Pharyngeal electrical stimulation for neurogenic dysphagia following stroke, traumatic brain injury or other causes: Main results from the PHADER cohort study.

BACKGROUND: Neurogenic dysphagia is common and has no definitive treatment. We assessed whether pharyngeal electrical stimulation (PES) is associated with reduced dysphagia. METHODS: The PHAryngeal electrical stimulation for treatment of neurogenic Dysphagia European Registry (PHADER) was a prospective single-arm observational cohort study. Participants were recruited with neurogenic dysphagia (comprising five groups - stroke not needing ventilation; stroke needing ventilation; ventilation acquired; traumatic brain injury; other neurological causes). PES was administered once daily for three days. The primary outcome was the validated dysphagia severity rating scale (DSRS, score best-worst 0-12) at 3 months. FINDINGS: Of 255 enrolled patients from 14 centres in Austria, Germany and UK, 10 failed screening. At baseline, mean (standard deviation) or median [interquartile range]: age 68 (14) years, male 71%, DSRS 11·4 (1·7), time from onset to treatment 32 [44] days; age, time and DSRS differed between diagnostic groups. Insertion of PES catheters was successfully inserted in 239/245 (98%) participants, and was typically easy taking 11·8 min. 9 participants withdrew before the end of treatment. DSRS improved significantly in all dysphagia groups, difference in means (95% confidence intervals, CI) from 0 to 3 months: stroke (n = 79) -6·7 (-7·8, -5·5), ventilated stroke (n = 98) -6·5 (-7·6, -5·5); ventilation acquired (n = 35) -6·6 (-8·4, -4·8); traumatic brain injury (n = 24) -4·5 (-6·6, -2·4). The results for DSRS were mirrored for instrumentally assessed penetration aspiration scale scores. DSRS improved in both supratentorial and infratentorial stroke, with no difference between them (p = 0·32). In previously ventilated participants with tracheotomy, DSRS improved more in participants who could be decannulated (n = 66) -7·5 (-8·6, -6·5) versus not decannulated (n = 33) -2·1 (-3·2, -1·0) (p<0·001). 74 serious adverse events (SAE) occurred in 60 participants with pneumonia (9·2%) the most frequent SAE. INTERPRETATION: In patients with neurogenic dysphagia, PES was safe and associated with reduced measures of dysphagia and penetration/aspiration. FUNDING: Phagenesis Ltd.

The PhINEST study - Pharyngeal ICU Novel Electrical Stimulation Therapy: Study protocol of a prospective, multi-site, randomized, sham-controlled, single-blind (outcome assessor-blinded) study.

INTRODUCTION: Post-extubation dysphagia is commonly observed in ICU patients and associated with increased aspiration rates, delayed resumption of oral intake/ malnutrition, prolonged ICU and hospital length of stay, decreased quality of life, and increased mortality. Conventional therapeutic approaches are limited. Pharyngeal electrical stimulation (PES) was previously shown to improve swallowing function and airway safety in severely dysphagic tracheostomised stroke patients. METHODS: In a multi-center, single-blind, 1:1 randomized controlled study, up to 400 (360 evaluable) mixed emergency adult ICU patients with recent extubation following mechanical ventilation and confirmed oropharyngeal dysphagia will be enrolled at investigational academic ICUs. Primary objective is to evaluate the effectiveness of PES in reducing the severity of unsafe swallows. Patients will be randomized to receive PES (or sham) treatment on 3 consecutive days in addition to best supportive care. Primary endpoint is a composite of 2 endpoints with hierarchy based on clinical priorities: DISCUSSION:: This study will evaluate the effects of PES on swallowing safety in critically ill ICU patients post mechanical ventilation with oropharyngeal dysphagia.

Pharyngeal electrical stimulation for early decannulation in tracheotomised patients with neurogenic dysphagia after stroke (PHAST-TRAC): a prospective, single-blinded, randomised trial.

