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.

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.

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.

The study data can be provided via contacting the Principal Investigator

From Dec 2027 onwards

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

Marco.Pang@polyu.edu.hk

The outcome assessors and participants were blinded to the participants' group allocation.