Awake Human Subjects Research Articles

Synthesis of K+ channel radioligand [18F]5-methyl-3-fluoro-4-aminopyridine and PET imaging in mice

[18F]3-fluoro-4-aminopyridine ([18F]3F4AP) is the first positron emission tomography (PET) radioligand that targets voltage-gated potassium (K+) channels in the brain for imaging demyelination. [18F]3F4AP exhibits high brain penetration, favorable kinetics for PET imaging, and high sensitivity to demyelinating lesions. However, recent studies in awake human subjects indicate lower metabolic stability than in anesthetized animals, resulting in reduced brain uptake. Therefore, there is a need for novel radioligands for K+ channels with suitable pharmacological properties and enhanced metabolic stability. Recent in vitro studies demonstrate that 5-methyl-3-fluoro-4-aminopyridine (5Me3F4AP) exhibits comparable binding affinity to K+ channels, pKa, logD, and membrane permeability as 3F4AP, and a slower enzymatic metabolic rate, suggesting its potential as a K+ channel PET tracer. In this study, we describe the radiochemical synthesis of [18F]5Me3F4AP using an isotope exchange method from the corresponding 3-fluoro-5-methyl-4-nitropyridine N-oxide, followed by a palladium on carbon mediated hydrogenation of the nitro and N-oxide groups. This method yielded [18F]5Me3F4AP with high purity and acceptable molar activity. PET/CT studies using naïve mice demonstrate that [18F]5Me3F4AP effectively crosses the blood–brain barrier and has comparable kinetics to [18F]3F4AP. These findings strongly suggest that [18F]5Me3F4AP is a promising candidate for neuroimaging applications and warrant further studies to investigate its sensitivity to lesions and in vivo metabolic stability.

Time-varying caloric vestibular stimulation for the treatment of neurodegenerative disease.

Time-varying caloric vestibular stimulation (tvCVS) is a new form of non-invasive neuromodulation similar to, but different from, diagnostic caloric vestibular stimulation (CVS). Using a non-invasive, solid-state delivery device, tvCVS has been successfully used in a human clinical trial with Parkinson's disease (PD) subjects. Additionally, the effects of tvCVS on brain activation have been studied in healthy human subjects using transcranial Doppler sonography (TCD) and functional magnetic resonance imaging (BOLD fMRI). A novel finding in the TCD and fMRI studies was the induction of cerebral blood flow velocity (CBFv) oscillations. How such oscillations might lead to the observed clinical effects seen in PD subjects will be discussed. Enabling studies of tvCVS with rodents is an attractive goal in support of explorations of the mechanism of action. Male Wistar rats were used in a proof-of-concept study described herein. Rats were anesthetized (isoflurane) and ventilated for the duration of the tvCVS runs. Time-varying thermal stimuli were administered using a digital temperature controller to modulate Peltier-type heater/cooler devices. Blunt ear bars conveyed the thermal stimulus to the external ear canals of the rats. Different thermal waveform combinations were evaluated for evidence of successful induction of the CVS effect. It was found that bilateral triangular thermal waveforms could induce oscillations in CBFv both during and after the application of tvCVS. These oscillations were similar to, but different from those observed in awake human subjects. The establishment of a viable animal model for the study of tvCVS will augment ongoing clinical investigations of this new form of neuromodulation in patients with neurodegenerative disease.

Surface kinematic and depth-resolved analysis of human vocal folds in vivo during phonation using optical coherence tomography.

