Brain Function in Focal Dystonia

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 interneurons 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.

19 patients with a focal upper limb dystonia and 24 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 2: PAS session, 3 hours; visit 3: a minimum of 7 days later, motor learning
session, 3 hours; visit 4: follow-up 24 hours later, 1hour and half; visit 5, follow-up 48
hours later, 1 hour and 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 interneurons.

In the control studies: subjects will complete a maximum of eight sessions. 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 flexors muscles; H reflexes will be
delivered alone or will be conditioned by cubital or radial nerve stimulation.

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 alone, the amounts of postactivation depression and those of presynaptic inhibition
before and after PAS.

- INCLUSION CRITERIA:

- Healthy volunteers (aged 18 or older) who are willing to participate.

- Patients (aged 18 and older) with an idiopathic upper limb dystonia, who are able to
practice the motor learning task.

EXCLUSION CRITERIA:

- Subjects with a history of neurological or psychiatric disorder, current use or a
history of alcohol or drug abuse, psychiatric disorders requiring hospitalization or
prolonged treatment such as substance abuser addiction, head injury with loss of
consciousness, epilepsy.

- Subjects with significant hearing loss.

- Subjects receiving drugs acting primarily on the central nervous system.

- Subjects who have been treated with botulinum toxin injections 3 months prior to
their participation in the study.

- Subjects who are taking any medication for dystonia at the time of the study.

- Subjects who have already participated in a protocol using a motor learning task.

- Subjects who practice intensively playing any kind of music instrument.

The following exclusion criteria are due to the use of transcranial magnetic stimulation:

- Subjects with cardiac pacemakers, intracardiac lines, implanted medication pumps.

- Subjects with eye, blood vessel, cochlear, or eye implants.

- Subjects with increased intracranial pressure as evaluated by clinical means.

- Subjects with metal in the cranium.

- Subjects with dental braces (but dental fillings are not a problem), metal fragments
from occupational exposure or surgical clips in or near the brain.

Women in the last trimester of pregnancy will not be studied because they will likely be
uncomfortable maintaining a motionless seated posture during the three hour experiment.