Individually targeted neuromodulation for contamination-based OCD

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PROJECT SUMMARY/ABSTRACT The symptoms of obsessive-compulsive disorder (OCD) appear linked to dysfunction in a cortico-striato- thalamo-cortical circuit. However, obsessions and compulsions vary widely among OCD patients, suggesting that other symptom-specific brain networks may accompany this core defect. Identifying such networks could lead to individualized treatments, improving upon current “one size fits all” approaches. Factor analyses have found distinct symptom dimensions in OCD, but the neural systems specific to these dimensions remain unclear. Using a novel individual-level approach to resting-state functional connectivity magnetic resonance imaging (fcMRI), we have shown that increased connectivity between right medial frontal gyrus (R MFG) and brain regions within the ventral attention network (VAN) – regions critical to reorienting attention in response to relevant external stimuli – specifically predicted the severity of contamination/washing (CONTAM) symptoms, and attenuation of this hyperconnectivity following treatment was associated with improvement in CONTAM symptoms. Based on these findings, we hypothesize that decreasing R MFG-VAN connectivity via transcanial magnetic stimulation (TMS) will normalize attentional reorienting and reduce CONTAM symptoms in individuals with contamination-based OCD. Therefore, consistent with the R61/R33 mechanism, we propose a two-phase program to investigate R MFG-targeted TMS as a potential intervention for contamination-based OCD. In the R61 phase, we will determine the optimal TMS paradigm to decrease R MFG-VAN connectivity by administering both continuous and intermittent theta burst stimulation (cTBS, iTBS) to individuals with contamination-based OCD using a novel individual-level approach to target the area of R MFG most strongly correlated with VAN based on each participant's pre-treatment connectivity data. If successful, we will proceed to the R33 phase in which we will use the TMS approach identified in the R61 phase to test the links between reduced R MFG-VAN connectivity, decreased VAN activation during attentional reorienting, and reduced CONTAM symptoms in a larger sample of OCD individuals with CONTAM. This project will yield several major advances. First, it will demonstrate a causal link between R MFG-VAN hyperconnectivity and CONTAM symptoms. Second, it will confirm that R MFG-VAN hyperconnectivity is a viable treatment target for contamination-based OCD, and demonstrate that decreasing R MFG-VAN connectivity leads to normalized attentional reorienting and reduced CONTAM symptoms. Third, it will provide initial evidence for R MFG- targeted TMS as a treatment for contamination-based OCD. Collectively, this work will be the first of its kind to identify a dimension-specific cortical target for neuromodulation in OCD, thus making a major advance toward precision medicine for this disorder, and highlighting the future application of this innovative research program to identify neuromodulatory targets for additional OCD symptom dimensions.