Prospective Assessment of Stereotactic Ablative
Surgery for Intractable Major Depression
Donald C. Shields, Wael Asaad, Emad N. Eskandar, Felipe A. Jain, G. Rees Cosgrove, Alice W. Flaherty,
Edwin H. Cassem, Bruce H. Price, Scott L. Rauch, and Darin D. Dougherty
Background: Despite therapeutic advances for major depression, a subset of patients with this disorder does not respond to conventional
treatment. Stereotactic ablative procedures such as anterior cingulotomy have been performed in severely affected, treatment-resistant
patients, but the long-term results of such procedures are not fully understood.
Methods: Findings are reported for 33 patients with severe treatment-resistant major depression who underwent ablative stereotactic
procedures (dorsal anterior cingulotomy followed if necessary by subcaudate tractotomy). Preoperative and long-term postoperative Beck
Depression Inventory scores were obtained along with postoperative Clinical Global Improvement values. Both were analyzed to evaluate
patients’ responses to the surgical procedure(s).
Results: At mean follow-up of 30 months after one or more stereotactic ablative procedures, 11 patients (33.3%) were classified as
responders, 14 (42.4%) were partial responders, and 8 (24.2%) did not respond to the surgical procedure(s). Among those (17) who
underwent only one procedure, seven (41.2%) responded, whereas six (35.3%) and four (23.5%) showed partial or no response, respectively.
Among patients who required multiple surgical procedures, four patients (25%) responded, whereas eight (50%) and four (25%) patients
demonstrated partial or no responses, respectively, at long-term follow-up evaluations.
Conclusions: Approximately 75% of depression patients previously resistant to antidepressant therapies received partial or substantial
benefit from stereotactic ablative procedures. Those requiring only a single anterior cingulotomy tended to demonstrate more pronounced
responses than patients who underwent multiple surgical procedures.
Key Words: Anterior cingulotomy, limbic leucotomy, major de-
pression, microelectrode recording, stereotactic ablation, subcau-
iology of major depression remains poorly understood, this
disorder represents a major public health problem. The effects of
persistent depression can be severe and include disruption of
relationships, lost work time, and suicide (1).
Advances in antidepressant therapies have significantly im-
proved the treatment of depression. However, a small but signifi-
cant percentage of patients (10%–20%) do not respond to psycho-
therapy medication and/or electroconvulsive therapy (ECT). Hence,
there is a growing interest in additional surgical and device-based
treatment options, such as stereotactic ablative procedures, trans-
cranial magnetic stimulation, vagal nerve stimulation, and deep
brain stimulation (2).
Psychiatric neurosurgical procedures typically involve disrup-
tion of frontolimbic circuits. Compared with the now infamous
lobotomy of the mid 20th century, which disrupted extensive
cortical connections and caused multiple side effects, modern
procedures employ much more careful patient selection, target
location, and surgical techniques. Selective stereotactic proce-
dures are reported to benefit treatment-resistant patients who
suffer from major depression, severe anxiety, and obsessive-
ajor depressive disorder is a commonly encountered
psychiatric condition with a lifetime incidence of 20% in
U.S. women and 12% in men. Although the pathophys-
compulsive disorders (3–5). These techniques dramatically re-
duce incidence of suicide in severely depressed patients from
15% to 1% (6). Contemporary procedures include anterior cin-
gulotomy, subcaudate tractotomy, limbic leucotomy (which is
the combination of anterior cingulotomy and subcaudate tracto-
tomy), and anterior capsulotomy. Each involves creation of
lesions in limbic or paralimbic structures believed to be involved
in the pathophysiology of major depression.
Because few patients have received modern ablative proce-
dures for major depression, there are few long-term outcome
data (7). The present report presents a prospective long-term
follow-up analysis of 33 patients who underwent stereotactic
anterior cingulotomy and/or limbic leucotomy for treatment-
resistant depression at the Massachusetts General Hospital.
Methods and Materials
Patient Evaluation Guidelines
Potential candidates for surgery were reviewed by a multidis-
ciplinary committee of psychiatrists, neurologists, and neurosur-
geons. Patients ultimately approved for surgery met DSM-III-R/IV
criteria for major depressive disorder. Patients were determined
to be treatment-resistant if they had not responded to at least four
medication trials of adequate dose and duration, failed multiple
augmentation trials, and failed to respond to ECT. Adequate
medication dosages were defined by Physicians’ Desk Reference
guidelines in each instance, and drug administration durations
were required to be at least 6 weeks for all new medications.
