Physiology & Behavior 143 (2015) 1–9

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Physiology & Behavior journal homepage: www.elsevier.com/locate/phb

Review

Transcranial non-invasive brain stimulation in swallowing rehabilitation following stroke — A review of the literature Sebastian H. Doeltgen a,⁎, Lynley V. Bradnam b, Jessica A. Young a, Eric Fong c a b c

Discipline of Speech Pathology and Audiology, Faculty of Medicine, Nursing and Health Sciences, Flinders University, GPO Box 2100, Adelaide, SA 5001, Australia Discipline of Physiotherapy, Faculty of Medicine, Nursing and Health Sciences, Flinders University, GPO Box 2100, Adelaide, SA 5001, Australia ENT Department, Flinders Medical Centre, Flinders Drive, Bedford Park, SA 5042, Australia

H I G H L I G H T S • • • •

Non-invasive brain stimulation is an emerging trend in dysphagia rehabilitation. We review the current evidence base for this approach in post-stroke dysphagia. Preliminary evidence suggests a promising potential in small patient groups. Current limitations of the evidence base and clinical implications are discussed.

a r t i c l e

i n f o

a b s t r a c t Background: This descriptive review of the literature outlines the current evidence-base underpinning the potential of transcranial brain stimulation techniques to modulate swallowing function in healthy individuals and in treating post-stroke dysphagia. Methods: Published research was identified by review of scientific databases (Scopus, Medline Ovid, Science Direct, AMED and Google Scholar) using relevant keywords. In addition, the reference lists of identified articles were scrutinized to identify further potentially relevant papers. Studies employing variants of transcranial magnetic or direct current stimulation for the purpose of modulating swallowing motor cortical excitability in healthy participants or dysphagia following stroke were included. Due to a significant heterogeneity in stimulation paradigms, all included studies were summarised and descriptively analysed in relation to the participants tested, cortical representations targeted by brain stimulation and outcome measures used. Results: Seventeen studies met inclusion criteria (seven evaluating healthy participants, 10 evaluating participants presenting with post-stroke dysphagia). Cortical stimulation most commonly targeted pharyngeal motor representations (13/17 studies). In the 10 clinical studies, stimulation was applied contralesionally (5/10 studies), ipsilesionally (3/10 studies) or bilaterally (2/10 studies). A range of behavioural and neurophysiological outcome measures demonstrated positive effects on swallowing function across studies. Conclusion: There is promising proof of concept that non-invasive brain stimulation may provide a useful adjunct to post-stroke swallowing rehabilitation practice. Eventual transition of optimal paradigms into routine clinical practice will be accompanied by practical considerations in relation to local and national frameworks, e.g. the prescription and provision of treatment. © 2015 Elsevier Inc. All rights reserved.

Article history: Received 27 August 2014 Received in revised form 11 February 2015 Accepted 16 February 2015 Available online 17 February 2015 Keywords: Transcranial magnetic stimulation Transcranial direct current stimulation Swallowing Dysphagia Stroke Neuroplasticity

Contents 1. 2.

Introduction . . . . . . Methods . . . . . . . 2.1. Literature review 2.2. Inclusion criteria

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⁎ Corresponding author. E-mail addresses: sebastian.doeltgen@flinders.edu.au (S.H. Doeltgen), lynley.bradnam@flinders.edu.au (L.V. Bradnam), jess.young@flinders.edu.au (J.A. Young), [email protected] (E. Fong).

http://dx.doi.org/10.1016/j.physbeh.2015.02.025 0031-9384/© 2015 Elsevier Inc. All rights reserved.

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S.H. Doeltgen et al. / Physiology & Behavior 143 (2015) 1–9

2.3. Exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Descriptive analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Literature review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Transcranial direct current stimulation in unimpaired swallowing and post-stroke dysphagia . . . 3.3. Repetitive transcranial magnetic stimulation in unimpaired swallowing and post-stroke dysphagia 3.4. Paired associative stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Descriptive analysis of selected study parameters . . . . . . . . . . . . . . . . . . . . . . . 3.5.1. Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.2. Cortical representations of interest . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.3. Outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Functional relevance of NBS for modulating swallowing behaviour . . . . . . . . . . . . . . . 4.2. Limitations of the current literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Clinical implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Swallowing disorders (dysphagia) are a common consequence of damage to the nervous system caused by a range of conditions, including neurodevelopmental disorders [10], traumatic brain injury [14,44], stroke [25,26] or neurodegenerative conditions [4,39]. Even in the general population without acute neurological damage, dysphagia is common [9]. Dysphagia is often associated with complications such as poor nutrition and hydration [33], choking, and aspiration pneumonia [23,24]. The number of elderly Australians dying from aspiration pneumonia is on the rise, with over twice the number of deaths recorded (1385 in total) in 2012 than in 2003 [2] and places a significant burden on any health care system. In addition to medical complications, dysphagia significantly impacts on the quality of life of patients [9] and carers [13,36]. Historically, central pattern generators located in the brainstem are thought to play a crucial role in the planning and execution of safe swallowing [16]. Since the development of brain imaging and noninvasive brain stimulation techniques, the contribution of the primary motor cortex (M1) to swallowing function is increasingly being recognised. For example, contralesional hemispheric reorganisation is associated with spontaneous recovery of swallowing function following stroke [12]. Furthermore, an increase in cortical excitability may compensate for degeneration of brainstem motor circuits in Kennedy Disease [8]. There is also increasing evidence from neuro-imaging studies demonstrating wide-spread cortical activation during swallowing, in particular in M1 [7]. Given the likely importance of primary motor networks in the control of swallowing, attention has turned to noninvasive brain stimulation (NBS) techniques to painlessly modulate M1 excitability. Non-invasive brain stimulation has been used to modify excitability of the corticospinal motor system controlling the muscles of the limbs. Research has demonstrated that neuroplastic reorganisation of corticospinal motor networks by NBS can alter hand motor function [1,41] and facilitate recovery of hand function following stroke [3,21]. Similarly, there is increasing evidence to suggest that neuroplastic reorganisation of corticobulbar motor networks using NBS can modify unimpaired swallowing function [17,18,28]. Furthermore, NBS may also facilitate the recovery of impaired swallowing function following neurological insult [19,22]. The aim of this literature review was to identify and review the current evidence base for the potential effectiveness of NBS to facilitate recovery of swallowing function following stroke. The following questions guided this narrative review: • Does modification of cortical motor networks by non-invasive brain stimulation change functional measures of swallowing in individuals without swallowing impairment?

