Abstract Number: Esoc2026a770 Neurotransmitter-Specific Circuit Disruption of the Language Network Unveils Distinct Aphasia Profiles and Predicts Drug Response

Abstract Background and aims Post-stroke aphasia causes substantial disability, and effective pharmacological treatments remain limited. Neurotransmitters shape cognitive circuits, yet trials targeting these systems have yielded mixed results. Identifying disrupted neurotransmitter circuits after stroke could guide personalized treatment. Recently, we developed NeuroT-Map, a tool that integrates PET neurotransmitter density maps with tractography to estimate circuit-specific disruption and distinguish pre- from postsynaptic injury. Using this framework, we mapped the neurochemical architecture of the language network, characterized neurotransmitter disruption in post-stroke aphasia, and assessed whether these profiles predicted treatment response. Methods Language regions were defined using task-fMRI from 806 healthy participants. PET maps for acetylcholine, dopamine, noradrenaline, serotonin, glutamate, and GABA were projected onto white-matter tracts connecting these regions. Lesions from 196 patients with chronic aphasia were analyzed with NeuroT-Map to quantify neurotransmitter circuit disruption. Treatment response was assessed in four trials of cholinergic or serotonergic drugs. Results Cortico-cortical language pathways were predominantly postsynaptic serotonergic, whereas thalamo-cortical projections were mainly postsynaptic cholinergic. Glutamatergic fibers predominated over GABAergic, except in the left anterior temporal region and anterior limb of the internal capsule (figure 1a-b). Neurotransmitter injury profiles clustered into five patterns. Lobar lesions showed dominant postsynaptic serotonergic injury, while subcortical lesions exhibited primarily presynaptic serotonergic and cholinergic disruption (figure 1c-d). Clinical improvement was more likely when drug treatment matched the dominant disrupted neurotransmitter circuit (χ2 = 4.13, P = 0.042). Conclusions The language network exhibits a distinct neurochemical organization, and lesion topography determines specific neurotransmitter vulnerabilities. Matching pharmacological treatment to individual neurotransmitter circuit disruption may improve post-stroke aphasia outcomes. Conflict of interest PNA is supported by the grant “Prémio Maria de Sousa 2024—Ordem dos Médicos e Fundação Bial.” MTdS is supported by HORIZON-INFRA-2022 SERV (Grant No. 101147319) “EBRAINS 2.0: A Research Infrastructure to Advance Neuroscience and Brain Health,” by the European Union’s Horizon 2020 research and innovation program under the European Research Council (ERC) Consolidator grant agreement No. 818521 (DISCONNECTOME), the University of Bordeaux’s IdEx “Investments for the Future” program RRI “IMPACT,” and the IHU “Precision & Global Vascular Brain Health Institute—VBHI” funded by the France 2030 initiative (ANR-23-IAHU-0001). SJF is supported by the Donders Mohrmann Fellowship (Grant No. 2401515, NEUROVARIABILITY), the Dutch Research Council (NWO) Aspasia Grant (No. 015.021.008, Human individuality: phenotypes, cognition, and brain disorders) and the NWO SSH Open Competition grant (No. 406.22.24GO.056, Neuroanatomy of speech production). Figure 1 - belongs to Results