Noninvasive Brain Stimulation for Mild Cognitive Impairment

Noninvasive Cortical Stimulation to Improve Memory in Mild Cognitive Impairment

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.

Study Overview

• Status: Completed
• Conditions: Cognitive Dysfunction; Mild Cognitive Impairment; Cognitive Decline; Memory Impairment; Memory Loss; Mild Neurocognitive Disorder; Mental Deterioration; Memory Decline
• Intervention / Treatment: Device: Active rTMS (Bilateral DLPFC); Device: Active rTMS (Bilateral LPC); Device: Placebo rTMS (Inactive)

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.

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • VA Palo Alto Health Care System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active repetitive transcranial magnetic stimulation (rTMS) (Bilateral DLPFC); One-third of participants will receive active rTMS to the right and left dorsolateral prefrontal cortex (DLPFC).	Device: Active rTMS (Bilateral DLPFC); 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).
Experimental: Active repetitive transcranial magnetic stimulation (rTMS) (Bilateral LPC); One-third of participants will receive active rTMS to the right and left lateral parietal cortex (LPC).	Device: Active rTMS (Bilateral LPC); 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).
Placebo Comparator: Placebo repetitive transcranial magnetic stimulation (rTMS) (Inactive); 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); 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Number of Words Correctly Recalled, List Learning, California Verbal Learning Test-II, Assessed 1 Week After Intervention and Adjusted for Baseline Performance	The California Verbal Learning Test, Second edition (CVLT-II) is a memory task that yields several indices of the ability to learn a list of semantically related words and remember the list after a delay interval. The target list ("List A") of the CVLT-II contains 16 words. There are 5 orally presented learning trials; each is followed by immediate recall of the words in any order. The total number of words correctly recalled on the 5 list-learning trials was computed (range = 0 to 80). Higher values represent a better outcome.	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Number of Words Correctly Recalled, List Learning, California Verbal Learning Test-II, Assessed 3 Months After Intervention and Adjusted for Baseline Performance	The California Verbal Learning Test, Second edition (CVLT-II) is a memory task that yields several indices of the ability to learn a list of semantically related words and remember the list after a delay interval. The target list ("List A") of the CVLT-II contains 16 words. There are 5 orally presented learning trials; each is followed by immediate recall of the words in any order. The total number of words correctly recalled on the 5 list-learning trials was computed (range = 0 to 80). Higher values represent a better outcome.	3 months after completing the 20-session intervention (acceptable window for assessment: 76-104 days after the final intervention session)
California Verbal Learning Test-II (CVLT-II) Semantic Clustering Score, 1 Week After Intervention and Adjusted for Baseline Performance	The California Verbal Learning Test, Second edition (CVLT-II) is a memory task that yields several indices of the ability to learn a list of 16 semantically related words and remember the list after a delay interval. There are 5 orally presented learning trials; each is followed by immediate recall of the words in any order. A measure of semantic clustering is calculated by a computer program. It is a measure of the participant's tendency to recall words in semantically organized clusters (e.g. the participant recalled "apple" and "orange" even though the two fruit words were not presented sequentially). The computer algorithm includes words recalled on Trials 1-5 and adjusts for the possibility that a semantic cluster occurred by chance. The range of CVLT-II Semantic Clustering Scores is -3 to 9. Higher values represent a better outcome.	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention.
Total Number of Words Correctly Recalled During the "Long Delay Free Recall" Component of the California Verbal Learning Test-II (CVLT-II), Assessed 1 Week After Intervention and Adjusted for Baseline Performance	The California Verbal Learning Test, Second edition (CVLT-II) is a memory task that yields several indices of the ability to learn a list of semantically related words and remember the list after a delay interval. The target list ("List A") of the CVLT-II contains 16 words. After 5 learning trials and a subsequent 20-minute delay filled with unrelated tests, the participant was asked to recall the 16-word target list of the CVLT-II again. The total number of words correctly recalled was computed (range = 0 to 16). Higher values represent a better outcome.	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention
Depressive Symptoms, as Measured by the Geriatric Depression Scale (GDS), Assessed 1 Week After Intervention and Adjusted for Baseline Performance	The 15-item Geriatric Depression Scale (GDS) was also used as an outcome measure. Five of the GDS items are oriented toward the absence of depressive symptoms (e.g., Do you feel full of energy?) and 10 are oriented toward current depressive symptoms (e.g., Do you often feel helpless?). The participant is asked to answer "yes" or "no" on the basis of how they have been feeling over the past week. The GDS total score ranges from 0 to 15. Lower values represent a better outcome.	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention.
Everyday Functional Outcomes, as Measured by the Everyday Cognition (ECog) Questionnaire (Participant Version) Completed 1 Week After Intervention	The Everyday Cognition (ECog) questionnaire is comprised of 39 items about the ability to perform everyday tasks. Each item relates to memory, language, visual-spatial, or executive function. Each item is rated on a scale from 1 to 4 (1 = better or no change…4 = consistently much worse compared to 10 years ago). For the Participant version of the ECog, the participant is asked to "Please rate your ability to perform certain everyday tasks now, as compared to your ability to do these same tasks 10 years ago." Total score range: 39-156. Higher values represent a worse outcome. The outcome score was adjusted for baseline.	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention
Everyday Functional Outcomes, as Measured by the Everyday Cognition Questionnaire (Informant /Study Partner Version) Completed 1 Week After Intervention	The Everyday Cognition (ECog) questionnaire is comprised of 39 items about the ability to perform everyday tasks. Each item relates to memory, language, visual-spatial, or executive function. Each item is rated on a scale from 1 to 4 (1 = better or no change…4 = consistently much worse compared to 10 years ago). For the Informant version of the ECog, the participant's study partner was asked to "Please rate the participant's ability to perform certain everyday tasks NOW, as compared to his/her ability to do these same tasks 10 years ago." Total score range: 39-156. Higher values represent a worse outcome. The outcome score was adjusted for baseline.	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention
Instrumental Activities of Daily Living (IADLs), as Measured by the Functional Assessment Questionnaire, Completed 1 Week After Intervention	Functional Assessment Questionnaire, completed by the study partner at end of treatment (1 week after intervention, adjusted for baseline). Each 10 item is rated on a scale from 0 to 3 (0 = Normal; 1 = Has difficulty, but does by self; 2 = Requires assistance; 3 = Dependent. Total score range: 0-30 (sum of 10 items). Interpretation: A total score of 9 (dependent in 3 or more activities) is the recommended cut-point for an indication of impaired function. Higher values represent a worse outcome.	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention.
Global Cognitive Function, as Measured by the Montreal Cognitive Assessment (MoCA), Assessed 1 Week After Intervention and Adjusted for Baseline	The Montreal Cognitive Assessment (MoCA) is a brief measure of global cognitive function. The total score has a range of 0 to 30; higher values represent a better outcome.	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention
Visuospatial Memory, as Measured by the Brief Visuospatial Memory Test-Revised (BVMT-R), assessed1 Week After Intervention and Adjusted for Baseline Performance	Brief Visuospatial Memory Test-Revised (BVMT-R) Trials 1-3 total recall raw score at end of treatment (1 week after intervention, adjusted for baseline); range: 0-36; higher values represent a better outcome	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention.
Language Function, as Measured by Category Fluency (CF), Assessed 1 Week After Intervention and Adjusted for Baseline Performance	Category Fluency is a measure of verbal fluency in which the participant is asked to generate different exemplars from a semantic category specified by the examiner. For example, if the examiner says, 'articles of clothing,' correct responses include exemplars such as, 'shirt,' 'tie,' or 'hat.' The participant is given one minute to say all the responses they can think of. The values reported reflect the total number of correct, unique responses produced. Higher values represent a better outcome.	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention.
Language Function, as Measured by 42-item Boston Naming Test (BNT), Assessed 1 Week After Intervention and Adjusted for Baseline Performance	The Boston Naming Test (BNT) assesses the ability to verbally name pictured objects. The subject is shown a series of line drawings and asked to name the object. The test items become progressively more difficult. (The 42 items are presented in order of decreasing frequency of the target word). The total number of correct responses can range from 0 to 42. Higher values represent a better outcome.	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention.
Visuoconstructional Function, as Measured by the Rey-Osterrieth Complex Figure (ROCF) Copy Score, assessed1 Week After Intervention and Adjusted for Baseline Performance.	Rey-Osterrieth Complex Figure (ROCF) Copy score at end of treatment (1 week after intervention, adjusted for baseline); range: 0-36; higher values represent a better outcome	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention.
Speed of Processing and Executive Function, as Measured by Trail Making Part B, Assessed 1 Week After Intervention and Adjusted for Baseline Performance	In the Trail Making Part B test, the response form has a series of 25 circles; each circle contains a number or a letter. The participant is asked to connect the circles in order by alternating between the numbers and letters. The maximum time allowed is 300 seconds. Trails B is thought to require executive skills as well as processing speed. The Trail Making B seconds-to-complete scores were log transformed because the distribution of scores was positively skewed. We also reverse scored the log scores so that higher values would indicate a better outcome. To reverse the log scores, we used the formula: reverse score = max(x) + 1 - x, where max(x) is the natural log of 300 or 5.70378. For example, if a participant's time-to-complete score was 74 seconds, the natural log transformed score was 4.304. Reverse scoring yields a value of 2.4 (2.4 = 5.70378 + 1 - 4.304). The reverse-scaled, log transformed seconds-to-complete scores were used in all statistical analyses.	1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention.
Attention, as Measured by the Attentional Network Task (ANT), Assessed 1 Week After Intervention and Adjusted for Baseline Performance	Attentional Network Task(ANT) correct reaction time, as measured by the ANT computerized test	planned: 1 week after completing the 20-session intervention, which was typically 4 weeks after starting the 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).	planned: 1 week after completing the 20-session intervention, which was typically 4 weeks after starting the intervention.
Pre-post Change in Peripheral Levels of Brain-derived Neurotrophic Factor (BDNF)	Brain-derived Neurotrophic Factor (BDNF) plasma levels were measured from blood samples that were collected during the first session and the last session of TMS intervention, after a minimum of 4 hours of fasting. Higher change scores represent a better outcome.	First Intervention session to Last Intervention session. The average time frame from the first to the 20th and last session is 18 days.

