Beyond the target area: remote effects of non-invasive brain stimulation in humans

Non-invasive brain stimulation of the human cerebral cortex is increasingly used to explore and modulate brain functions. Especially, stimulation protocols inducing long-lasting neuroplastic alterations of cortical excitability have attracted increasing attention for their ability to mimic and modulate respective naturally occurring dynamic alterations of brain function, their suitability to alter plasticity-related cognitive processes, such as learning and memory formation, and their potential to serve as a therapeutic tool for the treatment of neuropsychiatric diseases accompanied by pathological alterations of plasticity. One of these techniques is termed transcranial direct current stimulation (tDCS). Here the resting membrane potential of cortical neurons is modulated by tonic application of direct currents via scalp electrodes, resulting in stimulation polarity-dependent enhancement or reduction of cortical excitability over the target area, which can outlast the stimulation for more than 1 h, if tDCS is applied sufficiently long. Because of the duration of the aftereffects and their NMDA receptor dependency, these share some similarities with long term potentiation and depression, as obtained in animal experiments (Nitsche et al. 2008).

Most of the studies exploring the physiology of tDCS are dedicated to local effects on the hand area of the primary motor cortex, probably due to the relatively high proneness of this area to neuroplastic alterations, and the ease by which the respective excitability changes can be monitored by transcranial magnetic stimulation-induced motor evoked potentials (MEPs). In contrast, beyond the demonstration that anodal tDCS is able to enhance excitability of the respective target muscles (Jeffery et al. 2007), studies exploring the effects of tDCS on the excitability of the lower limb motor cortex are rare. The same holds true for effects of tDCS on the motor system level. With regard to the latter, so far only a few studies for motor hand representations are available, which have demonstrated that tDCS induces widespread changes of cerebral activity at cortical and subcortical levels, alters functional connectivity between the primary motor cortex and motor association cortices, and affects motor system excitability at the spinal network level (Lang et al. 2005; Roche et al. 2009; Polanía et al. 2011). Studies exploring the effects of motor cortex tDCS on excitability of lower limb representations in larger detail are thus urgently needed, both for exploring the physiology of the motor system in humans and for the development of stimulation protocols, which might be able to treat malfunctions of the motor system.

In an article in a recent issue of The Journal of Physiology, Roche et al. (2011) have addressed this need. They explored the effect of excitability-enhancing anodal tDCS with the electrode centred over the leg representation of primary motor cortex engaged in dorsiflection of the foot on excitability alterations of the soleus muscle (SOL), which is involved in plantarflexion, at global corticospinal and spinal levels. tDCS had specific effects on spinal network excitability, as reciprocal inhibition from the antagonist tibialis anterior muscle (TA) to SOL was diminished during tDCS, while recurrent intrinsic inhibition of SOL was enhanced. Moreover, in accordance with a fairly non-focal effect of tDCS, which was performed via relatively large stimulation electrodes (35 cm² size) centred over the hot spot of the TA, on motor cortex excitability, the results show an enhancement of corticospinal excitability of the SOL representation. These results enhance our knowledge about the effects of tDCS over leg representations of the primary motor cortex in at least two aspects: (a) motor cortex tDCS affects the balance of muscle activation partially via spinal mechanisms, and thus has remote systemic effects on motor system physiology, and (b) the impact of tDCS on motor cortex excitability is not restricted to the movement representation underlying the centre of the electrode.

A so far unanswered question is the origin of the respective spinal network excitability alterations. A peripheral source is improbable, since homonymous inhibition originating from peripheral sensory feedback was not altered by tDCS. Therefore, central mechanisms are likely to be involved. Interestingly, the spinal excitability patterns obtained in the present study mimic those of cocontractions of antagonistic muscles (Nielsen, 1998), which are suggested to be controlled by specific corticospinal projection neurons discernable from those involved in flexion or extension by their missing branch to Ia inhibitory interneurones, which control for relaxation of antagonist muscles (Nielsen et al. 1993). Thus it might be speculated that tDCS alters the activity of these cortical neurons, either directly or indirectly by simultaneous activation of antagonistic movement representations. Alternatively, subcortical contributions, especially of the striatum, which is involved in cocontraction, might apply. These presumed mechanisms of action should be explored in larger detail in future studies. Here use of smaller electrodes, which allow a more selective stimulation of motor cortical areas (Nitsche et al. 2007), might be helpful.

From a clinical perspective, the relation of the results of the current study to spinal mechanisms observed in cocontraction might also be relevant: cocontraction is important for stabilization of the body position, especially to counteract unforeseen perturbations, and is often impaired in neurological diseases affecting the motor system, such as stroke and Parkinson's disease. Therefore, it would be worth the effort to probe if tDCS can serve as a tool to stabilise stand and gait of the respective patients, maybe in combination with physiotherapeutic regimes, as shown already for motor performance of the upper extremities.