortical dysrhythmia. neurosurgery for. 283–301 Obsessive (continued ) current awareness of. induction of. 218–219 interruption of. 218–219. in subcaudate tractotomy. 231–232 pathophysiology of. 279 in obsessive-compulsive disorder. 214. neuroimaging in. See also Epilepsy. 207. 252–253.

286–287 repetitive. 280 for depression. 277. 231–232 T Talairach capsulotomy procedure. 280–281 preclinical investigations of. 251–265 pathophysiology of. for psychiatric disorders. 292 for movement disorders. 278–279 practical considerations in. 291–292. 287 drug use with. 288–293 maintenance.. 252–263 magnetoencephalography with. 238. 189 Weinberger. 275–282 anatomic considerations in. connections to in depression. 214 transcranial magnetic stimulation for. 293 functional imaging with. 260 patient selection for. 231–232 325 versus cingulotomy. 238–241. 204–205. 204–205.. transcranial magnetic stimulation for. 204–205. 204–205. 207. 285 for anxiety disorders. 286–288 safety of. 189 Trichotillomania. Stereotactic surgery cingulotomy. 252 results of. 284 research uses of. for psychiatric disorders. See Cingulotomy. subcaudate. on ethics of neuropsychiatric surgery. 306 . 251. 279–280 open-label study of. 293 for schizophrenia. for thalamocortical dysrhythmia. 275 clinical trials of. 259–263 strategy for. 252–253. 204–208 Tics. Elliot S. 286–287. 231–232 versus cingulotomy. 294 Transorbital lobotomy. 293 for mania. neuroimaging and neurocircuitry in. 241–242 postoperative.Index / Neurosurg Clin N Am 14 (2003) 321–325 diagnostic. 218. 207. 260 patient selection for. 218–219 Thermocapsulotomy. 293–294 for depression. 275–276 Valentine. 214. 259 Thalamotomy central lateral. 259. 252–263 magnetoencephalography with. 185–187. 231–232 Transcranial magnetic stimulation. 193 depression. 193 depression. 252–253. James. 253–256. 255. 294–295 for eloquent cortex localization. on psychiatric neurosurgery. Lawrence M. 293 electrical requirements of. 312 W Watts. 191 Thalamus. 253–256. 287 for epilepsy. 245–249 SPECT. See Single-photon emission computed tomography. 259–263 strategy for. 292 meta-analysis of. 216–219 in obsessive-compulsive disorder. 218. 191 Thalamocortical dysrhythmia. for psychiatric disorders. 207. 218 obsessive-compulsive disorder. electrical stimulation of clinical applications of. 283–301 animal models of. 190–193 Subcaudate tractotomy. 259 dorsomedial. 287–289. 276 long-term results of. 255. 278–279 mechanism of action of. for psychiatric disorders. 287–288 high-frequency. 293 Tourette syndrome neuroimaging and neurocircuitry in. 284–286 paired-pulse. history of. 262 surgery for. 277–278 placebo-controlled study of. psychiatric neurosurgical procedures of. 252 results of. 214 V Vagus nerve. 286 versus electroconvulsive therapy. 289–292 with intentional seizure generation. 218 obsessive-compulsive disorder. 207. 293 Tractotomy. 285–286 mechanisms of action of.