T reatment of most cases of obsessive-compulsive disorder (OCD) includes serotonin reuptake inhibitors (SRI), alone or in combination with other medications, and cognitive behavior therapy (CBT). However, unresponsiveness to available treatments may reach up to 30% to 40% of patients. 1 – 4 For them, different neurosurgical techniques have been employed. 5 Some of these interventions aim at the ventral anterior internal capsule and ventral striatum (VC/VS) to disrupt the frontal-basal ganglia-thalamic circuit, implicated in the pathogenesis of OCD. This can be achieved with ablative procedures such as thermocoagulation and Gamma Knife radiosurgery or with deep brain stimulation. Radiosurgery has the advantage of being noninvasive, which reduces possible complications related to neurosurgery. Studies with Gamma Knife anterior capsulotomy, with various response criteria, have suggested improvements in 55% to 70% of patients. 6, 7
A smaller double-shot, bilateral gamma knife anterior capsulotomy lesion has been recently proposed at Brown University, with few side effects and good efficacy profile, named (VC/VS) gamma capsulotomy. 8 Preliminary data indicated that clinical response (at least 35% reduction in Yale-Brown Obsessive Compulsive Scale [Y-BOCS] scores) was obtained in 13 out of 22 patients (59%) after 1 year and in 15 patients (69%) after 2 years of follow-up. 8
In this article we report preliminary findings from five patients who underwent VC/VS gamma capsulotomy for refractory OCD with a minimum follow-up period of 36 months. The aims of this study were to report preliminary findings of efficacy of the technique and to assess the safety of this procedure, including general medical and neurological adverse events/complications.
MATERIALS AND METHODS
Ethical Issues
This study complies with the guidelines for neurosurgery of severe psychiatric disorders in Brazil 9 and was approved by the Brazilian National Commission of Research Ethics (CONEP). Approval was also granted by local Ethics Committees at the University of São Paulo Medical School and Santa Paula Hospital, respectively, the institutions where the patients were clinically assessed and submitted to radiosurgery.
Written informed consent was obtained, with a member from the Brazilian OCD Patients Foundation present to ensure adequate protocol understanding from all patients. An independent panel composed of two psychiatrists appointed by the Regional Medical Council of São Paulo and the president of the Brazilian OCD Patients Foundation reviewed video-taped interviews confirming the patients’ adequate knowledge of benefits and risks related to gamma radiosurgery.
The research team will provide all patients with systematic assessments of adverse events and complications for a minimum follow-up period of 5 years.
Clinical Assessments
Patients included in the study were submitted to a detailed psychiatric history, as well as physical, neurological, and psychiatric examinations. Psychiatric axis I and axis II comorbidities were further assessed by the Structured Clinical Interview for DSM-IV (SCID) and the Structured Interview for DSM-IV Personality Disorders (SIDP-IV). 10, 11
Sample Selection
Thirteen severe OCD patients from various States in Brazil were initially screened as candidates for surgery. Only five patients (38.5%) fulfilled our inclusion and refractoriness criteria (see details in Table 1 ). The main reasons for exclusion were lack of adequate medication/CBT trials (four patients), a history of full treatment response after the introduction of a previous medication (one patient) and other main axis I/II diagnosis (three patients), namely factitious disorder, severe bipolar disorder and one case of prominent paranoid personality disorder.
TABLE 1. Inclusion, Refractoriness and Exclusion Criteria for the “(VC/VS) Gamma Capsulotomy Obsessive-Compulsive Disorder Study”
The five patients included (two men, three women, mean age 35.0±11.0 years, mostly single) had a median of 18 years of severe, disabling OCD symptoms and considerable psychosocial impairment. Three patients (A, C, E) were unable to complete their University degrees. Only one patient (D) was working regularly at the time of surgery ( Table 2 ).
TABLE 2. Preoperative Sociodemographic Characteristics of Five Obsessive Compulsive Patients Submitted to (VC/VS) Gamma Capsulotomy
All patients reported early onset of their obsessive-compulsive symptoms (before 10 years of age). Compulsions appeared first (median age for first compulsions was 8 years) ( Table 3 ). Obsessive-compulsive symptoms important enough to interfere with daily living activities were present, on average, by the age of 18.
TABLE 3. Psychopathological Features in Five Obsessive Compulsive Patients Submitted To (VC/VS) Gamma Capsulotomy
Major depressive and panic disorders were the most prevalent axis I comorbidities ( Table 3 ). Cluster C personality disorders such as dependent and avoidant personality disorders (patients B and C) and obsessive-compulsive personality disorder (patient E) were common ( Table 3 ). There were no comorbid tic disorders.
