Structural brain findings associated with clinical profiles but not diagnosis in unmedicated adults with obsessive-compulsive disorder: the Global OCD study

The Global OCD consortium investigated cortical and subcortical differences in the largest sample of unmedicated adults with obsessive-compulsive disorder (OCD) to date using T1-weighted MRI. We aimed to determine structural brain signatures of OCD clinical profiles, illness duration, comorbidity, and medication history. This preregistered study included 266 medication-free OCD adults and 254 healthy controls. We analyzed cortical thickness, surface area, and (sub)cortical and cerebellar volumes using FreeSurfer and voxel-based morphometry (VBM). Covariates included age, sex, IQ, and site. We found no significant differences in cortical thickness, surface area, or subcortical volumes between OCD and HC groups. However, OCD severity correlated negatively with surface area in the left lateral orbitofrontal cortex (OFC) (p_(FDR)=0.008), right medial OFC (p_(FDR)=0.009), and right insula (p_(FDR)=0.045), supported by VBM. Regarding dimensionality, harm/aggression scores correlated negatively with right medial OFC surface area (p(FDR)=0.030), while sexual/religious scores correlated positively with hippocampal volume (p(FDR)=0.017). Compared to those without, OCD cases with comorbid depression showed smaller surface area in inferior parietal (p_(FDR)=0.048) and middle temporal cortices (R:p_(FDR)=0.048; L:p_(FDR)=0.049). No associations were found for illness duration, onset, or medication history. In the largest prospective structural imaging study of unmedicated OCD to date, we found no significant case-control differences in cortical or subcortical morphology. Instead, structural associations were driven by clinical characteristics, including symptom severity, dimensionality, and comorbidity, supporting neuroanatomical models emphasizing the OFC and insula. The absence of case-control differences underscores the importance of studying large unmedicated samples with careful clinical characterization before concluding brain findings are related to the disorder.