.Significance: The human vocal fold (VF) oscillates in multiple vectors and consists of distinct layers with varying viscoelastic properties that contribute to the mucosal wave. Office-based and operative laryngeal endoscopy are limited to diagnostic evaluation of the VF epithelial surface only and are restricted to axial-plane characterization of the horizontal mucosal wave. As such, understanding of the biomechanics of human VF motion remains limited.Aim: Optical coherence tomography (OCT) is a micrometer-resolution, high-speed endoscopic imaging modality which acquires cross-sectional images of tissue. Our study aimed to leverage OCT technology and develop quantitative methods for analyzing the anatomy and kinematics of in vivo VF motion in the coronal plane.Approach: A custom handheld laryngeal stage was used to capture OCT images with 800 A-lines at 250 Hz. Automated image postprocessing and analytical methods were developed.Results: Novel kinematic analysis of in vivo, long-range OCT imaging of the vibrating VF in awake human subjects is reported. Cross-sectional, coronal-plane panoramic videos of the larynx during phonation are presented with three-dimensional videokymographic and space-time velocity analysis of VF motion.Conclusions: Long-range OCT with automated computational methods allows for cross-sectional dynamic laryngeal imaging and has the potential to broaden our understanding of human VF biomechanics and sound production.

Super-resolution ophthalmoscopy: Virtually structured detection for resolution improvement in retinal imaging.

Quantitative retinal imaging is essential for advanced study and clinical management of eye diseases. However, spatial resolution of retinal imaging has been limited due to available numerical aperture and optical aberration of the ocular optics. Structured illumination microscopy has been established to break the diffraction-limit resolution in conventional light microscopy. However, practical implementation of structured illumination microscopy for in vivo ophthalmoscopy of the retina is challenging due to inevitable eye movements that can produce phase artifacts. Recently, we have demonstrated the feasibility of using virtually structured detection as one alternative to structured illumination microscopy for super-resolution imaging. By providing the flexibility of digital compensation of eye movements, the virtually structured detection provides a feasible, phase-artifact-free strategy to achieve super-resolution ophthalmoscopy. In this article, we summarize the technical rationale of virtually structured detection, and its implementations for super-resolution imaging of freshly isolated retinas, intact animals, and awake human subjects.

Electrophysiological correlates of hyperoxia during resting-state EEG in awake human subjects.

Recreational use of concentrated oxygen has increased. Claims have been made that hyperoxic breathing can help reduce fatigue, increase alertness, and improve attentional capacities; however, few systematic studies of these potential benefits exist. Here, we examined the effects of short-term (15min) hyperoxia on resting states in awake human subjects by measuring spontaneous EEG activity between normoxic and hyperoxic situations, using a within-subject design for both eyes-opened and eyes-closed conditions. We also measured respiration rate, heart rate, and blood oxygen saturation levels to correlate basic physiological changes due to the hyperoxic challenge with any brain activity changes. Our results show that breathing short-term 100% oxygen led to increased blood oxygen saturation levels, decreased heart rate, and a slight, but nonsignificant, decrease in breathing rate. Changes of brain activity were apparent, including decreases in low-alpha (7-10Hz), high-alpha (10-14Hz), beta (14-30Hz), and gamma (30-50Hz) frequency ranges during eyes-opened hyperoxic conditions. During eyes-closed hyperoxia, increases in the delta (0.5-3.5Hz) and theta (3.5-7Hz) frequency range were apparent together with decreases in the beta range. Hyperoxia appeared to accentuate the decrease of low alpha and gamma ranges across the eyes-opened and eyes-closed conditions, suggesting that it modulated brain state itself. As decreased alpha during eyes-opened conditions has been associated with increased attentional processing and selective attention, and increased delta and theta during eyes-closed condition are typically associated with the initiation of sleep, our results suggest a state-specific and perhaps opposing influence of short-term hyperoxia.

Ultra-Slow Single-Vessel BOLD and CBV-Based fMRI Spatiotemporal Dynamics and Their Correlation with Neuronal Intracellular Calcium Signals

Functional MRI has been used to map brain activity and functional connectivity based on the strength and temporal coherence of neurovascular-coupled hemodynamic signals. Here, single-vessel fMRI reveals vessel-specific correlation patterns in both rodents and humans. In anesthetized rats, fluctuations in the vessel-specific fMRI signal are correlated with the intracellular calcium signal measured in neighboring neurons. Further, the blood-oxygen-level-dependent (BOLD) signal from individual venules and the cerebral-blood-volume signal from individual arterioles show correlations at ultra-slow (<0.1Hz), anesthetic-modulated rhythms. These data support a model that links neuronal activity to intrinsic oscillations in the cerebral vasculature, with a spatial correlation length of ∼2mm for arterioles. In complementary data from awake human subjects, the BOLD signal is spatially correlated among sulcus veins and specified intracortical veins of the visual cortex at similar ultra-slow rhythms. These data support the use of fMRI to resolve functional connectivity at the level of single vessels.