BACKGROUND: Dysphagia after stroke is common, especially in severely affected patients who have had a tracheotomy. In a pilot trial, pharyngeal electrical stimulation (PES) improved swallowing function in this group of patients. We aimed to replicate and extend this single-centre experience. METHODS: We did a prospective, single-blind, randomised controlled trial across nine sites (seven acute care hospitals, two rehabilitation facilities) in Germany, Austria, and Italy. Patients with recent stroke who required tracheotomy were randomly assigned to receive 3 days of either PES or sham treatment (1:1). All patients had the stimulation catheter inserted; sham treatment was applied by connecting the PES base station to a simulator box instead of the catheter. Randomisation was done via a computerised interactive system (stratified by site) in blocks of four patients per site. Patients and investigators applying PES were not masked. The primary endpoint was assessed by a separate investigator at each site who was masked to treatment assignment. The primary outcome was readiness for decannulation 24-72 h after treatment, assessed using fibreoptic endoscopic evaluation of swallowing and based on a standardised protocol, including absence of massive pooling of saliva, presence of one or more spontaneous swallows, and presence of at least minimum laryngeal sensation. We planned a sequential statistical analysis of superiority for the primary endpoint. Interim analyses were to be done after primary outcome data were available for 50 patients (futility), 70 patients, and every additional ten patients thereafter, up to 140 patients. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN18137204. FINDINGS: From May 29, 2015, to July 5, 2017, of 81 patients assessed, 69 patients from nine sites were randomly assigned to receive PES (n=35) or sham (n=34) treatment. Median onset to randomisation time was 28 days (IQR 19-41; PES 28 [20-49]; sham 28 [18-40]). The Independent Data and Safety Monitoring Board recommended that the trial was stopped early for efficacy after 70 patients had been recruited and primary endpoint data for 69 patients were available. This decision was approved by the steering committee. More patients were ready for decannulation in the PES group (17 [49%] of 35 patients) than in the sham group (three [9%] of 34 patients; odds ratio [OR] 7·00 [95% CI 2·41-19·88]; p=0·0008). Adverse events were reported in 24 (69%) patients in the PES group and 24 (71%) patients in the sham group. The number of patients with at least one serious adverse event did not differ between the groups (ten [29%] patients in the PES group vs eight [23%] patients in the sham group; OR 1·30 [0·44-3·83]; p=0·7851). Seven (20%) patients in the PES group and three (9%) patients in the sham group died during the study period (OR 2·58 [0·61-10·97]; p=0·3059). None of the deaths or serious adverse events were judged to be related to PES. INTERPRETATION: In patients with stroke and subsequent tracheotomy, PES increased the proportion of patients who were ready for decannulation in this study population, many of whom received PES within a month of their stroke. Future trials should confirm whether PES is beneficial in tracheotomised patients who receive stimulation similarly early after stroke and explore its effects in other cohorts. FUNDING: Phagenesis Ltd.

Design and implementation of Pharyngeal electrical Stimulation for early de-cannulation in TRACheotomized (PHAST-TRAC) stroke patients with neurogenic dysphagia: a prospective randomized single-blinded interventional study.

Rationale Ongoing dysphagia in stroke patients weaned from mechanical ventilation often requires long-term tracheotomy to protect the airway from aspiration. In a recently reported single-centre pilot study, a significantly larger proportion (75%) of tracheotomized dysphagic stroke patients regained sufficient control of airway management allowing tracheotomy tube removal (decannulation) 24-72 h after pharyngeal electrical stimulation (PES) compared to controls who received standard therapy over the same time period (20%). Aim To assess the safety and efficacy of PES in accelerating dysphagia rehabilitation and enabling decannulation of tracheotomized stroke patients. Design International multi-centre prospective randomized controlled single-blind trial in approximately 126 ICU patients (the 90th percentile of the calculated maximum sample size). Study outcomes Primary outcome: proportion of stroke patients considered safe for decannulation 24-72 h after PES compared to control patients who do not receive PES. Key secondary outcomes focus on: dysphagia severity, decannulation rates, decannulation rate after a repeat PES treatment in patients persistently dysphagic after an initial PES treatment, stroke severity, duration of ICU-stay, occurrence of adverse events including pneumonia and need for recannulation over 30 days or until hospital discharge (if earlier). Discussion Dysphagia and related airway complications are reported as one of the main reasons for stroke patients remaining tracheotomized once successfully weaned from ventilation. This study will evaluate if PES can improve airway safety sufficiently enough to allow earlier tracheotomy tube removal.

Pharyngeal Electrical Stimulation in Dysphagia Poststroke: A Prospective, Randomized Single-Blinded Interventional Study.

