Deep Brain Stimulation for Psychiatric Disorders
Paul Sloan Larson
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143-0112
Summary: Surgery for psychiatric disorders first began in the
early part of the last century when the therapeutic options for these
patients were limited. The introduction of deep brain stimulation
(DBS) has caused a new interest in the surgical treatment of these
disorders. DBS may have some advantage over lesioning proce-
dures used in the past. A critical review of the major DBS targets
under investigation for Tourette’s syndrome, obsessive-compul-
sive disorder, and major depression is presented. Current and
future challenges for the use of DBS in psychiatric disorders are
discussed, as well as a rationale for referring to this subspecialty as
limbic disorders surgery based on the parallels with movement
disorders surgery. Key Words: Deep brain stimulation,
Tourette’s syndrome, obsessive-compulsive disorder, major de-
pression, treatment-resistant depression, psychosurgery.
Perhaps no other word in the field of neurosurgery, or
medicine for that matter, conjures up a more negative
connotation than the word “psychosurgery.” Although
the history of this discipline may lead some to conclude
that its reputation is somewhat justified, the current era of
functional neurosurgery is providing new opportunities
for scientific advances in the surgical treatment of psy-
chiatric disorders, as well as a set of new challenges.
With thoughtful, methodical approaches to clinical trial
construction, surgical technique, and the sharing of
meaningful data, psychosurgery may well end up being
one of the most important and well-respected specialties
of the new century.
To understand the current work being done and where
these efforts may go in the future, it is important to
understand the history of psychosurgery. Although re-
ports of neurosurgical procedures for derangements in
behavior and thinking date back to the late 1800s, the
earliest formal series of procedures specifically aimed at
the treatment of psychiatric disorders were performed in
the mid 1930s. Egas Moniz, a Portuguese neurologist,
and Almeida Lima, a neurosurgeon, performed a series
of frontal leucotomies starting in November of 1935 after
hearing a lecture on frontal lobe function and anxiety
states in primates. In his subsequent publications describ-
ing these procedures, Moniz was the first to coin the term
“psychosurgery.”1Shortly thereafter, American neurolo-
gist Walter Freeman and a neurosurgical colleague,
James Watts, started performing a similar procedure in
1936, which they renamed the “frontal lobotomy” later
Although there was immediate skepticism and alarm
by many at the time, it is important to understand the
context in which these events occurred. In the 1930s, the
field of psychiatry was young and deeply divided be-
tween those who believed that psychiatric disease was a
disorder of thought best treated with psychoanalysis, and
those who believed such diseases were biological disor-
ders of the brain. More importantly, this was before the
advent of chlorpromazine or any psychiatric medica-
tions. The only treatment options were institutionaliza-
tion and the so-called “shock therapies” using insulin
(pentetrazol) or electricity. This lack of effective treat-
ment, in combination with the ever-growing numbers of
patients, caused a dramatic rise in the number of psychi-
atric inpatients in the 1920s and 1930s. By 1939, there
were 480,000 psychiatric hospital beds in the United
States, more than both the medical and surgical hospital
beds combined at the time. Many physicians were happy
to pursue any therapy that might successfully treat these
Although these early procedures were imprecise and
barbaric by today’s standards, many of the early practi-
tioners of psychosurgery were not always as reckless as
history remembers them. The earliest work by Moniz and
Freeman was based on primate experiments in frontal
Address correspondence and reprint requests to: Paul Sloan Larson,
MD, Department of Neurological Surgery, University of California,
San Francisco, 505 Parnassus Avenue, Box 0112, San Francisco, CA
94143-0112. E-mail: email@example.com.
Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics
Vol. 5, 50–58, January 2008 © The American Society for Experimental NeuroTherapeutics, Inc.
disconnection done at Yale by John Fulton and Carlyle
Jacobsen. Freeman and Watts sought and developed spe-
cific instruments and practiced the procedure on a ca-
daver first. Freeman almost obsessively followed-up with
his patients for years, even decades, after their proce-
dures. Some of the greatest neurosurgical names of the
day performed the procedures at one time or another.
