Intermittent Theta-burst Stimulation for Mild Cognitive Impairment

Optimizing Intermittent Theta-burst Stimulation for Enhancing Dual-Task Walking, Cognitive, and Physical Function in Mild Cognitive Impairment: a Randomized Double-Blind Controlled Trial

The objectives of this study are to:

1. Evaluating the Impact of iTBS on Cognitive and Physical Functions: The investigators will investigate the efficacy of intermittent theta burst stimulation (iTBS) in patients with mild cognitive impairment (MCI), focusing on its effects on dual-task walking abilities, balance abilities, and cognitive function.
2. Comparing Clinical Efficacy Based on Stimulation Sites: The investigators will compare the clinical efficacy of iTBS targeting the left dorsolateral prefrontal cortex (DLPFC) versus bilateral DLPFC stimulation. This comparison aims to directly examine potential differences in therapeutic outcomes based on the site of stimulation.
3. Investigating Neurophysiological Mechanisms: The investigators plan to elucidate the neurophysiological mechanisms underlying the improvements in cognitive functions and dual-task walking abilities in MCI patients facilitated by iTBS. This will be achieved using fNIRS neuroimaging of brain activity.

Study Overview

• Status: Recruiting
• Conditions: Mild Cognitive Impairment (MCI)
• Intervention / Treatment: Device: Intermittent Theta Burst Stimulation

Detailed Description

Mild cognitive impairment (MCI) is a syndrome characterized by cognitive decline that is greater than expected with normal aging; however, it is not severe enough to meet dementia criteria. Accordingly, MCI is considered a transitional state between normal aging and dementia, with a high risk of progression to Alzheimer's disease (AD). In MCI, memory and other cognitive domains such as executive function and visuospatial skills are typically affected. Furthermore, people with MCI have impaired dual-task walking function, decreased balance, and an increased risk of falls compared to cognitively normal older adults, thus affecting the ability to perform daily activities. Moreover, sleep disturbances, such as reduced efficiency and disruptions, are common in MCI, which exacerbates cognitive decline and accelerates the progression to dementia.

Non-invasive brain stimulation (NIBS) techniques have shown potential for enhancing both cognitive and functional outcomes in neuropsychiatric diseases. Transcranial magnetic stimulation (TMS) is the most common form of NIBS, which modulates cortical excitability and neuroplasticity by inducing electromagnetic pulses in targeted brain regions. TMS can be delivered in various forms based on frequency and intervals. Intermittent theta burst stimulation (iTBS) is a type of patterned TMS that mimics endogenous theta rhythms. It has shown cognitive benefits in healthy populations as well as those with AD, depression, and other conditions, but evidence regarding its efficacy in MCI is limited.

While interventions like dual-task training and non-invasive brain stimulation (e.g., tDCS) have shown promise in mitigating dual-task coordination impairments, research specifically focusing on the impact of iTBS on dual-task walking abilities in MCI patients remains scarce. Further research is needed to explore the potential of iTBS to improve dual-task walking ability, balance, and fall prevention in MCI populations.

Although the dorsolateral prefrontal cortex (DLPFC) is often targeted with NIBS due to its role in executive functions, comparisons of bilateral versus unilateral left DLPFC stimulation have not been conducted in MCI. Overall, there is a lack of empirical evidence supporting the use of iTBS protocols to improve cognition and functional activities in MCI. Elucidating the neurophysiological mechanisms underlying NIBS techniques like iTBS remains imperative.

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong, 000000
    • Recruiting
    • The Hong Kong Polytechnic University
    • Contact: Yihui CAI, Mphil; Phone Number: 85260739535; Email: yihui.cai@connect.polyu.hk
  • Hong Kong, Hong Kong, 000000
    • Not yet recruiting
    • The Hong Kong Polytechnic University
    • Contact: Marco Yiu Chung PANG, PhD; Phone Number: 2766-7156 852 2766-7156; Email: Marco.Pang@polyu.edu.hk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Aged≥65 years;
• Patient-reported subjective cognitive decline and the total score of the Hong Kong version of Montreal Cognitive Assessment (HK-MoCA) was between 19 and 25;
• Intact daily functioning in ADL scales and being independent in daily living, and ability to walk at least for 1 minute independently without an assistive device;
• No serious visual or hearing impairment and can complete relevant assessment and testing;
• Signed informed consent of patients and their families for iTBS treatment.

Exclusion Criteria:

• Identified with contraindications in the rTMS screening questionnaire;
• Cognitive dysfunction due to craniocerebral trauma or neurological diseases;
• Presence of severe physical illnesses such as speech disorders or unstable cardiac arrhythmias;
• Currently in a critical condition such as fever, infection, or organ failure;
• Significant damage to the left frontal lobe cortex;
• Currently taking antidepressants or psychostimulants;
• Unstable vital signs or organ failure;
• Neuropsychiatric comorbidity or affective disorder that could affect the test results;
• Patients with dementia.

