Showing papers on "Reflex published in 2007"

Adaptive Dynamic Walking of a Quadruped Robot on Natural Ground Based on Biological Concepts

Abstract: The paper reports on a project to make a quadruped robot walk with medium forward speed on irregular terrain in an outdoor environment using a neural system model The necessary conditions for stable dynamic walking on irregular terrain in general are proposed, and the neural system is designed by comparing biological concepts with those necessary conditions described in physical terms A PD-controller is used at joints to construct a virtual spring—damper system as the visco-elasticity model of a muscle The neural system model consists of a CPG (central pattern generator), responses and reflexes A response directly and quickly modulates the CPG phase, and a reflex directly generates joint torque The state of the virtual spring—damper system is switched, based on the CPG phase In order to make a self-contained quadruped (called Tekken2) walk on natural ground, several new reflexes and responses are developed in addition to those developed in previous studies A flexor reflex prevents a leg from stumbling on small bumps and pebbles A sideways stepping reflex stabilizes rolling motion on a sideways inclined slope A corrective stepping reflex/response prevents the robot from falling down in the case of loss of ground contact A crossed flexor reflex helps a swinging leg keep enough clearance between the toe and the ground The effectiveness of the proposed neural system model control and especially the newly developed reflexes and responses are validated by indoor and outdoor experiments using Tekken2 A CPG receives sensory feedback as a result of motions induced by reflexes, and changes the period of its own active phase Since a CPG has the ability of mutual entrainment with pitching motion of legs and rolling motion of the body in addition, the consistency between motion of a leg temporally modified by a reflex and motions of the other legs is maintained autonomously It is shown that CPGs can be the center of sensorimotor coordination, and that the neural system model simply defining the relationships between CPGs, sensory input, reflexes and mechanical system works very well even in complicated tasks such as adaptive dynamic walking on unstructured natural ground

The spinal pathophysiology of spasticity--from a basic science point of view.

Abstract: Spasticity is a term, which was introduced to describe the velocity-sensitive increased resistance of a limb to manipulation in subjects with lesions of descending motor pathways. This distinguishes spasticity from the changes in passive muscle properties, which are often seen in these patients, but are not velocity-sensitive. Increased excitability of the stretch reflex is thus a central component of the definition of spasticity. This review describes changes in cellular properties and transmission in a number of spinal reflex pathways, which may explain the increased stretch reflex excitability. The review focuses mainly on results derived from the use of non-invasive electrophysiological techniques, which have been developed during the past 20-30 years to investigate spinal neuronal networks in human subjects, but work from animal models is also considered. The reflex hyperexcitability develops over several months following the primary lesion and involves adaptation in the spinal neuronal circuitries caudal to the lesion. In animal models, changes in cellular properties (such as 'plateau potentials') have been reported, but the relevance of these changes to human spasticity has not been clarified. In humans, numerous studies have suggested that reduction of spinal inhibitory mechanisms (in particular that of disynaptic reciprocal inhibition) is involved. The inter-subject variability of these mechanisms and the lack of objective quantitative measures of spasticity have impeded disclosure of a clear causal relationship between the alterations in the inhibitory mechanisms and the stretch reflex hyperexcitability. Techniques which make such a quantitative measure possible as well as longitudinal studies where development of reflex excitability and changes in the inhibitory mechanisms are followed over time are in great demand.

Heart Rate Variability: Stress and Psychiatric Conditions

Abstract: levels of central control. Although Walter Cannon clearly articulated the impact of emotion and other psychological processes on autonomic states (Cannon 1928), he viewed the autonomic nervous system largely as a homeostatic regulatory mechanism (Cannon 1929). Recent research, however, has revealed a re-representation and layering of autonomic functions from the spinal cord to rostral brain networks sufficiently similar reminiscent of those for somatomotor control that they suggest a common evolutionary heritage. Homeostatic functions of the autonomic nervous system are illustrated by the baroreceptor-heart rate reflex, through which a perturbation in blood pressure triggers a tightly coupled, reciprocal change in the activities of the autonomic branches. Postural hypotension, for example, results in a reflexive decrease in parasympathetic control of the heart, together with a reciprocal withdrawal of sympathetic cardiac control, which synergistically increase heart rate (and contractility). Together with vascular components, these changes serve to compensate for the hypotensive perturbation and normalize blood pressure (e.g. Cacioppo et al. 1994). Baroreceptor reflexes are prototypic homeostatic mechanisms, and are organized largely within lower central autonomic substrates at brainstem levels. Through evolutionary development of rostral brain systems, however, these lower autonomic circuits become integrated with higher neural networks (Berntson & Cacioppo 2000). Limbic and forebrain areas implicated in behavioural processes, including the hypothalamus, amygdala and medial prefrontal cortex, have been shown to issue monosynaptic projections to brainstem reflex networks as well as to autonomic source Introduction