Freeman himself was extremely active in organized med-
icine and actively presented and published his work. His
downfall, and thus the downfall of the lobotomy, was
due in large part to his failure to objectively evaluate the
place surgery had in the treatment of psychiatric disor-
ders after the introduction of chlorpromazine, and his
increasingly overzealous advocacy of the procedure.2
With the development of human stereotactic tech-
niques by Spiegel and Wycis in the 1940s and later with
the introduction of computed tomography and MRI, our
ability to accurately and discretely place lesions in the
brain significantly improved. The establishment of clin-
ical definitions of the various psychiatric disorders and
the development of clinical rating scales for the disorders
gave investigators the substrate by which to objectively
evaluate and compare treatment outcomes. The develop-
ment of deep brain stimulation (DBS) in the 1990s led to
a renewed interest in the surgical treatment of psychiatric
DBS is perceived as having an advantage over prior
surgical procedures that carry the stigma of lesioning
targets in the brain permanently. DBS is adjustable, with
multiple stimulation parameters that can be manipulated
by the practitioner including amplitude, frequency, and
width of the stimulating pulse, and to a lesser extent the
location and shape of the stimulating field. In addition, it
is nondestructive and reversible, meaning that the pres-
ence of the electrode itself in the brain does not disrupt
the normal brain circuitry, and when the stimulator is off,
it is in essence “not there.” The latter provides the po-
tential for more rigorous clinical trials with subjects and
evaluators blinded to the stimulation condition, some-
thing that is impossible to accomplish with lesioning
procedures unless a placebo-controlled sham trial is
used. Although these points are valid, and DBS may
confer therapeutic advantages at the level of the brain, it
remains to be seen whether it really represents an advan-
tage to the patient. Hardware complications, such as lead
fracture, infection, patient compliance issues (e.g., basic
wound care problems at best, self mutilation of the im-
planted device at worst), and in some cases the need for
very frequent battery changes, are all potential disadvan-
tages of DBS over lesioning procedures.3–8
The three psychiatric disorders currently under inves-
tigation with DBS are Tourette’s syndrome (TS), obses-
sive-compulsive disorder (OCD), and treatment-resistant
depression (TRD). All three have a history of being
successfully treated with lesioning procedures in various
targets, making them a logical place to start. This is
analogous to the early adoption of DBS in movement
disorders, where thalamotomy and pallidotomy were re-
placed by thalamic and pallidal stimulation. It was ap-
parent as far back as Moniz’s original series of limbic
leucotomy that the psychotic disorders did not respond
well to the lesioning procedures, and this has held true,
by and large, since that time. There are no studies in the
use of DBS for schizophrenia currently underway.
The selection of targets for DBS is perhaps one of
the greatest challenges in treating psychiatric disor-
ders with this modality. The treatment of Parkinson’s
disease benefited from a widely used, although imper-
fect, primate model that has produced a reasonable and
predictive model for the possible neuronal circuitry
underlying the disorder. This model supported the use
of some targets for DBS (such as the pallidum) and led
to the discovery of others (such as the subthalamic
nucleus and pedunculopontine nucleus).9–11There is
not yet a well-validated animal model for any of the
psychiatric disorders, although efforts are under-
way.12,13As a result, target selection to date has been
largely based on prior lesioning experience. However,
functional neuroimaging and fortuitous discoveries
while using DBS to treat other conditions have also
led to trials of new targets, and these may play a larger
role as the discipline moves forward.
What follows is a brief overview of some of the
work being done in each of these disorders in the
current era. This is not meant to be an encyclopedic
catalogue of every target that has been explored for
DBS in psychosurgery, but rather a highlight of what
are considered to be some of the major candidate brain
targets for each disorder. One must keep in mind that
many of these are either single case reports or small
series, some in unblinded or less than optimally
blinded conditions. Therefore, the results must be con-
sidered in this context.
For each of the disorders reviewed, I have included an
accompanying table to outline the available information
regarding stimulation parameters. For the sake of space,
only the patients that were considered responders from
each trial are included. The stereotactic coordinates are
given relative to the anterior commissure (AC), the pos-
terior commissure (PC), or the midpoint between the two
(midcommissural point [MCP]). All coordinates are
given relative to the midcommissural point unless other-
wise noted. The stimulation mode and the number of
active contacts are given, where the internal pulse gen-
erator is referred to as the case (C), and each contact is
referred to as 0, 1, 2, and 3 (0 being most ventral) with
the appropriate sign for assignment of cathode (-) and
anode (?). Finally, the amplitude in volts (v), pulse
width (PW) in microseconds, and frequency in hertz (Hz)
DBS FOR PSYCHIATRIC DISORDERS51
Neurotherapeutics, Vol. 5, No. 1, 2008
interna of the globus pallidus in Parkinson’s disease. N Engl J Med
10. Bergman H, Wichmann T, DeLong MR. Reversal of experimental
parkinsonism by lesions of the subthalamic nucleus. Science 1990;
11. Mazzone P, Lozano A, Stanzione P, et al. Implantation of human
pedunculopontine nucleus: a safe and clinically relevant target in
Parkinson’s disease. Neuroreport 2005;16:1877–1881.
