Reflex Responses Research Articles

Central Neuropathic Pain Development Modulation Using Coffee Extract Major Polyphenolic Compounds in Spinal-Cord-Injured Female Mice.

It was recently shown that coffee polyphenolic extract exerts preventive effects on central neuropathic pain development, but it is unknown whether its beneficial effects are associated with only one of its major polyphenolic compounds or if the whole extract is needed to exert such effects. The main objective of this study was to determine whether the separate administration of major polyphenols from coffee extract exerts preventive effects on the development of central neuropathic pain in mice compared with the effects of the whole coffee extract. Thus, spinal-cord-injured female ICR-CD1 mice were daily treated with either coffee extract or its major polyphenolic compounds during the first week, and reflexive and nonreflexive pain responses were evaluated within the acute phase of spinal cord injury. In addition, the injury-induced gliosis and dorsal horn sprouting were evaluated with immunohistochemistry. The results showed that the coffee extract prevented spinal cord injury-induced neuropathic pain, whereas its major polyphenolic compounds resulted in reflexive pain response attenuation. Both preventive and attenuation effects were associated with gliosis and afferent fiber sprouting modulation. Overall, the results suggested that coffee extract effects may be associated with potential synergistic mechanisms exerted by its major polyphenolic compounds and not by the sole effect of only one of them.

Quantitatively characterizing reflexive responses to pitch perturbations.

Reflexive pitch perturbation experiments are commonly used to investigate the neural mechanisms underlying vocal motor control. In these experiments, the fundamental frequency-the acoustic correlate of pitch-of a speech signal is shifted unexpectedly and played back to the speaker via headphones in near real-time. In response to the shift, speakers increase or decrease their fundamental frequency in the direction opposing the shift so that their perceived pitch is closer to what they intended. The goal of the current work is to develop a quantitative model of responses to reflexive perturbations that can be interpreted in terms of the physiological mechanisms underlying the response and that captures both group-mean data and individual subject responses. A model framework was established that allowed the specification of several models based on Proportional-Integral-Derivative and State-Space/Directions Into Velocities of Articulators (DIVA) model classes. The performance of 19 models was compared in fitting experimental data from two published studies. The models were evaluated in terms of their ability to capture both population-level responses and individual differences in sensorimotor control processes. A three-parameter DIVA model performed best when fitting group-mean data from both studies; this model is equivalent to a single-rate state-space model and a first-order low pass filter model. The same model also provided stable estimates of parameters across samples from individual subject data and performed among the best models to differentiate between subjects. The three parameters correspond to gains in the auditory feedback controller's response to a perceived error, the delay of this response, and the gain of the somatosensory feedback controller's "resistance" to this correction. Excellent fits were also obtained from a four-parameter model with an additional auditory velocity error term; this model was better able to capture multi-component reflexive responses seen in some individual subjects. Our results demonstrate the stereotyped nature of an individual's responses to pitch perturbations. Further, we identified a model that captures population responses to pitch perturbations and characterizes individual differences in a stable manner with parameters that relate to underlying motor control capabilities. Future work will evaluate the model in characterizing responses from individuals with communication disorders.

Respite. Quiet. A House of Dreams.

Respite. Quiet. A House of Dreams.

Sensory Perturbations from Hindlimb Cutaneous Afferents Generate Coordinated Functional Responses in All Four Limbs during Locomotion in Intact Cats.

Coordinating the four limbs is an important feature of terrestrial mammalian locomotion. When the foot dorsum contacts an obstacle, cutaneous mechanoreceptors send afferent signals to the spinal cord to elicit coordinated reflex responses in the four limbs to ensure dynamic balance and forward progression. To determine how the locomotor pattern of all four limbs changes in response to a sensory perturbation evoked by activating cutaneous afferents from one hindlimb, we electrically stimulated the superficial peroneal (SP) nerve with a relatively long train at four different phases (mid-stance, stance-to-swing transition, mid-swing, and swing-to-stance transition) of the hindlimb cycle in seven adult cats. The largest functional effects of the stimulation were found at mid-swing and at the stance-to-swing transition with several changes in the ipsilateral hindlimb, such as increased activity in muscles that flex the knee and hip joints, increased joint flexion and toe height, increased stride/step lengths and increased swing duration. We also observed several changes in support periods to shift support from the stimulated hindlimb to the other three limbs. The same stimulation applied at mid-stance and the swing-to-stance transition produced more subtle changes in the pattern. We observed no changes in stride and step lengths in the ipsilateral hindlimb with stimulation in these phases. We did observe some slightly greater flexions at the knee and ankle joints with stimulation at mid-stance and a reduction in double support periods and increase in triple support. Our results show that correcting or preventing stumbling involves functional contributions from all four limbs.

