Individualized, connectome-based, non-invasive stimulation of OCD deep-brain targets: A proof-of-concept.

Treatment-resistant obsessive-compulsive disorder (OCD) generally improves with deep-brain stimulation (DBS), thought to modulate neural activity at both the implantation site and in connected brain regions. However, its invasive nature, side-effects, and lack of customization, make non-invasive treatments preferable. Harnessing the established remote effects of cortical transcranial magnetic stimulation (TMS), connectivity-based approaches have emerged for depression that aim at influencing distant regions connected to the stimulation site. We here investigated whether effective OCD DBS targets (here subthalamic nucleus [STN] and nucleus accumbens [NAc]) could be modulated non-invasively with TMS. In a proof-of-concept study with nine healthy individuals, we used 7T magnetic resonance imaging (MRI) and probabilistic tractography to reconstruct the fiber tracts traversing manually segmented STN/NAc. Two TMS targets were individually selected based on the strength of their structural connectivity to either the STN, or both the STN and NAc. In a sham-controlled, within-subject cross-over design, TMS was administered over the personalized targets, located around the precentral and middle frontal gyrus. Resting-state functional 3T MRI was acquired before, and at 5 and 25 min after stimulation to investigate TMS-induced changes in the functional connectivity of the STN and NAc with other regions of the brain. Static and dynamic seed-to-voxel correlation analyses were conducted. TMS over both targets was able to modulate the functional connectivity of the STN and NAc, engaging both overlapping and distinct regions, and unfolding following different temporal dynamics. Given the relevance of the engaged connected regions to OCD pathology, we argue that a personalized, connectivity-based procedure is worth investigating as potential treatment for refractory OCD.

Abnormal white-matter rich-club organization in obsessive-compulsive disorder.

Rich-club organization is key to efficient global neuronal signaling and integration of information. Alterations interfere with higher-order cognitive processes, and are common to several psychiatric and neurological conditions. A few studies examining the structural connectome in obsessive-compulsive disorder (OCD) suggest lower efficiency of information transfer across the brain. However, it remains unclear whether this is due to alterations in rich-club organization. In the current study, the structural connectome of 28 unmedicated OCD patients, 8 of their unaffected siblings and 28 healthy controls was reconstructed by means of diffusion-weighted imaging and probabilistic tractography. Topological and weighted measures of rich-club organization and connectivity were computed, alongside global and nodal measures of network integration and segregation. The relationship between clinical scores and network properties was explored. Compared to healthy controls, OCD patients displayed significantly lower topological and weighted rich-club organization, allocating a smaller fraction of all connection weights to the rich-club core. Global clustering coefficient, local efficiency, and clustering of nonrich club nodes were significantly higher in OCD patients. Significant three-group differences emerged, with siblings displaying highest and lowest values in different measures. No significant correlation with any clinical score was found. Our results suggest weaker structural connectivity between rich-club nodes in OCD patients, possibly resulting in lower network integration in favor of higher network segregation. We highlight the need of looking at network-based alterations in brain organization and function when investigating the neurobiological basis of this disorder, and stimulate further research into potential familial protective factors against the development of OCD.

The effects of deep-brain non-stimulation in severe obsessive-compulsive disorder: an individual patient data meta-analysis.

Non-intervention-related effects have long been recognized in an array of medical interventions, to which surgical procedures like deep-brain stimulation are no exception. While the existence of placebo and micro-lesion effects has been convincingly demonstrated in DBS for major depression and Parkinson's disease, systematic investigations for obsessive-compulsive disorder (OCD) are currently lacking. We therefore undertook an individual patient data meta-analysis with the aim of quantifying the effect of DBS for severe, treatment-resistant OCD that is not due to the electrical stimulation of brain tissue. The MEDLINE/PubMed database was searched for double-blind, sham-controlled randomized clinical trials published in English between 1998 and 2018. Individual patient data was obtained from the original authors and combined in a meta-analysis. We assessed differences from baseline in obsessive-compulsive symptoms following sham treatment, as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Four studies met the inclusion criteria, randomizing 49 patients to two periods of active or sham stimulation. To preclude confounding by period effects, our estimate was based only on data from those patients who underwent sham stimulation first (n = 24). We found that sham stimulation induced a significant change in the Y-BOCS score (t = -3.15, P < 0.005), lowering it by 4.9 ± 1.6 points [95% CI = (-8.0, -1.8)]. We conclude that non-stimulation-related effects of DBS exist also in OCD. The identification of the factors determining the magnitude and occurrence of these effects will help to design strategies that will ultimately lead to a betterment of future randomized clinical trials.