Collaborators and Investigators

• Sponsor: Palo Alto Veterans Institute for Research
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Joy L Taylor, Ph.D., Stanford/VA Aging Clinical Center

Publications and helpful links

General Publications

• Liao X, Li G, Wang A, Liu T, Feng S, Guo Z, Tang Q, Jin Y, Xing G, McClure MA, Chen H, He B, Liu H, Mu Q. Repetitive Transcranial Magnetic Stimulation as an Alternative Therapy for Cognitive Impairment in Alzheimer's Disease: A Meta-Analysis. J Alzheimers Dis. 2015;48(2):463-72. doi: 10.3233/JAD-150346.
• Taylor JL, Hambro BC, Strossman ND, Bhatt P, Hernandez B, Ashford JW, Cheng JJ, Iv M, Adamson MM, Lazzeroni LC, McNerney MW. The effects of repetitive transcranial magnetic stimulation in older adults with mild cognitive impairment: a protocol for a randomized, controlled three-arm trial. BMC Neurol. 2019 Dec 16;19(1):326. doi: 10.1186/s12883-019-1552-7.

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2018
• Primary Completion (Actual): December 19, 2022
• Study Completion (Actual): March 28, 2023

Study Registration Dates

• First Submitted: September 18, 2017
• First Submitted That Met QC Criteria: November 2, 2017
• First Posted (Actual): November 6, 2017

Study Record Updates

• Last Update Posted (Estimated): September 3, 2025
• Last Update Submitted That Met QC Criteria: August 13, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: mild cognitive impairment; noninvasive brain stimulation; non-pharmacological; transcranial magnetic stimulation; tms; rtms
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Neurobehavioral Manifestations; Cognition Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Cognitive Dysfunction; Neurocognitive Disorders; Memory Disorders
• Other Study ID Numbers: TAY0003AGG; R01AG055526 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No