Effects of capture on acute and long-term reflex impairment, survival, and health of a deepwater fish: Shortspine thornyhead (Sebastolobus alaskanus).

Shortspine thornyhead (Sebastolobus alaskanus) are a benthic, deepwater species in the family Scorpaenidae. They have been tagged annually in Alaska since 1992, but have a low tag return rate of 1.6%. This may be at least partially attributed to post-release mortality related to capture. In this study, 21 shortspine thornyhead were caught on bottom hook-and-line longline gear and immediately given reflex tests. Eighteen were transported to the laboratory and held for 10–42 days, given reflex tests again, and then given postmortem examinations, including histopathology of tissues; three were given postmortem examinations after reflex tests on the vessel. There were no histological findings that could be directly linked to capture and holding; however, there were occurrences of myxozoan (protozoa) and metazoan (nematode) parasites, sometimes associated with minor inflammation. The vibration response reflex was found in only 24% of fish on deck and in 56% of fish after holding in the laboratory. The vestibular-ocular response was present in 47% of fish on deck and 89% of fish in the laboratory. A fish’s ability to right itself was successful on deck in 43% of fish (an additional 19% responded slowly) and 100% in the laboratory. Some reflex impairments may be permanent or may take more than days or weeks to improve. Reflex responses to other tests, the tail grab, gag, and operculum flare, were 95–100% successful on deck and later in the laboratory. A lack of reflexes may increase the risk of predation after release and may affect other behaviors related to survival and productivity.

Low-dose dopamine improves ventilatory efficiency during exercise in heart failure with preserved ejection fraction through inhibition of tonic activity of peripheral chemoreceptors

Abstract Introduction Peripheral chemoreceptors (PChRs) play an important role in adequate oxygenation by 1) maintaining baseline ventilation (tonic activity) and 2) providing hyperventilation in response to acute hypoxia (reflexia). It has been previously shown that in patients with heart failure with reduced ejection fraction hypertonicity and/or hyperreflexia of PChRs contribute to exercise intolerance (ExIn). It is unknown whether similar mechanisms are present in heart failure with preserved ejection fraction (HFpEF) and which component of PChR functionality has a decisive role in this matter. Purpose The aim of this study was to evaluate the role of PChRs in ExIn in patients with HFpEF. Methods All patients underwent assessment of PChRs which included measurements of: 1) tonic activity (TA, decrease in ventilation following pharmacological inhibition of PChRs), 2) reflex response (RR; an increase in ventilation in the response to acute hypoxia). The inhibition of PChRs was achieved with low-dose dopamine infusion (3 μg kg–1 min–1) and the acute hypoxia was produced with brief nitrogen gas administrations. Enrolled patients underwent symptom-limited cardiopulmonary exercise test using cycle ergometer from which peak oxygen consumption (peakVO2) and the slope relating ventilation to carbon dioxide (VE/VCO2 slope) were derived. All measurements (including PChRs' function tests and cardiopulmonary exercise test) were performed twice in a randomized, double-blinded and placebo-controlled manner (dopamine vs normal saline). Results We included 12 stable patients with HFpEF (age: 73±7 years, LVEF: 58±3%). During exercise the inhibition of PChRs with dopamine resulted in the improvement (decrease) in VE/VCO2 slope comparing to placebo (36±3.6 vs 34.3±3.7, p=0.04) but no change regarding peakVO2. There was a correlation between TA and relative magnitude of improvement in VE/VCO2 following PChRs inhibition (R=0.76, p=0.005). We also found a trend for correlation between RR and VE/VCO2 measured during placebo (R=0.56, p=0.059). There was no correlation between TA and RR (p=0.24). Conclusion Both TA and RR of PChRs are involved in ventilatory inefficacy during exercise in HFpEF – but in different ways. While augmented RR is likely an indicator of high VE/VCO2, the elevated TA indicates the magnitude of the improvement in exercise tolerance following PChRs deactivation. Thus, further interventions aimed at the modulation of PChRs should enroll patients based on TA rather than RR. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Science Centre, PRELUDIUM grant

Do I Need to Ask Permission? Applying Fair Use to Educational Activities.