Reduced Sodium Current in Purkinje Neurons from NaV1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

Abstract: Loss-of-function mutations of Na(V)1.1 channels cause severe myoclonic epilepsy in infancy (SMEI), which is accompanied by severe ataxia that contributes substantially to functional impairment and premature deaths. Mutant mice lacking Na(V)1.1 channels provide a genetic model for SMEI, exhibiting severe seizures and premature death on postnatal day 15. Behavioral assessment indicated severe motor deficits in mutant mice, including irregularity of stride length during locomotion, impaired motor reflexes in grasping, and mild tremor in limbs when immobile, consistent with cerebellar dysfunction. Immunohistochemical studies showed that Na(V)1.1 and Na(V)1.6 channels are the primary sodium channel isoforms expressed in cerebellar Purkinje neurons. The amplitudes of whole-cell peak, persistent, and resurgent sodium currents in Purkinje neurons were reduced by 58-69%, without detectable changes in the kinetics or voltage dependence of channel activation or inactivation. Nonlinear loss of sodium current in Purkinje neurons from heterozygous and homozygous mutant animals suggested partial compensatory upregulation of Na(V)1.6 channel activity. Current-clamp recordings revealed that the firing rates of Purkinje neurons from mutant mice were substantially reduced, with no effect on threshold for action potential generation. Our results show that Na(V)1.1 channels play a crucial role in the excitability of cerebellar Purkinje neurons, with major contributions to peak, persistent, and resurgent forms of sodium current and to sustained action potential firing. Loss of these channels in Purkinje neurons of mutant mice and SMEI patients may be sufficient to cause their ataxia and related functional deficits.

Adaptations in the activation of human skeletal muscle induced by short-term isometric resistance training.

Abstract: This study employed longitudinal measures of evoked spinal reflex responses (Hoffman reflex, V wave) to investigate changes in the activation of muscle and to determine if there are “linked” neural...

Cardiovascular responses produced by 5-hydroxytriptamine:a pharmacological update on the receptors/mechanisms involved and therapeutic implications.

Abstract: The complexity of cardiovascular responses produced by 5-hydroxytryptamine (5-HT, serotonin), including bradycardia or tachycardia, hypotension or hypertension, and vasodilatation or vasoconstriction, has been explained by the capability of this monoamine to interact with different receptors in the central nervous system (CNS), on the autonomic ganglia and postganglionic nerve endings, on vascular smooth muscle and endothelium, and on the cardiac tissue. Depending, among other factors, on the species, the vascular bed under study, and the experimental conditions, these responses are mainly mediated by 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-ht5A/5B, and 5-HT7 receptors as well as by a tyramine-like action or unidentified mechanisms. It is noteworthy that 5-HT6 receptors do not seem to be involved in the cardiovascular responses to 5-HT. Regarding heart rate, intravenous (i.v.) administration of 5-HT usually lowers this variable by eliciting a von Bezold-Jarisch-like reflex via 5-HT3 receptors located on sensory vagal nerve endings in the heart. Other bradycardic mechanisms include cardiac sympatho-inhibition by prejunctional 5-HT1B/1D receptors and, in the case of the rat, an additional 5-ht5A/5B receptor component. Moreover, i.v. 5-HT can increase heart rate in different species (after vagotomy) by a variety of mechanisms/receptors including activation of: (1) myocardial 5-HT2A (rat), 5-HT3 (dog), 5-HT4 (pig, human), and 5-HT7 (cat) receptors; (2) adrenomedullary 5-HT2 (dog) and prejunctional sympatho-excitatory 5-HT3 (rabbit) receptors associated with a release of catecholamines; (3) a tyramine-like action mechanism (guinea pig); and (4) unidentified mechanisms (certain lamellibranch and gastropod species). Furthermore, central administration of 5-HT can cause, in general, bradycardia and/or tachycardia mediated by activation of, respectively, 5-HT1A and 5-HT2 receptors. On the other hand, the blood pressure response to i.v. administration of 5-HT is usually triphasic and consists of an initial short-lasting vasodepressor response due to a reflex bradycardia (mediated by 5-HT3 receptors located on vagal afferents, via the von Bezold-Jarisch-like reflex), a middle vasopressor phase, and a late, longer-lasting, vasodepressor response. The vasopressor response is a consequence of vasoconstriction mainly mediated by 5-HT2A receptors; however, vasoconstriction in the canine saphenous vein and external carotid bed as well as in the porcine cephalic arteries and arteriovenous anastomoses is due to activation of 5-HT1B receptors. The late vasodepressor response may involve three different mechanisms: (1) direct vasorelaxation by activation of 5-HT7 receptors located on vascular smooth muscle; (2) inhibition of the vasopressor sympathetic outflow by sympatho-inhibitory 5-HT1A/1B/1D receptors; and (3) release of endothelium-derived relaxing factor (nitric oxide) by 5-HT2B and/or 5-HT1B/1D receptors. Furthermore, central administration of 5-HT can cause both hypotension (mainly mediated by 5-HT1A receptors) and hypertension (mainly mediated by 5-HT2 receptors). The increasing availability of new compounds with high affinity and selectivity for the different 5-HT receptor subtypes makes it possible to develop drugs with potential therapeutic usefulness in the treatment of some cardiovascular illnesses including hypertension, migraine, some peripheral vascular diseases, and heart failure.

