Application of noninvasive brain stimulation for post stroke dysphagia rehabilitation + MODEL Kaohsiung Journal of Medical Sciences (2016) xx, 1e7 Available online at www sciencedirect com ScienceDire[.]
+ MODEL Kaohsiung Journal of Medical Sciences (2016) xx, 1e7 Available online at www.sciencedirect.com ScienceDirect journal homepage: http://www.kjms-online.com REVIEW ARTICLE Application of noninvasive brain stimulation for post-stroke dysphagia rehabilitation Zhuo Wang a, Wei-Qun Song a, Liang Wang b,* a Department of Rehabilitation, Xuanwu Hospital, Capital Medical University, Beijing, China Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China b Received 14 July 2016; accepted November 2016 KEYWORDS Dysphagia; Noninvasive brain stimulation; Stroke; Swallowing rehabilitation Abstract Noninvasive brain stimulation (NIBS), commonly consisting of transcranial magnetic stimulation (TMS), transcranial direct-current stimulation (tDCS), as well as paired associative stimulation (PAS), has attracted increased interest and been applied experimentally in the treatment of post-stroke dysphagia (PSD) This review presented a synopsis of the current research for the application of NIBS on PSD The intention here was to understand the current research progress and limitations in this field and to stimulate potential research questions not yet investigated for the application of NIBS on patients with PSD Here we successively reviewed advances of repetitive TMS (rTMS), tDCS, and PAS techniques on both healthy participants and PSD patients in three aspects, including scientific researches about dysphagia mechanism, applied studies about stimulation parameters, and clinical trials about their therapeutic effects The techniques of NIBS, especially rTMS, have been used by the researchers to explore the different mechanisms between swallowing recovery and extremity rehabilitation The key findings included the important role of intact hemisphere reorganization for PSD recovery, and the use of NIBS on the contra-lesional side as a therapeutic potential for dysphagia rehabilitation Though significant results were achieved in most studies by using NIBS on swallowing rehabilitation, it is still difficult to draw conclusions for the efficacy of these neurostimulation techniques, considering the great disparities between studies Copyright ª 2016, Kaohsiung Medical University Published by Elsevier Taiwan LLC This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/) Conflicts of interest: All authors declare no conflicts of interest * Corresponding author Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili Number 6, Dongcheng District, Beijing, 100050, China E-mail address: saintage7@126.com (L Wang) http://dx.doi.org/10.1016/j.kjms.2016.11.007 1607-551X/Copyright ª 2016, Kaohsiung Medical University Published by Elsevier Taiwan LLC This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Please cite this article in press as: Wang Z, et al., Application of noninvasive brain stimulation for post-stroke dysphagia rehabilitation, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.11.007 + MODEL Introduction Dysphagia, a swallowing disorder, can be divided into oropharyngeal dysphagia and esophageal dysphagia based on the different stages of deglutition Oropharyngeal dysphagia, resulting from either oropharyngeal swallowing dysfunction or perceived difficulty in the process of swallowing, is usually a manifestation of a systemic disease rather than a disease specific to the oropharynx [1] Stroke is a representative cause of oropharyngeal dysphagia, and in acute stroke, the prevalence of dysphagia has been reported as being between 37% and 78% [2] Post-stroke dysphagia (PSD), which is a common medical complication that affects many patients in the first few hours and days after ictus, is associated with increased mortality and morbidity, partially due to aspiration, pneumonia, and malnutrition [3] In most patients, PSD can improve spontaneously; however, in approximately 11e50% of patients, it is a long-term disability [2,3] The primary goal of treatment for dysphagia after stroke is to improve the amount and variety of food and liquid which are swallowed orally while minimizing the risk of aspiration and related complications The currently used treatment methods for PSD include posture training, dietary modifications, swallowing exercises, drug therapy, oromotor stimulation, neuromuscular electrical stimulation, botulinum toxin injection, and noninvasive brain stimulation (NIBS) [4] As a powerful method to modulate human brain function, NIBS commonly consists of transcranial magnetic stimulation (TMS), transcranial direct-current stimulation (tDCS), and paired associative stimulation (PAS) PAS is derived by combining peripheral stimulation to the targeted muscle with TMS or tDCS over the representational area of that muscle in the motor cortex [5,6] The reasons why NIBS can be utilized for the PSD