Spontaneous Swallowing Frequency in Post-Stroke Patients with and Without Oropharyngeal Dysphagia: An Observational Study.

Oropharyngeal dysphagia (OD) is a frequent complication after stroke (PSOD) that increases morbidity and mortality. Early detection of PSOD is essential to reduce morbidity and mortality in patients with acute stroke. In recent years, an association between reduced spontaneous swallowing frequency (SSF) and OD has been described. Likewise, the reduction of saliva substance P (SP) concentration has been associated with an increased risk of aspiration and a decrease in SSF. In this study we aimed to compare SSF, salivary SP concentration, hydration and nutritional status in post-stroke (PS) patients with and without OD. We included 45 acute PS patients (4.98 ± 2.80 days from stroke onset, 62.22% men, 71.78 ± 13.46 year). The Volume-Viscosity Swallowing Test (V-VST) was performed for clinical diagnosis of OD. SSF/minute was assessed through 10-min neurophysiological surface recordings including suprahyoid-electromyography and cricothyroid-accelerometry. Saliva samples were collected with a Salivette® to determine SP by ELISA. Hydration status was assessed by bioimpedance. Nutritional status was evaluated by Mini Nutritional Assessment Short Form (MNA-sf) and blood analysis. Twenty-seven PS patients (60%) had OD; 19 (40%), impaired safety of swallow. SSF was significantly reduced in PSOD, 0.23 ± 0.18 and PSOD with impaired safety, 0.22 ± 0.18 vs 0.48 ± 0.29 swallows/minute in PS without OD (PSnOD); (both p < 0.005). Nutritional risk was observed in 62.92% PSOD vs 11.11% PSnOD (p = 0.007) and visceral protein markers were also significantly reduced in PSOD (p < 0.05). Bioimpedance showed intracellular dehydration in 37.50% PSOD vs none in PSnOD. There were no differences for saliva SP concentrations. SSF is significantly reduced in PSOD in comparison with PSnOD. Acute PSOD patients present poor nutritional status, hydropenia, and high risk for respiratory complications.

Brain and Pharyngeal Responses Associated with Pharmacological Treatments for Oropharyngeal Dysphagia in Older Patients.

Impaired pharyngo-laryngeal sensory function is a critical mechanism for oropharyngeal dysphagia (OD). Discovery of the TRP family in sensory nerves opens a window for new active treatments for OD. To summarize our experience of the action mechanism and therapeutic effects of pharyngeal sensory stimulation by TRPV1, TRPA1 and TRPM8 agonists in older patients with OD. Summary of our studies on location and expression of TRP in the human oropharynx and larynx, and clinical trials with acute and after 2 weeks of treatment with TRP agonists in older patients with OD. (1) TRP receptors are widely expressed in the human oropharynx and larynx: TRPV1 was localized in epithelial cells and TRPV1, TRPA1 and TRPM8 in sensory fibers mainly below the basal lamina. (2) Older people present a decline in pharyngeal sensory function, more severe in patients with OD associated with delayed swallow response, impaired airway protection and reduced spontaneous swallowing frequency. (3) Acute stimulation with TRP agonists improved the biomechanics and neurophysiology of swallowing in older patients with OD TRPV1 = TRPA1 > TRPM8. (4) After 2 weeks of treatment, TRPV1 agonists induced cortical changes that correlated with improvements in swallowing biomechanics. TRP agonists are well tolerated and do not induce any major adverse events. TRP receptors are widely expressed in the human oropharynx and larynx with specific patterns. Acute oropharyngeal sensory stimulation with TRP agonists improved neurophysiology, biomechanics of swallow response, and safety of swallowing. Subacute stimulation promotes brain plasticity further improving swallow function in older people with OD.

Oropharyngeal Dysphagia in Older People is Associated with Reduced Pharyngeal Sensitivity and Low Substance P and CGRP Concentration in Saliva.

