A randomised, double-blind, sham-controlled trial of deep brain stimulation of the bed nucleus of the stria terminalis for treatment-resistant obsessive-compulsive disorder

Abstract

Deep brain stimulation (DBS) is a promising treatment for severe, treatment-resistant obsessive-compulsive disorder (OCD). Here, nine participants (four females, mean age 47.9 ± 10.7 years) were implanted with DBS electrodes bilaterally in the bed nucleus of the stria terminalis (BNST). Following a one-month postoperative recovery phase, participants entered a three-month randomised, double-blind, sham-controlled phase before a twelve-month period of open-label stimulation incorporating a course of cognitive behavioural therapy (CBT). The primary outcome measure was OCD symptoms as rated with the Yale-Brown Obsessive-Compulsive Scale (YBOCS). In the blinded phase, there was a significant benefit of active stimulation over sham (p = 0.025, mean difference 4.9 points). After the open phase, the mean reduction in YBOCS was 16.6 ± 1.9 points (χ2 (11) = 39.8, p = 3.8 × 10−5), with seven participants classified as responders. CBT resulted in an additive YBOCS reduction of 4.8 ± 3.9 points (p = 0.011). There were two serious adverse events related to the DBS device, the most severe of which was an infection during the open phase necessitating device explantation. There were no serious psychiatric adverse events related to stimulation. An analysis of the structural connectivity of each participant’s individualised stimulation field isolated right-hemispheric fibres associated with YBOCS reduction. These included subcortical tracts incorporating the amygdala, hippocampus and stria terminalis, in addition to cortical regions in the ventrolateral and ventromedial prefrontal cortex, parahippocampal, parietal and extrastriate visual cortex. In conclusion, this study provides further evidence supporting the efficacy and tolerability of DBS in the region of the BNST for individuals with otherwise treatment-refractory OCD and identifies a connectivity fingerprint associated with clinical benefit.

Connectomic Deep Brain Stimulation for Obsessive-Compulsive Disorder

“…A later study in the same OCD mouse model revealed that both DBS of the VS and ALIC resulted in a significant reduction in grooming independently J o u r n a l P r e -p r o o f (though the ALIC target was more effective on average), suggesting that both pathways are contributing to therapeutic success (59). Further evidence supporting the involvement of an affectrelated circuitry stems from the comprehensively discussed study by Mosley et al, where connectivity with the amygdala was also associated with DBS response, along modulation of the central ALIC (1). These different therapeutic circuitries could correspond to improvement of different symptom or neuropsychological dimensions of OCD.…”

“…Another recent report applied connectomics to study a cohort of 9 OCD patients undergoing DBS targeting the BNST (1). In a voxel-by-voxel analysis, structural connectivity to the right vlPFC and hippocampal regions, but also to parietal and dorsomedial prefrontal areas significantly explained variance of response to DBS.…”

“…While some of the aforementioned studies agreed on the critical role of the same fiber bundle published as a three-dimensional dataset (1,28,29,(32)(33)(34), others revealed seeming heterogeneity about which pathway would be critical to modulate for successful DBS in OCD. Namely, the study by J o u r n a l P r e -p r o o f Liebrand et al suggested that the MFB, connecting the PFC with the ventral tegmental area, would be associated with a beneficial response (26) whereas other studies highlighted streamlines within the ALIC as being critical for OCD-DBS (28,32,42).…”

“…Furthermore, an FDA approved H-coil transcranial magnetic stimulation (TMS) system targets the dACC and medial prefrontal cortex (50). Other DBS studies have also reported the importance of the vlPFC (1,29) and middle frontal gyrus (MFG)/dlPFC (25,28). As shown in figure 5, white matter tracts from the PFC/ACC travel through the ALIC in a topologically organized manner.…”

Identification of a personalized intracranial biomarker of depression and response to DBS therapy

“…Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) has shown promise as a therapy for refractory obsessive-compulsive disorder (OCD) [1,2] and major depressive disorder (MDD) [3]. DBS currently is 'open-loop' with stimulation parameters remaining fixed over time.…”