Extending the parameter range for tDCS: Safety and tolerability of 4 mA stimulation.

Non-invasive brain stimulation with direct currents (tDCS) is increasingly applied to modulate brain physiology, psychological and motor processes, and behavior in humans. The efficacy of tDCS, similar to other non-invasive brain stimulation (NIBS) protocols, is currently limited, including significant variability in individual response. The potential of tDCS to modify respective physiological and psychological processes safely and to a maximum extent, which is of critical importance for clinical application, has so far not been explored systematically for many potentially important parameters. These include electrode positioning, stimulation duration, intensity, timing in relation to task performance, individualization of stimulation protocols, amongst others. Taking into account non-linear features of neuroplasticity, such as the switch from long term depression to potentiation, depending on intraneuronal calcium concentration [1], and brain state-dependency of tDCS, optimization of stimulation effects is not trivial. Previous studies have shown that prolongation of stimulation duration can lead to a switch of directionality of effects [2], and a similar switch from long-term depression to potentiation-like plasticity has been demonstrated for higher stimulation intensity [3]. Moreover, dependent on baseline excitability, different stimulation intensities seem to have maximum efficacy [4]. Thus systematic exploration of safety and effects of extended tDCS protocols is critical for identification of maximally efficient stimulation approaches. One approach to potentially boost efficacy is increasing stimulation intensity from the conventional limit of 2 mA, but the assumption that higher current boost clinical outcome has not been systematically explored. While animal models suggest a relatively large intensity range of tDCS to enhance neuromodulation at high current densities [5] with no evidence of tissue damage [6], human neurophysiology shows potential non-monotonic effects [3]. Thus, systematic studies to probe extension of tDCS protocol intensity are important. A report in this issue [7] provides initial evidence for the safety of tDCS intensities up to 4 mA. The authors adapted a 3þ3 study design derived mainly from animal studies to probe safety and tolerability of stimulation intensities between 1 and 4 mA for a stimulation duration of 30 min in patients after ischemic stroke, and combined the intervention with occupational therapy. Safety and tolerability of respective protocols were determined via stopping rules in case of serious side effects, tolerability questionnaires, body resistance and skin temperature. The results of this study are in accordance with safety