rehabilitation mainly include the following: first, PSD has been believed to be associated with damage to the cortex and subcortical structures, including, but not limited to, the lower motor neurons of the swallowing center in the brainstem; second, cortical reorganization, known as neuroplasticity [7], which could be purposefully modulated by NIBS, as described below, leads to swallowing recovery Although the application of NIBS exhibited synergistic effects over time [4], it is still unreliable for proposing any specific recruitment criteria due to the limited number of well-designed, long-term follow-up studies Basically, the successful implementation of these techniques as interventional strategies will rely on an improved understanding of the underlying neuronal correlates of functional recovery [6] In this paper, we sequentially review the progress made by utilizing TMS, tDCS, and PAS on healthy participants and PSD patients, with the goals of investigating whether NIBS has brought light to the mechanism research of PSD, verifying whether the usage of NIBS on PSD rehabilitation has shown satisfactory results, and determining whether some methodological limitations remain in need of further investigation Utilization of TMS on PSD Approximately three decades ago, Barker et al [8] demonstrated that it was possible to stimulate both nerves and the Z Wang et al brain using external magnetic stimulation TMS then started to be used in clinical neurology to study the central motor conduction time Depending on the stimulation parameters, TMS can excite or inhibit the brain, thus allowing the functional mapping of cortical regions and the creation of transient functional lesions [9] Compared with single-pulse TMS, which can depolarize neurons and evoke measurable effects, trains of stimuli (repetitive TMS, rTMS) can provide novel insights into the pathophysiology of the neural circuitry, which have been widely utilized in the areas of motor and speech recovery [10] The application of TMS on dysphagia stroke can be summarized in the following three aspects The mechanistic research of PSD using TMS When discussing research on the mechanisms of dysphagia, it is necessary to mention Dr Hamdy et al [11] who were the first to use TMS on this subject They used TMS in 20 healthy participants, two decades ago, to describe the physiological characteristics of the corticofugal pathways to swallowing muscles [11] They found, for the first time, that the muscles involved in swallowing appeared to be represented bilaterally on the precentral cortex, which displayed interhemispheric asymmetry, independent of handedness These findings proved that the cortex plays an important role in regulating the brainstem swallowing program A year later, they published additional experimental results on this subject [12] To acquire cortical stimulations, TMS was used on 20 post-stroke patients with or without dysphagia for the first time The authors found that the PSD patients had smaller pharyngeal responses on the unaffected hemisphere than did patients who retained normal swallowing This result was consistent with their prior finding of the presence of interhemispheric asymmetry with the swallowing motor function and suggested that dysphagia after unilateral hemispheric stroke was related to the magnitude of pharyngeal motor representation in the unaffected hemisphere Based on these results, Hamdy et al [13] speculated that the recovery of swallowing in PSD patients could be explained by the compensatory reorganization of swallowing function in the intact hemisphere rather than the restoration of swallowing function in the damaged hemisphere, and they performed another clinical study to verify this speculation After months of follow-up for 28 patients who had a unilateral hemispheric stroke, the researchers demonstrated that the cortical map representation of the pharyngeal musculature in the undamaged hemisphere increased markedly in size in the PSD patients who recovered swallowing, but that there was no change in patients who had persistent dysphagia or who did not have dysphagia throughout These observations verified the speculation that the recovery of PSD may be dependent on compensatory strategies of cortical reorganization, through neuroplastic changes, which can mainly be observed in the undamaged hemisphere By using the TMS technique, these findings on the mechanism of PSD and its recovery have laid the theoretical foundations for PSD rehabilitation and have facilitated further research on the neuroplasticity of the pharyngeal motor cortex in association with its functional outcome [7,14] Please cite this article in press as: Wang Z, et al., Application of noninvasive brain stimulation for post-stroke dysphagia rehabilitation, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.11.007 + MODEL mo 10 for d Oesophageal Bilateral N/A Single Pharyngeal Unaffected N/A 10 for 10 d Pharyngeal Unaffected Unaffected