Samantha Jefferson

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.

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≤ 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≤ 0.001) and fast (−9 ± 4%, P≤ 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.

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.

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.

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.

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.

Val66Met in Brain-Derived Neurotrophic Factor Affects Stimulus-Induced Plasticity in the Human Pharyngeal Motor Cortex

BACKGROUND & AIMS Polymorphisms in brain-derived neurotrophic factor (BDNF) can affect brain and behavioral responses. However, little is known about the effects of a single nucleotide polymorphism (SNP) in BDNF, at codon 66 (the Val-Met substitution, detected in approximately 33% of the Caucasian population) on stimulation-induced plasticity in the cortico-bulbar system. We examined whether this SNP influenced outcomes of different forms of neurostimulation applied to the pharyngeal motor cortex. METHODS Thirty-eight healthy volunteers were assessed for corticobulbar excitability after single-pulse, transcranial magnetic stimulation of induced pharyngeal electromyographic responses, recorded from a swallowed intraluminal catheter. Thereafter, volunteers were conditioned with pharyngeal electrical stimulation, or 2 forms of repetitive (1 and 5 Hz) transcranial magnetic stimulation (rTMS). Repeated measurements of pharyngeal motor-evoked potentials were assessed with transcranial magnetic stimulation for as long as 1 hour after the 3 forms of neurostimulation and correlated with SNPs at codon 66 of BDNF (encoding Val or Met). RESULTS Pharyngeal electrical stimulation significantly increased the amplitude of motor-evoked potentials in individuals with the SNP that encoded Val66, compared to those that encoded Met66, with a strong GENOTYPE*TIME interaction (F₈,₁₁₂ = 2.4; P = .018). By contrast, there was a significant reduction in latencies of subjects with the SNP that encoded Met66 after 5-Hz rTMS (F₃,₆₀ = 4.9; P = .04). In addition, the expected inhibitory effect of 1-Hz rTMS on amplitude was not observed in subjects with the SNP that encoded Met66 in BDNF (F₇,₁₄₀ = 2.23; P = .035). CONCLUSIONS An SNP in human BDNF at codon 66 affects plasticity of the pharyngeal cortex to different forms of neurostimulation. Genetic analysis might help select specific forms of neurostimulation as therapeutics for patients with disorders such as dysphagic stroke.

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

Cortical control of swallowing exhibits functional asymmetry with brain lesions involving the strongest projection being implicated in the pathophysiology of dysphagia after unilateral stroke. Swallowing recovery is associated with neuroplastic adaptation in the unlesioned hemisphere, a process which can be facilitated by excitatory neurostimulation techniques including transcranial direct current stimulation (tDCS). Unilateral suppression of the strongest pharyngeal motor projection using 1 Hz repetitive transcranial magnetic stimulation (rTMS) can disrupt swallowing neurophysiology and behaviour making it a useful model for trialling novel neurostimulation interventions in healthy subjects. In this healthy participant study we examined the effects of tDCS after unilateral pre‐conditioning with 1 Hz rTMS to determine its ability to restore swallowing neurophysiology and behaviour. We show that application of optimised parameters of tDCS (anodal stimulation, 1.5 mA, 10 min) over the unconditioned hemisphere reverses the brain and behavioural consequences of inhibitory pre‐conditioning, supporting the use of tDCS in clinical trials.

S2.2 Non-invasive investigation of the neuroanatomical connectivity for human swallowing behaviours using diffusion weighted magnetic resonance imaging

