Neurotransmitter Systems Underlie Structure-Function Decoupling and Recovery in Post- Stroke Aphasia

Objectives : Although alterations in brain structure and function have been implicated in both post-stroke aphasia (PSA) and motor deficits, how structural-functional coupling (SFC) is affected in stroke patients with and without aphasia (nonPSA) remains unclear. This study aimed to characterize SFC alterations in PSA and examine their associations with neurotransmitter systems. Methods: Fifty-two patients with left-hemisphere stroke (PSA: n = 29; nonPSA: n = 23) and 19 demographically matched healthy controls were enrolled. Language function in PSA patients was assessed approximately 28 days and 3 months post-stroke using the Western Aphasia Battery (WAB). All participants underwent T1-weighted and resting-state functional MRI at baseline. Region-wise SFC was computed as the correlation between gray matter volume and the fractional amplitude of low-frequency fluctuations (fALFF). Group differences were assessed using one-way analyses of covariance. Relationships among SFC alterations, language outcomes, and lesion-derived neurotransmitter-informed network damage were further evaluated. Results: Group comparisons revealed distinct SFC alterations associated with motor and language deficits in PSA. Language-specific decoupling was observed in the contralesional putamen, middle temporal pole, and posterior cerebellum, whereasmotor-specific decoupling occurred in the contralesional prefrontal cortex, superior parietal lobule, precuneus, and inferior/superior temporal cortices, extending into cerebellar regions. Both domains shared a common decoupling pattern in the ipsilesional posterior cerebellum. Reduced SFC in the contralesional middle temporal pole correlated with poorer spontaneous speech performance. Compared with nonPSA, PSA patients exhibited greater lesion load, network disconnections, and pre-/post-synaptic disruption ratio associated with poorer aphasia recovery relative to nonPSA in several neurotransmitter systems, especially serotonergic system. Mediation analysis further indicated that SFC in the contralesional caudate partially mediated the relationship between neurotransmitter disruption and aphasia severity. Conclusions: Our findings suggest distinct and shared structural-functional decoupling for language and motor dysfunctions in the patients with aphasia after stroke, which was associated with specific neurotransmitter systems.