A review of transcranial electrical stimulation methods in stroke rehabilitation
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.258057
Source of Support: None, Conflict of Interest: None
Keywords: Transcranial alternating current stimulation, transcranial direct current stimulation, transcranial electrical stimulation
According to World Health Organization (WHO) statistics on 2016, cardiovascular diseases (CVD) are the foremost cause of death and adult disability worldwide., Stroke statistics in India show that the incidence of stroke was 435/100,000 population and only one in three stroke survivors are hospitalized and given further rehabilitation because treatment is expensive.
Stroke survivors are faced with paralysis of one side of the body, that is, the side contra-lateral to the affected side in the brain. Rehabilitation aims at strengthening these muscles to prevent wastage and bring back function to the maximum possible extent. Taking the upper extremity into consideration, a combination of muscle over-activity (spastic muscle) in certain groups and weakening in other groups causes poor motor control leading to deformities and inability to reach, grasp, and release objects.
Various therapies such as splinting, stretching exercises, functional electrical stimulation (FES), and mirror therapy are being used to treat this condition, with varying degrees of success. In an ideal situation, the aim of stroke rehabilitation is to recover the paralyzed limb to an extent that it is functionally useful. In this context, recent research is being conducted in neuroplasticity or motor-relearning. Neuroplasticity refers to the brain being able to adapt to changes in response to its external environment and stimulation. TES and transcranial magnetic stimulation (TMS) are the non-invasive brain stimulation (NIBS) methods that invoke this type of re-learning.,
NIBS methods include TMS and TES since they non-invasively stimulate the cortex. These methods are still under research for medical applications and were first introduced to treat psychiatric conditions such as insomnia, chronic anxiety, mild depression and post stroke aphasia.,, Recently, tDCS has also been tried on normal individuals and was shown to improve cognition, working memory, and performance.,, These methods are now gaining importance in stroke rehabilitation because they provide motor relearning probably through cortical reorganization, which occurs because the neural continuity between the brain and the periphery is intact.
This article attempts to review the stimulation protocols used for TES by various research groups and the results obtained. The first section begins with an introduction to non-invasive methods of brain stimulation followed by a brief summary on the history that led to the use of TES for stroke rehabilitation. Later sections deal with tDCS and tACS. The section on tDCS is further subdivided into tDCS alone and tDCS with adjuvant therapy. The tables give a list of the studies that have been carried out for neurorehabilitation, although it is not meant to be an exhaustive list.
NIBS is a broad term that includes all the different means of non-invasively stimulating the brain. The current NIBS approaches that are largely being researched in the field of psychiatry and stroke rehabilitation are tDCS, tACS, and TMS. A Cochrane review (2016) on these methods suggested that there was very little enhancement of motor activity when these techniques are used alone,, but enhanced results were obtained when they were combined with another modality such as peripheral nerve stimulation (PNS). Most of these techniques are still at the research level, not being used in normal clinical practice, and techniques such as tDCS and tACS are not clinically approved.
TES includes transcranial pulsed current stimulation, electrosleep therapy, transcutaneous cranial electrical stimulation, neuro-electric therapy, and so on, apart from tDCS and tACS. A few other variations such as polarizing current, galvanic vestibular stimulation, and transcranial micro-polarization were tried out, but did not evolve to contribute much. Gustov Theodor Fritsch and Eduard Hitzig first introduced electrical stimulation of the brain in 1870 by stimulating the exposed cerebral cortex of a dog to identify the functions of various parts of the brain. In the 1960s, animal experiments were conducted by Creutzfeldt et al., Bindman et al., and Debbane et al., and the results showed that stimulation could evoke neural activity in the brain, which had lasting effects.,, There are a number of studies done using TES for treating psychiatric conditions and some evidence in literature to prove that TES produces lasting effects for learning, memory, post-stroke aphasia, depression, and so on.,, Later, its efficacy for stroke rehabilitation was considered.
tDCS is done by passing a weak direct current (DC) current, ranging between 0.5 and 2 mA, through two electrodes placed on the scalp. Saline-soaked sponge electrodes of sizes in the range of 35 cm2 are generally used. In the case of stroke rehabilitation, the anode is placed over the ipsilesional motor cortex and the cathode on contra-lesional supra-orbital region. Boggio et al., Vines et al., and Ang et al., have tried techniques where the cathode was placed over the contra-lesional motor cortex region as they believed that it would suppress activity from the contralateral side.,, Following stimulation of the motor cortex for a duration ranging between 20 and 30 minutes, the subjects are asked to perform activities. During this period, the amplitude of motor evoked potentials (MEPs), motor responses, or additional stimulation is assessed.