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• Does non-invasive brain stimulation improve clinical and functional measures of swallowing in individuals presenting with dysphagia following stroke?

2. Methods 2.1. Literature review Major research computer data bases (Scopus, Medline Ovid, Science Direct, AMED and Google Scholar) were searched for relevant literature using key search terms describing the intervention (transcranial magnetic stimulation, transcranial direct current stimulation), target population (health, stroke, dysphagia), and outcome measure (motor cortical excitability, motor evoked potential, dysphagia, swallowing, videofluoroscopy, manometry). In addition, the reference lists of identified studies were searched individually for additional relevant publications. 2.2. Inclusion criteria Studies employing transcranial NBS techniques as a neuromodulatory intervention in relation to swallowing function in people experiencing swallowing disorders after stroke or adults without swallowing impairment were included. All types of strokes and stroke lesion sites were also included. Studies employing all types of NBS paradigms were reviewed, specifically anodal or cathodal tDCS, conventional repetitive or patterned repetitive TMS (rTMS), or paradigms combining peripheral electrical stimulation and single-pulse TMS, known as paired associative stimulation (PAS). 2.3. Exclusion criteria Studies were included only if they employed NBS to modify the excitability of cortical motor networks relevant to swallowing motor control. Studies that employed NBS to assess changes in motor cortical excitability, for example in response to a behavioural intervention, or those assessing the effect of NBS on cortical motor networks outside of swallowing muscles were excluded. Studies were also excluded if they investigated neuromodulatory stimulation techniques not applied to the central nervous system through the intact scalp (e.g. peripheral neuromuscular electrical stimulation, pharyngeal electrical stimulation) or were conducted on animal models of swallowing dysfunction. Animal studies were excluded as this review of the literature was undertaken with a focus on the role of NBS in the rehabilitation of post-stroke dysphagia as it applies to current clinical practice.

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2.4. Descriptive analysis A descriptive analysis of the included studies was undertaken in order to summarise key descriptive parameters, including (i) participant group studied, (ii) cortical representation targeted and (iii) outcome measures assessed. 3. Results 3.1. Literature review Seventeen studies met inclusion criteria, with the earliest dating back to 2007. The key features of each study are briefly outlined below. Detailed information regarding intervention paradigms employed and participants studied is presented in Tables 1 and 2. 3.2. Transcranial direct current stimulation in unimpaired swallowing and post-stroke dysphagia Transcranial direct current stimulation employs electrical currents that, under certain circumstances, can modify neuronal activation in stimulated brain areas. In general, anodal stimulation of cortical motor networks results in facilitation of neuronal excitability, whereas cathodal stimulation inhibits it. Three studies explored the effects of tDCS on swallowing in healthy individuals following modulation of the excitability of the pharyngeal motor representation on the primary motor cortex [18,43,45] (Table 1). Jefferson et al. [18] were the first to determine optimal stimulation parameters for tDCS applied over the pharyngeal motor representation. Employing the motor evoked potential (MEP) as a measure of corticobulbar motor excitability, this groups reported an increase in MEP amplitude, indicating facilitation of corticobulbar excitability, following 10 min of 1.5 mA or 20 min of 1 mA anodal stimulation of the dominant pharyngeal motor representation. In contrast, there was a decrease in pharyngeal motor excitability following 10 min of 1.5 mA cathodal tDCS. These changes in excitability were confined to the stimulated hemisphere and were not apparent in the contralateral hemisphere [18]. In another study, a virtual lesion was evoked in healthy participants using inhibitory 1 Hz rTMS over