Do I Need to Ask Permission? Applying Fair Use to Educational Activities.

Comparison of the efficiency of inhalation and injection anaesthesia for the castration of male suckling piglets in different organic farms

In Germany, injection and inhalation anesthesia with the addition of an analgesic drug are an interim solution to surgical castration under general anesthesia due to the ban on non-anesthetic castration of male suckling piglets under 8 days of age. However, the efficiency of both anesthetic procedures is submit to controversial discussion. Most of the studies addressing this question only examined one of the procedures in comparison to piglets castrated without anesthesia or uncastrated controls. Comparisons between the anesthesia methods, especially under conditions of organically working farms, are almost completely lacking. The aim of the present study was therefore to compare the efficacy of injection and inhalation anesthesia under practical conditions in 7 organic farms as well as to examine the effect of metamizole administered in addition to meloxicam. For this purpose, 514 male suckling piglets were examined with regard to anesthesia efficiency (reflex test, defence behaviour), body temperature, post-operative bleeding and wound healing, post-operative behavior and pain behavior as well as the course of the recovery phase. The results show a basic superiority of inhalation anesthesia over injection anesthesia, especially in the areas of anesthetic efficacy, thermoregulation and duration of the recovery phase. In 7.7 to 15 % of piglets, the perianal and interclaw reflexes studied were still present at the time of castration. Following injection and inhalation anesthesia, in total 83.6 (25.2 %) of the piglets showed at least one of the following criteria: positive reflex response, clear defensive movements or vocalisations. Body temperature dropped by 0.41 °C under inhalation anesthesia and by 1.82 °C under injection anesthesia. Post-castration bleeding and wound healing were hardly influenced by the type of anesthesia. Almost all piglets showed signs of pain and pain-associated behavior for 5 and 72 hours after castration, regardless of the type of anesthesia. The post-castration recovery phases lasted significantly longer after injection anesthesia (107 minutes) than following inhalation anesthesia (33.3 minutes) until the piglets were returned to the sow. Neither injection nor inhalation anesthesia in spite of additional administration of meloxicam, nor the supplementary use of metamizole, fulfil the EU requirements for painless castration. The necessary analgesia during and after castration of male suckling piglets is not achieved under either isoflurane or ketamine/azaperone anesthesia, despite the use of meloxicam and metamizole.

The influence of continuous prenatal exposure to valproic acid on physical, nociceptive, emotional and psychomotor responses during adolescence in mice: Dose-related effects within sexes.

Clinical findings show that the use of valproic acid (VPA) during pregnancy increases the risk of birth defects and autism spectrum disorder in offspring. Although there is a consensus that monitoring of potential long-term outcomes of VPA exposure is needed, especially in undiagnosed individuals, preclinical studies addressing this issue are rare. The present study examined the effects of continuous intrauterine exposure to a wide dose range of VPA (50, 100, 200, and 400 mg/kg/day) on the physical and behavioral response in peripubertal mice as a rodent model of adolescence. Body weight and the hot plate test [on postnatal days (PND) 25 and 32], the elevated plus-maze test (on PND35), and the open field test (on PND40) served to examine physical growth, the supraspinal reflex response to a painful thermal stimulus and conditional learning, anxiety-like/risk-assessment behavior, as well as novelty-induced psychomotor activity, respectively. VPA exposure produced the following responses: (i) a negative effect on body weight, except for the dose of 100 mg/kg/day in both sexes; (ii) an increase in the percentage of animals that responded to the thermal stimulus above the defined cut-off time interval and the response latency in both sexes; (iii) dose-specific changes within sexes in behavior provoked by a novel anxiogenic environment, i.e., in females less anxiety-like/risk-assessment behavior in response to the lowest exposure dose, and in males more pronounced anxiety-like/risk-assessment behavior after exposure to the highest dose and 100 mg/kg/day; (iv) dose-specific changes within sexes in novelty-induced psychomotor activity, i.e., in females a decrease in stereotypy-like activity along with an increase in rearing, and in males a decrease in stereotypy-like activity only. These findings show that continuous intrauterine exposure to VPA produces maladaptive functioning in different behavioral domains in adolescence and that the consequences are delicate to assess as they are dose-related within sexes.

