NGF contributes to activities of acid-sensing ion channels in dorsal root ganglion neurons of male rats with experimental peripheral artery disease.

A feature of peripheral artery diseases (PAD) includes limb ischemia/reperfusion (I/R) and ischemia. Both I/R and ischemia amplify muscle afferent nerve-activated reflex sympathetic nervous and blood pressure responses (termed as exercise pressor reflex). Nevertheless, the underlying mechanisms responsible for the exaggerated autonomic responses in PAD are undetermined. Previous studies suggest that acid-sensing ion channels (ASICs) in muscle dorsal root ganglion (DRG) play a leading role in regulating the exercise pressor reflex in PAD. Thus, we determined if signaling pathways of nerve growth factor (NGF) contribute to the activities of ASICs in muscle DRG neurons of PAD. In particular, we examined ASIC1a and ASIC3 currents in isolectin B4 -negative muscle DRG neurons, a distinct subpopulation depending on NGF for survival. Hindlimb I/R and ischemia were obtained in male rats. In results, femoral artery occlusion increased the levels of NGF and NGF-stimulated TrkA receptor in DRGs, whereas they led to upregulation of ASIC3 but not ASIC1a. In addition, application of NGF onto DRG neurons increased the density of ASIC3 currents and the effect of NGF was significantly attenuated by TrkA antagonist GW441756. Moreover, the enhancing effect of NGF on the density of ASIC3-like currents was decreased by the respective inhibition of intracellular signaling pathways, namely JNK and NF-κB, by antagonists SP600125 and PDTC. Our results suggest contribution of NGF to the activities of ASIC3 currents via JNK and NF-κB signaling pathways in association with the exercise pressor reflex in experimental PAD.

ASIC3 plays a protective role in delayed-onset muscle soreness (DOMS) through muscle acid sensation during exercise.

Immediate exercise-induced pain (IEIP) and DOMS are two types of exercise-induced muscle pain and can act as barriers to exercise. The burning sensation of IEIP occurs during and immediately after intensive exercise, whereas the soreness of DOMS occurs later. Acid-sensing ion channels (ASICs) within muscle afferents are activated by H+ and other chemicals and have been shown to play a role in various chronic muscle pain conditions. Here, we further defined the role of ASICs in IEIP, and also tested if ASIC3 is required for DOMS. After undergoing exhaustive treadmill exercise, exercise-induced muscle pain was assessed in wild-type (WT) and ASIC3-/- mice at baseline via muscle withdrawal threshold (MWT), immediately, and 24 h after exercise. Locomotor movement, grip strength, and repeat exercise performance were tested at baseline and 24 h after exercise to evaluate DOMS. We found that ASIC3-/- had similar baseline muscle pain, locomotor activity, grip strength, and exercise performance as WT mice. WT showed diminished MWT immediately after exercise indicating they developed IEIP, but ASIC3-/- mice did not. At 24 h after baseline exercise, both ASIC3-/- and WT had similarly lower MWT and grip strength, however, ASIC3-/- displayed significantly lower locomotor activity and repeat exercise performance at 24 h time points compared to WT. In addition, ASIC3-/- mice had higher muscle injury as measured by serum lactate dehydrogenase and creatine kinase levels at 24 h after exercise. These results show that ASIC3 is required for IEIP, but not DOMS, and in fact might play a protective role to prevent muscle injury associated with strenuous exercise.

Differential control of respiratory frequency and tidal volume during exercise.

