Abstract
Stroke remains a global leading cause of disability. Novel treatment approaches are required to alleviate impairment and promote greater functional recovery. One potential candidate is transcranial direct current stimulation (tDCS), which is thought to non-invasively promote neuroplasticity within the human cortex by transiently altering the resting membrane potential of cortical neurons. To date, much work involving tDCS has focused on upper limb recovery following stroke. However, lower limb rehabilitation is important for regaining mobility, balance, and independence and could equally benefit from tDCS. The purpose of this review is to discuss tDCS as a technique to modulate brain activity and promote recovery of lower limb function following stroke. Preliminary evidence from both healthy adults and stroke survivors indicates that tDCS is a promising intervention to support recovery of lower limb function. Studies provide some indication of both behavioral and physiological changes in brain activity following tDCS. However, much work still remains to be performed to demonstrate the clinical potential of this neuromodulatory intervention. Future studies should consider treatment targets based on individual lesion characteristics, stage of recovery (acute vs. chronic), and residual white matter integrity while accounting for known determinants and biomarkers of tDCS response.
1. Introduction
Stroke is the second leading cause of death and third leading cause of adult disability globally [1]. With advancement in acute medical care, more people now survive stroke, but frequently require extensive rehabilitative therapy to reduce impairment and improve quality of life. For those that survive stroke, the damaging effects not only impact the individual and their family, but there is also increased burden on health unit resources and community services as the person leaves hospital, potentially requiring assistance to live in the community. Novel treatments that can enable restoration and enhance potential for stroke recovery are desperately needed and will have significant value for many aspects of stroke care.
True recovery from stroke impairment is underpinned by neuroplasticity. Neuroplasticity describes the brain’s ability to change in structure or function in order to help restore behavior following neural damage. Mechanisms of neuroplasticity are available throughout life but appear enhanced during critical periods of learning [2]. Across several animal studies, it has been shown that there is a period of heightened neuroplasticity that appears to open within several days following stroke [2,3,4] and correlates with rapid recovery [5]. In humans, the timing and duration of a similar critical period of heightened neuroplasticity are not clear, but it likely emerges early after stroke. Understanding the characteristics of a potential critical period of heightened neuroplasticity in humans is important for optimizing stroke rehabilitation and is the subject of current trials [6]. However, the importance of neuroplasticity for stroke recovery in humans is unequivocal, with imaging and physiological studies providing extensive evidence of brain changes correlating with improved behavior [7,8,9,10,11,12,13].
Transcranial direct current stimulation (tDCS) is a promising, non-invasive, method to induce neuroplasticity within the cerebral cortex and augment stroke recovery. Importantly, tDCS has potential to bidirectionally and selectively alter corticospinal excitability for up to one hour after stimulation [14,15]. Animal models indicate that tDCS modulates resting membrane potential, with anodal stimulation leading to neuronal depolarization and cathodal stimulation leading to neuronal hyperpolarization over large cortical populations [16]. Stimulation-induced changes may be potentiated by changes in intracellular calcium concentrations. For example, anodal tDCS applied to the surface of the rat sensorimotor cortex led to a rise in the intracellular calcium concentrations [17]. Local increases in calcium can result in short- and long-term changes in synaptic function [18]. In humans, pharmacological studies have also provided indirect evidence to suggest that tDCS after effects are mediated by changes in synaptic plasticity through mechanisms that resemble long-term potentiation (LTP) and long-term depression-like effects [19]. Oral administration of the NMDA-receptor antagonist dextromethorphan was found to suppress the post-tDCS effects of both anodal and cathodal stimulation, suggesting that tDCS after effects involve NMDA receptors [19]. Importantly, modulation of cortical activity with tDCS changes human behavior [20]. For example, in randomized sham-controlled trials, anodal stimulation of the motor cortex (M1) in the lesioned hemisphere was found to improve upper limb outcomes in chronic [21,22,23] and subacute stroke survivors [24,25,26], with behavior changes underpinned by increased cortical activity within the M1 [27]. Although much work remains to be performed regarding optimal stimulation doses, cortical targets and electrode montages, these studies provide some indication that tDCS may be beneficial in stroke recovery.
