A Novel Multi-Modal Approach to Promote Functional Outcomes in Cognitively Frail Older Adults (TMS MRI TBS)

The goal of this clinical trial is to explore the effects of intermittent theta burst stimulation (iTBS) primed with theta burst stimulation (cTBS), on top of aerobic exercise, on cognitive function, mobility, and brain activity in older adults with cognitive frailty. Understanding these effects will help us develop intervention models that benefit cognitively frail older adults. The main questions it aims to answer are:

1. Does the combination of iTBS primed with cTBS and aerobic exercise lead to greater improvements in cognition and mobility in older adults with cognitive frailty compared to non-priming iTBS and sham stimulation?
2. What are the neural mechanisms responsible for the improvements in cognition and mobility associated with the combination of iTBS primed with cTBS and aerobic exercise in older adults with cognitive frailty?

Study Overview

• Status: Recruiting
• Conditions: Mild Cognitive Impairment; Frailty at Older Adults
• Intervention / Treatment: Device: Theta burst stimulation; Behavioral: Aerobic exercise

Detailed Description

Objectives: To compare the effects of intermittent theta burst stimulation (iTBS) primed with continuous theta burst stimulation (cTBS), nonpriming iTBS, and sham stimulation on top of aerobic exercise in terms of improving cognitive function, mobility, brain structure, and brain function in older adults with cognitive frailty.

Hypothesis to be tested: We hypothesize that iTBS primed with cTBS can maximize the induction of therapeutically beneficial metaplasticity, and that this will be reflected in improved brain structure and brain function, thereby enabling superior cognitive function and mobility improvement in older adults with cognitive frailty.

Design and subjects: A randomized controlled trial involving 60 older adults with cognitive frailty.

Study instruments: Transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI).

Interventions: Participants will be randomly allocated to receive a 39-session intervention with different TBS protocols (i.e., cTBS+iTBS, sham cTBS+iTBS, and sham cTBS+sham iTBS), delivered 3 times per week for 3 months. All participants will receive 60 minutes of aerobic exercise after each stimulation session for 6 months.

Main outcome measures: comprehensive neuropsychological battery covering major executive function (i.e., selective attention/response inhibition, psychomotor speed, set shifting), working memory, and verbal fluency; (2) mobility function evaluated via SPPB, Timed-Up-and-GO (TUG) test, functional gait analysis (i.e., gait speed, gait variability).

Secondary outcomes: underlying neural mechanisms of intervention-induced benefits will be assessed via functional and structural magnetic resonance imaging.

Data analysis: Analysis of variance (ANOVA)

• Study Type: Interventional
• Enrollment (Estimated): 45
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: JINGYI WU, MSc; Phone Number: +85260730847; Email: 24144838r@connect.polyu.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • The Hong Kong Polytechnic University, Department of Rehabilitation Sciences
    • Contact: Chun Liang HSU, PhD; Phone Number: 852-27666755; Email: chun-liang.hsu@polyu.edu.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. be between 60 and 90 years old;
2. scored < 9/12 on the SPPB;
3. scored >18/30 on the MoCA;
4. scored >9/42 on the PFFS;
5. lived in the community;
6. be able to ambulate up to four meters with or without assistive devices;
7. be able to provide written informed consent on their own behalf;
8. can understand verbal and written Cantonese and/or English.

Exclusion Criteria:

1. have magnetic resonance imaging (MRI) contraindications;
2. have aerobic exercise contraindications;
3. have transcranial magnetic stimulation contraindications;
4. be diagnosed with neurodegenerative conditions (i.e., dementia, Parkinson's, Alzheimer's disease, Amyotrophic lateral sclerosis, and stroke);
5. live in a nursing home or other care facilities/institutions;
6. bed taking fixed dose of medication or had been taking medications known to potentially affect cognitive and physical function (e.g., psychotropic medications), as identified through a review of their medication lists recorded in the health software. Medications were categorized by properties (e.g., antipsychotics, antidepressants, etc.) to inform eligibility decisions.
7. have a history indicative of carotid sinus sensitivity (i.e., falls due to loss of consciousness);
8. cancer and undergo radiation therapy.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: cTBS+iTBS, in addition to aerobic exercise; Participants will receive 600-pulse cTBS at the intensity of 80% RMT as the priming, followed by 600-pulse iTBS at the intensity of 80% RMT (i.e., priming iTBS). The stimulation will be delivered 3 sessions per week, lasting for 3 months. Participants will receive a 60-minute aerobic exercise after each stimulation session, lasting for 6 months	Device: Theta burst stimulation; Theta burst stimulation (TBS) will be administered using a figure-of-eight shaped cooling coil (Cool-B65 A/P), which generates auditory "clicks" for sham stimulation that are similar to those produced by active repetitive transcranial magnetic stimulation (rTMS). The placement of the coil will be guided by a navigation system (LOCALITE® TMS Navigator, Germany) using each participant's baseline T1-weighted MRI scans. TBS is a powerful form of rTMS. Standard 600-pulse intermittent theta burst stimulation (iTBS) can enhance corticomotor excitability, whereas standard 600-pulse continuous theta burst stimulation (cTBS) can suppress it.; Behavioral: Aerobic exercise; The aerobic exercise sessions will include a 10-minute warm-up, followed by 40 minutes of brisk walking and/or stationary exercises without weights, and will conclude with a 10-minute cooldown. The intensity of the aerobic exercise will be monitored using heart rate, starting at 40% of the age-specific heart rate reserve (HRR), which is calculated using the formula: 207 - (0.7 x age). Over the initial 12 weeks, the intensity will be gradually increased until the HRR reaches 65%, and this level will be maintained until the end of the trial.
Active Comparator: Sham cTBS + iTBS, in addition to aerobic exercise; Participants will receive sham 600-pulse cTBS at the intensity of 80% RMT as the priming, followed by 600-pulse iTBS at the intensity of 80% RMT (i.e., priming iTBS). The stimulation will be delivered 3 sessions per week, lasting for 3 months. Participants will receive a 60-minute aerobic exercise after each stimulation session, lasting for 6 months	Device: Theta burst stimulation; Theta burst stimulation (TBS) will be administered using a figure-of-eight shaped cooling coil (Cool-B65 A/P), which generates auditory "clicks" for sham stimulation that are similar to those produced by active repetitive transcranial magnetic stimulation (rTMS). The placement of the coil will be guided by a navigation system (LOCALITE® TMS Navigator, Germany) using each participant's baseline T1-weighted MRI scans. TBS is a powerful form of rTMS. Standard 600-pulse intermittent theta burst stimulation (iTBS) can enhance corticomotor excitability, whereas standard 600-pulse continuous theta burst stimulation (cTBS) can suppress it.; Behavioral: Aerobic exercise; The aerobic exercise sessions will include a 10-minute warm-up, followed by 40 minutes of brisk walking and/or stationary exercises without weights, and will conclude with a 10-minute cooldown. The intensity of the aerobic exercise will be monitored using heart rate, starting at 40% of the age-specific heart rate reserve (HRR), which is calculated using the formula: 207 - (0.7 x age). Over the initial 12 weeks, the intensity will be gradually increased until the HRR reaches 65%, and this level will be maintained until the end of the trial.
