Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines.

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1-2mA and during tACS at higher peak-to-peak intensities above 2mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity 'conventional' TES defined as <4mA, up to 60min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3-13A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6-7, 2016 and were refined thereafter by email correspondence.

Precaution for volume conduction in rodent cortical electroencephalography using high-density polyimide-based microelectrode arrays on the skull.

In humans, significant progress has been made to link spatial changes in electroencephalographic (EEG) spectral density, connectivity strength, and phase-amplitude modulation to neurological, physiological, and psychological correlates. In contrast, standard rodent EEG techniques employ only few electrodes, which results in poor spatial resolution. Recently, a technique was developed to overcome this limitation in mice. This technique was based on a polyimide-based microelectrode (PBM) array applied on the mouse skull, maintaining a significant number of electrodes with consistent contact, electrode impedance, and mechanical stability. The present study built on this technique by extending it to rats. Therefore, a similar PBM array, but adapted to rats, was designed and fabricated. In addition, this array was connected to a wireless EEG headstage, allowing recording in untethered, freely moving rats. The advantage of a high-density array relies on the assumption that the signal recorded from the different electrodes is generated from distinct sources, i.e., not volume-conducted. Therefore, the utility and validity of the array were evaluated by determining the level of synchrony between channels due to true synchrony or volume conduction during basal vigilance states and following a subanesthetic dose of ketamine. Although the PBM array allowed recording with high signal quality, under both drug and drug-free conditions, high synchronization existed due to volume conduction between the electrodes even in the higher spectral frequency range. Discrimination existed only between frontally and centrally/distally grouped electrode pairs. Therefore, caution should be used in interpreting spatial data obtained from high-density PBM arrays in rodents.