Electrical stimulation as a modality to improve performance of the neuromuscular system.

Abstract: Transcutaneous neuromuscular electrical stimulation (NMES) can modify the order of motor unit recruitment and has a profound influence on the metabolic demand associated with producing a given muscle force. Because of these differences, interventions that combine NMES with voluntary contractions can provide beneficial outcomes for some individuals. The adaptations evoked by NMES are not confined to the activated muscle but also involve neural adaptations through reflex inputs to the spinal cord and supraspinal centers.

Age-related hearing loss in C57BL/6J mice has both frequency-specific and non-frequency-specific components that produce a hyperacusis-like exaggeration of the acoustic startle reflex.

Abstract: Auditory brainstem-evoked response (ABR) thresholds were obtained in a longitudinal study of C57BL/6J mice between 10 and 53 weeks old, with repeated testing every 2 weeks. On alternate weeks, acoustic startle reflex (ASR) amplitudes were measured, elicited by tone pips with stimulus frequencies of 3, 6, 12, and 24 kHz, and intensities from subthreshold up to 110 dB sound pressure level. The increase in ABR thresholds for 3 and 6 kHz test stimuli followed a linear time course with increasing age from 10 to 53 weeks, with a slope of about 0.7 dB/week, and for 48 kHz a second linear time course, but beginning at 10 weeks with a slope of about 2.3 dB/week. ABR thresholds for 12, 24, and 32 kHz increased after one linear segment with a 0.7 dB slope, then after a variable delay related to the test frequency, shifted to a second segment having slopes of 3–5 dB/week. Hearing loss initially reduced the ASR for all eliciting stimuli, but at about 6 months of age, the response elicited by intense 3 and 6 kHz stimuli began to increase to reach values about three times above normal, and previously subthreshold stimuli came to elicit vigorous responses seen at first only for the intense stimuli. This hyperacusis-like effect appeared in all mice but was especially pronounced in mice with more serious hearing loss. These ABR data, together with a review of histopathological data in the C57BL/6 literature, suggest that the non-frequency-specific slow time course of hearing loss results from pathology in the lateral wall of the cochlea, whereas the stimulus-specific hearing loss with a rapid time course results from hair cell loss. Delayed exaggeration of the ASR with hearing loss reveals a deficit in centrifugal inhibitory control over the afferent reflex pathways after central neural reorganization, suggesting that this mouse may provide a useful model of age-related tinnitus and associated hyperacusis.

Spinal control of locomotion--from cat to man.

Abstract: For a large number of vertebrate species it is now indisputable that spinal networks have the capability of generating the basic locomotor rhythm. The aim of this review is to summarize the evidence for spinal pattern generators in cats and primates, including man and its interaction with sensory signals from the limbs. For all species the sensory feed-back from the moving limb is very important to achieve effective locomotor behaviour by adapting to the environment and compensating for unexpected postural disturbances. Sensory regulation of stepping can occur via reflex pathways to motoneurones (by-passing the locomotor rhythm generators) or by acting on the spinal locomotor networks themselves. The sensory feed-back serves to control the timing of the different phases in the step cycle, to shape the pattern of muscle activity, to contribute to the excitatory drive of the motoneurones and to the long-term adaptation of the locomotor activity. In this review we discuss the spinal locomotor circuits and the sensory feed-back in animals (mainly the cat) and human subjects. Special emphasis is given to work that has been of importance for the development of new rehabilitation paradigms following spinal cord injury.

Arterial chemoreceptors and sympathetic nerve activity: implications for hypertension and heart failure.

