Sleep as a model to understand and manipulate cortical activity in order to promote neuroplasticity and functional recovery after stroke

Major advances were made in stroke prevention and acute management. Conversely, recovery from stroke can be promoted only by neurorehabilitation. Animal and human data have shown that this occurs thank to neuroplasticity processes involving ipsi- and contralesional areas. Since sleep promotes learning and memory, and more generally neuroplasticity, we postulate that sleep- related mechanisms may modulate stroke recovery. Specifically, we hypothesize that perilesional slow waves -which reflect neuronal bistability (an alternation between depolarized ON and hyperpolarized OFF states)- may have a favorable function in the initial phase post-stroke promoting homeostatic adjustments of cortical excitability, while beeing detrimental in the chronic phase because disrupting intracortical information processing. In order to test these hypotheses, we designed a three-steps research strategy: 1) observational approach: ipsi- and contralesional sleep-wake high density EEG changes will be assessed in rodents and human with hemispheric stroke from the acute to the chronic stage and correlated with functional outcome; 2) perturbational approach: the reactivity and connectivity of the perilesional cortex -as measures of cortical bistability- will be assessed by transcranial magnetic stimulation (TMS) during functional recovery after stroke in humans; 3) interventional approach: manipulations of cortical bistability will be performed in mice (with optogenetics) and humans (with TMS) after stroke and assessed in terms of their effects on functional outcome. The multimodal and translational approach chosen for this proposal has never been used previously in this context. The methodological feasibility of the animal and clinical experiments and the ability to recruite stroke patients for clinical-neurophysiological projects were repeatedly proven in the past by the four research teams. The demonstration that sleep related rocesses may play a role in neuroplasticity and functional outcome after stroke and the understanding of the network and cellular mechanisms involved are expected to have major neuroscientific and clinical implications.