Background Pharyngeal electrical stimulation (PES) appears to promote cortical plasticity and swallowing recovery poststroke. Objective We aimed to assess clinical effectiveness with longer follow-up. Methods Dysphagic patients (n = 36; median = 71 years; 61% male) recruited from 3 trial centers within 6 weeks of stroke, received active or sham PES in a single-blinded randomized design via an intraluminal pharyngeal catheter (10 minutes, for 3days). The primary outcome measure was the Dysphagia Severity Rating (DSR) scale (<4, no-mild; ≥4, moderate-severe). Secondary outcomes included unsafe swallows on the Penetration-Aspiration Scale (PAS ≥ 3), times to hospital discharge, and nasogastric tube (NGT) removal. Data were analyzed using logistic regression. Odds/hazard ratios (ORs/HRs) >1 for DSR <4, hospital discharge, and NGT removal and OR <1 for PAS ≥3, indicated favorable outcomes for active PES. Results Two weeks post-active PES, 11/18 (61%) had DSR <4: OR (95% CI) = 2.5 (0.52, 14). Effects of active versus sham for secondary outcomes included the following: PAS ≥3 at 2 weeks, OR (95% CI) = 0.61 (0.27, 1.4); times to hospital discharge, 39 days versus 52 days, HR (95% CI) = 1.2 (0.55, 2.5); NGT removal 8 versus 14 days, HR (95% CI) = 2.0 (0.51, 7.9); and DSR <4 at 3 months, OR (95% CI) = 0.97 (0.13, 7.0). PES was well tolerated, without adverse effects or associations with serious complications (chest infections/death). Conclusions Although the direction of observed differences were consistent with PES accelerating swallowing recovery over the first 2 weeks postintervention, suboptimal recruitment prevents definitive conclusions. Our study design experience and outcome data are essential to inform a definitive, multicenter randomized trial.

High-frequency focal repetitive cerebellar stimulation induces prolonged increases in human pharyngeal motor cortex excitability.

KEY POINTS: Neurostimulation is a rapidly emerging approach to swallowing rehabilitation, but cerebellar stimulation has not been explored as a treatment. Such proposed therapies for post-stroke dysphagia have required confirmation of physiological effects and optimisation of parameters in healthy humans prior to translational progression into patient groups. There is strong evidence for a role of the cerebellum in swallowing physiology, but this relationship has been under-explored. Recently, single pulses of cerebellar magnetic stimulation have been shown to directly evoke responses from pharyngeal musculature and produce short-term enhancement of cortico-pharyngeal motor evoked potentials, suggesting the feasibility of a cerebellar approach to neurostimulation in the swallowing system. We therefore examined multiple parameters of repetitive cerebellar magnetic stimulation and have described the optimal settings to provoke longer-lasting changes in swallowing neurophysiology. Based on evidence from the post-stroke dysphagia neurostimulation literature, these changes may have a therapeutic potential for swallowing rehabilitation. ABSTRACT: Brain neurostimulation has been shown to modulate cortical swallowing neurophysiology in post-stroke dysphagia with therapeutic effects which are critically dependent on the stimulation parameters. Cerebellar neurostimulation is, however, a novel, unexplored approach to modulation of swallowing pathways as a prelude to therapy for dysphagia. Here, we randomised healthy human subjects (n = 17) to receive one of five cerebellar repetitive TMS (rTMS) interventions (Sham, 1 Hz, 5 Hz, 10 Hz and 20 Hz) on separate visits to our laboratory. Additionally, a subset of subjects randomly received each of three different durations (50, 250, 500 pulses) of optimal frequency versus sham cerebellar rTMS. Prior to interventions subjects underwent MRI-guided single-pulse transcranial magnetic stimulation (TMS) to co-localise pharyngeal and thenar representation in the cortex and cerebellum (midline and hemispheric) before acquisition of baseline motor evoked potential (MEP) recordings from each site as a measure of excitability. Post-interventional MEPs were recorded for an hour and compared to sham using repeated measures ANOVA. Only 10 Hz cerebellar rTMS increased cortico-pharyngeal MEP amplitudes (mean bilateral increase 52%, P = 0.007) with effects lasting 30 min post-intervention with an optimal train length of 250 pulses (P = 0.019). These optimised parameters of cerebellar rTMS can produce sustained increases in corticobulbar excitability and may have clinical translation in future studies of neurogenic dysphagia.

fMRI and MRS measures of neuroplasticity in the pharyngeal motor cortex.