Abstract: Chronic elevation in sympathetic nerve activity (SNA) is associated with the development and maintenance of certain types of hypertension1 and contributes to the progression of chronic heart failure (CHF).2 The mechanisms involved in sympathetic dysfunction in these disorders appear to be complex and multifactorial. A unified hypothesis is likely to encompass alterations in multiple autonomic reflex pathways, central integratory sites, and chemical mediators that control sympathetic outflow. For example, tonic restraint of sympathetic outflow by arterial and cardiopulmonary baroreflexes is depressed in CHF2 and depressed or reset in hypertension.3 Moreover, maladaptive changes also occur in the central nervous system at integrative sites for autonomic control in both disease processes.4,5 It is also clear that sympathoexcitatory cardiac,6 somatic,7 and central/peripheral chemoreceptor reflexes8 are enhanced in CHF and hypertension. Arterial chemoreceptors serve an important regulatory role in the control of alveolar ventilation, but they also exert a powerful influence on cardiovascular function.9 Activation of arterial chemoreceptors by hypoxemia increases sympathetic outflow to systemic vascular beds to compensate for the direct vasodilating effects of hypoxia on these vessels and to redistribute blood flow to essential organs. In this review, we highlight relevant information that implicates the arterial chemoreflex as a contributory mechanism for the sympathetic hyperactivity in CHF and hypertension and illustrate proposed mechanisms for this altered function. Arterial chemoreceptors located in the aortic and carotid bodies (CBs) respond to hypoxemia and hypercapnia. Because central chemoreceptors also respond to hypercapnia, hypoxia is typically used as a specific stimulus to arterial chemoreceptors. In some mammals, such as rats and rabbits, reflex responses to hypoxemia arise solely from the CB, whereas in other species, the aortic chemoreceptor contribution can be significant. However, it is not possible to experimentally separate the relative contribution of the aortic and …

Evaluation of phosphenes elicited by extraocular stimulation in normals and by suprachoroidal-transretinal stimulation in patients with retinitis pigmentosa

Abstract: To determine the efficient parameters to evoke electrical phosphenes is essential for the development of a retinal prosthesis. We studied the efficient parameters in normal subjects and investigated if suprachoroidal-transretinal stimulation (STS) is effective in patients with advanced retinitis pigmentosa (RP) using these efficient parameters. The amplitude of pupillary reflex (PR) evoked by transcorneal electrical stimulation (TcES) was determined at different frequencies in eight normal subjects. The relationship between localized phosphenes elicited by transscleral electrical stimulation (TsES) and the pulse parameters was also examined in six normal subjects. The phosphenes evoked by STS were examined in two patients with RP with bare light perception. Biphasic pulses (cathodic first, duration: 0.5 or 1.0 ms, frequency: 20 Hz) were applied through selected channel(s). The size and shape of the phosphenes perceived by the patients were recorded. The maximum PR was evoked by TcES with a frequency of 20 Hz. The brightest phosphene was elicited by TsES with a pulse train of more than 10 pulses, duration of 0.5–1.0 ms and a frequency of 20 to 50 Hz. In RP patients, localized phosphenes were elicited with a current of 0.3–0.5 mA (0.5 ms) in patient 1 and 0.4 mA (1.0 ms) in patient 2. Two isolated or dumbbell-shaped phosphenes were perceived when the stimulus was delivered through two adjacent channels. Biphasic pulse trains (≥10 pulses) with a duration of 0.5–1.0 ms and a frequency of 20–50 Hz were efficient for evoking phosphenes by localized extraocular stimulation in normal subjects. With these parameters, STS is a feasible method to use with a retinal prosthesis even in advanced stages of RPs.

Neural regulation of rhythmic arm and leg movement is conserved across human locomotor tasks

Abstract: It has been proposed that different forms of rhythmic human limb movement have a common central neural control (‘common core hypothesis’), just as in other animals We compared the modulation patterns of background EMG and cutaneous reflexes during walking, arm and leg cycling, and arm-assisted recumbent stepping We hypothesized that patterns of EMG and reflex modulation during cycling and stepping (deduced from mathematical principal components analysis) would be comparable to those during walking because they rely on similar neural substrates Differences between the tasks were assessed by evoking cutaneous reflexes via stimulation of nerves in the foot and hand in separate trials The EMG was recorded from flexor and extensor muscles of the arms and legs Angular positions of the hip, knee and elbow joints were also recorded Factor analysis revealed that across the three tasks, four principal components explained more than 93% of the variance in the background EMG and middle-latency reflex amplitude Phase modulation of reflex amplitude was observed in most muscles across all tasks, suggesting activity in similar control networks Significant correlations between EMG level and reflex amplitude were frequently observed only during static voluntary muscle activation and not during rhythmic movement Results from a control experiment showed that strong correlation between EMG and reflex amplitudes was observed during discrete, voluntary leg extension but not during walking There were task-dependent differences in reflex modulation between the three tasks which probably arise owing to specific constraints during each task Overall, the results show strong correlation across tasks and support common neural patterning as the regulator of arm and leg movement during various rhythmic human movements

The peristaltic reflex induced by short-chain fatty acids is mediated by sequential release of 5-HT and neuronal CGRP but not BDNF

Abstract: Short-chain fatty acids (SCFAs) accelerate colonic transit. This study examined whether this action was mediated by activation of the peristaltic reflex. SCFAs (acetate, butyrate, or propionate) we...