Those who failed to respond to ECT did not demonstrate a
reduction in depressive symptoms as defined by the Beck
Depression Inventory (BDI) or were unable to complete the full
course of treatment due to side effects. Before referral for
surgery, common pharmacological therapies included selective
serotonin reuptake inhibitors, monoamine oxidase inhibitors,
tricyclic antidepressants, mood stabilizers, lithium augmentation,
cognitive therapy, and/or triiodothyronine augmentation. In in-
From the Departments of Neurosurgery (DCS, WA, ENE, GRC), Neurology
Hospital, Harvard Medical School, Boston, Massachusetts.
Address reprint requests to Darin D. Dougherty, M.D., Massachusetts Gen-
eral Hospital, Department of Psychiatry, 149 Thirteenth Street, Charles-
town, MA 02129; E-mail: email@example.com.
BIOL PSYCHIATRY 2008;64:449–454
© 2008 Published by Society of Biological Psychiatry
stances where a sufficiently extensive array of treatment trials had
not yet been tried, the Committee would recommend further
nonsurgical treatment before considering neurosurgical interven-
tion. Approximately 25% of referred patients received recom-
mendations for additional nonsurgical therapies, and about 50%
of all patients were not considered suitable candidates or were
postponed by the Committee due to insufficient data from
referring physicians. Contraindications for surgery included evi-
dence of a severe personality disorder, continuing substance
abuse, or active suicidal behavior. Patients were also cleared for
surgery by their primary care physicians, such that patients with
poorly controlled chronic conditions (i.e., uncontrolled diabetes),
previously diagnosed intracranial masses, or intracerebral vascular
abnormalities were excluded from surgical consideration.
After the initial screening candidates were invited for an
on-site review, at which time they were assessed to obtain a
preoperative baseline measure with a battery of tests including
the Structured Clinical Interview for DSM-IV and BDI, a com-
monly used 21-item self-report scale to assess severity of depres-
sive symptoms (8). After the intended procedure was explained
to each patient before surgery, each was required to exhibit the
capacity to render informed consent and provide written consent
for the procedure. The ability to render informed consent was
formally assessed in the context of a comprehensive clinical
evaluation, establishing that each patient had a clear appreciation
of how the risks, benefits, and alternatives of the procedure
applied to them personally.
Cingulotomy techniques evolved during the 11-year period of
study. Initially, single lesions were placed in the cingulate gyrus,
bilaterally. Patients who failed to respond were then treated with
additional cingulate lesions placed anterior to the first lesion.
Patients who initially received single lesions often failed to
respond; therefore, three bilateral cingulate lesions were created
in the initial surgery. If patients still failed to respond after 1 year,
bilateral subcaudate tractotomies were performed.
Before the procedure, a magnetic resonance image of the
brain was obtained for localization of the anterior cingulate
cortex. On the day of surgery, a CRW frame (Integra Radionics,
Burlington, Massachusetts) was placed after infiltration of the
scalp with 1% lidocaine at each of the pin sites. With the frame
secured, patients underwent a computed tomography scan for
localization. The initial target for cingulotomy was at a point
20–25 mm posterior to the anterior aspect of the frontal horn of
the lateral ventricle, 5 mm superior to the corpus callosum, and
7 mm lateral to the midline. Subsequent lesions were positioned
7 mm anterior/2 mm inferior and 14 mm anterior/4 mm inferior
to the first lesion, to follow the contour of the anterior cingulate
gyrus. The target for the first lesion of a subcaudate tractotomy
was at a point 7 mm anterior to the sylvian fissure, 5 mm above the
floor of the anterior cranial fossa, and 7 mm lateral to the midline.
The second lesion was positioned 7 mm lateral to the first.
All procedures were performed with patients awake, with
local anesthesia and sedation as needed. This is standard practice
for all such stereotactic procedures at Massachusetts General
Hospital. Patients were positioned in a semi-sitting position, and
the stereotactic frame was affixed to the operating table. The
scalp was infiltrated with 1% lidocaine with epinephrine. A single
transverse incision was made 1 cm anterior to the coronal suture.
Two burr-holes were then created 1.5 cm lateral to the midline.
Most patients underwent physiological localization via micro-
electrode recordings. After the cannula (attached to the stereo-
tactic arc and aligned to the burr holes) passed through the dural
opening and into the brain, microelectrodes were inserted into
the shaft of the cannula for recording. Continuous extracellular
recordings of single-unit and multiunit neuronal discharges were
amplified, displayed on a monitor, and fed into an audio unit.
Neuronal firing/bursting patterns, action potential characteristics,
quiet intervals, and background activity provided valuable infor-
mation about anatomical target localization in relation to the
measured depth of the microelectrode.
