Safety parameter considerations of anodal transcranial Direct Current Stimulation in rats

Abstract

A commonly referenced transcranial Direct Current Stimulation (tDCS) safety threshold derives from tDCS lesion studies in the rat and relies on electrode current density (and related electrode charge density) to support clinical guidelines. Concerns about the role of polarity (e.g. anodal tDCS), sub-lesion threshold injury (e.g. neuroinflammatory processes), and role of electrode montage across rodent and human studies support further investigation into animal models of tDCS safety. Thirty-two anesthetized rats received anodal tDCS between 0–5 mA for 60 minutes through one of three epicranial electrode montages. Tissue damage was evaluated using hemotoxylin and eosin (H&E) staining, Iba-1 immunohistochemistry, and computational brain current density modeling. Brain lesion occurred after anodal tDCS at and above 0.5 mA using a 25.0 mm2 electrode (electrode current density: 20.0 A/m2). Lesion initially occurred using smaller 10.6 mm2 or 5.3 mm2 electrodes at 0.25 mA (23.5 A/m2) and 0.5 mA (94.2 A/m2), respectively. Histological damage was correlated with computational brain current density predictions. Changes in microglial phenotype occurred in higher stimulation groups. Lesions were observed using anodal tDCS at an electrode current density of 20.0 A/m2, which is below the previously reported safety threshold of 142.9 A/m2 using cathodal tDCS. The lesion area is not simply predicted by electrode current density (and so not by charge density as duration was fixed); rather computational modeling suggests average brain current density as a better predictor for anodal tDCS. Nonetheless, under the assumption that rodent epicranial stimulation is a hypersensitive model, an electrode current density of 20.0 A/m2 represents a conservative threshold for clinical tDCS, which typically uses an electrode current density of 2 A/m2 when electrodes are placed on the skin (resulting in a lower brain current density).

Charge density, not current density, is a more comprehensive safety measure of transcranial direct current stimulation

“…1 that the transcranial direct current stimulation (tDCS) threshold for causing brain lesion in a rat model is well below that previously reported by Liebetanz et al . 2 Jackson et al .…”

“…1–3 To conclude, by expressing tDCS dosage levels with current density instead of charge density, we believe that Jackson et al . 1 have reached an incorrect conclusion regarding safety limits for animal brain. We mathematically demonstrate that when charge density is used to represent tDCS dosage, the safety limits established by Liebetanz et al .…”

“…2 Jackson et al . 1 used current density at the electrode as the primary measure of tDCS dosage, effectively ignoring that the duration of stimulation was 6-times that used in Liebetanz et al . 2 However, duration is an important factor in electrical stimulation protocols.…”

Quantitative reassessment of safety limits of tDCS for two animal studies

“…[1] with great interest. The authors concluded that the threshold for causing a brain lesion in a rat model using transcranial direct current stimulation (tDCS) is well below the level previously reported by Liebetanz et al [2] Using a computational modeling approach, they also indicated that current density at the level of the brain is a better predictor of brain damage than current density at the level of electrode or electrode-skin interface.…”

“…[2] still offers an estimate of tDCS dose that may result in brain injury that is conservative by an order of magnitude. [1]…”