A Randomized Trial Directly Comparing Ventral Capsule and Anteromedial Subthalamic Nucleus Stimulation in Obsessive-Compulsive Disorder: Clinical and Imaging Evidence for Dissociable Effects

Abstract

Background Deep brain stimulation (DBS) is an emerging treatment for severe obsessive-compulsive disorder (OCD). We compared the efficacy of ventral capsule/ventral striatal (VC/VS) and anteromedial subthalamic nucleus (amSTN) DBS in the same patients and tested for mechanistic differences on mood and cognitive flexibility and associated neural circuitry. The possible synergistic benefit of DBS at both sites and cognitive behavioral therapy was explored. Methods Six patients with treatment-refractory OCD (5 men; Yale-Brown Obsessive Compulsive Scale score >32) entered double-blind counterbalanced phases of 12-week amSTN or VC/VS DBS, followed by 12-week open phases when amSTN and VC/VS were stimulated together, in which optimal stimulation parameters were achieved and adjunctive inpatient cognitive behavioral therapy was delivered. OCD and mood were assessed with standardized scales and cognitive flexibility with the Cambridge Neuropsychological Test Automated Battery Intra-Extra Dimensional Set-Shift task. Diffusion-weighted and intraoperative magnetic resonance imaging scans were performed for tractography from optimally activated electrode contacts. Results DBS at each site significantly and equivalently reduced OCD symptoms with little additional gain following combined stimulation. amSTN but not VC/VS DBS significantly improved cognitive flexibility, whereas VC/VS DBS had a greater effect on mood. The VC/VS effective site was within the VC. VC DBS connected primarily to the medial orbitofrontal cortex, and amSTN DBS to the lateral orbitofrontal cortex, dorsal anterior cingulate cortex, and dorsolateral prefrontal cortex. No further improvement followed cognitive behavioral therapy, reflecting a floor effect of DBS on OCD. Conclusions Both the VC/VS and amSTN are effective targets for severe treatment-refractory OCD. Differential improvements in mood and cognitive flexibility and their associated connectivity suggest that DBS at these sites modulates distinct brain networks.

Toward a unified connectomic target for deep brain stimulation in obsessive-compulsive disorder

“…The resulting positive discriminative tract traversed slightly dorsal to the group of electrodes of the ALIC-cohort and coursed centrally or slightly ventral to the electrodes of the STN cohort. This tract was then used to predict outcome in two completely independent test-cohorts of patients that underwent surgery in a third and fourth represented an "optimized" phase following nine months of a clinical trial 16 .…”

“…In case of the London cohort, this followed a four-step clinical trial (2x3 months blinded stimulation at one target followed by 6 months of stimulation at both targets, the last three months using clinically optimized parameters. For details see 16 ).…”

“…Second, in addition, they may modulate not only one (shared) network but other networks that are not shared, resulting in different changes across other behavioral domains. This can be seen by widely different connectivity profiles of the targets (Figure 2 top row) and differential effects of STN vs. ALIC stimulation on depressive / cognitive functions described by Tyagi et al 16 . Thus, one may speculate that networks are symptom-specific (and not disease-specific).…”

“…DBS electrodes were localized using Lead-DBS software (http://www.lead-dbs.org) as described in 86 In the Grenoble, Cologne and Madrid groups, Volumes of Tissue Activated (VTA) were estimated using a finite element method (FEM) as described in 83 For the London test cohort, we chose to use the original VTAs of the published study by Tyagi et al 16 . These had instead been processed using Medtronic SureTune™️ software and transferred into MNI space within the original study.…”

“…A variety of other targets have been proposed, however, including the STN 3,4 , the NAcc 5-7 , ventral capsule/ventral striatum (VC/VS) 8 , inferior thalamic peduncle (ITP) 9,10 , bed nucleus of the stria terminalis (BNST) 11 , anteromedial globus pallidus interna (amGPi) 12 , superolateral branch of the medial forebrain bundle (slMFB) 13 and medial dorsal and ventral anterior nuclei of the thalamus (MD/vANT) 14 (for an overview of targets see 15 ). A recent prospective clinical trial implanted four electrodes per patient with one pair in the STN and one in the ALIC 16 .…”