Transcranial direct current stimulation for the treatment of motor impairment following traumatic brain injury

Traumatic brain injury (TBI) is defined as “an alteration in brain function (loss of consciousness, post-traumatic amnesia, and neurologic deficits) or other evidence of brain pathology (visual, neuroradiologic, or laboratory confirmation of damage to the brain) caused by external force” [1]. The incidence and prevalence of TBI are substantial and increasing in both developing and developed countries. TBI in older age groups due to falling has been on the rise in recent years, becoming the prevalent condition in all age groups [2, 3]. TBI causes broad spectrum of impairments, including cognitive, psychological, sensory or motor impairments [4, 5], which may increase the socioeconomic burdens and reduce the quality of life [6, 7]. Although motor impairment, such as limb weakness, gait disturbance, balance problem, dystonia or spasticity, is less common than neurocognitive or behavioral problems after TBI, about 30% of TBI survivors have reported motor deficits that severely limited activities of daily living or participation [8].

Motor impairment after TBI is caused by both focal and diffuse damages, making it difficult to determine the precise anatomo-clinical correlations [9, 10]. According to previous clinical studies, recovery after TBI also seems worse than that after stroke, although the neuroplasticity after TBI may also play an important role for recovery [11]. Therefore, a single unimodal approach for motor recovery, including conventional rehabilitation, may be limiting, and hence, requiring a novel therapeutic modality to improve the outcome after TBI.

Transcranial direct current stimulation (tDCS) – one of the noninvasive brain stimulation (NIBS) methods – can increase or decrease the cortical excitability according to polarity (anodal vs. cathodal) and be used to modulate the synaptic plasticity to promote long-term functional recovery via long-term depression or potentiation [12, 13]. Recent clinical trials evaluating patients with stroke have reported the potential benefits of tDCS for motor recovery [14]. Neuroplastic changes after TBI and results from animal studies also suggest that tDCS could improve the motor deficit in TBI, although clinical trials using tDCS for motor recovery in TBI are currently lacking [14].

In this review, we will cover (1) the pathophysiology and possible neuroplastic changes in TBI; (2) physiology of tDCS; (3) current clinical evidence of tDCS in TBI for motor recovery; (4) general current concept of tDCS application for motor recovery; and (5) the future developments and perspectives of tDCS for motor recovery after TBI. Although the scope of motor recovery is wide, this review will focus primarily on the recovery of limb function, especially that of the upper limb. We expect that this review can provide insights on further successful development and clinical application of tDCS in motor rehabilitation after TBI.

tDCS delivers direct constant electrical currents to the cortical area of brain between two electrodes (anode and cathode), modulating the neuronal excitability by changing the resting membrane potential level [37]. The change in the direction of excitability after tDCS mainly depends on the electrode montages [38]. For instance, an anodal stimulation over the motor cortex increases the excitability, whereas a cathodal stimulation decreases the excitability [39]. Short-term effects of tDCS appear to be caused by alterations in hydrogen ions and transmembrane proteins, which is a nonsynaptic mechanism [40]. The long-term effects of tDCS may depend on synaptic modulation, which is long-term potentiation or long-term depression [38, 41]. Anodal tDCS could induce long-term potentiation by modulating GABA_Aergic and glutamatergic synapses [42, 43], whereas cathodal tDCS could induce the long-term depression by reducing the glutamatergic activity [44].

Therefore, according to various changes in different stages after TBI, different tDCS protocols can be considered [45]. Cathodal tDCS can be considered during the acute stage to decrease the glutamate-mediated excitotoxicity. In the subacute stage, anodal tDCS can be considered to reduce the GABA-mediated inhibition. Moreover, tDCS with behavioral interventions can be considered during the chronic stages to overcome maladaptive plasticity. These are only suggestions and future clinical trials are needed to prove the efficacy of tDCS and to define the optimal location for stimulation as well as the parameters associated with tDCS in patients with TBI.

Although there have been studies investigating the effect of NIBS on the non-motor impairments (e.g. depression, memory, attention) in patients with TBI [14, 46], studies for motor recovery is lacking. In the study including only two patients with TBI, bi-hemispheric tDCS on C3 and C4 (1.5 mA for 15 min/session, total 24 sessions) improved the upper extremity Fugl-Meyer scores for up to 6 months after treatment [47]. Some recent animal studies with the TBI model have also been published. In a unilateral controlled cortical impact model, Jefferson et al. reported greater behavioral improvements and increased wrist motor cortical presentation after ipsilesional 100 Hz cortical stimulation with reaching training when compared with the reaching training only [48]. However, the overall degree of recovery was modest and less than the recovery level in similar stroke studies [49, 50], which may implicate that the parameters of cortical stimulation from stroke studies are suboptimal in moderate and severe TBI. Recovery and neuroplastic mechanism after TBI could be different from that after stroke [51], and a future study using tDCS to prove the efficacy and define the parameters for better recovery (e.g. stimulation location, mode, duration) in TBI is needed.

