Mild Cognitive Impairment, Parkinson Disease
Conditions
Keywords
Transcranial Magnetic Stimulation, Theta Burst Stimulation, Parkinson's Disease, Cognitive Impairment, Neuromodulation
Brief summary
The goal of this study is to determine the whether a short-term, high-dose form of non-invasive brain stimulation (intermittent theta burst stimulation; iTBS) is a promising and safe treatment for mild cognitive impairment in Parkinson's disease (PD-MCI).
Detailed description
Dementia occurs in 80% of people with Parkinson's disease (PD) within 20 years of diagnosis. Cognitive interventions in PD have centered on individuals with mild cognitive impairment (PD-MCI). A lack of efficacy of pharmacological interventions in PD-MCI has driven interest in nonpharmacological approaches. The most promising of these is intermittent theta burst stimulation (iTBS), a noninvasive brain stimulation method that is FDA-approved for several psychiatric conditions. Though iTBS has shown little to no benefit in PD-MCI thus far, there are modifiable issues with past interventions including exclusively targeting prefrontal cortex when cholinergic denervation in posterior cortex is strongly associated with cognitive decline in PD, and substantial underdosing compared to efficacious iTBS interventions (6,000 vs at least 18,000 pulses). Interventions will likely have better outcomes if they target the right superior parietal lobule (rSPL), a cortical region impacted by cholinergic denervation in PD that is essential to maintaining attention, and use accelerated iTBS (a-iTBS) to deliver a stimulation dose commensurate with FDA-approved protocols in a shorter timeframe. However, before the efficacy of such an intervention can be evaluated, it must be established as safe, tolerable and feasible in PD-MCI. This project therefore aims to evaluate the safety, tolerability and feasibility of a three-day a-iTBS intervention stimulating the rSPL with 18,000 total pulses.
Interventions
DEVICEAccelerated intermittent theta-burst stimulation (iTBS) rTMS to right superior parietal lobule (rSPL)
Participants in this single-arm study will receive a accelerated course of intermittent theta burst stimulation (iTBS) over superior parietal lobule, which is identified with MNI coordinates from past studies. The stimulation will be delivered using a MagVenture MagPro TMS System with a butterfly, active cooling coil at 120% of resting motor threshold. Each participant will complete 3 consecutive treatment days, undergoing10 rTMS sessions per day (600 pulses/session), totaling 18,000 pulses across the study. Safety, tolerability, adherence, and feasibility data will be collected for the intervention.
Sponsors
Medical University of South Carolina
National Institutes of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* 50-85 years of age * Diagnosis of Parkinson's disease based on UK Brain Bank diagnostic criteria * Parkinson's disease with mild cognitive impairment (PD-MCI) diagnosis per Movement Disorders Society Task Force Level II Diagnostic Criteria4 (i.e., scores ≥1.5 standard deviations below appropriate norms on 2 neuropsychological tests) as determined by a clinical neuropsychologist * Stable on Parkinson's disease medications for 30 days (not expected to change through the course of the treatment) * Has a caregiver willing and able to reliably complete a questionnaire focused on the participant's daily functioning
Exclusion criteria
* Claustrophobia or inability to lie supine in the scanner for an extended period of time * Barriers to making contact between the TMS coil and the skin (e.g. braids that cannot be removed) * Contraindications to MRI/TMS safety screening: This includes but is not limited to implanted medical devices (e.g., pacemakers), metallic objects or fragments, non-removable hair clips or piercings, and medications that reduce seizure threshold. * Individuals with a diagnosis of bipolar disorder, schizophrenia, and/or active substance abuse disorder. * History of significant or unstable condition/s or treatments for these condition/s that may impact cognition (as determined by the study investigators) such as significant cardiac (e.g. heart failure), infectious (e.g. HIV, urinary tract infection), or metabolic disease (e.g. labile diabetes), cancer (e.g. brain cancer, chemotherapy-induced cognitive impairment), developmental disorder (e.g. autism spectrum disorder, intellectual disability), or other neurologic disease (e.g. multiple sclerosis, moderate to severe brain injury, seizures). * History of a seizure disorder.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serious Adverse Events | Week 4, 5 minutes before and 5 minutes after stimulation sessions on Days 1-3 | Number of serious adverse events experienced by study participants caused by the iTBS protocol |
