Movement Diagnostic System: Quantitative diagnosis of patients with Parkinson's Disease, essential tremor and dystonia, a closed-loop approach with fMRI.

Rationale:

Essential tremor (ET), Parkinsonian tremor (PD-T) and limb dystonia (DYS) are ubiquitous and disabling. Diagnostic tools are limited, especially in early disease stages leading to a delay in targeted therapy. ET, PD-T and DYS are diseases of the central nervous system (CNS), with different pathological changes. Functional MRI (fMRI) combined with measures of movement including electromyography (EMG) allows to relate voluntary and involuntary movements directly to brain activity providing a promising diagnostic in movement disorders. Combination with a wrist perturbator, influencing motor and sensory inputs and outputs allows ‘closed-loop system identification’ and may further improve movement disorders diagnostics.



Objective:

Our goal is to develop and validate a Movement Diagnostic System (MDS) to accurately locate specific CNS pathological changes in ET, PD-T and DYS, with the use of fMRI and scanner compatible EMG, accelerometry, video, and wrist perturbator.
Study design: This is a pilot prospective cohort study. The study consists of Part A, outside the scanner, including a standardized neurological assessment with standardized rating scales and a measurement with wrist perturbator, EMG, accelerometry and electroencephalogram (EEG) followed by Part B the main experiment inside the scanner, including the MR-compatible devices with fMRI as a diagnostic tool. Before this visit, a first visit is scheduled during which the eligibility of the participants will be evaluated.



Study population:

Patient groups with ET, PD-T and DYS of twenty-five patients each, and twenty-five healthy subjects will be included. To test the feasibility and to optimize the measurement protocol we will first include five participants of each group, after which we will add 20 more participants to each of the four groups.



Main study parameters/endpoints:

Differentiation between ET, PD-T and DYS based on brain activations specifically related to involuntary movements. With external measures and perturbation of the closed sensorimotor loop during fMRI we expect to find involvement of the olivocerbellar networks in ET, the striatum in PD-T and a widespread involvement of basal ganglia, thalamus, and cerebral cortex in dystonia.



Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Participants will undergo one or two site visits. The first visit will take about 1 hour during which the eligibility of the participants will be evaluated by performing standardized clinical evaluations with the aid of an inclusion questionnaire and a short neurological examination. Preferably, this visit is planned after a regular hospital visit. Patients are requested to slowly reduce medication that suppresses the hyperkinetic symptoms prior to the second visit. During this visit, two consecutive experimental set-ups will be performed. In part A of the protocol, after clinical evaluation, participants will perform motor tasks while perturbation torques are applied to the subject’s wrist by a wrist perturbator. Recordings are made with surface EMG electrodes, kinematic sensors, and EEG electrodes. This will take up to 1½ hours including preparation. After an hour break we will continue with part B. In this stage, the severity of the symptoms is known and the perturbation protocol is tailored to the specific participants. Participants will perform motor tasks and perturbation torques are applied during fMRI measurement. Motor responses are measured with the same EMG electrodes and kinematic sensors as in part A. Participants will be in the scanner for one hour. The second visit will take approximately 3.5 hours in total, including one hour break.

Differentiation between ET, PD-T and DYS based on brain activations specifically related to involuntary movements. With external measures and perturbation of the closed sensorimotor loop during fMRI we expect to find involvement of the olivocerbellar networks in ET, the striatum in PD-T and a widespread involvement of basal ganglia, thalamus, and cerebral cortex in dystonia.

Participants will undergo one or two site visits. The first visit will take about 1 hour during which the eligibility of the participants will be evaluated by performing standardized clinical evaluations with the aid of inclusion questionnaire and a short neurological examination. Preferably, this visit is planned after a regular hospital visit.
During this visit, two consecutive experimental set-ups will be performed. In part A of the protocol, after clinical evaluation, participants will perform motor tasks while perturbation torques are applied to the subject’s wrist by a wrist manipulator. Recordings are made with surface EMG electrodes, kinematic sensors, and EEG electrodes. This will take up to 1½ hours including preparation. After an hour break we will continue with part B, where the entire experimental setup will be applied, including fMRI.

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