Prognostic factors for trigeminocardiac reflex during cerebrovascular intervention operation.

IntroductionTrigeminocardiac reflex (TCR) is a brainstem reflexive response of hemodynamic instability during surgery. Identification of risk factors relevant to TCR during cerebrovascular intervention procedures is helpful to efficiently prevent and treat its occurrence. The purpose of this study was to demonstrate the risk factors for Onyx embolization during cerebrovascular intervention operation so as to optimize perioperative management strategies on TCR.MethodsWe performed a retrospective study on the patients with Onyx embolization under general anaesthesia over 6-years period from 2013 to 2018. 354 patients were finally eligible for inclusion, and then divided into TCR group (group T) and control group (group N). Patient characteristics, clinical diagnosis, comorbidities, lesion sites, hemodynamics changes, and complications were compared between two groups. Several multivariable regression models were applied to analyze the risk factors associated with TCR.ResultsTCR occurred in 59 patients (16.7%) among 354 patients. There was no significant difference in patient characteristics between two groups (P > 0.05). During DMSO/Onyx injection, HR and MAP were much lower in group T than group N (P < 0.01). Notably, univariable analysis revealed that the patients with dural arteriovenous fistula (DAVF) and middle meningeal artery being affected were associated with a higher incidence of TCR (P < 0.01). Furthermore, multivariable analysis showed that there was a close link of TCR with DAVF [OR = 4.12; 95% CI (1.83–10.65)] and middle meningeal artery embolization [OR = 3.90; 95% CI (1.58–9.63)]. Further stratified analysis of patients with TCR found that patients with middle meningeal artery embolization were more likely to experience hypotension during TCR episode (P < 0.05). Finally, more incidence of postoperative adverse events was observed when TCR episode (P < 0.05).ConclusionWe found that DAVF and middle meningeal artery embolization were independent risk factors for TCR episodes during Onyx endovascular embolization, highly likely leading to intraoperative hemodynamics fluctuations and postoperative adverse events.

Pain and masochistic behaviour: The role of descending modulation.

The mechanisms of pain perception in individuals with masochistic behaviour (MB) remain poorly documented. We hypothesized that MB is associated with context-specific changes in descending pain modulation. We compared the effects of four standardized sets of images with positive (erotic), negative (mutilations), masochistic or neutral emotional valences on the RIII nociceptive reflex evoked by electrical stimulation of the sural nerve and recorded on the ipsilateral biceps femoris in 15 controls and 15 men routinely engaging in MB. We systematically assessed the RIII reflex threshold and recruitment curves (up to the tolerance threshold), thermal (heat and cold) pain thresholds measured on the upper and lower limbs and responses to the pain sensitivity questionnaire, to compare basal pain perception between our two groups of participants. We also assessed anxiety, depression, empathy, alexithymia, high sensation seeking and catastrophizing, to investigate their potential influence on the emotional modulation of pain. Thermal pain thresholds, RIII reflex recruitment curves, and responses to the psychological and pain sensitivity questionnaires were similar in the two groups. Neutral, positive and negative images modulated the RIII reflex similarly in the two groups. By contrast, masochistic images induced a significant (p&lt; 0.01) decrease in RIII reflex responses in subjects with MB, whereas it tended to increase these responses in control subjects. Our data suggest that psychological profile, basal pain sensitivity and the emotional modulation of pain are normal in individuals with MB but that these subjects selectively engage descending pain inhibition in the masochistic context. Decrease pain perception related to masochistic behaviours is associated with specific activation of descending pain inhibition.

Divergent splanchnic sympathetic efferent nerve pathways regulate interleukin-10 and tumour necrosis factor-α responses to endotoxaemia.

