Propensity to Develop Plasticity in the Parieto- and Cerebello-Motor Networks in Dystonia From the Perspective of Abnormal High-Order Motor Processing

Objective

The purpose of this protocol is to improve understanding of the pathophysiology of dystonia
by performing an electrophysiological study using plasticity induction protocols based on
dual-site transcranial magnetic stimulation (TMS). We hypothesize that dystonic patients have
enhanced responsiveness to plasticity induction in the parieto-motor network. In another
exploratory study, we will also explore the responsiveness to plasticity induction of the
cerebello-motor network. The clinical significance of such an enhanced plasticity will be
evaluated by correlating the plasticity measurements with subjects' performance on two tasks
engaging high-order motor processing and involving the parietal cortex and the cerebellum.

Study Population

There will be one main study and one exploratory study with similar designs; the former will
explore the parieto-motor network (PAR study) and the latter, the cerebello-motor network
(CER study). There will be two independent arms in each study: one will compare patients with
writer s cramp (WC) and age-matched healthy volunteers (HV); and the other one will compare
patients with cervical dystonia (CD) with age-matched HVs. The power analysis of the main
(PAR) study indicates that we need to enroll 17 patients and 17 healthy volunteers in each
arm, with an additional 3 added to account for drop-outs. Therefore, we request a maximum of
20 subjects per patient group and 40 subjects for the control groups. A second power analysis
for the exploratory CER study indicates that we need to enroll 13 healthy volunteers and 13
patients in each arm, with an additional 3 added to account for drop-outs. Thus, we request a
maximum of 16 subjects per patient group and 32 subjects in the control groups.

Design

Subjects will come for one screening visit and two outpatient study visits. During the first
study visit patients will be scored clinically for dystonia and cerebellar signs. They will
also undergo a structural magnetic resonance imaging (MRI) to locate the parietal target
during the stimulation session. They will perform two motor learning tasks: a reaching task
with visuomotor conflict and a predictive motor timing task. At least 24 hours later, during
study visit two, subjects will receive TMS. TMS-induced electromyographic (EMG) activity of
hand muscles will be recorded as motor evoked potentials (MEPs). Using single TMS shocks, we
will measure at baseline, the input-output (I-O) curve for the right first dorsal
interosseous (FDI) muscle MEPs. Then, the subjects will receive a plasticity induction
protocol aiming to induce plasticity in the pathway linking the posterior parietal (PP)
cortex and the primary motor cortex (M1). To that end, transcranial stimulation will be
applied repeatedly (100 pairs) to the left angular gyrus in the PP cortex and to the left M1.
At the end of the intervention, the I-O curve will be measured again over the next 50
minutes. The exploratory CER study will have the same experimental design. It differs from
the PAR study only by the type of plasticity induction protocol used. Specifically, the
cerebellum will be stimulated rather than the PP cortex.

Outcome Measures

The amplitude of the MEPs in the I-O curves gives information about corticospinal
excitability as a function of TMS stimulation. The primary outcome measure will be MEP size
with respect to time (before and 15-20 min after the plasticity intervention). The difference
in MEP size will be compared between the HV and the patient groups using a T test. The
performances on the behavioral tasks will be correlated with the primary outcome measure.

- INCLUSION CRITERIA:

- Between the ages of 18 and 65 years

- Right-handed

- English speaking

- For patients only: confirmed diagnosis of cervical dystonia (CER-CD and PAR-CD
studies) or writer s cramp (for CER-WC and PAR-WC studies).

- For patients treated with anticholinergics and/or benzodiazepines, they must be
willing and safely able to abstain from any of these medication for a period of at
least 5 plasma half-lives of the individual drug prior to study participation (2 days
for trihexyphenidyl which has a plasma half life around 4 hours; 12 days, for
clonazepam which has a half-life of 18-50 hours).

- For HVs only: absence of dystonia or other neurological disorder with any effect on
the motor or sensory systems

- Ability to give informed consent

- Ability to comply with all study procedures, based on the judgment by the
investigator(s).

EXCLUSION CRITERIA:

Any of the following will exclude patients from the study:

- Secondary forms of dystonia, including tardive dyskinesia.

- Dystonic tremor where the tremor is the sole or principal abnormality.

- Botulinum toxin treatment < 3 months prior to visit.

Any of the following will exclude patients or healthy controls from the study:

- Illegal drug use within the past 6 months based on history alone. The intent is to
exclude those with drug use that may affect study results.

- Self-reported consumption of 7 alcoholic drinks a week for women and >14 alcoholic
drinks a week for man.

- Abnormal findings on neurologic exam (other than dystonia in patient group).

- History of or current brain tumor, stroke, head trauma with loss of consciousness >
few seconds, epilepsy or seizures.

- Current diagnosis of major depression or any major mental disorders (axis I
disorders).

- Current diagnosis of neurologic disorder other than dystonia.

- Presence of pacemaker, intracardiac lines, implanted pumps or stimulators, or metal
objects inside the eye or skull. Dental fillings and dental braces are allowed.

- Known hearing loss.

- Open scalp wounds or scalp infection.

- Current pregnancy.

- Taking benzodiazepines at the time of the study or within 12 days prior to the study.

- Taking anticholinergics at the time of the study or within 2 days prior to the study.

- Taking at the time of the study or within 2 weeks prior to the study any medication
that acts as a central nervous system stimulant or that is known to lower seizure
threshold, including, imipramine, amitriptyline, doxepine, nortriptyline, maprotiline,
chlorpromazine, foscarnet, ganciclovir, ritonavir, amphetamines, ketamine,
gamma-hydroxybutyrate (GHB), theophylline, mianserin, fluoxetine, fluvoxamine,
paroxetine, sertraline, citalopram, reboxetine, venlafaxine, duloxetine, bupropion,
mirtazapine, fluphenazine, pimozide, haloperidol, olanzapine, quetiapine,
aripiprazole, ziprasidone, risperidone, chloroquine, mefloquine, imipenem, penicillin,
ampicillin, cephalosporins, metronidazole, isoniazid, levofloxacin, cyclosporin,
chlorambucil, vincristine, methotrexate, cytosine arabinoside, BCNU, lithium,
antihistamines, and sympathomimetics.