INTRODUCTION: Paired associative stimulation (PAS), is a novel non-invasive technique where two neural substrates are employed in a temporally coordinated manner in order to modulate cortico-motor excitability within the motor cortex (M1). In swallowing, combined pharyngeal electrical and transcranial-magnetic-stimulation induced beneficial neurophysiological and behavioural effects in healthy subjects and dysphagic stroke patients. Here, we aimed to investigate the whole-brain changes in neural activation during swallowing using functional magnetic resonance imaging (fMRI) following PAS application and in parallel assess associated GABA changes with magnetic resonance spectroscopy (MRS). METHODS: Healthy adults (n=11, 38±9years old) were randomised to receive real and sham PAS to the 'stronger' motor cortex pharyngeal representation, on 2 separate visits. Following PAS, event-related fMRI was performed to assess changes in brain activation in response to water and saliva swallowing and during rest. Data were analysed (SPM8) at P<.001. MRS data were acquired using MEGA-PRESS before and after the fMRI acquisitions on both visits and GABA concentrations were measured (AMARES, jMRUI). RESULTS: Following real PAS, BOLD signal changes (group analyses) increased at the site of stimulation during water and saliva swallowing, compared to sham PAS. It is also evident that PAS induced significant increases in BOLD signal to contralateral (to stimulation) hemispheric areas that are of importance to the swallowing neural network. Following real PAS, GABA:creatine ratio showed a trend to increase contralateral to PAS. CONCLUSION: Targeted PAS applied to the human pharyngeal motor cortex induces local and remote changes in both primary and non-primary areas for water and saliva tasks. There is a possibility that changes of the inhibitory neurotransmitter, GABA, may play a role in the changes in BOLD signal. These findings provide evidence for the mechanisms underlying the beneficial effects of PAS on the brain swallowing network.

Characterizing the mechanisms of central and peripheral forms of neurostimulation in chronic dysphagic stroke patients.

BACKGROUND: Swallowing problems following stroke may result in increased risk of aspiration pneumonia, malnutrition, and dehydration. OBJECTIVE/HYPOTHESIS: Our hypothesis was that three neurostimulation techniques would produce beneficial effects on chronic dysphagia following stroke through a common brain mechanism that would predict behavioral response. METHODS: In 18 dysphagic stroke patients (mean age: 66 ± 3 years, 3 female, time-post-stroke: 63 ± 15 weeks [±SD]), pharyngeal electromyographic responses were recorded after single-pulse transcranial magnetic stimulation (TMS) over the pharyngeal motor cortex, to measure corticobulbar excitability before, immediately, and 30 min, after real and sham applications of neurostimulation. Patients were randomized to a single session of either: pharyngeal electrical stimulation (PES), paired associative stimulation (PAS) or repetitive TMS (rTMS). Penetration-aspiration scores and bolus transfer timings were assessed before and after both real and sham interventions using videofluoroscopy. RESULTS: Corticobulbar excitability of pharyngeal motor cortex was beneficially modulated by PES, PAS and to a lesser extent by rTMS, with functionally relevant changes in the unaffected hemisphere. Following combining the results of real neurostimulation, an overall increase in corticobulbar excitability in the unaffected hemisphere (P = .005, F1,17 = 10.6, ANOVA) with an associated 15% reduction in aspiration (P = .005, z = -2.79) was observed compared to sham. CONCLUSIONS: In this mechanistic study, an increase in corticobulbar excitability the unaffected projection was correlated with the improvement in swallowing safety (P = .001, rho = -.732), but modality-specific differences were observed. Paradigms providing peripheral input favored change in neurophysiological and behavioral outcome measures in chronic dysphagia patients. Further larger cohort studies of neurostimulation in chronic dysphagic stroke are imperative.

Transcranial direct current stimulation reverses neurophysiological and behavioural effects of focal inhibition of human pharyngeal motor cortex on swallowing.