Effects of neonatal maternal separation on neurochemical and sensory response to colonic distension in a rat model of irritable bowel syndrome

Abstract: Early life stress has been implicated as a risk factor for irritable bowel syndrome (IBS). We studied the effect of neonatal maternal separation on the visceromotor response and the expression of c-fos, 5-HT, and its receptors/transporters along the brain-gut axis in an animal model of IBS. Male neonatal Sprague-Dawley rats were randomly assigned to a 3-h daily maternal separation (MS) or nonhandling (NH) on postnatal days 2-21. Colorectal balloon distention (CRD) was performed for assessment of abdominal withdrawal reflex as a surrogate marker of visceral pain. Tissues from dorsal raphe nucleus in midbrain, lumbar-sacral cord, and distal colon were harvested for semiquantitative analysis of c-fos and 5-HT. The expression of 5-HT expression, 5-HT3 receptors, and 5-HT transporter were analyzed by RT-PCR. Pain threshold was significantly lower in MS than NH rats. The abdominal withdrawal reflex score in response to CRD in MS rats was significantly higher with distension pressures of 40, 60, and 80 mmHg. In MS rats, the number of c-fos-like immunoreactive nuclei at dorsal horn of lumbar-sacral spinal cord increased significantly after CRD. 5-HT content in the spinal cord of MS rats was significant higher. In the colon, both 5-HT-positive cell number and 5-HT content were comparable between MS and NH groups before CRD. Post-CRD only MS rats had significant increase in 5-HT content. Protein and mRNA expression levels of 5-HT3 receptors and 5-HT transporter were similar in MS and NH rats. Neonatal maternal separation stress predisposes rats to exaggerated neurochemical responses and visceral hyperalgesia in colon mimicking IBS.

Local ascorbate administration augments NO- and non-NO-dependent reflex cutaneous vasodilation in hypertensive humans

Abstract: Full expression of reflex cutaneous vasodilation (VD) is dependent on nitric oxide (NO) and is attenuated with essential hypertension. Decreased NO-dependent VD may be due to 1) increased oxidant s...

Training-Specific Adaptations of H- and Stretch Reflexes in Human Soleus Muscle

Abstract: The authors investigated the effect of physical exercise on reflex excitability in a controlled intervention study. Healthy participants (N = 21) performed 4 weeks of either power training (ballistic strength training) or balance training (sensorimotor training [SMT]). Both training regimens enhanced balance control and rate of force development, whereas reductions in peak-to-peak amplitudes of stretch reflexes and in the ratio of the maximum Hoffman reflex to the maximum efferent motor response (Hmax:Mmax) measured at rest were limited to SMT. The differences in reflex excitability between the training regimens indicated different underlying neural mechanisms of adaptation. The reduced reflex excitability following SMT was most likely induced by supraspinal influence. The authors discuss an overall increase in presynaptic inhibition of Ia afferent fibers as a possible mechanism.

Nasonasal reflexes, the nasal cycle, and sneeze.

Abstract: The nasal mucosa is a complex tissue that interacts with its environment and effects local and systemic changes. Receptors in the nose receive signals from stimuli, and respond locally through afferent, nociceptive, type C neurons to elicit nasonasal reflex responses mediated via cholinergic neurons. This efferent limb leads to responses in the nose (eg, rhinorrhea, glandular hyperplasia, hypersecretion with mucosal swelling). Anticholinergic agents appear useful against this limb for symptomatic relief of a "runny nose." Chronic exposure to allergens can lead to hyperresponsiveness of the nasal mucosa. As a result, receptors upregulate specific ion channels to increase the sensitivity and potency of their reflex response. Nasal stimuli also affect distant parts of the body. Nerves in the sinus mucosa cause vasodilation; the lacrimal glands can be stimulated by nasal afferent triggers. Even the cardiopulmonary system can be affected via the trigeminal chemosensory system, where sensed irritants can lead to changes in tidal volume, respiratory rate, and blink frequency. The sneeze is an airway defense mechanism that removes irritants from the nasal epithelial surface. It is generally benign, but can lead to problems in certain circumstances. The afferent pathway involves histamine-mediated depolarization of H1 receptor-bearing type C trigeminal neurons and a complex coordination of reactions to effect a response.

