Pathophysiology of Dystonia and Complex Regional Pain Syndrome

Objective:

The current exploratory study aims at detailed evaluation of pathophysiology of Complex
Regional Pain Syndrome (CRPS) dystonia compared to Focal Hand Dystonia (FHD) with focus on
the involvement of the parietal area.

Study population:

The study will enroll patients with (FHD), CRPS dystonia, CRPS without dystonia and Healthy
Volunteers (HVs).

Design:

Prospective study using MRI and Physiology experiments using EMG and TMS based protocols to
evaluate the differences between the groups.

Outcome measures:

The evaluation using fMRI will be performed under 3 conditions; 1. Rest 2. Voluntary activity
3. Motor imagery task.

Outcome measures (fMRI based):

- We will explore the differences in BOLD signal in the parietal lobe, in CRPS dystonia
compared to FHD, in the different conditions. We will look for changes in the BOLD
signal in the parietal sensorimotor integration area.

- We will further explore the differential activation in CRPS dystonia vs CRPS without
dystonia to identify any specific features inherent to patients with CRPS dystonia
compared to CRPS alone.

The Physiology experiments aim to explore abnormalities and differences in the baseline motor
cortical excitability between the groups and evaluated the influence of continuous Theta
Burst Stimulation (cTBS) on these measures. We will study the influence of cTBS on the
phenomenon Cortical Silent Period ( cSP) in CRPS dystonia and FHD.

We will also be studying the baseline Spatial and Temporal Discrimination (SDTs and TDTs),
which are measures of sensory surround inhibition. TDT and SDT abnormalities have been noted
to be endophenotypic of dystonia, however the comparative characteristics between FHD and
CRPS dystonia are not known.

Physiology outcomes:

- Baseline differential influences of PMv and IPL on motor cortical excitability and
changes after cTBS of dIPL.

- Baseline cortical Silent Period (cSP) in the involved and uninvolved limb in FHD and
CRPS dystonia and the influence of cTBS on cSP between the groups in the involved limb.

- The TDTs/ SDTs in both the involved and uninvolved limbs in FHD and CRPS dystonia
compared to HVs.

- INCLUSION CRITERIA:

Healthy research volunteers, adult patients with FHD, CRPS patients with dystonia involving
at least one hand and CRPS patients without dystonia will be eligible for the study.

- Age between 18 - 70 years.

- Able to give informed consent.

- Able to comply with all study procedures.

- Subjects must be willing to abstain from alcohol for at least 48 hours prior to the
study.

- Adult patients with an established diagnosis of FHD.

- Healthy volunteers will be healthy subjects without neurological or psychiatric
disorders established by history and physical/neurological examination.

- Adult CRPS patients, diagnosed based on the Budapest Clinical diagnostic criteria by
an experienced Neurologist, with the presence of dystonia involving at least one hand.

- Adult CRPS patients, diagnosed based on the Budapest Clinical diagnostic criteria by
an experienced Neurologist, without the presence of dystonia in any limbs.

- Patients receiving botulinum toxin injections will be evaluated after 3 months since
their last injection.

- All participants must be able to obtain an MRI (No contraindications per MRI safety
checklist) which will be part of the initial evaluation.

EXCLUSION CRITERIA:

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

- Patients on daily chronic opioid or benzodiazepine use.

- Patients treated with anticholinergics, who are not willing and/or unable to withhold
taking them for 1 week prior and for the duration of the study participation.

- Patients taking opioids and/or benzodiazepines on an as needed basis, who are not
willing and/or unable to withhold taking them for 1 week or time interval equivalent
to 5 half-lives (whichever is shorter) prior to study participation and for the days
during study participation.

- Abnormal findings on neurological examination including cognitive impairment, except
diagnosis of interest (FHD, CRPS with/without dystonia) in patients.

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

- Past or present medical history of (a) neurological disorders, such as stroke,
movement disorders (other than dystonia in the patient group), ataxias, myopathies,
myasthenia gravis, demyelinating diseases, alcoholism, drug dependence; (B)
ventricular arrhythmias, renal and hepatic insufficiency, vascular headache, or
carcinoid syndrome.

- Subjects with Baclofen pumps and/or neuro stimulators for pain.

- Current episode of major depression or any major psychiatric illness. Note: SSRI use
is not exclusionary.

- Pregnant or breastfeeding women. Aside from history obtained at the screening,
pregnancy status in women with childbearing potential is also established by urine
pregnancy testing no more than 24 hours before each MRI and TMS sessions.

- Subjects who have contraindications to MRI:

- You have metal in your body which would make having an MRI scan unsafe, such as
pacemakers, stimulators, pumps, aneurysm clips, metallic prostheses, artificial
heart valves, cochlear implants or shrapnel fragments, or if you were a welder or
metal worker, since you may small metal fragments in the eye.

- You are uncomfortable in small closed spaces (you have claustrophobia) so that
you would feel uncomfortable in the MRI machine.

- You are not able to lie comfortably on your back for approximately 2 hours.

- Subjects who have contra-indications for TMS

- You have a pacemaker, implanted pump, stimulator, cochlear implant or metal
objects inside the eye or skull.

- You have hearing loss (assessed by participant self-report or history).

- You are pregnant