Objectives The main objectives of this proposal are (1) to characterize motor learning abnormalities in patients with focal dystonia; (2) to show, using transcranial magnetic stimulation, that this abnormal motor learning went together with an impaired modulation by somatosensory inputs of short and long-interval paired-pulse inhibitions (sICI, lICI) and facilitations (sICF, ICF) of MEPs (ICIs and ICFs are thought to reflect activity of inhibitory and excitatory interneuron's in the primary motor cortex M1); (3) to show that abnormalities of long-term potentiation and long-term depression (LTP/LTD)-like mechanisms (tested using a paired associative stimulation (PAS) intervention), thought to play a crucial role in learning, are associated in dystonia with an abnormal modulation of ICIs and ICFs by somatosensory inputs. Study population 30 patients with a focal upper limb dystonia and 45 healthy volunteers will take part in the main study. 7 patients with a focal upper limb dystonia and 12 healthy volunteers will take part in the control study. Design In the main study: subjects will complete 5 different sessions: visit 1: clinical screening, 1 hour; visit PAS session, 3 hours; visit 3: a minimum of 7 days later, motor learning session, 3 hours; visit 4: follow-up 24 hours later, 1 hour and a half; visit 5, follow-up 48 hours later, 1 hour and a half. During the PAS session they will receive 15 minutes of repeated paired stimulations (transcranial magnetic stimulation -TMS- and peripheral stimulation) thought to produce LTP/LTD like phenomena in M1. During the motor learning sessions they will be asked to perform, as fast as possible, a metronome-paced (0.5 Hz) pinch of their index finger and thumb. They will have 3 blocks of motor practice during the motor learning session. Between each block of motor practice and before and after PAS, while they rest, subjects will receive paired-pulse transcranial magnetic stimulations (TMS) associated or not with peripheral nerve stimulation in order to assess interactions at M1 cortical level between somatosensory incoming volleys and intracortical inhibitory and excitatory interneuron's. In the control study: subjects will complete a unique session. They will receive a PAS intervention. Before and after the PAS intervention, spinal excitability will be tested by the means of H reflexes evoked in wrist flexor muscles. Outcome measures: The behavioral effect of the motor training or of the PAS intervention will be assessed by measuring the mean peak acceleration (MPA) of thumb movement during the blocks of motor practice and the mean maximal peak force (MPF) between the index finger and thumb before and after the blocks of motor practice. The activity of different sets of intracortical interneurons (short and long interval GABA related inhibitions: sICI, lICI, intracortical glutamate-related facilitation: ICF and short interval facilitation: sICF) can be tested using paired-pulse TMS paradigms. The effect of learning (or of PAS intervention) on the interaction between somatosensory afferent input and intracortical processes will be assessed by comparing the amount of sICI, lICI, ICF and sICF when associated or not with a peripheral nerve stimulation (median and ulnar nerve stimulation) in a trained muscle (flexor pollicis brevis: FPB) and a non-trained muscle (abductor digiti minimi: ADM) at different times during and after the motor learning or the PAS intervention. The effect of PAS on spinal cord excitability will be assessed by comparing the size of the H reflex before and after PAS.
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