Interactions Between Striatum and Cerebellum in ADCY5 and PRRT2 Dystonias

Study Overview
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Brief Summary
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The investigators will study the relationship between the basal ganglia and the cerebellum in dystonia by associating cerebellar stimulations with functional magnetic resonance imaging analysis.

Detailed Description
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Although dysfunctions in both basal ganglia and cerebellum in dystonia are well documented, the functional relationships between these two important motor control networks remains unclear in the context of dystonia. Here the investigators propose to tackle this issue by associating cerebellar stimulations with functional analysis using fMRI in dystonic patients. The working hypothesis is that the primary torsion dystonia (PTD) pathophysiology involves dysfunction of striatum that is amplified by dysregulation of the cerebello-thalamo-striatal pathway. The project is to study dystonia forms resulting primarily from dysfunctions of the striatum (patients with mutation of the ADCY5 gene) and compare them with patients with putative dysfunction of the cerebellum (patients with mutation of the PRRT2 gene) and healthy controls. In these patients, the investigators will look for (1) how cerebello-thalamo striatal pathway can be influenced by striatal dysfunctions and (2) whether cerebellar stimulation may prevent (or worsen?) the disrupted activity in the basal ganglia and (3) whether striatum-related dystonia share the same abnormal network with another form of dystonia resulting from another dysfunction (patients with PRRT2 mutation).

Official Title
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Interactions Between Striatum and Cerebellum in ADCY5 and PRRT2 Dystonias

Conditions
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Dystonia

Intervention / Treatment
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* Other: transcranial magnetic stimulation of the cerebellum


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: clinical diagnosis of Dystonia characterized ADCY5 or PRRT2 mutation must have a European Social Security card or a parent having an European Social Security card must be older than > 15 years 3 months must be able to give informed consent or, for minor patients, parents must be able to give informed consent must be able to comply with all study procedures, based on the judgment by the investigator(s). Exclusion Criteria: major depression or any major mental disorders (axis I disorders) neurologic disorder other than dystonia presence of pacemaker, intracardiac lines, implanted pumps or stimulators, or metal objects inside the eye or skull, cochlear implant Permanent makeup of lips or eyelids Black large tattoo close to the head Severe claustrophobia Current pregnancy or breast feeding Copper intrauterine device Subjects with one of the following exclusion criteria will not receive cerebellar stimulation Open scalp wounds or scalp infection, epilepsy or seizures Taking at the time of the study: ketamine, antidepressants, ganciclovir, ritonavir, amphetamines, antiemetic.

Ages Eligible for Study
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Minimum Age: 183 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham cerebellar stimulation<br>Participants will receive a Sham stimulation (inefficient probe) applied over the cerebellum. | Other: transcranial magnetic stimulation of the cerebellum<br>* The intervention will consist in a continuous theta burst stimulation of the cerebellum under neuronavigation.<br>|
| Active Comparator: Real cerebellar stimulation<br>Participants will receive a real continuous theta burst stimulation (cTBS) applied over the cerebellum. | Other: transcranial magnetic stimulation of the cerebellum<br>* The intervention will consist in a continuous theta burst stimulation of the cerebellum under neuronavigation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resting state functional connectivity between the cerebellum and the striatum | Synchrony between the cerebellum and the striatum, calculated from resting state fMRI done at visit2 will be compared between the 3 groups (healthy controls, ADCY5 patients, PRTT2 patients) | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amplitude of Low Frequency Fluctuation (ALFF) of blood oxygen level-dependent signal in the cerebellum | ALFF of Blood oxygen level-dependent signal in the cerebellum will be compared between the 3 groups (healthy controls, ADCY5 patients, PRTT2 patients | 6 weeks | 
| Fractional anisotropy (FA) of the cerebello-striatal tract | FA of the disynaptic tract between the cerebellum and the striatum will be compared between the 3 groups. | 1 day | 
| Creatine concentration in the striatum measured with diffusion weighted spectroscopy. | Creatine concentration in the striatum measured from the spectroscopy, will be compared between the 3 groups | 6 weeks | 
| Amplitude of Low Frequency Fluctuation (ALFF) of blood oxygen level-dependent signal in the striatum | ALFF of Blood oxygen level-dependent signal in the striatum will be compared between the 3 groups (healthy controls, ADCY5 patients, PRTT2 patients | 6 weeks | 
| Resting state functional connectivity between the cerebellum and the thalamus | Synchrony between the cerebellum and the thalamus, calculated from resting state fMRI done at visit2 will be compared between the 3 groups (healthy controls, ADCY5 patients, PRTT2 patients) | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cerebellum, Striatum, Human, fMRI, Transcranial magnetic stimulation, Genetic dystonia