Longitudinal evaluation of the mechanisms supporting post-stroke motor recovery using TMS-EEG coupling

Stroke is the main source of long-lasting disability, affecting dominantly motor functions. The extent and course of recovery are highly heterogeneous between patients, with a minority of patients fully recovering from their initial impairments, leaving 85% persisting deficits. The pathophysiological mechanisms underlying inter-patients heterogeneity are still not fully understood. Most motor recovery is taking place during the first months after a stroke, with limited improvement after that time, emphasizing the importance of this early period. These first months after a stroke are characterized by dynamic modulations of excitatory and inhibitory processes in the brain. Most notably, modulation of intracortical inhibition is thought to promote both neuronal protection from further damage in the hyperacute phase and functional reorganization to compensate for the lesioned brain regions in the following phases. Previous research in animal models and stroke patients has highlighted specifically the importance of the GABAergic system, the main actor of inhibition in the brain. However, the specific functional role and the time course of changes of GABAergic inhibition in the course of recovery are only partially understood.To better characterize the spatial and temporal properties of the inhibiting mechanisms occurring after a stroke and their association with motor recovery, we investigated the neurophysiological changes of 66 stroke patients longitudinally from the first week to 3 months post stroke. Cortical excitability and inhibition were determined by transcranial magnetic stimulation (TMS) coupled with electroencephalography (EEG).The present results revealed two disinhibition phases with distinct regionality and timing patterns. In Study I, a local ipsilesional disinhibition, expressed by larger evoked activity, in the acute phase was related with better motor recovery at 3 months post stroke. Patients recovering the most showed a return to normal excitatory/inhibitory balance between the acute and early chronic stage. In Study II, global excitatory and inhibitory activity were evaluated through a data-driven analysis of TMS-induced braion oscillatory modes. The late alpha-oscillations, a proxy of GABAergic activity, displayed a small increase in the acute stage followed by a large decrease between the subacute and early chronic stage. This global disinhibition was correlated with greater recovery of fine upper-limb motor function. This thesis underlines the importance of GABAergic disinhibition, both locally and globally, for motor recovery after a stroke and determined its specific time courses. The acquired knowledge will provide the basis to pave the way to electrophysiological biomarkers for individual phenotyping of patients. Personalized interventional strategies targeting changes in cortical excitability have to potential to maximize functional recovery in each individual patient.