The efferent branches of the splanchnic sympathetic nerves that enhance interleukin-10 (IL-10) and suppress tumour necrosis factor-α (TNF) levels in the reflex response to systemic immune challenge were investigated in anaesthetized, ventilated rats. Plasma levels of TNF and IL-10 were measured 90min after intravenous lipopolysaccharide (LPS, 60µg/kg). Splanchnic nerve section, ganglionic blockade with pentolinium tartrate or β2 adrenoreceptor antagonism with ICI 118551 all blocked IL-10 responses. Restoring plasma adrenaline after splanchnic denervation rescued IL-10 responses. TNF responses were disinhibited by splanchnic denervation or pentolinium treatment, but not by ICI 118551. Splanchnic nerve branches were cut individually or in combination in vagotomized rats, ruling out any vagal influence on results. Distal splanchnic denervation, sparing the adrenal nerves, disinhibited TNF but did not reduce IL-10 responses. Selective adrenal denervation depressed IL-10 but did not disinhibit TNF responses. Selective denervation of either spleen or liver did not affect IL-10 or TNF responses, but combined splenic and adrenal denervation did so. Finally, combined section of the cervical and lumbar sympathetic nerves did not affect cytokine responses to LPS. Together, these results show that the endogenous anti-inflammatory reflex is mediated by sympathetic efferent fibres that run in the splanchnic, but not other sympathetic nerves, nor the vagus. Within the splanchnic nerves, divergent pathways control these two cytokine responses: neurally driven adrenaline, acting via β2 adrenoreceptors, regulates IL-10, while TNF is restrained by sympathetic nerves to abdominal organs including the spleen, where non-β2 adrenoreceptor mechanisms are dominant. KEY POINTS: An endogenous neural reflex, mediated by the splanchnic, but not other sympathetic nerves, moderates the cytokine response to systemic inflammatory challenge. This reflex suppresses the pro-inflammatory cytokine tumour necrosis factor-α (TNF), while enhancing levels of the anti-inflammatory cytokine interleukin-10 (IL-10). The reflex enhancement of IL-10 depends on the splanchnic nerve supply to the adrenal gland and on β2 adrenoreceptors, consistent with mediation by circulating adrenaline. After splanchnic nerve section it can be rescued by restoring circulating adrenaline. The reflex suppression of TNF depends on splanchnic nerve branches that innervate abdominal tissues including, but not restricted to, spleen: it is not blocked by adrenal denervation or β2 adrenoreceptor antagonism. Distinct sympathetic efferent pathways are thus responsible for pro- and anti-inflammatory cytokine components of the reflex regulating inflammation.

The Double Insult of Neonatal Cystitis Plus Adult Somatic Inflammation Results in Corticotropin Releasing Factor Type II Receptor-Dependent Bladder Hypersensitivity in Female Rats

The spinal mechanisms of visceral hypersensitivity are poorly understood, particularly when there is an interaction with somatic systems. Recently we demonstrated that rats which were pretreated with neonatal bladder inflammation (NBI) and subsequently pretreated as adults with bladder re-inflammation had augmented reflex and neuronal responses to urinary bladder distension via a corticotropin-releasing factor receptor type II (CRFR2) mechanism. Another insult producing similar augmented responses is somatic inflammation induced by Complete Freund's Adjuvant (CFA) in the hindlimb. Using neurochemical measures and both reflex and neuronal responses to urinary bladder distension as endpoints, the present study probed the role of CRFR2-related mechanisms in bladder hyperalgesia secondary to NBI and CFA-induced hindlimb inflammation. ELISA measures of the lumbosacral spinal cord demonstrated increased CRFR2 protein following pretreatment with NBI+CFA. Intrathecal CRFR2 antagonists blocked the augmentation of visceromotor responses to distension following pretreatment with both NBI+CFA. Lumbosacral dorsal horn neuronal responses to bladder distension in rats pretreated with NBI+CFA were attenuated by the spinal topical administration of a CRFR2 antagonist. These findings are the first demonstration of a somatovisceral interaction working via CRFR2 receptors and support the therapeutic value of these agents in the treatment of painful bladder disorders, particularly when triggered by somatic events. (Word Count 199). PerspectiveBladder hypersensitivity occurs following neonatal cystitis and an adult insult such as somatic inflammation. This paper demonstrates that CRFR2-related mechanisms are associated with this hypersensitivity. This supports the therapeutic value of these agents in the treatment of painful bladder disorders, particularly when triggered by somatic events.

Effect of medetomidine, midazolam, ketamine, propofol and isoflurane on spinal reflexes in healthy dogs.