Substance P (SP) and Calcitonine gene-related peptide (CGRP) are released by sensory nerve fibers in the oropharynx. Patients with oropharyngeal dysphagia (OD) present reduced oropharyngeal sensitivity and low SP concentration in saliva. We aimed to assess the concentration of salivary SP and CGRP in healthy volunteers, and older people without and with OD, and the relationship with pharyngeal sensory threshold. We included 15 healthy volunteers, 14 healthy elderly and 14 elderly with OD. Swallow function was assessed by videofluoroscopy (VFS). Pharyngeal sensory threshold was assessed by intrapharyngeal electrical stimulation. Hydration and phase angle were assessed by bioimpedance. Saliva samples were collected with a Salivette® to determine SP and CGRP concentration by ELISA. Elderly patients with OD presented impaired safety of swallow (PAS 4.38 ± 0.77 p < 0.0001 vs. healthy volunteers = 1 and healthy elderly = 1.43 ± 0.51). Healthy elderly and elderly with OD presented a reduction in intracellular water and saliva volume (healthy elderly, 592.86 ± 327.79 µl, p = 0.0004; elderly with OD, 422.00 ± 343.01 µl, p = 0.0001 vs healthy volunteers, 1333.33 ± 615.91 µl, r = 0.6621, p < 0.0001). Elderly patients with OD presented an impairment in pharyngeal sensory threshold (10.80 ± 3.92 mA vs. healthy volunteers, 5.74 ± 2.57 mA; p = 0.007) and a reduction in salivary SP (129.34 pg/ml vs. healthy volunteers: 173.89 pg/ml; p = 0.2346) and CGRP levels (24.17 pg/ml vs. healthy volunteers: 508.18 pg/ml; p = 0.0058). There was a negative correlation between both SP and CGRP concentrations and pharyngeal sensory threshold (r = - 0.450, p = 0.024; r = - 0.4597, p = 0.036, respectively), but only SP identified elderly patients with OD with higher pharyngeal sensory threshold. Elderly patients with OD presented hydropenia and sarcopenia, reduced salivary SP and CGRP and impaired pharyngeal sensitivity. Our study suggests SP levels in saliva as a potential biomarker to monitor pharyngeal sensitivity in elderly patients with OD.

A Comparative Study on the Effect of Acute Pharyngeal Stimulation with TRP Agonists on the Biomechanics and Neurophysiology of Swallow Response in Patients with Oropharyngeal Dysphagia.

Fluid thickening is the main compensatory strategy for patients with oropharyngeal dysphagia (OD) associated with aging or neurological diseases, and there is still no pharmacological treatment. We aimed to compare the effects of increasing bolus viscosity with that of acute stimulation with TRPV1, TRPA1 or TRPM8 agonists on the biomechanics and neurophysiology of swallow response in patients with OD. We retrospectively analyzed seven studies from our laboratory on 329 patients with OD. The effect of increasing shear viscosity up to 3682 mPa·s was compared by videofluoroscopy and pharyngeal sensory evoked potentials (pSEP) with that of adding to the bolus: capsaicin (TRPV1, 150 µM/10 µM), piperine (TRPA1/V1, 1 mM/150 µM), menthol (TRPM8, 1 mM/10 mM), cinnamaldehyde-zinc (TRPA1, 100 ppm−70 mM), citral (TRPA1, 250 ppm) or citral-isopulegol (TRPA1-TRPM8, 250 ppm−200 ppm). Fluid thickening improved the safety of swallow by 80% (p < 0.0001) by delaying bolus velocity by 20.7 ± 7.0% and time to laryngeal vestibule closure (LVC) by 23.1 ± 3.7%. Capsaicin 150µM or piperine 1 mM significantly improved safety of swallow by 50% (p < 0.01) and 57.1% (p < 0.01) by speeding time to LVC by 27.6% (p < 0.001) and 19.5% (p < 0.01) and bolus velocity by 24.8% (p < 0.01) and 16.9% (p < 0.05), respectively. Cinnamaldehyde-zinc shortened the P2 latency of pSEPs by 11.0% (p < 0.01) and reduced N2-P2 amplitude by 35% (p < 0.01). In conclusion, TRPV1 and TRPV1/A1 agonists are optimal candidates to develop new pharmacological strategies to promote the recovery of brain and swallow function in patients with chronic OD.

Comparing biomechanics and neurophysiology between different phenotypes of patients with oropharyngeal dysphagia.

The pathophysiology of oropharyngeal dysphagia (OD) across patient phenotypes may differ. The aim of this study was to compare the biomechanics and neurophysiology of swallowing between healthy volunteers (HVs) and patients with dysphagia as a consequence of aging (OOD), post-stroke (PSOD), Parkinson's disease (POD), or dementia (DOD). A retrospective study including 35 HVs and 109 OOD, 195 PSOD, 78 POD, and 143 DOD patients was performed. Videofluoroscopic data of signs of impaired efficacy and safety, penetration-aspiration scale (PAS) score, and the biomechanics of laryngeal vestibule closure (LVC) and opening (LVO) and of upper esophageal sphincter opening (UESO) were collected. Neurophysiology was assessed with pharyngeal sensory evoked potentials and neurotopography maps. All OD phenotypes showed signs of impaired efficacy and safety of swallowing, increased PAS score (p < 0.001), and delayed time to LVC (p < 0.0001). OOD (p < 0.0001), PSOD (p < 0.0001), and POD (p = 0.0065) patients also had delayed time to LVO, and OOD (p = 0.0062) and DOD (p = 0.0016) patients to UESO. Regarding neurophysiology, all phenotypes presented impaired pharyngeal sensitivity, a significant reduction in cortical activation, and impaired sensory input integration. Additionally, only PSOD was associated with impaired conduction of sensory stimuli. In conclusion, we found common but also specific pathophysiological elements. These results improve our understanding of OD pathophysiology and may help pave the way for phenotype-specific treatments.