Specific treatments were usually sought at a median age of 20.5 years, or 2.5 median years after full-blown OCD. The mean number of previous medication trials was 14.6—more specifically, 5.4 different SRI trials, one of which was with clomipramine ( Table 4 ). All patients had received adequate CBT treatment, except for patient E, who tolerated only very few sessions. Patients were told to maintain their medications unchanged after surgery. However, prescription modifications were necessary in two patients (C and E), and one of the responders independently reduced his dosage (A).
TABLE 4. Preoperative History of Previous Treatment Trials of Five Obsessive Compulsive Patients Submitted To (VC/VS) Gamma Capsulotomy
Follow-up Assessments
Clinical global changes were prospectively assessed by the Clinical Global Impression (CGI) Scale and Global Assessment of Functioning (GAF) Scale. 12, 13 The presence and severity of OC symptoms and tics were respectively determined by the Y-BOCS and the Yale Global Tic Severity Scale. 14 – 16 The Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI) were administered to all patients. 17, 18 All inventories were applied before surgery and at every subsequent follow-up visit. Patients who missed their follow-up appointments were interviewed by phone to minimize loss of data collection.
Sleep and cognitive, emotional and/or physical adverse events were prospectively assessed by a detailed questionnaire (SAFTEE Event List and Interview). 19
Postoperative follow-up visits were scheduled at 2 weeks, 1 month, 2 months, and subsequently at 3, 6, 9, 12, 24, and 36 months after surgery. At 48 months of follow-up, two patients (B and D) completed a full follow-up visit, whereas three patients (A, C, and E) were interviewed by telephone.
Clinical Response Criteria
Response criteria were defined as a minimum of 35% reduction in Y-BOCS scores and an “improved” or “much improved” score on the CGI.
Operative Technique
A preoperative stereotactic MRI was obtained, and determination of dose planning and target selection was performed using a dedicated software (Leksell GammaPlan, 5.32, 2002).
The final step of the procedure was the exposure of the targets with the patient in the Leksell Gamma Knife model B. Bilateral, double-shot capsulotomy lesions were targeted at the ventral portions of the anterior limb of the internal capsule, approximately 10 mm rostral to the anterior commissure. The target at the anterior limb of the internal capsule was covered by a 50% isodose line; maximum dose at 100% was 180 Gy. The bilateral targets were each exposed by two focus positions (“shots”) from the converging sharply collimated beams of gamma radiation from 201 60 Co sources, using 4 mm collimators. Sensitive structures such as the optic nerves and lenses were protected, maintaining radiation below a safe threshold in these regions. The mean total time of exposure to radiation was 480 minutes (or 240 minutes for each hemisphere). Radiation rate from the 60 Co sources was 1.788 Gy/min.
The American (BG and GN) and the Brazilian team (ACL, MC, ECM) worked together to determine optimal target localization and dose planning for all patients, either in person (cases A, B and C) or through electronic communication (cases D and E). Agreement from all members of the team was achieved previous to each procedure.
MRI Acquisition
Structural MRI scans were acquired for all five OCD patients pre- and postoperatively (range 9 to 24 months) using a 1.5 Tesla Signa LX CVi scanner (version 9.1, 2004, General Electric, Milwaukee, Wisconsin).
Statistical Analysis
All variables were summarized using descriptive statistics (frequency, median, mean and SD). Small sample sizes and noncontinuous variables precluded parametric or nonparametric statistical analysis.
RESULTS
Assessment of Efficacy of the Procedure
Among the five patients submitted to gamma-capsulotomy, patients A and B (40%) fulfilled our response criteria after 12 months, and three patients (60%), including patient D, fulfilled criteria after 48 months of follow-up. Y-BOCS reductions ranged from 38% to 69% ( Table 5, Figure 1, and Figure 2 ) among responders. Mean Y-BOCS scores changed from 32.2±0.67 (standard error of mean [SEM]) to 20.6 ± 5.49 (SEM) after 48 months of follow-up. GAF improvements also reflected these changes ( Figure 3 ). Patient C met our response criteria until 9 months of postoperative follow-up, with a subsequent relapse; she again became a responder when 36 months of follow-up was reached, but relapsed 4 years after surgery. Patient D showed only 18% reduction of the Y-BOCS at the 36th month of follow-up, but became a full responder (38% reduction of the Y-BOCS) by 48 months of follow-up. On the other hand, patient E’s OCD symptoms deteriorated after 24 months of follow-up (25% increase on the Y-BOCS).