The lack of a testable model explaining how ventilation is regulated in different exercise conditions has been repeatedly acknowledged in the field of exercise physiology. Yet, this issue contrasts with the abundance of insightful findings produced over the last century and calls for the adoption of new integrative perspectives. In this review, we provide a methodological approach supporting the importance of producing a set of evidence by evaluating different studies together-especially those conducted in 'real' exercise conditions-instead of single studies separately. We show how the collective assessment of findings from three domains and three levels of observation support the development of a simple model of ventilatory control which proves to be effective in different exercise protocols, populations and experimental interventions. The main feature of the model is the differential control of respiratory frequency (fR) and tidal volume (VT); fR is primarily modulated by central command (especially during high-intensity exercise) and muscle afferent feedback (especially during moderate exercise) whereas VT by metabolic inputs. Furthermore, VT appears to be fine-tuned based on fR levels to match alveolar ventilation with metabolic requirements in different intensity domains, and even at a breath-by-breath level. This model reconciles the classical neuro-humoral theory with apparently contrasting findings by leveraging on the emerging control properties of the behavioural (i.e. fR) and metabolic (i.e. VT) components of minute ventilation. The integrative approach presented is expected to help in the design and interpretation of future studies on the control of fR and VT during exercise.

Task-Specific Lingual Dystonia During Japanese Religious Services.

INTRODUCTION: Lingual dystonia is a subtype of oromandibular dystonia characterized by involuntary contractions of the tongue muscles, often provoked by speaking or eating. METHODS: This study reports six Japanese cases (four female and two male, mean age at onset of 49.5 years) with task-specific lingual dystonia during praying. In the early phase, all patients experienced lingual protrusion exclusively during Japanese religious services. When the patients start speaking, the tongues protrude forward, making it difficult to pronounce words. The patients were treated with multimodal treatment, including muscle afferent block (MAB) therapy comprising local anesthetic injection, botulinum toxin (onabotulinumtoxinA) injection, and a sensory trick splint. RESULTS: MAB therapy was conducted in five patients (mean time: 5.8), and botulinum toxin injection was administered in four patients (mean time: 8). The injected muscles were the genioglossal muscles and, in one case, the lateral pterygoid muscle. Sensory trick splints were inserted in three patients. After the multimodal therapy, the patients were able to pronounce words smoothly and clearly. Oromandibular Dystonia Rating Scale scores improved significantly (P<0.005) from baseline (187 points) to endpoint (47 points) with a mean follow-up of 4.7 years. CONCLUSION: Although this entity is rare, medical and dental professionals should be aware of this peculiar symptom. Multimodal therapy is required to ensure effective treatment of praying-induced lingual dystonia.

Sympathetic Nerve Activity and Blood Pressure Response to Exercise in Peripheral Artery Disease: From Molecular Mechanisms, Human Studies, to Intervention Strategy Development.

Sympathetic nerve activity (SNA) regulates the contraction of vascular smooth muscle and leads to a change in arterial blood pressure (BP). It was observed that SNA, vascular contractility, and BP are heightened in patients with peripheral artery disease (PAD) during exercise. The exercise pressor reflex (EPR), a neural mechanism responsible for BP response to activation of muscle afferent nerve, is a determinant of the exaggerated exercise-induced BP rise in PAD. Based on recent results obtained from a series of studies in PAD patients and a rat model of PAD, this review will shed light on SNA-driven BP response and the underlying mechanisms by which receptors and molecular mediators in muscle afferent nerves mediate the abnormalities in autonomic activities of PAD. Intervention strategies, particularly non-pharmacological strategies, improving the deleterious exercise-induced SNA and BP in PAD, and enhancing tolerance and performance during exercise will also be discussed.

ASIC3 knockout alters expression and activity of P2X3 in muscle afferent nerves of rat model of peripheral artery disease.

