DISRUPTED HIGHER-ORDER TOPOLOGY IN OCD BRAIN NETWORKS REVEALED BY HODGE LAPLACIAN – AN ENIGMA STUDY

Obsessive–compulsive disorder (OCD) is a disabling psychiatric condition associated with widespread alterations in large-scale brain circuits, classically involving the cortico–striatal–thalamic–cortical (CSTC) loop and, more recently, sensorimotor pathways. However, conventional fMRI analyses are largely restricted to pairwise functional connectivity (FC), which fails to capture the intrinsically higher-order, multi-nodal organization of brain networks. Here, we applied a Hodge Laplacian–based topological data analysis (TDA) framework to a large, multi-site ENIGMA-OCD resting-state fMRI dataset (1024 patients, 1028 controls from 28 centers) to identify OCD-related alterations in higher-order network topology. Brain networks were modeled as 1-dimensional simplicial complexes, and all possible 1-dimensional cycles were systematically enumerated through a persistent homology–guided graph filtration. Using Hodge Laplacian, we extracted algebraic representations of all 1-cycles, quantified subject-level 1-cycle strengths and assessed group differences with site-stratified Freedman-Lane permutation test and family-wise error correction. We identified 93 significant 1-cycles showing reduced strength in OCD compared with controls (FWER-corrected p < 0.05; Cohen’s d = 0.22–0.28). Agglomerative clustering revealed five distinct functional profiles involving the frontoparietal, default mode, visual/dorsal attention, somatomotor, and salience networks. Specifically, OCD patients exhibited weaker integration in these network-specific cycles which mostly spanned both hemispheres. The majority of edges composing these abnormal cycles did not exhibit significant pairwise FC differences, demonstrating that these disruptions are largely invisible to conventional FC analyses. Our findings suggest that OCD pathology involves abnormal recurrent higher-order multi-region interactions, providing new insights into the brain's functional organization and offering potential biomarkers for clinical application.