Interactions Between Striatum and Cerebellum in ADCY5 and PRRT2 Dystonias (AMEDYST)

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.

Study Overview

• Status: Completed
• Conditions: Dystonia
• Intervention / Treatment: Other: transcranial magnetic stimulation of the cerebellum

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Paris, France
    • Département de Neurologie, Fédération des Maladies du Système Nerveux, GH Pitié-Salpêtrière, 47 Bd de l'Hôpital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Investigators: Principal Investigator: Emmanuel Flamand-Roze, MD, PhD, Pitie-Salpetriere

Publications and helpful links

General Publications

• Ekmen A, Meneret A, Valabregue R, Beranger B, Worbe Y, Lamy JC, Mehdi S, Herve A, Adanyeguh I, Temiz G, Damier P, Gras D, Roubertie A, Piard J, Navarro V, Mutez E, Riant F, Welniarz Q, Vidailhet M, Lehericy S, Meunier S, Gallea C, Roze E. Cerebellum Dysfunction in Patients With PRRT2-Related Paroxysmal Dyskinesia. Neurology. 2022 Mar 8;98(10):e1077-e1089. doi: 10.1212/WNL.0000000000200060. Epub 2022 Jan 20.
• Ekmen A, Doulazmi M, Meneret A, Jegatheesan P, Herve A, Damier P, Gras D, Roubertie A, Piard J, Mutez E, Tarrano C, Welniarz Q, Vidailhet M, Worbe Y, Gallea C, Roze E. Non-Motor Symptoms and Quality of Life in Patients with PRRT2-Related Paroxysmal Kinesigenic Dyskinesia. Mov Disord Clin Pract. 2023 Jun 5;10(7):1082-1089. doi: 10.1002/mdc3.13795. eCollection 2023 Jul.

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2018
• Primary Completion (Actual): August 4, 2023
• Study Completion (Actual): August 4, 2024

Study Registration Dates

• First Submitted: March 20, 2018
• First Submitted That Met QC Criteria: March 27, 2018
• First Posted (Actual): March 29, 2018

Study Record Updates

• Last Update Posted (Estimated): November 18, 2025
• Last Update Submitted That Met QC Criteria: November 14, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: fMRI; Transcranial magnetic stimulation; Human; Cerebellum; Striatum; Genetic dystonia
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Dyskinesias; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Dystonia
• Other Study ID Numbers: C16-128; 2017-A01843-50 (Registry Identifier: RCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No