The cerebellum: Comparative and animal studies.

Abstract: The cerebellum has a uniform cellular structure and microcircuitry, but the size of its subdivisions varies greatly among vertebrates. This variability is a challenge to anatomists to attempt to relate size differences to differences in characteristic behaviour. Here we review the early work of Lodewijk Bolk on the mammalian cerebellum and relate his observations to unfolded maps of the rodent cerebella. We further take insights from the comparative anatomy of the bird cerebella and find that cerebellar enlargement in large brains is not a passive consequence of overall brain enlargement, but is related to specific behaviour. We speculate that for some rodents (e.g., squirrels), primates and some large-brained birds (crows, parrots and woodpeckers), specifically enlarged cerebella are associated with either the elaboration of forelimb control (squirrels and primates) or in the case of the birds with beak control. The elaboration of such motor behaviour combined with increased visual control could have helped to furnish manipulative skills in these animals. Finally, we review the connections of the mammalian cerebellum and show that several pieces of experimental evidence point to an important function of the cerebellum in sensory control of movement reflex adjustment, and motor learning.

The quaternary lidocaine derivative, QX-314, produces long-lasting local anesthesia in animal models in vivo.

Abstract: Background: QX-314 is a quaternary lidocaine derivative considered to be devoid of clinically useful local anesthetic activity. However, several reports document that extracellular QX-314 application affects action potentials. Hence, the authors tested the hypothesis that QX-314 could produce local anesthesia in animal models in vivo. Methods: The authors tested QX-314 (10, 30, and 70 mM )i n three standard in vivo local anesthetic animal models, using a randomized, blinded experimental design with negative (placebo) and positive (70 mM lidocaine) controls. The guinea pig intradermal wheal assay (n 29) was used to test for peripheral inhibition of the cutaneous trunci muscle reflex, the mouse tail-flick test (n 30) was used to test for sensory blockade, and the mouse sciatic nerve blockade model (n 45) was used to test for motor blockade. Results: In all three animal models, QX-314 concentrationdependently and reversibly produced local anesthesia of long duration, at concentrations equivalent to those clinically relevant for lidocaine. In the guinea pig intradermal wheal assay, QX-314 produced peripheral nociceptive blockade up to 6 times longer than lidocaine (650 171 vs. 100 24 min [mean SD]; n 6 per group; P < 0.0001). In the mouse tail-flick test, QX-314 produced sensory blockade up to 10 times longer than lidocaine (540 134 vs. 50 11 min; n 6 per group; P < 0.0001). Finally, in the mouse sciatic nerve model, QX-314 produced motor blockade up to 12 times longer compared with lidocaine (282 113 vs. 23 10 min; n 9 or 10 per group; P < 0.0001). The onset of QX-314‐mediated blockade was consistently slower compared with lidocaine. Animals injected with saline exhibited no local anesthetic effects in any of the three models. Conclusion: In a randomized, controlled laboratory study, the quaternary lidocaine derivative, QX-314, concentration-dependently and reversibly produced long-lasting local anesthesia with a slow onset in animal models in vivo. The authors’ results raise the possibility that quaternary ammonium compounds may produce clinically useful local anesthesia of long duration in humans and challenge the conventional notion that these agents are ineffective when applied extracellularly. LOCAL anesthetic research during the past four decades has demonstrated that amino-ester and amino-amide local anesthetics block the generation and propagation of action potentials via an intracellular site of action at the voltage-gated Na channel. 1– 4 Many of the underlying experiments were performed using QX-314 (lidocaine N-ethyl chloride; N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium chloride; molecular weight, 298.9), a lidocaine derivative whose sole structural difference to the mother compound is in the presence of an additional N-ethyl group. This permanently renders the amino group quaternary, i.e., positively charged. As a result, the agent cannot readily pass biologic membranes. Indeed, a series of in vitro experiments where QX-314 was applied extracellularly found this agent to be ineffective in blocking action potentials. 5– 8 In contrast, intracellular application of QX-314 to peripheral and central neurons produces marked local anesthetic actions, blocking both fast, Na-dependent action potentials and voltage-dependent, noninactivating Na conductances. 5–10 However, various studies on a range of other quaternary cationic compounds have shown that these can block electrical conductances in axons when applied outside of the cell. Such studies involved QX572, 11,12 quaternary tropine esters, 7,13 tonicaine, 14 –16

