Noninvasive Capsulotomy for Refractory Depression by Frameless Stereotactic Radiosurgery

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.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.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.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.