Accelerated Intermittent Theta-burst Stimulation to Modify Cognitive Function and Balance in Dementia and Memory Loss

The process of aging is accompanied by normal deterioration of body systems, leading to a decline in various functional domains including cognitive, visual, vestibular, somatosensory, and motor function. With this functional decline, there is an increasing burden of care due to the rise of injury, direct and indirect healthcare costs, and the loss of independence in performing daily activities. Notably, falls in the older population represents one of the greatest costs incurred by Canadians annually.

The study investigates whether rTMS delivered to M1 will lead to greater improvement in balance compared to rTMS delivered to DLPFC. Determining this answer will allow greater success in TMS target refinement. Given the profound burden that geriatric medicine has on the Canadian healthcare system, understanding the link between balance and cognition can significantly impact the approach to management of this population.

Approximately 20-30% of Canadian adults \>65 years old experience falls each year, and this rate drastically increases for those \>85 years of age \[2\]. With the aging population, the number of annual reported falls has increased by 47% from 2008 to 2020 \[3\]. Individuals with cognitive impairment exhibit an 8x higher risk of falls compared to those without \[4\]. Balance is a key risk factor for falls \[5-7\], and there is evidence suggesting that balance control is a marker of cognitive decline \[8\]. For example, cognitive function is significantly correlated with postural control \[9\] and postural sway \[10\]. In Parkinson's disease, balance has been linked to greater executive dysfunction and slower processing speed \[11\].

Synaptic plasticity induced via neuromodulatory techniques can lead to improvements in motor and cognitive function. One such technique is Transcranial magnetic stimulation (TMS), a non-invasive form of neuromodulation. To induce synaptic plasticity, magnetic stimuli are delivered via TMS in theta-burst patterns. This includes continuous theta burst stimulation (cTBS) that induces long term depression (LTD)-like changes in neuronal excitability and intermittent theta burst stimulation (iTBS) that induces long term potentiation (LTP)-like changes in neuronal excitability \[12\]. Previous literature suggests that iTBS may be an effective tool for modulating cognition and motor function.

Wu et al. (2022) found an improvement in memory function of Alzheimer disease patients following a 14-day course of iTBS delivered to the dorsolateral prefrontal cortex (DLPFC) \[13\]. Trung et al. (2019) showed that 3 days of iTBS delivered to the DLPFC led to cognitive improvements in a sample of Parkinson's disease patients with mild cognitive impairment (MCI) \[14\]. Regarding balance, iTBS has been shown to be an effective intervention for balance recovery when delivered to the cerebellum \[16,17\] or the primary motor cortex (M1) \[16\]. Improvements in gait performance have also been seen following other patterns of stimulation including repetitive TMS (rTMS) in the post-stroke population \[18-20\]. These improvements in cognition and balance following iTBS may be linked to plastic changes in neuronal structure, as seen in animal models \[21\].

Accelerated intermittent theta-burst stimulation (iTBS) encompass multiple sessions of iTBS administered within a singular day over the course of several days, consequently diminishing the duration of the treatment regimen. aiTBS has been shown to be a tolerable and safe form of non-invasive brain stimulation with rapid antidepressant efficacy and anti-suicidal effects in patients with major depressive disorder \[22-27\]. Previous studies have demonstrated aiTBS paradigm which consisted of iTBS delivered 3 times per day separated by 15 min intervals, over the course of 14 days, resulted in an improvement in memory function in individuals with Alzheimer disease \[13, 27\].

For this study question we have chosen two different stimulation sites. DLFPC is known for its contributions to learning and memory. Individuals with dementia typically receive rTMS stimulation to DLPFC to explore whether cognitive function can be improved (Wu et al., 2020). It has been seen that individuals with dementia suffer from a greater number of falls, it is unclear whether rTMS to DLPFC will improve balance performance and risk of falls better than rTMS delivered to M1, a typical site of stimulation for balance related studies. iTBS has been shown to be an effective intervention for balance recovery when delivered to the primary motor cortex (M1) (Liao et al., 2024). Improvements in gait performance have also been seen following other patterns of stimulation including repetitive TMS (rTMS) in the post-stroke population when delivered to M1 (Wang et al., 2012; Wang et al., 2019; Rastgoo et al., 2016). These improvements in cognition and balance following iTBS may be linked to plastic changes in neuronal structure, as seen in animal models (Tsang et al., 2021).

We there ask the study question whether rTMS delivered to M1 will lead to greater improvement in balance compared to rTMS delivered to DLPFC. Determining this answer will allow greater success in TMS target refinement. Given the profound burden that geriatric medicine has on the Canadian healthcare system, understanding the link between balance and cognition can significantly impact the approach to management of this population

Eligibility Criteria:
Inclusion Criteria:

1. Individuals must be diagnosed with Dementia and/or memory loss by a clinician.
2. Individuals must exhibit adequate oral communication skills and cognitive function sufficient to obtain a score ranging between 10-27 on the Mini-Mental State Exam (Wu et al., 2022).
3. Instructions will be delivered in English; therefore participants must demonstrate an understanding of instruction provided in English or have a caregiver present who can translate and be presented during all study sessions.
4. Individuals must be able to walk or stand with or without personnel or assistive devices.
5. Individuals must be greater than or equal to 50 years of age.

Exclusion Criteria:

* 1. Contraindications to rTMS; presence of a pacemaker, metal/electrical/magnetic implants not including titanium, known history of untreated or uncontrolled psychological disorders, pregnancy, history of seizure or diagnoses of epilepsy, are taking any prescription medications that increase the risk of seizure.