Transcranial Direct Current Stimulation as a Novel Method for Enhancing Aphasia Treatment Effects
Abstract
Abstract. Neuromodulation is an exciting area of development. Currently, there is significant interest in academia, industry, and clinical practice where an effective and acceptable transcranial direct current stimulation (tDCS) kit for use in clinical rehabilitation would offer much benefit to patients’ treatment. In this review, I discuss the latest group studies investigating current tDCS methods for enhancing aphasia treatment effects in post-stroke (sub-acute and chronic) and primary progressive aphasia (PPA) patient populations. This field is still new, and many more investigations with larger samples of patients are needed. Nevertheless, in the studies completed to date, on-line tDCS paired with language rehabilitation was feasible, safe, well tolerated, and sham controlled. Results on the effectiveness of tDCS at boosting recovery outcomes are preliminary but promising with a number of themes emerging. I highlight some of these themes and future directions toward identifying those patients who are likely to respond to specific tDCS and behavioral therapies. This would provide an empirical basis from which to investigate specific aphasia interventions in future multicenter clinical trials and could greatly improve the quality of aphasia treatment for stroke and PPA patients.
Being able to communicate is something most of us take for granted. But when a person has aphasia (acquired language disorder), most commonly caused by stroke, this becomes a source of profound frustration and anxiety for them and their families. While some people do recover, many do not. Aphasia is an unpleasant disorder, with a high social cost (Lam & Wodchis, 2010). Patients with impoverished speech are more likely to withdraw socially and suffer from depression (Northcott & Hilari, 2011). Speech and language disorders are the most feared outcome by patients at risk of stroke (Samsa et al., 1998). Indeed, aphasia is the second most common major impairment after stroke, with a prevalence of ~ 250,000 in the UK and 1 million in the USA.
Speech and language therapy (SALT) is effective at treating aphasia. The recent Cochrane review (Brady, Kelly, Godwin, & Enderby, 2012) concluded “Significant differences [SALT vs. no SALT] were evident in measures of spoken language.” Treatment of aphasia can also improve post-stroke depression (Ayerbe, Ayis, Rudd, Heuschmann, & Wolfe, 2011). Importantly, therapy-driven gains can be made at any point after stroke, not just the early phase (Moss & Nicholas, 2006). As such, SALT works (Brady et al., 2012), but the big issue is making sure aphasic patients with language impairments have access to the correct therapies. Indeed, aphasia may respond to therapy many months and years after the stroke occurs, but a very large dose is required to improve. Meta-analysis studies show that aphasic patients need to complete around 100 hr of behavioral therapy to significantly improve their real-world communicative outcomes (Bhogal, Teasell, & Speechley, 2003).
Unfortunately, provision of SALT is far below that needed to provide optimal rehabilitation (Code & Heron, 2003) and the majority of patients do not get the correct dose (Code, 2003; Code & Heron, 2003). Depressingly, most patients in the UK get around 10 hr total therapy input from the national healthcare service – NHS (Code, 2003). This is very disabling and frustrating for patients and their families. It can impair patient’s participation and compliance with rehabilitation programs for associated disabilities (Hilari, 2011; Hilari, Needle, & Harrison, 2012; Jette, Warren, & Wirtalla, 2005). This is unacceptable and healthcare commissioners need to address this growing unmet need urgently. However, it is not economically feasible to solve this unmet need by massively increasing the amount of SALT face-to-face time.
To address how the treatment of aphasia might be made more effective, researchers are now investigating using an emerging, safe, low-cost brain stimulation method called transcranial direct current stimulation (tDCS). The aim is to test whether tDCS paired with SALT is an effective and acceptable method to boost aphasic patients’ language functioning. Research to date has primarily assessed whether aphasic stroke patients can improve their spoken language function with targeted and sustained computer delivered practice (Palmer et al., 2012) in combination with tDCS brain stimulation technology. For a more general overview and background to this topic, readers are directed to de Aguiar, Paolazzi, and Miceli’s (2015) recent review paper of the role of brain stimulation parameters, aphasia behavioral treatment, and patient characteristics. In contrast, this review focuses on detailing the recent on-line tDCS studies enhancing aphasia treatment effects in both post-stroke and primary progressive aphasia (PPA) patient populations. Only the latest group studies (minimum six patients) that have used on-line tDCS as an adjunct to SALT in aphasia treatment have been included. It begins with studies of (1) chronic aphasia post-stroke as this is where we have most evidence to date. Studies are discussed according to which brain region was targeted with tDCS – (a) left hemisphere peri-lesional cortices, (b) right hemisphere language cortices, and (c) dual/ bi-hemisphere stimulation. The next two sections cover studies in (2) sub-acute post-stroke aphasia and (3) primary progressive aphasia (PPA). The final section highlights emerging themes and future directions for brain stimulation as a novel therapeutic intervention in aphasia treatment.