TABLE 5. Symptom Changes of Five Patients Submitted to (VC/VS) Gamma Capsulotomy, up to 48 Months of Follow-Up
FIGURE 1. Yale-Brown Obsessive Compulsive Scale (Y-BOCS) Scores Over 48 Months of Follow-Up for Five Patients Who Underwent Ventral Capsular/Ventral Striatal Gamma Capsulotomy
FIGURE 2. Pre-Op and Post-Op Clinical Global Impression (CGI) Scores of Five Patients Who Underwent Ventral Capsular/Ventral Striatal Gamma Capsulotomy
FIGURE 3. Global Assessment of Functioning (GAF) Scores Over 48 Months of Follow-Up for Five Patients Who Underwent Ventral Capsular/Ventral Striatal Gamma Capsulotomy
Beck Depression Inventory scores oscillated considerably along follow-up visits. Nevertheless, full and partial responders tended to present important reductions of the BDI scores, except for patient A, who developed a relapse of depressive symptoms at 36 months of follow-up (56% increase of scores from baseline) ( Table 5, Figure 4 ). Patient E, a nonresponder, also showed further impairment (60% increase of BDI scores from baseline). A similar pattern was found with BAI scores, with more robust anxiety decrements (mainly with patients B, C and D) ( Table 5, Figure 5 ).
FIGURE 4. Beck Depression Inventory (BDI) Scores Over 36 Months of Follow-Up for Five Patients Who Underwent Ventral Capsular/Ventral Striatal Gamma Capsulotomy
FIGURE 5. Beck Anxiety Inventory (BAI) Scores Over 36 Months of Follow-Up for Five Patients Who Underwent Ventral Capsular/Ventral Striatal Gamma Capsulotomy
Three patients had their medications changed during the study. Patient A did not tolerate higher dosages of antidepressants. He spontaneously changed his medication, from fluvoxamine, 100 mg/day, venlafaxine, 150 mg/day, quetiapine, 100 mg/day and clonazepam, 2 mg/day, to fluvoxamine, 50 to 100 mg/day, quetiapine, 25 mg/day, and clonazepam, 2 mg/day. For patient C, clomipramine dosage was increased from 225 mg/day to 300 mg/day, plus risperidone, 4 mg/day, and diazepam, 10 mg/day, during the study, due to depressive symptoms. By 36 months of follow-up, she was no longer taking risperidone, but OCD symptoms had improved. Patient D was initially taking citalopram, 60 mg/day, plus olanzapine, 2.5 mg/day, with no subsequent improvements on OCD. It was changed to fluoxetine, 40 mg/day, plus ziprasidone, 40 mg/day.
Assessment of General Medical and Neurological Adverse Events
Table 6 describes adverse events reported by patients, according to the Systematic Assessment for Treatment Emergent Events (SAFTEE) scale. Headaches (lasting days to weeks), light-headedness/vertigo, weight changes and episodic nausea/vomiting were observed. Headaches were usually responsive to nonsteroidal anti-inflammatory drugs, except for patient C, who required steroids for a few weeks. Another patient required bladder catheterization during the surgical procedure, presenting hematuria that resolved after 1 day (patient D).
TABLE 6. Symptoms and Signs Reported Over 36 Months of Follow-up by Patients Who Underwent (VC/VS) Gamma Capsulotomy, According to SAFTEE Scale
MRI Assessments
Post operative MRI scans showed that all radiosurgical targets located exactly where planned preoperatively ( Figure 6 ). All patients, with the exception of patient E, showed postoperative bilateral double-shot anterior capsulotomy lesions, indicated by hypointense rounded volumes on T1-weighted, T2-weighted and FLAIR images, with hyperintense borders on FLAIR and T2-weighted images and peripheral ring enhancement following paramagnetic contrast media administration, adjacent to the head of the caudate nuclei. Patient E, however, showed only minimal lesions in target areas, especially in the left hemisphere, as indicated in most image series ( Figure 6 and Figure 7 ).
Patient A, who does not show marked lesions in this acquisition, demonstrated clear lesions on other acquisitions (see Fig. 7). This is not the case of patient E, who showed only minimal lesions on the left hemisphere in all acquisitions.
FIGURE 7. T1-Weighted Axial and Coronal MRI Slices With Para-Magnetic Contrast (Gadolinium) Depicting Postoperative Ventral Capsular/Ventral Striatal Gamma Capsulotomy Lesions in Patients A and E
DISCUSSION
Procedure Efficacy
Previous anterior capsulotomy techniques produced a relatively high incidence of side effects, possibly as a consequence of larger lesions. 20, 21 Aiming to improve results and reduce side effects, smaller and standardized capsulotomy lesions were developed (the VC/VS gamma capsulotomy). 8 This improved procedure is based on a more precise target definition within the internal capsule, employing smaller collimator sizes (4 mm), consequently aimed at producing smaller lesions albeit not compromising efficacy.
