Neuromodulation for motor recovery in stroke patients

Abstract

Stroke is a leading cause of disability worldwide. Seeking new therapeutic options is mandatory for improving existing motor rehabilitation techniques to obtain a better motor recovery. Stroke patients undergo some spontaneous degree of functional recovery; this process may occur even beyond the resolution of acute changes and could be due to the reorganization of remaining neural circuits. This reorganization falls into the concept of plasticity that could be defined as any enduring change in cortical properties. Plasticity is continuously modified by experience and learning and seems to be enhanced after brain lesions. In the last decades, plasticity of human brain after a lesion has been studied in vivo by means of non invasive brain stimulation (NIBS): neurophysiologic and biologic substrate of plasticity should provide a rational basis for tailoring specific strategies for therapeutic intervention for stroke recovery. Functional neuroimaging studies have demonstrated that recovered motor function in the paretic hand of chronic stroke patients relies predominantly on reorganized activity within motor areas of the affected hemisphere. Furthermore, changes in gamma-aminobutyric acid (GABA)-ergic activity in perilesional cortex after stroke seem to have a central role in recovery. It can be hypothesized that shaping reorganization in the adjacent intact cortex, and contralateral healthy hemisphere could facilitate functional recovery of the brain after stroke. NIBS can modulate cerebral cortex excitability not invasively and seem to be a promising tool for driving plasticity in damaged brain. The changes induced by NIBS are related to long-term changes in synaptic transmission analogue to long-term potentiation (LTP) and long-term depression (LTD) seen in the hippocampus after repeated activation. Several recent studies demonstrated that induction of LTP-like effects (by facilitatory rTMS and tDCS) in the stroke hemisphere and LTD-like effects (by inhibitory rTMS and tDCS) in healthy hemisphere can enhance the effects of motor rehabilitation after stroke, following the “rivalry” model theory. Nonetheless, the effects were limited and variable. On the other hand, it was recently demonstrated that rTMS could improve learning via a different mechanism that involves the phenomenon of “homeostatic” plasticity: a protocol capable of inducing LTD-like effects strongly facilitates motor learning while protocols inducing LTP-like effects have a less pronounced and short-lived facilitatory effect on learning. In the context of stroke this would predict that, contrary to usual practice that uses facilitatory protocols on the affected hemisphere, an inhibitory rTMS protocol (that induces LTD-like effects) over the stroke hemisphere would lead to better relearning in stroke patients through mechanisms of homeostatic metaplasticity. In sum, non-invasive brain stimulation techniques offer the opportunity to evaluate the stroke-induced change in motor cortex functionality and to modify the intra-cortical networks to promote recovery. To this aim, in a group of acute stroke patients we explored intracortical excitability of both hemisphere and looked for a possible correlation with motor recovery. Subsequently, in a different study, we tested whether the contemporary application of an excitatory neuromodulation over the affected hemisphere and an inhibitory neuromodulation over the unaffected hemisphere (following the idea of the rivalry theory) in the sub-acute phase of a stroke could enhance motor recovery. Furthermore we also tested, in a different group of patients, if the application of an inhibitory neuromodulation over the affected hemisphere, in chronic stroke patients could improve motor functionality by means of homeostatic metaplasticity. We found that the acute stroke-induced reduction of intracortical inhibition, indexed by short latency afferent inhibition (SAI), positively correlated with motor improvement at 6 months after stroke. Nevertheless, when a contemporary inhibition of the excitability of healthy hemisphere and a facilitation of the affected hemisphere were induced by means of bilateral tDCS (delivered for 40 minutes daily for 5 consecutive days) during the acute phase after a stroke, a significantly reduction of inter-hemispheric imbalance between affected and unaffected hemispheres was found without any significant change in hand motor function. At last, when an inhibitory plasticity was induced in the affected hemisphere (to achieve any metaplastic change to promote re-learning of motor function) in chronic stroke patients by means of cTBS (1 daily session for 2 weeks), a short lasting improvement in hand motor function was seen. Our studies demonstrated that NIBS, by means of repetitive TMS or tDCS, could be considered a safe procedure to apply in stroke patients both in the acute and chronic phases. On the other hand, we demonstrated that NIBS are able to change motor cortex excitability in stroke patients toward an inter-hemispheric re-balance when applied to increase stroke hemisphere excitability (or decrease unaffected hemisphere excitability) Furthermore, although larger and multi-centric studies are warranted to draw stronger conclusions, the induction of metaplasticity in the affected hemisphere by means of inhibitory protocols could be considered as a useful and promising tool to restore learning and improve motor function also years after a stroke.