Noninvasive Brain Stimulation for Mild Cognitive Impairment

Study Overview
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Brief Summary
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The goal of this study is to test the efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) as a treatment for Mild Cognitive Impairment (MCI). Participants will be randomly assigned to one of three treatment groups: Group 1: Active Dorsolateral Prefrontal Cortex (DLPFC) rTMS; Group 2: Active Lateral Parietal Cortex (LPC) rTMS; and Group 3: Inactive rTMS (Placebo) control (evenly split between each coil location). Participation in the study takes approximately 7 ½ months-including a 2-to 4-week treatment phase (20 rTMS sessions) and a 6-month follow-up phase.

Detailed Description
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This study aims to test the efficacy of a non-pharmacological treatment for MCI that involves noninvasive brain stimulation (NIBS). Early studies in Alzheimer's disease (AD) dementia patients have found that repetitive transcranial magnetic stimulation (rTMS, a form of NIBS) improved global cognitive function and activities of daily living. Given that in AD, neuronal loss and synaptic dysfunction progress along brain networks, the results of these early studies of brain stimulation suggest there is sufficient neuroplasticity in AD for efficacious effects of brain stimulation. Of the very few rTMS studies in MCI that have been published, the effect size appears to be moderately large. However, it is not clear whether the dorsolateral prefrontal cortex (DLPFC), the stimulation site used in the most of the prior MCI/AD rTMS trials, is the optimal site for achieving the most efficacious effects including effects on episodic memory. Importantly, when other investigators used rTMS to stimulate a lateral parietal cortical (LPC) site in healthy young adults, significant effects of rTMS on memory were measureable weeks later. Moreover, functional connectivity of brain regions was selectively increased, including the posterior cingulate cortex (PCC), a hub of brain networks that is affected in amnestic MCI. Because stimulation of the DLPFC and the LPC may each have distinct effects, we designed this pilot trial to have two active rTMS treatment groups: DLPFC and LPC. A third group will receive inactive (placebo) rTMS to achieve a controlled, randomized, double-blind trial. For each of the three groups, stimulation will be bilateral, based on effects achieved in the AD studies. The primary hypothesis is that active rTMS (to either site of stimulation) will be superior to inactive (placebo) rTMS in improving memory. Measures of change in functional connectivity will be computed to examine whether there is evidence that rTMS changes connectivity of the PCC with other regions of the brain. In addition to looking at effects of rTMS on functional connectivity and cognition in relation to the cortical site stimulated, genetic markers will be collected toward addressing heterogeneity of response. To track the durability of rTMS effects on memory, participants will be followed longer than in any prior study (up to 6 months after the intervention). If this study finds rTMS improves memory in older adults with MCI, further clinical development of this non-pharmacological treatment could ultimately improve the lives of millions of older adults who have MCI and are at an increased risk of developing dementia.

Official Title
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Noninvasive Cortical Stimulation to Improve Memory in Mild Cognitive Impairment

Conditions
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Mild Cognitive Impairment, Mild Neurocognitive Disorder, Cognitive Decline, Mental Deterioration, Cognitive Dysfunction, Memory Decline, Memory Loss, Memory Impairment

Intervention / Treatment
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* Device: Active rTMS (Bilateral DLPFC)
* Device: Active rTMS (Bilateral LPC)
* Device: Placebo rTMS (Inactive)


