Trial document




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  DRKS00017021

Trial Description

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Title

Comparing examination of the effect of transcranial direct current stimulation (tDCS) of genetically defined ataxias and in a mouse model.

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Trial Acronym

CBI-SCA6

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URL of the Trial

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Brief Summary in Lay Language

Difficulties with motor coordination that occur in disorders of the cerebellum are called ataxias. Ataxia is a common neurological symptom with challenging effects on daily life. The causes of ataxias are heterogenous, and the possibilities of treatment are limited. There is an urgent need for new treatment methods. A fundamental pathogenic principle of ataxias is the change of electrical activity within the cerebellum. This is a possible target for future treatments. Non-invasive, i.e. external, stimulation methods of the brain, such as transcranial direct current stimulation (tDCS), can change the activity of brain cells in the long term. In tDCS a weak direct current is applied over a distinct brain area, e.g. the cerebellum. A reduction of motor problems after stroke has been achieved following stimulation of the cerebrum. Concerning a stimulation of the cerebellum, yet only single results exist that show an improvement of motor learning in healthy subjects. The transferability of them onto patients with cerebellar disorders has not been resolved so far. The application of tDCS in treatment of cerebellar diseases presumes a detailed knowledge of the effects of tDCS on the healthy and sickened cerebellum. This is where the present project sets in. Cooperating partners at the chair of General Zoology and Neurobiology of the Ruhr-University Bochum study a mouse model of spinocerebellar ataxia type 6 (SCA6), a hereditary ataxia, while we examine patients with SCA6 in our own project. We investigate if an optimized stimulation protocol, derived from former studies of our group, improves known problems in patients with SCA6 and if these effects outlast the time of the stimulation. Effects on the electrical activity of the cerebellum are studied using Cerebellar Brain Inhibition (CBI), a measure for the strength of the natural regulation of the cerebrum by the cerebellum. It is generated by paired magnetic impulses (by transcranial magnet stimulation; TMS) over the cerebellum and the cerebrum and it is known to be reduced or not detectable at all in patients with SCA6. Behavioral effects are studied using classical eyeblink conditioning. It serves as a simple applicable model for motor learning and is markedly impaired in patients with SCA6. The tDCS effect on eyeblink conditioning or CBI could possibly serve as a predictor for the success of physiotherapeutic interventions in future studies.

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Brief Summary in Scientific Language

Deficits in motor coordination that occur in cerebellar ataxias are a common neurological symptom with challenging effects on functions of daily life. The aetiology of ataxias is heterogenous and the possibilities of therapy are limited. There is an urgent need for novel, innovative treatment methods. A fundamental pathogenic principle of ataxias is the change of excitability and activity within the cerebellar cortex. This is a possible target for future therapies. Non-invasive stimulation methods of the brain, such as transcranial direct current stimulation (tDCS), can change the excitability of neurons in the long term. In tDCS a weak direct current is applied over a distinct brain area, e.g. the cerebellum. A reduction of motor deficits after stroke has been achieved following stimulation of the cerebrum. Concerning a stimulation of the cerebellum, yet only single results exist that show an improvement of motor learning in healthy subjects. The transferability of them onto patients with cerebellar disorders has not been resolved so far. The application of tDCS in therapy of cerebellar diseases presumes a detailed knowledge of the effects of tDCS on the healthy and sickened cerebellum. This is where the present project sets in. Cooperating partners at the chair of General Zoology and Neurobiology of the Ruhr-University Bochum study a mouse model of spinocerebellar ataxia type 6 (SCA6), a hereditary ataxia with almost pure cerebellar affection, while we examine patients with SCA6 in our own project. We investigate if an optimized stimulation protocol, derived from former studies of our group, improves known physiological and functional deficits in patients with SCA6 and if these effects outlast the time of the stimulation. Physiological effects are studied using the so-called Cerebellar Brain Inhibition (CBI), a measure for the strength of the physiological regulation of the cerebrum by the cerebellum. It is generated by paired magnetic impulses (by transcranial magnet stimulation; TMS) over the cerebellum and the cerebrum and it is known to be reduced or not detectable at all in patients with SCA6. Functional effects are studied using classical eyeblink conditioning. It serves as a simple applicable model for motor learning and is markedly impaired in patients with SCA6. The individual tDCS effect on eyeblink conditioning or CBI could possibly serve as a predictive biomarker for the success of physiotherapeutic interventions in future studies.

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Do you plan to share individual participant data with other researchers?

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00017021
  •   2019/06/12
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  •   yes
  •   Approved
  •   15-6324-BO, Ethik-Kommission der Medizinischen Fakultät der Universität Duisburg-Essen
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Secondary IDs

  • [---]*
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Health Condition or Problem studied

  •   SCA6
  •   G11.2 -  Late-onset cerebellar ataxia
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Interventions/Observational Groups

  •   I. CBI

    Subjects:

    15 patients with genetically proven spinocerebellar ataxia type 6 (SCA6).

    Baseline measures:

    General medical and neurologic examination to exclude disorders other than SCA6 in patients.

