Acute perilesional excitability explains long-term motor recovery after stroke

Stroke is a leading cause of disability, and changes in neuronal excitability in perilesional regions may critically influence patients recovery. While reduced excitability is often associated with impaired recovery, increased excitability following injury may support reparative mechanisms. Although animal studies have shown how synaptic transmission adapts after stroke, a mechanistic understanding of how these excitability changes in the perilesional area relate to recovery in acute patients remains unclear. Here, we apply patient-specific (N = 96) computational whole-brain models to infer regional excitability, focusing on both perilesional and non-perilesional sites. Specifically, we estimate the firing sensitivity of local excitatory neuronal populations. Our findings indicate large inter-subject variability, with patients displaying both relative perilesional hypo- and hyper-excitability. Notably, perilesional excitability emerges as a robust predictor (P = 0.002) of motor recovery one year after the stroke, but not of acute post-stroke motor impairment, emphasizing its significance in specifically shaping long-term recovery. This synaptic modulation of excitability exhibits a strong correlation with gamma-aminobutyric acid A (GABA-A) receptor density distributions before the stroke, providing a potential biological substrate. These findings highlight the subject-specific nature of perilesional excitability, positioning it as a compelling target for personalized interventions to optimize post-stroke motor recovery.