Unaffected Affected Mylohyoid “hot spot” Pharyngeal 20 for 10 d 20 for 10 d N/A N/A DOSS/BI positive FDS/PAS positive mo 10 for d Oesophageal Affected Hz (130%rMT) Hz (90%rMT) Acutebrainstem infarct 22 CT RCT > wk 18 (6) rTMS vs PES vs PAS rTMS Hz (90%rMT) RCT > mo 18 1Hz (100%rMT) Hz (100%rMT) rTMS vs CDT vs NMES rTMS CT Subacute 47 (14) Lim et al., 2014 [20] Park et al., 2013 [22] Michou et al., 2014 [23] Khedr & Abo-Elfetoh, 2010 [24] Infarct; hemorrhage; TBI 30 RCT rTMS Hz (100%rMT) 10 blocks of 30 pulses 20 blocks of 50 pulses; block of 1200 pulses block of 1200 pulses 10 blocks of 50 pulses blocks of 50 pulses 10 blocks of 30 pulses Hz (120%rMT) rTMS RCT Acute 26 Schedule Location Hemisphere Protocol design Stimulation Interventions Study design Targeted lesion No Study Summary of clinical studies on PSD using rTMS Regarding the clinical utilization of rTMS on PSD patients, well-designed clinical trials have been reported since 2009, although they utilized different protocols, as shown in Table Khedr et al [18] reported the clinical effects of PSD with rTMS for the first time in 2009 To increase the cortical excitability of the lesioned hemisphere, they used a 3-Hz rTMS on the affected hemisphere in the real group of patients with acute PSD due to monohemispheric stroke Real rTMS led to a significantly greater improvement in dysphagia and motor disability that was maintained over months of follow-up compared with the sham group Kim et al [19] then compared the effect of low-frequency (1 Hz) and high-frequency (5 Hz) rTMS on recovery of the swallowing function in patients with a brain injury, including infarction, hemorrhage, and brain injury It was found that inhibitory stimulation of low-frequency rTMS on the contra-lesional hemisphere facilitated the recovery of PSD Furthermore, years later, another group from South Korea completed a Table Clinical research of rTMS on PSD patients Follow-up An important issue to note concerns the experiments that aimed to find the optimal parameters of TMS As mentioned previously [10], a train of TMS pulses of the same intensity applied to a single brain area at a given frequency that can range from one stimulus per second to 20 or more is known as rTMS It is known that the frequency and intensity of a single TMS are associated with the disruption of cortical function rTMS can also induce a modulation of cortical excitability This effect may range from inhibition to facilitation, depending on the stimulation variables (particularly frequency of stimulation) According to Maeda et al [15], low-frequency rTMS, which was defined by stimulation at frequencies Hz, reduced neuronal excitability, whereas high-frequency rTMS, which was defined by stimulation at frequencies Hz, increased limb motor cortical excitability Two experiments conducted by Dr Hamdy et al [16,17] further investigated the relationship between the frequency of rTMS and the associated excitability of the pharyngeal cortex and verified this discrepancy for different frequencies of rTMS on the pharyngeal cortex By comparing the effects of a different number of pulses in trains of Hz, 250 stimulation pulses were found to be as effective as longer 5-Hz rTMS trains (1000 pulses) at inducing increases in cortico-bulbar motor evoked potentials (MEPs) from the pharyngeal motor cortex [16] By contrast, a 1-Hz rTMS paradigm for 10 minutes (600 pulses) at 120% of the pharyngeal threshold was able to generate a unilateral “virtual lesion”, which can inhibit the cortico-bulbar output from the pharyngeal motor cortex and interfere with swallowing behavior for up to 45 minutes [17] The development of this inhibitory pre-conditioning protocol of rTMS in the pharyngeal motor system facilitated the preclinical applications of these NIBS techniques in a controlled environment to assess the efficacy of these interventions in a disrupted system, as described below Khedr et al., 2009 [18] Kim et al., 2011 [19] Outcomes Studies about rTMS protocols for healthy participants BI Z Barthel Index; CT Z controlled trial; DOSS Z Dysphagic Outcome and Severity Scale; FDS Z Functional Dysphagia Scale; PAS Z Penetration-Aspiration Scale; RCT Z Random Controlled Trial FDS/PAS positive PAS positive PAS Negative DOSS/BI positive Application of NIBS for PSD rehabilitation Please cite this article in press as: Wang Z, et al., Application of noninvasive brain stimulation for post-stroke dysphagia rehabilitation, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.11.007 + MODEL comprehensive comparison of the effect of low-frequency rTMS and neuromuscular electrical stimulation (NMES) on subacute PSD [20] They used the same rTMS protocol as Kim et al [19] and proved that both low-frequency rTMS and NMES could induce early recovery from dysphagia It is important to note that the goal of these three clinical trials was either to provide excitatory stimulation over the lesion hemisphere or to decrease the transcallosal