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M1 representations of the pharyngeal muscles. Repetitive TMS was followed by anodal tDCS applied over the contralateral hemisphere [45]. Following anodal tDCS, pharyngeal MEPs were increased in amplitude for up to 60 min, accompanied by an improvement in swallowing performance assessed by a swallowing reaction time task. In a sham controlled study, Suntrup et al. [43] applied anodal tDCS (20 min of 1 mA tDCS) to increase pharyngeal motor cortex excitability over left or right pharyngeal M1 representations. Magnetoencephalography was used to assess swallowing-related cortical activation and demonstrated a significant increase in swallowing-related cortical activation in the theta frequency band bilaterally following anodal tDCS over either hemisphere. Interestingly, application of anodal tDCS over the left hemisphere improved precision in a swallowing reaction time task, where participants were instructed to swallow in a certain time window following a visual go signal [43]. Taken together, these studies in healthy participants demonstrate that anodal tDCS can increase excitability of the pharyngeal M1 representation and that this cortical facilitation may be associated with subtle improvements in swallowing function. The transferability of tDCS into clinical application was explored by three studies evaluating the effects of tDCS on swallowing function in post-stroke dysphagia [22,40,48] (Table 2). Anodal tDCS (2 mA for 30 min over five consecutive days) applied over the contralesional inferior sensorimotor cortex in subacute stroke patients (1–7 days postinfarct), in conjunction with conventional swallowing exercises, improved clinically assessed swallowing function [22]. An improvement in swallowing function was represented by a mean 2.6 point increase on the 7-point videofluoroscopy-based Dysphagia Outcome and Severity Scale (DOSS) [34] with six out of seven patients in the active group improving by at least two points. The sham control group demonstrated a much smaller mean increase in DOSS score (1.25/7 points), with three out of seven patients improving by at least two points. Shigematsu et al. [40] employed the DOSS to assess swallowing function following anodal tDCS in a group of chronic stroke patients (more than 4 weeks postinfarct). The tDCS paradigm consisted of 10 days of 20 min of anodal tDCS at 1 mA over ipsilesional pharyngeal motor cortex. Average DOSS scores increased by 1.4/7 points immediately following the two week intervention period and continued to increase to 2.8/7 points at a

Table 1 Studies with healthy participants. Citation

Demographics

Intervention

Number tested (n=), age, gender

NBS type

Hemisphere stimulated

Stimulation dose

Neurophysiological

Clinical

Jefferson et al. [18]

n = 17, mean age 37.6 years, 10 females

Pharyngeal motor cortex

1 or 1.5 mA over 10 s, for 10 or 20 min

Increased pharyngeal MEPs

n/a

Suntrup et al. [43]

n = 21, mean age 26.76 years, 11 females

tDCS anodal vs. cathodal vs. sham Anodal tDCS

Left or right swallowing motor cortex, sham stimulation

1 mA over 20 min

Altered swallow-related activation via MEG measurement

Vasant et al. [45]

n = 15, mean age 35 years, 7 females,

tDCS vs. sham

1.5 mA over 10 min

Increased pharyngeal MEPs

Mistry et al. [32]

n = 9, mean age 34 years, 3 females n = 23, mean age 37 years, 15 females

rTMS

After contra-lateral rTMS pre-conditioning of side with stronger pharyngeal projection Both hemispheres

Increase in percentage of ‘hits’ on challenged swallow task No effect on PANAS scores Improved performance on challenged swallow task

1 Hz over 10 min

rTMS

Contra-lesional pharyngeal motor cortex

5 Hz

Increased pharyngeal MEPs Increased pharyngeal MEPs

Mistry et al. [31]

n = 15, age 22–59 years, 6 females

TMS (iTBS)

Both hemispheres

Michou et al. [30]

n = 18, mean age 39 years, 14 females

TMS (PAS) vs. sham

Pharyngeal motor cortex; bilateral

Three pulses at 50 Hz; every 200 ms (iTBS protocol) Paired pulses every 20 s for 10 min

Jefferson et al. [17]

Outcome

Increased pharyngeal MEPs Increased pharyngeal MEPs

n/a Improved performance on challenged swallow task score n/a

n/a

Acronyms: NBS = non-invasive brain stimulation; tDCS = transcranial direct current stimulation; mA = milliampere, a measure of electric current; MEPs = motor evoked potentials; n/a = not applicable; MEG = magnetoencephalography; PANAS = Positive and Negative Affect Schedule; rTMS = repetitive transcranial magnetic stimulation; Hz = hertz; TMS = transcranial magnetic stimulation; iTBS = intermittent theta-burst stimulation; and PAS = paired associative stimulation.

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Table 2 Studies with participants presenting with post-stroke dysphagia. Citation

Demographics

Intervention

Outcome

Time post-onset

Number tested (n=), age, gender

NBS type

Hemisphere stimulated

Stimulation dose

Neuro-physiological Clinical

Kumar et al. [22]

Unilateral hemispheric infarction

24–168 h

Anodal tDCS vs. sham

Contra-lesional, lateral sensorimotor cortex

2 mA for 30 min for 5 consecutive days

n/a

Improved DOSS scores

Yang et al. [48]

Hemispheric lesion 8 right, 8 left

Mean 25.2 days

tDCS vs. sham

Ipsi-lesional pharyngeal motor representation

1 mA for 20 min for 10 days

n/a

Improved FDS score VFSS: transit time unchanged

Shigematsu et al. [40]