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: Left DLPFC stimulation group; 80% resting motor threshold (RMT) iTBS stimulated the left DLPFC 4 sessions per day at 15 min intervals (3min per session), 3 days per week for 3 weeks. Sham stimulation of the right DLPFC will be performed.	Device: Intermittent Theta Burst Stimulation; A novel transcranial magnetic stimulation protocol called intermittent theta pulse stimulation (iTBS) effectively mimics the brain's naturally occurring theta rhythms and promotes significant synaptic changes. Compared to traditional stimulation methods, iTBS is more effective at initiating long-term potential (LTP) and produces significant excitatory effects in a shorter period of time.
Experimental: Bilateral DLPFC stimulation group; 80% RMT iTBS stimulated the bilateral DLPFC 4 sessions per day at 15 min intervals (2 sessions on the left, 2 sessions on the right, 3 min per session), 3 days per week for 3 weeks.	Device: Intermittent Theta Burst Stimulation; A novel transcranial magnetic stimulation protocol called intermittent theta pulse stimulation (iTBS) effectively mimics the brain's naturally occurring theta rhythms and promotes significant synaptic changes. Compared to traditional stimulation methods, iTBS is more effective at initiating long-term potential (LTP) and produces significant excitatory effects in a shorter period of time.
Sham Comparator: Sham stimulation group; Sham coil stimulates the left and right DLPFC.	Device: Intermittent Theta Burst Stimulation; A novel transcranial magnetic stimulation protocol called intermittent theta pulse stimulation (iTBS) effectively mimics the brain's naturally occurring theta rhythms and promotes significant synaptic changes. Compared to traditional stimulation methods, iTBS is more effective at initiating long-term potential (LTP) and produces significant excitatory effects in a shorter period of time.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dual-task cost in gait (gait speed)	Gait speed under dual-task condition will be recorded	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Dual-task cost in cognition (Reaction time)	Reaction time will be measured during dual-task conditions	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Dual-task cost in cognition (Accuracy)	Accuracy will be measured during dual-task conditions	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood oxygenation level changes of the brain	Blood oxygenation level changes will be measured using Functional Near-Infrared Spectroscopy during dual-task conditions	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Dual-task gait performance 1 (gait variability)	Gait variability will be measured during dual-task walking	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Dual-task gait performance 2 (stride length)	Stride length will be measured during dual-task walking	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Dual-task gait performance 3 (walking distance)	Walking distance will be measured during dual-task walking	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Dual-task gait performance 4 (gait cadence)	Gait cadence will be measured during dual-task walking	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Dual-task gait performance 5 (trunk stability)	Trunk stability will be measured during dual-task walking	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hong Kong Montreal Cognitive Assessment (HK-MoCA)	Hong Kong Montreal Cognitive Assessment (HK-MoCA) will be used to global cognitive function, with total points from 0-30. Higher points indicate better performance.	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
N-back test	N-back test will be used to assess executive function.	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Modified-Wisconsin Card Sorting Test	Modified-Wisconsin Card Sorting Test will be used to assess executive function.	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Hong Kong List Learning Test (HKLLT)	The Hong Kong List Learning Test (HKLLT) will be used to assess memory function.	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Brief assessment of prospective memory (short form).	A brief assessment of prospective memory (short form) will be used to assess memory function.	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Timed Up and Go test	Timed Up and Go test will be used used to assess mobility.	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Single Leg Stance test	Single Leg Stance test will be used used to assess balance ability.	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Hong Kong Lawton Instrumental Activities of Daily Living Scale (HKLIADL)	Hong Kong Lawton Instrumental Activities of Daily Living Scale (HKLIADL) will be used to assess the ability of Instrumental Activities of Daily Living, with total points from 0-27. Higher points indicate better performance.	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Fall incidence	Monthly telephone interviews for recording fall incidence.	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Pittsburgh Sleep Quality Index	The Pittsburgh Sleep Quality Index will be used to assess sleep quality. Each item is scored from 0 to 3, with a total score of 0 to 21. A higher total score indicates poorer sleep quality.	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Depression, Anxiety, and Stress Scale (DASS-21)	The Depression, Anxiety, and Stress Scale (DASS-21) will be used to assess mental health. It contains 21 items divided into three dimensions, with seven items in each dimension. Scores for each dimension range from 0 to 42, with higher scores representing higher levels of depression, anxiety, and stress.	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment
Physical Activity Scale for the Elderly (PASE)	The Physical Activity Scale for the Elderly (PASE) will be used to assess physical activity. There is no set range for the total PASE score; usually a higher score represents a higher level of physical activity.	before the initiation of treatment, after 3 weeks of treatment, 4 weeks after termination of the treatment

Collaborators and Investigators

• Sponsor: The Hong Kong Polytechnic University

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2024
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): October 31, 2027

Study Registration Dates

• First Submitted: September 19, 2024
• First Submitted That Met QC Criteria: September 19, 2024
• First Posted (Actual): September 23, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 11, 2025
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: cognitive function; Dorsolateral Prefrontal Cortex (DLPFC); dual task walking; Intermittent Theta Burst Stimulation (iTBS)
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction
• Other Study ID Numbers: Marco_PANG_2024_July

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The study data can be provided via contacting the Principal Investigator
• IPD Sharing Time Frame: From Dec 2027 onwards

IPD Sharing Access Criteria

By contacting the Principal Investigator (Prof. Marco PANG):

Marco.Pang@polyu.edu.hk

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

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