Priori et al., and Nitsche and Paulussuccessfully applied tDCS on human motor cortex and they described the changes that took place when low-amplitude currents were passed over the skull through the motor cortex., Nitsche and Paulusshowed experimentally that tDCS enhances motor cortical excitability under anodal electrode and decreases cortical excitability under cathodal electrode., Schlaug et al., explained that when tDCS is applied, it alters the blood flow in the region, indicating that the underlying tissue is being excited. Nitsche et al., and Vines et al., observed that the positions and size of the electrode largely determine the extent of motor relearning., Islam et al., showed that repeated tDCS on rat motor cortex showed increasing elevation of calcium levels, thereby giving rise to long-term potentiation (LTP) like plasticity. The same is applicable to human brain since Nitsche and Paulus determined that the effects of motor cortex excitability could be extended and improved by a longer duration of stimulation and increased amplitude of stimulation.,
As tDCS is non-invasive, painless, portable, and not known to cause any major side effects, exploratory research is being conducted on this front. Johansson et al., in his study on brain plasticity and stroke rehabilitation, observed that activity-based regular therapy enhances the outcome of stroke rehabilitation. In a study (2015), it was shown that anodal tDCS (a-tDCS) on the lesioned hemisphere improved shoulder abduction at lighter loads and had no improvement on increasing the load, but on the non-lesioned side, it had no improvement, whereas cathodal tDCS (c-tDCS) on the non-lesioned side significantly decreased shoulder abduction.
Later, c-tDCS of the dominant motor cortex combined with a-tDCS of the non-dominant motor cortex showed an improvement in the motor performance. A list of studies on tDCS for improvement of motor control and stroke rehabilitation is given in [Table 1]. The table lists the electrodes used, current, duration of stimulation, electrode montage, and the results obtained. Combinations with other modalities of therapy are now becoming common. tDCS is shown to enhance the effect of concomitant therapies by cortical reorganization. Various permutations and combinations of therapies are now being carried out to evoke motor relearning and provide lasting effects.
Although significant improvement of motor functions by tDCS in stroke is yet to be reported, it provides various benefits such as being painless, easy to administer, and has no major side effects. It also takes the intact neural connectivity into consideration, in contrast to any other mode of therapy, which is seen as the biggest advantage of tDCS. Further research was, therefore, directed toward using tDCS in combination with any other mode of therapy to obtain additional benefits. These combinations were again first introduced in psychiatry, where tDCS was used in combination with medication to provide enhanced effects., Similarly, for stroke rehabilitation, tDCS was combined with various therapies to provide enhanced results and some of these methods are discussed below.
Bi-hemispheric tDCS (anodal and cathodal stimulation) and constraint-induced movement therapy (CIMT) showed that tDCS improves gain, inter-hemispheric balance, and motor control because of reduced cortical activity of the intact side and increased cortical activity on the affected side. A combination of tDCS and neuro-muscular electrical stimulation (NMES) showed improvement in gait abilities in a patient with hemiparesis. tDCS was applied on motor cortex and NMES on tibialis anterior to correct foot drop in the patient. The effects of PNS combined with tDCS were studied on unilateral ischemic stroke patients for motor sequence performance with the stroke affecting radial and ulnar nerve stimulation. The results showed that there was an increase in performance accuracy rather than timing in these patients. A similar study on patients in their first week of stroke showed that motor recovery was positively influenced in the group receiving tDCS with PNS and the effects lasted at least for a month. Takeuchi et al., used a combination of tDCS and repetitional transcranial magnetic stimulation (rTMS) on a group of 27 participants with chronic sub-cortical stroke. The results showed that the group receiving both types of stimulation was able to perform bimanual tasks better than the control group. Straudi et al., suggested that the combination of robot-assisted therapy with tDCS shows drastic improvement for a patient with chronic and subcortical stroke rather than acute and cortical stroke. Cho and Cha conducted mirror therapy and tDCS on a group of 27 chronic stroke patients and the results showed that there was significant improvement of motor performance by the group receiving mirror therapy, compared with those whose vision was blocked from viewing the normal hand. [Table 2] gives a list of the studies that used combination therapy. The vast number of studies conducted using tDCS with another modality showed significant results in motor improvement and further research is being directed at improving these combinations.
tDCS uses two large electrodes for stimulation, although the area to be stimulated is small. Therefore, a greater area of the brain is stimulated rather than what is required. The need for focally delivering stimulation led to the introduction of high-definition transcranial direct current (HD-tDCS). In this variation, various configurations of an array of smaller electrodes are used. Research on HD-tDCS is being conducted for pain management, stimulation of the visual cortex, and psychiatry., Muthalib et al., were the first to study the effect of HD-tDCS on sequential finger movements by stimulating the human sensorimotor cortex. HD-tDCS was recently introduced and research is being conducted in modelling smaller electrodes with different configurations. Currently, the areas being concentrated on are psychiatry, visual cortex, and auditory cortex.