Cortical Responses to Input From Distant Areas are Modulated by Local Spontaneous Alpha/Beta Oscillations.

Any given area in human cortex may receive input from multiple, functionally heterogeneous areas, potentially representing different processing threads. Alpha (8-13 Hz) and beta oscillations (13-20 Hz) have been hypothesized by other investigators to gate local cortical processing, but their influence on cortical responses to input from other cortical areas is unknown. To study this, we measured the effect of local oscillatory power and phase on cortical responses elicited by single-pulse electrical stimulation (SPES) at distant cortical sites, in awake human subjects implanted with intracranial electrodes for epilepsy surgery. In 4 out of 5 subjects, the amplitudes of corticocortical evoked potentials (CCEPs) elicited by distant SPES were reproducibly modulated by the power, but not the phase, of local oscillations in alpha and beta frequencies. Specifically, CCEP amplitudes were higher when average oscillatory power just before distant SPES (-110 to -10 ms) was high. This effect was observed in only a subset (0-33%) of sites with CCEPs and, like the CCEPs themselves, varied with stimulation at different distant sites. Our results suggest that although alpha and beta oscillations may gate local processing, they may also enhance the responsiveness of cortex to input from distant cortical sites.

"Real-time" imaging of cortical and subcortical sites of cardiovascular control: concurrent recordings of sympathetic nerve activity and fMRI in awake subjects.

We review our approach to functionally identifying cortical and subcortical areas involved in the generation of spontaneous fluctuations in sympathetic outflow to muscle or skin. We record muscle sympathetic nerve activity (MSNA) or skin sympathetic nerve activity (SSNA), via a tungsten microelectrode inserted percutaneously into the common peroneal nerve, at the same time as performing functional magnetic resonance imaging (fMRI) of the brain. By taking advantage of the neurovascular coupling delay associated with BOLD (blood oxygen level dependent) fMRI, and the delay associated with conduction of a burst of sympathetic impulses to the peripheral recording site, we can identify structures in which BOLD signal intensity covaries with MSNA or SSNA. Using this approach, we found MSNA-coupled increases in BOLD signal intensity in the mid-insula and dorsomedial hypothalamus on the left side, and in dorsolateral prefrontal cortex, posterior cingulate cortex, precuneus, ventromedial hypothalamus and rostral ventrolateral medulla on both sides. Conversely, spontaneous bursts of SSNA were positively correlated with BOLD signal intensity in the ventromedial thalamus and posterior insula on the left side, and in the anterior insula, orbitofrontal cortex and frontal cortex on the right side, and in the mid-cingulate cortex and precuneus on both sides. Inverse relationships were observed between MSNA and BOLD signal intensity in the right ventral insula, nucleus tractus solitarius and caudal ventrolateral medulla, and between SSNA and signal intensity in the left orbitofrontal cortex. These results emphasize the contributions of cortical regions of the brain to sympathetic outflow in awake human subjects, and the extensive interactions between cortical and subcortical regions in the ongoing regulation of sympathetic nerve activity to muscle and skin in awake human subjects.

Outer Hair Cell Damage: A Completely Different Listening Experience

Outer Hair Cell Damage: A Completely Different Listening Experience

Inter-individual responses to experimental muscle pain: Baseline anxiety ratings and attitudes to pain do not determine the direction of the sympathetic response to tonic muscle pain in humans

