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Noninvasive Brain Stimulation for Mild Cognitive Impairment

Primary Purpose

Mild Cognitive Impairment, Mild Neurocognitive Disorder, Cognitive Decline

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Active rTMS (Bilateral DLPFC)

Active rTMS (Bilateral LPC)

Placebo rTMS (Inactive)

About this trial

This is an interventional treatment trial for Mild Cognitive Impairment focused on measuring mild cognitive impairment, tms, rtms, transcranial magnetic stimulation, noninvasive brain stimulation, non-pharmacological

Eligibility Criteria

55 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

VA Palo Alto Health Care System

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Arm Label

Active rTMS (Bilateral DLPFC)

Active rTMS (Bilateral LPC)

Placebo rTMS (Inactive)

Arm Description

One-third of participants will receive active rTMS to the right and left dorsolateral prefrontal cortex (DLPFC).

One-third of participants will receive active rTMS to the right and left lateral parietal cortex (LPC).

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.

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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)

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)

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)

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)

Change from Baseline in CVLT-II Semantic clustering

CVLT-II Semantic clustering (chance-adjusted) Trials 1-5

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)

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)

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)

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)

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)

Change from Baseline in speed of processing, as measured by Trail making

Trail making time to complete

Change from Baseline in attention, as measured by the Attentional Network Test (ANT)

ANT correct reaction time

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).

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.

Full Information

NCT ID

NCT03331796

First Posted

September 18, 2017

Last Updated

May 24, 2023

Sponsor

Palo Alto Veterans Institute for Research

Collaborators

National Institute on Aging (NIA)

1. Study Identification

Unique Protocol Identification Number

NCT03331796

Brief Title

Noninvasive Brain Stimulation for Mild Cognitive Impairment

Official Title

Noninvasive Cortical Stimulation to Improve Memory in Mild Cognitive Impairment

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Completed

Study Start Date

May 16, 2018 (Actual)

Primary Completion Date

December 19, 2022 (Actual)

Study Completion Date

March 28, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Palo Alto Veterans Institute for Research

Collaborators

National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Product Manufactured in and Exported from the U.S.

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

mild cognitive impairment, tms, rtms, transcranial magnetic stimulation, noninvasive brain stimulation, non-pharmacological

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

40 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Active rTMS (Bilateral DLPFC)

Arm Type

Experimental

Arm Description

One-third of participants will receive active rTMS to the right and left dorsolateral prefrontal cortex (DLPFC).

Arm Title

Active rTMS (Bilateral LPC)

Arm Type

Experimental

Arm Description

One-third of participants will receive active rTMS to the right and left lateral parietal cortex (LPC).

Arm Title

Placebo rTMS (Inactive)

Arm Type

Placebo Comparator

Arm Description

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.

Intervention Type

Device

Intervention Name(s)

Active rTMS (Bilateral DLPFC)

Intervention Description

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).

Intervention Type

Device

Intervention Name(s)

Active rTMS (Bilateral LPC)

Intervention Description

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).

Intervention Type

Device

Intervention Name(s)

Placebo rTMS (Inactive)

Intervention Description

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).

Primary Outcome Measure Information:

Title

Change from Baseline in memory score, as measured by the California Verbal Learning Test-II (CVLT-II)

Description

CVLT-II Trials 1-5 Total raw score (range: 0-80; higher values represent a better outcome)

Time Frame

Baseline, 1 week after completing the 20-session intervention

Secondary Outcome Measure Information:

Title

Change from Baseline in memory score, as measured by the California Verbal Learning Test (CVLT-II) Trials 1-5 Total raw score

Description

CVLT-II Trials 1-5 Total raw score (range: 0-80; higher values represent a better outcome)

Time Frame