Ventral targeted anterior capsulotomy for treatment-resistant depression and obsessive-compulsive disorder: A treatment method with cases.

BACKGROUND: Ablative surgery using bilateral anterior capsulotomy (BAC) is an option for treatment resistant depression (TRD) and obsessive-compulsive disorder (TROCD). The location and extent of the lesion within anterior limb of the internal capsule (ALIC) remains uncertain. Accumulating evidence has suggested that the lesion should be located ventrally while limiting the dorsal extent. Our center is now targeting specific fiber tracts within the lower half of the ALIC. METHOD: Presurgical diffusion tensor Magnetic Resonance Imaging (MRI) was used to identify individual fibre tracts within the ventral aspect of the ALIC in the last two patients who underwent BAC at our center. One patient had TRD and the other had both TROCD and TRD. Radiofrequency-induced thermal lesions were created in the identified targets with lesion volumes between 20 and 229 mm3 (average 95 mm3). FINDINGS: Both patients were responders with neither experiencing significant side effects including compromised executive functions. LIMITATIONS: The generalizability of our findings is limited because the outcome is based on two subjects. CONCLUSION: This work suggests that BAC can be individually tailored and more limited to the ventral aspect of the ALIC and is effective and safe for TRD and TROCD. Accumulating data also suggests that to be clinically effective the length of the capsulotomy should be about 10mm. BAC's use may increase with the growing utilization and mastery of magnetic resonance guided focused ultrasound.

Ablation Surgeries for Treatment-Resistant Depression: A Meta-Analysis and Systematic Review of Reported Case Series.

BACKGROUND AND OBJECTIVES: Ablative lesion procedures remain as the last option in treatment of refractory depression. Contemporary ablative psychosurgeries involve producing lesions in the anterior limb of the internal capsule (bilateral anterior capsulotomy - BAC), the supragenual anterior cingulate gyrus and cingulum (bilateral anterior cingulotomy - BACING), and subgenual anterior cingulate gyrus and subcortical orbitofrontal white matter (bilateral subcaudate tractotomy - BST). A combination of BACING and BST is known as limbic leukotomy (bilateral limbic leukotomy - BLL). All procedures claim some success, but cohorts are small, depression assessment instruments differ, and inclusion and outcome criteria and follow-up duration vary. In some cohorts, more than one type of surgery was performed in several patients, further confounding interpreting the available data. Current evidence is equivocal on which surgical target works best. Method and Aim: This systematic review and meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) standard on published cohorts was conducted to review and identify which is the best standalone ablative procedure for treatment-resistant depression (TRD) based on response rate (event rate) and adverse-effect profile using the Comprehensive Meta-Analysis software. RESULTS AND CONCLUSION: As a standalone neurosurgical procedure, we found that BAC appears to be the most effective and safest of all the ablative targets for TRD. A major limitation of this conclusion is the paucity of published case series where sample sizes are small and all are open label.

Gamma knife radiosurgery versus deep brain stimulation for treatment-refractory depression and obsessive-compulsive disorder: A brief comparative summary.

Both gamma knife surgery (GKS) and deep brain stimulation (DBS) have documented success in management of treatment-refractory major depressive disorder (MDD) and obsessive-compulsive disorder (OCD), but there are no formal randomized controlled trials to compare these treatment modalities in cases of psychiatric illnesses. In this brief review, comparison of GKS and DBS for management of MDD and OCD was done with regard to their efficacy, accompanying risks, reversibility of therapeutic effects, costs, availability, and daily life issues. Currently available evidence does not support the superiority of either evaluated treatment modality over each other in terms of clinical efficacy in cases of MDD and OCD. Nevertheless, with regard to risks, costs, device maintenance, and daily life issues, GKS definitely seems more advantageous. Reversibility of therapeutic effects of DBS is certainly highly attractive, while may be a bit overhyped. In any case, synergy between GKS and DBS for management of mental illnesses lies in the continuing pursuit of improvement and raising the bar of excellence.

Noninvasive Capsulotomy for Refractory Depression by Frameless Stereotactic Radiosurgery.