Sometimes it is necessary to use sedatives or even general anaesthetics to examine animals with spinal cord injuries. These drugs may affect spinal reflexes, alter the outcome of neurological examinations, and make it difficult to diagnose location of the lesion. The aim of this study was to evaluate the effects of five pre-anaesthetic and anaesthetic agents commonly used in clinics on spinal reflexes in dogs. Ten native adult dogs were participated in three groups. In all groups, the dogs were premedicated with medetomidine and midazolam; then, in the first group, ketamine, in the second group, propofol and in the third group, isoflurane were used for induction of anaesthesia. The spinal reflexes were evaluated before injection, 15 min after medetomidine, 20 min after midazolam, and at 15, 30, 45 and 60 min after induction of anaesthesia. Medetomidine did not reduce monosynaptic reflexes (patellar and cranial tibial reflexes) but increased them while it had no effect on the polysynaptic limb withdrawal reflexes. Midazolam had no effect on the spinal reflexes; Ketamine did not affect the patellar, cranial tibial and extensor carpi radialis reflexes, but reduced polysynaptic pain-related reflexes; and propofol and isoflurane abolished the all spinal reflexes. Medetomidine, midazolam and ketamine have no effect on reducing monosynaptic reflexes (patellar and cranial tibial reflexes) and may be used for neurological examination of restless animals in the clinic. Propofol and isoflurane eliminated all spinal reflex responses and are not suitable for neurological examinations.

Differences in central sensitisation between healthy men and women in Switzerland: a single-centre trial

<h2>Abstract</h2><h3>Background</h3> Many chronic pain conditions exhibit differences between men and women regarding prevalence, pain intensity, or treatment effects. Mechanisms underlying these differences are poorly understood. Central sensitisation, defined as an increased responsiveness of nociceptive neurons in the CNS to normal or subthreshold afferent input, is considered an important mechanism that can differ between men and women with chronic pain conditions. We aimed to assess differences in central sensitisation between healthy men and women, with the hypothesis that central sensitisation is more pronounced in healthy women than in men. <h3>Methods</h3> This single-centre trial followed a within-subject design and was conducted at the Balgrist University Hospital in Switzerland after approval by the Cantonal Ethics Board of Zurich. Healthy, pain-free adults aged 18–40 years with a BMI of less than 30 kg/m² and no history of chronic pain were recruited using advertisement and word-of-mouth. Biological sex (male or female) was self-reported. A validated sensitisation protocol was used by applying a contact thermode to the innervation area of the sural nerve on one foot. A sham protocol was used on the other foot. The protocols were performed in counterbalanced order. All participants were masked to the study design and protocols. The primary endpoint before and after the protocols, was the area of secondary hyperalgesia relative to the thermode, serving as a proxy of central sensitisation. Additionally, the nociceptive withdrawal reflex was repeatedly elicited at the sural nerve with two currents (corresponding to 120% and 140% of the individual reflex threshold current) and recorded from the biceps femoris by surface electromyography. The magnitude of the reflex response in the 90 ms to 150 ms post-elicitation interval was compared before and after the protocols. This study was registered with ClinicalTrials.gov, NCT05031286. <h3>Findings</h3> Between April 22, 2021, and Feb 19, 2022, 66 healthy participants were included in the trial. The median age of participants was 26 years (IQR 21–31) and 33 (50%) were women. Following the sensitisation protocol, secondary hyperalgesia was greater in women than men (12·4 cm² [SD 8·41] <i>vs</i> 8·2 cm² [6·90]; two-sided <i>t</i> test p=0·031). The effect of the sensitisation protocol on the magnitude of the biceps femoris nociceptive withdrawal reflex was stronger in women than in men for both currents (Cohen's d 0·32 <i>vs</i> 0·07 for 120% and 0·31 <i>vs</i> 0·15 for 140% reflex threshold current) with 99·6% versus 95·6% probability (Bayesian normal–normal model). No adverse effects were recorded during the trial. <h3>Interpretation</h3> The two tested outcomes (extent of secondary hyperalgesia and magnitude of the nociceptive withdrawal reflex) indicate that central sensitisation processes are more pronounced in healthy women than men. Because central sensitisation is suggested to influence pain chronification, more pronounced central sensitisation processes might constitute a sex-specific risk factor for developing chronic pain. <h3>Funding</h3> The Swiss National Science Foundation.