| Feasibility of the study protocol | Week 0 through completion of study (8 weeks) | Feasibility will be defined as the proportion of participants enrolled that complete all intervention procedures |
| Tolerability of TMS procedures | Week 4, 5 minutes before and 5 minutes after stimulation sessions on Days 1-3 | A questionnaire evaluating the presence and severity of commonly experienced side effects of TMS (i.e. headache, pain, scalp irritation, facial twitching, fatigue, fear/anxiety) within the past 24 hours and during stimulation. Ratings will be on a 6-point Likert scale from 0 (no symptoms) to 5 (severe symptoms). |
| Test-retest reliability of the Continuous Temporal Expectancy Test (CTET) | Week 0 (4 weeks pre-intervention) to Week 4, Day 1 (30 minutes prior to intervention) | The CTET is a tablet-administered measure designed to assess sustained attention and distractibility. Participants will be shown a grid with black and white squares on a tablet that rotate after either a longer duration (target stimulus; 1070ms) or a shorter duration (non-target stimulus; 800ms) and must press the screen when they identify a target stimulus. Participants will complete 10 one-minute trials. Half of the trials are performed without a distractor present, and the other half are performed with an audio-video distractor presented on an adjacent laptop screen. The primary outcome is the distractibility score, defined as the difference in latency (in ms) to identifying the target stimulus between distractor and non-distractor trials. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Continuous Temporal Expectancy Task (CTET) Distractibility Score | Week 4, Day 1 (30 minutes prior to intervention) to Week 4, Day 3 (15 minutes after intervention) to Week 8 (4 weeks post-intervention) | Change in CTET Distractibility Score (\[distraction trial latency in ms\] - \[non-distraction trial latency in ms\]). Higher scores indicate worse performance. |
| Change in NIH Toolbox Cognitive Battery (NIHTB-CB) Composite Scores | Week 4, Day 1 (30 minutes prior to intervention intervention) to Week 4, Day 3 (15 minutes after intervention) to Week 8 (4 weeks post-intervention) | The NIHTB-CB is a performance-based, iPad-administered suite of 7 tests that ascertain abilities in different cognitive domains (i.e. executive function, episodic memory, working memory, processing speed, language). It was developed using advanced psychometric techniques to minimize measurement error and produces normed subtest and composite scores. We will use the fully-corrected T-score (range T=0-100; Mean T=50, SD=10; higher scores indicating better cognition) of the Fluid Cognition Composite and Crystallized Cognition Composite, which are normed for age, sex, years of education, and race/ethnicity. |
| Change in daily functioning | Week 0 (1 month pre-intervention) to Week 8 (1 month post-intervention) | Change in caregiver ratings on the ECog-12, a questionnaire designed to measure the participant's everyday cognition and functional decline based on 12 Likert scale items ranging from 1 (no change compared to 10 years earlier) to 4 (consistently much worse). |
| Change in Beck Depression Inventory II (BDI-II) Raw Score | Week 4, Day 1 (pre-intervention) to Week 8 (1 month post-intervention) | The Beck Depression Inventory II (BDI-II) is a self-report measure of depressive symptoms comprised of 21 questions rated on a Likert scale from 0 (least severe) to 3 (most severe). |
| Change in Beck Anxiety Inventory (BAI) Score | Week 1, Day 1 (pre-intervention) to Week 8 (one-month follow-up) | The Beck Anxiety Inventory (BAI) is a self-report measure of depressive symptoms comprised of 21 questions rated on a Likert scale from 0 (least severe) to 3 (most severe). |
| Change in Apathy Evaluation Scale (AES) Raw Score | Week 4, Day 1 (pre-intervention) to Week 8 (1-month post-intervention) | The Apathy Evaluation Scale is a self-report measure of apathy symptoms comprised of 18 Likert scale items rated from 0 (least severe) to 3 (most severe). |
Countries
United States
Outcome results
None listed