Tales from the (closed) loop; Studying the impact of electrical stimulation on brain injuries

Restoring function after brain injuries is a widely recognized priority in healthcare as disorders of the nervous system that cause motor impairment, such as stroke, are among the most common causes of adult-onset disability. Recently, brain stimulation techniques have been employed to promote post-injury recovery of the motor function. One type of intracortical microstimulation known as Activity Dependent Stimulation (ADS) uses a closed loop paradigm to link brain activity and stimulation and has shown promising results in preclinical settings, both increasing behavioral recovery after localized brain damage and promoting changes in existing functional connectivity. The purpose of this PhD work is to elucidate the mechanisms underlying ADS's effect both in physiological and pathological conditions, by fulfilling the following three main scientific and technological objectives: (1) understanding the short and long term effects of intracortical microstimulation; (2) Investigating the impact of a focal lesion on adjacent spared regions and its interplay with intracortical stimulation; (3) Developing a novel software pipeline able to integrate the analysis of low-high frequency electrophysiological signals (i.e. spikes and LFPs) and the behavioral performances. To accomplish those objectives, several experimental campaigns were performed both on anesthetized and behaving animals. To evaluate the impact of a brain damage, a focal lesion was induced in the motor cortex by using a potent vasoconstrictor, to ensure behavioral impairment. The obtained results indicate that ADS contributes to induce significant electrophysiological changes associated with behavioral recovery. Specifically, intracortical microstimulation is likely to modulate neuronal growth processes, leading to adaptive plasticity that could account for some of the major changes observed at the level of the electrophysiological activity. In particular, it was found that ADS drives the cortical network to the greatest neuronal activity changes, thus suggesting its better ability, with respect to open loop stimulation strategies, to make the most out of the functional connections in the spared areas and possibly induce new ones. The implications of these results have the potential to lead to novel treatments for various neurological disorders and inspire new neurorehabilitation therapies.