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

Primary Purpose

Dystonia

Status
Unknown status
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
transcranial magnetic stimulation of the cerebellum
Sponsored by
Institut National de la Santé Et de la Recherche Médicale, France
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Dystonia focused on measuring Cerebellum, Striatum, Human, fMRI, Transcranial magnetic stimulation, Genetic dystonia

Eligibility Criteria

183 Months - undefined (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Sham Comparator

    Active Comparator

    Arm Label

    Sham cerebellar stimulation

    Real cerebellar stimulation

    Arm Description

    Participants will receive a Sham stimulation (inefficient probe) applied over the cerebellum.

    Participants will receive a real continuous theta burst stimulation (cTBS) applied over the cerebellum.

    Outcomes

    Primary Outcome Measures

    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)

    Secondary Outcome Measures

    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
    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.
    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
    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
    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)

    Full Information

    First Posted
    March 20, 2018
    Last Updated
    March 27, 2018
    Sponsor
    Institut National de la Santé Et de la Recherche Médicale, France
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    1. Study Identification

    Unique Protocol Identification Number
    NCT03481491
    Brief Title
    Interactions Between Striatum and Cerebellum in ADCY5 and PRRT2 Dystonias
    Acronym
    AMEDYST
    Official Title
    Interactions Between Striatum and Cerebellum in ADCY5 and PRRT2 Dystonias
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2018
    Overall Recruitment Status
    Unknown status
    Study Start Date
    May 4, 2018 (Anticipated)
    Primary Completion Date
    July 3, 2021 (Anticipated)
    Study Completion Date
    July 3, 2022 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Institut National de la Santé Et de la Recherche Médicale, France

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    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
    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).

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Dystonia
    Keywords
    Cerebellum, Striatum, Human, fMRI, Transcranial magnetic stimulation, Genetic dystonia

    7. Study Design

    Primary Purpose
    Basic Science
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Masking
    Participant
    Masking Description
    Participants will be blinded to the TMS procedure (SHAM or real stimulation).
    Allocation
    Non-Randomized
    Enrollment
    104 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Sham cerebellar stimulation
    Arm Type
    Sham Comparator
    Arm Description
    Participants will receive a Sham stimulation (inefficient probe) applied over the cerebellum.
    Arm Title
    Real cerebellar stimulation
    Arm Type
    Active Comparator
    Arm Description
    Participants will receive a real continuous theta burst stimulation (cTBS) applied over the cerebellum.
    Intervention Type
    Other
    Intervention Name(s)
    transcranial magnetic stimulation of the cerebellum
    Intervention Description
    The intervention will consist in a continuous theta burst stimulation of the cerebellum under neuronavigation.
    Primary Outcome Measure Information:
    Title
    Resting state functional connectivity between the cerebellum and the striatum
    Description
    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)
    Time Frame
    6 weeks
    Secondary Outcome Measure Information:
    Title
    Amplitude of Low Frequency Fluctuation (ALFF) of blood oxygen level-dependent signal in the cerebellum
    Description
    ALFF of Blood oxygen level-dependent signal in the cerebellum will be compared between the 3 groups (healthy controls, ADCY5 patients, PRTT2 patients
    Time Frame
    6 weeks
    Title
    Fractional anisotropy (FA) of the cerebello-striatal tract
    Description
    FA of the disynaptic tract between the cerebellum and the striatum will be compared between the 3 groups.
    Time Frame
    1 day
    Title
    Creatine concentration in the striatum measured with diffusion weighted spectroscopy.
    Description
    Creatine concentration in the striatum measured from the spectroscopy, will be compared between the 3 groups
    Time Frame
    6 weeks
    Title
    Amplitude of Low Frequency Fluctuation (ALFF) of blood oxygen level-dependent signal in the striatum
    Description
    ALFF of Blood oxygen level-dependent signal in the striatum will be compared between the 3 groups (healthy controls, ADCY5 patients, PRTT2 patients
    Time Frame
    6 weeks
    Title
    Resting state functional connectivity between the cerebellum and the thalamus
    Description
    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)
    Time Frame
    6 weeks

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    183 Months
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    Eligibility Criteria
    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.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Emmanuel Flamand-Roze, MD, PhD
    Phone
    +33(0)142 16 27 48
    Email
    emmanuel.flamand-roze@psl.aphp.fr
    First Name & Middle Initial & Last Name or Official Title & Degree
    Karim Ammour
    Phone
    +33(0)144 23 60 67
    Email
    karim.ammour@inserm.fr

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    35058336
    Citation
    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.
    Results Reference
    derived

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    Interactions Between Striatum and Cerebellum in ADCY5 and PRRT2 Dystonias

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