PURPOSE: Effective treatment options for refractory depression are needed. Recent advancements permit both precise ablative radiation and functional neurologic connectome analysis using standard magnetic resonance imaging. We combined these innovations to perform stereotactic radiosurgical capsulotomy for the treatment of medically refractory major depressive disorder and study connectome response using a novel tractography-based approach. METHODS AND MATERIALS: Patients with medically refractory depression were enrolled on a prospective pilot single-arm observational trial from 2020 to 2021 at a single academic tertiary referral center. Bilateral ablation of the anterior limb of the internal capsule was accomplished by mask-based linear accelerator stereotactic radiosurgery. Beck's Depression Inventory measured efficacy. Montreal Cognitive Assessment evaluated cognition. RESULTS: Three patients were enrolled. Depression burden was improved by 88% at 12-month follow-up and by 55% at 18-month follow-up for patient 1 and 2, respectively. Patient 1 discontinued ketamine therapy, and patient 2 discontinued electroconvulsive therapy. Patient 3 reported global improvement in symptoms and function at 3 months. All 3 patients had reduction or resolution of suicidal ideation. No patient experienced cognitive decline or neurologic toxicity, and Montreal Cognitive Assessment score, as well as subjective patient-reported evaluations of concentration and attention, were superior after treatment. Tractography confirmed intended disruption of the cortico-striatal-thalamo-cortical loop with structural reorganization in the connectome. Connectome change was consistent between patients. Observed increases in caudate and putamen connectivity and decreases in thalamic connectivity may explain improved concentration, attention, and depression. The diversity and magnitude of connectome change may correlate with degree of clinical response. CONCLUSIONS: In 3 patients with refractory depression, radiosurgical capsulotomy significantly reduced the burden of depression. Functional connectome reorganization offers neurobiological evidence to support further investigations of the role of radiosurgery in depression.

Characterization of brain functional connectivity in treatment-resistant depression.

OBJECTIVE: To characterize the functional connectivity (FC) of target brain regions for deep brain stimulation (DBS) in patients with treatment-resistant depression (TRD), and to evaluate its gender and brain lateralization dependence. METHODS: Thirty-one TRD patients and twenty-nine healthy control (HC) subjects participated. FC of subcallosal cingulate gyrus (SCG), ventral caudate (VCa), nucleus accumbens (NAc), lateral habenula (LHb), and inferior thalamic peduncle (ITP) were evaluated using resting-state fMRI. FC was characterized by calculating the nodal 'degree', a major feature of the graph theory. RESULTS: The degree measures of the left and right VCa, the left LHb, and the left ITP were significantly greater in the TRD than in the HC group. The degree was greater in females with TRD in all these regions except the right LHb. Finally, the left hemisphere was generally more affected by depression and presented significant degrees in LHb and ITP regions of the patients. CONCLUSION: Our findings demonstrate the ability of degree to characterize brain FC and identify the regions with abnormal activities in TRD patients. This implies that the degree may have the potential to be used as an important graph-theoretical feature to further investigate the mechanisms underlying TRD, and consequently along with other diagnostic markers, to assist in the determination of the appropriate target region for DBS treatment in TRD patients.

An Analysis of Clinical Outcome and Tractography following Bilateral Anterior Capsulotomy for Depression.

INTRODUCTION: Bilateral anterior capsulotomy (BAC) is an effective surgical procedure for patients with treatment-resistant major depression (TRMD). In this work, we analyze the connectivity of the BAC lesions to identify connectivity "fingerprints" associated with clinical outcomes in patients with TRMD. METHODS: We performed a retrospective study of ten patients following BAC surgery. These patients were divided into "responders" and "non-responders" based on the relative change in the Beck depression inventory (BDI) score after surgery. We generated the dorsolateral prefrontal associative (DLPFC) pathways and the ventromedial prefrontal limbic (vmPFC) pathways going through the anterior limb of the internal capsule and analyzed if the overlap of the BAC lesions with these pathways was associated with either outcome. Finally, we used the BAC lesions of our patients to generate group-averaged connectivity "fingerprints" associated with either outcome. RESULTS: Six patients were responders (≥50% improvement in BDI), four patients were non-responders (<50% improvement). No significant impairments were found in most neuropsychological tests after surgery. The overlap analysis showed that in the responder group, there was less involvement of the DLPFC pathways than the vmPFC pathways (p = 0.001). Conversely, in the non-responder group, there was no significant difference between the involvement of both pathways (p = 0.157). The responder and non-responder connectivity fingerprint showed significant connections with the vmPFC limbic areas. However, the non-responder connectivity fingerprint also showed stronger connectivity to associative areas including the DLPFC and lateral orbitofrontal cortices. CONCLUSIONS: The optimum outcome following BAC surgery in this cohort was associated with interruption of vmPFC pathways and the relative preservation of DLPFC pathways.