inhibition to the affected hemisphere by inhibitory stimulation over the healthy side, which was consistent with the rationale behind limb motor recovery As mentioned previously, the mechanism of dysphagia recovery has been proven to be different from that of limb motor recovery, as the role of intact hemisphere reorganization is important for PSD recovery [21] Several clinical trials have been performed to determine the therapeutic effect of excitatory stimulation over the unaffected pharyngeal motor cortex conducted by high-frequency rTMS A randomized controlled trial (RCT) performed by a study team of South Koreans was completed in 2013 [22] The experimental group received high-frequency (5 Hz) rTMS over the contra-lesional pharyngeal motor cortex According to their results, the prevalence rates of aspiration and pharyngeal residue were reduced by half, which meant that high-frequency rTMS on the contra-lesional pharyngeal motor cortex can be viewed as a new and effective treatment method for PSD patients Another RCT compared the effect of high-frequency rTMS on the contra-lesional pharyngeal motor cortex with two other neurostimulation techniques [pharyngeal electrical stimulation ( PES) and PAS] [23] The results showed that the corticobulbar excitability of the pharyngeal motor cortex was beneficially modulated by PES and PAS and, to a lesser extent, by rTMS, with functionally relevant changes in the unaffected hemisphere This result further verified prior results of mechanistic studies on PSD, indicating that an increase in corticobulbar excitability in the unaffected projection was correlated with an improvement in swallowing safety This result also suggested that it is necessary to conduct more detailed trials on different stimulation montages of rTMS to determine its long-term effects on swallowing In addition, some studies of rTMS on dysphagia rehabilitation caused by brainstem infarctions have been completed Khedr et al [18] and Khedr and Abo-Elfetoh [24] used the same parameters of rTMS as their prior trial on 22 patients with acute brainstem stroke who had severe bulbar manifestation The major difference from other studies was that bilateral pharyngeal motor cortex stimulation of rTMS was chosen for these patients As a result, active rTMS improved dysphagia compared with sham rTMS, which meant that rTMS could be a useful adjuvant strategy in the neurorehabilitation of dysphagia due to brainstem infarction Utilization of tDCS on PSD As a novel, noninvasive brain stimulation technique that delivers a small electric current continuously across the cerebral cortex, tDCS appears to be both safe and well tolerated, and it can directly alter excitability within the brain for periods outlasting the duration of stimulation [25] Research on the effects of tDCS on dysphagia was Z Wang et al conducted not only much later than that of rTMS but also far behind research on the use of this technique on limb motor rehabilitation Parameters and reactions of tDCS on the healthy pharyngeal motor cortex The first report on the application of tDCS on a human pharyngeal motor cortex was published in 2009 by Dr Hamdy et al [26].They studied the effects of differing doses of tDCS on the physiology of a healthy human pharyngeal motor cortex Both 10-minute 1.5 mA and 20minute mA anodal stimulation were found to induce increases in cortical excitability in the stimulated hemisphere They concluded that anodal tDCS can alter pharyngeal motor cortex excitability in an intensitydependent manner with little evidence for transcallosal spread, and they speculated that the anodal stimulation of tDCS may provide a useful way of promoting recovery in dysphagic patients In a later study, the authors paired swallowing training and sucking flavored lollipop interventions with tDCS in an undisrupted system and reported a bilateral increase in swallow-related brain activation on magnetoencephalography (MEG) after tDCS [27] This result was contradictory to the prior study, which can, to some extent, be explained by its newly involved task of swallowing training Clinical applications of tDCS on PSD patients To date, only three RCTs have been published on the effectiveness of tDCS in PSD patients, the main parameters of which are labelled in Table Similar to the clinical usage of rTMS on PSD patients, the greatest discrepancy of the experimental designs of these RCTs existed in the targeted hemisphere of the cortical stimulation In the first pilot study [28], 14 patients with subacute unilateral hemispheric infarction were randomized to anodal tDCS versus sham stimulation to the motor cortical representation of swallowing in the unaffected hemisphere with concurrent standardized swallowing maneuvers The positive results verified that measures that enhance cortical input and sensorimotor control of brainstem swallowing may be beneficial for dysphagia recovery However, this research was criticized for using