Motor-related reorganization in left inferior frontal gyrus after subcortical stroke: neurochemical basis and response to targeted neuromodulation

BACKGROUND: The left inferior frontal gyrus (IFG) is implicated in both language and motor processes. Its functional reorganization post-stroke, particularly in motor dysfunction without aphasia, remains poorly understood. We investigated effective connectivity (EC) alterations of the left IFG and their neurochemical basis, and responsiveness to neuromodulation in subcortical stroke. METHODS: Cross-sectional analysis included 32 left (LSS) and 27 right (RSS) stroke patients and 40 healthy controls (HCs). Seed-based EC of the left IFG was derived from resting-state fMRI and was compared between groups. Relationships between EC, neurotransmitter density, lesion-derived neurotransmitter indices, and Fugl-Meyer Assessment (FMA) scores were examined. Longitudinally, 30 patients received 14 sessions of cathodal-contralesional sensorimotor cortex (SMC), anodal-ipsilesional M1, or sham transcranial direct current stimulation (tDCS), synchronized with upper limb training. Pre-post FMA and EC changes were compared. RESULTS: Both LSS and RSS groups showed increased EC from the left IFG to the right cerebellum posterior lobe (CPL) and superior frontal gyrus (SFG), whereas only LSS group showed decreased EC from the left CPL to the left IFG. EC from the left IFG to the right CPL positively correlated with FMA, while EC from the left CPL to the left IFG negatively correlated with FMA in LSS. These EC alterations were significantly associated with serotonergic, dopaminergic, and GABAergic neurotransmitter densities. Crucially, IFG-to-SFG connectivity mediated the relationship between lesion-derived neurotransmitter network damage and lower-limb motor deficits. Longitudinal intervention revealed that different tDCS protocols distinctively modulated the left IFG's EC, with the most robust changes induced by cathodal stimulation of the contralesional SMC. CONCLUSIONS: Collectively, motor-related reorganization occurs in the left IFG post-stroke, characterized by altered EC patterns that are (1) correlated with motor performance, (2) underpinned by specific neurochemical systems, and (3) mediate post-stroke motor impairment. These reorganizations are plastic and respond specifically to targeted neuromodulation, highlighting the left IFG as a potential novel therapeutic target for motor recovery and informing personalized rehabilitation strategies. TRIAL REGISTRATION: All data used in the present study were obtained from the research trials registered on ClinicalTrials.gov (NCT05648552; submitted 5 December 2022) and www.chictr.org.cn (ChiCTR2100044970; submitted 3 April 2021).