Chronic Aphasia (Post-Stroke)
In one of the earliest group studies of tDCS and aphasia, Monti et al. (2008) found that a single session of off-line cathodal (but not anodal) stimulation over the left fronto-temporal areas leads to a transient improvement of naming abilities in eight nonfluent aphasic patients. However, a more recent study that applied tDCS offline, that is, in isolation or not concurrently with SALT found no effect on chronic aphasic patients’ language function (Volpato et al., 2013). A negative result such as this can never confirm or refute the hypothesis that off-line tDCS is inefficient. Nevertheless, it may be argued that, in post-stroke chronic aphasic patients, simultaneously coupling tDCS online with specific synaptic activation may be necessary. Indeed, there is a precedent for combining on-line tDCS with anomia (word-finding problems) treatment with positive results. The hypothesis underlying this approach is that tDCS itself will not produce any lasting changes in language function; instead, it temporarily creates a state that optimizes learning or, in the case of aphasic patients, relearning and rehabilitation. Consistent with this hypothesis, longer-term consolidation of these learning/relearning processes requires pairing of tDCS with training (co-stimulation) to promote Hebbian learning (Reis et al., 2009). This, in turn, could enable the short-lasting gain observed from a single session of tDCS paired with training to accumulate with repeated sessions and eventually lead to a permanent improvement in function. Supporting behavioral evidence comes from facilitatory effects observed in multiple-exposure tDCS studies of healthy participants learning new information and associations (e.g., de Vries et al., 2010; Fiori et al., 2011; Floël, Rosser, Miichka, Knecht, & Breitenstein, 2008).
Specifically for language learning, anodal stimulation applied to left Broca’s area online during the acquisition phase of an artificial grammar enhanced subjects’ performance at detecting syntactic violations along with an increased use of rule-based decision making (de Vries et al., 2010). Similarly, anodal stimulation applied to left Wernicke’s area during acquisition of an artificial lexicon increased the rate and overall success of language learning compared to sham stimulation (Floël et al., 2008). In aphasic patients it is hoped that tDCS could lead to additional improvements in language function, on top of the main effect of SALT by boosting natural learning processes and lead to better recovery outcomes. Interestingly, most tDCS studies in chronic aphasic stroke patients have focused on the treatment of speech production (see Table 1). This approach has been influenced, at least in part, by the favorable behavioral effects of mass practice seen in anomia behavioral training studies that can be easily combined with tDCS. However, not only the behavioral task but also the cortical area being targeted by tDCS will have an impact on the efficacy of the intervention. With this in mind, I will discuss these studies, according to which hemisphere was targeted during stimulation.
Targeting Left Hemisphere, Peri-Lesional Cortices
In relatively well-recovered aphasic patients, as in normal individuals, successful speech production has been correlated with brain activity in the peri-lesional left hemisphere (Fridriksson, Bonilha, Baker, Moser, & Rorden, 2010; Fridriksson, Richardson, Fillmore, & Cai, 2012). This suggests that excitatory tDCS delivered to the patient’s structurally intact, residual language cortices may be a mechanism to facilitate activity in these peri-lesional regions and thereby boost speech recovery. Preliminary results suggest that this is indeed the case. Five tDCS group studies (see Table 1, study numbers 1, 2, 6, 8, 9) adopted this approach. Using a repeated intervention protocol in chronic aphasic patients that spanned several days, they applied anodal tDCS to patients’ remaining structurally intact cortex in the lesioned left hemisphere during speech production training. Studies 6 and 8 are the latest papers by two groups who have published additional papers using similar protocols/data so I will not refer to their earlier papers here.
In the first treatment study (Table 1, study 1), 10 aphasic speakers were trained for five consecutive days using a spoken word-to-picture matching task. During training they received 20 min of anodal (1 mA) or sham stimulation delivered to left frontal and precentral cortex (Baker, Rorden, & Fridriksson, 2010). To ensure the active (anode) electrode was placed over structurally intact cortex, tDCS positioning was guided using a priori functional MRI results for each individual from an overt naming experiment. Patients’ naming accuracy improved significantly following both interventions. Behavioral training alone (sham tDCS) resulted in a 6% improvement in naming. After anodal tDCS paired with behavioral training, there was a 14% improvement in naming, that is, tDCS had an additive effect of 8% on top of the behavioral training alone. Importantly, naming improvements were retained for at least 1 week after training. Consistent with the behavioral rehabilitation literature, the naming improvements were restricted to trained items only. In a second study by this group (Table 1, study 2), the same treatment paradigm was used in eight mild fluent aphasic patients with lesions restricted to left posterior cortical and subcortical regions. This time, anodal stimulation was applied to viable left posterior peri-lesional cortex, again determined by results from an fMRI naming study (Fridriksson, Richardson, Baker, & Rorden, 2011). These patients had good naming accuracy but were slow to respond. So the primary outcome measure used was a change in naming reaction time. Anodal stimulation resulted in faster naming responses compared to sham stimulation. This naming improvement persisted for at least 3 weeks. Again, the facilitatory effect of anodal stimulation was restricted to the treated items only.