parameters that were previously untested in the pharyngeal system with limited measurable effects on swallowing behavior A further study was reported by Dr Hamdy et al [29] In the first step of their research and to acquire a virtual dysphagia, 1-Hz rTMS pre-conditioning to the strongest pharyngeal projection was used in 15 healthy participants utilizing the method previously mentioned [17] Next, the optimal tDCS parameters (anodal, 1.5 mA, 10 minutes) were applied contralaterally As a result, tDCS to the contralateral pharyngeal motor cortex reversed both the neurophysiological and behavioral effects of focal cortical inhibition on swallowing These results supported their prior findings that swallowing recovery was associated with neuroplastic adaptation in the unlesioned hemisphere and that tDCS on the contra-lesional side can be used as a therapeutic potential for dysphagia rehabilitation Please cite this article in press as: Wang Z, et al., Application of noninvasive brain stimulation for post-stroke dysphagia rehabilitation, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.11.007 + MODEL FDS Positive DOSS Positive mo On the contrary, two clinical trials that focused on the ipsilateral hemisphere were performed in South Korea and Japan [30,31] Both trials used evidence-based parameters (anodal, mA, 20 minutes, 10 days) of tDCS to stimulate the lesioned hemisphere They achieved positive results, as expected, and concluded that anodal tDCS to the ipsilesional hemisphere could significantly improve swallowing function It is necessary to mention that the patients in the trial conducted by Shigematsu et al [31] received intensive swallowing therapies with simultaneous brain stimulation Therefore, their results were criticized for the possible interference of simultaneous peripheral sensorimotor activities Due to the different molecular mechanisms from rTMS, tDCS has shown little evidence for transcallosal spread [26], which indicates that the choice of the stimulation hemisphere is very important Based on these three clinical trials and one experiment with virtual dysphagia, it is still impossible to determine the optimal hemisphere for tDCS Further clinical studies are needed to make a direct comparison between stimulations on the lesioned hemisphere and contra-lesional side mo DOSS Positive N/A Utilization of PAS on PSD The technique of PAS-induced heterosynaptic plasticity in the motor and somatosensory cortical areas is done by combining peripheral stimulation with the targeted muscle with cortical stimulations, including TMS and tDCS, over the representational area of that muscle in the motor cortex [6] By combining these two modalities, peripheral and central, and separating them with a specific time interval, excitation of the pharyngeal motor cortex can be strongly induced DOSS Z Dysphagic Outcome and Severity Scale; FDS Z Functional Dysphagia Scale mA mA Prospective, single-center, blinded pilot trial Prospective, single-center, single-blind trial Within mo after onset At least mo after onset Yang et al., 15 2012 [30] Shigematsu 20 et al., 2013 [31] Schedule Location Hemisphere Design 5 consecutive d Contralesional Sensory & motor 30 for d cortical area for swallowing Once/d & Ipsilesional N/A 20 for 10 d blocks of d Once/d & Ipsilesional Pharyngeal motor 20 for 10 d blocks of d cortex mA Stimulation Study design 14 Kumar et al., 2011 [28] 1e7 d after onset No Targeted lesion Study Summary of clinical trials on PSD using tDCS Table Prospective, single-center, blinded pilot trial Follow-up Outcomes Application of NIBS for PSD rehabilitation Parameter study of PAS It is worth noting that Dr Hamdy et al [32], the pioneers who first introduced this technique into PSD rehabilitation, performed a series of experiments to investigate the optimal parameters The first pilot study included 15 healthy volunteers, and the optimal parameters and interhemispheric interactions of PAS in the bilaterally represented pharyngeal system initially were investigated [32] PAS was delivered by pairing a PES (0.2-millisecond pulse) with a single TMS pulse on the pharyngeal motor cortex at the intensity of motor threshold plus 20% of stimulator output, and the greatest increase in cortical pharyngeal excitability was seen when the interstimulus interval was 100 milliseconds Cortical excitability in the ipsilateral hemisphere increased over hours with analogous, albeit lesser, changes in the contralateral hemisphere The optimal duration of PAS for neurophysiological changes was then found to be 10 minutes, according to their further study that included 12 healthy participants [5] Furthermore, by using the same parameters as before, this study team found that participants who did not respond to an initial application of excitatory stimulation (PAS, 10 minutes) showed an increase in MEP responses after a repeated stimulation, which had implications for double PAS application for PSD patients who may