13 supratentorial, 7 infratentorial 12 left, 8 right

5–38 weeks (mean 12)

tDCS vs. sham

Ipsi-lesional pharyngeal motor representation

1 mA over 20 min sessions for 10 days

n/a

Improved DOSS scores

Verin and Leroi [46]

4 right (cingula, parietofrontal, pedoncula, cerebellum) 3 left (cingula, internal capsule, cerebellum)

11–120 months

n = 14 mean age 79.7 years (anodal), 70 years (sham), 7 females n = 16 mean age 70.44 years (tDCS), 70.57 years (sham), 7 females n = 20 mean age 66.9 years, 6 females n=7 mean age 65 years, 3 females

TMS (non-controlled pilot)

Contra-lesional mylohyoid motor representation

1 Hz for 20 min for 4 days

n/a

Michou et al. [28]

Cerebral infarct Side of symptoms 5 left, 1 right

9–160 weeks (mean 38.8)

PAS

Contra-lesional pharyngeal motor representation

Three PAS durations (10 min, 20 min, 30 min) and sham PAS, optimal protocol then used in stroke population

Increased pharyngeal MEPs

Improved DHI scores VFSS: shorter swallow reaction time, reduced aspiration score for liquids and residue score for paste VFSS: shortened swallowing reaction and transit times Reduced penetration–aspiration scores

Khedr et al. [20]

Monohemispheric stroke (14 right hemiplegia, 12 left hemiplegia) 10 massive, 13 subcortical, 3 cortical 11 lateral medullary infarct, 11 other brainstem infarction

5–10 days

rTMS vs. sham

Ipsi-lesional oesophageal motor representation

10 trains of 3 Hz for 10 s for 10 min for 5 days

Increased oesophageal MEPs

Improved dysphagia rating, Barthel index (BI) and trend toward improved hand-grip strength

rTMS vs. sham

Bilateral oesophageal motor representation

3 Hz for 10 min for 5 days

n/a

Improved dysphagia rating and BI

45–91 days (mean 59.9)

rTMS vs. sham

Contra-lesional pharyngeal motor representation

5 Hz for 10 min for 10 days

n/a

VFSS: improved dysphagia severity, reduced penetration–aspiration score

Michou et al. [29]

Unilateral hemispheric stroke (11 MCA territory, 4 basal ganglia, 3 striatocapsular) Experimental (6 right, 3 left) Control (4 right, 5 left) Side of symptoms 6 right, 9 left, 3 bilateral

8–160 weeks (mean 63)

n = 18 mean age 66 years, 3 females

PES PAS rTMS

Contra-lesional pharyngeal motor representation

Increased pharyngeal MEPs

VFSS: reduced penetration–aspiration score

Rhee et al. [37]

Lateral medullar infarction

33 days

n=1 52 year old male

rTMS

Bilateral pharyngeal motor representation

Single session PES: 5 Hz for 10 min rTMS: 5 Hz for 250 pulses PAS: PES + single TMS 5 Hz for 10 s for 10 min for 10 days

n/a

Decreased FDS score; decrease in vallecular and piriform sinus residue, pharyngeal coating and transit time

Khedr and Abo-Elfetoh [19] Park et al. [35]

1–3 months

n = 18 12 healthy mean age 38.1 years, 10 females; 6 dysphagic mean age 74 years, 1 female n = 26 mean age 57.3 years, 16 females

n = 22 mean age 56.4 years (LMI), 58.2 years (brainstem), 6 females n = 18 mean age 71.3 years, 8 females

Acronyms: CVA = cerebrovascular accident; NBS = non-invasive brain stimulation; n/a = not applicable; tDCS = transcranial direct current stimulation; mA = milliampere, a measure of electric current; DOSS = Dysphagia Outcome and Severity Scale; MEPs = motor evoked potentials; rTMS = repetitive transcranial magnetic stimulation; Hz = hertz; TMS = transcranial magnetic stimulation; iTBS = intermittent theta-burst stimulation; PAS = paired associative stimulation; VFSS = videofluoroscopic swallow study; LMI = lateral medullary infarct; NIHSS = National Institutes of Health Stroke Severity Scale; MCA = middle cerebral artery; PES = pharyngeal electrical stimulation; DHI = Dysphagia Handicap Index; and FDS = Functional Dysphagia Scale.