Lesions were created with a 1.2-mm insulated radiofrequency
thermistor electrode (10 mm exposed tip) inserted at the same
trajectory as that of the microelectrode (Figure 1). The probe was
connected to a radiofrequency lesion generator that monitored
tip temperature and electrode impedance during electrical cur-
rent application. The lesions were created at 85°C for 60 sec.
Morphometric imaging studies at Massachusetts General Hospital
have shown the mean lesion volumes to be 3.58 cm3(SD 1.2;
range 1.97–5.83) (9). For patients who had limited benefit 1 year
after anterior cingulotomy (three lesions bilaterally), those ap-
proved for a subsequent stereotactic procedure underwent a
subcaudate tractotomy. Thus, this procedure effectively resulted
in a limbic leucotomy.
After discharge from the hospital, patients were followed
closely by their referring psychiatrist, who also administered a
BDI at 6 months after surgery to evaluate depressive symptoms.
If after this time the referring psychiatrist believed a second
procedure was warranted for the patient, the Massachusetts
General Hospital Psychiatric Neurosurgery Committee reviewed
the patient’s progress and made recommendations regarding a
subsequent procedure. The BDI and Clinical Global Improve-
ment (CGI) Scales were administered, and patients who did not
achieve both a 35% reduction in BDI scores and a CGI of 2 or less
were classified as nonresponders to be considered for subse-
quent procedures. Each patient also received long-term follow-
up evaluations, and data regarding postoperative results were
obtained via self-administration of these inventories at a mean of
30 months after their last surgical procedure.
The CGI scales were also used to assess postoperative out-
comes at approximately 1 year after the last surgery. For instance,
patients were asked, “How would you rate yourself now as
compared to prior to surgery?” Symptoms were rated on the
following scale: 1 ? very much improved, 2 ? much improved,
3 ? minimally improved, 4 ? no change, 5 ? minimally worse,
6 ? much worse, 7 ? very much worse. The mean BDI and CGI
values and corresponding SDs were calculated and compared for
significance with a two-tailed, paired Student t test. Patient
responses were classified by percent improvement in BDI after
surgery. Those patients who reported a 50% improvement in BDI
scores, a CGI score of 2 or less, and attributed improvement to
the surgical intervention were considered responders. Those
considered partial responders had either a 35% improvement in
BDI scores, a CGI score of 2 or less, or achieved both of these,
but attributed the improvement to another treatment such as
previous changes in medication dosages or preoperative ECT
Thirty-three patients (20 women and 13 men) were accepted
for and underwent one or more stereotactic ablative procedures
450 BIOL PSYCHIATRY 2008;64:449–454
D.C. Shields et al.
between 1993 and 2004. The mean patient age was 43.2 years
(SD 12.3; range 23–65).
Response in Patients with Single Cingulotomy
Of the 33 patients, 17 underwent stereotactic anterior cingu-
lotomies without subsequent surgical procedures. The mean
preoperative BDI score for this group was 40.6 (SD 7.4) with a
long-term follow-up mean BDI of 19.8 (SD 17.4; p ? .001,
Student t test, paired two-tailed). The mean CGI value at this time
was 2.6 (SD 1.7). Seven patients (41.2%) were classified as
responders, whereas 6 (35.3%) were partial responders, and 4
(23.5%) did not respond to the procedure (Table 1).
To compare the response rates of initial patients who under-
went only single cingulotomy lesions versus later patients who
received three bilateral lesions, we compared the percent reduc-
tion of BDI scores in each group of patients. Those with single
lesions were found to have a 49.6% reduction in BDI scores,
whereas patients with three bilateral lesions demonstrated a
46.2% reduction (p ? .73; Student t test, paired two-tailed). This
nonsignificant difference was supported by the fact that 25.0% of
those with single-lesion cingulotomies were recommended for
subcaudate tractotomies compared with a similar percentage
(23.1%) of those receiving three lesions bilaterally.
Response in Patients with Multiple Ablative Procedures
Of 33 patients, 16 were treated with stereotactic anterior
cingulotomies, and after 6-month follow-up evaluations were
recommended for further surgical intervention. Nine patients
(initially treated with single bilateral cingulate lesions) under-
went repeat anterior cingulotomies (ablative lesions positioned
anterior to the original site), whereas seven patients were treated
with limbic leucotomies. One patient underwent two anterior
cingulotomy procedures with a subsequent subcaudate tractotomy.
The mean preoperative BDI score for this group was 36.9 (SD
11.2) with a long-term follow-up mean BDI of 22.1 (SD 13.7; p ?
