Jonathan A Norton (1,2), Hollie A Power (1), & K Ming Chan (1,3)
1: Centre for Neuroscience, 2: Department of Surgery and 3: Division of Physical Medicine and Rehabilitation, University of Alberta, Edmonton, Alberta, Canada

https://doi.org/10.36866/pn.70.28

In recent years there has been an increase in interest in techniques that can modify the excitability of the motor cortex. It is widely believed, with some experimental evidence, that if the excitability of the cortex can be increased then rehabilitation strategies after neurological insults may be more efficacious. Three techniques have emerged, or re-emerged, that offer the potential to modify the excitability of the cortex: repetitive transcranial magnetic stimulation (rTMS), paired associative stimulation (PAS) and direct current stimulation (tDCS). While the first two of these approaches may act through spike-timing dependent plasticity (at least for PAS), the third approach is different in nature. In this strategy, a comparatively low level constant DC field is applied across the motor cortex through electrodes placed on the scalp. The time course of the intervention and the effects are similar across all three protocols, with each intervention lasting about 10 minutes and its effects lasting for around an hour. Clinically tDCS shows considerable promise since the effects appear comparable to other cortical excitability modifying protocols but the equipment is substantially cheaper than that required for either PAS or rTMS. Since the intervention does not require the application of any large magnetic fields, it can be applied to a wider population, including those who have had neurosurgical aneurysm clipping (i.e. in some stroke and traumatic brain injured patients).

We have recently shown that DC stimulation affects the cortical control of a movement, as assessed by intermuscular coherence (Power et al. 2006). Typically the currents applied at the scalp are of the order of 1mA. The two electrodes are positioned over motor cortex, contralateral to the muscle/limb of interest and over the opposite forehead (i.e. ipsilateral to the muscle/limb of interest). In Fig. 1 we illustrate a tDCS experimental set-up, and typical results from an experiment in which cathodal stimulation was applied. Briefly, there is a decrease in the amplitude of the MEPs, area of β-band coherence and region of activation of the cortex assessed using fMRI. In this review, we will examine some of the recent evidence regarding the possible cellular mechanisms of action of tDCS (Fig. 2).

It appears that the response to tDCS is not just at the level of the pyrimdal tract neuron (PTN) itself but rather primarily at the level of the interneurons projecting onto the PTNs, since tDCS does not alter the amplitude of TES-evoked MEPs. NMDA-glutamate receptors are known to be important for the induction of cortical neuroplasticity in long-term potentiation and depression. Strikingly, administration of the NMDA receptor-antagonist dextrometh-orphane completely eliminated both the short- and long-lasting after-effects of tDCS, independent of stimulation polarity (Liebetanz et al. 2002; Nitsche et al. 2003). In addition, GABAergic mechanisms are also likely involved in the after-effects of tDCS as Nitsche et al. (2004) showed that administration of lorazepam, a GABAA receptor agonist, resulted in late enhance-ment of excitability following anodal tDCS. The reasons for the delay are not clear, even though remote mechanisms such as connections with cortico-thalamic and nigrostriatal neurons could be at play because they primarily use GABA as their inhibitory neurotransmitter. In contrast, cathodal tDCS after-effects were not affected by lorazepam. Since benzodiazepines do not directly activate GABA receptors themselves, but rather facilitate the transmission of already active receptors, this finding cannot exclude inhibition of the GABAergic system in the cathodal after-effects.

Several animal studies have demonstrated the importance of dopaminergic mechanisms in NMDA receptor-mediated neuroplasticity. Similarly, studies examining various types of learning have shown that dopaminergic systems are important in human neuroplasticity. Nitsche et al. (2006) found that by administering a D2-receptor antagonist, sulpiride, the after-effects of tDCS were completely abolished. However, co-administration of pergolide, a D2/D1-receptor agonist with sulpiride, could not re-establish the excitability changes induced by tDCS, indicating that D1 receptor activation alone is not capable of restoring tDCS after-effects. In contrast, when pergolide was administered alone without sulpiride, it caused the tDCS-generated excitability changes to last for up to 24 hours after stimulation, suggesting that activation of D2-receptors has a consolidation-enhancing effect on the excitability changes induced by tDCS. These findings are potentially interesting because the administration of D2 agonists may allow use of tDCS as a therapeutic tool to produce sustained changes in motor cortical excitability.

Additionally, non-synaptic mechanisms are likely also involved in the after effects of tDCS. Liebetanz et al. (2002) showed that administration of carbamazepine, a Na+ channel blocker, selectively eliminated the short-lasting after-effects of anodal tDCS. This result is in accordance with early animal studies demonstrating that anodal tDCS involves depolarization of the neuronal membrane. A similar result was obtained for the Ca2+ channel blocker flunarizine (Nitsche et al. 2003). The fact that these voltage-dependent drugs had no effect on cathodal stimulation is perhaps not surprising since the hyperpolarization that occurs with cathodal tDCS already results in inactivation of the Na+ and Ca2+ channels.

Taking the studies demonstrating changes in TMS, but not TES evoked MEPs, the functional imaging studies and the new data on intermuscular coherence it is becoming increasingly evident that the intra-cortical networks are predominantly affected by the actions of tDCS. In addition to establishing the basis of tDCS as a potentially useful therapeutic method, these mechanistic insights may also allow tDCS to be used as a diagnostic tool.

Acknowledgements

Work in the authors’ laboratories is supported by the Alberta Heritage Foundation for Medical Research, the Canadian Institutes of Health Research, the National Institutes of Health and the Canadian Foundation for Innovation. The authors are grateful to their colleagues in the Centre for Neuroscience, especially MA Gorassini, KE Jones and RB Stein for many helpful discussions concerning cortical excitability and rehabilitation.

References

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