In a recent study with controlled cortical impact model, a standalone ipsilesional 30 Hz cortical stimulation demonstrated no significant behavioral improvements or lesion size difference using FDG-microPET when compared with no stimulation [52]. This result corresponds with the opinion of Talelli et al., who asserted that cortical stimulation alone could not induce the brain to from appropriate connections needed for recovery [53], implying that behavioral therapy must be combined with cortical stimulation for motor recovery.

Stroke causes motor impairment as a result of cortical or subcortical damages and motor recovery is associated with neuroplastic changes, which is similar with TBI [54]. Therefore, clinical studies evaluating tDCS in patients with stroke could provide implications for its applicability in TBI. Recent Cochrane review showed a positive effect of tDCS on activities of daily living performance compared with the sham intervention at the end of the intervention period and at the end of the 3-month follow-up period [36]. However, tDCS on the upper extremity function revealed no evidence of a better effect than the control. In a recent study using a network meta-analysis of randomized controlled trials, only cathodal tDCS demonstrated a positive effect on improving the activities of daily living capacity but arm function measured by the Fugl-Meyer upper extremity assessment was not improved by tDCS [55]. Therefore, the effect of tDCS on motor recovery is still modest even in patients with stroke and a well-designed study with a larger number of patients is needed.

Traditionally, the interhemispheric inhibition model was proposed to develop a strategy for neuromodulation after stroke. Although the pathophysiology could be different in patients with TBI, this concept may be applicable to those with TBI who have hemiparesis or hemiplegia due to the focal brain parenchymal lesion. In patients with stroke, the motor cortex activations in the bilateral hemispheres are counterbalanced by the interhemispheric inhibition [56]. The intact contralesional motor cortex will drive higher inhibitory signals to the ipsilesional motor cortex and then ipsilesional motor cortex will be over-inhibited (maladaptive plasticity), which will lead to poor motor recovery (Fig. 2) [57, 58]. Therefore, cathodal tDCS over the contralesional motor cortex to inhibit the over-inhibition of ipsileional motor cortex or direct excitation of ipsilesional motor cortex by anodal tDCS over the ipsilesional motor cortex can be considered for reducing the maladaptive plasticity (Fig. 2). However, the interhemispheric inhibition model is challenged, because this model is based on the studies only in the chronic and mild stroke patients [56, 59]. For example, in stroke patients with severe motor impairments due to extensive injury of corticospinal tract, increase in the activation of contralesional motor cortex might be important for the recovery [60‐62]. Cathodal tDCS over the contralesional hemisphere induced no significant recovery in patients with extensive corticospinal tract damage, whereas it was effective in patients with small corticospinal tract damage [63]. Therefore, Pino et al. suggested the bimodal balance-recovery model, which is modulated by the degree of structural reserve [61]. If the structural reserve is high, interhemispheric inhibition model plays an important role in recovery. Conversely, if the structural reserve is low, the role of interhemispheric inhibition model is less important for recovery and the activation of contralesional hemisphere may play a more important role; hence anodal tDCS over the contralesional hemisphere may be beneficial. Further studies to prove this bimodal balance-recovery model in various stages (acute, subacute, chronic) and severities of stroke are needed for a more tailored tDCS protocol.

There are several concerns regarding the use of tDCS in a real clinical setting due to the associated intra- and inter-individual variabilities with respect to electrical current, responses and optimal stimulation target. Although tDCS offers greater convenience than magnetic stimulation, its accessibility to users, clinicians or patients, remains low. Appropriate task-oriented training must be implemented to augment the effect of tDCS for motor recovery [52, 53]. Therefore, further research and development of tDCS is necessary to address such limitations and to maximize the effect of tDCS on motor recovery after TBI.

After TBI, tDCS can modulate the neuroplasticity and has the potential to promote motor recovery. Different changes in the brain at different times after the onset of TBI reveal the need for different neuromodulation approaches in accordance with the chronicity. Although many stroke studies have provided some implications of using tDCS in TBI for motor recovery, TBI is associated with different pathophysiology and more diffuse network disruptions; hence a well-designed clinical trial is needed in the future to prove the efficacy of tDCS and define the optimal stimulation parameters.

For more individualized approaches, imaging-based modelling or brain signal monitoring system can be combined with tDCS. By combining these technologies, optimal targeting may be possible, inducing a more favorable neuroplasticity. A combination of task-oriented training using a novel modern technology such as VR with tDCS can promote neuroplastic changes for motor recovery, which may lead to be a potent tele-rehabilitation tool in the home setting. Therefore, the development of a combination approach with tDCS and clinical trials to investigate the effect of this approach is required.