SARR

Treatment tested

• Lokomat training
• Nabiximols

Inclusion Criteria: Inclusion criteria were: * age of 18-65 years, * diagnosis of definite relapsing-remitting or primary-progressive Multiple Sclerosis, -absence of clinical relapses from no gadolinium enhanced lesions on brain and spinal cord MRI performed at least six months prior to study entry, * no mood or sleep disorders (Hamilton score of \<17), * a moderate to severe spasticity in at least two districts of upper and/or lower limbs; -absence of clinical or neuroradiological relapses from at least six months prior to study entry, * Expanded Disability Status Scale (EDSS) total score between 3.5 and 7.0, * no history of psychosis, * no presence of pace-maker, aneurysms clips, neurostimulator or brain/subdural electrodes (safety TMS procedure), * right handedness, * central conduction time in upper limbs of \<8 ms; * no robotic gait traing contraindications. Exclusion Criteria: * History of psychosis, * presence of pace-maker, aneurysms clips, neurostimulator or brain/subdural electrodes (safety TMS procedure), * central conduction time in upper limbs of \<8 ms; * robotic gait traing contraindications.

Spasticity is frequently experienced by people with Multiple Sclerosis (MS), negatively impacting on patient's motor functional outcome, including walking. Currently, none of the available MS disease-modifying medications has been shown to stop or reverse gait disability. Recently the nabiximols has been tested for the treatment of spasticity and walking impairment in MS. Nabiximols (trade name Sativex®) is an oromucosal spray formulation containing 1:1 fixed ratio of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) derived from cloned Cannabis sativa L. plant. The main active substance, THC, acts as a partial agonist at human cannabinoid receptors (CB1 and CB2), and may modulate the effects of excitatory (glutamate-GLU-) and inhibitory (gamma-aminobutyric acid -GABA-) neurotransmitters, leading to muscle relaxation, which in turn is responsible for spasticity improvement. Cannabinoid receptors may modulate both excitatory and inhibitory transmission at central synapses, and have been heavily implicated, in animal models, in multiple forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). Indeed, in a previous study implying transcranial magnetic stimulation (TMS) technique, it has been hypothesized that the activation of cannabinoid receptors by Sativex® could modulate the balance between LTP and LTD like plasticity by changing the state of cortical excitability. In a recently study it has been proposed that Sativex may modulate the cortical excitability changing the activity of inhibitory GABAergic cortico-cortical synapses. Aim of our study is to clarify the role of Sativex coupled to a robotic neurehabilitation training in MS patients in improving the motor outcome, by means of clinical, kinematic, beside some neurophysiological and measures.