Enhancement of Hippocampal Plasticity Using Repetitive Transcranial Magnetic Stimulation

The ultimate goal of this study is to develop non-invasive, painless repetitive transcranial magnetic stimulation (rTMS) protocols to prevent cognitive decline in patients with mild cognitive impairment (MCI) and cognitively normal individuals at high risk of developing Alzheimer's disease (AD). Currently, 1 in 9 adults over the age of 65 have AD, which currently totals more than 5 million Americans and this number is expected to rise as high as 16 million by 2050.

MCI is a clinical syndrome that represents the gray area between healthy aging and dementia. Those with amnestic MCI (aMCI) have memory problems more severe than normal for their age and education, but their symptoms are not as severe as those of people with AD. Patients with aMCI are at high risk for AD. Notably, roughly half of those with MCI will continue to progress and convert to clinical dementia within 3 years. Alternatively, it is also worthwhile to study cognitively healthy older adults who carry genes that may increase the risk of AD. The frequency of the human APOE gene ε4 allele increases in patients with AD and the ε4 allele is also associated with an earlier age of disease onset.

Currently, there are no known therapies that can effectively modify the progression and hallmark symptoms of AD. Therefore, it is crucial to provide an early intervention in patients with aMCI to delay or prevent the progression to AD.

More specifically, this project has two specific aims:

1. To plan personalized non-invasive brain stimulation location by brain Imaging with Magnetic Resonance Imaging (MRI) in Mild Cognitive Impairment (MCI)
2. To identify potential personalized cognitive enhancement strategy (such as dosage or patterns) of Transcranial Magnetic Stimulation (TMS) in MCI.

Techniques to artificially and precisely stimulate brain tissue are increasingly recognized as valuable tools both in clinical practice and in cognitive neuroscience studies among healthy individuals and people with clinical conditions. With these practices, researchers can safely stimulate specific regions of the brain to explore causal relationships that comprise the brain's circuitry and modulate behavior.

Study Overview

• Status: Completed
• Conditions: Mild Cognitive Impairment
• Intervention / Treatment: Device: TBS

Detailed Description

In total, 60 participants (50-85 years old) with MCI will be recruited to participate in this trial.

Participants will be asked to receive 30 intervention sessions for three different protocols (10 sessions for each). Before and after the interventions, MRI and Cognitive tasks will be utilized again as the outcome measurements. There is a one-month interval between each protocol. Each intervention will be around half hour to an hour and each outcome measurement will take another two hours.

Each block includes:

• MRI+ Memory pre-assessment (2 hours/session)
• TMS * 10 (10 sessions; 0.5 hours/session)
• MRI+ Memory post-assessment (2 hours/session) Participants will experience each of the three TMS protocols. The total time commitment across these sessions will be approximately 27 hours.

There will be another 2 testing sessions to evaluate intervention effects. They will be scheduled at the beginning, and 1 month after the end of the intervention sessions. All sessions will take place in the Biosciences Research Laboratories (BSLR) Building (1230 N. Cherry Ave., Tucson, AZ 85721). The schematic below outlines the components of the sessions.

The investigators will acquire the following data during components for primary outcome measures and secondary measures.

1) Brain imaging data 2) Neuropsychological data and demographic data 3) Cognitive tasks 4) Biological sample

• Study Type: Interventional
• Enrollment (Actual): 97
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • Bioscience Research Laboratory

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Individuals with mild cognitive impairment (MCI Group)

Inclusion Criteria:

• Age 50-85 years
• MCI clinical criteria: (a) typical comprehensive criteria (at least one cognitive test <= -1.5 SD), or (b) Jak/Bondi criteria (2 tests within the same domain <= -1SD or 3 tests total <= -1SD)
• Right handed
• English speaking
• Able to attend daily intervention (Monday-Friday) for 4 weeks
• Not enrolled in another interventional study within 6 months prior to beginning this study

Exclusion Criteria:

• Contraindications to transcranial magnetic stimulation (TMS) or magnetic resonance imaging (MRI)
• Other neurological disorders (e.g. stroke, head injuries, or multiple sclerosis)
• Current cancer treatment or other medical problems that might independently affect cognitive function

Cognitively Normal Individuals:

Inclusion Criteria:

• Age 50-85 years
• Right handed
• English speaking
• Able to attend daily intervention (Monday-Friday) for 4 weeks
• Not enrolled in another interventional study within 6 months prior to beginning this study

Exclusion Criteria:

• Contraindications to transcranial magnetic stimulation (TMS) or magnetic resonance imaging (MRI)
• Other neurological disorders (e.g. stroke, head injuries, or multiple sclerosis)
• Current cancer treatment or other medical problems that might independently affect cognitive function
• No dementia or impaired cognitive functioning, assessed using the NACC battery.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Excitatory TBS	Device: TBS; TMS is a non-invasive brain stimulation technique. The primary aim of the study will be to verify the deliverability of the TMS effect on the hippocampus and determine which stimulation protocol is more beneficial to each participant.; Other Names: Theta Burst Stimulation (TBS)
Experimental: Inhibitory TBS	Device: TBS; TMS is a non-invasive brain stimulation technique. The primary aim of the study will be to verify the deliverability of the TMS effect on the hippocampus and determine which stimulation protocol is more beneficial to each participant.; Other Names: Theta Burst Stimulation (TBS)
Placebo Comparator: Sham TBS	Device: TBS; TMS is a non-invasive brain stimulation technique. The primary aim of the study will be to verify the deliverability of the TMS effect on the hippocampus and determine which stimulation protocol is more beneficial to each participant.; Other Names: Theta Burst Stimulation (TBS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain imaging data	The investigators will acquire MRI images to measure structural and functional connectivity, respectively.	Baseline
Correction rate in memory association recall	Memory tasks will be implemented and measure the correct rate to assess memory function.	Baseline
NACC Neuropsychological batteries	The investigators will use Neuropsychological batteries, which would calculate the Z-score, for measuring cognitions. With Z-score, the investigators can classify participants into MCI or non-MCI group.	Baseline
Specimen sample	A specimen for DNA will be collected and determine whether participants have APOE genotype.	1 day (Only once in the beginning phase)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain imaging data	The investigators will acquire MRI images to measure structural and functional connectivity, respectively.	2 weeks after the intervention phase begin
Correction rate in memory association recall	Memory tasks will be implemented and measure the correct rate to assess memory function.	2 weeks after the intervention phase begin

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain imaging data	The investigators will acquire MRI images to measure structural and functional connectivity, respectively.	an average of 1 month
Brain imaging data	The investigators will acquire MRI images to measure structural and functional connectivity, respectively.	3 months after the intervention phase complete
NACC Neuropsychological batteries	The investigators will use Neuropsychological batteries, which would calculate the Z-score, for measuring cognitions function. With Z-score, the investigators can classify participants into MCI or non-MCI group.	an average of 1 month
NACC Neuropsychological batteries	The investigators will use Neuropsychological batteries, which would calculate the Z-score, for measuring cognitions. With Z-score, the investigators can classify participants into MCI or non-MCI group.	3 months after the intervention phase complete
Correction rate in memory association recall	Memory tasks will be implemented and measure the correct rate to assess memory function.	an average of 1 month
Correction rate in memory association recall	Memory tasks will be implemented and measure the correct rate to assess memory function.	3 months after the intervention phase complete

Collaborators and Investigators

• Sponsor: University of Arizona
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Ying-hui Chou, ScD, University of Arizona

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2020
• Primary Completion (Actual): September 24, 2025
• Study Completion (Actual): September 24, 2025

Study Registration Dates

• First Submitted: January 14, 2019
• First Submitted That Met QC Criteria: May 23, 2019
• First Posted (Actual): May 24, 2019

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 8, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Mild Cognitive Impairment; Transcranial Magnetic Stimulation
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction
• Other Study ID Numbers: 1812171968; R01AG062543 (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