A systematic review and meta-analysis of transcranial direct-current stimulation effects on cognitive function in patients with Alzheimer's disease.

Transcranial direct-current stimulation (tDCS) appears to enhance cognitive function in Alzheimer's disease (AD). Accordingly, over the last two decades, the number of studies using tDCS for AD has grown. This study aimed to provide a quantitative assessment of the efficacy of tDCS in improving cognitive function in patients with AD. We systematically searched the literature until May 2021 to identify relevant publications for inclusion in our systematic review and meta-analysis. Eligible studies were sham-controlled trials assessing the impacts of anodal or cathodal tDCS on cognitive function in patients with AD. The outcome measure of this study was the effects of tDCS on distinct cognitive domains including memory, attention, and global cognitive function. The initial search yielded a total of 323 records. Five other articles were found using manual search of the databases. Of these, 13 publications (14 different studies) with a total of 211 patients of various degrees of AD severity underwent meta-analysis. Meta-analysis revealed the non-significant effects of tDCS on attention (0.425 SMD, 95% CI, -0.254 to 1.104, p = 0.220), and significant positive impacts on the amelioration of general cognitive measures (1.640 SMD, 95% CI, 0.782 to 2.498, p < 0.000), and memory (1.031 SMD, 95% CI, 0.688 to 1.373, p < 0.000) dysfunction in patients with AD. However, the heterogeneity of the studies were high in all subdomains of cognition (Ï°2 = 22.810, T2 = 0.552, d.f. = 5, I2 = 78.80%, p < 0.000 for attention, Ï°2 = 96.29, T2 = 1.727, d.f. = 10, I2 = 89.61%, p < 0.000 for general cognition, and Ï°2 = 7.253, T2 = 0.085, d.f. = 5, I2 = 31.06%, p = 0.203 for memory). Improved memory and general cognitive function in patients with AD was shown in this meta-analysis. However, due to the small number of studies and the high heterogeneity of the data, more high-quality studies using standardized parameters and measures are needed before tDCS can be considered as a treatment for AD.

tDCS peripheral nerve stimulation: a neglected mode of action?

Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation method widely used by neuroscientists and clinicians for research and therapeutic purposes. tDCS is currently under investigation as a treatment for a range of psychiatric disorders. Despite its popularity, a full understanding of tDCS's underlying neurophysiological mechanisms is still lacking. tDCS creates a weak electric field in the cerebral cortex which is generally assumed to cause the observed effects. Interestingly, as tDCS is applied directly on the skin, localized peripheral nerve endings are exposed to much higher electric field strengths than the underlying cortices. Yet, the potential contribution of peripheral mechanisms in causing tDCS's effects has never been systemically investigated. We hypothesize that tDCS induces arousal and vigilance through peripheral mechanisms. We suggest that this may involve peripherally-evoked activation of the ascending reticular activating system, in which norepinephrine is distributed throughout the brain by the locus coeruleus. Finally, we provide suggestions to improve tDCS experimental design beyond the standard sham control, such as topical anesthetics to block peripheral nerves and active controls to stimulate non-target areas. Broad adoption of these measures in all tDCS experiments could help disambiguate peripheral from true transcranial tDCS mechanisms.

Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer's disease.

Early Alzheimer's disease (AD) is associated with hippocampal hyperactivity and decreased sleep quality. Here we show that homeostatic mechanisms transiently counteract the increased excitatory drive to CA1 neurons in AppNL-G-F mice, but that this mechanism fails in older mice. Spatial transcriptomics analysis identifies Pmch as part of the adaptive response in AppNL-G-F mice. Pmch encodes melanin-concentrating hormone (MCH), which is produced in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH downregulates synaptic transmission, modulates firing rate homeostasis in hippocampal neurons and reverses the increased excitatory drive to CA1 neurons in AppNL-G-F mice. AppNL-G-F mice spend less time in rapid eye movement (REM) sleep. AppNL-G-F mice and individuals with AD show progressive changes in morphology of CA1-projecting MCH axons. Our findings identify the MCH system as vulnerable in early AD and suggest that impaired MCH-system function contributes to aberrant excitatory drive and sleep defects, which can compromise hippocampus-dependent functions.