Neuromodulation of Memory in Aging (TMS-AD)

Adaptive Neuromodulation of Working Memory Networks in Aging and Dementia

The proposed research will use closed-loop transcranial magnetic stimulation (TMS) based on individualized brain networks to establish parameters that can reliably control brain states. This will be tested in healthy aging and mild cognitive impairment (MCI) cohorts. The investigators will study network activation and neural oscillatory mechanisms underlying the network that regulates working memory and then target this network using closed-loop TMS to the Prefrontal Cortex. Investigators will measure the impact of TMS on working memory performance and task-based neural activity. The project will use brain stimulation and network modeling techniques to enhance working memory in healthy older adults and MCI and will demonstrate the value of closed-loop, network-guided TMS for future clinical applications.

Study Overview

• Status: Recruiting
• Conditions: Mild Cognitive Impairment; MCI
• Intervention / Treatment: Device: Transcranial Magnetic Stimulation

Detailed Description

Dementia due to Alzheimer's disease (AD) is a leading public health concern in the US with enormous care costs and no effective pharmacotherapy despite multiple clinical trials. Multiple studies have shown mild cognitive impairment (MCI) to be a precursor risk for AD and to be more amenable to intervention. While preclinical studies have shown that directly modulating activity in the prefrontal cortex (PFC) using non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS), can modulate cognitive function in healthy older adults, there is little evidence of reliable efficacy in MCI.

The investigators posit three reasons for this lack of efficacy. First, there is no established means of estimating a reliable biomarker and unique dose-response relationship between TMS intensity and brain activity. Second, standard TMS protocols fail to capture the dynamic nature of cognitive states and the reaction of endogenous brain states to exogenous neuromodulation. Third, no studies using TMS in AD-related populations have accounted for the influence of cerebrovascular disease in the response to TMS. The investigators propose to address these shortcomings by using closed-loop TMS, based on individualized brain networks to establish parameters that can reliably control brain states during normal memory functioning in healthy aging and MCI.

To achieve this goal, the investigators will study network activation and neural oscillatory mechanisms underlying the network that regulates working memory (WM), a cognition function with a reliable prefrontal cortex (PFC) network characterization. The investigators will then target this network using closed-loop TMS to the PFC and measure the impact on WM performance and task-based neural activity. This approach uses concurrent TMS-fMRI to identify dose-response relationships in the working memory network. Next, the investigators apply novel closed-loop TMS to perturb this network using temporally-precise TMS-EEG. Lastly, the investigators will integrate information collected via fMRI and EEG into a single computational framework to model spatiotemporal dynamics of the global brain network and predict the success of the TMS-related response in our MCI cohort. The project will use cutting-edge brain stimulation and network modeling techniques to enhance WM in healthy older adults and MCI and will provide a demonstration of the value of closed-loop, network-guided TMS for future clinical applications.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Simon W Davis, PhD; Phone Number: 9196841243; Email: simon.davis@duke.edu
• Study Contact Backup: Name: Emily Finch, BA; Phone Number: 9196682842; Email: emily.finch@duke.edu

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Duke University Hospital
      • Contact: Simon Davis, PhD; Phone Number: 919-668-0437; Email: simon.davis@duke.edu
      • Contact: Emily Finch, BS; Phone Number: 9196682299; Email: emily.finch@duke.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• English Speaking
• Willing to provide consent

Exclusion Criteria:

• History of any Axis I DSM-V disorder, excluding major depressive disorder or generalized anxiety disorders
• Current history of substance abuse or dependence (excluding nicotine)
• Intracranial implants (e.g. aneurysms clips, shunts, stimulators, cochlear implants, or electrodes), cardiac pacemakers, or vagus Nerve stimulation device
• Increased risk of seizure for any reason, including prior diagnosis of epilepsy, seizure disorder, increased intracranial pressure, or history of significant head trauma with loss of consciousness for ≥ 5 minutes.
• Neurological disorder including, but not limited to: space occupying brain lesion; any history of seizures, history of cerebrovascular accident; fainting, cerebral aneurysm, Dementia, Hungtington chorea; Multiple Sclerosis.
• Current use of medications known to lower the seizure threshold and/or affect working memory