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CVA location

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1-month follow-up, with nine out of ten patients improving by at least two points at the 1 month follow-up. Patients receiving sham stimulation improved to a lesser degree (0.5/7 and 1.2/7 points immediately and 1 month following intervention, respectively, with four out of ten patients improving by at least two points at the 1 month follow-up). Finally, Yang et al. [48] demonstrated an improvement in swallowing function as assessed by a videofluoroscopy-based assessment, the Functional Dysphagia Scale (FDS), in both an active and sham anodal tDCS group. The stimulation paradigm was 10 days of 1 mA anodal tDCS applied for 20 min over the ipsilesional hemisphere at the beginning of a 30 min conventional swallowing training session. There was no difference between groups immediately after the intervention period; however, mean swallowing function scores improved significantly more in the active tDCS group at 3 months post-intervention follow-up. In two patients (one from each group), cerebral glucose metabolism was assessed using positron emission tomography. Immediately postintervention, the patient receiving active anodal tDCS showed increased metabolic activity in the postcentral gyrus of the unaffected hemisphere in comparison to the patient receiving sham stimulation [48]. Together these studies demonstrate that anodal tDCS paradigms applied over either the ipsilesional or contralesional hemisphere have the potential to improve swallowing function in people with stroke after repeated tDCS sessions. It is interesting to note that the stimulation paradigms used in all three clinical studies differed from those used in healthy volunteers. The parameters differed either in the intensity used [30 min of 2 mA anodal tDCS [22] vs. 10 min of 1.5 mA or 20 min of 1 mA of anodal tDCS [18]] or site of stimulation [lesioned hemisphere [40,48] vs. contralesioned hemisphere in virtual lesion model of unimpaired swallowing [45]]. This highlights the heterogeneity of tDCS paradigms employed in clinical studies to date and underscores the need to further explore parameters of stimulation that optimally facilitate the recovery of swallowing function in clinical populations. In the clinical tDCS studies anodal stimulation was applied alongside “conventional” dysphagia intervention. This raises the important question whether NBS should be provided as an intervention in its own right, or used as an adjunct to conventional rehabilitation practice? In the latter scenario, application of NBS may provide a “therapeutic” window during which behavioural intervention may be more effective in facilitating recovery of swallowing function than conventional intervention alone. Preliminary evidence for this premise is available in the literature, where there is evidence for combined paradigms in the corticospinal motor system [27]. The effectiveness of combined interventions compared to brain stimulation alone in swallowing rehabilitation is worthy of further investigation. 3.3. Repetitive transcranial magnetic stimulation in unimpaired swallowing and post-stroke dysphagia Transcranial magnetic stimulation is governed by the principles of electromagnetism. Trains of single magnetic pulses, known as repetitive transcranial magnetic stimulation (rTMS), can modify the excitability of the stimulated motor networks, which can outlast the stimulation period by several hours. The potential role of rTMS in swallowing rehabilitation was explored in parallel to the emerging evidence-base for the use of tDCS. Four studies were identified that evaluated the effects of various rTMS paradigms on the excitability of the pharyngeal cortical motor representation in unimpaired swallowing [17,30–32] (Table 1). One study compared two inhibitory rTMS paradigms; 1 Hz rTMS and continuous theta burst stimulation (a patterned form of rTMS) [32]. These authors found that 1 Hz rTMS applied at high intensity (120% of pharyngeal resting motor threshold) over the dominant pharyngeal M1 representation was more effective in reducing the excitability of the pharyngeal motor cortex. This reduced pharyngeal motor cortex excitability of the dominant hemisphere was accompanied by shortened swallowing response times during a swallowing reaction time challenge

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task following a visual go-signal [32]. In a later study [31], the same group used intermittent theta-burst stimulation (iTBS) a patterned form of rTMS evoking facilitatory effects in the corticospinal motor system [15] to increase excitability of the pharyngeal M1 representation. They found that there was only an increase in excitability of the contralateral (non-dominant, non-stimulated) hemisphere and only if iTBS was applied over the swallowing dominant hemisphere. Furthermore, there was no effect of iTBS on corticomotor excitability of a hand muscle (abductor pollicis brevis), suggesting that effects are local to the stimulated M1 representations [31]. The finding that swallowing response time was shortened by inhibitory rTMS is interesting in light of the fact that the 1 Hz rTMS paradigm was used as a ‘virtual lesion’ model in subsequent studies of unimpaired swallowing, e.g. [17,28,45]. Using this virtual lesion approach, suppression of the dominant swallowing pharyngeal motor representation by 1 Hz rTMS, as per [32], was abolished by a facilitatory 5 Hz rTMS paradigm applied over the contralateral hemisphere. The reduction of swallowing response time following the initial virtual lesion was reversed by the subsequent 5 Hz rTMS [17]. This finding indicates the importance of the degree of balance of excitability between the two hemispheres for swallowing motor function and may provide an insight into mechanisms underlying swallowing dysfunction after stroke. Taken together, these studies suggest that rTMS can inhibit or facilitate the excitability of the pharyngeal M1 representation in unimpaired swallowing and alter swallowing function. Furthermore, inhibitory rTMS in adults with unimpaired swallowing appears to provide a suitable model of impaired swallowing by evoking a virtual lesion, by transiently reducing the excitability of the stimulated target area. The effect of this would be to generate a temporary change in the interhemispheric balance of cortical motor networks involved in swallowing, potentially similar to that observed following hemispheric stroke [47]. Seven studies were identified that evaluated the potential role of rTMS in the recovery of impaired swallowing in people who have experienced a stroke [19,20,28,29,35,37,46] (Table 2). Of these, 5 studies used rTMS only [19,20,35,37,46], one study used PAS [28] and one compared rTMS and PAS [29]. An early pilot investigated the effect of inhibitory 1 Hz rTMS (20 min on each of five consecutive days) to the contralesional M1 representation of the mylohyoid musculature in seven patients with chronic hemispheric or subhemispheric infarcts [46]. Following the intervention period, mean clinical scores of swallowing function were increased, assessed by a Dysphagia Handicap Index incorporating physical, functional and emotional aspects of swallowing. In addition, swallowing response times of a paste consistency bolus, assessed by videofluoroscopic swallowing study (VFSS), were decreased [46]. Average aspiration scores for liquids and penetration scores for paste were also reduced following 1 Hz rTMS [46]. This study indicates that inhibitory stimulation over the contralesional hemisphere improves functional swallowing outcomes. This appears inconsistent with previous work demonstrating that spontaneous recovery of swallowing function post-stroke is associated with an increase of contralesional hemisphere excitability [12]. Further exploration of the role of inhibitory rTMS to contralesional M1 in post-stroke swallowing rehabilitation is warranted. Two studies have investigated the effects of facilitatory 3 Hz rTMS applied over the oesophageal M1 representation [19,20]. In one study, facilitatory rTMS or sham rTMS was applied over the lesioned hemisphere for 10 min on each of five consecutive days in people presenting with monohemispheric stroke [20]. The real rTMS group showed greater overall improvement on the DOSS scale (approximately 2.4/7 points, data extracted from figure) compared to the sham group at a two month follow-up (approximately 0.5/7 points, data extract from figure). The improvement in swallowing performance was accompanied by an increase in cortico-oesophageal excitability one month following the intervention [20]. Subsequently, these authors investigated the effects of 3 Hz rTMS applied over 5 consecutive days in people presenting with a stroke infarct in the lateral medullary region (N = 11) or in other