The human cortical swallowing system exhibits bilateral but functionally asymmetric representation in health and disease as evidenced by both focal cortical inhibition (pre-conditioning with 1 Hz repetitive transcranial magnetic stimulation; rTMS) and unilateral stroke, where disruption of the stronger (dominant) pharyngeal projection alters swallowing neurophysiology and behaviour. Moreover, excitatory neurostimulation protocols capable of reversing the disruptive effects of focal cortical inhibition have demonstrated therapeutic promise in post-stroke dysphagia when applied contralaterally. In healthy participants (n = 15, 8 males, mean age (±SEM) 35 ± 9 years), optimal parameters of transcranial direct current stimulation (tDCS) (anodal, 1.5 mA, 10 min) were applied contralaterally after 1 Hz rTMS pre-conditioning to the strongest pharyngeal projection. Swallowing neurophysiology was assessed in both hemispheres by intraluminal recordings of pharyngeal motor-evoked responses (PMEPs) to single-pulse TMS as a measure of cortical excitability. Swallowing behaviour was examined using a pressure-based reaction time protocol. Measurements were made before and for up to 60 min post intervention. Subjects were randomised to active or sham tDCS after 1 Hz rTMS on separate days and data were compared using repeated measures ANOVA. Active tDCS increased PMEPs bilaterally (F1,14 = 7.4, P = 0.017) reversing the inhibitory effects of 1 Hz rTMS in the pre-conditioned hemisphere (F1,14 = 10.1, P = 0.007). Active tDCS also enhanced swallowing behaviour, increasing the number of correctly timed challenge swallows compared to sham (F1,14 = 6.3, P = 0.025). Thus, tDCS to the contralateral pharyngeal motor cortex reverses the neurophysiological and behavioural effects of focal cortical inhibition on swallowing in healthy individuals and has therapeutic potential for dysphagia rehabilitation.

Priming pharyngeal motor cortex by repeated paired associative stimulation: implications for dysphagia neurorehabilitation.

BACKGROUND: Several stimulation parameters can influence the neurophysiological and behavioral effects of paired associative stimulation (PAS), a neurostimulation paradigm that repeatedly pairs a peripheral electrical with a central cortical (transcranial magnetic stimulation [TMS]) stimulus. This also appears to be the case when PAS is applied to the pharyngeal motor cortex (MI), with some variability in excitatory responses, questioning its translation into a useful therapy for patients with brain injury. OBJECTIVE: To investigate whether repeated PAS in both "responders" and "nonresponders" could enhance cortical excitability in pharyngeal MI more robustly. METHODS: Based on their responses after single PAS, healthy participants were stratified into 2 groups of "responders" and "nonresponders" and underwent 2 periods (60 minutes inter-PAS interval) of active and sham PAS in a randomized order. Neurophysiological measurements with single TMS pulses from pharyngeal motor representation were collected up to 90 minutes after the second PAS period. RESULTS: Repeated PAS increased cortical excitability up to 95% at 60 minutes following the second PAS in both the "responders" and "nonresponders." Moreover, cortical excitability in the "nonresponders" was significantly different after repeated PAS compared with single and sham application (P = .02; z = -2.2). CONCLUSIONS: Double dose PAS switched "nonresponders" to "responders." These results are important for PAS application to dysphagic stroke patients who do not initially respond to a single application.

Examining the role of carbonation and temperature on water swallowing performance: a swallowing reaction-time study.

Various therapeutic approaches for dysphagia management are based on modifications of bolus properties to change swallowing biomechanics and increase swallowing safety. Limited evidence exists for the effects of carbonation and bolus temperature on swallowing behavior. Here, we investigated the effects of carbonation and temperature on swallowing behavior using a novel automated and complex swallowing reaction time task via pressure signal recordings in the hypopharynx. Healthy participants (n = 39, 27.7±5 years old) were randomized in two different experiments and asked to perform 10 normal-paced swallows, 10 fast-paced swallows, and 10 challenged swallows within a predetermined time-window of carbonated versus still water (experiment 1) and of cold (4 °C) versus hot (45 °C) versus room temperature (21 °C) water (experiment 2). Quantitative measurements of latencies and percentage of successful challenged swallows were collected and analyzed nonparametrically. An increase in successfully performed challenged swallowing task was observed with carbonated water versus still water (P = 0.021), whereas only cold water shortened the latencies of normally paced swallows compared with room (P = 0.001) and hot (P = 0.004) temperatures. Therefore, it appears that chemothermal stimulation with carbonation and cold are most effective at modulating water swallowing, which in part is likely to be driven by central swallowing afferent activity.

Remote effects of intermittent theta burst stimulation of the human pharyngeal motor system.

