Empowering the brain. Induction of Hebbian-like plasticity in cortico-cortical neural networks with transcranial magnetic stimulation (TMS): investigations of functional connectivity in healthy subjects and clinical trials in stroke patients

The present proposal rests on 3 concepts: 1) TMS can be used to alter cortical excitability and promote neural plasticity in stroke patients, however to date TMS interventions: i) have been rarely combined with specific motor training; i) have been limited to the stimulation of single brain regions; 2) The circuits composed by the premotor and the motor cortex (PMC-M1) appear as a critical novel target for specific TMS interventions in stroke treatment. 3) A novel, physiological inspired, TMS method (we called cortico-cortical Paired Associative Stimulation, ccPAS) can specifically induce Hebbian-like plasticity in the PMC-M1 circuits and this approach can be combined with physical therapy to promote functional recovery in stroke patients. The goal of this project is to develop a new physiologically-inspired TMS paradigm to induce plasticity in specific cortico-cortical neural networks and to test the effect of such non-invasive interventions on brain and behavior of healthy and stroke individuals. The final goal is to induce plasticity in PMC-M1 networks and promote functional recovery after brain damage. This general goal will be pursued in 4 distinct Work Packages (WP) whose specific aims are: WP1: ccPAS definition. To develop a novel Hebbian-like ccPAS paradigm based on the synchronous stimulation of 2 connected brain regions (e.g. ventral premotor- motor cortex, vPMC-M1; supplementary motor area-motor cortex, SMA-M1) and to directly test its effect on the strength of the connection between the stimulated regions and on behavioral motor performance To this aim a series of paired-pulse TMS experiments using a sham-controlled, cross-over design in healthy individuals will be carried out. WP2: ccPAS on large-scale networks. To test the effect of ccPAS (developed in WP1) at a large-scale networks level using sham-controlled, cross-over design and EEG and fMRI techniques in healthy individuals and to link changes in brain connectivity to changes in behavior and to structural connectivity (assessed with DTI). WP3: Single-dose trial in stroke patients. To test, using a sham-controlled, cross-over design, the effect of single-doses of different ccPAS protocols (developed in WP1) in chronic stroke patients with mild-to-moderate motor deficits and select the protocol associated to the best outcome. WP4: Prospective trial in stroke patients. To combine, in a prospective, randomized, parallel and sham-controlled clinical trial, multiple sessions of ccPAS and physical therapy to boost motor recovery in chronic stroke patients and to assess long-lasting changes in brain and motor behavior. Overall we expect to provide novel information about the mechanisms underlying cortical plasticity in humans and to improve current motor rehabilitation treatments in stroke patients. The proposed research will pave the way further applications for brain disorders characterized by reduced or altered brain connectivity.