Exploit the Functional Higher Neural Connectivity and Electrophysiological Intervention of Freezing of Gait in PD and PSP During Different Ambulatory Complexities

Study Overview
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Brief Summary
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In the current proposal, investigators will investigate three crucial issues of FOG. Firstly, investigators will identify the possible source(s) of FOG in PD and PSP patients during unconstrained walking using a 64-channel ambulatory recorder. The investigators will explore the electric neural sources of FOG and brain connectivity. Secondarily, fMRI during motor imagery will be performed to examine the brain regions involved in the FOG patients. The investigators will merge the electrophysiological and imaging findings to detect the possible neurovascular coupling or uncoupling. Thirdly, electric intervention with transcranial direct current stimulation (tDCS) will be conducted to see whether the FOG situation can be ameliorated in PD and PSP patients. The investigators will deliver a 5-day session of tDCS to the leg motor cortex of the FOG patients to examine whether the intervention will benefit the patients in a double blind randomized design. Six assessments with different combinations of clinical scaling, gait analysis, electrophysiological investigation and fMRI examinations before and after tDCS will be conducted. Besides, there is no long-term cohort investigation of tDCS on neurodegenerative patients with FOG. The investigators will have a 3-year follow-up with a 1-month interval open-label stimulation paradigm for the patients who remained voluntarily after the termination of the initial short-term trials.

Detailed Description
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The main goal of the first part of the 3-year project is to identify the source(s) of FOG with electrophysiological recording. The investigators will conduct concomitant high density Electroencephalographic and leg electromyographic recording to investigate subjects with and without FOG under unrestrained walking in the gait laboratory. The acquisitive signals from 64 montages will be decomposed first by independent component analysis (ICA) for further source localization of FOG. The event (FOG) related synchronization and desynchronization of different frequency bands of EEG will also be investigated to understand the neurophysiological implications of brain wave oscillations for the generation of FOG. In addition, the cerebello-thalamo-cortical pathway function will be assessed with magnetic paired associative stimulation in patients to probe the role of cerebellum in the pathogenesis of FOG. In the second part of the project, fMRI study will be adopted by having the subjects perform video-guided motor imagery of simple and complex walking situations. Block design paradigms will be delivered for signal acquisition. The signals will be analyzed by ICA before further processing for activation analysis. The connectivity map will beoverlaid with that of electric recording to examine the neurovascular coupling or uncoupling. In the third part of the project, investigators will deliver a 5-day session of transcranial direct current stimulation (tDCS) to the leg motor cortex of the FOG patients to examine whether the intervention will benefit the patients in a doubleblind randomized cross-over design.

Official Title
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Exploit the Functional Higher Neural Connectivity and Electrophysiological Intervention of Freezing of Gait in Parkinson's Disease and Supranuclear Palsy During Different Ambulatory Complexities

Conditions
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Transcranial Direct Current Stimulation

Intervention / Treatment
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* Device: Transcranial direct current stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients meet the diagnosis of PD or PSP based on the established consensus criteria Exclusion Criteria: Impairment of cognition that leads unable to fully cooperate with the oral commands during examinations Functional III or above congestive heart failure, or cancer with distant metastasis Hoehn and Yahr stage 5 in PD or PSP

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 85 Years

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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: real tDCS<br>In transcranial direct current stimulation, the anodal pad was tapped over the primary motor cortex and the cathode pad was adhered of the contralateral frontal region. A constant current of 2.0 mA will be apply for up to 20 mins. | Device: Transcranial direct current stimulation<br>* A consecutive 5-days course of tDCS will be delivered. In treatment group, true stimulation will be administrated and sham stimulation will be delivered in control group.<br>|
| Sham Comparator: sham tDCS<br>In transcranial direct current stimulation, the sham stimulation will be 30s stimulation with ramp up and ramp off for 10s at 2.0 mA. | Device: Transcranial direct current stimulation<br>* A consecutive 5-days course of tDCS will be delivered. In treatment group, true stimulation will be administrated and sham stimulation will be delivered in control group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Electroencephalogram recording before and after the tDCS session | Gait recording by 64 channels EEG device. Four different frequency bands ( theta, alpha, beta, and gamma) will be investigated. Variables in gait analysis: 1.Gait initiation, 2.Level walking, 3.Gait termination. | baseline / 2 days, 2 and 4 weeks after the end of the tDCS session | 
| Electromyography recording before and after the tDCS session | The 4 pairs of leg EMG recording during 50 meters walking. The EMG signals will be filtered with a band pass ranging from 0.05 to 70 Hz. Variables in gait analysis: 1.Gait initiation, 2.Level walking, 3.Gait termination. | baseline / 2 days, 2 and 4 weeks after the end of the tDCS session | 
| Functional magnetic resonance images examination before and after the tDCS session | fMRI scan will be performed on a 3.0T MR imager to detect the brain BOLD signal change in FOG. When fMRI was conducted, four different video tapes will be presented to the subjects：1.normal walking, 2.normal turning, 3.FOG during forward straight walking and 4.FOG during turning. | baseline / 2 days after the end of the tDCS session | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Unified Parkinson's Disease Rating Scale (UPDRS) Part III before and after the tDCS session | UPDRS contains four parts, the third part of which is reported in this outcome. Part III is clinician-scored monitored motor evaluation (14 questions, ranges from 0=normal to 4= Severe). The scoring of Part III varies between 0-56. The higher score indicates the worse motor function. Negative change from baseline values indicate improvement. | baseline / 2 days, 2 and 4 weeks after the end of the tDCS session | 
| Change in Progressive Supranuclear Palsy Rating Scale (PSPRS) | PSPRS is composed of 28 questions, divided into 6 parts: History, Mentation, Bulbar, Ocular, Limb and Gait. The scores are weighted sums of the questions in each section. Scores range from 0-100 (higher scores = more disability, lower scores = less disability). Negative change from baseline values indicate improvement. | baseline / 2 days, 2 and 4 weeks after the end of the tDCS session |