Radiosurgery for Behavioral Disorders.

Psychiatric illnesses create great suffering for patients and the medical solution is sometimes limited. The experience observed after treating patients with obsessive-compulsive disorder (OCD), depression, and anorexia nervosa by Gamma Knife radiosurgery (GKRS) is presented. Ten patients with medically refractory OCD, 3 patients with depression resistant to medical treatment and electroconvulsive therapy, and 5 patients with refractory anorexia nervosa have been treated. Bilateral anterior capsulotomy has been performed to treat OCD and bilateral cingulotomy has been applied to treat severe depression and anorexia nervosa. The accumulated experience about treatment of OCD by GKRS is reviewed. In our experience, 70% of OCD patients achieved a full response. We observed a significant improvement in patients with depression and anorexia nervosa evidenced by the scales of assessment (mean reduction of 40% in the Beck Depression Inventory at 1-year follow-up and 40% average increase of body mass index at 6-month follow-up). No side effects have been observed. These procedures are effective in reducing obsession, compulsion, depression, and anxiety, improving the quality of life of the patients without side effects.

The History and Future of Ablative Neurosurgery for Major Depressive Disorder.

BACKGROUND: There is an urgent need to develop safe and effective treatments for patients with treatment-resistant depression (TRD). Several neurosurgical procedures have been developed to treat the dysfunctional brain circuits implicated in major depression. OBJECTIVES: This review describes the most common ablative procedures used to treat major depressive disorder: anterior cingulotomy, subcaudate tractotomy, limbic leucotomy, and anterior capsulotomy. The efficacy and safety of each are discussed and compared with other current and emerging modalities, including deep brain stimulation (DBS) and MR-guided focused ultrasound (MRgFUS). METHODS: The PubMed and MEDLINE electronic databases were used in this study, through July 2016. Keywords, including "treatment resistant depression," and "ablative neurosurgery," etc. were used to generate reference hits. RESULTS: Approximately a third to half of patients who underwent ablative procedures achieved a treatment response and/or remission. The efficacy and safety profiles corresponding to both ablative procedures and DBS were very similar. CONCLUSIONS: The longitudinal experience with ablative procedures shows that there remains an important role for accurate, discrete lesions in disrupting affective circuitry in the treatment of TRD. New modalities, such as MRgFUS, have the potential to further improve the accuracy of ablative procedures, while enhancing safety by obviating the need for open brain surgery.

Surgical Approaches in Psychiatry: A Survey of the World Literature on Psychosurgery.

Brain surgery to promote behavioral or affective changes in humans remains one of the most controversial topics at the interface of medicine, psychiatry, neuroscience, and bioethics. Rapid expansion of neuropsychiatric deep brain stimulation has recently revived the field and careful appraisal of its 2 sides is warranted: namely, the promise to help severely devastated patients on the one hand and the dangers of premature application without appropriate justification on the other. Here, we reconstruct the vivid history of the field and examine its present status to delineate the progression from crude freehand operations into a multidisciplinary treatment of last resort. This goal is accomplished by a detailed reassessment of numerous case reports and small-scale open or controlled trials in their historical and social context. The different surgical approaches, their rationale, and their scientific merit are discussed in a manner comprehensible to readers lacking extensive knowledge of neurosurgery or psychiatry, yet with sufficient documentation to provide a useful resource for practitioners in the field and those wishing to pursue the topic further.

Clinical improvements following bilateral anterior capsulotomy in treatment-resistant depression.

BACKGROUND: The purpose of this study was to evaluate a programme of lesion surgery carried out on patients with treatment-resistant depression (TRD). METHOD: This was a retrospective study looking at clinical and psychometric data from 45 patients with TRD who had undergone bilateral stereotactic anterior capsulotomy surgery over a period of 15 years, with the approval of the Mental Health Act Commission (37 with unipolar depression and eight with bipolar disorder). The Beck Depression Inventory (BDI) before and after surgery was used as the primary outcome measure. The Montgomery-Asberg Depression Rating Scale was administered and cognitive aspects of executive and memory functions were also examined. We carried out a paired-samples t test on the outcome measures to determine any statistically significant change in the group as a consequence of surgery. RESULTS: Patients improved on the clinical measure of depression after surgery by -21.20 points on the BDI with a 52% change. There were no significant cognitive changes post-surgery. Six patients were followed up in 2013 by phone interview and reported a generally positive experience. No major surgical complications occurred. CONCLUSIONS: With the limitations of an uncontrolled, observational study, our data suggest that capsulotomy can be an effective treatment for otherwise TRD. Performance on neuropsychological tests did not deteriorate.

