Repetitive Transcranial Magnetic Stimulation: a Novel Approach for Treating Oropharyngeal Dysphagia.

In recent years, repetitive transcranial magnetic stimulation, a technique used to produce human central neurostimulation, has attracted increased interest and been applied experimentally in the treatment of dysphagia. This review presents a synopsis of the current research for the application of repetitive transcranial magnetic stimulation (rTMS) on dysphagia. Here, we review the mechanisms underlying the effects of rTMS and the results from studies on both healthy volunteers and dysphagic patients. The clinical studies on dysphagia have primarily focussed on dysphagia post-stroke. We discuss why it is difficult to draw conclusions for the efficacy of this neurostimulation technique, given the major differences between studies. The intention here is to stimulate potential research questions not yet investigated for the application of rTMS on dysphagic patients prior to their translation into clinical practice for dysphagia rehabilitation.

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.

Genetic influences on the variability of response to repetitive transcranial magnetic stimulation in human pharyngeal motor cortex.

BACKGROUND: Recent studies have reported substantial variability in response to repetitive transcranial magnetic stimulation (rTMS). We hypothesized that an individual's genetic predisposition may contribute to such variability in the pharyngeal motor cortex. This study aimed to investigate the response to 1 and 5 Hz rTMS paradigms on pharyngeal motor cortex in healthy participants and its relationship with genetic predisposition. METHODS: Forty-one healthy participants (25.4 ± 4.6 years old) received either or both 1 Hz (n = 39) and 5 Hz rTMS (n = 40) over pharyngeal motor cortex. Pharyngeal and thenar motor-evoked potentials were recorded at baseline and for 1 hour post-rTMS. The participants were then classified according to their response. The associations between rTMS response and gender, time of day of the stimulation, and eight prespecified single nucleotide polymorphisms (SNPs) were analyzed. KEY RESULTS: There was no direction-specific response to either paradigm (1 Hz: F[3.69, 129.21] = 0.78, P = 0.56; 5 Hz: F[4.08, 146.85] = 1.38, P = 0.25). Only 13% of participants showed the expected bidirectional response (inhibition for 1 Hz and excitation for 5 Hz). Significant associations were found between response and COMT (1 Hz: P = 0.03) and DRD2 (1 Hz: P = 0.02; 5 Hz: P = 0.04) polymorphisms. Carriers of minor allele G from SNP rs6269 (COMT) were more likely to show inhibitory or excitatory outcomes after 1 Hz rTMS. By contrast, carriers of minor allele A from SNP rs1800497 (DRD2) were more likely to show no response to 1 Hz rTMS and inhibition after 5 Hz rTMS. CONCLUSIONS & INFERENCES: Two SNPs from COMT and DRD2 genes may partially explain the response variability to rTMS in the pharyngeal motor system. Further research should focus on stratified approaches for neurostimulatory dysphagia treatment using rTMS.

Genetic determinants of swallowing impairment, recovery and responsiveness to treatment.

PURPOSE OF REVIEW: Here we review the latest literature and evidence in the field of genetics and determinants of swallowing and its treatments-specifically, this is a very recent concept in the field of oropharyngeal dysphagia, with only now an emerging research interest in the relationship between our genetic makeup and the effect this has on swallowing function and dysfunction. As such our review will look at preclinical, clinical and hypothesis generating research covering all aspects of the genetics of swallowing, giving new importance to the genotype-phenotype influences pertaining to dysphagia and its recovery. RECENT FINDINGS: There appear to be a number of candidate gene systems that interact with swallowing or its neurophysiology, which include brain-derived neurotrophic factor, apolipoprotein E and catechol-O-methyltransferase, that have been shown to impact on either swallowing function or the brain's ability to respond to neurostimulation and induce plasticity. In addition, a number of genetic disorders, where dysphagia is a clinical phenomenon, have given us clues as to how multiple genes or the polygenetics of dysphagia might interact with our swallowing phenotype. SUMMARY: There is currently limited research in the field of genetic factors that influence (human) swallowing and oropharyngeal dysphagia, but this is an emerging science and one which, in the future, may herald a new era in precision medicine and better targeting of therapies for dysphagia based on an individual's genetic makeup.

Genetic determinants of swallowing impairments among community dwelling older population.

BACKGROUND: Swallowing difficulties (dysphagia) affect a significant proportion of community dwelling older individuals, being more prevalent in age-associated neurological conditions such as stroke and Parkinson's disease. The genetic determinants of dysphagia are still being explored and have largely been studied through candidate gene analysis approaches. The aim of the study was to perform a genome-wide association study (GWAS) of common genetic single nucleotide polymorphisms (SNP) and self-reported swallowing impairments in a longitudinal cohort of community dwelling older adults. MATERIALS AND METHODS: We performed a case-control genome-wide association study of self-reported swallowing symptoms using the Sydney Swallow Questionnaire. The analysis included 555 community dwelling, unrelated, older adults (mean years of age=81.4; SD=5.349) with known phenotype and genetic information consisting of 512,806 single nucleotide polymorphisms. Gene-based association analysis of these traits was also conducted. RESULTS: Analysis of the cohort confirmed European ancestry with no major population stratification. Further analysis for association with swallowing impairment identified one SNP rs17601696 which achieved genome-wide significance (P-value=5×10(-8)) within a non-coding region of chromosome 10. Gene-based analysis did not result in any genome-wide significant association. CONCLUSION: SNP rs17601696 may have an impact on swallowing impairment among elderly individuals. The results require replication in an independent cohort with appropriate phenotype/genotype data.