Participation Criteria
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Eligibility Criteria
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Both Veterans and Non-Veterans may enroll if they meet the following criteria ** Inclusion Criteria: Diagnosed with amnestic Mild Cognitive Impairment (aMCI); Stable medications (including any dementia-related meds) for at least 4 weeks prior to Baseline; Geriatric Depression Scale score less than 6; Ability to obtain a motor threshold, determined during the screening process; Study partner available; living situation enables attendance at clinic visits; Visual and auditory acuity adequate for neuropsychological testing; Good general health with no diseases expected to interfere with the study; Participant is not pregnant or of childbearing potential (i.e. women must be 2 years post-menopausal or surgically sterile); Modified Hachinski Ischemic score less than or equal to 4; Agree to DNA extraction for single nucleotide polymorphism (SNP) genotyping; Able to understand study procedures and comply with them for the entire length of the study. Exclusion Criteria: Prior exposure to rTMS within the past 12 months; Magnetic field safety concern such as a cardiac pacemaker, cochlear implant, implanted device in the brain (deep brain stimulation), or metal fragments or foreign objects in the eyes, skin or body; Any significant neurological disease other than suspected incipient Alzheimer's disease; Unstable cardiac disease or recent (< 3 months previous) myocardial infarction. Any significant systemic illness or unstable medical condition that could lead to difficulty with protocol adherence; History of epilepsy or repetitive seizures, as determined by patient report or chart review; History of a medical condition or current use/abuse of medications and substances that increase the risk of a seizure, specifically: Traumatic brain injury within 2 months that would increase the risk for seizure; Unable to safely withdraw, at least 4 weeks prior to Baseline, from medications that substantially increase the risk of having seizures (for example: theophylline, clozapine, and methylphenidate). Current or past history of a mass lesion, cerebral infarct, or other noncognitive active neurological disease that would increase the risk for seizure. Stimulant abuse within the previous 90 days. Cocaine and abuse of amphetamine and methylphenidate are associated with an increased risk of seizures; Major depression or bipolar disorder (DSM-IV) within the past 1 year, or psychotic features within the last 3 months that could lead to difficulty with protocol adherence; Taking sedative hypnotics or medications with anti-cholinergic properties and unable to withdraw at least 4 weeks prior to Baseline; Current alcohol or substance abuse (not including caffeine or nicotine) within the past 1 year, as determined by chart review, participant or study partner report, or greater than moderate alcohol use defined by the Quantity-Frequency-Variability Index (Cahalan, Cisin, & Crossley, 1969); Any contraindications for magnetic resonance imaging (MRI) studies, e.g. severe claustrophobia, weight above 350 lb maximum allowed by MRI scanner, pregnancy; Participation in another concurrent clinical trial; Inability or unwillingness of individual or legal representative to give written informed consent.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active rTMS (Bilateral DLPFC)<br>One-third of participants will receive active rTMS to the right and left dorsolateral prefrontal cortex (DLPFC). | Device: Active rTMS (Bilateral DLPFC)<br>* TMS Stimulation Parameters for the active DLPFC rTMS intervention group will be: 10 Hz, 4-second train duration and 11-second inter-train interval. During each session, 2,000 pulses will be applied for each hemisphere (for a total of 4,000 pulses per session). Participants will receive 20 sessions (1 or 2 sessions per day, M-F).<br>|
| Experimental: Active rTMS (Bilateral LPC)<br>One-third of participants will receive active rTMS to the right and left lateral parietal cortex (LPC). | Device: Active rTMS (Bilateral LPC)<br>* TMS Stimulation Parameters for the active LPC rTMS intervention group will be: 10 Hz, 4-second train duration and 11-second inter-train interval. During each session, 2,000 pulses will be applied for each hemisphere (for a total of 4,000 pulses per session). Participants will receive 20 sessions (1 or 2 sessions per day, M-F).<br>|
| Placebo Comparator: Placebo rTMS (Inactive)<br>One-third of participants will receive placebo/inactive rTMS, either to the DLPFC or the LPC. Those receiving placebo rTMS will serve as the control group. | Device: Placebo rTMS (Inactive)<br>* For the Placebo rTMS (Inactive) group, the participant will wear scalp electrodes through which a low voltage, low electric current (2-20mA at no more than 100V) is passed to mimic the sensation of receiving actual rTMS. Participants will receive 20 sessions (1 or 2 sessions per day, M-F).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in memory score, as measured by the California Verbal Learning Test-II (CVLT-II) | CVLT-II Trials 1-5 Total raw score (range: 0-80; higher values represent a better outcome) | Baseline, 1 week after completing the 20-session intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in memory score, as measured by the California Verbal Learning Test (CVLT-II) Trials 1-5 Total raw score | CVLT-II Trials 1-5 Total raw score (range: 0-80; higher values represent a better outcome) | Baseline, 6 months after completing the 20-session intervention | 
| Change from Baseline in depressive symptoms, as measured by the Geriatric Depression Scale (GDS) | GDS Total score (range: 0-15; higher values represent a worse outcome) | Baseline, 6 months after completing the 20-session intervention | 
| Change from Baseline in everyday functional outcomes, as measured by the Everyday Cognition (ECog) Questionnaire | ECog Scale Total score (range: 39-156; higher values represent a worse outcome) | Baseline, 6 months after completing the 20-session intervention | 
| Change from Baseline in global cognition, as measured by the Montreal Cognitive Assessment (MoCA) | MoCA Total score (range: 0 to 30; higher values represent a better outcome) | Baseline, 6 months after completing the 20-session intervention | 
| Change from Baseline in CVLT-II Semantic clustering | CVLT-II Semantic clustering (chance-adjusted) Trials 1-5 | Baseline, 6 months after completing the 20-session intervention | 
| Change from Baseline in CVLT-II Short-delay free recall | CVLT-II Short-delay free recall correct (range: 0-16; higher values represent a better outcome) | Baseline, 6 months after completing the 20-session intervention | 
| Change from Baseline in visuospatial memory, as measured by the Brief Visuospatial Memory Test-Revised (BVMT-R) | BVMT-R Trials 1-3 Total raw score (range: 0-18; higher values represent a better outcome) | Baseline, 6 months after completing the 20-session intervention | 
| Change from Baseline in language function, as measured by Category Fluency (CF) | CF Total number of correct responses in 60 sec (higher values represent a better outcome) | Baseline, 6 months after completing the 20-session intervention | 
| Change from Baseline in language function, as measured by 42-item Boston Naming Test (BNT) | BNT Total number of correct responses (range: 0-42; higher values represent a better outcome) | Baseline, 6 months after completing the 20-session intervention | 
| Change from Baseline in visuoconstructional function, as measured by the Rey-Osterrieth Complex Figure (ROCF), Copy score | ROCF Copy score (range: 0-36; higher values represent a better outcome) | Baseline, 6 months after completing the 20-session intervention | 
| Change from Baseline in speed of processing, as measured by Trail making | Trail making time to complete | Baseline, 6 months after completing the 20-session intervention | 
| Change from Baseline in attention, as measured by the Attentional Network Test (ANT) | ANT correct reaction time | Baseline, 6 months after completing the 20-session intervention | 
| Change from Baseline in brain functional connectivity | Change from Baseline in Functional connectivity metrics (derived from the pre- and the post-intervention functional magnetic resonance imaging (fMRI) scans rs-fMRI scans) will be computed with respect to: connectivity within the Default Mode Network (DMN), and connectivity between the DMN and the Central Executive Network (CEN). | Baseline, 1 week after completing the 20-session intervention | 
| Change from Baseline in levels of brain-derived neurotrophic factor (BDNF) | Plasma levels of BDNF will be measured from fasting blood samples that are collected at the first and last intervention sessions. | First Intervention session, to Last Intervention session (The average time frame from the first to the 20th and final session is 18 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mild cognitive impairment, tms, rtms, transcranial magnetic stimulation, noninvasive brain stimulation, non-pharmacological