.001, Student t test, paired two-tailed). The mean CGI value was
2.6 (SD 1.6). Four patients (25%) met the criteria for classification
as responders, whereas eight (50%) were partial responders, and
four (25%) did not respond to the procedure (Table 1).
Long-Term Response After Final Procedure in All Patients
At long-term follow-up evaluations among all 33 patients after
their final procedure, the mean BDI score was significantly
(arrows). Stereotactic limbic leucotomy lesions (arrows) are shown on sagittal (C) and axial (D) magnetic resonance image cuts. The dashed lines noted in
sagittal images denote the corresponding axial plane of images B and D.
D.C. Shields et al.
BIOL PSYCHIATRY 2008;64:449–454 451
decreased from 38.8 (SD 9.5) to 20.9 (SD 15.5) (p ? .001, Student
t test, paired two-tailed) with a CGI value of 2.6 (SD 1.7). Eleven
patients (33.3%) were classified as responders, whereas 14
patients (42.4%) were partial responders, and 8 (24.2%) did not
respond to the surgical procedure(s). Among specific aspects of
depression as compiled in the BDI score, different patients
demonstrated improvement in various areas; however, improved
anxiety was most commonly observed after surgical intervention.
Eight patients (24.2%) reported adverse effects after a proce-
dure (Table 2). Four patients (12.1%) reported transient urinary
incontinence. In 3 cases the incontinence lasted a few days, but
one patient noted periodic incontinence for several months
postoperatively. One patient also described subjective anxiety
that was noticeably different from her preoperative state. In
addition, she described periodic involuntary limb movements
and difficulty with pronunciation of some words, which im-
proved without additional therapy several months after surgery.
Another patient reported subjective long- and short-term mem-
ory impairment after surgery. A third patient had new onset
tonic-clonic seizures that required ongoing phenytoin adminis-
tration. The most serious complication was experienced by a
patient who became obtunded 3 weeks after surgery. She was
found to have an intracranial abscess requiring surgical drainage.
After 2 months of successful antibiotic administration she noted
significant improvement in her depressive symptoms, and no
abscess-related sequelae were detected.
Long-term follow-up evaluations of these patients revealed
that approximately 75% of patients with severe treatment-resis-
tant major depression demonstrated at least partial benefit from
stereotactic ablative procedures. Almost one-half of the patients
underwent a second procedure, because 6-month evaluations
revealed insufficient response to the initial surgery. Adverse
events related to surgery were time-limited or medically con-
trolled. Thus, stereotactic anterior cingulotomies/limbic leucoto-
mies seem to be relatively safe and effective procedures for
patients with treatment-resistant depression.
These results are in agreement with a previous series of
treatment-resistant depression patients who underwent stereo-
tactic ablative procedures. Mitchell-Heggs et al. (10) reported
78% of severely depressed patients demonstrated clinical im-
provement at 16 months after stereotactic limbic leucotomy
procedures. Although the number of patients studied in these
reports was relatively small, Kim et al. (11) more recently
described significant neuropsychological improvement in pa-
tients with severe depression and anxiety who underwent ste-
reotactic subcaudate tractotomies with or without cingulotomies.
The relatively small number of patients in this study who
underwent limbic leucotomies as well as the heterogeneity of the
sample and the staged nature for the procedures precludes a
meaningful analysis regarding the relative efficacy of subcaudate
tractotomies versus anterior cingulotomies. Patients who had the
full limbic leucotomy demonstrated less robust responses than
those who received only one surgery. Only those individuals
who failed to respond to the initial procedure advanced to
subsequent procedures. Therefore, by definition, the multiple
procedure group was composed of individuals who were more
resistant to neurosurgical intervention. No apparent age or
gender differences were observed to explain why some patients
responded better to anterior cingulotomy than others. Respond-
ers and nonresponders also did not demonstrate any clearly
identifiable demographic or BDI item score differences to ex-
plain these effects.
The mechanism whereby targeted ablative procedures relieve
depressive symptoms is poorly understood. This effect often
Table 1. Long-Term Follow-Up Assessment of 33 Treatment-Resistant Depression Patients Who Underwent
Stereotactic Ablation Procedures
All Patients (N ? 33)
Clinical ratings Preoperative BDI
38.8 (SD 9.5)
20.9 (SD 15.5)
2.6 (SD 1.7)
Single Cingulotomy (n ? 17)
Clinical ratingsPreoperative BDI
40.6 (SD 7.4)
19.8 (SD 17.4)
2.6 (SD 1.7)
Multiple Procedures (n ? 16)
Clinical ratings Preoperative BDI
36.9 (SD 11.2)
22.1 (SD 13.7)
2.6 (SD 1.6)
Response to treatment was defined as a reported 50% improvement in Beck Depression Inventory (BDI) scores, a
Clinical Global Improvement (CGI) score of 1 or 2, and improvement attributed to the surgical intervention. Partial
responders reported 35% improvement in BDI scores or a CGI score of 1 or 2 or achieved both but attributed the
improvement to another treatment. Patients rated CGI compared with preoperative condition (before the initial
anterior cingulotomy) with the following: 1 ? very much improved, 2 ? much improved, 3 ? minimally improved,
4 ? no change, 5 ? minimally worse, 6 ? much worse, 7 ? very much worse.