Neurophysiological characterization of oropharyngeal dysphagia in older patients.

OBJECTIVE: To characterize swallowing biomechanics and neurophysiology in older patients with oropharyngeal dysphagia (OD). METHODS: Observational study in 12 young healthy volunteers (HV), 9 older HV (OHV) and 12 older patients with OD with no previous diseases causing OD (OOD). Swallowing biomechanics were measured by videofluoroscopy, neurophysiology with pharyngeal sensory (pSEP) and motor evoked-potentials (pMEP) to intrapharyngeal electrical and transcranial magnetic stimulation (TMS), respectively, and salivary neuropeptides with enzyme-linked immunosorbent assay (ELISA). RESULTS: 83.3% of OOD patients had unsafe swallows (Penetration-Aspiration scale = 4.3 ± 2.1; p < 0.0001) with delayed time to laryngeal vestibule closure (362.5 ± 73.3 ms; p < 0.0001) compared to both HV groups. OOD patients had: (a) higher pharyngeal sensory threshold (p = 0.009) and delayed pSEP P1 and N2 latencies (p < 0.05 vs HV) to electrical stimulus; and (b) higher pharyngeal motor thresholds to TMS in both hemispheres (p < 0.05) and delayed pMEPs latencies (right, p < 0.0001 HV vs OHV/OOD; left, p < 0.0001 HV vs OHV/OOD). CONCLUSIONS: OOD patients have unsafe swallow and delayed swallowing biomechanics, pharyngeal hypoesthesia with disrupted conduction of pharyngeal sensory inputs, and reduced excitability and delayed cortical motor response. SIGNIFICANCE: These findings suggest new elements in the pathophysiology of aging-associated OD and herald new and more specific neurorehabilitation treatments for these patients.

Therapeutic Effect on Swallowing Function and on Hydration Status of a New Liquid Gum-Based Thickener in Independently-Living Older Patients with Oropharyngeal Dysphagia.

ThickenUp® Gel Express (TUGE) is a new, xanthan- and acacia-gum-based, liquid, thickening product. In independently living older adults with oropharyngeal dysphagia (OD), we assessed: (1) the rheological properties of TUGE; (2) its therapeutic effect at four viscosity levels (achieved by 5 g, 10 g, 20 g and 30 g of TUGE in water + Omnipaque X-ray contrast) versus thin liquid; and (3) the effect on hydration status and gastrointestinal tolerance after fourteen days. Shear viscosity of TUGE was measured in SI units (mPa·s at 50 s-1). The Penetration Aspiration Scale (PAS) score and the swallow response at each viscosity level was assessed with videofluoroscopy (VFS), and in the 14-day study we assessed fluid intake, hydration, and tolerance. Thickened fluids with TUGE were unaffected (-0.3%) by α-salivary amylase (α-SA). The shear viscosity values with VFS were 49.41 ± 2.38, 154.83 ± 10.22, 439.33 ± 11.72 and 672.5 ± 35.62 mPa·s. We studied 60 independently living adults (70 ± 11.4 years) with mild OD (PAS 4.1 ± 2.2, 25% aspirations). TUGE caused a shear-viscosity-dependent improvement in PAS at 150-670 mPa·s and in safety of swallow, slightly increased oral residue, did not affect pharyngeal residue and reduced time to laryngeal vestibule closure (-27%) at 670 mPa·s. Fluid intake with TUGE (1488 mL/day) was well tolerated, and hydration status improved. In conclusion, TUGE was unaffected by α-SA and strongly improved safety of swallow in a viscosity-dependent manner without affecting pharyngeal residue. Fourteen-day treatment of thickened fluids with TUGE is safe and well tolerated and improves hydration status in older adults with dysphagia.