In peripheral artery disease (PAD), the metaboreceptor and mechanoreceptor in muscle afferent nerves contribute to accentuated sympathetic outflow via a neural reflex termed exercise pressor reflex (EPR). Particularly, lactic acid and adenosine triphosphate (ATP) produced in exercising muscles respectively stimulate acid sensing ion channel subtype 3 (ASIC3) and P2X3 receptors (P2X3) in muscle afferent nerves, inducing the reflex sympathetic and BP responses. Previous studies indicated that those two receptors are spatially close to each other and AISC3 may have a regulatory effect on the function of P2X3. This inspired our investigation on the P2X3-mediated EPR response following AISC3 abolished, which was anticipated to shed light on the future pharmacological and genetic treatment strategy for PAD. Thus, we tested the experimental hypothesis that the pressor response to P2X3 stimulation is greater in PAD rats with 3 days of femoral artery occlusion and the sensitizing effects of P2X3 are attenuated following ASIC3 knockout (KO) in PAD. Our data demonstrated that in wild type (WT) rats femoral occlusion exaggerated BP response to activation of P2X3 using α,ß-methylene ATP injected into the arterial blood supply of the hindlimb, meanwhile the western blot analysis suggested upregulation of P2X3 expression in dorsal root ganglion supplying the afferent nerves. Using the whole cell patch-clamp method, we also showed that P2X3 stimulation enhanced the amplitude of induced currents in muscle afferent neurons of PAD rats. Of note, amplification of the P2X3 evoked-pressor response and expression and current response of P2X3 was attenuated in ASIC3 KO rats. We concluded that the exaggerated P2X3-mediated pressor response in PAD rats is blunted by ASIC3 KO due to the decreased expression and activities of P2X3 in muscle afferent neurons.

Passive Proprioceptive Training Alters the Sensitivity of Muscle Spindles to Imposed Movements.

Humans rely on precise proprioceptive feedback from our muscles, which is important in both the acquisition and execution of movements, to perform daily activities. Somatosensory input from the body shapes motor learning through central processes, as demonstrated for tasks using the arm, under active (self-generated) and passive conditions. Presently, we investigated whether passive movement training of the ankle increased proprioceptive acuity (psychophysical experiment) and whether it changed the peripheral proprioceptive afferent signal (microneurography experiment). In the psychophysical experiment, the ankle of 32 healthy human participants was moved passively using pairs of ramp-and-hold movements in different directions. In a pretraining test, participants made judgements about the movement direction in a two-alternative forced choice paradigm. Participants then underwent passive movement training, but only half were cued for learning, where a reference position was signaled by a sound and the participant had to learn to recognize this position; they then completed a post-training test. In a paradigm using the same setup, nine healthy participants underwent microneurography recordings of Ia muscle afferents from the peroneal nerve, where all were cued during training. In the psychophysical experiment, proprioceptive acuity improved with training only in the cued group. In the microneurography experiment, we found that muscle afferent firing was modulated, via an increase in the dynamic index, after training. We suggest that changes in muscle afferent input from the periphery can contribute to and support central perceptual and motor learning, as shown under passive conditions using ankle movements, which may be exploited for movement rehabilitation.

Exaggerated blood pressure response to static exercise in hindlimb ischemia-reperfusion.

Peripheral artery disease (PAD) reduces the blood flow supply in the affected limbs as one of the significant cardiovascular concerns. Revascularization surgery in the femoral artery plays a central role in treating PAD. Exercise is also a rehabilitation strategy suggested for PAD patients to improve vascular functions. However, the effects of limb ischemia-reperfusion (IR), one of the most predominant complications in revascularization surgery, on exercise-induced arterial blood pressure (BP) response are poorly understood. In the present study, we determined 1) the blood flow status in the hindlimb muscles of rats (plantar muscle, red and white portions of gastrocnemius) with different time points of the hindlimb IR; and 2) the BP response to static muscle contraction in rats at different time points after the blood flow reperfusion procedure. Results of this study indicated that, compared with the Sham group, the blood flow in the hindlimb muscles evaluated by Evans blue concentration was significantly reduced at 6 h of femoral artery occlusion (FAO 6 h) (vs. sham control, p < 0.05). The decreased blood flow was gradually recovered after the blood flow reperfusion for 18 (IR 18 h), 66 (IR 66 h), and 114 (IR 114 h) hours (p < 0.05 vs. FAO 6 h for all IR groups). The response of mean arterial pressure was 20 ± 4 mmHg in Sham rats (n = 7); 32 ± 10 mmHg in IR 18 h rats (n = 10); 27 ± 7 mmHg in IR 66 h rats (n = 13); 26 ± 4 mmHg in IR 114 h rats (n = 9) (p < 0.05 vs. Sham for all groups). No significant difference was observed in the peak-developed tension during muscle contraction among all the groups (p > 0.05). In conclusion, static exercise-induced BP response is exaggerated following IR. Whereas the BP response is not statistically significant but tends to decrease with a prolonged IR time, the exaggerated BP response remains through time points from post-IR 18 h-114 h.

Vesicle-released glutamate is necessary to maintain muscle spindle afferent excitability but not dynamic sensitivity in adult mice.

KEY POINTS: Muscle spindle afferents are slowly adapting low threshold mechanoreceptors that report muscle length and movement information critical for motor control and proprioception. The rapidly adapting cation channel PIEZO2 has been identified as necessary for muscle spindle afferent stretch sensitivity, although the properties of this channel suggest that additional molecular elements are necessary for mediating the complex slowly adapting response of muscle spindle afferents. We report that glutamate increases muscle spindle afferent static sensitivity in an ex vivo mouse muscle nerve preparation, although blocking glutamate packaging into vesicles by the sole vesicular glutamate transporter, VGLUT1, either pharmacologically or by transgenic knockout of one allele of VGLUT1 decreases muscle spindle afferent static but not dynamic sensitivity. Our results confirm that vesicle-released glutamate is an important contributor to maintained muscle spindle afferent excitability and may suggest a therapeutic target for normalizing muscle spindle afferent function. ABSTRACT: Muscle spindle afferents are slowly adapting low threshold mechanoreceptors that have both dynamic and static sensitivity to muscle stretch. The exact mechanism by which these neurons translate muscle movement into action potentials is not well understood, although the PIEZO2 mechanically sensitive cation channel is essential for stretch sensitivity. PIEZO2 is rapidly adapting, suggesting the requirement for additional molecular elements to maintain firing during stretch. Spindle afferent sensory endings contain glutamate-filled synaptic-like vesicles that are released in a stretch- and calcium-dependent manner. Previous work has shown that glutamate can increase and a phospholipase-D coupled metabotropic glutamate antagonist can abolish firing during static stretch. Here, we test the hypothesis that vesicle-released glutamate is necessary for maintaining muscle spindle afferent excitability during static but not dynamic stretch. To test this hypothesis, we used a mouse muscle-nerve ex vivo preparation to measure identified muscle spindle afferent responses to stretch and vibration. In C57BL/6 adult mice, bath applied glutamate significantly increased the firing rate during the plateau phase of stretch but not during the dynamic phase of stretch. Blocking the packaging of glutamate into vesicles by the sole vesicular glutamate transporter, VGLUT1, either with xanthurenic acid or by using a transgenic mouse with only one copy of the VGLUT1 gene (VGLUT1+/- ), decreased muscle spindle afferent firing during sustained stretch but not during vibration. Our results suggest a model of mechanotransduction where calcium entering the PIEZO2 channel can cause the release of glutamate from synaptic-like vesicles, which then helps to maintain afferent depolarization and firing.

The effect of pedalling cadence on respiratory frequency: passive vs. active exercise of different intensities.

PURPOSE: Pedalling cadence influences respiratory frequency (fR) during exercise, with group III/IV muscle afferents possibly mediating its effect. However, it is unclear how exercise intensity affects the link between cadence and fR. We aimed to test the hypothesis that the effect of cadence on fR is moderated by exercise intensity, with interest in the underlying mechanisms. METHODS: Ten male cyclists performed a preliminary ramp incremental test and three sinusoidal experimental tests on separate visits. The experimental tests consisted of 16 min of sinusoidal variations in cadence between 115 and 55 rpm (sinusoidal period of 4 min) performed during passive exercise (PE), moderate exercise (ME) and heavy exercise (HE). The amplitude (A) and phase lag (φ) of the dependent variables were calculated. RESULTS: During PE, fR changed in proportion to variations in cadence (r = 0.85, P < 0.001; A = 3.9 ± 1.4 breaths·min-1; φ = - 5.3 ± 13.9 degrees). Conversely, the effect of cadence on fR was reduced during ME (r = 0.73, P < 0.001; A = 2.6 ± 1.3 breaths·min-1; φ = - 25.4 ± 26.3 degrees) and even more reduced during HE (r = 0.26, P < 0.001; A = 1.8 ± 1.0 breaths·min-1; φ = - 70.1 ± 44.5 degrees). No entrainment was found in any of the sinusoidal tests. CONCLUSION: The effect of pedalling cadence on fR is moderated by exercise intensity-it decreases with the increase in work rate-and seems to be mediated primarily by group III/IV muscle afferents, at least during passive exercise.

The role of muscle mechano and metaboreflexes in the control of ventilation: breathless with (over) excitement?

Mechanically and metabolically sensitive thin fibre (group III and IV) muscle afferents are activated during exercise, causing reflex cardiovascular responses that are essential to normal cardiovascular control. Impaired exercise performance in some disease states can be linked to abnormal muscle mechanoreflex and muscle metaboreflex activity. A role for this same afferent feedback in contributing to the hyperpnoea of exercise and the dyspnoea experienced by some patient groups on exercise has recently received increased attention. Evidence is summarised here that supports a role for muscle mechanoreflex and muscle metaboreflex involvement in the human ventilatory response to exercise and also their synergistic interaction with the central chemoreflex during muscular activity. The effects of local muscle training induced attenuation of the human muscle metaboreflex on this synergistic interaction and associated decrease in ventilation is discussed.

ASICs are required for immediate exercise-induced muscle pain and are downregulated in sensory neurons by exercise training.

Exercise training is an effective therapy for many pain-related conditions, and trained athletes have lower pain perception compared with unconditioned people. Some painful conditions, including strenuous exercise, are associated with elevated levels of protons, metabolites, and inflammatory factors, which may activate receptors and/or ion channels, including acid-sensing ion channels (ASICs), on nociceptive sensory neurons. We hypothesized that ASICs are required for immediate exercise-induced muscle pain (IEIP) and that exercise training diminishes IEIP by modulating ASICs within muscle afferents. We found high-intensity interval training (HIIT) reduced IEIP in C57BL/6 mice and diminished ASIC mRNA levels in lumber dorsal root ganglia, and this downregulation of ASICs correlated with improved exercise capacity. Additionally, we found that ASIC3 -/- mice did not develop IEIP; however, the exercise capacity of ASIC3 -/- was similar to wild-type mice. These results suggest that ASICs are required for IEIP and that diminishment of IEIP after exercise training correlates with downregulation of ASICs in sensory neurons.NEW & NOTEWORTHY Exercise performance can be limited by the sensations of muscle fatigue and pain transmitted by muscle afferents. It has been proposed that exercise training abrogates these negative feedback signals. We found that acid-sensing ion channels (ASICs) are required for immediate exercise-induced muscle pain (IEIP). Moreover, exercise training prevented IEIP and was correlated with downregulation of ASICs in sensory neurons.

Enhancement by TNF-α of TTX-resistant NaV current in muscle sensory neurons after femoral artery occlusion.

Femoral artery occlusion in rats has been used to study human peripheral artery disease (PAD). Using this animal model, a recent study suggests that increases in levels of tumor necrosis factor-α (TNF-α) and its receptor lead to exaggerated responses of sympathetic nervous activity and arterial blood pressure as metabolically sensitive muscle afferents are activated. Note that voltage-dependent Na+ subtype NaV1.8 channels (NaV1.8) are predominately present in chemically sensitive thin fiber sensory nerves. The purpose of this study was to examine the role played by TNF-α in regulating activity of NaV1.8 currents in muscle dorsal root ganglion (DRG) neurons of rats with PAD induced by femoral artery occlusion. DRG neurons from control and occluded limbs of rats were labeled by injecting the fluorescent tracer DiI into the hindlimb muscles 5 days before the experiments. A voltage patch-clamp mode was used to examine TTX-resistant (TTX-R) NaV currents. Results were as follows: 72 h of femoral artery occlusion increased peak amplitude of TTX-R [1,922 ± 139 pA in occlusion (n = 11 DRG neurons) vs. 1,178 ± 39 pA in control (n = 10), means ± SE; P < 0.001 between the 2 groups] and NaV1.8 currents [1,461 ± 116 pA in occlusion (n = 11) and 766 ± 48 pA in control (n = 10); P < 0.001 between groups] in muscle DRG neurons. TNF-α exposure amplified TTX-R and NaV1.8 currents in DRG neurons of occluded muscles in a dose-dependent manner. Notably, the amplification of TTX-R and NaV1.8 currents induced by TNF-α was attenuated in DRG neurons with preincubation with respective inhibitors of the intracellular signaling pathways p38-MAPK, JNK, and ERK. In conclusion, our data suggest that NaV1.8 is engaged in the role of TNF-α in amplifying muscle afferent inputs as the hindlimb muscles are ischemic; p38-MAPK, JNK, and ERK pathways are likely necessary to mediate the effects of TNF-α.

Modulation of Muscle Pain Is Not Somatotopically Restricted: An Experimental Model Using Concurrent Hypertonic-Normal Saline Infusions in Humans.

We have previously shown that during muscle pain induced by infusion of hypertonic saline (HS), concurrent application of vibration and gentle brushing to overlying and adjacent skin regions increases the overall pain. In the current study, we focused on muscle-muscle interactions and tested whether HS-induced muscle pain can be modulated by innocuous/sub-perceptual stimulation of adjacent, contralateral, and remote muscles. Psychophysical observations were made in 23 healthy participants. HS (5%) was infused into a forearm muscle (flexor carpi ulnaris) to produce a stable baseline pain. In separate experiments, in each of the three test locations (n = 10 per site)-ipsilateral hand (abductor digiti minimi), contralateral forearm (flexor carpi ulnaris), and contralateral leg (tibialis anterior)-50 µl of 0.9% normal saline (NS) was infused (in triplicate) before, during, and upon cessation of HS-induced muscle pain in the forearm. In the absence of background pain, the infusion of NS was imperceptible to all participants. In the presence of HS-induced pain in the forearm, the concurrent infusion of NS into the ipsilateral hand, contralateral forearm, and contralateral leg increased the overall pain by 16, 12, and 15%, respectively. These effects were significant, reproducible, and time-locked to NS infusions. Further, the NS-evoked increase in pain was almost always ascribed to the forearm where HS was infused with no discernible percept attributed to the sites of NS infusion. Based on these observations, we conclude that intramuscular infusion of HS results in muscle hyperalgesia to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.

Control of exercise hyperpnoea: Contributions from thin-fibre skeletal muscle afferents.