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brainstem regions (N = 11) [19]. Facilitatory rTMS or sham rTMS was applied over both left and right M1 representations of the oesophageal musculature. Similar to the previous findings in people who had experienced a hemispheric stroke, the mean DOSS score improved to a greater extend in the real rTMS groups (approximately 2.3/7 points for each lesion group, data extracted from figure) compared to than sham group for up to two months following the intervention period. In addition, following active intervention the Barthel index improved for patients presenting with lateral medullary infarct up to two months. Taken together, these studies indicate that rTMS to increase the excitability of oesophageal M1 representations may benefit people with infarcts at either cortical or brainstem levels. Future studies are warranted to investigate how changes in the excitability of oesophageal M1 representation correlate to changes in oesophageal motility. Park et al. [35] applied facilitatory 5 Hz rTMS to the contralesional pharyngeal motor cortex for 10 min per day over two weeks in 18 patients presenting with unilateral hemispheric stroke and chronic dysphagia. In these patients, active rTMS improved swallowing function, as assessed by the Videofluoroscopic Dysphagia Scale in four out of nine patients by at least 10/60 points. Interestingly, when the Dysphagia Scale was divided into scores representing oral or pharyngeal phase function, improvements were only observed in the pharyngeal phase of swallowing. Consistent with this finding, average scores on a Penetration–Aspiration Scale also improved in the active rTMS group by at least two points in three out of seven patients. There were no improvements in the group undergoing sham rTMS [35]. Finally, Rhee et al. [37] conducted a descriptive case study of a single patient with lateral medullary infarct who underwent repeated sessions of 5 Hz rTMS over two weeks. This intervention was found to qualitatively improve swallowing function as assessed by the Functional Dysphagia Scale [37]. Improved swallowing was accompanied by a qualitatively characterised improvement in pharyngeal and oesophageal peristaltic pressure patterns as assessed by five-channel manometry immediately post-intervention. On balance, these studies demonstrate that modulation of M1 excitability of muscles involved in swallowing function by rTMS has the potential to improve impaired swallowing function. However, there is inconsistency in the application of rTMS paradigms, with stimulation over the ipsilesional, contralesional or bilateral motor cortices all showing positive benefits on swallowing function. It may be that all approaches have some therapeutic merit for stroke patients but further investigations with greater numbers of patients are needed. The variability of rTMS paradigms and stimulation sites severely limits the generalizability of NBS techniques to routine clinical practice at the present time. Further research optimising rTMS protocols to individual presentations of stroke or types of swallowing dysfunction is warranted. 3.4. Paired associative stimulation Paired associative stimulation (PAS) is a brain stimulation technique that repetitively pairs the application of an electrical stimulus to a target muscle with TMS applied to the same muscle M1 representation at millisecond intervals [42]. Michou et al. [28] optimised this technique for the corticobulbar motor system controlling the pharyngeal musculature. In a “virtual lesion” model generated by inhibitory 1 Hz rTMS of M1 in a group of healthy participants, facilitatory PAS over the contralateral motor cortex reversed cortical suppression in both hemispheres. The facilitation observed in M1 bilaterally was accompanied by a greater percentage of successful swallows in a challenged swallow reaction time task. In the same study, six patients with chronic dysphagia following cortical stroke underwent a single application of facilitatory PAS over the contralesional hemisphere. Following PAS, there was an increase in excitability of the contralesional corticobulbar motor projection, accompanied by decreased scores on the Penetration-Aspiration Scale [38] and reduced pharyngeal response and bolus transit times [28]. This group then investigated whether repeated application of PAS increased the effects seen following a single application of