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TMS-Randomized; Three different closed-loop conditions will be tested, each triggered by the presence of a sustained period of alpha-band power. In the first condition, arrhythmic TMS trains with a stochastic (randomized) inter-pulse interval, will be used to disrupt cortical alpha oscillations and thus be expected to enhance memory performance.	Device: Transcranial Magnetic Stimulation; Transcranial magnetic stimulation (TMS) is a noninvasive procedure that uses magnetic fields to stimulate nerve cells in the brain to improve a variety of cognitive conditions, and to probe the dynamics of normal brain function.; Other Names: TMS rTMS
Experimental: TMS-Ordered; Three different closed-loop conditions will be tested, each triggered by the presence of a sustained period of alpha-band power. In the second condition, rhythmic (ordered) alpha-frequency TMS trains, with the expectation that this alpha stimulation will further entrain a synchronization during the task and thereby worsen memory performance.	Device: Transcranial Magnetic Stimulation; Transcranial magnetic stimulation (TMS) is a noninvasive procedure that uses magnetic fields to stimulate nerve cells in the brain to improve a variety of cognitive conditions, and to probe the dynamics of normal brain function.; Other Names: TMS rTMS
Sham Comparator: TMS-Sham; Three different closed-loop conditions will be tested, each triggered by the presence of a sustained period of alpha-band power. In a third condition, sham stimulation will be delivered at the same randomized inter-pulse interval, but with no TMS delivered to the brain.	Device: Transcranial Magnetic Stimulation; Transcranial magnetic stimulation (TMS) is a noninvasive procedure that uses magnetic fields to stimulate nerve cells in the brain to improve a variety of cognitive conditions, and to probe the dynamics of normal brain function.; Other Names: TMS rTMS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Working Memory Task	The difference in memory accuracy between TMS conditions (random vs. ordered vs. sham stimulation) on a working memory task. Each trial of the task consists of stimulus presentation of an array of letters, a delay period in which subjects alphabetize the letters, and probe period where subjects indicate whether the number corresponds to the alphabetized position of the letter probe presented. Memory is subsequently assessed as a function of TMS condition.	Collected during TMS-EEG (Day 4)
Functional network connectivity	Functional network connectivity/activity is estimated by comparing the hemodynamic time courses of two or more regions of the brain. The correlation between the time courses of each pair of regions is termed functional network connectivity. The Working Memory Network (WMN) is identified by comparing fMRI-based functional network connectivity for high vs low working memory load (e.g., remembering 4 versus 3 items).	Collected during the initial neuroimaging session (Day 2)
Vascular density (VAD)	This measure of neurovascular brain health, vascular density (VAD), as estimated by an automated method of segmenting veins with a magnetic resonance imaging (MRI) sequence known as susceptibility weighted imaging. This measure can be used to estimate the dilation of cerebral veins, and therefore VAD.	Collected during the second neuroimaging session (Day 3)
EEG-based connectivity	EEG data will be source reconstructed to a fine-grained grid and timecourses of the solution points are averaged per region and per subject. The imaginary part of the coherence (iCoh) of averaged EEG source signals will be assessed within the alpha and theta frequency bands to build EEG-based connectivity matrices ("connectomes") for alpha- and theta-based connectivity, for each subject.	Collected during TMS-EEG (Day 4)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montreal Cognitive Assessment (MoCA)	The MoCA was designed as a rapid screening instrument for mild cognitive dysfunction. This widespread tool is used to assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. The principle outcome measure is a summary score combining performance on each subtest. Scores range from 0 to 30. A higher score indicates intact cognitive functions.	Collected during the initial screening visit (Day 1)
National Institutes of Health (NIH) Toolbox Cognitive Battery	The primary outcome measure of the NIH Toolbox is a Crystallized or Fluid Intelligence score. Fluid intelligence involves comprehension, reasoning and problem solving, while crystallized intelligence involves recalling stored knowledge and past experiences. These scores are normalized and scaled to reflect a 1-100 range. Higher scores indicate better performance.	Collected during the initial screening visit (Day 1)
Hopkins Verbal Learning Test (HVLT-2)	The Hopkins Verbal Learning Test (HVLT-R) consists of memorization of a list of words to test the ability to recall immediately after memorization (immediate recall) and after a 20-minute delay (delayed recall). These scores are normalized to reflect a 1-100 percentile range. Higher scores indicate better performance.	Collected during the initial screening visit (Day 1)
Brief Visuospatial Memory Test (BVMT-R)	The BVMT-R is a commonly used assessment tool to measure visuospatial learning and memory. A visual display of six simple figures arranged in a 2 × 3 matrix is shown to participants for three consecutive 10-second trials. Scoring of the immediate and delayed recall as well as copy trials are based on the accuracy of the drawings and the location of the figures. These scores are normalized to reflect a 1-100 percentile range. Higher scores indicate better performance.	Collected during the initial screening visit (Day 1)
Number Span Forwards/ Backwards	Span tests measure the ability of a subject to remember a series of numbers in forward or reverse order. These scores are normalized to reflect a 1-100 percentile range. Higher scores indicate better performance.	Collected during the initial screening visit (Day 1)
Category & Phonemic Verbal Fluency	Fluency tests measure the participant's ability to generate new exemplars for each categorical (e.g., farm animals) or phonemic (e.g., words starting with "b") prompts. The number of exemplars generated is recorded as the primary outcome for this test. These scores are normalized to reflect a 1-100 percentile range. Higher scores indicate better performance.	Collected during the initial screening visit (Day 1)
Trail Making Test	The purpose of the "Trails" test is to gauge the ability of the participant to trace paths between a series of letters and numbers on a sheet of paper, and can provide insights into a person's cognitive function based on how fast they can search, scan, and process visual information. These scores are normalized to reflect a 1-100 percentile range. Higher scores indicate better performance.	Collected during the initial screening visit (Day 1)

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Simon W Davis, PhD, Duke University; Principal Investigator: Andy Liu, MD, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2024
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: June 6, 2022
• First Submitted That Met QC Criteria: July 14, 2022
• First Posted (Actual): July 15, 2022

Study Record Updates

• Last Update Posted (Estimated): October 14, 2025
• Last Update Submitted That Met QC Criteria: October 9, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Memory; Transcranial Magnetic Stimulation; TMS
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Therapeutics; Magnetic Field Therapy; Transcranial Magnetic Stimulation
• Other Study ID Numbers: Pro00110872

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.: Yes