NEW FINDINGS: What is the topic of this review? In this review, we examine the evidence for control mechanisms underlying exercise hyperpnoea, giving attention to the feedback from thin-fibre skeletal muscle afferents, and highlight the frequently conflicting findings and difficulties encountered by researchers using a variety of experimental models. What advances does it highlight? There has been a recent resurgence of interest in the role of skeletal muscle afferent involvement, not only as a mechanism of healthy exercise hyperpnoea but also in the manifestation of breathlessness and exercise intolerance in chronic disease. ABSTRACT: The ventilatory response to dynamic submaximal exercise is immediate and proportional to metabolic rate, which maintains isocapnia. How these respiratory responses are controlled remains poorly understood, given that the most tightly controlled variable (arterial partial pressure of CO2 /H+ ) provides no error signal for arterial chemoreceptors to trigger reflex increases in ventilation. This review discusses evidence for different postulated control mechanisms, with a focus on the feedback from group III/IV skeletal muscle mechanosensitive and metabosensitive afferents. This concept is attractive, because the stimulation of muscle mechanoreceptors might account for the immediate increase in ventilation at the onset of exercise, and signals from metaboreceptors might be proportional to metabolic rate. A variety of experimental models have been used to establish the contribution of thin-fibre muscle afferents in ventilatory control during exercise, with equivocal results. The inhibition of afferent feedback via the application of lumbar intrathecal fentanyl during exercise suppresses ventilation, which provides the most compelling supportive evidence to date. However, stimulation of afferent feedback at rest has no consistent effect on respiratory output. However, evidence is emerging for synergistic interactions between muscle afferent feedback and other stimulatory inputs to the central respiratory neuronal pool. These seemingly hyperadditive effects might explain the conflicting findings encountered when using different experimental models. We also discuss the increasing evidence that patients with certain chronic diseases exhibit exaggerated muscle afferent activation during exercise, resulting in enhanced cardiorespiratory responses. This might provide a neural link between the well-established limb muscle dysfunction and the associated exercise intolerance and exertional dyspnoea, which might offer therapeutic targets for these patients.

Muscle metaboreflex activation increases ventilation and heart rate during dynamic exercise in humans.

NEW FINDINGS: What is the central question of this study? Classically, the stimulation of thin-fibre skeletal muscle afferents, via the application of postexercise circulatory occlusion (PECO) at rest, fails to generate ventilatory responses. We used a new experimental protocol to examine whether the involvement of these metabosensitive afferents in ventilatory control can only be revealed during exercise, when other potentially synergistic inputs that increase central respiratory drive are activated. What is the main finding and its importance? We found that PECO of one leg augmented the ventilatory and heart rate responses to single-legged exercise of the contralateral leg, suggesting that metaboreceptive muscle afferents contribute to the control of the exercise hyperpnoea. ABSTRACT: Inhibition of thin-fibre skeletal muscle afferent neurotransmission attenuates ventilatory and cardiovascular responses to exercise. However, stimulation of muscle metaboreceptive afferents at rest, via postexercise circulatory occlusion (PECO), classically fails to generate increases in ventilation or heart rate. It is possible that the involvement of muscle afferent feedback in ventilatory control can only be revealed during exercise, when other potentially synergistic inputs that increase central respiratory drive are activated. Therefore, we assessed the cardiorespiratory responses to single-legged cycling exercise with or without PECO of the contralateral leg. Thirteen healthy participants performed left-legged cycling exercise (40 or 60 W) followed by either: (i) no PECO (Con trial); or (ii) PECO (PECO trial) of the left leg for 3 min. During this 3 min period, right-legged cycling exercise was performed at the same workload as the preceding left-legged exercise (40 or 60 W). During 60 W right-legged cycling, ventilation relative to baseline was significantly higher in the PECO versus Con trial (22.9 ± 2 versus 18.7 ± 1.8 l min-1 ; P < 0.05), but there was no difference between the trials performed at 40 W. The change in heart rate was significantly greater during right-legged cycling in the PECO versus Con trial in the 40 (41.2 ± 4 versus 34.1 ± 3.1 beats min-1 ; P < 0.05) and 60 W trials (49.7 ± 2.7 versus 43.4 ± 3.7 beats min-1 ; P < 0.05). There were no differences in oxygen uptake, carbon dioxide production and ratings of perceived exertion between trials. These findings suggest that stimulation of muscle metaboreceptive afferents can drive increases in ventilation and heart rate during dynamic exercise.

Lidocaine injections and neck corset wearing improve dropped head syndrome in Parkinson's disease and related disorders.

