Brain Wave Informed Non-invasive Brain Stimulation: Improving Neural Networks of Working Memory in Dementia: a Proof-of-concept Study

Dementia is cognitive decline severe enough to interfere with daily function and is more severe than cognitive decline normally occurring as a result of aging. Two major cognitive domains which are typically impaired in dementia include executive function and learning/memory. Impairments in executive function interfere with an individual's ability to plan, organize, and switch between tasks, with impairments in this domain significantly reducing an individual's ability to perform activities of daily living (ADL). In the learning/memory domain, episodic memory and working memory are altered. Impairments in episodic memory lead to individuals being unable to recall past events or experiences, as well as being unable to learn and retain details about new experiences. Impairments in working memory lead to individuals being unable to retain information for short periods of time during the execution of a task, such as remembering what was said earlier in a conversation or remembering a set of instructions while executing them. Similar to executive function, decline in episodic and/or working memory is related to reduced ADL. Lower ADL in patients with dementia is associated with higher burden on their caregivers. Dementia caregivers in Canada provide over 580 million hours of care annually. Dementia produces a ripple effect for all Canadians through hospital stays and emergency department visits, loss of productivity from absenteeism, presenteeism, and early retirement of caregivers leading to an overall annual economic burden of over $10 billion CAD. At present, there is no gold standard treatment for reducing cognitive impairment in dementia.

While dementia is thought to be a result of a combination of structural and chemical changes in the brain, recent work has highlighted the interaction between these changes and how the brain functionally adapts to them. The 2024 Lancet Neurology Commission on dementia highlights some individuals may have the chemical and structural brain changes associated with dementia, but do not suffer cognitive decline beyond what is associated with normal aging. More specifically, a community-based autopsy study of 4,354 individuals over the age of 80 in the United Kingdom measured the number of neuropathologies including severe neuritic plaques, neurofibrillary tangles, micro \& macroinfarcts, and Lewy bodies, found that 51% of individuals with two or more significant neuropathologies did not have a clinical diagnosis of dementia. The brain's ability to withstand neuropathology without leading to cognitive decline is defined as cognitive reserve. Cognitive reserve is thought to allow recruitment of brain networks typically used for other functions or more efficient use of existing brain networks. On a neurophysiological level, it is thought that individuals with higher cognitive reserve generally have higher resting state functional connectivity between regions involved in cognition. Thus, increasing functional connectivity between brain regions involved in cognitive domains impaired in dementia may be able to improve cognitive reserve, reducing cognitive impairment in dementia.

Electroencephalography (EEG) is an effective method for measuring functional connectivity between brain regions non-invasively. EEG functional connectivity associated with proper functioning of cognitive domains impaired in dementia may provide a target biomarker to improve cognitive reserve. While EEG functional connectivity during executive function and episodic memory have been measured, there is a large degree of overlap in functional connectivity changes between executive function and working memory, likely due to both sharing some cognitive processes. Further, there are multiple studies demonstrating the causal role of EEG functional connectivity measures in working memory. Thus, EEG functional connectivity associated with working memory may provide a more promising biomarker to target for cognitive reserve.

EEG functional connectivity is a measure of the synchrony between EEG waves from two different brain regions. During successful working memory maintenance, the level of synchrony in the theta band between the frontal and temporal cortex has been shown to increase in healthy adults. Frontotemporal theta band synchrony is most commonly measured through phase-locking value (PLV). High PLV is thought to indicate stronger communication between cortices. Further, temporarily enhancing frontotemporal theta PLV using non-invasive brain stimulation known as transcranial alternating current stimulation (tACS) has been shown to restore working memory performance in older adults to the level of healthy young adults. Additionally, a metanalysis of 28 placebo-controlled studies determining the effects of different tACS protocols on working memory, found that only two forms of tACS improved working memory performance: frontotemporal theta and occipitoparietal gamma. Occipitoparietal gamma was thought to improve working memory performance as a result of many of the included studies using visual based working memory tasks. Nonetheless, these findings provide strong evidence for the role of frontotemporal theta PLV in working memory and highlight the potential for improving cognition by improving frontotemporal theta PLV long-term. At present, tACS is the only approach that can effectively improve PLV between two brain regions. However, its effects are typically temporary, lasting between 30min-70min after stimulation. Thus, enhancing PLV between two brain regions long-term may potentially produce lasting improvements in cognition in dementia.

High PLV is thought to occur due to strong synapses between two populations of neurons being recorded via EEG. If the strength of the synapses between these two populations were increased, then, theoretically their PLV would likely also increase. In the context of working memory, strengthening the synapses between neurons in the frontal and temporal cortex that generally contribute to the EEG theta band may result in a significant increase in frontotemporal theta PLV on EEG. These synapses can potentially be strengthened through a form of neuroplasticity known as long-term potentiation (LTP). LTP can potentially be induced through spike-timing dependent plasticity. Spike-timing dependent plasticity occurs through co-incident firing of the sending and receiving neurons. Considering that the frontal cortex is largely considered to be the hub for most cognitive functions, it is suggested that the frontal cortex projects onto the temporal cortex. Therefore, stimulating the frontal cortex when neurons in the temporal cortex contributing to the theta band are most likely to fire action potentials, through spike-timing dependent plasticity, may result in theta band specific LTP between the frontal and temporal cortex, in turn producing long-term enhancements in frontotemporal theta PLV.

The probability that a population of neurons will fire an action potential has previously been shown to be related to the phase of the EEG band. More specifically, non-invasive brain stimulation known as transcranial magnetic stimulation (TMS), synchronized to mu (8-13Hz) troughs results in significantly greater muscle activity than peaks or random phases. This is thought to be a result of the cortex being more excitable at troughs than any other phase. Therefore, triggering TMS over the frontal cortex at temporal cortex theta troughs, while accounting for conduction delay between the two cortices, may induce EEG theta band specific LTP between the two cortices. This approach has not been used in healthy adults or in clinical populations including Alzheimer's disease and related dementias.

The goal of this study open-label proof-of-concept study is to determine the feasibility and potential efficacy of the approach of temporal cortex theta trough triggered frontal TMS. This study will inform the design of a powered study to observe effects of EEG-TMS on working memory and will inform future work to identify and target biomarkers of other impacted cognitive domains in dementia. This study also aims to determine the potential of this technique to produce long-term improvements in working memory \& cognition in individuals suffering from dementia as well as improvements in frontotemporal theta PLV.

By improving working memory in dementia, overall cognition may be improved, dementia patients' ADL may increase, and strain on their caregivers may be reduced. This study paves the way for future work that aims to improve the cognitive domains impaired in dementia by targeting the neurophysiological biomarkers of good function in those domains. Overall, this work may provide significant benefit to individuals suffering from dementia through potentially improved cognition and independence, while also providing long-term benefits for future research aiming to improve cognition in dementia.