12. Grabli D, McCairn K, Hirsch EC, et al. Behavioural disorders
induced by external globus pallidus dysfunction in primates: I.
behavioural study. Brain 2004;127:2039–2054.
13. Francois C, Grabli D, McCairn K, et al. Behavioural disorders
induced by external globus pallidus dysfunction in primates II.
anatomical study. Brain 2004;127:2055–2070.
14. Hassler R, Dieckmann G. [Stereotaxic treatment of tics and inar-
ticulate cries or coprolalia considered as motor obsessional phe-
nomena in Gilles de la Tourette’s disease]. Revue neurologique
15. Vandewalle V, van der Linden C, Groenewegen HJ, et al. Stereo-
tactic treatment of Gilles de la Tourette syndrome by high fre-
quency stimulation of thalamus. Lancet 1999;353:724.
16. Temel Y, Visser-Vandewalle V. Surgery in Tourette syndrome.
Mov Disord 2004;19:3–14.
17. Diederich NJ, Kalteis K, Stamenkovic M, et al. Efficient internal
pallidal stimulation in Gilles de la Tourette syndrome: a case
report. Mov Disord 2005;20:1496–1499.
18. Ackermans L, Temel Y, Cath D, et al. Deep brain stimulation in
Tourette’s syndrome: two targets? Mov Disord 2006;21:709–713.
19. Coffey BJ, Miguel EC, Biederman J, et al. Tourette’s disorder with
and without obsessive-compulsive disorder in adults: are they dif-
ferent? J Nerv Ment Dis 1998;186:201–206.
20. Lippitz BE, Mindus P, Meyerson BA, et al. Lesion topography and
outcome after thermocapsulotomy or gamma knife capsulotomy
for obsessive-compulsive disorder: relevance of the right hemi-
sphere. Neurosurgery 1999;44:452–458; discussion 458-460.
21. Sturm V, Lenartz D, Koulousakis A, et al. The nucleus accumbens:
a target for deep brain stimulation in obsessive-compulsive- and
anxiety-disorders. J Chem Neuroanat 2003;26:293–299.
22. Greenberg BD, Price LH, Rauch SL, et al. Neurosurgery for in-
tractable obsessive-compulsive disorder and depression: critical
issues. Neurosurg Clin N Am 2003;14:199–212.
23. Dougherty DD, Baer L, Cosgrove GR, et al. Prospective long-term
follow-up of 44 patients who received cingulotomy for treatment-
refractory obsessive-compulsive disorder. Am J Psychiatry 2002;
24. Jenike MA. Neurosurgical treatment of obsessive-compulsive dis-
order. Br J Psychiatry 1998:79-90.
25. Cosgrove GR. Surgery for psychiatric disorders. CNS Spectr 2000;
26. Hodgkiss AD, Malizia AL, Bartlett JR, et al. Outcome after the
psychosurgical operation of stereotactic subcaudate tractotomy,
1979-1991. J Neuropsychiatry Clin Neurosci 1995;7:230–234.
27. Montoya A, Weiss AP, Price BH, et al. Magnetic resonance im-
aging-guided stereotactic limbic leukotomy for treatment of intrac-
table psychiatric disease. Neurosurgery 2002;50:1043–1049; dis-
28. Flaherty AW, Williams ZM, Amirnovin R, et al. Deep brain stim-
ulation of the anterior internal capsule for the treatment of Tourette
syndrome: technical case report. Neurosurgery 2005;57:E403; dis-
29. Rezai A, Friehs G, Malone D, et al. Deep brain stimulation for
treatment of intractable major depression: preliminary results from
a multi-center prospective trial. Annual Meeting of the American
Association of Neurological Surgeons, San Francisco, CA, 2006.
30. Haber SN, Fudge JL, McFarland NR. Striatonigrostriatal pathways
in primates form an ascending spiral from the shell to the dorso-
lateral striatum. J Neurosci 2000;20:2369–2382.
