David Liebetanz

Pharmacological Modulation of Cortical Excitability Shifts Induced by Transcranial Direct Current Stimulation in Humans

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.

Facilitation of Implicit Motor Learning by Weak Transcranial Direct Current Stimulation of the Primary Motor Cortex in the Human

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.

Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex.

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.

Modulation of cortical excitability by weak direct current stimulation--technical, safety and functional aspects.

Publisher Summary Achieving short- or even long-term neuroplastic functional modifications of cortical networks through the modulation of activity and excitability of neuronal ensembles has been the focus of many research activities in the last decades. The application of weak direct currents has been shown to elicit cortical excitability and activity shifts during, and after the end of stimulation in animals and humans, and thus could evolve as a promising technique in this field of research. In animals, intracortical or epidural electrodes have been used for direct current (DC) stimulation. Weak direct currents can be applied to humans non-invasively, transcranially and painlessly to induce focal, prolonged, but yet reversible shifts of cortical excitability, the duration and direction of which depend on stimulation duration and polarity. This chapter provides an overview of the basic and functional effects of weak direct current stimulation in animals and in humans. The chapter discusses the technical considerations and summarizes the available safety criteria that are expected to prevent harmful or unwanted effects of the stimulation.

Induction of Late LTP-Like Plasticity in the Human Motor Cortex by Repeated Non-Invasive Brain Stimulation

BACKGROUND Non-invasive brain stimulation enables the induction of neuroplasticity in humans, however, with so far restricted duration of the respective cortical excitability modifications. Conventional anodal transcranial direct current stimulation (tDCS) protocols including one stimulation session induce NMDA receptor-dependent excitability enhancements lasting for about 1 h. OBJECTIVE We aimed to extend the duration of tDCS effects by periodic stimulation, consisting of two stimulation sessions, since periodic stimulation protocols are able to induce neuroplastic excitability alterations stable for days or weeks, termed late phase long term potentiation (l-LTP), in animal slice preparations. Since both, l-LTP and long term memory formation, require gene expression and protein synthesis, and glutamatergic receptor activity modifications, l-LTP might be a candidate mechanism for the formation of long term memory. METHODS The impact of two consecutive tDCS sessions on cortical excitability was probed in the motor cortex of healthy humans, and compared to that of a single tDCS session. The second stimulation was applied without an interval (temporally contiguous tDCS), during the after-effects of the first stimulation (during after-effects; 3, or 20 min interval), or after the after-effects of the first stimulation had vanished (post after-effects; 3 or 24 h interval). RESULTS The during after-effects condition resulted in an initially reduced, but then relevantly prolonged excitability enhancement, which was blocked by an NMDA receptor antagonist. The other conditions resulted in an abolishment, or a calcium channel-dependent reversal of neuroplasticity. CONCLUSION Repeated tDCS within a specific time window is able to induce l-LTP-like plasticity in the human motor cortex.

Consolidation of Human Motor Cortical Neuroplasticity by D -Cycloserine

D-Cycloserine (CYC), a partial N-methyl-D-aspartate (NMDA) agonist, has been shown to improve cognitive functions in humans. However, the neurophysiological basis of this effect is unclear so far. We studied the impact of this drug on long-lasting after-effects of transcranial direct current (tDCS)-generated motor cortical excitability shifts, as revealed by transcranial magnetic stimulation-elicited motor-evoked potentials. While anodal tDCS enhances motor cortical excitability, cathodal tDCS diminishes it. Both effects seem to be NMDA receptor dependent. D-CYC selectively potentiated the duration of motor cortical excitability enhancements induced by anodal tDCS. D-CYC alone did not modulate excitability. The potency of this drug to consolidate neuronal excitability enhancements, most probably by stabilizing the strengthening of NMDA receptors, which is a probable neurophysiological derivate of learning processes, makes it an interesting substance to improve cognitive functions.

