Building a Comprehensive Model of Individual Variations in Responsiveness to Electrical Brain Stimulation (1/4)

Noninvasive Electric Brain Stimulation (EBS) has become an increasingly popular tool, both for researchers and clinicians, to modulate brain activities in humans. EBS uses mild electric current to stimulate the cortex noninvasively from scalp, and can be done in the form of direct current (tDCS), alternating current (tACS), and random-noise alternating current (tRNS) forms. Due to the several advantages of EBS such as its noninvasiveness, portability, affordability, directionality, entrainability, and maskability, EBS-related publications have surged to over 100,000 publications and 14,000 patents worldwide as of 2020. Yet, despite its advantages, EBS is not yet currently approved by the Food and Drug Administration (FDA) to treat any kind of neurological diseases and psychiatric disorders (whereas TMS is already FDA-approved for treating treatment-resistant depression). Similarly, in cognitive neuroscience, many EBS findings have been difficult to replicate because of the high degrees of variability arising from individual differences (i.e., participants’ responsiveness to EBS). This variability does not seem to be coming from one single factor; rather, it appears to be a complex interaction of multiple factors that many studies have independently reported over the years. The key challenge for EBS is basic and clinical research is simple: individual differences in responsiveness. There have been many findings about different factors, as well as the interactions between them, that are known to impact the responsiveness to EBS in each individual participant. These factors are 1) individualistic baseline in cognitive performance, 2) task difficulty and its consequent cognitive demand, 3) stimulation protocols such as the interaction between frequency and phase and montage distance, 4) functional connectivity between different brain regions, and 5) anatomical factors such as skull thickness and density. To address the challenges mentioned above, the current proposal aims to tackle these factors by systematically investigating them in order to build a model that incorporates predictive information about the responsiveness of each individual participant. We will 1) use 3 well-defined cognitive tasks to assess individualistic cognitive baseline, 2) use 3 levels of task difficulty to elucidate the interaction between cognitive load and EBS responsiveness, 3) use 3 stimulation techniques and 2 montage pairs to disambiguate the relative contributions of various stimulation protocols, 4) use pre- and post-EBS resting sessions to investigate interregional EEG coherence and characterize interregional functional connectivity, 5) incorporate anatomical measures of skull thickness and density into the model, 6) use EEG entropy-based “reactivity” measures to develop a novel marker for cortical responsiveness, and finally 7) builde a comprehensive model of individual variations in responsiveness to electrical brain stimulation. This proposal supersedes previous attempts in the field as previous work has only examined each single factor separately. Importantly, in so doing, we believe findings from this project will also create a clear path for future studies to develop individualized stimulation protocols that can maximize the responsiveness in every individual, and increase EBS response rate. Naturally, the more we understand about the factors that contribute to individual differences in EBS responsiveness (current proposal), the more we can achieve precision customizability (the ultimate goal).