Lesion-Network Mapping of Post-Stroke Depressive Symptoms: Evidence from Two Prospective Ischemic Stroke Cohorts

BackgroundPost-stroke depression (PSD) affects up to one-third of stroke survivors, significantly impacting rehabilitation success and quality of life. However, its underlying pathophysiology remains unclear. MethodsWe analyzed two independent, prospective ischemic stroke cohorts (PROSCIS-B NCT01363856 and BAPTISe NCT01954797; total N=377) to identify brain regions and networks associated with depressive symptoms post-stroke. Lesion-symptom mapping (LSM) assessed associations between lesion location and depressive symptoms measured via the Center for Epidemiologic Studies Depression Scale (CES-D) up to 12 months post-stroke, while lesion network mapping (LNM) evaluated lesion connectivity with brain networks. We explored correlations between spatial similarity to the LNM-identified network and CES-D scores using linear regression models. ResultsLSM revealed no significant associations between lesion location and depressive symptoms. In contrast, LNM showed that lesion connectivity to brain regions--including the frontal pole, middle and inferior frontal gyri, inferior temporal gyrus, supramarginal gyrus, angular gyrus, frontal orbital cortex, and thalamus--correlated with CES-D scores (r=0.12, p=0.02). These regions overlapped with canonical resting-state networks, such as the frontoparietal (Dice coefficient [DC] = 0.28), salience (DC = 0.27), and default-mode networks (DC = 0.20), as well as a previously published depression circuit (DC = 0.43). ConclusionsLesion location alone was not associated with depressive symptoms post- stroke. However, lesion connectivity analysis revealed associations with brain networks, particularly the frontoparietal, salience, and default-mode networks, suggesting that disruption to these circuits may contribute to the development of PSD up to one-year post-stroke.