In another naming study (Table 1, study 6), Fiori et al. (2013) trained seven nonfluent aphasic patients to name 102 nouns and 102 verbs they could comprehend but not accurately produce. Naming practice was paired with 1 mA of anodal tDCS applied to left Wernicke’s area, left Broca’s area, and with sham stimulation of the same region. Overall, patients improved naming accuracy in response to the behavioral training (12% sham) after five days of intervention. The authors further discuss how patients were much more accurate in noun naming after anodal left temporal stimulation (Wernicke’s-31%, Broca’s-12%, Sham-10%) and in verb naming after anodal left frontal stimulation (Wernicke’s-15%, Broca’s-42%, Sham-13%). Importantly, these gains were maintained 4 weeks after tDCS. However, considering it was a small study and all of their patients had left-hemisphere damage involving the temporal lobe to some degree, it is not clear how many patients actually had structurally intact cortex underneath the anode electrode for each intervention.
No MRI data was used to ensure the active electrode was placed over functionally viable cortex. Therefore, the authors’ claims that better recovery observed after left temporal and frontal stimulation, respectively, for nouns and verbs, could be directly related to differential activation of these areas needs further investigation. The same criticism about tDCS electrode positioning can be applied to Marangolo et al.’s study (2014) (Table 1, study 8). Here, the authors extended their speech training approach to look at the differential effects of frontal versus temporal tDCS on conversational therapy outcomes. However, out of the eight patients, only four had preserved frontal cortices, the rest having both temporal and frontal damage. It was perhaps not surprising then that only frontal tDCS had an additive effect resulting in a significant improvement in the patients’ speech coherence directly after treatment compared to behavioral training alone.
These studies highlight a crucial point: behavioral change following tDCS combined with training depends on which cortical areas are targeted. One tDCS electrode montage does not fit all patients with the same behavioral profile. tDCS effects cannot be predicted without precise anatomy of individual patient’s lesion and careful positioning of electrodes to ensure tDCS is delivered to structurally intact cortices for each patient. Fridriksson and colleagues (2012) suggest acquiring additional fMRI data as a tool to define individual cortical targets for brain stimulation. However, there is a lot of individual variability in fMRI results; it depends on task used, statistical threshold, whether you predict an increase or decrease in the BOLD signal relative to rest or the control condition. In addition, an fMRI scan as a requirement for entry into tDCS treatment studies significantly limits the number of patients that can be investigated, along with impacting its future application and translational potential. Whether the intended cortical area is functionally viable for an individual will depend on their anatomical lesion – gray and white matter damage. An alternative approach would be to acquire a high-resolution structural brain scan for each patient to ensure the targeted anatomical region for stimulation is intact. Response variability to the interventions (behavioral alone and with tDCS) could then be investigated by modeling the anatomical variability in the lesion damage. Advances in detailed anatomical models for language function derived from volumetric brain MRI scans are underway (Hope, Seghier, Leff, & Price, 2013). It is hoped that this approach will help in developing stratified treatments, optimizing individual patient’s treatment.
Advances are also underway in the development of a technique thought to increase tDCS current focality and field intensities at desired cortical targets: high-definition tDCS (HD-tDCS). Conventional bipolar tDCS is applied with two large (35 cm2) rectangular electrodes, resulting in directional modulation of neuronal excitability. A newly designed 4 × 1 HD-tDCS protocol has been proposed for more focal stimulation according to the results of computational modeling (Datta et al., 2009). HD-tDCS utilizes small disk electrodes deployed in 4 × 1 ring configuration whereby the physiological effects of the induced electric field are thought to be grossly constrained to the cortical area circumscribed by the ring. A physiological study of motor cortex excitability demonstrated that single dose HD-tDCS resulted in larger and longer-lasting motor evoked potential changes in comparison to conventional tDCS (Kuo et al., 2013). This led Richardson, Datta, Dmochowski, Parra, and Fridriksson (2015) to ask whether multiple-session HD-tDCS would lead to larger and longer-lasting changes in naming compared to conventional tDCS paired with anomia treatment (Table 1, study 9). Eight aphasic stroke patients took part in a randomized, crossover design study of tDCS versus HD-tDCS combined with 5 days of computerized anomia training. The electrode montage for each condition was visibly different (4 electrodes vs. 2), so no blind design was possible. An additional difference was that 1 mA conventional anodal tDCS was applied compared to 2 mA anodal HD-tDCS. Naming accuracy and response time improved significantly following both interventions. There were no significant differences in outcome between the two tDCS conditions. A nonsignificant trend was noted in change in accuracy of trained items. After HD-tDCS, compared to conventional tDCS, naming was numerically higher for six out of the eight patients immediately post-treatment and five patients 1 week later. Richardson et al. (2015) acknowledged that this trend may not have occurred had 2 mA been used across both conditions. Therefore, a different modulatory effect due to a higher intensity of electric current cannot be ruled out as a cause of the differences in the results. However, this does highlight that tDCS dosage, defined by electrical field at the target site, may impact on the size of behavioral effects for individual patients. Future work is needed to identify and understand dose-response relationships for tDCS and cognitive behavioral outcomes.
