Neurotransmitter‑related structural network damage and language performance after stroke

Abstract Background Aphasia commonly occurs after left-hemispheric stroke, yet substantial inter-individual variability in language outcomes remains insufficiently explained by established clinical systems neuroscience concepts. Emerging evidence suggests that the integrity of specific neurotransmitter systems may influence functional outcomes after stroke. This study examined whether the damage to neurotransmitter-related structural networks is associated with post-stroke language impairment. Methods Data of 270 patients with left-hemispheric stroke from two openly available cohorts were analyzed: the acute Washington Stroke Cohort and the chronic Aphasia Recovery Cohort. Neurotransmitter-related network damage was quantified by embedding individual stroke lesion masks into normative connectomes weighted by PET-derived density maps of 16 neurotransmitter receptors and transporters. Partial least squares (PLS) regression identified informative predictors of language functioning, followed by linear regression analyses adjusted for age, sex, lesion volume, and time post-stroke. Results Across both cohorts, PLS analyses converged on a neurochemical profile in which damage to networks related to serotonergic (5-HT 1a , 5-HT 2a ) and dopaminergic (D1) receptor distributions showed the strongest associations with poorer language performance. Damage to the 5-HT 1a and D1-related networks remained significant in fully adjusted models, leading to substantially improved model fit. Conclusion The disruption of large-scale serotonergic (5-HT 1a ) and dopaminergic (D1) brain networks is associated with language impairment in acute and chronic stroke. Neurotransmitter-related network damage explained additional variability in language performance beyond clinical variables and lesion burden. This work adds a neurochemically informed network perspective to aphasia research and may pave the way for future biological patient stratification to support targeted rehabilitation strategies, such as pharmacological interventions.