31. Heimer L. The legacy of the silver methods and the new anatomy
of the basal forebrain: implications for neuropsychiatry and drug
abuse. Scand J Psychol 2003;44:189–201.
32. Nauta WJ, Domesick VB. Afferent and efferent relationships of the
basal ganglia. Ciba Found Symp 1984;107:3–29.
33. Fontaine D, Mattei V, Borg M, et al. Effect of subthalamic nucleus
stimulation on obsessive-compulsive disorder in a patient with
Parkinson disease. Case report. J Neurosurg 2004;100:1084–1086.
34. Aouizerate B, Cuny E, Martin-Guehl C, et al. Deep brain stimu-
lation of the ventral caudate nucleus in the treatment of obsessive-
compulsive disorder and major depression. Case report. J Neuro-
35. Mallet L, Mesnage V, Houeto JL, et al. Compulsions, Parkinson’s
disease, and stimulation. Lancet 2002;360:1302–1304.
36. Nuttin B, Cosyns P, Demeulemeester H, et al. Electrical stimula-
tion in anterior limbs of internal capsules in patients with obses-
sive-compulsive disorder. Lancet 1999;354:1526.
37. McIntyre CC, Savasta M, Kerkerian-Le Goff L, et al. Uncovering
the mechanism(s) of action of deep brain stimulation: activation,
inhibition, or both. Clin Neurophysiol 2004;115:1239–1248.
38. Spiegel EA, Wycis HT, Freed H, et al. A follow-up study of
patients treated by thalamotomy and by combined frontal and
thalamic lesions. J Nerv Ment Dis 1956;124:399–404.
39. Greenberg BD, Malone DA, Friehs GM, et al. Three-year out-
comes in deep brain stimulation for highly resistant obsessive-
compulsive disorder. Neuropsychopharmacology 2006;31:2384–
40. Fava M. Diagnosis and definition of treatment-resistant depression.
Biol Psychiatry 2003;53:649–659.
41. Efficacy and safety of electroconvulsive therapy in depressive
disorders: a systematic review and meta-analysis. Lancet 2003;
42. Franzini A, Ferroli P, Leone M, et al. Stimulation of the posterior
hypothalamus for treatment of chronic intractable cluster head-
aches: first reported series. Neurosurgery 2003;52:1095–1099; dis-
43. Mayberg HS, Liotti M, Brannan SK, et al. Reciprocal limbic-
cortical function and negative mood: converging PET findings in
depression and normal sadness. Am J Psychiatry 1999;156:675–
44. Mayberg HS. Modulating dysfunctional limbic-cortical circuits in
depression: towards development of brain-based algorithms for
diagnosis and optimised treatment. Br Med Bull 2003;65:193–207.
45. Schlaepfer TE, Cohen MX, Frick C, et al. Deep brain stimulation
to reward circuitry alleviates anhedonia in refractory major depres-
sion. Neuropsychopharmacology 2007 Apr 11; [Epub ahead of
46. Mink JW, Walkup J, Frey KA, et al. Patient selection and assess-
ment recommendations for deep brain stimulation in Tourette syn-
drome. Mov Disord 2006;21:1831–1838.
47. Rauch SL, Whalen PJ, Curran T, et al. Probing striato-thalamic
function in obsessive-compulsive disorder and Tourette syndrome
using neuroimaging methods. Adv Neurol 2001;85:207–224.
48. Rauch SL, Kim H, Makris N, et al. Volume reduction in the
caudate nucleus following stereotactic placement of lesions in the
anterior cingulate cortex in humans: a morphometric magnetic
resonance imaging study. J Neurosurg 2000;93:1019–1025.
49. Rauch SL, Savage CR, Alpert NM, et al. Probing striatal function
in obsessive-compulsive disorder: a PET study of implicit se-
quence learning. J Neuropsychiatry Clin Neurosci 1997;9:568–
50. Rauch SL, Dougherty DD, Malone D, et al. A functional neuro-
imaging investigation of deep brain stimulation in patients with
obsessive-compulsive disorder. J Neurosurg 2006;104:558–565.
51. Mink JW. Basal ganglia dysfunction in Tourette’s syndrome: a
new hypothesis. Pediatr Neurol 2001;25:190–198.
52. Mink JW. Neurobiology of basal ganglia circuits in Tourette syn-
drome: faulty inhibition of unwanted motor patterns? Adv Neurol
Neurotherapeutics, Vol. 5, No. 1, 2008