Inhibition of peripheral chemoreceptors improves ventilatory efficiency during exercise in heart failure with preserved ejection fraction − a role of tonic activity and acute reflex response

Peripheral chemoreceptors (PChRs) play a significant role in maintaining adequate oxygenation in the bloodstream. PChRs functionality comprises two components: tonic activity (PChT) which regulates ventilation during normoxia and acute reflex response (peripheral chemosensitivity, PChS), which increases ventilation following a specific stimulus. There is a clear link between augmented PChS and exercise intolerance in patients with heart failure with reduced ejection fraction. It has been also shown that inhibition of PChRs leads to the improvement in exercise capacity. However, it has not been established yet: 1) whether similar mechanisms take part in heart failure with preserved ejection fraction (HFpEF) and 2) which component of PChRs functionality (PChT vs. PChS) is responsible for the benefit seen after the acute experimental blockade. To answer those questions we enrolled 12 stable patients with HFpEF. All participants underwent an assessment of PChT (attenuation of minute ventilation in response to low-dose dopamine infusion), PChS (enhancement of minute ventilation in response to hypoxia) and a symptom-limited cardiopulmonary exercise test on cycle ergometer. All tests were placebo-controlled, double-blinded and performed in a randomized order. Under resting conditions and at normoxia dopamine attenuated minute ventilation and systemic vascular resistance (p = 0.03 for both). These changes were not seen with placebo. Dopamine also decreased ventilatory and mean arterial pressure responses to hypoxia (p < 0.05 for both). Inhibition of PChRs led to a decrease in V˙E/V˙CO2 comparing to placebo (36 ± 3.6 vs. 34.3 ± 3.7, p = 0.04), with no effect on peak oxygen consumption. We found a significant relationship between PChT and the relative decrement of V˙E/V˙CO2 on dopamine comparing to placebo (R = 0.76, p = 0.005). There was a trend for correlation between PChS (on placebo) and V˙E/V˙CO2 during placebo infusion (R = 0.56, p = 0.059), but the relative improvement in V˙E/V˙CO2 was not related to the change in PChS (dopamine vs. placebo). We did not find a significant relationship between PChT and PChS. In conclusion, inhibition of PChRs in HFpEF population improves ventilatory efficiency during exercise. Increased PChS is associated with worse (higher) V˙E/V˙CO2, whereas PChT predicts an improvement in V˙E/V˙CO2 after PChRs inhibition. This results may be meaningful for patient selection in further clinical trials involving PChRs modulation.

The Evoked Potential Operant Conditioning System (EPOCS): A Research Tool and an Emerging Therapy for Chronic Neuromuscular Disorders.

The Evoked Potential Operant Conditioning System (EPOCS) is a software tool that implements protocols for operantly conditioning stimulus-triggered muscle responses in people with neuromuscular disorders, which in turn can improve sensorimotor function when applied appropriately. EPOCS monitors the state of specific target muscles-e.g., from surface electromyography (EMG) while standing, or from gait cycle measurements while walking on a treadmill-and automatically triggers calibrated stimulation when pre-defined conditions are met. It provides two forms of feedback that enable a person to learn to modulate the targeted pathway's excitability. First, it continuously monitors ongoing EMG activity in the target muscle, guiding the person to produce a consistent level of activity suitable for conditioning. Second, it provides immediate feedback of the response size following each stimulation and indicates whether it has reached the target value. To illustrate its use, this article describes a protocol through which a person can learn to decrease the size of the Hoffmann reflex-the electrically-elicited analog of the spinal stretch reflex-in the soleus muscle. Down-conditioning this pathway's excitability can improve walking in people with spastic gait due to incomplete spinal cord injury. The article demonstrates how to set up the equipment; how to place stimulating and recording electrodes; and how to use the free software to optimize electrode placement, measure the recruitment curve of direct motor and reflex responses, measure the response without operant conditioning, condition the reflex, and analyze the resulting data. It illustrates how the reflex changes over multiple sessions and how walking improves. It also discusses how the system can be applied to other kinds of evoked responses and to other kinds of stimulation, e.g., motor evoked potentials to transcranial magnetic stimulation; how it can address various clinical problems; and how it can support research studies of sensorimotor function in health and disease.