BACKGROUND: Patients with Parkinson's disease and related disorders (PDRD) may exhibit dropped head syndrome (DHS), which does not yet have an effective treatment. OBJECTIVES: To evaluate the effect of combining lidocaine injection into the bilateral scalene muscles and neck corset wearing on dropped head syndrome. METHODS: We performed needle electromyography assessments of the scalene, sternocleidomastoid (SCM), levator scapulae, splenius capitis, and trapezius muscles. Patients received 2.5-5 ml injections of 1% lidocaine into both sides of the scalene muscles for 4/5 consecutive days and were instructed to wear a neck corset. We measured the neck flexion angle, which formed between the horizontal line and the straight line passing through the ear canal and orbital fossa, before (baseline) and after (Day 8 and Day 90) the intervention. RESULTS: Seven males and eight females (mean age, 68.9 years; range 56 to 85 years) who had PDRD with dropped head syndrome were enrolled in this study. Needle electromyography examination revealed abnormal discharge of the scalene muscles in all patients when the neck position was corrected; however, some patients did not show abnormal discharge of the SCM muscle. At Day 8, we observed an improvement of the neck flexion angle in 13 of the 15 patients, from an average of 27.7°â€¯±â€¯13.9° to 11.7 ±â€¯14.6°. At Day 90, the average neck flexion angle was 15.3°â€¯±â€¯17.2°. CONCLUSIONS: Combining lidocaine injection into the scalene muscles and neck corset wearing is an effective treatment regimen for DHS in patients with PDRD.

Compact Neural Interface Using a Single Multichannel Cuff Electrode for a Functional Neuromuscular Stimulation System.

Cuff electrodes have been introduced into functional neuromuscular stimulation systems to either obtain neural signals or elicit limb movements. Multiple electrodes must be implanted to construct a feedback control loop, including one electrode for acquisition and another for stimulation. Existing approaches require too much space inside the body and a complicated surgical procedure. This paper proposes a novel neural interface method that uses a single cuff electrode with multichannel capability to simultaneously acquire multichannel recordings and induce electrical stimulation at the proximal nerve trunk of the sciatic nerve. Recordings and stimulation are conducted in a time-shared manner using a path controller. Using the proposed method, joint positions are estimated from multichannel recorded neural signals during electrical stimulation as neural signals are continuously recorded. In addition, the proposed system is shown to be suitable for controlling joint position. The proposed neural interface method overcomes the spatial limitations of electrode implantation and thus offers a new approach to developing compact neural interface systems.

Role of TNF-α in Regulating the Exercise Pressor Reflex in Rats With Femoral Artery Occlusion.

Responses of sympathetic nerve activity and arterial blood pressure are augmented during activation of the exercise pressor reflex in rats with femoral artery occlusion. The present study examined the role played by proinflammatory tumor necrosis factor-α (TNF-α) in regulating augmented sympathetic responsiveness induced by stimulation of muscle metabolic receptors and static muscle contraction following 72 h of femoral artery occlusion. We first observed that the levels of TNF-α and protein expression of TNF-α receptor type 1 (TNFR1) were increased in the dorsal root ganglion (DRG) of hindlimbs with femoral artery occlusion. Note that TNF-α was observed within DRG neurons of C-fiber afferent nerves. Capsaicin (TRPV1 agonist) and AITC (TRPA1 agonist) were injected into arterial blood supply of the hindlimbs to stimulate metabolically sensitive thin-fiber muscle afferents. The effects of these injections on the sympathetic and pressor responses were further examined in control rats and rats with femoral artery occlusion. As TNF-α synthesis suppressor pentoxifylline (PTX) was previously administered into the hindlimb with femoral artery occlusion, sympathetic, and pressor responses induced by capsaicin and AITC were attenuated. In occluded rats, PTX also attenuated the exaggeration of blood pressure response induced by muscle contraction, but not by passive tendon stretch. Overall, the results suggest that TNF-α plays a role in modulating exaggerated sympathetic nervous activity via the metabolic component of the exercise pressor reflex when the hindlimb muscles are ischemic in peripheral arterial disease.