Studies on tACS are very few, and the acceptable current and frequency required to elicit cortical excitation and sustained effects are still under research. Studies applying tACS to regions other than the motor cortex show that tACS alters rhythmic neuronal activity and, therefore, find applications in visual and cognitive fields. Kanai et al., applied stimulation on the visual cortex and observed a frequency-dependent (at 20 Hz) increase in excitability. Zaehle et al., show that tACS enhances alpha oscillations and can, therefore, be used to treat neurological conditions that occur because of disruption of neuronal oscillations, such as Alzheimer's disease.
The effect of tACS on the motor cortex was first studied by Antal et al., (2008) on healthy volunteers. Very low frequency stimulations between 1 and 45Hz were applied for 2–10 min over the motor cortex. The placement of electrodes was similar to that of tDCS, with the active electrode placed on the motor cortex and the reference electrode on contra-lateral supra-orbital region. The results were not as favourable as those obtained with tDCS, but the authors believed that changing the stimulation parameters a bit might obtain comparable results. Zaghi et al., applied tACS on the motor cortex at a higher current density of 0.8 A/m2, 15 Hz for a longer duration of 20 min, which decreased cortical excitability and they concluded that tACS prevents the summation of subthreshold potentials both spatially and temporally. Moliadze et al., applied tACS in the high-frequency range of 140 Hz to the motor cortex to produce excitability analogous to that obtained by tDCS. Later, stimulation frequencies of 1, 2, and 5 kHz at an intensity of 1 mA were applied on the human motor cortex. Stimulation at 2 and 5 kHz produced lasting changes in the motor cortical excitability and this was attributed to modulation in the neuronal membrane activity. A study conducted on normal human subjects used tACS at 1 mA peak-to-peak amplitude and frequencies within the recorded electroencephalography (EEG) range, that is, 5, 10, 20, and 40 Hz. A single TMS pulse was delivered and the amplitude of the resulting MEP was determined. There was an increase in the MEP amplitude when tACS was applied in the 20 Hz (β frequency) range indicating that some synchronization of activity could be taking place at the β frequency range. Motor cortical activity is enhanced with a-tDCS, but tACS modifies neuronal oscillatory outputs to produce enhanced brain activity.
tDCS seems to be a promising method for rehabilitation, considering that its effects are long lasting. It has been shown in most of the studies that there is some improvement of motor function using tDCS. At the same time, it has also been shown from a few studies that motor control and co-ordination are improved by combining tDCS with any other form of rehabilitative therapy. tDCS makes use of two large electrodes of the range 35 cm2. This covers more than the required area to be stimulated. In a study carried out on pain perception, smaller sized electrodes were used, and improved results were obtained. Similarly, smaller electrodes can be used to check for improved results in stroke rehabilitation. Fleming et al., showed that the placement of electrodes plays a major role in the effect of tDCS. Contrary to the belief that suppressing activity in the contralesional hemisphere and enhancing activity in the ipsilesional hemisphere would provide added motor benefits, studies by Fleming et al., and O'Shea et al., disproved this theory., Anodal stimulation of contralesional cortex, which has not been done so far, will provide an insight into this theory.
A Cochrane review conducted on the effectiveness of tDCS for improvement of activities of daily living, whose results included studies that were conducted till February 2015, showed that there was very low evidence for adverse events and discontinuation of the procedure, therefore proving that it is a harmless technique. Later, tDCS was used with adjunct therapy and improved results were obtained. Safety is one of the major concerns of any medical device. Matsumoto and Ugawa concluded that the adverse effects of tACS and tDCS were mainly skin lesions and hypomania, which were transient symptoms and not persistent [Figure 1].
NIBS methods are gaining increasing importance in the field of stroke rehabilitation because they offer the advantage of cortical reorganisation and, therefore, enhance motor re-learning.,,, tDCS and tACS are portable and have shown the least amount of side effects, but these devices are yet to be Food and Drug Administration-approved. Combinations of various therapies, using some form of brain stimulation, are becoming increasingly popular because of the underlying need to involve the brain and, therefore, improve performance. Brain stimulation is still at the research level, and a lot is left yet to be uncovered. HD-tDCS and tACS have recently been introduced and there are a very few groups involved in this research. HD-tDCS is slowly gaining popularity and could be a promising method in the field of stroke rehabilitation.
From this review, it is clear that tDCS is a very simple mode for improving motor cortex excitability and the effect can be enhanced by coupling it with adjuvant forms of rehabilitative therapies. The most significant results are obtained by a combination of tDCS and electrical stimulation or mirror therapy. HD-tDCS could be used to focally deliver stimulation, and currently studies on HD-tDCS are still basic and in-depth research is being carried out. A way forward will be to try combinations with electrical stimulation or mirror therapy to provide significant results.
Financial support and sponsorship
The author would like to thank the Department of Science and Technology (DST) for providing funding to carry out this research under the DST Women Scientists Scheme (WOS)-A scheme. (Ref No. SR/WOS-A/ET-69/2017).
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2]