Sham Comparator: Sham cTBS + sham iTBS, in addition to aerobic exercise; Participants will receive sham 600-pulse cTBS at the intensity of 80% RMT as the priming, followed by sham 600-pulse iTBS at the intensity of 80% RMT (i.e., priming iTBS). The stimulation will be delivered 3 sessions per week, lasting for 3 months. Participants will receive a 60-minute aerobic exercise after each stimulation session, lasting for 6 months	Device: Theta burst stimulation; Theta burst stimulation (TBS) will be administered using a figure-of-eight shaped cooling coil (Cool-B65 A/P), which generates auditory "clicks" for sham stimulation that are similar to those produced by active repetitive transcranial magnetic stimulation (rTMS). The placement of the coil will be guided by a navigation system (LOCALITE® TMS Navigator, Germany) using each participant's baseline T1-weighted MRI scans. TBS is a powerful form of rTMS. Standard 600-pulse intermittent theta burst stimulation (iTBS) can enhance corticomotor excitability, whereas standard 600-pulse continuous theta burst stimulation (cTBS) can suppress it.; Behavioral: Aerobic exercise; The aerobic exercise sessions will include a 10-minute warm-up, followed by 40 minutes of brisk walking and/or stationary exercises without weights, and will conclude with a 10-minute cooldown. The intensity of the aerobic exercise will be monitored using heart rate, starting at 40% of the age-specific heart rate reserve (HRR), which is calculated using the formula: 207 - (0.7 x age). Over the initial 12 weeks, the intensity will be gradually increased until the HRR reaches 65%, and this level will be maintained until the end of the trial.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montreal Cognitive Assessment	General cognitive function will be measured by Montreal Cognitive Assessment	Baseline, 3 months, and 6 months
Short Physical Performance Battery	Mobility will be measured by Short Physical Performance Battery	Baseline, 3 months, and 6 months
Pictorial Fit-Frail Scale	The assessment of frailty in older adults will be conducted using the Pictorial Fit-Frail Scale.	Baseline, 3 months, and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Six Minutes Walking Test	The Six Minutes Walking Test is a standard assessment for mobility	Baseline, 3 months, and 6 months
Timed-Up-and-Go Test	The Timed-Up-and-Go Test is a standard assessment for mobility and gait	Baseline, 3 months, and 6 months
Task Switch Test	The Task Switch Test is a standard assessment for executive function	Baseline, 3 months, and 6 months
Digit Span Test	The Digit Span Test is a standard assessment for executive function	Baseline, 3 months, and 6 months
Digit Symbol Substitution Test	The Digit Symbol Substitution Test is a standard assessment for executive function	Baseline, 3 months, and 6 months
Stroop Test	The Stroop Test is a standard assessment for executive function	Baseline, 3 months, and 6 months
Trail Making Test	The Trail Making Test is a standard assessment for executive function	Baseline, 3 months, and 6 months
Sit to stand	The Sit to stand is a standard assessment for mobility	Baseline, 3 months, and 6 months
cortical and subcortical volume	Cortical and subcortical volume will be examined in all participants using MRI. Participants will undergo structural MRI on the 3T Siemens scanner at the University Research Facility in Behavioral and Systems Neuroscience. Participants will complete T1 and T2 high resolution anatomical scans.	Baseline, 3 months, and 6 months
Resting State-Functional Connectivity-Functional MRI	Participants will be instructed to rest with eyes open for approximately 12 minutes. This will allow the investigators to examine activation in the resting state network.	Baseline, 3 months, and 6 months
Physical Activity Scale for the Elderly	Physical activity will be assessed by Physical Activity Scale for the Elderly	Baseline, 3 months, and 6 months
Geriatric Depression Scale	Depression will be measured by Geriatric Depression Scale	Baseline, 3 months, and 6 months
Fatigue Severity Scale	Physical fatigue will be measured by Fatigue Severity Scale	Baseline, 3 months, and 6 months
Functional Comorbidity Index	Total number of comorbid conditions will be assessed through the Functional Comorbidity Index	Baseline, 3 months, and 6 months
Functional Activities Questionnaire	The difficulties in activities of daily living will be assessed using the Functional Activities Questionnaire.	Baseline, 3 months, and 6 months

Collaborators and Investigators

• Sponsor: The Hong Kong Polytechnic University
• Investigators: Principal Investigator: Chun Liang HSU, PhD, The Hong Kong Polytechnic University

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2025
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: March 23, 2026
• First Submitted That Met QC Criteria: March 23, 2026
• First Posted (Actual): March 27, 2026

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: aerobic exercise; fMRI; cTBS; iTBS; cognitive frailty
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Exercise
• Other Study ID Numbers: HSEARS20240614001; P0048639 (Other Grant/Funding Number: The Hong Kong Polytechnic University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No