Effects of non-invasive brain stimulation on post-stroke dysphagia: A systematic review and meta-analysis of randomized controlled trials

Highlights

• We synthesize evidence for non-invasive brain stimulation on post-stroke dysphagia.

• Transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) significantly increased swallowing outcomes in stroke patients.

• Stimulating the unaffected hemisphere resulted in a significant pooled effect size.

Abstract

Objective

The primary aim of this review is to evaluate the effects of non-invasive brain stimulation on post-stroke dysphagia.

Methods

Thirteen databases were systematically searched through July 2014. Studies had to meet pre-specified inclusion and exclusion criteria. Each study’s methodological quality was examined. Effect sizes were calculated from extracted data and combined for an overall summary statistic.

Results

Eight randomized controlled trials were included. These trials revealed a significant, moderate pooled effect size (0.55; 95% CI = 0.17, 0.93; p = 0.004). Studies stimulating the affected hemisphere had a combined effect size of 0.46 (95% CI = −0.18, 1.11; p = 0.16); studies stimulating the unaffected hemisphere had a combined effect size of 0.65 (95% CI = 0.14, 1.16; p = 0.01). At long-term follow up, three studies demonstrated a large but non-significant pooled effect size (0.81, p = 0.11).

Conclusions

This review found evidence for the efficacy of non-invasive brain stimulation on post-stroke dysphagia. A significant effect size resulted when stimulating the unaffected rather than the affected hemisphere. This finding is in agreement with previous studies implicating the plasticity of cortical neurons in the unaffected hemisphere.

Significance

Non-invasive brain stimulation appears to assist cortical reorganization in post-stroke dysphagia but emerging factors highlight the need for more data.

Introduction

Studies report that 50–81% of people who have a stroke experience swallowing problems (Hamdy, 2010, Meng et al., 2000). This impact is staggering when the cost implications and morbidity of post-stroke dysphagia are considered. Stroke patients with dysphagia cost more to treat (about $4,510 more per patient than a stroke patient without dysphagia) because their hospital stay is nearly doubled, they require more therapy, and they have more complications with worse outcomes (Bonilha et al., 2014, Altman et al., 2010). Further, mortality is significantly higher in stroke patients with dysphagia; they have a 2.6-fold increased rate of death (Sharma et al., 2001; Smithard et al., 1996).

Considering these statistics, the lack of an effective and quick rehabilitation for post-stroke dysphagia is surprising. Relying on natural recovery is a slow and incomplete approach. Compensatory strategies, such as prescribing thickened liquids and tucking the chin, are likely to negatively impact the patient’s quality of life or, with non-compliance, lead to a negative outcome. Further, exercise for dysphagia requires weeks of intensive training before sufficient strengthening occurs (Burkhead et al., 2007). A more efficient rehabilitation is needed.

Researchers have looked to non-invasive brain stimulation as a means to rehabilitate dysphagia, and various small studies have investigated whether non-invasive brain stimulation could be used as a treatment for post-stroke dysphagia. The state of the research is at the point where a synthesis of the extant literature would help to elucidate this treatment’s overall effect.

The purpose of this systematic review and meta-analysis is to review non-invasive brain stimulation on post-stroke dysphagia by examining evidence produced by randomized controlled trials and synthesizing their results. The research question is: Are the effects of non-invasive brain stimulation on swallowing in post-stroke dysphagic patients positive, and what can be learned about the best use of these technologies to improve outcomes? Variables of interest include: hemispheric targets in swallowing innervation, duration of stimulation, stimulation modality, and long-term follow up.

Non-invasive brain stimulation is based on the principle of neuroplasticity, best defined as changes in neuronal pathways to increase neural functioning via synaptogenesis, reorganization, and network strengthening and suppression. The two most commonly used techniques are tDCS and TMS.

Transcranial direct current stimulation (tDCS) provides a steady flow of low-intensity, electrical current between a positive and negative electrode placed strategically to target an area of the cortex. Anodal tDCS increases the excitability of cortical neurons by shifting the polarity of their resting membrane potential, thereby increasing the chance of depolarization. It has short-term effects that are mediated through changes in membrane potentials via sodium and calcium channels and other processes like GABAergic inhibition (Stagg et al., 2009, Ardolino et al., 2005, Islam et al., 1995). It also has been shown to have longer lasting effects, which occur through N-methyl-D-aspartate (NMDA) receptors, seen in long term potentiation and long term depression, via neurotrophic factors such as brain-derived neurotrophic factor (BDNF) (Fritsch et al., 2010, Liebetanz et al., 2002).