PAS [30]. Following two applications of PAS 60 min apart, both those participants who responded after the first application and those who initially did not respond after the first application of PAS, showed increased pharyngeal motor cortex excitability. In a subsequent sham controlled study comparing the neurophysiological and behavioural effects of facilitatory PAS, facilitatory 5 Hz rTMS and facilitatory pharyngeal electrical stimulation (PES) in chronic cortical stroke, Michou et al. [29] demonstrated that all three neurostimulation paradigms increased excitability of the pharyngeal M1 representation. There were varying degrees of facilitation of pharyngeal motor excitability, with only PES and PAS resulting in facilitation that was significantly greater than following the respective sham paradigm. An increase in corticobulbar excitability in the contralesional hemisphere correlated with reduced scores on the Penetration-Aspiration Scale [38], a correlation that was weaker for the ipsilesional than the contralesional hemisphere. The studies evaluating the role of PAS in post-stroke swallowing rehabilitation support the potential usefulness of rTMS to facilitate recovery of swallowing function after stroke. Furthermore, studies using PAS suggest that provision of sensory input from the body may be superior to paradigms only employing magnetic stimuli to the brain. Further evaluation of rTMS paradigms that involve sensory input in stroke patients with swallowing dysfunction is, therefore, warranted. 3.5. Descriptive analysis of selected study parameters In light of the potential future clinical application of NBS in swallowing rehabilitation, a more specific qualitative analysis was undertaken. This qualitative analysis focused on the participants that were investigated, the cortical representations that were targeted by NBS, and the outcome measures that were used to assess swallowing function. A greater understanding of these variables will inform the future development of optimal treatment paradigms. 3.5.1. Participants Across the studies there were a total of 148 patients presenting with dysphagia following stroke of various aetiologies. Of these, 92 underwent active NBS and 80 underwent sham NBS, with 24 patients undergoing both active and sham NBS in separate sessions within the same study. 14 patients were in the acute phase (b 7 days), 101 in subacute phase (7 days–3 months) and 33 in the chronic phase (N 3 months). Overall, participant age ranged from 31 to 91 years. Non-invasive brain stimulation was applied to a total of 130 healthy participants with unimpaired swallowing, all of which whom underwent at least one active NBS paradigm. Overall, unimpaired participants ranged from 21 to 61 years of age, as far as this was specifically reported. No adverse effects were reported in any of the studies in people with either unimpaired or impaired swallowing, except for mild tingling under the electrodes upon commencement of stimulation using tDCS in one study [40], which is common in tDCS [11]. There were no withdrawals for reasons specifically relating to NBS reported in any study reviewed. As far as studies reported data of individual participants, no deterioration of swallowing function was identified. 3.5.2. Cortical representations of interest In general, NBS was targeted at primary motor cortical representations of muscles involved in swallowing, specifically the pharyngeal musculature (13/17 studies) [17,18,28–32,35,37,40,43,45,48], oesophageal musculature (2/17 studies) [19,20] or floor of mouth muscle group (1/17 studies) [46]. One study applied NBS over an area specified only as the lateral sensorimotor cortex (1/17 studies) [22]. Of the 10 studies involving patients with dysphagia following stroke, five studies applied NBS over the contralesional hemisphere [22,28,29,35,47] and three studies applied NBS over the ipsilesional hemisphere [20,40,48]. Two studies applied NBS over both hemispheres, but it is unclear whether NBS was applied sequentially or simultaneously over both hemispheres

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[19,37]. In healthy participants with unimpaired swallowing, four studies applied interventional NBS over the swallowing dominant hemisphere. One study investigated the effect of applying tDCS over either the dominant or non-dominant hemispheres in separate sessions. Two studies applied NBS over the non-dominant hemisphere following virtual lesion to reduce excitability of the dominant hemisphere. 3.5.3. Outcome measures A variety of functional and neurophysiological outcome measures were used across the studies. Neurophysiological outcome measures were evaluated in 11 studies, including assessment of changes in the excitability of corticobulbar motor projections to the target musculature. Corticobulbar excitability was represented by the MEP in nine studies and the degree of cortical activation was as assessed by magnetoencephalography in one study and positron emission tomography in one study. Functional outcome measures included assessment of swallowing using rating scales completed by a clinician. Ratings scales were generally based on videofluoroscopic assessment of swallowing function, e.g. Functional Dysphagia Scale, Dysphagia Outcome and Severity Scale or Penetration–Aspiration Scale. In four studies, secondary clinical measures not directly related to swallowing function were assessed, e.g. Barthel index or National Institutes of Health Stroke Scale (NIHSS) score. Of note, only four of the 10 clinical studies evaluating functional outcomes [20,28,29,48] also evaluated neurophysiological outcomes measures, one of which only evaluated a subgroup of two patients [48]. 4. Discussion This review of the literature identified and described the current evidence for the potential effectiveness of non-invasive brain stimulation to assist the recovery of swallowing function following stroke. A total of 17 studies evaluating various NBS paradigms in dysphagia following stroke and in healthy adults with unimpaired swallowing were reviewed. These studies provide preliminary evidence that both TMS and tDCS of M1 have the potential to modify swallowing biomechanics in unimpaired swallowing and facilitate the recovery of impaired swallowing following stroke. 4.1. Functional relevance of NBS for modulating swallowing behaviour A single application of either tDCS or rTMS in participants with unimpaired swallowing can induce an increase or decrease in motor cortical excitability that outlasts the stimulation period. It is difficult to assess changes in swallowing function in response to NBS in a system that already operates at optimal capacity, limiting the applicability of studies in healthy adults. For this reason, researchers have identified two methods to challenge the unimpaired swallowing system, either by inducing a targeted “virtual lesion” using inhibitory NBS, or assessing swallowing function in extremely challenged, i.e. reaction-timed, swallowing conditions. Importantly for future clinical application, the neuromodulatory effects observed in studies employing these assessment strategies were accompanied by subtle improvements in unimpaired swallowing behaviour. The reports that inhibiting the dominant swallowing hemisphere is accompanied by shortened swallowing onset [32] may be of clinical relevance for patients who present with delayed swallowing onset post-stroke. A possible mechanism for this finding may relate to NBS-induced changes in the contribution of primary motor circuits to the swallowing motor plan. Interestingly, any neurophysiological and functional effects induced by experimentally reducing excitability of the swallowing dominant hemisphere could be reversed using facilitatory NBS over the contralateral hemisphere [31,45]. These findings are in line with previous clinical research of increased contralesional M1 excitability in patients whose swallowing function recovers spontaneously following stroke [12]. The findings suggest that facilitation of the contralesional swallowing motor network is a promising

