Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans

Abstract

Transcranial direct current stimulation (tDCS) of the human motor cortex results in polarity-specific shifts of cortical excitability during and after stimulation. Anodal tDCS enhances and cathodal stimulation reduces excitability. Animal experiments have demonstrated that the effect of anodal tDCS is caused by neuronal depolarisation, while cathodal tDCS hyperpolarises cortical neurones. However, not much is known about the ion channels and receptors involved in these effects. Thus, the impact of the sodium channel blocker carbamazepine, the calcium channel blocker flunarizine and the NMDA receptor antagonist dextromethorphane on tDCS-elicited motor cortical excitability changes of healthy human subjects were tested. tDCS-protocols inducing excitability alterations (1) only during tDCS and (2) eliciting long-lasting after-effects were applied after drug administration. Carbamazepine selectively eliminated the excitability enhancement induced by anodal stimulation during and after tDCS. Flunarizine resulted in similar changes. Antagonising NMDA receptors did not alter current-generated excitability changes during a short stimulation, which elicits no after-effects, but prevented the induction of long-lasting after-effects independent of their direction. These results suggest that, like in other animals, cortical excitability shifts induced during tDCS in humans also depend on membrane polarisation, thus modulating the conductance of sodium and calcium channels. Moreover, they suggest that the after-effects may be NMDA receptor dependent. Since NMDA receptors are involved in neuroplastic changes, the results suggest a possible application of tDCS in the modulation or induction of these processes in a clinical setting. The selective elimination of tDCS-driven excitability enhancements by carbamazepine proposes a role for this drug in focussing the effects of cathodal tDCS, which may have important future clinical applications.

Figures

Figure 1. Drug-induced modulation of tDCS-driven cortical excitability changes during stimulation

As the results show, the enhancement in anodal tDCS-generated cortical excitability is eliminated by CBZ and reduced by FLU, but not modulated by DMO. Conversely, none of the applied drugs changed the cathodal stimulation-elicited cortical excitability reduction. Due to different subject groups, PLC values differ from FLU values on the one hand and DMO/CBZ values on the other. Asterisks indicate significant deviations of the current from the non-current conditions and differences between the drug conditions regarding identical current conditions (Student's t test, two-tailed, paired samples, P < 0.05). Error bars indicate s.e.m.

Figure 2. The neuronal excitability shifts during tDCS are localised proximal to the spinal motor neurone

TMS-generated MEPs and F-waves were elicited during short-lasting tDCS, which elicits no after-effects. Whereas anodal tDCS diminished the MEP amplitudes and area under the curve significantly, and cathodal stimulation resulted in reverse effects, F-waves were not changed by tDCS. Asterisks indicate significant deviations of the current from the respective non-current conditions (Student's t test, two-tailed, repeated measures, P < 0.05). Error bars indicate s.e.m.

Figure 3. Sodium channel blockade selectively prevents the anodal stimulation after-effect

Blocking sodium channels with the aid of the voltage-dependently acting CBZ resulted in complete abolition of the prolonged excitability enhancement caused by anodal tDCS in the PLC condition. Asterisks indicate significant differences between the drug conditions regarding identical current conditions and time points, filled symbols represent significant deviations from baseline in regard to each drug condition (Student's t test, two-tailed, repeated measures, P < 0.05). a, anodal; c, cathodal. Error bars indicate s.e.m.

Figure 4. Calcium channel blockade eliminates only the anodal tDCS-induced after-effects on cortical excitability

Blocking calcium channels with the aid of FLU resulted in complete abolition of the prolonged excitability enhancement caused by anodal tDCS in the PLC condition. Asterisks indicate significant differences between the drug conditions regarding identical current conditions and time points, filled symbols signify significant deviations from baseline in regard to each drug condition (Student's t test, two-tailed, repeated measures, P < 0.05). Error bars indicate s.e.m.

Figure 5. The NMDA receptor antagonist DMO eliminates the after-effects induced by both anodal and cathodal tDCS

Blocking NMDA receptors abolished any after-effect caused by prolonged tDCS, thus favouring a prominent role of this receptor in the evolvement of neuroplastic effects induced by this kind of stimulation. Asterisks indicate significant differences between the drug conditions regarding identical current conditions and time points, filled symbols significant deviations from baseline in regard to each drug condition (Student's t test, two-tailed, repeated measures, P < 0.05). Error bars indicate s.e.m.