Intermittent theta burst stimulation (iTBS) is a novel, non-invasive form of brain stimulation capable of facilitating excitability of the human primary motor cortex with therapeutic potential in the treatment of neurological conditions, such as multiple sclerosis. The objectives of this study were to evaluate the effects of iTBS on cortical properties in the human pharyngeal motor system. Transcranial magnetic stimulation (TMS)-evoked pharyngeal motor responses were recorded via a swallowed intra-luminal catheter and used to assess motor cortical pathways to the pharynx in both hemispheres before and for up to 90 min after iTBS in 15 healthy adults (nine male/six female, 22-59 years old). Active/sham iTBS comprised 600 intermittent repetitive TMS pulses, delivered in a double-blind pseudo-randomised order over each hemisphere on separate days at least 1 week apart. Abductor pollicis brevis (APB) recordings were used as control. Hemispheric interventional data were compared with sham using repeated-measures anova. iTBS was delivered at an average intensity of 43±1% of stimulator output. Compared with sham, iTBS to the hemisphere with stronger pharyngeal projections induced increased responses only in the contralateral weaker projection 60-90 min post-iTBS (maximum 54±19%, P≤0.007), with no change in stronger hemisphere responses. By contrast, iTBS to weaker projections had no significant effects (P=0.39) on either hemisphere. APB responses similarly did not change significantly (P=0.78) across all study arms. We conclude that iTBS can induce remote changes in corticobulbar excitability. While further studies will clarify the extent of these changes, iTBS holds promise as a potential treatment for dysphagia after unilateral brain damage.

Targeting unlesioned pharyngeal motor cortex improves swallowing in healthy individuals and after dysphagic stroke.

BACKGROUND & AIMS: Patients with stroke experience swallowing problems (dysphagia); increased risk of aspiration pneumonia, malnutrition, and dehydration; and have increased mortality. We investigated the behavioral and neurophysiological effects of a new neurostimulation technique (paired associative stimulation [PAS]), applied to the pharyngeal motor cortex, on swallowing function in healthy individuals and patients with dysphagia from stroke. METHODS: We examined the optimal parameters of PAS to promote plasticity by combining peripheral pharyngeal (electrical) with cortical stimulation. A virtual lesion was used as an experimental model of stroke, created with 1-Hz repetitive transcranial magnetic stimulation over the pharyngeal cortex in 12 healthy individuals. We tested whether hemispheric targeting of PAS altered swallowing performance before applying the technique to 6 patients with severe, chronic dysphagia from stroke (mean of 38.8 ± 24.4 weeks poststroke). RESULTS: Ten minutes of PAS to the unlesioned pharyngeal cortex reversed (bilaterally) the cortical suppression induced by virtual lesion (lesioned: F(1,9) = 21.347, P = .001; contralesional: F(1,9) = 9.648, P = .013; repeated-measures analysis of variance) compared with sham PAS. It promoted changes in behavior responses measured with a swallowing reaction time task (F(1,7) = 21.02, P = .003; repeated-measures analysis of variance). In patients with chronic dysphagia, real PAS induced short-term bilateral changes in the brain; the unaffected pharyngeal cortex had increased excitability (P = .001; 95% confidence interval, 0.21-0.05; post hoc paired t test) with reduced penetration-aspiration scores and changes in swallowing biomechanics determined by videofluoroscopy. CONCLUSIONS: The beneficial neurophysiological and behavioral properties of PAS, when applied to unlesioned brain, provide the foundation for further investigation into the use of neurostimulation as a rehabilitative approach for patients with dysphagia from stroke.

Adjunctive functional pharyngeal electrical stimulation reverses swallowing disability after brain lesions.

BACKGROUND & AIMS: Oropharyngeal dysphagia is an important disability that occurs after stroke; it contributes to aspiration pneumonia and death, and current modalities for rehabilitation of dysphagia have uncertain efficacy. We therefore examined the role of pharyngeal electrical stimulation (PES) in expediting human swallowing recovery after experimental (virtual) and actual (stroke) brain lesions. METHODS: First, healthy subjects (n = 13) were given 1-Hz repetitive transcranial magnetic stimulation to induce a unilateral virtual lesion in pharyngeal motor cortex followed by active or sham (control) PES. Motor-evoked potentials and swallow accuracy were recorded before and after the lesion to assess PES response. Thereafter, 50 acute dysphagic stroke patients underwent either a dose-response study, to determine optimal parameters for PES (n = 22), or were assigned randomly to groups given either active or sham (control) PES (n = 28). The primary end point was the reduction of airway aspiration at 2 weeks postintervention. RESULTS: In contrast to sham PES, active PES reversed the cortical suppression induced by the virtual lesion (F(7,70) = 2.7; P = .015) and was associated with improvement in swallowing behavior (F(3,42) = 5; P = .02). After stroke, 1 PES treatment each day (U = 8.0; P = .043) for 3 days (U = 10.0) produced improved airway protection compared with controls (P = .038). Active PES also reduced aspiration (U = 54.0; P = .049), improved feeding status (U = 58.0; P = .040), and resulted in a shorter time to hospital discharge (Mantel-Cox log-rank test, P = 0.038). CONCLUSIONS: This pilot study of PES confirms that it is a safe neurostimulation intervention that reverses swallowing disability after virtual lesion or stroke.