Methods: Among the patients selected for presurgical investigation in the last 10 years, two independent observers selected and analyzed seizures with oro-alimentary (OA) manifestations (67 patients, 248 seizures). A study of video-EMG-EEG/SEEG correlations has been carried out, in order to classify clinical OA subgroups and to investigate their possible localizing value. The study consisted with: (a) clinical analysis of ictal and postical OA manifestations; (b) analysis of the EMG features of the muscles of perioral and branchial regions (morphology, duration and period of single bursts); (c) evaluation of the EEG/SEEG correlate of each single OA pattern. Results: We observed three main clinical-polygraphic subgroups of OA automatisms: (1) chewing pattern, (2) masticatory-deglutitory pattern, (3) complex ictal oro-alimentary automatisms. Different OA pattern could emerge at different time during the same seizure. Both OA patterns type 1 and 2 were prolonged/rhythmic manifestations that differentiated for the shape of EMG bursts, for their latency of appearance (longer in type 2) and for the topography of the concomitant ictal discharge. OA automatism of type 3 were an heterogeneous entity composed brief, monophasic and never postictal manifestation with variable latency and duration. OA type 1 were often preceded by epigastric rising aura (25%) or fear (25%), OA type 2 were preceded by epigastric not rising (20%) or acoustic aura (20%), whilst the aura preceding OA type 3 was variable. The ictal discharge during OA type 1 involved temporo-mesial regions, whilst during OA automatisms of type 2 and 3 the discharge was olo-temporal and extra temporal (insular and opercular regions). The same pattern of chewing has been observed comparing ictal and postictal automatisms of type 1 and voluntary mastication in the same patient, while eating. Conclusions: We propose a clinical division in subgroups of oroalimentary ictal patterns, suggesting the involvement of different motor circuits. Ictal chewing could result from the involvement of the anteromesial temporal structures (epigastric or emotional aura), while a mild mastication with swallowing corresponds to a wider diffusion of the ictal discharge to T and extra-T (operculum, insula) structures. Both are probably expression of the liberation of the masticatory Central Pattern Generator, possibly through the disinhibition of the amygdalo-pontine circuitry.

A PRELIMINARY STUDY OF NEUROSTIMULATION BASED INTERVENTIONS IN THE TREATMENT OF CHRONIC DYSPHAGIA POST-STROKE

Introduction Oropharyngeal dysphagia after stroke has an incidence up to 45% and when chronic, leads to increased risk of institutionalisation and death in the long term. Pharyngeal electrical stimulation (PES),1 repetitive transcranial magnetic stimulation (rTMS)2 and paired associative stimulation (PAS)3 are three neurostimulation techniques developed to increase cortical excitability of pharyngeal motor cortex, with therapeutic potential. However the effects of these techniques on chronic but stable swallowing problems in stroke patients remain unknown. We therefore investigated the effects of these interventions in stroke patients with dysphagia persisting for >6 weeks. Methods In 12 dysphagic stroke patients (69±9 years (mean±SD), 79±25 weeks post-stroke (mean±SD), 6 left, 5 right hemispheric, 1 undetermined) pharyngeal electromyographic responses were recorded using an intraluminal catheter after the application of single TMS pulses over pharyngeal motor cortex, in order to measure cortico-bulbar excitability before, immediately and 30 minutes after real and sham applications of either: a) PES (10 mins of 5 Hz), b) rTMS (250 repeated TMS pulses at 5 Hz), or c) PAS (10 mins of repeated pairs of pharyngeal and TMS pulse every 20 s). In nine subjects, swallowing performance and safety (aspiration-penetration scores, APs) were assessed with videofluoroscopy before and after both real and sham neurostimulation techniques. Results Compared to sham, the application of all neurostimulation interventions showed a significant increase in cortical excitability in the unaffected hemisphere by 54%±17% (mean±SEM) immediately post (repeated measures ANOVA p<0.001, Time*Intervention p=0.005), not observed in the affected hemisphere (p=0.12). In addition, after active neurostimulation, APs were reduced by −14%±6% (mean±SEM) compared to sham (Wilcoxons test, p=0.05). Moreover, the delay between the oral and pharyngeal phases of swallowing, important for swallowing safety, was shortened by −56%±13% (mean±SEM) after real neurostimulation (Wilcoxons test, p=0.01) compared to sham. There was no consistent difference in cortical or swallowing response between the interventions. Conclusion These preliminary results show that neurostimulation interventions have beneficial neurophysiological and behavioural effects in chronic stroke patients with dysphagia, increasing cortical excitability and improving swallowing safety. These findings provide support for neurostimulation being a useful adjunct in swallowing rehabilitation, even in chronic neurologic illness, and lay the foundation for further clinical trials of these forms of intervention.