Importantly, all these studies demonstrate that using anodal tDCS stimulation in the vicinity of peri-lesional tissue can be safe, well tolerated, and sham controlled. Encouragingly, the results suggest anodal tDCS can enhance chronic patient’s response to SALT. This confirms the importance of coupling tDCS with the behavioral training not only for immediate but also for longer-term spoken language gains.
Targeting Right Hemisphere Language Cortices
An alternative possibility for aphasia recovery and treatment approaches relies on recruitment of the structurally intact right hemisphere to facilitate language improvement. Previous neuroimaging and behavioral studies found that right hemisphere homologs of “classical” language regions are activated by language tasks in aphasic stroke patients (Blank, Bird, Turkheimer, & Wise, 2003; Crinion & Price, 2005; Leff et al., 2002; Saur et al., 2006). What is not always clear is whether this right hemisphere activation might be the consequence of either (i) a loss of active interhemispheric inhibition from homologous regions in the lesioned left hemisphere or (ii) a compensatory neural response, contributing to functional recovery (Geranmayeh, Brownsett, & Wise, 2014; Saur & Hartwigsen, 2012). What is clear is that there is little evidence for “take-over” of function in areas previously unrelated to language processing. A comprehensive review of both aphasic and normative fMRI language studies found that the right hemisphere regions activated in aphasic patients appear to be components of a preexisting, bilateral language network also found in healthy control subjects (Turkeltaub, Messing, Norise, & Hamilton, 2011). For aphasic patients with extensive left hemisphere lesions, upregulation of right hemispheric language homologs might be crucial, being their only option for recovery (Schlaug, Marchina, & Norton, 2009; Winhuisen et al., 2005). This is the approach used by Vines, Norton, and Schlaug (2011) (Table 1, study 4). They paired anodal tDCS delivered to right Inferior Frontal Gyrus (IFG) with melodic intonation therapy (MIT) in six severely aphasic patients with extensive left IFG lesions. Patients’ speech fluency improved when patients had tDCS paired with MIT but not when they had MIT alone (sham). Unfortunately, no supporting neuroimaging data was collected in the study. Nevertheless, the authors proposed that the observed improvement in patients’ speech may be due to a positive change in functional contribution from right IFG, boosted by tDCS.
However, right IFG activation is not always deemed beneficial for speech production post-stroke. For example, an open-protocol transcranial magnetic stimulation (TMS) study showed that 10 sessions of inhibitory TMS over the right pars triangularis significantly improved picture naming in four chronic aphasic patients. This effect was maintained 2 months later (Naeser et al., 2005). The inferred mechanism was that language improvement was due to suppression of maladaptive activity in the “overactive” right hemisphere. That is, TMS downregulated abnormally increased activity in right IFG. This in turn reduced the interhemispheric inhibition from the right, contralesional (healthy) hemisphere to the left, ipsilesional (damaged) hemisphere. This theory borrows directly from the motor recovery literature where recovery after stroke is seen as a dynamic process that involves a variety of changes in both hemispheres to achieve interhemispheric balance (Fregni & Pascual-Leone, 2006; Mansur et al., 2005; Oliveri et al., 2001; Ward & Cohen, 2004). In the case of tDCS, inhibitory cathodal tDCS applied to the primary motor cortex decreased motor cortical excitability at this site (Nitsche et al., 2003; Nitsche & Paulus, 2000; Purpura & McMurtry, 1965; Wassermann & Grafman, 2005). Furthermore, when used in chronic stroke patients, contralesional cathodal tDCS improved motor function (Boggio et al., 2007; Hummel et al., 2005). This led Kang, Kim, Sohn, Cohen, and Paik (2011) (Table 1, study 3) to investigate whether cathodal tDCS applied to the right IFG (homolog of Broca’s area) simultaneously with word-retrieval training might improve picture-naming task performance in chronic post-stroke aphasics.
