Neurotransmitter-Informed Connectome Approach to Language Impairment After Stroke

BACKGROUND: Variability in poststroke language outcomes remains insufficiently explained by established clinical system neuroscience concepts. This study examined whether damage to neurotransmitter-informed structural networks is associated with poststroke language impairment. METHODS: Two openly available cohorts of patients with left-hemispheric stroke were analyzed: the Washington Stroke Cohort (St. Louis), including patients after a first symptomatic stroke (acute phase), and the Aphasia Recovery Cohort (South Carolina), focusing on chronic recovery. Language performance was assessed cross-sectionally using either a comprehensive language battery (Washington Stroke Cohort; 1–2 weeks poststroke) or the Western Aphasia Battery-Revised (Aphasia Recovery Cohort; chronic stage). Individual stroke lesion masks were embedded into normative connectomes weighted by positron-emission tomography–derived density maps of 16 neurotransmitter receptors/transporters. Partial least squares regression and adjusted linear regressions (age, sex, lesion volume, and time poststroke) identified predictors of language functioning. RESULTS: Two hundred seventy patients were included. Washington Stroke Cohort (n=44): mean age, 54.2±12.3 years; 45.5% female; median, 12 days poststroke (interquartile range, 10–14). Aphasia Recovery Cohort (n=226): mean age, 57.8±11.2 years; 38.4% female; and median, 721 days poststroke (interquartile range, 403–1765). Across both cohorts, partial least squares analyses converged on a neurochemical profile in which damage to networks related to serotonergic (5-HT 1a and 5-HT 2a ) and dopaminergic (D1) receptor distributions showed the strongest associations with poorer language performance. Damage to 5-HT 1a and D1 networks remained significant in fully adjusted models, improving fit over covariate-only models (all P FDR <0.001; Washington Stroke Cohort: ∆AIC 5-HT1a = 1.77 and ∆AIC D1 =0.96; Aphasia Recovery Cohort: ∆AIC 5-HT1a =25.29 and ∆AIC D1 =19.96). CONCLUSIONS: The disruption of large-scale serotonergic (5-HT 1a ) and dopaminergic (D1) networks is associated with language impairment in acute to subacute and chronic stroke. Neurotransmitter-related network damage, based on normative positron-emission tomography–derived maps serving as a structural proxy of neurotransmitter systems, explained additional variability beyond clinical variables and lesion burden, providing a neurochemically informed network framework for understanding variability in poststroke aphasia. However, given the indirect nature of the measures, implications for clinical translation and targeted rehabilitation strategies remain preliminary.