Characterizing the application of transcranial direct current stimulation in human pharyngeal motor cortex.

Transcranial direct current stimulation (tDCS) is a novel intervention that can modulate brain excitability in health and disease; however, little is known about its effects on bilaterally innervated systems such as pharyngeal motor cortex. Here, we assess the effects of differing doses of tDCS on the physiology of healthy human pharyngeal motor cortex as a prelude to designing a therapeutic intervention in dysphagic patients. Healthy subjects (n = 17) underwent seven regimens of tDCS (anodal 10 min 1 mA, cathodal 10 min 1 mA, anodal 10 min 1.5 mA, cathodal 10 min 1.5 mA, anodal 20 min 1 mA, cathodal 20 min 1 mA, Sham) on separate days, in a double blind randomized order. Bihemispheric motor evoked potential (MEP) responses to single-pulse transcranial magnetic stimulation (TMS) as well as intracortical facilitation (ICF) and inhibition (ICI) were recorded using a swallowed pharyngeal catheter before and up to 60 min following the tDCS. Compared with sham, both 10 min 1.5 mA and 20 min 1 mA anodal stimulation induced increases in cortical excitability in the stimulated hemisphere (+44 +/- 17% and +59 +/- 16%, respectively; P < 0.005) whereas only 10 min 1.5 mA cathodal stimulation induced inhibition (-26 +/- 4%, P = 0.02). There were neither contralateral hemisphere changes nor any evidence for ICI or ICF in driving the ipsilateral effects. In conclusion, anodal tDCS can alter pharyngeal motor cortex excitability in an intensity-dependent manner, with little evidence for transcallosal spread. Anodal stimulation may therefore provide a useful means of stimulating pharyngeal cortex and promoting recovery in dysphagic patients.

Reversal of a virtual lesion in human pharyngeal motor cortex by high frequency contralesional brain stimulation.

BACKGROUND & AIMS: Excitatory brain stimulation with repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for dysphagia after stroke. Moreover, 1-Hz rTMS can induce a "virtual lesion" in the human pharyngeal motor cortex that suppresses brain activity and temporarily disrupts swallowing. We thus examined if rTMS could reverse the disrupted brain and swallowing functions following a unilateral virtual lesion in the pharyngeal motor cortex, such that rTMS might be developed as a therapy. METHODS: Healthy subjects (n = 23) were given varying conditions of 5-Hz rTMS over the pharyngeal motor cortex to determine the most effective excitatory parameters. Thereafter, a unilateral virtual lesion was made in the pharyngeal motor cortex using 1-Hz rTMS, followed by contralateral active or sham 5-Hz rTMS. Motor evoked potentials and serial swallowing reaction times were recorded before and for 60 minutes postlesion to assess reversibility of the disruption to the brain and swallowing. RESULTS: The greatest increase in pharyngeal motor cortex excitability was seen following 250 pulses of 5-Hz rTMS (F(1,11) = 10.3, P = .008), an effect that lasted over 2 hours. In contrast to sham rTMS, active contralateral 5-Hz rTMS completely abolished the cortical suppression induced by the virtual lesion, with effects occurring for up to 50 minutes in both unlesioned (F(1,11) = 6, P = .03) and lesioned (F(1,11) = 67, P < .001) hemispheres. Active rTMS also reversed the changes in swallowing behavior (F(1,8) = 9, P = .018), restoring function to prelesional levels. CONCLUSIONS: Contralesional-targeted neurostimulation modulates brain activity and swallowing motor behavior after experimental disruption and might be usefully applied in stroke-affected patients as a therapy for dysphagia.

A magnetic resonance spectroscopy study of brain glutamate in a model of plasticity in human pharyngeal motor cortex.