Genioglossus reflex inhibition to upper-airway negative-pressure stimuli during wakefulness and sleep in healthy males

Abstract: During wakefulness, obstructive sleep apnoea patients appear to compensate for an anatomically narrow upper airway by increasing upper airway dilator muscle activity, e.g. genioglossus, at least partly via a negative-pressure reflex that may be diminished in sleep. Previous studies have assessed the negative-pressure reflex using multi-unit, rectified, moving-time-average EMG recordings during brief pulses of negative upper-airway pressure. However, moving-time averaging probably obscures the true time-related reflex morphology, potentially masking transient excitatory and inhibitory components. This study aimed to re-examine the genioglossus negative-pressure reflex in detail, without moving-time averaging. Bipolar fine-wire electrodes were inserted per orally into the genioglossus muscle in 17 healthy subjects. Two upper airway pressure catheters were inserted per nasally. Genioglossus EMG reflex responses were generated via negative-pressure stimuli (approximately -10 cmH2O at the choanae, 250 ms duration) delivered during wakefulness and sleep. Ensemble-averaged, rectified, genioglossus EMG recordings demonstrated reflex activation (onset latency 26+/-1 ms; peak amplitude 231+/-29% of baseline) followed by a previously unreported suppression (peak latency 71+/-4 ms; 67+/-8% of baseline). Single-motor-unit activity, clearly identifiable in approximately 10% of trials in six subjects, showed a concomitant increase in the interspike interval from baseline (26+/-9 ms, P=0.01). Genioglossus negative-pressure reflex morphology and amplitude of the initial peak were maintained in non-rapid eye movement (NREM) sleep but suppression amplitude was more pronounced during NREM and declined further during REM sleep compared to wakefulness. These data indicate there are both excitatory and inhibitory components to the genioglossus negative-pressure reflex which are differentially affected by state.

Quantifying the effects of voluntary contraction and inter-stimulus interval on the human soleus H-reflex

Abstract: The human soleus H-reflex is commonly tested as an indicator of the reflex excitability of the calf muscles with infrequent stimuli to a subject seated and at rest. However, the reflex varies widely with the level of voluntary contraction and with the time history of stimulation. We studied two aspects of this variation. Antagonist (tibialis anterior) activation decreases the response, while increasing agonist (soleus) activation increases the H-reflex to a peak after which it declines. In subjects with large H-reflexes at rest, the reflex peaked at low levels of contraction. In contrast, in subjects with small H-reflexes at rest, the reflex peaked at higher levels of contraction for reasons that were elucidated using a realistic computer model. A parabolic curve fitted the maximum amplitude of the H-reflex in the model and over the entire range of contractile levels studied. The second aspect studied was post-activation depression or homosynaptic depression (HD), which has been described previously as a reduction of a second H-reflex elicited shortly after an initial reflex. We confirmed the presence of HD in resting, seated subjects for intervals up to 4 s. However, by voluntarily activating the soleus muscle, HD was drastically reduced when seated and abolished when standing. This suggests that HD may be absent in normal, functional movements and perhaps in clinical conditions that alter H-reflexes. Meaningful, quantitative measurements of reflex excitability can only be made under voluntary activity that mimics the condition of interest.

Activity of vestibular nuclei neurons during vestibular and optokinetic stimulation in the alert mouse.

Abstract: As a result of the availability of genetic mutant strains and development of noninvasive eye movements recording techniques, the mouse stands as a very interesting model for bridging the gap among behavioral responses, neuronal response dynamics studied in vivo, and cellular mechanisms investigated in vitro. Here we characterized the responses of individual neurons in the mouse vestibular nuclei during vestibular (horizontal whole body rotations) and full field visual stimulation. The majority of neurons ( approximately 2/3) were sensitive to vestibular stimulation but not to eye movements. During the vestibular-ocular reflex (VOR), these neurons discharged in a manner comparable to the "vestibular only" (VO) neurons that have been previously described in primates. The remaining neurons [eye-movement-sensitive (ES) neurons] encoded both head-velocity and eye-position information during the VOR. When vestibular and visual stimulation were applied so that there was sensory conflict, the behavioral gain of the VOR was reduced. In turn, the modulation of sensitivity of VO neurons remained unaffected, whereas that of ES neurons was reduced. ES neurons were also modulated in response to full field visual stimulation that evoked the optokinetic reflex (OKR). Mouse VO neurons, however, unlike their primate counterpart, were not modulated during OKR. Taken together, our results show that the integration of visual and vestibular information in the mouse vestibular nucleus is limited to a subpopulation of neurons which likely supports gaze stabilization for both VOR and OKR.

