Sophie M. D. D. Fitzsimmons

Background: Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment for obsessive-compulsive disorder (OCD), but response rates are variable. Pre-treatment characteristics of the stimulated region can influence rTMS treatment outcome. Objective/hypothesis: We investigated the relationship between network features of the rTMS stimulation location and treatment outcome in a randomised trial of rTMS for OCD, using graph analysis of single-layer functional and structural brain networks, and of structural-functional multilayer networks. Methods: We analysed data from 58 treatment-refractory adult OCD patients. Participants received either: high frequency (HF) rTMS to the left dorsolateral prefrontal cortex (DLPFC) (n=19); HF rTMS to the left pre-supplementary motor area (preSMA) (n=21); or control rTMS to the vertex (n=18). We used pre-treatment resting state functional MRI (rs-fMRI) and diffusion MRI (dMRI) scans to construct single-layer and structural-functional multilayer networks for each participant. We computed various centrality measures of the stimulated location and connected subnetwork, and examined their relationship with treatment outcome. Results: We found no associations between functional or structural single-layer network characteristics and treatment outcome. However, higher average multilayer betweenness centrality of the stimulated subnetwork in the DLPFC rTMS group (but not in the preSMA or vertex groups) was associated with greater symptom reduction (p=0.013). Conclusions: Participants with greater integration of the stimulated subnetwork with the rest of the structural-functional network showed greater improvement following DLPFC rTMS. Our results give a preliminary indication that the outcome of rTMS treatment for OCD is dependent on the interplay between structural and functional networks.

Objective Obsessive-compulsive disorder (OCD) is a chronic condition in which impaired inhibitory control and excessive error monitoring may contribute to the maintenance of obsessions and compulsions. This mega-analysis investigates neural activation during response inhibition and error processing using adult and pediatric data from the ENIGMA-OCD consortium and the ABCD study. Methods Individual participant data was uniformly processed using HALFpipe to extract statistical maps for response inhibition and error processing contrasts. Bayesian multilevel models were used to assess regional and whole-brain effects of OCD, with additional analyses examining the association between the OCD clinical profile and task-related activation. Results Across inhibitory control tasks, both individuals with OCD and control participants showed robust activation in regions implicated in response inhibition and error processing. During response inhibition, compared to controls, adults with OCD showed stronger somatomotor cortex activation, while children with OCD showed stronger occipital cortex activation. Children with likely OCD from the ABCD cohort showed reduced activity in the frontoparietal network in the anterior insula/frontal operculum region. During error processing, relative to controls, adults with OCD showed weaker activation in fronto-striatal regions, while children with OCD showed stronger activation in frontoparietal and attention networks. Greater OCD symptom severity was associated with weaker task-related activation in adults and stronger activation in children during response inhibition. Conclusion Case-control differences in brain activation during inhibitory control varied by age group and task contrast. Symptom severity emerged as the main clinical correlate of activation during inhibition, suggesting that inhibitory control deficits in OCD may be both state-dependent and developmentally specific.

Background: Predicting treatment efficacy in psychiatric disorders remains challenging, despite the availability of effective interventions. Previous studies suggest a link between brain network topology and treatment efficacy in individual disorders, but cross-disorder investigations are lacking. Methods: We analyzed pre-treatment MRI data from 177 individuals (113 females) with either obsessive-compulsive disorder (OCD) or post-traumatic stress disorder with comorbid personality disorders (PTSD) that received different non-pharmacological treatments. Using diffusion and resting-state MRI, we constructed structural, functional, and multilayer connectomes and calculated network measures at the global and mesoscale for network integration (global efficiency, eccentricity), segregation (modularity) and their balance (small-worldness). We assessed the relationship between these pre-treatment network measures and treatment improvement using mixed-model and Bayesian analyses and compared them to healthy controls. We also investigated associations between response and treatment-induced changes in network measures. Results: Across disorders and treatments, psychiatric cases showed a 41.6±29.6% symptom improvement (62% response rate) after treatment and pre-treatment differences in functional and multilayer network topology compared to healthy controls. Symptom improvement was associated with pre-treatment functional (P=0.04) and structural small-worldness (P=0.01), and multilayer eccentricity (P=0.01), while responders had higher functional modularity (P=0.02). Results were robust across trials and treatments, when adjusting for medication status and showed high credibility in Bayesian analyses. Network change associations with treatment response were only modest. Conclusions: Pre-treatment connectome characteristics are related to treatment response, regardless of treatment and psychiatric disorder, and suggest that individual differences in intrinsic features of the human connectome underlie amenability to treatment.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment option for obsessive-compulsive disorder (OCD). The neurobiological mechanisms of rTMS in OCD have, however, been incompletely characterized. We compared clinical outcomes and changes in task-based brain activation following three different rTMS stimulation protocols, all combined with exposure and response prevention (ERP). Methods: In this three-arm proof-of-concept randomized controlled clinical trial, 61 treatment-refractory adult OCD patients received 16 sessions of rTMS immediately prior to ERP over 8 weeks, with task-based functional MRI (tb-fMRI) scans and clinical assessments pre- and post-treatment. Patients received either: high frequency (HF) rTMS to the left dorsolateral prefrontal cortex (DLPFC) (n=19 (6M/13F)); HF rTMS to the left pre-supplementary motor area (preSMA) (n=23 (10M/13F)); or control rTMS to the vertex (n=19 (6M/13F)). Changes in tb-fMRI activation pre-post treatment were compared using both a Bayesian region-of-interest and a general linear model whole-brain approach. Results: Mean OCD symptom severity decreased significantly in all treatment groups (delta=- 10.836, p<0.001, 95% CI [-12.504, -9.168]), with no differences between groups. Response rate in the entire sample was 57.4%. Groups receiving DLPFC or preSMA rTMS showed, respectively, a decrease in planning and error processing task-related activation after treatment that was associated with symptom improvement, while individuals in the vertex rTMS group with greater symptom improvement showed an increase in inhibition-related activation. Conclusions: PreSMA and DLPFC rTMS combined with ERP led to significant symptom improvement related to activation decreases in targeted task networks, although we observed no differences in symptom reduction between groups. This trial was registered at clinicaltrials.gov ( NCT03667807 )

Temporal lobe epilepsy (TLE) patients are at risk of memory deficits, which have been linked to functional network disturbances, particularly of integration of the default mode network (DMN). However, the cellular substrates of functional network integration are unknown. We leverage a unique cross-scale dataset of drug-resistant TLE patients (n = 31), who underwent pseudo resting-state functional magnetic resonance imaging (fMRI), resting-state magnetoencephalography (MEG) and/or neuropsychological testing before neurosurgery. fMRI and MEG underwent atlas-based connectivity analyses. Functional network centrality of the lateral middle temporal gyrus, part of the DMN, was used as a measure of local network integration. Subsequently, non-pathological cortical tissue from this region was used for single cell morphological and electrophysiological patch-clamp analysis, assessing integration in terms of total dendritic length and action potential rise speed. As could be hypothesized, greater network centrality related to better memory performance. Moreover, greater network centrality correlated with more integrative properties at the cellular level across patients. We conclude that individual differences in cognitively relevant functional network integration of a DMN region are mirrored by differences in cellular integrative properties of this region in TLE patients. These findings connect previously separate scales of investigation, increasing translational insight into focal pathology and large-scale network disturbances in TLE.