Ten right-handed patients were enrolled in this double-blind, counterbalanced sham controlled study. Each patient received an intervention of cathodal tDCS (2 mA for 20 min) and of sham tDCS (2 mA for 1 min) delivered to right IFG daily for five consecutive days in a randomized crossover manner. There was a minimum interval of 1 week between interventions. tDCS was delivered simultaneously with daily sessions of conventional word-retrieval training. tDCS was found to have a small (4%) but significant improvement in picture naming 1 hr following the last (5th) cathodal tDCS treatment session. It was not assessed whether these effects persisted. No statistically significant changes were observed after sham tDCS (2%). It is of interest to directly contrast the size of these effects with the study by Baker et al. (2010) discussed in the previous section (Table 1, study 1). Baker and colleagues also combined tDCS with anomia treatment for 5 days but used anodal tDCS (2 mA for 20 min) delivered to left Broca’s area. They found that anodal tDCS resulted in large effects (14% improvement in naming compared to only 6% in the sham condition) that persisted for at least 1 week after intervention. This highlights an important point: tDCS does not have a simple effect on behavior. Baker et al.’s sham treatment resulted in a 6% improvement in speech recovery which was greater than Kang et al.’s (2011) 4% tDCS effect and 2% treatment effect in the sham condition. In these two studies, tDCS interacted with ongoing behavioral rehabilitation training to offer an additive effect to patients’ language recovery. This means the amount of potential tDCS “boost” crucially depends on the efficacy of the behavioral intervention. Choosing the “correct” behavioral training task is key to treatment success. This is not only for observing statistically significant treatment and adjuvant tDCS effects but also clinically meaningful language effects that enhance aphasic’s recovery immediately post-treatment and longer-term.
Adopting a different approach, Floël et al. (2011) (Table 1, study 5) delivered anodal, cathodal, and sham tDCS to right temporo-parietal regions during anomia treatment. Patients all had large left hemisphere lesions. The behavioral training required them to practice a small number of items over 3 days that they consistently could not name at baseline (0%) until they reached 80% accuracy. The resulting sham effect (behavioral treatment alone) in their study was therefore very high – 83%. This meant the tDCS effect could maximally be 17%, that is, if the patients’ naming improved to a perhaps unrealistic 100%. Nevertheless, the patients’ naming did statistically improve further to 89% following anodal tDCS paired with training. This effect persisted for 2 weeks post-treatment. Cathodal tDCS had no effect in these patients. Taking this study’s behavioral result together with that reported by Kang et al.’s (2011), one could speculate that, in the context of a strong behavioral treatment effect, cathodal tDCS delivered to right hemisphere might offer little advantage but anodal tDCS may still boost language recovery. Miniussi, Harris, and Ruzzoli (2013) discuss the potential physiological mechanisms underlying why this may be the case. An alternative explanation may be that right temporal and frontal regions respond differently to anodal and cathodal tDCS when paired with anomia treatment.
Dual/Bi-Hemisphere Stimulation
Dual-site stimulation using tDCS has received some attention recently in the motor recovery literature for the purpose of developing more effective methods of brain stimulation. It is based on the interhemispheric rivalry theory discussed in the previous section. Theoretically, bi-hemispheric stimulation could concurrently increase the excitability of the ipsilesional cortical region and decrease the excitability of the contralesional, unaffected cortical region thereby restoring the balance between both hemispheres and promoting recovery. For example, Vines, Cerruti, and Schlaug (2008) applied simultaneous dual-hemispheric tDCS to healthy subjects, using anodal tDCS over the nondominant and cathodal tDCS over the dominant motor cortices. They found an additive effect on motor function of the nondominant hand compared with single-site stimulation.
In terms of language function, the study by Lee, Cheon, Yoon, Chang, and Kim (2013) (Table 1, study 7) is the first to adopt this approach. They aimed to investigate the effect of simultaneous dual tDCS applied over the bi-hemispheric language-related regions in chronic aphasic stroke patients. Eleven patients took part in a within-subject crossover design study. Thirty minutes of tDCS was delivered concurrently with 15 min of naming practice and reading aloud on two separate occasions. One-day patients had 2 mA of anodal tDCS delivered to left IFG and on the other 4 mA of dual tDCS consisting of 2 mA anodal tDCS delivered to left IFG and 2 mA cathodal tDCS to right IFG. Both single and dual tDCS methods produced an improvement in accuracy in the picture-naming test with no adverse effect. The authors also reported a small but significant improvement in naming response time following dual tDCS but not single tDCS. These results need to be taken as preliminary due to the significant limitations of the study. In particular the authors reported, “the right tDCS electrode was only switched on for 5 s”. So it is not at all clear what dose of dual tDCS patients actually received. In addition, lesion location was not documented or investigated in the study so we do not know how many had viable tissue in the targeted regions and how this may have impacted on the data. Nevertheless, the study does highlight an alternative and interesting approach that was tolerated in chronic aphasic stroke patients as an adjunct to aphasia intervention.
Sub-Acute Aphasia (Post-Stroke)
Consistent with Volpato et al.’s (2013) study of off-line tDCS in chronic aphasics, Polanowska, Lesniak, Seniow, and Czlonkowska (2013), who studied patients in the sub-acute phase, found that off-line tDCS offered no benefit to their patients’ language outcomes. Therefore, in this section the focus is on three recent group studies where tDCS was delivered online with behavioral rehabilitation in sub-acute aphasic stroke patients (see Table 2). The hope with early intervention post-stroke is that it will significantly boost language recovery (as patients are on a steeper part of their recovery curve) and thus prevent chronic aphasia. The first two studies investigated tDCS as an adjunct to conventional SALT and its impact on standard clinical aphasia outcomes. Jung, Lim, Kang, Sohn, and Paik (2011) (Table 2, study 2) applied 1 mA cathodal tDCS to Broca’s area in all patients. The rationale behind their unexpected choice of cathodal tDCS delivered to Broca’s area as opposed to anodal tDCS, consistent with the previous literature, was not explained. There was no sham tDCS delivered nor was behavioral intervention alone delivered so it is not possible to judge the effects of tDCS on behavioral outcomes. Patients with both infarction and hemorrhagic stroke, where the risk of epileptic fits in the first-year post-stroke is higher, were included. Lesion distribution was not controlled and it is not clear how many patients had structurally intact tissue in the vicinity of the stimulating electrode. Nonetheless, 10 days SALT paired with tDCS was well tolerated by all, and no adverse events were reported. Behaviorally, the least aphasic patients made the best language improvements, that is, recovered quickly, while more severely aphasic patients changed little.
You, Kim, Chun, Jung, and Park (2011) (Table 2, study 1) conducted a between-group study in 21 aphasics. Patients were divided into three groups depending on whether they received SALT paired with 2 mA tDCS delivered as (1) cathodal tDCS to right Superior Temporal Gyrus (STG); (2) anodal tDCS to left STG; or (3) sham tDCS. The cathodal tDCS group recovered significantly more auditory comprehension (17%) than the sham group (10%) and the anodal tDCS group (10%). The authors interpret this result as evidence that suppression of activity in the “overactive” right hemisphere after left-hemisphere stroke may promote recovery. However, on closer examination, patients assigned to the cathodal group were behaviorally the least impaired on auditory comprehension testing at baseline. This suggests that their tDCS effect may be confounded by aphasia severity. In addition, when baseline performance is not stable or equivalent between groups, failing to detect a difference between groups is more likely, especially if the effects of the treatment are small or variable (such as here, sham = anodal). Contributing to this variability, lesion distribution was not equivalent in all three groups. Of particular note is that four of the seven patients in the anodal tDCS group had lesions involving the left temporal lobe. The authors do not state whether the patients had structurally intact cortex underneath the left STG stimulating electrode. Nevertheless, their result is consistent with Jung et al.’s (2011) study, showing that aphasia severity may be a reliable predictor of aphasia treatment outcome in the sub-acute stage post-stroke.
The third study and final study in this section was performed by Wu, Wang, and Yuan (2015) (Table 2, study 3). In this study, they targeted Wernicke’s area in a group of 12 aphasic stroke patients. Each tDCS block (sham, anodal, and then sham again) was paired with picture-naming treatment for five consecutive days. Following the anodal tDCS block, patients were found to have improved not only naming abilities but also auditory word comprehension significantly more than following the two other blocks of treatment with sham tDCS. This is the only study that has reported an improvement in speech comprehension. It is also the only study that reported an improvement in both language comprehension and production. This suggests that, early post-stroke, there may be potential for generalization of tDCS and language treatment effects across both comprehension and production abilities. This has not been reported in the chronic aphasic stroke patient treatment studies to date.
The four studies of chronic aphasic patients that targeted Wernicke’s area all reported changes only in naming and speech production coherence (see Table 1, studies 2, 6, 8, 9). There are a number of reasons as to why this may be the case. Chronic speech comprehension impairments, especially at the single word level, are rare post aphasic stroke. Anomia is the most common symptom post aphasic stroke irrespective of the lesion location. It is the symptom that frustrates patients and their families the most. Most interventions in chronic aphasic patients therefore reflect this need and focus on improving speech production abilities. Nevertheless, it is of interest that Fridriksson and colleagues in their two studies (Table 1, studies 2 and 9) chose to use an auditory comprehension task: single word-to-picture matching, as the behavioral adjunct to tDCS to improve naming abilities in their patients. A comprehension difficulty was not reported in their patients and no change in speech comprehension abilities was documented. None of the chronic studies from Table 1 reported if there had been any change in their patients’ auditory sentence comprehension abilities that can be commonly affected long-term post-stroke. In light of Wu et al.’s study (2015), this would be of interest.
In conclusion, it is impossible to judge at this stage whether tDCS offers any significant benefit to aphasia treatment in the sub-acute stage post-stroke. Not one of the studies followed up their patients to see the longer-term impact on language recovery. Importantly however, these three studies have shown in a relatively large number of patients (n = 70) that 2 mA, 1 mA, and 1.2 mA cathodal and anodal tDCS can be well tolerated and safe when delivered for 10–15 days in combination with SALT. This is encouraging and suggests that tDCS and aphasia treatment studies in this early stage post-stroke are feasible.
