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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.

Transcranially applied weak direct currents are capable of modulating motor cortical excitability in the human. Anodal stimulation enhances excitability, cathodal stimulation diminishes it. Cortical excitability changes accompany motor learning. Here we show that weak direct currents are capable of improving implicit motor learning in the human. During performance of a serial reaction time task, the primary motor cortex, premotor, or prefrontal cortices were stimulated contralaterally to the performing hand. Anodal stimulation of the primary motor cortex resulted in increased performance, whereas stimulation of the remaining cortices had no effect. We conclude that the primary motor cortex is involved in the acquisition and early consolidation phase of implicit motor learning.

Transcranial DC stimulation (tDCS) induces stimulation polarity-dependent neuroplastic excitability shifts in the human brain. Because it accomplishes long-lasting effects and its application is simple, it is used increasingly. However, one drawback is its low focality, caused by 1) the large stimulation electrode and 2) the functionally effective reference electrode, which is also situated on the scalp. We aimed to increase the focality of tDCS, which might improve the interpretation of the functional effects of stimulation because it will restrict its effects to more clearly defined cortical areas. Moreover, it will avoid unwanted reversed effects of tDCS under the reference electrode, which is of special importance in clinical settings, when a homogeneous shift of cortical excitability is needed. Because current density (current strength/electrode size) determines the efficacy of tDCS, increased focality should be accomplished by 1) reducing stimulation electrode size, but keeping current density constant; or 2) increasing reference electrode size under constant current strength. We tested these hypotheses for motor cortex tDCS. The results show that reducing the size of the motor cortex DC-stimulation electrode focalized the respective tDCS-induced excitability changes. Increasing the size of the frontopolar reference electrode rendered stimulation over this cortex functionally inefficient, but did not compromise the tDCS-generated motor cortical excitability shifts. Thus tDCS-generated modulations of cortical excitability can be focused by reducing the size of the stimulation electrode and by increasing the size of the reference electrode. For future applications of tDCS, such paradigms may help to achieve more selective tDCS effects.

Weak transcranial direct current stimulation (tDCS) of the human motor cortex results in excitability shifts which occur during and after stimulation. These excitability shifts are polarity-specific with anodal tDCS enhancing excitability, and cathodal reducing it. To explore the origin of this excitability modulation in more detail, we measured the input-output curve and motor thresholds as global parameters of cortico-spinal excitability, and determined intracortical inhibition and facilitation, as well as facilitatory indirect wave (I-wave) interactions. Measurements were performed during short-term tDCS, which elicits no after-effects, and during other tDCS protocols which do elicit short-and long-lasting after-effects. Resting and active motor thresholds remained stable during and after tDCS. The slope of the input-output curve was increased by anodal tDCS and decreased by cathodal tDCS. Anodal tDCS of the primary motor cortex reduced intracortical inhibition and enhanced facilitation after tDCS but not during tDCS. Cathodal tDCS reduced facilitation during, and additionally increased inhibition after its administration. During tDCS, I-wave facilitation was not influenced but, for the after-effects, anodal tDCS increased I-wave facilitation, while cathodal tDCS had only minor effects. These results suggest that the effect of tDCS on cortico-spinal excitability during a short period of stimulation (which does not induce after-effects) primarily depends on subthreshold resting membrane potential changes, which are able to modulate the input-output curve, but not motor thresholds. In contrast, the after-effects of tDCS are due to shifts in intracortical inhibition and facilitation, and at least partly also to facilitatory I-wave interaction, which is controlled by synaptic activity.

Transcranial direct current stimulation (tDCS) of the primary motor hand area (M1) can produce lasting polarity-specific effects on corticospinal excitability and motor learning in humans. In 16 healthy volunteers, positron emission tomography (PET) of regional cerebral blood flow (rCBF) at rest and during finger movements was used to map lasting changes in regional synaptic activity following 10 min of tDCS (± 1 mA). Bipolar tDCS was given through electrodes placed over the left M1 and right frontopolar cortex. Eight subjects received anodal or cathodal tDCS of the left M1, respectively. When compared to sham tDCS, anodal and cathodal tDCS induced widespread increases and decreases in rCBF in cortical and subcortical areas. These changes in rCBF were of the same magnitude as task-related rCBF changes during finger movements and remained stable throughout the 50-min period of PET scanning. Relative increases in rCBF after real tDCS compared to sham tDCS were found in the left M1, right frontal pole, right primary sensorimotor cortex and posterior brain regions irrespective of polarity. With the exception of some posterior and ventral areas, anodal tDCS increased rCBF in many cortical and subcortical regions compared to cathodal tDCS. Only the left dorsal premotor cortex demonstrated an increase in movement related activity after cathodal tDCS, however, modest compared with the relatively strong movement-independent effects of tDCS. Otherwise, movement related activity was unaffected by tDCS. Our results indicate that tDCS is an effective means of provoking sustained and widespread changes in regional neuronal activity. The extensive spatial and temporal effects of tDCS need to be taken into account when tDCS is used to modify brain function.

Recent experimental work in animals has emphasized the importance of homeostatic plasticity as a means of stabilizing the properties of neuronal circuits. Here, we report a phenomenon that indicates a homeostatic pattern of cortical plasticity in healthy human subjects. The experiments combined two techniques that can produce long-term effects on the excitability of corticospinal output neurons: transcranial direct current stimulation (TDCS) and repetitive transcranial magnetic stimulation (rTMS) of the left primary motor cortex. "Facilitatory preconditioning" with anodal TDCS caused a subsequent period of 1 Hz rTMS to reduce corticospinal excitability to below baseline levels for Ͼ20 min. Conversely, "inhibitory preconditioning" with cathodal TDCS resulted in 1 Hz rTMS increasing corticospinal excitability for at least 20 min. No changes in excitability occurred when 1 Hz rTMS was preceded by sham TDCS. Thus, changing the initial state of the motor cortex by a period of DC polarization reversed the conditioning effects of 1 Hz rTMS. These preconditioning effects of TDCS suggest the existence of a homeostatic mechanism in the human motor cortex that stabilizes corticospinal excitability within a physiologically useful range.

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