    Intervention:

    Each patient receives cerebellar transcranial direct current stimulation (each one session on different days with cathodal, anodal or sham stimulation).
    Interval between sessions is at least 7 days, at most 10 days. The active electrode is placed over the right cerebellar hemisphere, the reference electrode is placed over the right buccinator muscle. Stimulation parameters: electrode size 25 cm², stimulation intensity 2 mA, stimulation duration 20 minutes, blinding by local application of von Emla Creme (lidocaine 2,5 % and prilocaine 2,5 %) at sites of electrode placement.

    Endpoints:

    Registration of excitability change of the motor cortex (CBI) elicited by double pulse TMS (of the primary motor cortex and associated cerebellär TMS). Hereby induced motor evoked potentials (MEP) are measured over the abductor digiti minimi muscle. 5 times 15 single and 5 times 15 double pulse MEPs are elicited immediately before and after tDCS as well as one and two hours after tDCS with 5 different intensities of TMS stimulation (-5, -10, -15, -20, und -25% below the brainstem threshold). Additionally, clinical parameters are taken before and after sessions using well established ataxia rating scales (Scale for the Assessment and Rating of Ataxia = SARA und SCA Functional Index = SCAFI).

    Statistics:

    A mixed model ANOVA with repeated measures for tDCS protocol, stimulation intensities and time course as well as the inter-subject-factor group (patients vs. controls) will be used as the primary test. Dependent variables will be the MEP-amplitude, SARA und SCAFI scores. Depending on significances in the ANOVA post hoc t-tests will be done.

    II. Classical conditioning of the eyeblink reflex

    Subjects:

    15 patients with genetically proven spinocerebellar ataxia type 6 (SCA6).

    Baseline measures:

    General medical and neurologic examination to exclude disorders other than SCA6 in patients.

    Intervention:

    Each subject runs through 3 sessions of approximately 2,5 hours each. A delay eyeblink reflex conditioning paradigm will be used according to well established protocols in our group. A tone serves as conditioned stimulus (CS), an air puff into the eye serves as unconditioned stimulus (US). The unconditioned reaction (UR) and the conditioned reaction (CR) will be recorded using surface EMG (EMG = electromyography). Application of 100 CS-US (acquisition) and 30 CS-alone (extinction) stimuli.
    Induction of neuroplasticity using excitatory anodal and inhibitory cathodal tDCS respective sham stimulation according to the protocol mentioned above on day 1. Registration of long-term effects on days 2 and 8.

    Endpoints:

    Registration of conditioning efficacy of the eyeblink reflex during tDCS. Additionally, clinical parameters are taken before and after sessions using well established ataxia rating scales (Scale for the Assessment and Rating of Ataxia = SARA und SCA Functional Index = SCAFI).

    Statistics:

    A mixed model ANOVA with repeated measures for time course on each examination day and between examination days 1, 2 and 8 as well as tDCS protocol and the inter-subject-factor group (patients vs. controls) will be used as the primary test. Dependent variables will be the CR incidence, SARA und SCAFI scores. Depending on significances in the ANOVA post hoc t-tests will be done.
  •   15 healthy and age-matched controls receive the same interventions as the patients in experiments I and II.

    Baseline measures:

    General medical and neurologic examination to exclude disorders in controls.

    Endpoints and statistics are the same as in patients (as described above).
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Characteristics

  •   Interventional
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  •   Non-randomized controlled trial
  •   Blinded
  •   assessor, data analyst
  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   II
  •   N/A
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Primary Outcome

Change of Cerebellar Brain Inhibition by application of cerebellar transcranial Direct Current Stimulation

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Secondary Outcome

1. Change of eyeblink conditioning by application of cerebellar tDCS
2. Correlation between disease duration and change of CBI
3. Correlation between ataxia severity (using ataxia-scores; SARA, ICARS, SCAFI) and change in CBI
4. Comparison with the mouse model of SCA6

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Planned
  •   2019/07/01
  •   30
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   99   Years
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Additional Inclusion Criteria

1. Written informed consent of the patient/paticipant
2. Minimum age: 18 years
3. Patients: Existence of a genetically secured SCA6
4. Sufficient knowledge of the German language to understand the written consent and the experimental instructions

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Exclusion Criteria

1. Healthy controls: Existence of a neurological (incl. epileptic seizures), psychiatric or severe orthopaedic disorders
2. SCA6 patients: Existence of neurological disorders other than SCA6 (incl. epileptic seizures), psychiatric or severe orthopaedic disorders
3. Drug oder alcohol abuse
4. Intake of centrally-acting drugs
5. Persons with consuming diseases or in bad general health condition
6. (Adult) persons that are not contractually capable and persons in regulatory or judical custody

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Addresses

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    • Klinik für Neurologie, Universitätsklinikum Essen
    • Ms.  Prof. Dr. med.  Dagmar  Timmann-Braun 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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    • Klinik für Neurologie, Universitätsklinikum Essen
    • Mr.  Dr. med.  Andreas  Gustafsson Thieme 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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    • Klinik für Neurologie, Universitätsklinikum Essen
    • Mr.  Dr. med.  Andreas  Gustafsson Thieme 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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Sources of Monetary or Material Support

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    • Mercur Research Center Ruhr
    • Huyssenallee 52-56
    • 45128  Essen
    • Germany
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    • Klinik für Neurologie, Universitätsklinikum Essen
    • Ms.  Prof. Dr. med.  Dagmar  Timmann-Braun 
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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Status

  •   Recruiting planned
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.