Our preliminary findings suggest that this procedure holds promise for selected severe and treatment resistant OCD patients. Among the five patients enrolled in this study, at the end of a 3-year follow-up period, three (60%) presented full response after surgery (67%, 69% and 38% reductions in Y-BOCS severity), and one had a partial response (33%). On the other hand, the one patient who was a nonresponder to surgery also developed worse OCD symptoms in the long-term follow-up, though maintaining his previous psychosocial impairment.
The three patients who improved the most and the partial responder showed markedly increased personal autonomy and reintegration into society, in addition to relief of persistent subjective distress.
Although comparison across studies is limited for methodological reasons (see Greenberg et al. 22 for discussion), clinically significant improvement after larger capsulotomy lesions (including an earlier gamma capsulotomy technique) was previously reported in five out of nine patients (55%) and seven out of 10 patients (70%). 6, 7 These rates are comparable to ours (3 out of 5 patients or 60%). However, we used more stringent response criteria. Previous studies were less rigorous regarding OC symptom amelioration and did not include measures of global improvements (such as CGI scores). Analyzing data from previous Gamma Knife techniques, but response criteria similar to ours, Rück 21 described response rates similar to ours (five out of eight patients, 62.5%).
The delayed amelioration of symptoms observed in our study could result from multiple sources and even be unrelated to the surgery. However, the latter interpretation is less likely, since OCD in the overwhelming majority of our patients was a chronic illness (mean OCD duration of 17.4 years), unresponsive to multiple conventional treatment schemes.
It remains unclear how gamma capsulotomy lesions result in OCD symptom improvement. One hypothesis is that bilateral lesions of the anterior capsule could alter information flow in thalamo-orbital and thalamo-cingulate neuronal circuitry (particularly the subgenual cingulate), which is related to the pathophysiology of OCD, and thus be involved in the changes in OCD symptoms observed after surgery. Interestingly, functional imaging data from a small cohort of patients with severe anxiety disorders undergoing this type of neurosurgery showed reduced activity within medial orbitofrontal cortex after the intervention. 22, 23
In addition, edema and necrosis produced by gamma radiation surrounding the targets may compromise the adjacent striatum 24 and nucleus accumbens. Therefore, it is possible that additional cortico-striato-pallido-thalamico-cortical circuits are interrupted, especially those involving the ventral striatal-pallidal system and the extended amygdala. 25 – 27
It is unknown whether unilateral lesions would be as efficacious as bilateral targeting. One previous MRI study of anterior capsulotomy for OCD suggested that appropriate lesioning of the right anterior capsule might be critical to subsequent therapeutic response. 7 It is noteworthy in our study that the only patient who did not show any clinical response to surgery had a minimal left anterior capsule lesion, whereas all the other patients showed clear bilateral lesions.
It is not surprising that most of our patients also reported postoperative reductions in anxiety and depression scores. Anxiety disorders and refractory depression have been successfully treated with anterior capsulotomy by thermolesion. 28, 29 In our sample, persisting reductions in anxiety scores were more prominent than reductions in depressive symptoms (mean reduction of 15 score points or 54%, versus 8.6 score points or 34%). Patient A presented with worse scores on BDI and BAI in his last follow-up visit, and this may be attributed to his inadequate compliance with medications. He nonetheless maintained low Y-BOCS scores. Patient E, a treatment nonresponder, showed marked worsening of BDI and BAI scores, and OCD symptoms deteriorated. Therefore, it is possible that the improvement in anxiety and depressive symptoms by surgical intervention may contribute to the amelioration of OCD symptoms directly or indirectly, although not explaining the maintenance of low Y-BOCS scores in the postoperative follow-up period.
General Medical and Neurological Adverse Events
According to the SAFTEE scale, most adverse events were transient, not interfering with functioning or requiring treatment or hospitalization. Only headache, in one patient, lasted more than a few weeks. In this only case with persistent headache (around 2 weeks’ duration), no evidence of brain swelling was found on MRI, although the patient was empirically treated with corticosteroids for a few weeks. None of these initial symptoms persisted 36 months after surgery. However, it is still early to draw definite conclusions regarding potential long-term adverse effects.