Shear-Viscosity-Dependent Effect of a Gum-Based Thickening Product on the Safety of Swallowing in Older Patients with Severe Oropharyngeal Dysphagia.

Fluid thickening is a valid therapeutic strategy for patients with oropharyngeal dysphagia (OD). The main aim of this study was to determine the therapeutic effect of the xanthan-gum-based thickener Tsururinko Quickly (TQ, Morinaga Milk Co., Tokyo, Japan) in older patients with severe OD. A total of 85 patients (83.32 ± 6.75 y) with OD and a penetration-aspiration score (PAS) of n ≥ 3 were studied by videofluoroscopy while swallowing duplicate 10 mL boluses at <50 mPa·s, 100, 200, 400, 800, and 1600 mPa·s, to assess the safety and efficacy of swallowing and the biomechanics of a swallowing response at each viscosity level. At <50 mPa·s, only 16.25% patients swallowed safely, 45% had penetrations (PAS 3-5), and 38.75% had aspirations (PAS 6-8). Fluid thickening with TQ greatly increased the prevalence of patients with safe swallowing from 62.90% at 100 mPa·s to 95.24% at 1600 mPa·s in a shear-viscosity-dependent manner. The penetrations and aspirations were significantly reduced to 3.60% and 1.19%, respectively, at 1600 mPa·s. The threshold viscosity was 100 mPa·s and the increasing viscosity above 800 mPa·s did not further improve the therapeutic effect significantly. Increasing the shear viscosity significantly reduced the time to laryngeal vestibule closure (-16.70%), increased the time to upper oesophageal sphincter opening (+26.88%), and reduced the pharyngeal bolus velocity (-31.62%) without affecting the pharyngeal residue. TQ has a strong shear-viscosity-dependent effect on the safety of swallowing in older patients with severe OD without increasing the pharyngeal residue. The therapeutic range for TQ is 100-800 mPa·s, with 200 and 800 mPa·s being the optimal doses to cover the needs of older patients with OD.

Proposal for a Standard Protocol to Assess the Rheological Behavior of Thickening Products for Oropharyngeal Dysphagia.

Increasing shear viscosity (ShV) in thickening products (TP) is a valid therapeutic strategy for oropharyngeal dysphagia (OD). However, salivary amylase in the oral phase and shear rate in the pharyngeal phase of swallowing can change the viscosity of TPs when swallowed. This study aims to design and validate a rheological protocol to reproduce the oral and pharyngeal factors that affect the therapeutic effect of TPs and report the viscosity measurements in a standardized scientific and precise manner. We measured (a) the variability of the ShV measurements across several laboratories; (b) the in vitro and ex vivo properties of TPs and (c) the impact of the X-ray contrast Omnipaque, temperature and resting time on the rheological properties of TPs. A common protocol was applied in four international laboratories to assess five ShV values (100, 200, 400, 800 and 1600 mPa·s) for the xanthan-gum TP Tsururinko Quickly (TQ). The protocol included the dose (g/100 mL water), stirring procedure and standing time before measurement. Each value was characterized at the shear rate of 50 and 300 s-1 pre- and post-oral incubation in eight volunteers. The effect of temperature, standing time and Omnipaque was assessed. The main results of the study were: (a) The mean intra-laboratory variability on the ShV at all levels was very low: 0.85%. The mean inter-laboratory variability was higher: 9.3%; (b) The shear thinning of TQ at 300 s-1 was 75-80%. Increasing the temperature or standing time did not affect the ShV, and oral amylase caused a small decrease; (c) Omnipaque slightly decreased the dose of TP and hardly affected the amylase resistance or shear thinning. This study showed that different laboratories can obtain very accurate and similar ShV measurements using this protocol which uses scientific, universal SI units (mPa·s). Our protocol accurately reproduces oral and pharyngeal factors affecting the therapeutic effect of TPs. The addition of X-ray contrast did not produce significant changes.

The Hydration Status of Adult Patients with Oropharyngeal Dysphagia and the Effect of Thickened Fluid Therapy on Fluid Intake and Hydration: Results of Two Parallel Systematic and Scoping Reviews.

BACKGROUND: The effect of oropharyngeal dysphagia (OD) and thickened fluid (TF) therapy on hydration status has not been well defined in the literature. We aimed to assess the hydration status in patients with OD and the effect TF therapy has on it. METHODS: Two literature reviews following PRISMA methodology (each one including a systematic and a scoping review) were performed: (R1) hydration status in adult patients with OD; (R2) effect of TF therapy on fluid intake and dehydration. Narrative and descriptive methods summarized both reviews. Quality assessment was assessed by Joanna Briggs Institute tools and GRADE. RESULTS: (R1) Five out of twenty-two studies using analytical parameters or bioimpedance showed poorer hydration status among OD and 19-100% prevalence of dehydration; (R2) two high quality studies (total of 724 participants) showed positive effects of TF on hydration status. Among the articles included, nine out of ten studies that evaluated fluid intake reported a reduced TF intake below basal water requirements. CONCLUSIONS: Dehydration is a highly prevalent complication in OD. There is scientific evidence on the positive effect of TF therapy on the hydration status of patients with OD. However, strict monitoring of fluid volume intake is essential due to the low consumption of TF in these patients.

Effect of Aging, Gender and Sensory Stimulation of TRPV1 Receptors with Capsaicin on Spontaneous Swallowing Frequency in Patients with Oropharyngeal Dysphagia: A Proof-of-Concept Study.

Spontaneous swallowing contributes to airway protection and depends on the activation of brainstem reflex circuits in the central pattern generator (CPG). We studied the effect of age and gender on spontaneous swallowing frequency (SSF) in healthy volunteers and assessed basal SSF and TRPV1 stimulation effect on SSF in patients with post-stroke oropharyngeal dysphagia (OD). The effect of age and gender on SSF was examined on 141 healthy adult volunteers (HV) divided into three groups: GI-18-39 yr, GII-40-59 yr, and GIII->60 yr. OD was assessed by the Volume-Viscosity Swallowing Test (VVST). The effect of sensory stimulation with capsaicin 10-5 M (TRPV1 agonist) was evaluated in 17 patients with post-stroke OD, using the SSF. SSF was recorded in all participants during 10 min using surface electromyography (sEMG) of the suprahyoid muscles and an omnidirectional accelerometer placed over the cricothyroid cartilage. SSF was significantly reduced in GII (0.73 ± 0.50 swallows/min; p = 0.0385) and GIII (0.50 ± 0.31 swallows/min; p < 0.0001) compared to GI (1.03 ± 0.62 swallows/min), and there was a moderate significant correlation between age and SFF (r = -0.3810; p < 0.0001). No effect of gender on SSF was observed. Capsaicin caused a strong and significant increase in SSF after the TRPV1 stimulation when comparing to basal condition (pre-capsaicin: 0.41 ± 0.32 swallows/min vs post-capsaicin: 0.81 ± 0.51 swallow/min; p = 0.0003). OD in patients with post-stroke OD and acute stimulation with TRPV1 agonists caused a significant increase in SSF, further suggesting the potential role of pharmacological stimulation of sensory pathways as a therapeutic strategy for CPG activation in patients with OD.

Effect of Transcutaneous Electrical Stimulation in Chronic Poststroke Patients with Oropharyngeal Dysphagia: 1-Year Results of a Randomized Controlled Trial.

Background. Chronic poststroke oropharyngeal dysphagia (CPSOD) is associated with impaired oropharyngeal sensory/motor function. We aimed to assess effect of sensory (SES) and motor (NMES) transcutaneous electrical stimulation (TES) on safety of swallow and clinical outcomes in patients with CPSOD in a one-year follow-up randomized controlled trial. Methods. Ninety patients (74.1 ± 11.5 y, modified Rankin score 2.6 ± 1.7) with CPSOD and impaired safety of swallow were randomized to (a) compensatory treatment (CT), (b) CT + SES, and (c) CT + NMES. Patients were treated with up to two cycles (6 months apart) of 15 × 1 hour TES sessions over two weeks and followed up with 4-5 clinical and videofluoroscopic assessments during one year. Key results. Baseline penetration-aspiration scale (PAS) was 4.61 ± 1.75, delayed time to laryngeal vestibule closure (LVC) 396.4 ± 108.7 ms, and impaired efficacy signs 94.25%. Swallowing parameters significantly improved between baseline and 1-year follow-up in SES and NMES groups for prevalence of patients with a safe swallow (P < .001), mean PAS (P < .001), time to LVC (P < .01), and need for thickening agents (P < .001). Patients in the CT presented a less intense improvement of signs of impaired safety of swallow without significant changes in time to LVC. No differences between groups were observed for 1-year mortality (6.1%), respiratory infections (9.6%), nutritional and functional status, QoL, and hospital readmission rates (27.6%). No significant adverse events related to TES were observed. Conclusions and inferences. Transcutaneous electrical stimulation is a safe and effective therapy for older patients with CPSOD. After 1-year follow-up, TES greatly improved the safety of swallow and reduced the need for fluid thickening in these patients.

A Systematic and a Scoping Review on the Psychometrics and Clinical Utility of the Volume-Viscosity Swallow Test (V-VST) in the Clinical Screening and Assessment of Oropharyngeal Dysphagia.

(1) Background: The volume-viscosity swallow test (V-VST) is a clinical tool for screening and diagnosis of oropharyngeal dysphagia (OD). Our aims were to examine the clinical utility of the V-VST against videofluoroscopy (VFS) or fiberoptic endoscopic evaluation of swallow (FEES) and to map the V-VST usage with patients at risk of OD across the years since it was described for the first time, carrying a systematic and a scoping review. (2) Methods: We performed both a systematic review (SR) including studies that look at the diagnostic test accuracy, and a scoping review (ScR) with articles published from September 2008 to May 2020. Searches were done in different databases, including PubMed and EMBASE from September 2008 until May 2020, and no language restrictions were applied. A meta-analysis was done in the SR to assess the psychometric properties of the V-VST. Quality of studies was assessed by Dutch Cochrane, QUADAS, GRADE (SR), and STROBE (ScR) criteria. The SR protocol was registered on PROSPERO (registration: CRD42020136252). (3) Results: For the diagnostic accuracy SR: four studies were included. V-VST had a diagnostic sensitivity for OD of 93.17%, 81.39% specificity, and an inter-rater reliability Kappa = 0.77. Likelihood ratios (LHR) for OD were 0.08 (LHR-) and 5.01 (LHR+), and the diagnostic odds ratio for OD was 51.18. Quality of studies in SR was graded as high with low risk of bias. In the ScR: 34 studies were retrieved. They indicated that V-VST has been used internationally to assess OD's prevalence and complications. (4) Conclusions: The V-VST has strong psychometric properties and valid endpoints for OD in different phenotypes of patients. Our results support its utility in the screening and clinical diagnosis and management of OD.

Short-term neurophysiological effects of sensory pathway neurorehabilitation strategies on chronic poststroke oropharyngeal dysphagia.

BACKGROUND: Neurorehabilitation strategies for chronic poststroke (PS) oropharyngeal dysphagia (OD) have been mainly focused on the neurostimulation of the pharyngeal motor cortex with only marginal effects. In contrast, treatments targeting the PS oropharyngeal sensory pathway dysfunction offer very promising results, but there is little knowledge on the underlying mechanisms. We aimed to explore the neurophysiological mechanisms behind the effect of three sensory neurostimulation strategies. METHODS: We carried out a randomized two-blinded parallel group's crossover sham-controlled clinical trial in 36 patients with unilateral stroke and chronic unsafe swallow to investigate the effect of repetitive transcranial magnetic stimulation (rTMS) of the primary sensory cortex (A), oral capsaicin (B) and intra-pharyngeal electrical stimulation (IPES; C). The effect was evaluated immediately after the interventions with videofluoroscopy (VFS) and motor/sensory evoked potentials (MEP/SEP). KEY RESULTS: Interventions induced no changes in the biomechanics of the swallow response during VFS. However, an enhancement of motor cortex excitability (latency shortening and increased size of thenar MEP) was found with active interventions (A + B + C, and B/C alone; P < .05 for all) but not with sham. Active but not sham interventions shortened pharyngeal SEP latency in the ipsilesional hemisphere (A + B + C: P2-peak, P = .039; A: N2-peak, P = .034) and antagonized the physiological habituation in pharyngeal MEP (A + B + C and A alone, P < .05 for both). CONCLUSIONS AND INFERENCES: Sensory pathway neurostimulation strategies caused immediate enhancement of motor cortex excitability with peripheral strategies (capsaicin and IPES) and of pharyngeal sensory conduction with rTMS. These changes support the use of sensory neurorehabilitation strategies in promoting swallow recovery in chronic PS-OD.

Therapeutic Effect, Rheological Properties and α-Amylase Resistance of a New Mixed Starch and Xanthan Gum Thickener on Four Different Phenotypes of Patients with Oropharyngeal Dysphagia.

Thickened fluids are a therapeutic strategy for oropharyngeal dysphagia (OD). However, its therapeutic effect among different phenotypes of OD patients has not yet been compared. We aimed to assess the therapeutic effect and α-amylase resistance of a mixed gum/starch thickener [Fresubin Clear Thickener® (FCT)] on four phenotypes of OD patients: G1) 36 older; G2) 31 head/neck cancer (HNC); G3) 30 Parkinson's disease; and G4) 31 chronic post-stroke. Therapeutic effect of FCT was assessed during videofluoroscopy using the Penetration-Aspiration Scale (PAS), for 5/20 mL boluses, at four levels of shear-viscosity (<50, 250, 1000 and 2000 mPa·s). The effect of α-amylase was assessed after 30 s of oral incubation. Patients had high prevalence of VFS signs of impaired efficacy (98.44%) and safety (70.31%) of swallow with a severe PAS score (4.44 ± 0.20). Most severe OD was in HNC (80.6% unsafe swallows). FCT showed a strong therapeutic effect on the safety of swallow at a range between 250-1000 mPa·s (74.19-96.67%, safe swallows in G1, G3, G4, and 58.06% in G2), without increasing pharyngeal residue. Viscosity was unaffected by α-amylase. Increasing shear-viscosity with FCT causes a strong viscosity-dependent therapeutic effect on the safety of swallow. This effect depends on the phenotype and is similar among older, Parkinson's and post-stroke patients.

Neurophysiological and Biomechanical Evaluation of the Mechanisms Which Impair Safety of Swallow in Chronic Post-stroke Patients.

Oropharyngeal dysphagia (OD) is a common post-stroke complication and is associated with respiratory infections. The aim was to assess the biomechanical impairments in swallow function and the afferent and efferent swallowing pathways impairing swallow safety in chronic post-stroke patients. We studied 30 patients with unilateral stroke and chronic OD (> 3 months from stroke onset) with impaired safety of swallow (Penetration-Aspiration Scale [PAS] ≥ 2). We evaluated the efficacy, safety, and kinematics of the swallow response (residue, PAS, laryngeal vestibule closure time [LVCT]) with videofluoroscopy, sensory evoked potentials to pharyngeal electrical stimulation (pSEP), and pharyngeal motor evoked potentials (pMEP) to transcranial magnetic stimulation of both hemispheres. Mean age of patients was 70.1 ± 10.9 years (7 women). Stroke severity at onset was moderate (NIHSS median 10 [IQ range 3-11.5]), and modified Rankin Scale 2.8 ± 1.3. Mean PAS was 5.1 ± 1.9; prevalence of delayed LVCT was 86.7% and 30% presented aspirations. Pharyngeal hypoesthesia was present in 46.7% of patients and 92.3% showed abnormally asymmetrical pSEPs when comparing the ipsilesional with the contralesional hemisphere. Increased duration of swallow was associated with lower pSEP amplitude (P1-N2) in the contralesional hemisphere (p = 0.033). Patients with right hemispheric strokes showed greater reduction of pSEPs amplitude (N1-P1, p = 0.049). In contrast, pharyngeal resting motor threshold and pMEPs were symmetric in 73.3% patients without the physiologic hemispheric dominance. Mild-to-moderate disabled chronic post-stroke patients with OD presented severe impaired biomechanics of swallow response and high prevalence of aspirations. Initial results from the neurophysiological evaluation demonstrated prevalent impairments with disrupted integration of pharyngeal sensory inputs and reduced cortical excitability of efferent pathways. Patients with right hemispheric strokes showed poorer neurophysiological responses.

A randomized clinical trial on the acute therapeutic effect of TRPA1 and TRPM8 agonists in patients with oropharyngeal dysphagia.

BACKGROUND: Oropharyngeal dysphagia (OD) treatment is moving away from compensatory strategies toward active treatments that improve swallowing function. The aim of this study was to assess the acute therapeutic effect of TRPA1/M8 agonists in improving swallowing function in OD patients. METHODS: Fifty-eight patients with OD caused by aging, stroke, or neurodegenerative disease were included in a three-arm, quadruple-blind, randomized clinical trial (NCT02193438). Swallowing safety and efficacy and the kinematics of the swallow response were assessed by videofluoroscopy (VFS) during the swallow of 182 ± 2 mPa·s viscosity (nectar) boluses of a xanthan gum thickener supplemented with (a) 756.6 µmol/L cinnamaldehyde and 70 µmol/L zinc (CIN-Zn) (TRPA1 agonists), (b) 1.6 mmol/L citral (CIT) (TRPA1 agonist), or (c) 1.6 mmol/L citral and 1.3 mmol/L isopulegol (CIT-ISO) (TRPA1 and TRPM8 agonists). The effects on pharyngeal event-related potentials (ERP) were assessed by electroencephalography. KEY RESULTS: TRPA1 stimulation with either CIN-Zn or CIT reduced time to laryngeal vestibule closure (CIN-Zn P = .002, CIT P = .023) and upper esophageal sphincter opening (CIN-Zn P = .007, CIT P = .035). In addition, CIN-Zn reduced the penetration-aspiration scale score (P = .009), increased the prevalence of safe swallows (P = .041), and reduced the latency of the P2 peak of the ERP. CIT-ISO had no positive effect on biomechanics or neurophysiology. No significant adverse events were observed. CONCLUSIONS AND INFERENCES: TRPA1 stimulation with CIN-Zn or CIT improves the swallow response which, in the case of CIN-Zn, is associated with a significant improvement in cortical activation and safety of swallow. These results provide the basis for the development of new active treatments for OD using TRPA1 agonists.

Acute and subacute effects of oropharyngeal sensory stimulation with TRPV1 agonists in older patients with oropharyngeal dysphagia: a biomechanical and neurophysiological randomized pilot study.

BACKGROUND: Older people with oropharyngeal dysphagia (OD) present a decline in pharyngeal sensory function. The aim of this proof-of-concept study was to assess the biomechanical and neurophysiological effects of acute and subacute oropharyngeal sensory stimulation with transient receptor potential vanilloid 1 (TRPV1) agonists (capsaicinoids) in older patients with OD. METHODS: We studied the effect of a single dose versus multiple doses (2 weeks) of oral capsaicin treatment (10-5 M) or placebo in 28 older patients with OD (81.2 ± 4.6 years) using videofluoroscopy (penetration-aspiration scale [PAS], timing of swallow response) and electroencephalography (EEG) (latency and amplitude of pharyngeal event-related potential [ERP]). RESULTS: Acute stimulation by capsaicinoids 10-5 M did not improve swallow function and did not produce significant changes in pharyngeal ERP. In contrast, after 10 days of treatment, patients presented a clinically relevant and statistically significant reduction in the laryngeal vestibule closure (LVC) time (22.5%, p = 0.042), and in the PAS (24.2%, p = 0.038), compared with the placebo group. EEG results showed a reduction in the latency of the N1 peak (28.6%, p = 0.007) and an increase of the amplitude of the P1-N2 (59.4%, p = 0.038) and the N2-P2 (43.6%, p = 0.050) peaks. We observed a strong and significant correlation between the reduction in the latency of the N1 peak and change in LVC time after subacute treatment (r = 0.750, p = 0.003). CONCLUSIONS: After 2 weeks of treatment, oropharyngeal sensory stimulation with capsaicinoids induced cortical changes that were correlated with improvements in swallowing biomechanics in older patients with OD. These results further show that sensory stimulation by TRPV1 agonists can become a useful pharmacological treatment for older patients with OD.

Defective Conduction of Anorectal Afferents Is a Very Prevalent Pathophysiological Factor Associated to Fecal Incontinence in Women.

BACKGROUND/AIMS: Fecal incontinence (FI) is a prevalent condition among women. While biomechanical motor components have been thoroughly researched, anorectal sensory aspects are less known. We studied the pathophysiology of FI in community-dwelling women, specifically, the conduction through efferent/afferent neural pathways. METHODS: A cross-sectional study was conducted on 175 women with FI and 19 healthy volunteers. The functional/structural study included anorectal manometry/endoanal ultrasound. Neurophysiological studies including pudendal nerve terminal motor latency (PNTML) and sensory-evoked-potentials to anal/rectal stimulation (ASEP/RSEP) were conducted on all healthy volunteers and on 2 subgroups of 42 and 38 patients, respectively. RESULTS: The main conditions associated with FI were childbirth (79.00%) and coloproctological surgery (37.10%). Cleveland score was 11.39 ± 4.09. Anorectal manometry showed external anal sphincter and internal anal sphincter insufficiency in 82.85% and 44.00%, respectively. Sensitivity to rectal distension was impaired in 27.42%. Endoanal ultrasound showed tears in external anal sphincter (60.57%) and internal anal sphincter disruptions (34.80%). Abnormal anorectal sensory conduction was evidenced through ASEP and RSEP in 63.16% and 50.00% of patients, respectively, alongside reduced activation of brain cortex to anorectal stimulation. In contrast, PNTML was delayed in only 33.30%. Stools were loose/very loose in 56.70% of patients. CONCLUSIONS: Pathophysiology of FI in women is mainly associated with mechanical sphincter dysfunctions related to either muscle damage or, to a lesser extent, impaired efferent conduction at pudendal nerves. Impaired conduction through afferent anorectal pathways is also very prevalent in women with FI and may play an important role as a pathophysiological factor and as a potential therapeutic target.