The effects of the short-term and long-term mechanisms have been witnessed from one hour up to weeks after the stimulation (Brunoni et al., 2012, Priori, 2003). For these reasons, tDCS has a posited therapeutic application to post-stroke rehabilitation.

Another technique is transcranial magnetic stimulation (TMS). Here, a copper wire coil is placed over the targeted area of the cortex. During TMS, a brief, high current pulse is produced in a coil of wire, which in turn produces a magnetic field with lines of flux traversing perpendicularly to the plane of the coil. At the right strength, it can cause depolarization of the targeted neurons. Repetitive TMS (rTMS) is simply the repeated application of TMS. Pulses at a low frequency (∼1 Hz) have an inhibitory effect by slowing neuronal excitability. On the other hand, pulses at a high frequency (⩾3 Hz) increase the excitability of the neurons.

Studies have demonstrated that the neurophysiological effects of TMS include short-term effects via voltage-gated channels and sodium and calcium flow velocity (Wagner et al., 2007, Theodore, 2003). Other studies have demonstrated its influence on neurotransmitters. TMS has demonstrated an increase in glutamate and a decrease in GABA_A (Ridding and Rothwell, 2007, Michael et al., 2003, Zangen and Hyodo, 2002). As in tDCS, post-stimulatory effects of TMS lasting beyond the treatment session have been documented. Longer lasting effects are likely due to factors like increases in NMDA-receptor activation (Quartarone, 2013).

Both tDCS and TMS are relatively safe forms of non-invasive brain stimulation. The word ‘relatively’ is preferred because even though there is no reason to suspect harm from the low-intensity protocols, much is unknown about the limits of current density, repeated applications, and long-term safety. Common safety concerns include seizures, scalp irritation or burns, and a localized headache or discomfort. For more detailed discussions about safety concerns, the reader is referred to other publications (tDCS: Bikson et al., 2009; Nitsche et al., 2003, Priori, 2003, McCreery et al., 1990, Agnew and McCreery, 1987; TMS: Rossi et al., 2009, Machii et al., 2006, Wassermann, 1998).

No studies investigating motor improvement have documented drastically different outcomes between the two techniques (Takeuchi and Izumi, 2012). Both have the potential to be performed as sham stimulation, an important quality for clinical trials (although Fregni and Pascual-Leone, 2007 suggest that TMS is more difficult to produce as an active sham). The two techniques can also be adjusted to upregulate, downregulate, and target different areas of the cortex.

However, there are several important differences between the techniques. First, and most clearly, TMS is magnetic stimulation resulting from rapidly changing magnetic fields, and tDCS is electric, driven by a battery-powered device. Second, TMS generates depolarization whereas tDCS only modifies the excitability threshold of targeted neurons. This can be seen by a level of current density nearly 30 times as intense (A/m²) with TMS than with tDCS at the level of cortical grey matter (Wagner et al., 2007). Third, the wire coils for rTMS focus the magnetic field, compared to the wide electrodes used for tDCS. TDCS has been shown to provide a wider spread of current density magnitudes, suggesting that more tissue receives the stimulation with tDCS than with TMS (Wagner et al., 2007). It should be noted, however, that spread does still occur in rTMS. Fourth, models have shown that the skull shunts tDCS currents across the scalp’s surface. TMS currents appear to reach their maximum current density slightly deeper at the level of the cerebral spinal fluid (Wagner et al., 2007). Lastly, TMS can be applied in a fraction of a second with one pulse whereas tDCS does not have this capability. Of particular interest to this review is how tDCS and TMS, looked at together and separately, influence dysphagia in the post-stroke population.

Although swallowing is a bilaterally innervated process, strong evidence by multiple researchers suggests that there is lateralization to a dominant hemisphere (Lowell et al., 2012, Li et al., 2009, Malandraki et al., 2009, Hamdy et al., 1998a, Hamdy et al., 1997, Hamdy et al., 1996, Robbins et al., 1993, Barer, 1989, Robbins and Levine, 1988, Gordon et al., 1987). A lesion in the dominant hemisphere is likely to result in oropharyngeal dysphagia leaving intact, but weaker, projections from the non-dominant side (Teismann et al., 2011, Li et al., 2009, Khedr et al., 2008, Hamdy et al., 1998b, Hamdy et al., 1997, Hamdy et al., 1996). Multiple studies have shown that re-organizing and increasing the strength of the contralesional hemispheric projections help to rehabilitate dysphagia (Park et al., 2013, Michou et al., 2012, Teismann et al., 2011, Fraser et al., 2002).