Primary Progressive Aphasia
An important avenue more recently being pursued is the application of tDCS as an adjunct to SALT in patients with primary progressive aphasia (PPA). PPA is a neurodegenerative condition that involves a progressive loss of language function. In general, it begins very gradually and initially is experienced as difficulty in thinking of common everyday words while speaking or writing. It then progressively worsens to the point where verbal communication (including language comprehension) by any means is very difficult. In the early stages, memory, reasoning, and visual perception are not affected by the disease. This means that individuals with early stage PPA can function normally in many routine daily living activities despite the aphasia, and they also retain the cognitive capacity to learn. However, as the illness progresses, other cognitive abilities also decline. Therefore, early behavioral intervention is key to facilitate language function.
PPA is caused by Alzheimer’s disease (AD) in approximately 30–40% of cases and by fronto-temporal lobar degeneration (FTLD) in approximately 60–70% of cases (Cairns et al., 2007; Rogalski & Mesulam, 2009). Because of the 30–40% probability of Alzheimer’s disease (AD), AD drugs such as Exelon (rivastigmine), Razadyne (galantamine), Aricept (donepezil), or Namenda (memantine) have been tried. None have been shown to improve PPA. SALT can improve the patient’s quality of life. The primary goal of treatment is to improve the ability to communicate. However, the emphasis in PPA, as opposed to aphasia post-stroke, is to enable individuals to maintain their language abilities for as long as possible, that is, long-term to slow down the rate of language decline rather than recovery of function.
Researchers investigating PPA currently recognize three behavioral (language) subtypes: agrammatic, logopenic, and semantic. Cotelli et al. (2014) (Table 3, study 1) targeted 16 patients with FTLD and a 2-year symptomatic history of agrammatic PPA. Patients with this subtype have nonfluent, effortful speech, reduced in quantity: pronouns, conjunctions, and articles are often lost first. Sentences become gradually shorter and word-finding difficulties become more frequent, occasionally giving the impression of stammering or stuttering. tDCS was delivered to left dorsolateral prefrontal cortices concurrently with SALT focused on picture naming for 10 days. Half of the patients had sham while the others had 25 min of 2 mA anodal tDCS. The patients who received anodal tDCS learnt significantly more treated items than those who had SALT and sham. The effects were maintained for 3 months. Just like in the studies of aphasic stroke patients, there was no generalization of improvements to untreated items. However, unlike all the previous tDCS studies in aphasic stroke patients, the size of the tDCS effect in these patients was much smaller than the behavioral effect: 12% versus 34%. Possible causes for this include: differences in the underlying nature of their brain disease (degeneration vs. stroke); the brain region targeted with tDCS – which in this study was the left DLPFC which, located dorsal to Broca’s area in the middle frontal gyrus, is not a classical language area and is rarely activated in fMRI studies using picture-naming tasks. Thus, tDCS may not have been optimally targeting the brain regions engaged by the behavioral training (using picture-naming tasks). Had the authors targeted Broca’s area (left IFG), they might have seen a larger tDCS effect when paired with the anomia therapy.
The second study (Table 3, study 2), reported by Tsapkini, Frangakis, Gomez, Davis, and Hillis (2014), targeted a mixed group of agrammatic (n = 2) and logopenic (n = 4) PPA patients. Logopenic PPA has a particularly high probability of being caused by AD and often is associated with atrophy in temporo-parietal regions. Speech is fluent during informal conversations but is marked with mispronunciations and word-finding difficulties on confrontation naming tasks. Spelling errors are common in both PPA subtypes especially early on. Tsapkini and colleagues delivered spelling behavioral therapy in conjunction with tDCS delivered to left IFG. Left IFG is an area commonly associated with spelling function. The 1–2 mA anodal/sham tDCS was delivered to six patients in a 2-month within-subject crossover design study. The spelling training worked, as it led to a 16% improvement. Following 3 weeks of anodal tDCS, delivered in conjunction with the behavioral training, there was an additional 19% improvement in spelling. Importantly, the effects were maintained 2 months later. The sample size tested in this study is small but it does suggest two things. Firstly, large tDCS effect sizes in PPA patients are possible, that is, of comparable size (at least) to the behavioral intervention. Secondly, delivering SALT concurrently with tDCS delivered to a brain area known to be actively involved in the behavioral intervention can boost the efficacy of therapy.