While there is indication that tDCS has potential to improve stroke recovery of the upper limb [28], there are comparatively fewer studies that have investigated tDCS for lower limb recovery after stroke. Lower limb rehabilitation is especially important, as the simple act of regaining the ability to walk has subsequent effects on the ability to engage in activities of daily living [29,30]. Furthermore, those receiving therapy targeting mobility have been shown to have reduced levels of depression and anxiety [31], which are important determinants of stroke recovery [32,33,34]. Therefore, novel interventions capable of enhancing lower limb recovery might improve not only lower limb motor performance but could have added benefit for stroke rehabilitation in general. The purpose of this review is to discuss tDCS as a technique to modulate brain activity and promote recovery of walking following stroke. Within this review, we will outline current studies that have investigated tDCS to improve lower limb motor performance in both healthy adults and people with stroke. Additionally, we propose a best-practice model of experimental design for lower limb tDCS to guide future application for lower limb stroke recovery.
2. Is it Possible to Modify Lower Limb Motor Networks with Transcranial Direct Current Stimulation?
One approach to modify activity of the lower limb motor network with tDCS is to target the M1, similar to studies involving the upper limb. However, targeted application with tDCS is challenging as, compared with upper limb representations, the lower limb M1 representations are more medial and deeper within the interhemispheric fissure (Figure 1). This presents two notable difficulties. First, the ability of targeted stimulation to the lower limb M1 within one hemisphere (e.g., the lesioned hemisphere in stroke) is challenging, as tDCS electrodes can be relatively large compared to the size of cortical representations, resulting in current spread that may inadvertently lead to stimulation within the opposite hemisphere. Second, the depth of the lower limb M1 representations may present a challenge to current penetration and depth with traditional tDCS applications. However, there is evidence to indicate that it is possible to modulate activity of the lower limb M1 with tDCS. Computational modelling has revealed that traditional anodal tDCS electrode montages (anode overlying the lower limb M1 and cathode overlying the contralateral orbit; Figure 1) can lead to the expected cortical excitability enhancement in the target cortex [35]. Indeed, reducing the size of the anode (3.5 cm × 1 cm) was found to improve the specificity of the current delivered to the cortex, while positioning the return electrode (cathode) to a more lateral position (T7/8 on the 10–10 EEG system) further improved current specificity, leading to greater changes in cortical excitability [35]. Experimental evidence also suggests that tDCS targeting the lower limb M1 can modify excitability. Jeffrey and colleagues [36] utilized an anodal-tDCS montage (2 mA, 10 min) over the lower limb M1 and found that motor-evoked potentials (MEPs) of the tibialis anterior muscle increased by as much as 59% compared to sham conditions. Along similar lines, 10 sessions of anodal tDCS (2 mA, 10 min) targeting the lower limb M1 was found to increase the amplitude of MEPs recorded from the paretic tibialis anterior compared to sham stimulation [37]. This empirical evidence provides some support to the computational modelling to suggest that the use of tDCS targeting the lower limb M1 can modify corticospinal excitability.
Figure 1. Transcranial direct current stimulation targeting the lower limb motor cortex in humans. (A) An example of the motor homunculus in humans. The motor strip on the cortex is highlighted in blue. Note that the lower limb representation is medial and deep within the motor cortex, presenting a challenge to target brain stimulation to this region. (B) An example of a standard transcranial direct current stimulation montage for targeting the lower limb motor cortex. The anode is shown in red and approximately overlies the lower limb motor cortex. The cathode (return) electrode is shown in blue and is typically positioned over the contralateral orbital region.
Although M1 has received attention as a stimulation target to modify excitability of the lower limb M1, there is potential for cerebellar tDCS to induce similar, or possibly more prominent, behavioral and neurophysiological changes. It is noteworthy that a computational modelling study that compared electrode montages targeting M1 and the cerebellum found that cerebellar stimulation produced substantially higher electric field strengths in the target area compared to M1 stimulation, suggesting the cerebellum may indeed be a suitable target for tDCS [38]. Behaviorally, the cerebellum contributes to motor planning, learning, and control; this influence is in part mediated by connections to M1 via the cerebellothalamocortical tracts, previously reported to play a key role in motor skill learning in mice [39]. Although this stimulation technique has received comparatively little attention compared to M1 stimulation, there is some indication that it is possible to modify cerebellar excitability in a focal and polarity specific manner [40]. Whether cerebellar tDCS is required to modify excitability of M1 for behavioral change is unclear. However, if a desired outcome was to modify M1 excitability with cerebellar stimulation, a pertinent challenge would be whether cerebellar tDCS can achieve the specificity required to precisely target the lower limb M1 in one hemisphere. Although speculative, one approach could be to pre-activate M1 through a contralateral lower limb motor task in order to bias the effects of tDCS towards those networks activated to perform the task. In support, there is some evidence in the upper limb that performance of a task during cerebellar tDCS does interact with the change in M1 excitability [41].[…]
TBI Rehabilitation 