Individual differences in the responsiveness of the brain to transcranial electrical stimulation (tES) is increasingly demonstrated in large variability in the tES effects. Anatomically detailed computational brain models have been developed to address this variability; however, static brain models are not ‘realistic’ in accounting for the dynamic state of the brain. Therefore, human-in-the-loop optimization is proposed in this perspective article based on an extensive systems analysis of the tES neurovascular effects. First, modal analysis was conducted using a physiologically detailed neurovascular model that found stable modes in the 0 Hz to 0.05 Hz range for the pathway for vessel response through the smooth muscle cells, measured with functional near-infrared spectroscopy (fNIRS). tES effects in the 0 Hz to 0.05 Hz range can also be measured with functional magnetic resonance imaging (fMRI)-tDCS data with a maximum TR=10sec. Therefore, we investigated an open-source fMRI-tDCS dataset that used a TR=3.36sec. We found that both the anodal tDCS condition and sham tDCS condition had similar Finite Impulse Response at the region of interest underlying the anode and a remote location, which indicated a global hemodynamic effect of sham tDCS beyond the intended transient sensations. Here, transient sensations can have arousal effects on the hemodynamics so we conducted a healthy case series for black box modeling of fNIRS-pupillometry of short-duration tDCS effects. The block exogeneity test rejected the claim that tDCS is not a 1-step Granger-cause of the fNIRS total hemoglobin changes (HbT) and pupil dilation changes (p<0.05). Also, grey-box modeling using fNIRS of the tDCS effects in chronic stroke showed HbT response to be significantly different (paired-sample t-test, p<0.05) between the ipsilesional and the contralesional hemisphere for primary motor cortex tDCS and cerebellar tDCS which was subserved by the smooth muscle cells. Here, our perspective is that various physiological pathways subserving tES effects can lead to state-trait variability that can be challenging for clinical translation. Therefore, we conducted a case study on human-in-the-loop optimization using our reduced dimension model and a stochastic, derivative-free Covariance Matrix Adaptation Evolution Strategy. Future studies need to investigate human-in-the-loop optimization of tES for reducing inter-subject and intra-subject variability in tES effects.

Dementia, characterized by cognitive decline beyond age-related expectations, poses a formidable global health challenge. With an estimated 55 million individuals affected worldwide and 10 million new cases annually, dementia profoundly impacts memory, comprehension, language, and behavior. Then, the global diabetes population increased from 108 million in 1980 to 422 million in 2014, with a more rapid rise in prevalence observed in low- and middle-income countries compared to high-income countries. Individuals with diabetes have an increased risk of cognitive problems, including a higher likelihood of developing dementia, Alzheimer's disease, and vascular dementia, especially in older age. Managing diabetes through diet, physical activity, medication, and consistent screening and treatment for complications can prevent or delay its consequences.Globally ranking as the seventh leading cause of death, dementia's societal implications are substantial. The chapter delves into Mild Cognitive Impairment (MCI), a precursor to dementia, emphasizing its global epidemiological trends. Neuroimaging, particularly Functional Near-Infrared Spectroscopy (fNIRS), emerges as a non-invasive diagnostic tool, surpassing traditional imaging methods' portability. The chapter investigates the effects of non-invasive electrical stimulation on neurovascular tissues, shedding light on its impact including potential to address metaboreflex related reduced exercise tolerance. Furthermore, the chapter presents a clinical trial (ClinicalTrials.gov NCT04626453 and NCT04812288) examining the effects of a 2-month exercise program on cognitive function and muscular oxidative capacity in older adults with type 2 diabetes. The study's design, individualized exercise regimens to address muscle mechanoreflex and metaboreflex responses, and their physiological changes during exercise are discussed, offering insights into the interplay between exercise tolerance, cognition, and vascular health. The findings contribute to tailored and effective interventions for cognitive well-being. Here, our exploration extends to the application of transcranial electrical stimulation (tES) in optimizing exercise performance, with a focus on its various forms, including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS). A physiological modeling approach based on the neurovascular unit (NVU) is employed, revealing potential avenues for also treating vascular dementia (often noted to have a strong association with type 2 diabetes) through tACS, guided by human-in-the-loop approaches. Here, modal analysis for control is applied to assess the NVU model's characteristic dynamics under tACS, providing a comprehensive understanding of neurovascular coupling modes.In summary, this chapter synthesizes diverse facets in type 2 diabetes comorbidity and cognitive decline, ranging from global impact and diagnostic criteria to innovative interventions like exercise and transcranial electrical stimulation. The multidisciplinary approach integrates epidemiology, clinical trials, and physiological modeling, contributing valuable insights into the holistic management of cognitive health and neurovascular function.