Implication of Cognitive Reserve in Non-pharmacological Intervention Outcomes

Overview

Cognitive reserve (CR) is defined as the gradual accumulation of neural resources and their adaptability (i.e., efficiency, capacity, flexibility) due to genetic and/or lifelong environmental factors that mitigate the cognitive effects of age-related processes and brain diseases. Transcranial alternating current stimulation (tACS) can be used to entrain underlying neuronal networks, promoting firing at specific frequencies. Recent studies have demonstrated that fronto-parietal theta oscillatory activity entrainment via tACS leads to working memory enhancement in healthy subjects. However, there remains significant variability in stimulation-induced aftereffects across individuals. Emerging literature suggests that individual differences, such as CR levels, may be crucial in predicting the benefits of treatment interventions, as they reflect available neural capacity and flexibility. A novel interventional approach is proposed to study CR, utilizing both conventional static proxies, such as premorbid intellect and educational attainment, and dynamic markers, including pupillometry, resting-state, and task-induced functional MRI. By employing cutting-edge noninvasive brain stimulation (NIBS) techniques, the study will acutely modulate network properties to examine the influence of CR on immediate cognitive and brain functional aftereffects induced by the intervention. In addition to focusing on cognitively healthy older adults, this study will, for the first time, include patients with mild cognitive impairment with Lewy bodies (MCI-LB), a prodromal stage of the second most common degenerative dementia after Alzheimer's disease.

A novel interventional approach is proposed for studying cognitive reserve (CR) using dynamic biomarkers, including: Neuromelanin-sensitive MRI sequences to evaluate signal intensity of the locus coeruleus, Resting-state functional MRI (rs-fMRI) to evaluate network properties such as modularity and local and global efficiency, Baseline dynamic rs-fMRI to evaluate mean dwell time and number of transitions between states, and Baseline task-induced activation to evaluate engagement of "domain-specific" and "domain-general" regions during the 'offline' transfer working memory (WM) task performance, i.e., tasks solved after transcranial alternating current stimulation (tACS). These dynamic biomarkers are used in addition to established conventional static proxies (education and premorbid intellect). Specifically, the study aims to: Assess which CR biomarkers and conventional CR proxies, alone or in combination, best predict the tACS-induced magnitude of cognitive enhancement of the 'online' WM task (solved while stimulated). Evaluate the influence of CR on the recruitment of compensatory mechanisms (as assessed by task-induced fMRI and rs-fMRI) induced by tACS for solving challenging WM tasks. Investigate how the CR level moderates the relationship between the magnitude and spatial patterns of brain flexibility changes induced by an acute tACS (as measured by pupil dilation during the online WM task performance and pre-post tACS resting-state functional connectivity changes within and between large-scale brain networks) and cognitive tACS-induced enhancement (as measured by 'online' WM task performance and changes in the 'offline' transfer task performance solved after stimulation).