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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)
Sponsored by
Palo Alto Veterans Institute for Research
About
Eligibility
Locations
Arms
Outcomes
Full info

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

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

First Posted
September 18, 2017
Last Updated
May 24, 2023
Sponsor
Palo Alto Veterans Institute for Research
Collaborators
National Institute on Aging (NIA)
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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
No
Studies a U.S. FDA-regulated Device Product
Yes
Product Manufactured in and Exported from the U.S.
No

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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
55 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joy L Taylor, Ph.D.
Organizational Affiliation
Stanford/VA Aging Clinical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
VA Palo Alto Health Care System
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
26402010
Citation
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.
Results Reference
background
PubMed Identifier
31842821
Citation
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.
Results Reference
derived

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Noninvasive Brain Stimulation for Mild Cognitive Impairment

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