Some of the symptoms and signs assessed by the SAFTEE scale may be attributed either to the direct effects of radiation, or to the effects of anesthesia and head positioning in the Gamma Knife equipment or even be unrelated to surgery. Headaches, nausea, vertigo, weight changes, postoperative throat swelling, 1 day hematuria, local dermatitis, and discrete pain on the scalp were probably related to the surgical procedure. Even though weight changes were common in four patients, only one patient (C) developed a considerable weight gain. Most side effects were mild and lasted for only a few days. We suppose that other symptoms/signs may or may not have been related to surgery.
A less favorable profile of adverse events was reported in previous radiosurgical studies using larger targets. 21, 29 Rück 21 reported the results of nine patients with OCD submitted to Gamma Knife capsulotomies. Three to four bilateral isocenters and 4 mm collimators were used for lesions in five patients, delivering more than 200 Gy at the center of the lesion on each side. 21 Frontal lobe complications were evident in two patients, as well as urinary incontinence and seizures. It is unclear, however, if this was due to larger lesion volume, higher doses, and/or different targeting.
Limitations
This pilot study has several limitations. First, it included a small cohort and used an open design. Second, as patients came from regions distant to the study site, some follow-up data were obtained only by telephone interview (especially at 48 months of follow-up). For the same reason, postoperative MRI scans schedule was different among patients (range=9 months to 24 months postsurgery). It was not possible to control for medication changes. Furthermore , patient C presented a quite variable clinical course over the 48 months of follow-up, demanding further assessment to reassure her response condition. Finally, neuropsychological and personality changes associated with this surgical procedure are not provided in this article, but they will be described in other publications.
CONCLUSION
In conclusion, this pilot study supports the view that the VC/VS Gamma Knife capsulotomy for resistant OCD may hold promise for a selected group of patients who have otherwise no therapeutic options. Our findings suggest that this procedure may be effective and well-tolerated overall, particularly when compared to the previous Gamma Knife technique that employed larger lesions. These conclusions, however, must be tentative, given the limitations of the short follow-up period (4 years) and our open study design. So far, only a few pilot trials of neurosurgery for resistant OCD have used a controlled design, all of them with small sample sizes. 30, 31 Our group is currently conducting the first double-blind, randomized controlled trial on radiosurgery to address this gap in knowledge.
Acknowledgments
We thank Dr. Navid Tahamtani, Dr. George Schahin, Dr. Soraya Cecílio, Dr. Douglas Castro, Sérgio Franco, Dr. Lauro Morubaiashi, Dr. Adriana Pinto, Dr. Ademir Bonassa, Prof. Raul Marino Jr, Prof. Valentim Gentil Filho, Prof. José Alberto Del Porto, Dr. Rui Castello Branco, Dr. Carlos Longo, Cláudia Midori Yamao, Patrícia Yamashita, and Gláucia Macedo whose help was fundamental to the execution of this project.
This study received financial support in the form of grants to Dr. Miguel from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Foundation for the Support of Research in the State of São Paulo; grant #1999/08560-6 and #2005/55628-08) and from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazilian Council for Scientific and Technological Development; grant no. 305548/2005-0).
Footnote
Received March 11, 2008; revised June 29 and August 29, 2008; accepted September 22, 2008. Drs. Lopes, Busatto, Mathis, Taub, D’Alcante, Gouvea, Cecconi, Gentil, Ferrão, Fuentes, Duran, and Miguel are affiliated with the Department and Institute of Psychiatry, University of São Paulo School of Medicine (FMUSP), São Paulo, Brazil; Drs. Greenberg, Norén and Rasmussen are affiliated with the Department of Psychiatry and Human Behavior and Department of Clinical Neurosciences - Neurosurgery, The Warren Alpert Medical School of Brown University; Providence, R.I.; Drs. Canteras and Salvajoli are affiliated with the Institute of Neurological Radiosurgery- Hospital Santa Paula, São Paulo; Dr. Hoexter is affiliated with the Department of Psychiatry, Federal University of São Paulo, UNIFESP, São Paulo; Dr. de Castro is affiliated with the Heart Institute (INCOR), FMUSP, São Paulo; Dr. Leite is affiliated with the Department of Radiology, FMUSP, São Paulo. Address correspondence to Antonio Carlos Lopes, Obsessive Compulsive Spectrum Disorders Program (PROTOC), Department of Psychiatry, University of São Paulo School of Medicine, R. Dr. Ovídio Pires de Campos, 785, 3° andar, sala 9, São Paulo, SP, Brazil 01060-970; [email protected] (e-mail).
Pallanti S, Hollander E, Bienstock C, et al: Treatment non-response in OCD: methodological issues and operational definitions. Int J Neuropsychopharmacol 2002; 5:181–191
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