Summary
By linking data and approaches from these complementary studies, I hoped to deliver an integrated picture of current aphasia rehabilitation research using tDCS. The field is still new and clearly many more studies with larger samples of patients are needed but a number of themes have emerged. I highlight a few of these below:
- •The majority of studies to date have focused on tDCS as an adjunct to treatment of speech production difficulties. The most compelling evidence to date comes from studies of chronic aphasics post-stroke. Here, anodal tDCS has been most effective when delivered to the patient’s residual spoken language network (left hemisphere if preserved or when extensively damaged right hemisphere homolog).
- •It looks promising that tDCS delivered over multiple sessions may boost consolidation of aphasia rehabilitation rather than a simple (or temporary, immediate) effect on language performance. Too few multiple-session studies exist for a valid meta-analysis. A challenge for future tDCS research with this population will be optimizing techniques, such as the dose.
- •In the majority of studies, irrespective of the patient population, the reported effects of anodal tDCS were greater than or at least equivalent to the size of the behavioral treatment effects alone (see Tables 1–3). Studies that found large tDCS effect sizes tended to also have large SALT effect sizes. tDCS therefore appears to offer little advantage if the behavioral treatment effects are small. It is a true interaction between the two interventions. Stimulation/activation of a brain region by a therapy task in conjunction with tDCS targeting the same brain region appears to be a valid technique for optimizing the efficacy of SALT.
- •Where tDCS had a positive effect on patients’ language function, there was no reported cognitive cost. However, it is not clear from the reported studies how many formally evaluated this.
- •Paired with SALT, tDCS is feasible in sub-acute stroke and PPA patients. But too few studies have been done to assess its efficacy.
- •We are far from tailoring treatment to individual patients. As illustrated in this review, huge variability exists in the reported effects of SALT, with great variability in the tDCS effect sizes and even contradictory results reported. There are many interindividual factors that may contribute to this variability including baseline behavior, anatomy, age, and the inherent variability in the injured brain (see Li, Uehara, & Hanakawa, 2015). Future studies in larger groups of patients that control for lesion distribution and aphasia severity may provide us with a means of identifying those who are likely to respond to specific tDCS and behavioral therapies. This would provide an empirical basis from which to investigate specific aphasia interventions in future multicenter clinical trials and could greatly improve the quality of aphasia treatment for stroke patients.
Future Directions
tDCS Brain Current Flow and Anatomy (Structural and Functional) Models
How current flow is affected by variation in normal anatomy (sulci and gyri) of the targeted cortices and different lesions in the vicinity of the stimulating electrodes is an important emerging theme in tDCS research. In chronic stroke patients, even when electrodes are placed on an area of the scalp away from the lesion, cerebrospinal fluid-filled lesions may alter current flow and serve as an attractor for current. A single case study by Datta, Baker, Bikson, and Fridriksson (2011) demonstrated how different electrode configurations influenced the flow of electrical current through brain tissue in a chronic stroke patient with a large lesion who responded positively to tDCS paired with anomia treatment. Individualized tDCS modeling and targeting procedures have been developed to take into account the patients’ lesions (Dmochowski et al., 2013) with the aim of achieving maximum stimulation intensity at the target cortical regions. Richardson et al. (2015) implemented these techniques in their study of chronic aphasic patients demonstrating they are feasible in a clinical population. However, the data is insufficient to judge whether they had an impact on tDCS efficacy.
Hence, the complexity of tDCS current flow modulation by detailed normal and pathologic brain anatomy needs further understanding. Galletta and colleagues (2015) have started developing computational models to understand the impact of the lesion on resting state tDCS current flow. The next step will be to understand the impact of the lesion on interactions between tDCS current flow and ongoing task-driven functional brain activation during SALT.
tDCS as a Novel Therapeutic Intervention?
Presently, there is insufficient data to establish if tDCS may be useful in clinical treatment of aphasia populations. tDCS use in aphasia is currently largely restricted as small-scale lab-based experiments limiting its translational impact. The aim for future studies is to combine the benefits of tDCS, namely low-intensity, safe, neuromodulation with detailed behavioral interventions (SALT) to assess its effectiveness in boosting language recovery outcomes. This approach could provide clinical researchers with a compelling platform and much promise as an adjunct to neurorehabilitation. If successful, tDCS could increase the amount of aphasia recovery individual patients make, as well as free up more SALT time. Further tDCS studies in larger samples of aphasic patients are necessary to identify which patients (lesion location × language impairment × time post-stroke) and which tDCS protocol (electrode montage × stimulation type (anodal vs. cathodal)) may be the best candidates for this approach. Development of current models to account for these multiple factors would ensure translation and successful implementation of treatment research findings into novel and timely clinical practice.
Jenny Crinion is a Welcome Trust Senior Research Fellow in Clinical Science and joint leader of the Neurotherapeutics Group at the Institute of Cognitive Neuroscience, University College London, UK. Her research focuses on understanding the neural mechanisms underpinning language recovery. The group’s mission is to develop novel, evidenced-based therapies for patients with aphasia and related disorders and to investigate how, at a neural network level, these therapies work.
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