BACKGROUND & AIMS: Coordinated delivery of peripheral and cortical stimuli (paired associative stimulation [PAS]) has been shown to induce plasticity in limb motor cortex, however, its application in pharyngeal motor cortex and the molecular mechanisms involved in human neuroplasticity remain uncertain. Because neuroplasticity appears to form the basis for functional recovery of digestive functions such as swallowing after brain injury, the aim of this study was to characterize the induction of cortical plasticity in human pharyngeal motor cortex through PAS applied to pharyngeal musculature and investigate the potential role of glutamate in this process. METHODS: Fifteen healthy volunteers completed a series of experiments in which cortical excitability was assessed through pharyngeal motor evoked potential amplitudes in response to transcranial magnetic stimulation. The optimal parameters and interhemispheric interactions of PAS in the bilaterally represented pharyngeal system initially were investigated. Cortical glutamate after PAS then was assessed with magnetic resonance spectroscopy. RESULTS: The greatest increase in cortical pharyngeal excitability was seen if paired stimuli were separated by 100 ms (F[15,210] = 2.28; P < or = .05). Cortical excitability increased over 2 hours with analogous albeit lesser changes in the contralateral hemisphere. A focal and transient reduction in glutamate was found in the stimulated pharyngeal motor cortex (F[1,12] = 21.9; P = .001), without changes in any other measured brain metabolites. CONCLUSIONS: This study shows that PAS-induced plasticity in the human pharyngeal motor system is both timing- and hemisphere-dependent and provides novel evidence for the potential role of glutamate in modulating this effect.

Neural control of feeding and swallowing.

Eating and drinking are basic pleasures in life that most of us take for granted, yet the ease with which we perform these tasks belies their complex neurologic system of control. Recent studies of human swallowing have begun to unravel some of these complexities, evolving our understanding and thus ultimately helping to generate novel therapies for the treatment of swallowing problems after cerebral injury, such as stroke. This article provides a general overview of current knowledge of the neural control mechanisms that underlie the coordination of mastication, oral transport, swallowing, and respiration in humans.

Unilateral suppression of pharyngeal motor cortex to repetitive transcranial magnetic stimulation reveals functional asymmetry in the hemispheric projections to human swallowing.

Inhibitory patterns of repetitive transcranial magnetic stimulation (rTMS) were applied to pharyngeal motor cortex in order to establish its role in modulating swallowing activity and provide evidence for functionally relevant hemispheric asymmetry. Healthy volunteers underwent single pulse TMS before and for 60 min after differing intensities of 1 Hz rTMS (n = 9, 6 male, 3 female, mean age 34 +/- 3 years) or theta burst stimulation (TBS) (n = 9, 6 male, 3 female, mean age 37 +/- 4 years). Electromyographic responses recorded from pharynx and hand were used as a measure of cortico-motor pathway excitability. Swallowing behaviour was then examined with a reaction time protocol, before and for up to 60 min after the most effective inhibitory protocol (1 Hz) applied to each hemisphere. Interventions were conducted on separate days and compared to sham using ANOVA. Only high intensity 1 Hz rTMS consistently suppressed pharyngeal motor cortex immediately and for up to 45 min (-34 +/- 7%, P < or = 0.001). Adjacent hand and contralateral pharyngeal motor cortex showed no change in response (-15 +/- 12%, P = 0.14 and 15 +/- 12%, P = 0.45, respectively). When used to unilaterally disrupt each hemisphere, rTMS to pharyngeal motor cortex with the stronger responses altered normal (-12 +/- 3%, P < or = 0.001) and fast (-9 +/- 4%, P < or = 0.009) swallow times, not seen following rTMS to the contralateral cortex or after sham. Thus, suppression of pharyngeal motor cortex to rTMS is intensity and frequency dependent, which when applied to each hemisphere reveals functionally relevant asymmetry in the motor control of human swallowing.

Modulation of human cortical swallowing motor pathways after pleasant and aversive taste stimuli.

Human swallowing involves the integration of sensorimotor information with complexities such as taste; however, the interaction between the taste of food and its effects on swallowing control remains unknown. We assessed the effects of pleasant (sweet) and aversive (bitter) tastes on human cortical swallowing motor pathway excitability. Healthy adult male volunteers underwent a transcranial magnetic stimulation (TMS) mapping study (n = 9, mean age: 34 yr) to assess corticobulbar excitability before and up to 60 min after 10-min liquid infusions either 1) as swallowing tasks or 2) delivered directly into the stomach. Infusions were composed of sterile water (neutral), 10% glucose (sweet), and 0.5 mM quinine hydrochloride (bitter). The order of delivery was randomized, and each infusion was given on separate days. Pharyngeal motor-evoked potentials (PMEPs) were recorded from an intraluminal catheter as a measure of corticobulbar excitability and compared using repeated-measures and one-way ANOVA. After the swallowing task (water, glucose, or quinine), repeated-measures ANOVA revealed a significant time interaction across tastants (P