Quite simple at first glance – complex at a second: modulating neuronal activity by tDCS

Transcranial direct current stimulation (tDCS) is a simple and comfortable way to influence brain activity compared to other methods such as transcranial magnetic stimulation (TMS). It is also easily portable and cheap, and has therefore become a popular method of non-invasive brain stimulation that can be used for example, during walking, or at home. In contrast to TMS, tDCS does not elicit action potentials in neurones; instead it is thought to increase or decrease neuronal excitability and spontaneous activity in the same way as some neuromodulatory transmitters such as noradrenaline. tDCS is usually given via two electrodes placed on the scalp, one above a target brain region, which is often assumed to be a cortical area, and the other at a remote site such as the opposite side of the head. A small (1–2 mA) constant current is passed between the electrodes, part of which enters the brain and polarizes cell membranes, in the same way as it might affect a series of electrical capacitors. Most interestingly, tDCS not only modifies neural activity during stimulation, it also has after-effects that outlast the stimulation. The effects vary with duration and polarity of the applied electrical field. Stimulation over the motor cortex increases corticospinal excitability as tested by TMS if the electrode is connected to the positive pole of the tDCS (anode), whereas it is reduced if the electrode is connected to the cathode (for a review of tDCS effects see Brunoni et al. 2012). It is assumed that similar effects occur in all other areas of cortex. It is likely that polarization changes the resting membrane potential of neurones and thereby affects voltage- or charge-gated ion channels such as NMDA receptors, and other molecules within the membrane or peri-membrane matrix (see Brunoni et al. 2012). The cells most likely to be affected by tDCS are the pyramidal neurones, with their long apical dendrites. The bipolar characteristic of the pyramidal neurones, aligned perpendicular to the cortical surface, generates an across-layer electrical field during natural activity that is the basis of EEG measurement. The same characteristic makes them sensitive to artificially induced electric fields. Anodal tDCS should hyperpolarize the apical dendrite and depolarize the soma and initial axon element, lowering the threshold for action potential generation. In addition, lasting changes in neuronal excitability may result from altered calcium influx during stimulation which interacts with mechanisms of synaptic plasticity, or changes the local distribution of receptors and ion channels. Up to this point, the story is quite simple, suggesting that it is possible to increase or decrease the excitability of a specific cortical area with the correct placement and polarity of the stimulating electrodes. Now, two excellent studies, performed by the group of Elzbieta Jankowska in rats (Bolzoni et al. 2013a) and cats (Bolzoni et al. 2013b) and published in this and a recent issue of The Journal of Physiology, respectively, demonstrate that tDCS not only influences neurons remote from the electrodes but that the effects of tDCS polarity can be opposite in different experimental models. In the first study, Bolzoni et al. (2013b) recorded descending volleys of motor activity from the surface of the cervical spinal cord of cats by electrically stimulating red nucleus (RN), medial longitudinal fascicle (MLF) and pyramidal tract (PT). Application of anodal tDCS to the scalp increased the size and shortened the latency of these volleys, while cathodal stimulation tended to do the opposite. Indirect volleys evoked trans-synaptically in neurons of the RN and mesencephalic reticular formation (MRF) were more affected than direct volleys evoked by stimulating their spinally projecting axons. Thus, in this model, neurons within RN and MRF of cat show (i) much the same facilitation of evoked activity as assumed for corticospinal output in humans, and (ii) the effect is particularly strong on synaptic inputs to these neurons. The question is whether tDCS might also activate these brain regions in humans. The authors analysed images in a PET study performed by Lang et al. (2005) during tDCS of human M1 and pointed out that anodal tDCS, changed blood flow in many other regions than M1, and in particular increased regional blood flow in the region of RN and MRF. In a follow-up study, the authors tested if the same tDCS effects occur in the smaller brains of rats. They recorded EMG responses in addition to the motor volleys descending in spinal cord (Bolzoni et al. 2013a). Two surprising findings emerged: (i) in rats, cathodal tDCS facilitated brain stem evoked motor activity whereas anodal tDCS tended to have a depressive effect; and (ii) EMG responses were facilitated more than descending volleys, indicating that the increase in RN and MRF is further amplified at the level of the spinal motor neurons. The differences in polarity-related effects are likely to be related to differences between humans, cats and rats in geometry and density of the induced intracranial current, possibly resulting in a different composition of cortical and subcortical structures with increased or decreased excitability. The two studies indicate that much more happens between two tDCS electrodes than has been usually assumed, and that subcortical structures can potentiate or counteract the cortical effect depending on intracranial electric field geometry and morphology of the stimulated neurons.