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.

Introduction: Kilohertz frequency spinal cord stimulation (kHz-SCS) deposits significantly more power in tissue compared to SCS at conventional frequencies, reflecting increased duty cycle (pulse compression). We hypothesize kHz-SCS increases local tissue temperature by joule heat, which may influence the clinical outcomes. Methods: To establish the role of tissue heating in KHZ-SCS, a decisive first step is to characterize the range of temperature changes expected during conventional and KHZ-SCS protocols. Fiber optic probes quantified temperature increases around an experimental SCS lead in a bath phantom. These data were used to verify a SCS lead heat-transfer model based on joule heat. Temperature increases were then predicted in a seven-compartment (soft tissue, vertebral bone, fat, intervertebral disc, meninges, spinal cord with nerve roots) geometric human spinal cord model under varied parameterization. Results: The experimentally constrained bio-heat model shows SCS waveform power (waveform RMS) determines tissue heating at the spinal cord and surrounding tissues. For example, we predict temperature increased at dorsal spinal cord of 0.18–1.72 °C during 3.5 mA peak 10 KHz stimulation with a 40–10–40 μs biphasic pulse pattern, 0.09–0.22 °C during 3.5 mA 1 KHz 100–100–100 μs stimulation, and less than 0.05 °C during 3.5 mA 50 Hz 200–100–200 μs stimulation. Notably, peak heating of the spinal cord and other tissues increases superlinearly with stimulation power and so are especially sensitive to incremental changes in SCS pulse amplitude or frequency (with associated pulse compression). Further supporting distinct SCS intervention strategies based on heating; the spatial profile of temperature changes is more uniform compared to electric fields, which suggests less sensitivity to lead position. Conclusions: Tissue heating may impact short and long-term outcomes of KHZ-SCS, and even as an adjunct mechanism, suggests distinct strategies for lead position and programming optimization.

Background: Higher tDCS current may putatively enhance efficacy, with tolerability the perceived limiting factor. Objective: We designed and validated electrodes and an adaptive controller to provide tDCS up to 4 mA, while managing tolerability. The adaptive 4 mA controller included incremental ramp up, impedancebased current limits, and a Relax-mode where current is transiently decreased. Relax-mode was automatically activated by self-report VAS-pain score >5 and in some conditions by a Relax-button available to participants. Methods: In a parallel-group participant-blind design with 50 healthy subjects, we used specialized electrodes to administer 3 daily session of tDCS for 11 min, with a lexical decision task as a distractor, in 5 study conditions: adaptive 4 mA, adaptive 4 mA with Relax-button, adaptive 4 mA with historical-Relaxbutton, 2 mA, and sham. A tablet-based stimulator with a participant interface regularly queried VAS pain score and also limited current based on impedance and tolerability. An Abort-button provided in all conditions stopped stimulation. In the adaptive 4 mA with Relax-button and adaptive 4 mA with historical-Relax-button conditions, participants could trigger a Relax-mode ad libitum, in the latter case with incrementally longer current reductions. Primary outcome was the average current delivered during each session, VAS pain score, and adverse event questionnaires. Current delivered was analyzed either excluding or including dropouts who activated Abort (scored as 0 current). Results: There were two dropouts each in the adaptive 4 mA and sham conditions. Resistance based current attenuation was rarely activated, with few automatic VAS pain score triggered relax-modes. In conditions with Relax-button option, there were significant activations often irrespective of VAS pain score. Including dropouts, current across conditions were significantly different from each other with maximum current delivered during adaptive 4 mA with Relax-button. Excluding dropouts, maximum current was delivered with adaptive 4 mA. VAS pain score and adverse events for the sham was only significantly lower than the adaptive 4 mA with Relax-button and adaptive 4 mA with historical-Relaxbutton. There was no difference in VAS pain score or adverse events between 2 mA and adaptive 4 mA. Conclusions: Provided specific electrodes and controllers, adaptive 4 mA tDCS is tolerated and effectively blinded, with acceptability likely higher in a clinical population and absence of regular querying. Indeed, presenting participants with overt controls increases rumination on sensation.

Objective: A recently introduced Spinal Cord Stimulation (SCS) system operates at 10 kHz, faster than conventional SCS systems, resulting in significantly more power delivered to tissues. Using a SCS heat phantom and bioheat multi-physics model, we characterized tissue temperature increases by this 10 kHz system. We also evaluated its Implanted Pulse Generator (IPG) output compliance and the role of impedance in temperature increases. Materials and Methods:The 10 kHz SCS system output was characterized under resistive loads (1-10 KΩ). Separately, fiber optic temperature probes quantified temperature increases (ΔTs) around the SCS lead in specially developed heat phantoms. The role of stimulation Level (1-7; ideal pulse peak-to-peak of 1-7mA) was considered, specifically in the context of stimulation current Root Mean Square (RMS). Data from the heat phantom were verified with the SCS heat-transfer models. A custom high-bandwidth stimulator provided 10 kHz pulses and sinusoidal stimulation for control experiments.Results: The 10 kHz SCS system delivers 10 kHz biphasic pulses (30-20-30 μs). Voltage compliance was 15.6V. Even below voltage compliance, IPG bandwidth attenuated pulse waveform, limiting applied RMS. Temperature increased supralinearly with stimulation Level in a manner predicted by applied RMS. ΔT increases with Level and impedance until stimulator compliance was reached. Therefore, IPG bandwidth and compliance dampen peak heating. Nonetheless, temperature increases predicted by bioheat multi-physic models (ΔT = 0.64 C and 1.42 C respectively at Level 4 and 7 at the cervical segment; ΔT = 0.68 C and 1.72 C respectively at Level 4 and 7 at the thoracic spinal cord)-within ranges previously reported to effect neurophysiology.Conclusions: Heating of spinal tissues by this 10 kHz SCS system theoretically increases quickly with stimulation level and load impedance, while dampened by IPG pulse bandwidth and voltage compliance limitations. If validated in vivo as a mechanism of kHz SCS, bioheat models informed by IPG limitations allow prediction and optimization of temperature changes.

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