Semantic focus mediates pitch auditory feedback control in phrasal prosody

ABSTRACT This study investigated the effect of semantic focus on pitch auditory feedback control in the production of phrasal prosody through an experiment using pitch-shifted auditory feedback. We hypothesized that pitch-shift responses would be mediated by semantic focus because highly informative focus types, such as corrective focus, impose more specific constraints on the prosodic form of a phrase and require greater consistency in the production of pitch excursions compared to sentences with no such focus elements. Twenty-eight participants produced sentences with and without corrective focus while their auditory feedback was briefly and unexpectedly perturbed in pitch by +/−200 cents at the start of the sentence. The magnitude and latency of the reflexive pitch-shift responses were measured as a reflection of auditory feedback control. Our results matched our prediction that corrective focus would elicit larger pitch-shift responses, supporting our hypothesis that auditory feedback control is mediated by semantic focus.

Sympathetic activation in heart failure.

Sympathetic activation has been long appreciated exclusively as a fundamental compensatory mechanism of the failing heart and, thus, welcome and to be supported. In the initial clinical phases of heart failure (HF), the sympathetic nervous system overdrive plays a compensatory function aimed at maintaining an adequate cardiac output despite the inotropic dysfunction affecting the myocardium. However, when the sympathetic reflex response is exaggerated it triggers a sequence of unfavourable remodelling processes causing a further contractile deterioration that unleashes major adverse cardiovascular consequences, favouring the HF progression and the occurrence of fatal events. Eventually, the sympathetic nervous system in HF was demonstrated to be a ‘lethality factor’ and thus became a prominent therapeutic target. The existence of an effective highly specialized intracardiac neuronal network immediately rules out the old concept that sympathetic activation in HF is merely the consequence of a drop in cardiac output. When a cardiac damage occurs, such as myocardial ischaemia or a primary myocardial disorder, the adaptive capability of the system may be overcame, leading to excessive sympatho-excitation coupled with attenuation till to abolishment of central parasympathetic drive. Myocardial infarction causes, within a very short time, both a functional and anatomical remodelling with a diffuse up-regulation of nerve growth factor (NGF). The subsequent nerve sprouting signal, facilitated by a rise in the levels of NGF in the left stellate ganglion and in the serum, triggers an increase in cardiac nerve density in both peri-infarct and non-infarcted areas. Finally, NFG production decreases over time, supposedly as an adaptative response to the prolonged exposure to sympathetic overactivity, leading in the end to a reduction in sympathetic nerve density. Accordingly, NGF levels were markedly reduced in patients with severe congestive heart failure. The kidney is the other key player of the sympathetic response to HF as it indeed reacts to under-perfusion and to loop diuretics to preserve filtration at the cost of many pathological consequences on its physiology. This vicious loop ultimately participates to the chronic and disruptive sympathetic overdrive.In conclusion, sympathetic activation is the natural physiological consequence to life stressors but also to any condition that may harm our body. It is the first system of reaction to any potential life-threatening event. However, in any aspect of life over reaction is never effective but, in many instances, is, actually, life threatening. One for all is the case of ischaemia-related ventricular fibrillation which is, strongly facilitated by sympathetic hyperactivity. The take home message? When, in a condition of harm, everybody is yelling failure is just around the corner.

Electrophysiological and kinesiological analysis of deep tendon reflex responses, importance of angular velocity.

Deep tendon reflexes are one of the main parameters of the neurological examination in many diseases. Reflex responses increase in upper motor neuron diseases due to a lack of suprasegmental control such as spasticity and rigidity. This information provided by the reflex response makes it an indispensable element of neurological examination. However, an important limitation is that this assessment is subjective. In this study, EMG and kinesiology measurements were recorded together during the assessment of the patellar T reflex in healthy control, spasticity, and Parkinson's disease groups. Nine kinesiologic and three electrophysiologic features were extracted. We validated the proposed method with three healthy participants by ten repeated measurements on 6 different days and we observed that angular velocity is the most stable parameter. Clustering of different groups determined with K-clustering and artificial neural network used for classification with kinesiological and EMG inputs. Our findings show that reflex grade can be determined with high accuracy (Acc = 98.6) in a large population for both pathological and healthy groups and angular velocity is sufficient for reflex grading. Therefore, we think that our study will contribute to the literature by providing an approach with high reliability and reproducibility in the quantitative assessment of reflexes.