We have recently shown that intramuscular infusion of hypertonic saline, causing pain lasting ~60min, increases muscle sympathetic nerve activity (MSNA) in one group of subjects, yet decreases it in another. Across subjects these divergent sympathetic responses to long-lasting muscle pain are consistent over time and cannot be foreseen on the basis of baseline MSNA, blood pressure, heart rate or sex. We predicted that differences in anxiety or attitudes to pain may account for these differences. Psychometric measures were assessed prior to the induction of pain using the State and Trait Anxiety Inventory (STAI), Pain Vigilance and Awareness Questionnaire (PVAQ), Pain Anxiety Symptoms Scale (PASS) and Pain Catastrophising Scale (PCS); PCS was also administered after the experiment. MSNA was recorded from the common peroneal nerve, before and during a 45-minute intramuscular infusion of hypertonic saline solution into the tibialis anterior muscle of 66 awake human subjects. Forty-one subjects showed an increase in mean burst amplitude of MSNA (172.8±10.6%) while 25 showed a decrease (69.9±3.8%). None of the measured psychological parameters showed significant differences between the increasing and the decreasing groups. We conclude that inter-individual anxiety or pain attitudes do not determine whether MSNA increases or decreases during long-lasting experimental muscle pain in healthy human subjects.

The vestibular system does not modulate fusimotor drive to muscle spindles in relaxed leg muscles of subjects in a near-vertical position.

It has been shown that sinusoidal galvanic vestibular stimulation (sGVS) has no effect on the firing of spontaneously active muscle spindles in either relaxed or voluntarily contracting human leg muscles. However, all previous studies have been conducted on subjects in a seated position. Given that independent vestibular control of muscle spindle firing would be more valuable during postural threat, we tested the hypothesis that this modulation would become apparent for subjects in a near-vertical position. Unitary recordings were made from 18 muscle spindle afferents via tungsten microelectrodes inserted percutaneously into the common peroneal nerve of awake human subjects laying supine on a motorized tilt table. All recorded spindle afferents were spontaneously active at rest, and each increased its firing rate during a weak static contraction. Sinusoidal bipolar binaural galvanic vestibular stimulation (±2 mA, 100 cycles) was applied to the mastoid processes at 0.8 Hz. This continuous stimulation produced a sustained illusion of "rocking in a boat" or "swinging in a hammock." The subject was then moved into a near-vertical position (75°), and the stimulation repeated. Despite robust vestibular illusions, none of the fusimotor-driven spindles exhibited phase-locked modulation of firing during sinusoidal GVS in either position. We conclude that this dynamic vestibular stimulus was insufficient to modulate the firing of fusimotor neurons in the near-vertical position. However, this does not mean that the vestibular system cannot modulate the sensitivity of muscle spindles via fusimotor neurons in free unsupported standing, when reliance on proprioceptive feedback is higher.

Multifaceted origins of sex differences in the brain.

Studies of sex differences in the brain range from reductionistic cell and molecular analyses in animal models to functional imaging in awake human subjects, with many other levels in between. Interpretations and conclusions about the importance of particular differences often vary with differing levels of analyses and can lead to discord and dissent. In the past two decades, the range of neurobiological, psychological and psychiatric endpoints found to differ between males and females has expanded beyond reproduction into every aspect of the healthy and diseased brain, and thereby demands our attention. A greater understanding of all aspects of neural functioning will only be achieved by incorporating sex as a biological variable. The goal of this review is to highlight the current state of the art of the discipline of sex differences research with an emphasis on the brain and to contextualize the articles appearing in the accompanying special issue.

Inter-Individual Responses to Experimental Muscle Pain: Baseline Physiological Parameters Do Not Determine Whether Muscle Sympathetic Nerve Activity Increases or Decreases During Pain.