Safety limits of cathodal transcranial direct current stimulation in rats

OBJECTIVE The aim of this rat study was to investigate the safety limits of extended transcranial direct current stimulation (tDCS). tDCS may be of therapeutic value in several neuro-psychiatric disorders. For its clinical applicability, however, more stable effects are required, which may be induced by intensified stimulations. METHODS Fifty-eight rats received single cathodal stimulations at 1-1000 microA for up to 270 min through an epicranial electrode (3.5 mm(2)). Histological evaluation (H&E) was performed 48 h later. A threshold estimate was calculated from volumes of DC-induced lesions. RESULTS Brain lesions occurred at a current density of 142.9 A/m(2) for durations greater than 10 min. For current densities between 142.9 and 285.7 A/m(2), lesion size increased linearly with charge density; with a calculated zero lesion size intercept of 52,400 C/m(2). Brains stimulated below either this current density or charge density threshold, including stimulations over 5 consecutive days, were morphologically intact. CONCLUSION The experimentally determined threshold estimate is two orders of magnitude higher than the charge density currently applied in humans (171-480 C/m(2)). In relation to transcranial DC stimulation in humans the rat epicranial electrode montage may provide for an additional safety margin. SIGNIFICANCE Although these results cannot be directly transferred to humans, they encourage the development intensified tDCS protocols. Further animal studies are required, before such protocols can be applied in humans.

Dopaminergic modulation of long-lasting direct current-induced cortical excitability changes in the human motor cortex

Dopaminergic mechanisms participate in N‐methyl‐d‐aspartate (NMDA) receptor‐dependent neuroplasticity, as animal experiments have shown. This may be similar in humans, where dopamine influences learning and memory. We tested the role of dopamine in human cortical neuroplasticity. Changes of excitability were induced by transcranial direct current stimulation (tDCS). D2 receptor blocking by sulpiride abolished the induction of after‐effects nearly completely. D1 activation alone in the presence of D2 receptor blocking induced by co‐administration of sulpiride and pergolide did not re‐establish the excitability changes induced by tDCS. This suggests that D2 receptors play a major supporting role in inducing neuroplasticity in the human motor cortex. Enhancement of D2 and, to a lesser degree, D1 receptors by pergolide consolidated tDCS‐generated excitability diminution until the morning after stimulation. The readiest explanation for this pattern of results is that D2 receptor activation has a consolidation‐enhancing effect on tDCS‐induced changes of excitability in the human cortex. The results of this study underscore the importance of the dopaminergic system for human neuroplasticity, suggest a first pharmacological add‐on mechanism to prolong the excitability‐diminishing effects of cathodal tDCS for up to 24 h after stimulation, and thus render the application of tDCS practicable in diseases displaying enhanced cortical excitability, e.g. migraine and epilepsy.

GABAergic modulation of DC stimulation-induced motor cortex excitability shifts in humans.

Weak transcranial DC stimulation (tDCS) of the human motor cortex results in excitability shifts during and after the end of stimulation, which are most probably localized intracortically. Anodal stimulation enhances excitability, whereas cathodal stimulation reduces it. Although the after‐effects of tDCS are NMDA receptor‐dependent, nothing is known about the involvement of additional receptors. Here we show that pharmacological strengthening of GABAergic inhibition modulates selectively the after‐effects elicited by anodal tDCS. Administration of the GABAA receptor agonist lorazepam resulted in a delayed, but then enhanced and prolonged anodal tDCS‐induced excitability elevation. The initial absence of an excitability enhancement under lorazepam is most probably caused by a loss of the anodal tDCS‐generated intracortical diminution of inhibition and enhancement of facilitation, which occurs without pharmacological intervention. The reasons for the late‐occurring excitability enhancement remain unclear. Because intracortical inhibition and facilitation are not changed in this phase compared with pre‐tDCS values, excitability changes originating from remote cortical or subcortical areas could be involved.

A technical guide to tDCS, and related non-invasive brain stimulation tools.

Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain.