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

UDBELLATERRASpontaneous 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

Alteraciones de la excitabilidad refleja y del control motor en esclerosis múltiple

[spa] INTRODUCCIÓN: En Esclerosis Múltiple (EM) el sustrato neuropatológico típicamente muestra un patrón de distribución aleatoria de lesiones desmielinizantes, con particular predilección por estructuras comisurales y subcorticales tales como el cuerpo calloso y el tronco del encéfalo. En estos pacientes, es común observar fenómenos subclínicos pocos explorados, tales como la hiperactividad facial, la lentitud motora y la falta de control motor, que pueden estar relacionados al daño encefálico multifocal que ocurre en vías neurales y circuitos específicos por alteración en los mecanismos de conducción y excitabilidad. HIPÓTESIS: Los pacientes con EM presentan signos neurofisiológicos subclínicos indicativos de alteraciones en la excitabilidad de los circuitos reflejos tronco-encefálicos y del control motor en la ejecución de tareas unimanuales. Estas alteraciones se correlacionan con lesiones cerebrales subcorticales, especialmente comisurales. MÉTODOS: Veintiún pacientes con EM en estadio leve de enfermedad fueron sometidos a 2 diseños experimentales. Primero, la excitabilidad del reflejo de parpadeo fue evaluada en ambos lados del rostro mediante el estudio del tamaño de las respuestas obtenidas por diversas técnicas electrofisiológicas (estimulación única trigeminal y somatosensorial, estimulación pareada y condicionada con prepulso somato-sensorial), y correlacionada con el patrón de distribución hemisférica de lesiones desmielinizantes. Segundo, en un paradigma de tiempo de reacción “cruzado” (extensión de la muñeca ante un estímulo somato-sensorial aplicado en la mano contralateral como señal imperativa) que involucra necesariamente la transferencia inter-hemisférica de impulsos, se estudió la asociación entre el retraso del tiempo de reacción con: el tiempo de tránsito transcalloso (medido por estimulación magnética transcraneal), la excitabilidad de estructuras subcorticales involucradas en la preparación del acto motor (mediante el estudio del efecto StartReact), y la presencia de actividad involuntaria electromiográfica “en espejo”. Tales anormalidades fueron comparadas con los datos obtenidos en sujetos sanos, y correlacionadas con medidas de daño estructural y microestructural por resonancia magnética nuclear en cuerpo calloso y tronco del encéfalo. RESULTADOS: 1. En un subgrupo de pacientes en un estadio más precoz de enfermedad (35%) se observó una asimetría en la “excitabilidad” del reflejo de parpadeo que se asoció a una distribución asimétrica de lesiones hemisféricas, a diferencia de lo observado en pacientes en un estadio más avanzado (40%) que mostraron un retraso en la “conducción” de las respuestas del reflejo de parpadeo y una distribución hemisférica simétrica de lesiones. 2. En pacientes, se observó que la lentitud de reacción motora se asocia a una reducción en el efecto StartReact, y que el retraso del tiempo de reacción en tareas “cruzadas” se correlaciona con una prolongación en el tiempo de tránsito transcalloso. 3. En tareas motoras “cruzadas”, los pacientes mostraron una actividad “en espejo” exagerada que se asocia a un mayor daño microestructural de fibras callosas y a atrofia del tronco del encéfalo. CONCLUSIONES: En pacientes con EM es frecuente encontrar alteraciones subclínicas de la excitabilidad en los circuitos reflejos y estructuras subcorticales y a falta de control motor, revelados mediante estudios neurofisiológicos. Tales alteraciones se explican mayormente por el daño multifocal encefálico con afectación predominante de los hemisferios cerebrales, cuerpo calloso y tronco del encéfalo.[eng] INTRODUCTION: Multifocal distribution of demyelinating lesions in the brain affecting mainly the brainstem and the corpus callosum (CC) are common findings in magnetic resonance (MRI) of patients with multiple sclerosis (MS). These patients may present with subclinical signs (myokymia, bradykinesia or lack of motor control) representing altered excitability in specific neural circuits. HYPOTHESIS: Signs of altered excitability in MS show in the study of brainstem reflex circuits or during the hand movement execution in reaction time paradigms requiring transcallosal pathways (“crossed” motor tasks). These abnormalities combine with distant lesions in cerebral hemispheres or with focal lesions in brainstem and CC. METHODS: We studied 21 mildly-disabled MS patients and 11 healthy volunteers in two experimental conditions. First, the blink reflex excitability was examined in both sides to single stimulation of trigeminal and median nerves, and to paired trigeminal stimulation and conditioned with a somato-sensory prepulse. These measures were associated with the distribution of hemispheric demyelinating MRI-lesions. Second, in the context of a “crossed” reaction time paradigm, participants were requested to perform unilateral wrist-extension movements to a sensory stimulus applied in the contralateral hand used as imperative signal. “Crossed” reaction time was correlated to transcallosal conduction time measured with transcranial-magnetic-stimulation, and associated to the startling- acceleration in the reaction time (a.k.a. StartReact effect) and with the presence of mirror electromyographic activity (mEMG). Abnormalities were correlated with MRI- measures of structural/ultrastructural damage in brainstem and CC. RESULTS: In 35% of patients we found an asymmetric blink reflex excitability in absence of brainstem lesions which associated with an asymmetric distribution of hemispheric lesions, whereas in 40% of patients we found delayed blink responses which associated with brainstem lesions and symmetric distribution of hemispheric lesions. In patients, slowness of reaction associated with reduced StartReact effect, and delayed “crossed” reaction time correlated with lengthening in transcallosal conduction time. In "crossed” reaction time, patients showed enhanced mEMG which associated with increased ultrastructural callosal damage and brainstem atrophy. CONCLUSIONS: MS patients show altered excitability in brainstem reflex circuits and subcortical structures and lack of motor control. These abnormalities are related to lesion involvement of cerebral hemispheres, CC and brainstem

Physiology and pathophysiology of oropharyngeal dysphagia in older persons

Deglutition or swallowing is a complicated sensorimotor act that involves the activation of more than 30 pairs of muscles controlled by more than five cranial nerves to be completed in a coordinated and safe manner. Deglutition involves both voluntary and reflexive actions. Although historically, swallowing has been a reflex, the newest evidence demonstrates that swallowing is a highly coordinated sensorimotor response rather than a true reflex. For the patterned response called swallowing, there is not a specific area in the central nervous system that controls the action, as happens for a true reflex, and the completion of the motor output of the swallow is adaptable to factors that are present, such as bolus volume, viscosity, temperature, or even changes or alterations of anatomical nature. This chapter aims to describe swallowing physiology and its pathophysiology in older patients.</p

Abnormal Control of Orbicularis Oculi Reflex Excitability in Multiple Sclerosis

Brain lesions in patients with multiple sclerosis may lead to abnormal excitability of brainstem reflex circuits because of impairment of descending control pathways. We hypothesized that such abnormality should show in the analysis of blink reflex responses in the form of asymmetries in response size. The study was done in 20 patients with relapsing-remitting multiple sclerosis and 12 matched healthy subjects. We identified first patients with latency abnormalities (AbLat). Then, we analyzed response size by calculating the R2c/R2 ratio to stimulation of either side and the mean area of the R2 responses obtained in the same side. Patients with significantly larger response size with respect to healthy subjects in at least one side were considered to have abnormal response excitability (AbEx). We also examined the blink reflex excitability recovery (BRER) and prepulse inhibition (BRIP) of either side in search for additional indices of asymmetry in response excitability. Neurophysiological data were correlated with MRI-determined brain lesion-load and volume. Eight patients were identified as AbLat (median Expanded Disability Status Scale-EDSS = 2.75) and 7 of them had ponto-medullary lesions. Nine patients were identified as AbEx (EDSS = 1.5) and only 2 of them, who also were AbLat, had ponto-medullary lesions. In AbEx patients, the abnormalities in response size were confined to one side, with a similar tendency in most variables (significantly asymmetric R1 amplitude, BRER index and BRIP percentage). AbEx patients had asymmetric distribution of hemispheral lesions, in contrast with the symmetric pattern observed in AbLat. The brainstem lesion load was significantly lower in AbEx than in AbLat patients (p = 0.04). Asymmetric abnormalities in blink reflex response excitability in patients with multiple sclerosis are associated with lesser disability and lower tissue loss than abnormalities in response latency. Testing response excitability could provide a reliable neurophysiological index of dysfunction in early stages of multiple sclerosis

Depletion of nucleus accumbens dopamine leads to impaired reward and aversion processing in mice: Relevance to motivation pathologies

Dopamine (DA) neurotransmission, particularly the ventral tegmental area-nucleus accumbens (VTA-NAcc) projection, underlies reward and aversion processing, and deficient DA function could underlie motivational impairments in psychiatric disorders. 6-hydroxydopamine (6-OHDA) injection is an established method for chronic DA depletion, principally applied in rat to study NAcc DA regulation of reward motivation. Given the increasing focus on studying environmental and genetic regulation of DA function in mouse models, it is important to establish the effects of 6-OHDA DA depletion in mice, in terms of reward and aversion processing. This mouse study investigated effects of 6-OHDA-induced NAcc DA depletion using the operant behavioural test battery of progressive ratio schedule (PRS), learned non-reward (LNR), learned helplessness (LH), treadmill, and in addition Pavlovian fear conditioning. 6-OHDA NAcc DA depletion, confirmed by ex vivo HPLC-ED, reduced operant responding: for gustatory reward under effortful conditions in the PRS test; to a stimulus recently associated with gustatory non-reward in the LNR test; to escape footshock recently experienced as uncontrollable in the LH test; and to avoid footshock by physical effort in the treadmill test. Evidence for specificity of effects to NAcc DA was provided by lack of effect of medial prefrontal cortex DA depletion in the LNR and LH tests. These findings add significantly to the evidence that NAcc DA is a major regulator of behavioural responding, particularly at the motivational level, to both reward and aversion. They demonstrate the suitability of mouse models for translational study of causation and reversal of pathophysiological DA function underlying motivation psychopathologies