not respond to single-dose stimulation [33] As described in the newly published report [34], 11 healthy adults were recruited to receive real and sham PAS Please cite this article in press as: Wang Z, et al., Application of noninvasive brain stimulation for post-stroke dysphagia rehabilitation, Kaohsiung Journal of Medical Sciences (2016), http://dx.doi.org/10.1016/j.kjms.2016.11.007 + MODEL to the “stronger” motor cortex pharyngeal representation, with an aim to investigate the specific metabolic mechanism of PAS Following PAS, event-related functional magnetic resonance imaging (fMRI) was performed to assess changes in brain activation in response to swallowing and during rest Finally, PAS was verified to induce functional alterations in both targeted ipsilateral and contralateral areas of the swallowing network in health Such changes highlighted the functionality of transcallosal interactions in the swallowing network These findings should be viewed as a complement to the mechanism of dysphagia and its recovery and illustrated that PAS exerts its effects on the swallowing network level not only on the targeted cortical motor area Z Wang et al mechanism of PSD; equally, there is no doubt that these techniques of NIBS will be viewed as promising methods in the hand of a rehabilitation clinician to deal with PSD in the future Given the limitations of the relevant studies, there are three issues that require further study First, although rTMS has a wider application in clinical and scientific research, more detailed comparisons about the therapeutic effects among these techniques should be performed Second, additional well-designed RCTs that have a larger sample size and long-term follow-up are needed Third, to avoid selection bias as much as possible, the targeted population of the clinical trials should be more clearly defined, and the enrolled patients with subacute or chronic dysphagia stroke should not be ambiguous Clinical study about PAS on PSD In a pilot study of PAS on six patients with chronic and severe dysphagic stroke, the application of PAS on the contralesional pharyngeal motor cortex significantly increased the cortical excitability of the unaffected hemisphere and showed immediate behavioral and neurophysiological effects [5] Based on these preclinical tests, an RCT was completed to compare the beneficial effects of three neurostimulation techniques, including PES, PAS, and rTMS, on chronic PSD patients, as previously mentioned [23] The results demonstrated that a single application of either PES or PAS increased cortical excitability and was associated with reductions in aspiration, whereas 5-Hz rTMS was less effective when it was performed on the contra-lesional side This result was speculated to be caused by either the different stimulation mechanisms between PAS and rTMS or the defective study design because a single stimulation of rTMS was not sufficient to acquire an obvious reaction In these experiments on healthy participants and patients, PAS was seen to induce beneficial neurophysiological and behavioral effects in the subjects Although it is the most promising technique, research on PAS has just started More studies on the different stimulation choices of PAS, including a combination of tDCS with PES, on patients with PSD may lead to new findings in future work Recently, there have been several trends for the utilization of the NIBS techniques in the area of PSD First, researchers have tried to combine these techniques with new neuroradiology techniques, such as fMRI, MRS, MEG, and even neuro-navigation systems [27,34,35] With the advantage of neuroradiology, researchers are able to obtain information other than behavior reactions Second, other related cortices, such as the cerebellar cortex, have been tested for their effects on pharyngeal cortical excitability and swallowing responses [36,37] According to the reports [36], high-frequency cerebellar rTMS (10 Hz) can robustly produce physiologically relevant effects on the excitability of frequency-specific corticobulbar projections to the pharynx These results raise the possibility that excitatory neurostimulation of the cerebellum may be therapeutically useful in promoting recovery of PSD Summary There is no doubt that rTMS, tDCS, and PAS have been used as powerful tools in researching the neurophysiological Acknowledgments The National Natural Science Foundation of China (Grant No 81371194) provided financial support for this study References [1] Cook IJ, Kahrilas PJ AGA technical review on management of oropharyngeal dysphagia Gastroenterology 1999;116:455e78 [2] Kumar S, Selim MH, Caplan LR Medical complications after stroke Lancet Neurol 2010;9:105e18 [3] Cohen DL, Roffe C, Beavan J, Blackett B, Fairfield CA, Hamdy S, et al Post-stroke dysphagia: A review and design considerations for future trials Int J Stroke 2016;11:399e411 [4] Yang SN, Pyun SB, 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