A causal role for the anterior mid-cingulate cortex in negative affect and cognitive control.

Converging evidence has linked the anterior mid-cingulate cortex to negative affect, pain and cognitive control. It has previously been proposed that this region uses information about punishment to control aversively motivated actions. Studies on the effects of lesions allow causal inferences about brain function; however, naturally occurring lesions in the anterior mid-cingulate cortex are rare. In two studies we therefore recruited 94 volunteers, comprising 15 patients with treatment-resistant depression who had received bilateral anterior cingulotomy, which consists of lesions made within the anterior mid-cingulate cortex, 20 patients with treatment-resistant depression who had not received surgery and 59 healthy control subjects. Using the Ekman 60 faces paradigm and two Stroop paradigms, we tested the hypothesis that patients who received anterior cingulotomy were impaired in recognizing negative facial affect expressions but not positive or neutral facial expressions, and impaired in Stroop cognitive control, with larger lesions being associated with more impairment. Consistent with this hypothesis, we found that larger volume lesions predicted more impairment in recognizing fear, disgust and anger, and no impairment in recognizing facial expressions of surprise or happiness. However, we found no impairment in recognizing expressions of sadness. Also consistent with the hypothesis, we found that larger volume lesions predicted impaired Stroop cognitive control. Notably, this relationship was only present when anterior mid-cingulate cortex lesion volume was defined as the overlap between cingulotomy lesion volume and Shackman's meta-analysis-derived binary masks for negative affect and cognitive control. Given substantial evidence from healthy subjects that the anterior mid-cingulate cortex is part of a network associated with the experience of negative affect and pain, engaging cognitive control processes for optimizing behaviour in the presence of such stimuli, our findings support the assertion that this region has a causal role in these processes. While the clinical justification for cingulotomy is empirical and not theoretical, it is plausible that lesions within a brain region associated with the subjective experience of negative affect and pain may be therapeutic for patients with otherwise intractable mood, anxiety and pain syndromes.

Neurosurgical Treatments for Patients with Chronic, Treatment-Refractory Depression: A Retrospective, Consecutive, Case Series Comparison of Anterior Capsulotomy, Anterior Cingulotomy and Vagus Nerve Stimulation.

BACKGROUND: The evidence base to guide therapeutic choices for patients with chronic and treatment-refractory depression (TRD) remains weak. There is limited comparative information available to guide the choice of intervention for patients with the most severe and disabling forms of illness. OBJECTIVES: The aim of this work was to describe the 12-month clinical outcomes of patients with chronic TRD treated with anterior capsulotomy (ACAPS; n = 5), anterior cingulotomy (ACING; n = 5) or vagus nerve stimulation (VNS; n = 5). METHODS: We performed a retrospective, consecutive, case series comparison. RESULTS: With clinical response defined as a ≥50% reduction from the baseline MADRS score, response rates were 40% for ACAPS, 60% for ACING and 20% for VNS. Adverse effects from all three procedures were relatively mild, consistent with previous reports and, in most cases, transient. Adverse effects from VNS were related to active stimulation, and were modifiable and diminished in severity over time. There were no deaths. CONCLUSIONS: Although based on a small sample, our data represent a unique comparison of ACAPS, ACING and VNS for chronic TRD. The three cohorts were broadly equivalent in terms of baseline clinical characteristics, indices of chronicity, illness severity and estimates of previous failed treatments. ACING and ACAPS, but not VNS, were associated with favourable response rates at 12 months.

Neurosurgical treatments of depression.

