The purpose of this study is to tested the effect of combination of a paired associative stimulation of two functional interconnected areas of the cerebral cortex (posterior-parietal cortex and primary motor cortex) with robot-assisted therapy in the recovery of upper limb after stroke.

BACKGROUND

Stroke survivors reported upper limb impairment that contribute to reducing the overall quality of life, social participation and professional activities. The impairment of the upper limb is due to motor and sensory alteration that could compromise the sensorimotor integration. The posterior parietal cortex (PPC) is a potential circuit where this integration could occur during active somatosensation. Indeed, PPC is a site of massive confluence of visual, tactile, proprioceptive, and vestibular signals. This area may be involved in transforming information about the location of targets in space, into signals related to motor intentions. This process likely occurs through parietal-motor connections, which are known to be involved in the transfer of relevant sensitive information for planning, reaching, and grasping. Paired associative stimulation (PAS) of PPC and primary motor area (M1), by means of bi-focal trans-cranial magnetic stimulation, can modulate M1 excitability. This information reinforces the hypothesis that modulation of PPC-M1 connectivity can be used as a new approach to modify motor excitability and sensorimotor interaction. Parallel, robot assisted training (RAT) can induce a plastic reorganization at the muscular afferents, spinal motor neurons, interneuron system and beyond and facilitates neural plasticity and motor relearning through goal-oriented training. The robotics device allows to train patients in an intensive, task-oriented, and top-down therapy way, increasing patients' compliance and motivation. The cognitive top-down stimulation is allowed by means of the introduction of visual feedback performed through exergaming. Recently, it has been proposed the development of new intervention strategies that combine neurostimulation of a target brain area with neurorehabilitation, such as physical therapy or virtual reality. Although both TMS and RAT have shown individually promising effects in upper limb recovery after a stroke, their combination has not been tested to date.

AIMS

1. To determine whether robot-assisted therapy combined with cortico-cortical non-invasive stimulation of M1 and PPC areas can improve functional recovery of upper extremity in patients with hemiparesis due to stroke.
2. To evaluate the feasibility of robot-assisted training exergaming technology for reaching and grasping training for stroke rehabilitation.
3. To investigate the neurophysiological changes in PPC-M1 connectivity (through TMS EEG) to clarify the effectiveness of PAS on neuromodulation of the PPC-M1 network.

Inclusion Criteria:

1. first ever chronic ischemic stroke;
2. hemiparesis due to left or right subcortical or cortical lesion in the territory of the middle cerebral artery;
3. severe or moderate residual upper limb impairment (FMA < 52 in the motor domain A/D)

Exclusion Criteria:

1. history of seizures;
2. severe general impairment or concomitant diseases;
3. treatment with benzodiazepines, baclofen, and antidepressants;
4. Intracranial metal implants;
5. cardiac pacemaker;
6. pregnancy status;
7. orthopedic contraindications for upper limb;
8. upper limb pain;
9. cognitive impairment (MMSE < 23);
10. presence of unilateral spatial neglect

The recruiters, outcomes assessors, physical therapists, participants and their caregivers will be blinded with respect to participants' allocation for the entire period of the study.