Repetitive Transcranial Magnetic Stimulation (TMS) for Progressive Supranuclear Palsy and Corticobasal Degeneration

Study Overview
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Brief Summary
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Drug therapy of atypical parkinsonism is generally considered either ineffective or minimal 1. Therefore, there is an urgent need to find alternative therapies to treat atypical parkinsonian disorders. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive tool that modulates cortical excitability with minimal discomfort and holds therapeutic promise in treating neurological and psychiatric disorders. The basal ganglia-thalamocortical circuits that are affected in Progressive Supranuclear Palsy (PSP) and Corticocbasal Ganglionic Degeneration (CBGD) are likely structurally and functionally segregated. The 'motor' circuit is implicated in parkinsonian akinesia and hypokinesia; a 'prefrontal' circuit is implicated in working memory and mood regulation, and linked with non-motor symptoms such as depression and apathy. In this proposal, we characterize motor and prefrontal network dysfunction in PSP and CBGD patients, and propose that high-frequency and low-frequency rTMS directed over separate motor and prefrontal cortical targets of each network may show specific and selective beneficial effects on motor vs. cognitive function in PSP and CBGD patients, respectively. Quantitative motor outcome measures include timed finger tapping tasks. Quantitative cognitive outcome measures comprise a visual analogue scale (VAS). If successful, this pilot study will provide proof of principle data to suggest potential benefits for rTMS in PSP/CBGD patients, and provide sufficient data and experience to support future PSP/CBGD studies that include the use of rTMS to investigate the pathophysiology of motor and non-motor features of PSP and CBGD patients.

Detailed Description
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Background: Drug therapy of atypical parkinsonism is generally ineffective or minimal, and novel therapy approaches for atypical parkinsonian disorders are needed. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive tool that modulates cortical excitability and holds promise in treating neurological/psychiatric disorders. The 'motor' basal ganglia-cortical circuit is implicated in parkinsonian akinesia and hypokinesia; a 'prefrontal' circuit is implicated in working memory (WM) and mood regulation, possibly linked to depression and apathy. Hypothesis: Motor deficits in Progressive Supranuclear Palsy (PSP) and Corticobasal Ganglionic Degeneration (CBGD) are associated with a dysfunctional motor network; emotional deficits in PSP/CBGD are associated with a dysfunctional prefrontal network. We hypothesize that high-frequency and low-frequency rTMS over cortical targets will selectively and specifically improve tasks and symptoms relevant to that target in PSP and CBGD patients, respectively. Aims: To contrast cortical excitability characteristics and motor and emotional function between PSP and CBGD patients. To determine selective and specific beneficial rTMS effects over primary motor (M1) and dorsolateral prefrontal (DLPFC) cortex on cortical excitability characteristics and motor and emotional function in PSP and CBGD patients. Design: Ten individuals with PSP and ten with CBGD will participate in a within-subject cross-sectional design. Motor outcome measures include a timed finger tapping task at comfortable and maximal speed. Quantitative cognitive outcome measures comprise a visual analogue scale of mood states (VAS). After a first baseline visit, PSP patients will receive high-frequency 5 Hz rTMS in two separate visits to two site conditions (left DLPFC vs. the more affected side of M1) across subjects with two within-session task conditions (motor vs. cognitive). They will also receive sham stimulation in a separate visit. These three stimulation visits will be randomized. CBGD patients will receive the same treatment with the only difference that they will receive low-frequency 1 Hz rTMS instead. Relevance: If successful, we will demonstrate a double-dissociation and causal functional significance between rTMS modulation of M1 in motor tasks and DLPFC in emotional function in PSP Vs. CBGD. Exploratory aims will be conducted. Sufficient data and experience for future PSP/CBGD intervention studies will help identify candidate TMS parameters that are optimal for given symptoms.

Official Title
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Noninvasive Cortical Stimulation (rTMS) for Motor and Non-Motor Features of Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD)

Conditions
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Progressive Supranuclear Palsy, Corticobasal Degeneration, Parkinsonism

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: If you are an adult with PSP or CBGD: 1. Must be in good physical health. If you are neurologically healthy volunteers: 1. Must be older than 35 years Exclusion Criteria: Must have no implanted metal. Dental fillings are acceptable. Must have no personal seizure or 1st degree relative with history of seizures Must not take any medication that lowers seizure threshold.

Ages Eligible for Study
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Minimum Age: 35 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| PSP patients<br>People that have been clinically diagnosed with atypical parkinsonism, i.e., PSP | |
| CBD patients<br>People that have been clinically diagnosed with atypical parkinsonism, i.e., CBD | |
| Age-matched healthy controls<br>People that have not been diagnosed with any kind of neurologic movement disorder. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cortical excitability (CE) measures expressed in motor evoked potentials (MEP) | We assess cortical excitability (CE) with motor evoked potentials (MEP) and cortical silent periods (CSP) before and after repetitive Transcranial Magnetic Stimulation (TMS). | 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| visual analog scale (VAS) | We assess mood with a visual analog scale (VAS) of 5 emotions and 1 overall feeling of well-being. | 2 min | 
| tapping speed | tapping speed (movement time and reaction time) will be measured | 5 min | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcranial magnetic stimulation, Cortical excitability, parkinsonism, Progressive Supranuclear Palsy, Corticobasal Degeneration, PSP, CBD, CBGD