The neurosurgical treatment of treatment-resistant depression (TRD) has entered a new era with more and more patients being treated with deep brain stimulation (DBS) via surgically implanted intracerebral electrodes. Although the mechanisms of action of DBS are still not fully understood, preclinical studies are being conducted to elucidate how the treatment might work. DBS in its present form can be considered as a relatively new neurosurgical treatment for TRD. However, the use of neurosurgery in the management of depression has a much longer history particularly with ablative procedures but also vagal nerve stimulation. Here, we provide a review of the clinical neurosurgical treatments for TRD, with a main emphasis on DBS. In addition, we discuss relevant preclinical data that are revealing new information about DBS mechanisms.

Practical considerations in the development and refinement of subcallosal cingulate white matter deep brain stimulation for treatment-resistant depression.

BACKGROUND: Deep brain stimulation has been investigated in the past decade as a viable intervention for treatment-resistant depression. METHODS: Several anatomic targets have been tested, with the most extensive published experience found for the subcallosal cingulate (SCC) white matter. RESULTS: This article reviews the current state of clinical research of SCC deep brain stimulation for treatment-resistant depression, including an overview of the rationale for targeting SCC, practical considerations for subject recruitment and evaluation, surgical planning, and stimulation parameters. CONCLUSION: Clinical management of patients in the initial and long-term naturalistic phases of treatment, including the potential role for psychotherapeutic rehabilitation, is discussed.

Bilateral anterior capsulotomy for intractable depression.

A group of eight patients with severe depression lasting 6 years or longer were treated with anterior capsulotomy and followed prospectively. Stereotactic surgery was used to produce radiofrequency lesions in the anterior limbs of both internal capsules. For all patients, there are follow-up data for at least 24 months. At 24-to-36 months postoperatively, four patients were either not-depressed or mildly depressed; one was mildly-to-moderately depressed; one was moderately-to-severely depressed; and only one remained severely depressed. One patient developed a progressive vascular dementia with parkinsonism caused by autopsy-proven arteriolosclerosis.

Informed consent for clinical trials of deep brain stimulation in psychiatric disease: challenges and implications for trial design.

Advances in neuromodulation and an improved understanding of the anatomy and circuitry of psychopathology have led to a resurgence of interest in surgery for psychiatric disease. Clinical trials exploring deep brain stimulation (DBS), a focally targeted, adjustable and reversible form of neurosurgery, are being developed to address the use of this technology in highly selected patient populations. Psychiatric patients deemed eligible for surgical intervention, such as DBS, typically meet stringent inclusion criteria, including demonstrated severity, chronicity and a failure of conventional therapy. Although a humanitarian device exemption by the US Food and Drug Administration exists for its use in obsessive-compulsive disorder, DBS remains a largely experimental treatment in the psychiatric context, with its use currently limited to clinical trials and investigative studies. The combination of a patient population at the limits of conventional therapy and a novel technology in a new indication poses interesting challenges to the informed consent process as it relates to clinical trial enrollment. These challenges can be divided into those that relate to the patient, their disease and the technology, with each illustrating how traditional conceptualisations of research consent may be inadequate in the surgical psychiatry context. With specific reference to risk analysis, patient autonomy, voluntariness and the duty of the clinician-researcher, this paper will discuss the unique challenges that clinical trials of surgery for refractory psychiatric disease present to the consent process. Recommendations are also made for an ethical approach to clinical trial consent acquisition in this unique patient population.

Unilateral right anterior capsulotomy for refractory major depression with comorbid obsessive-compulsive disorder.

BACKGROUND: Treatment-resistant major depression (MDD) and obsessive-compulsive disorder (OCD) remain a major cause of suffering and disability. These disorders may be treated with functional neurosurgery that almost always is bilateral but some patients might benefit from unilateral procedures. METHODS: We performed a unilateral right anterior capsulotomy (AC) in a 45-year-old right-handed woman with MDD and comorbid OCD. This unilateral procedure was based on the results of neuropsychological testing and an 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) that revealed right hemisphere deficits in this patient. RESULTS: Following surgery, Hamilton Depression scale (HAM-D) decreased 57% at 1 and 2 years and 54% at 3 years and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) decreased 58% at 1 year, 77% at 2 years, and 96% at 3 years. There was a slight decrement of verbal memory and phonemic fluency after the procedure that could also be related to changes in medication. Right basal ganglia abnormalities revealed by FDG-PET remained unchanged 16 months postoperatively. CONCLUSIONS: Overall this unilateral right AC was effective for the treatment of this woman's disorders with minimal adverse side effects.