Genioglossus premotoneurons and the negative pressure reflex in rats

Abstract: Reflex increases in genioglossus (GG) muscle activity in response to negative pharyngeal pressure are important for maintenance of upper airway patency in humans. However, little is known of the central circuitry that mediates this negative pressure reflex (NPR). We used two approaches to determine which GG premotoneurons relay negative pressure-related information to the hypoglossal motor nucleus. First, to identify GG premotoneurons, we injected pseudorabies virus (PRV152) into the GG muscle. We found that medullary GG premotoneurons were concentrated mainly in the reticular formation adjacent to the hypoglossal motor nucleus. Second, in order to determine whether these perihypoglossal neurons were involved in the NPR, we quantified GG EMG responses to negative pressure applied to the isolated upper airway in anaesthetized rats before and after microinjection of muscimol (9 nl; 0.25 mm), a GABA-A receptor agonist, into the perihypoglossal premotor field. Pressures as low as −4 cmH2O increased inspiratory phase-related GG activity. The NPR was abolished following bilateral injections of muscimol into the perihypoglossal premotor field at and up to 500 μm rostral to the obex. Muscimol in this location also increased the amplitude of basal, unstimulated phasic GG activity. By contrast, inhibition of neurons caudal to the obex decreased phasic GG activity but had no impact on the NPR. These results suggest that perihypoglossal GG premotoneurons near the obex mediate the NPR and those caudal to the obex are important mediators of respiratory-related GG activity but are not involved in the NPR.

Recent advances in enteric neurobiology: mechanosensitive interneurons.

Abstract: Until recently, it was generally assumed that the only intrinsic sensory neuron, or primary afferent neuron, in the gut was the after-hyperpolarizing AH/Type II neuron. AH neurons excited by local chemical and mechanical stimulation of the mucosa appear to be necessary for activating the peristaltic reflex (oral excitation and anal inhibition of the muscle layers) and anally propagating ring like contractions (peristaltic waves) that depend upon smooth muscle tone. However, our recent findings in the guinea-pig distal colon suggest that different neurochemical classes of interneuron in the colon are also mechanosensitive in that they respond directly to changes in muscle length, rather than muscle tone or tension. These interneurons have electrophysiological properties consistent with myenteric S-neurons. Ascending and descending interneurons respond directly to circumferential stretch by generating an ongoing polarized peristaltic reflex activity (oral excitatory and anal inhibitory junction potentials) in the muscle for as long as the stimulus is maintained. Some descending (nitric oxide synthase +ve) interneurons, on the other hand, appear to respond directly to longitudinal stretch and are involved in accommodation and slow transit of faecal pellets down the colon. This review will present recent evidence that suggests some myenteric S interneurons, in addition to AH neurons, behave as intrinsic sensory neurons.

Asymmetry in noise-induced hearing loss: relevance of acoustic reflex and left or right handedness.

Abstract: Objective:Noise-induced hearing loss (NIHL) is more severe in the left ear than the right ear. The aim of this study was to examine the possible association of handedness and acoustic reflex parameters on right or left NIHL predominance.Study Design:Retrospective case review and prospective series.S

Bimodal recovery pattern in human skeletal muscle induced by exhaustive stretch-shortening cycle exercise.

Abstract: Introduction/Purpose: Recovery of force and stretch reflex from exhaustive stretch-shortening cycle (SSC) exercise is usually bimodal, characterized as immediate exercise-induced performance reduction, with its quick recovery followed by a longer-lasting reduction in performance. A clear parallel exists between the respective changes in performance, neural activation, and metabolic or structural exercise-induced changes. This implies the existence of potential coupling between muscle failure and the induced neural adjustments that take place along its recovery. The present study was designed to explore the evidence of this coupling more thoroughly. Methods: H- and stretch reflexes were measured before and periodically after exhaustive SSC exercise in human subjects. Several markers of muscle damage and inflammation were also measured during the 8-d postexercise follow-up period. Results: The results indicate that acute changes of H- and stretch reflex patterns and maximal isometric force are associated with significant increases in lactate, interleukin 6, and prostaglandin E2 concentrations. The delayed changes in reflexes and isometric force occurred concomitantly with increases in muscle thickness, C reactive protein, and substance P concentrations and also in serum creatine kinase activity. Conclusion: The immediate postexercise decreases in H- and stretch reflexes are probably partially caused by activation of group III and IV afferent fibers by high lactate concentration in combination with possible increases in potassium outflow. Both of these parameters recovered quickly (i.e., 2 h after exercise). The events after the 2-h postexercise point are very likely to be related to muscle damage and associated inflammation. Group III and IV afferent fibers are probably reactivated during this period by mechanical factors.