Neurotransmitter circuits of the human language network and their disruption in post-stroke aphasia

Abstract

Language depends on distributed brain networks whose neurochemical organisation remains largely unknown. Here, we combine large-scale functional MRI, positron-emission tomography-derived receptor and transporter maps, and structural connectomics to characterise the neurotransmitter architecture of the human language network and its disruption in post-stroke aphasia. We show that language circuits are organised by connection class: cortico-cortical pathways are dominated by serotonergic and glutamatergic signalling, thalamo-cortical projections are predominantly cholinergic, and anterior temporal connections show GABAergic circuit enrichment. In 239 stroke patients, aphasia was associated with distinct neurochemical disruption profiles, with lobar lesions showing postsynaptic serotonergic injury and subcortical aphasia showing preferential presynaptic cholinergic or serotonergic disruption. These findings map the neurochemical architecture of the language network and establish a neurotransmitter circuit-level framework for post-stroke aphasia. The post-hoc analysis of four pharmacological trials revealed an association between treatment-to-neurotransmitter matching and aphasia improvement, suggesting that personalised pharmacological strategies may enhance behavioural intervention responsiveness.