Table 2. Adverse Effects After Anterior Cingulotomy or Subcaudate
Adverse EffectNumber of Patients
Transient Urinary Incontinence
Involuntary Limb Movements with Speech Difficulty
New Onset Tonic-Clonic Seizures
drainage and antibiotic administration.
452 BIOL PSYCHIATRY 2008;64:449–454
D.C. Shields et al.
occurs in a delayed fashion, even months after surgery, suggest-
ing the involvement of network effects, which might include
alterations of traversing white matter tracts. Specifically, the
dorsal anterior cingulate (Brodmann area 24) is interconnected
with the hippocampus as part of Papez circuit and has prominent
interconnections with the lateral prefrontal cortex (Figure 2). The
subgenual cingulate (Brodmann area 25), which is lesioned as
part of subcaudate tractotomies, has significant connections with
the amygdala as well as with visceromotor regions of the
brainstem. Whereas the dorsolateral, orbitofrontal, and anterior
cingulate circuits have been implicated in mood regulation, a
specific, causal role for either the dorsal anterior cingulate or the
subgenual cingulate in depression has not been established
(12–15). Moreover, widespread frontal cortical and subcortical
atrophy is consistently noted in anatomical studies of major
depressive disorder, and functional imaging studies (both
positron emission tomography and functional magnetic reso-
nance imaging) reveal perturbations across wide networks of
limbic and frontal structures in major depression (16–20). There-
fore, the delayed effects of cingulotomy or subcaudate tractot-
omy could be mediated by compensatory responses in some or
all of these associated structures. Patients who demonstrated
further improvement after subcaudate tractotomies might also
have particularly benefited from changes in amygdala-related
networks, which might be less robust in the anterior cingulate
Although relatively few studies point to a privileged role for
specific cortical regions, positron emission tomography studies
suggest selective hypermetabolism in the subgenual cingulate/
prefrontal cortex predicts a response to antidepressant medica-
tion and stereotactic anterior cingulotomies (21,22). An early
report also suggests that deep brain stimulation of this region
might alleviate depression in some severely affected patients
(23). In light of these findings, disruption of frontal-subcortical
circuits by stereotactic ablative procedures might be regarded as
diminishing the downstream impact of these hyperactive dorsal and
subgenual cingulate areas. To what degree, if any, the activity or
neuroimaging findings in these regions is predictive of individual
symptoms and/or response to ablation is unknown.
Because patients in the present study continued to use
antidepressants after surgery, it is difficult to ascertain whether
clinical improvements were due solely to surgery or to interac-
tion with medications that had been less effective preoperatively.
Likewise, ineffective preoperative psychotherapies might dem-
onstrate improved efficacy after surgery. In addition, no sham
comparison group was used as a control. Sham procedures—
such as burr hole placement alone—with little to no likelihood of
efficacy are ethically problematic, because the risks of the
procedure outweigh the potential benefits (24). Although the
present study did not include a nonsurgical control group,
previous studies including subjects with similar inclusion/exclu-
sion criteria have demonstrated that depressed patients requiring
three or more medication trials exhibited a very poor long-term
treatment response to standard therapies (25). Thus, the present
study primarily provides data regarding the safety and effective-
ness of stereotactic ablative surgical procedures in patients with
treatment-resistant depression. Because most (75%) but not all
subjects reported benefits from surgery, future studies might
delineate readily identifiable predictors of treatment response so
that the risk-to-benefit ratio can be more clearly defined.
The work of Bruce H. Price, M.D. is supported in part by the
Sydney R. Baer Jr. Foundation. We wish to thank Valerie
Giorgione and Mariko Jameson for their contributions to this
Drs. Shields, Asaad, Eskandar, Jain, Cosgrove, Flaherty, Cas-
sem, Price, and Rauch reported no biomedical financial interests
or potential conflicts of interest. Dr. Dougherty discloses support/
honoraria from Cyberonics and McNeil and research support
from Medtronic, Northstar Neuroscience, Pfizer, Eli Lilly, Forest,
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