Stimulating the lesioned or unlesioned hemisphere remains a controversial topic, as evidence is mixed as to which method best optimizes the recovery of post-stroke dysphagia. That is, some studies have stimulated the lesioned hemisphere (Yang et al., 2012, Khedr et al., 2009). This is believed to either restore output from the lesioned side (as it does for corticospinal pathways Pomervoy et al., 2007) or counteract suppressive effects from the contralesional hemisphere. Other studies aim to inhibit the intact, contralesional projections that are believed to be hyperactive post-stroke (Yun et al., 2011, Verin and Leroi, 2009). The theory behind this approach is that there is increased transcallosal inhibition that occurs after stroke and decreasing it helps to recover the swallow. And yet other studies have stimulated the contralesional hemisphere as a means to encourage excitability and plasticity in what is believed to be the ‘weaker side’ (Vasant et al., 2014, Park et al., 2013, Kumar et al., 2011). Clearly, research is still investigating the mechanisms at play in lesioned or contralesional hemispheric stimulation.

While published studies have not generally provided a rationale, it is likely that the choice of stimulation duration is made considering safety guidelines. In general, tDCS studies tend to apply stimulation for 5–30 min and rTMS for 5–20 min, although rTMS duration depends on the number of pulses and how many trains of pulses. It is unclear how this parameter contributes to rehabilitation. A review of anodal tDCS to the motor cortex in healthy and stroke participants suggested larger effects with 13 min of stimulation than 10 min (Bastani and Jaberzadeh, 2012). No studies could be found investigating the influence of rTMS duration per session on outcomes. However, studies have shown that the pattern of rTMS pulses can influence outcomes. In fact, long continuous theta bursts 40 seconds long have been shown to produce effects opposite of the excitatory results seen with 2-second intermittent bursts: longer trains of rTMS stimulation were more suppressive (Cantarero et al., 2013, Huang et al., 2005).

The rationale for duration in terms of the number of days of stimulation is even more unclear. Study protocols have ranged from 1 to 20 days in daily or twice daily sessions without any stated rationale (Wagner et al., 2007). On the whole, there is limited data to clarify the impact of stimulation duration on outcomes, in both time per session and number of days.

Another consideration of unknown influence is tDCS versus TMS. The question here is if there is a difference in outcomes depending on the stimulation type. Until now, no studies have attempted to answer this question despite a myriad of reviews comparing the two techniques. This may be because they are too different to be compared, namely in their stimulation type, strength, focal beam, and duration. TMS has parameters like frequency, intensity, and number of pulses that distinguish it from tDCS parameters such as the amplitude and stimulation duration (see Section 1.2.3). In these ways, the applications are not comparable. Yet this study suggests that a realistic question is which type of stimulation should be used? In 2012, a review of non-invasive brain stimulation on post-stroke motor recovery posed this question (Takeuchi and Izumi, 2012), as did a more recent review (Simonetta-Moreau, 2014). Neither article found an answer. This review will stratify the identified studies by stimulation type as a means to begin a discussion to address this question.

Several studies have investigated the lasting effects of non-invasive brain stimulation on post-stroke motor outcomes and have reported results in favor of the extended effects from 6 days to even 6 months after stimulation (Khedr et al., 2013, Hesse et al., 2011, DiLazzaro et al., 2010, Kim et al., 2009, Boggio et al., 2007). Caution must be taken before jumping to conclusions, however, because multiple syntheses of these data have yielded non-significant results, although they trend in a positive direction (Ludemann-Podubecka et al., 2014, Marquez et al., 2013, Bastani and Jaberzadeh, 2012).

To date, only a handful of studies have reported on long-term outcome measures specifically related to swallowing (Park et al., 2013, Shigematsu et al., 2013, Yang et al., 2012, Khedr et al., 2009). It has been suggested that “repeated sessions, with cumulative effect, seem to be superior to a single session, and are needed to induce a sustained effect” (Fregni and Pascual-Leone, 2007, p. 390). On the other hand, two reviews have noted that there is no evidence to suggest that non-invasive brain stimulation is capable of long-lasting effects and, if it was, then it would be unethical to use it on healthy subjects (Doeltgen, 2014, Ridding and Rothwell, 2007). Non-invasive brain stimulation clearly has created more questions than answers due to its multifaceted variables as simple as type, duration, and long-term efficacy.