This review updates and consolidates evidence on the safety of transcranial Direct Current Stimulation (tDCS). Safety is here operationally defined by, and limited to, the absence of evidence for a Serious Adverse Effect, the criteria for which are rigorously defined. This review adopts an evidence-based approach, based on an aggregation of experience from human trials, taking care not to confuse speculation on potential hazards or lack of data to refute such speculation with evidence for risk. Safety data from animal tests for tissue damage are reviewed with systematic consideration of translation to humans. Arbitrary safety considerations are avoided. Computational models are used to relate dose to brain exposure in humans and animals. We review relevant dose-response curves and dose metrics (e.g. current, duration, current density, charge, charge density) for meaningful safety standards. Special consideration is given to theoretically vulnerable populations including children and the elderly, subjects with mood disorders, epilepsy, stroke, implants, and home users. Evidence from relevant animal models indicates that brain injury by Direct Current Stimulation (DCS) occurs at predicted brain current densities (6.3–13 A/m2) that are over an order of magnitude above those produced by conventional tDCS. To date, the use of conventional tDCS protocols in human trials (≤40 min, ≤4 mA, ≤7.2 Coulombs) has not produced any reports of a Serious Adverse Effect or irreversible injury across over 33,200 sessions and 1,000 subjects with repeated sessions. This includes a wide variety of subjects, including persons from potentially vulnerable populations.

The hypothalamo-pituitary-adrenocortical (HPA) axis is responsible for initiation of glucocorticoid stress responses in all vertebrate animals. Activation of the axis is regulated by diverse afferent input to the hypothalamic paraventricular nucleus (PVN). This review discusses brain mechanisms subserving generation and inhibition of stress responses focusing on the contribution of the limbic system and highlighting recent conceptual advances regarding organization of stress response pathways in the brain. First, control of HPA axis responses to psychogenic stimuli is exerted by a complex neurocircuitry that involves oligosynaptic networks between limbic forebrain structures and the PVN. Second, individual stress-modulatory structures can have a heterogeneous impact on HPA axis responses, based on anatomical microorganization and/or stimulus properties. Finally, HPA axis hyperactivity pursuant to chronic stress involves a substantial functional and perhaps anatomical reorganization of central stress-integrative circuits. Overall, the data suggest that individual brain regions do not merely function as monolithic activators or inhibitors of the HPA axis and that network approaches need be taken to fully understand the nature of the neuroendocrine stress response. KeywordsHPA axis; hippocampus; amygdala; medial prefrontal cortex; glucocorticoidThe hypothalamo-pituitary-adrenocortical (HPA) axis is a critical adaptive system that maximizes survival potential in the face of physical or psychological challenge. The principal end-products of the HPA axis, glucocorticoid hormones, act on multiple organ systems, including the brain, to maintain homeostatic balance. While glucocorticoids are beneficial for short-term survival, prolonged exposure can lead to serious metabolic, immune and psychological dysfunction,1 requiring that glucocorticoid secretion be a tightly regulated process. Therefore, termination of the glucocorticoid response is well-controlled by efficient feedback inhibition mechanisms.Activation of the HPA axis can occur reflexively in response to physical challenge. These 'reactive' responses are driven by ascending brain systems or circumventricular organs, which send direct projections to the hypothalamic paraventricular nucleus (PVN) (FIG. 1).2 Neurons of the PVN produce corticotrophin releasing hormone (CRH), the primary ACTH secretagogue, and thereby control ACTH release and subsequent glucocorticoid secretion. Reactive responses are initiated by stimuli that signal a direct threat to homeostasis or survival (so-called 'systemic stressors'). Activation of the HPA axis and glucocorticoid Address correspondence to: Ryan Jankord, PhD, Department of Psychiatry, University of Cincinnati, 2170 East Galbraith Road, Cincinnati, (FIG. 1).2Temporal prolongation of stress exposure ('chronic stress') causes marked enhancement in basal HPA tone as well as stress reactivity. These changes occur despite high resting or cumulative glucocorticoid secretion, suggesting that mechanisms are in place to bypass n...

The US Air Force Office of Scientific Research convened a meeting of researchers in the fields of neuroscience, psychology, engineering, and medicine to discuss most pressing issues facing ongoing research in the field of transcranial direct current stimulation (tDCS) and related techniques. In this study, we present opinions prepared by participants of the meeting, focusing on the most promising areas of research, immediate and future goals for the field, and the potential for hormesis theory to inform tDCS research. Scientific, medical, and ethical considerations support the ongoing testing of tDCS in healthy and clinical populations, provided best protocols are used to maximize safety. Notwithstanding the need for ongoing research, promising applications include enhancing vigilance/attention in healthy volunteers, which can accelerate training and support learning. Commonly, tDCS is used as an adjunct to training/rehabilitation tasks with the goal of leftward shift in the learning/treatment effect curves. Although trials are encouraging, elucidating the basic mechanisms of tDCS will accelerate validation and adoption. To this end, biomarkers (eg, clinical neuroimaging and findings from animal models) can support hypotheses linking neurobiological mechanisms and behavioral effects. Dosage can be optimized using computational models of current flow and understanding dose–response. Both biomarkers and dosimetry should guide individualized interventions with the goal of reducing variability. Insights from other applied energy domains, including ionizing radiation, transcranial magnetic stimulation, and low-level laser (light) therapy, can be prudently leveraged.