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approach toward assisting functional recovery of dysphagia after stroke. This idea is further supported by the five clinical studies reporting favourable effects on swallowing function following application of facilitatory NBS over the contralesional hemisphere in chronic stroke patients. It is noteworthy, however, that application of facilitatory NBS over the ipsilesional hemisphere also facilitated swallowing function (3/10 studies), warranting further investigation into the role of hemispheric excitability changes and how this influences swallowing function. 4.2. Limitations of the current literature Critical review of the included studies identified several limitations that need to be taken into consideration. One of the limitations inherent in the majority of studies was the use of outcome measures based on subjective clinical assessment, often in the absence of clinician, assessor and/or patient blinding. Non-blinded assessment has the potential to introduce observer bias that may affect the outcome measured and ultimately the validity of the reported effects. In addition, only few of the clinical studies evaluated neurophysiological outcome measures alongside the reported clinical effects. This limits the evaluation of potential underlying neural mechanisms that may be driving the clinical improvements observed following NBS of M1. Likewise, justification of sample size is often lacking which makes it difficult to assess whether the reported effects are statistically sufficiently powered. Although a total of 92 patients underwent active NBS, the documented evidence for positive clinical outcomes and treatment safety for each individual NBS paradigm is based on small clinical samples, ranging from 1 to 18 participants. In addition, conclusions drawn are naturally based on group analyses, with few studies reporting individual treatment effects. These can be highly variable, based on the specific data provided in some studies or the standard deviations reported in others. This highlights the importance of monitoring each individual patient's response to NBS as treatment progresses. The issues of sample size and response variability are magnified by the significant variability of stimulation parameters used across the studies included in this review. These include differences in stimulus intensity, dose (number of days applied) and the hemisphere targeted. The heterogeneity across study designs is not unexpected given that the clinical evaluation of NBS is in its infancy; however, inconsistency in NBS paradigms precludes meta-analysis of outcome measures across studies. For this reason, the current literature review cannot draw any conclusions regarding the clinical effectiveness, or safety, of any specific paradigm, but can only broadly comment on the potential role that NBS may play as an adjunct to swallowing rehabilitation. Another limitation of the current evidence base is the heterogeneity of lesion location in people who have experienced stroke across and even within studies. Given the assumption that specific motor networks at various levels of the swallowing motor system contribute specific information to the overall swallowing motor plan, lesion location will be an important variable to consider. This understanding is important for clinical translation as lesion location may be useful for informing the selection of NBS paradigms for clinical application in individual stroke patients. Future meta-analyses of evidence specific to different lesion locations may help optimise stimulation protocols and ultimately increase rehabilitation outcomes. The lack of consistency in research design and intervention paradigms in the identified studies reflects the complexity of this field of research. International collaboration must be encouraged to perform trials with sufficient numbers to accurately determine which paradigms may be superior to others in order to facilitate the eventual progression of the most effective and safe paradigms into clinical practice. 4.3. Clinical implications As demonstrated in this review and previous commentaries [5,6], the current evidence base is in a process of rapid growth with the

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promising implication that NBS may provide an effective and safe adjunct to swallowing rehabilitation practice. There are several practical implications that accompany the eventual progression of NBS paradigms into clinical practice. These include considerations regarding who will prescribe specific stimulation protocols to patients and who will provide the NBS interventions. It is also unclear whether NBS will form an adjunct to traditional exercise-based approaches or be used as an intervention in its own right. Legal frameworks and history of local practice will likely influence the development of NBS as a routine swallowing rehabilitation tool. In the context of evidence-based practice, the implementation of optimal NBS paradigms into clinical application will likely be facilitated by the involvement of clinical stakeholders in carefully designed clinical trials and will ultimately be shaped by client preferences [5].

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Acknowledgments The authors gratefully acknowledge the valuable contributions made by Rebecca Mossop, Debra Verner and Alicia Wallace in the early stages of this project.

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