Dysfunctional Cortical Gradient Topography in Treatment-Resistant Major Depressive Disorder

BACKGROUND: Treatment-resistant depression (TRD) refers to patients with major depressive disorder who do not remit after 2 or more antidepressant trials. TRD is common and highly debilitating, but its neurobiological basis remains poorly understood. Recent neuroimaging studies have revealed cortical connectivity gradients that dissociate primary sensorimotor areas from higher-order associative cortices. This fundamental topography determines cortical information flow and is affected by psychiatric disorders. We examined how TRD impacts gradient-based hierarchical cortical organization. METHODS: In this secondary study, we analyzed resting-state functional magnetic resonance imaging data from a mindfulness-based intervention enrolling 56 patients with TRD and 28 healthy control subjects. Using gradient extraction tools, baseline measures of cortical gradient dispersion within and between functional brain networks were derived, compared across groups, and associated with graph theoretical measures of network topology. In patients, correlation analyses were used to associate measures of cortical gradient dispersion with clinical measures of anxiety, depression, and mindfulness at baseline and following the intervention. RESULTS: Cortical gradient dispersion was reduced within major intrinsic brain networks in patients with TRD. Reduced cortical gradient dispersion correlated with increased network degree assessed through graph theory–based measures of network topology. Lower dispersion among default mode, control, and limbic network nodes related to baseline levels of trait anxiety, depression, and mindfulness. Patients’ baseline limbic network dispersion predicted trait anxiety scores 24 weeks after the intervention. CONCLUSIONS: Our findings provide preliminary support for widespread alterations in cortical gradient architecture in TRD, implicating a significant role for transmodal and limbic networks in mediating depression, anxiety, and lower mindfulness in patients with TRD.