Safety limits of cathodal transcranial direct current stimulation in rats
Introduction
Weak direct current stimulation is capable of inducing lasting alterations of cortical excitability. The direction of these excitability shifts is determined by current polarity, while their stability is controlled by stimulation duration as well as by current intensity (Bindman et al., 1962, Creutzfeldt et al., 1962, Landau et al., 1963, Purpura and McMurtry, 1965). During recent years, the technique of transcranial direct current stimulation (tDCS) has been successfully transferred to the human cortex (Nitsche and Paulus, 2000, Nitsche and Paulus, 2001, Nitsche et al., 2003a) and has increasingly gained interest among clinical neuroscientists.
Clinical and functional studies propose beneficial effects of tDCS in several neurological and psychiatric disorders including patients with chronic stroke (Hummel et al., 2005, Hummel et al., 2006, Fregni et al., 2005), epilepsy (Fregni et al., 2006a, Liebetanz et al., 2006a), chronic pain (Fregni et al., 2006b), Parkinson’s disease (Fregni et al., 2006c) and major depression (Fregni et al., 2006d, Boggio et al., 2007). Other studies aimed at investigating pharmacological interactions or functional aspects of the induced after effect excitability changes (Liebetanz et al., 2002, Liebetanz et al., 2006b, Antal et al., 2004, Antal et al., 2006, Nitsche et al., 2004a, Nitsche et al., 2004b, Nitsche et al., 2004c, Nitsche et al., 2005, Nitsche et al., 2006, Kincses et al., 2004, Accornero et al., 2007). Although functional and preliminary clinical effects may indicate its therapeutic potential, the after effects of tDCS so far have been limited in their duration to a few hours.
Clinicians would potentially aim for excitability changes lasting up to several weeks, or at least several days. As early as the 1960s Lynn Bindman found that after effects can be enhanced by using repeated DC stimulations (Bindman et al., 1964). Although the latter approach has hitherto not been approved in humans, two clinical studies applied tDCS in a repetitive design, assuming that the induced effects would become more prominent and stable (Fregni et al., 2006a, Fregni et al., 2006d). Finally, in addition to physical parameters, tDCS after effects have been stabilized for at least 24 h when combined with pharmacological interventions (Nitsche et al., 2004b, Nitsche et al., 2004c, Nitsche et al., 2005, Nitsche et al., 2006).
However, a major concern for treatment with tDCS is related to its safeness, particularly when paradigms with increased intensities or prolonged stimulation durations are applied. While current safety considerations for the application of tDCS in humans are based on measurements of neuron-specific enolase, MRI and EEG data from human tDCS studies (Nitsche et al., 2003a, Nitsche et al., 2004d, Iyer et al., 2005) as well as on the adoption of safety limits stated by Agnew and McCreery (1987) for pulsed electrical stimulation, no studies are available which explored the safety limits of tDCS systematically. Moreover, most animal studies investigated only behavioural and neurophysiologic effects but not specifically the safety aspects of DC stimulation. Therefore, only little is known about potential harmful effects of continuous weak DC stimulation. At present, our incomplete knowledge about potentially deleterious effects limits the development of intensified tDCS regimes, which could prove to be therapeutically relevant in neurological and psychiatric disorders which would benefit from long-lasting changes of cortical excitability. To partly close this gap, we present here a first experimental approach to the potentially harmful effects and safety limits of cathodal tDCS in a recently introduced tDCS rat model (Liebetanz et al., 2006a, Liebetanz et al., 2006b).
Section snippets
Material and methods
All experiments were conducted in accordance with the “Guide for the Care and Use of Laboratory Animals of the NIH” and were ethically approved by the Government of Lower Saxony. The experiments were performed on 62 Wistar rats of both sexes (mean body weight 310 ± 24 g). Animals were kept in single cages under standard laboratory conditions, with food and water ad libitum.
Threshold for brain lesion of cathodal tDCS
Histological analysis of the escalating stimulation regime revealed no signs of any current-induced neurotrauma from single tDCS when applying current strength intensities from 1 to 100 μA at stimulation durations from 10 to 270 min (see Table 1). However, when applied above a certain threshold, tDCS resulted in a focal brain lesion directly beneath the epicranial cathode (Fig. 2). The earliest visible signs of such lesions were detected in brains which received cathodal tDCS for 10 min at a
Discussion
The results of this systematic animal safety study demonstrate that cathodal tDCS is able to cause severe neuronal damage when it is applied above a certain charge density. For cathodal current densities between 142.9 and 287 A/m2, no pathological brain lesions were observed below a charge density threshold of 52400 C/m2. This threshold is at least 2 orders of magnitude higher than those charge densities currently being applied in clinical studies (171–480 C/m2). Moreover, for cathodal current
Acknowledgements
We thank C. Bunker for revising the English and A. Dettmar for technical assistance. This project was supported by the Deutsche Forschungsgemeinschaft (DL) (Grant No. Li/1016/3-1).
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