We have previously reported that there are inter-individual differences in the cardiovascular responses to experimental muscle pain, which are consistent over time: intramuscular infusion of hypertonic saline, causing pain lasting ~60 min, increases muscle sympathetic nerve activity (MSNA)—as well as blood pressure and heart rate—in certain subjects, but decrease it in others. Here, we tested the hypothesis that baseline physiological parameters (resting MSNA, heart rate, blood pressure, heart rate variability) determine the cardiovascular responses to long-lasting muscle pain. MSNA was recorded from the common peroneal nerve, together with heart rate and blood pressure, during a 45-min intramuscular infusion of hypertonic saline solution into the tibialis anterior of 50 awake human subjects (25 females and 25 males). Twenty-four subjects showed a sustained increase in mean amplitude of MSNA (160.9 ± 7.3%), while 26 showed a sustained decrease (55.1 ± 3.5%). Between the increasing and decreasing groups there were no differences in baseline MSNA (19.0 ± 1.5 vs. 18.9 ± 1.2 bursts/min), mean BP (88.1 ± 5.2 vs. 88.0 ± 3.8 mmHg), HR (74.7 ± 2.0 vs. 72.8 ± 1.8 beats/min) or heart rate variability (LF/HF 1.8 ± 0.2 vs. 2.2 ± 0.3). Furthermore, neither sex nor body mass index had any effect on whether MSNA increased or decreased during tonic muscle pain. We conclude that the measured baseline physiological parameters cannot account for the divergent sympathetic responses during tonic muscle pain.

Inter-individual responses to experimental muscle pain: baseline anxiety ratings and attitudes to pain do not determine the direction of the sympathetic response to tonic muscle pain in humans

Event Abstract Back to Event Inter-individual responses to experimental muscle pain: baseline anxiety ratings and attitudes to pain do not determine the direction of the sympathetic response to tonic muscle pain in humans Sophie Kobuch1*, Rachael Brown1, Azharuddin Fazalbhoy2 and Vaughan G. Macefield1 1 Western Sydney University, Medicine, Australia 2 Royal Melbourne Institute of Technology, Australia Sustained experimental muscle pain has been shown to bring about inter-individual differences in the cardiovascular responses, which are consistent over time (Fazalbhoy et al., 2012, 2014). Intramuscular infusion of hypertonic saline, causing pain lasting ~60 minutes results in a sustained increase in muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate in certain people, while evoking a decrease in these parameters in others (Fazalbhoy et al., 2012). What brings about this divergence is unknown. Here we aimed to identify whether anxiety levels and attitudes to pain could be responsible for these divergent responses. Psychological parameters were assessed prior to the induction of pain using the State and Trait Anxiety Inventory (STAI), Pain Vigilance and Awareness Questionnaire (PVAQ), Pain Catastrophising Scale (PCS), and Pain Anxiety Symptoms Scale (PASS). PCS was also evaluated for the pain pertaining to the experiment. MSNA was recorded from the common peroneal nerve, during a 45-minute intramuscular infusion of hypertonic saline solution in the tibialis anterior of 68 awake human subjects. Fourty-one subjects showed an increase in MSNA amplitude, while 27 showed a decrease. Neither of the measured psychological parameters showed significant differences between the increasing and the decreasing groups. These results suggest that our measured psychological levels do not influence the direction of the sympathetic response to long-lasting experimental muscle pain in healthy human subjects. References Fazalbhoy, A., Birznieks, I., & Macefield, V. G. (2012). Individual differences in the cardiovascular responses to tonic muscle pain: parallel increases or decreases in muscle sympathetic nerve activity, blood pressure and heart rate. Experimental Physiology, 97, 1084–1092. Fazalbhoy, A., Birznieks, I., & Macefield, V. G. (2014). Consistent interindividual increases or decreases in muscle sympathetic nerve activity during experimental muscle pain. Experimental Brain Research, 232(4), 1309-13015; doi: 10.1007/s00221-014-3847-7. Keywords: Muscle pain, Anxiety, Pain vigilance, Pain catastrophising, Pain anxiety, muscle sympathetic nerve activity Conference: ASP2015 - 25th Annual Conference of the Australasian Society for Psychophysiology, Sydney, Australia, 2 Dec - 4 Dec, 2015. Presentation Type: Oral Presentation Topic: Psychophysiology Citation: Kobuch S, Brown R, Fazalbhoy A and Macefield VG (2015). Inter-individual responses to experimental muscle pain: baseline anxiety ratings and attitudes to pain do not determine the direction of the sympathetic response to tonic muscle pain in humans. Conference Abstract: ASP2015 - 25th Annual Conference of the Australasian Society for Psychophysiology. doi: 10.3389/conf.fnhum.2015.219.00050 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 24 Oct 2015; Published Online: 30 Nov 2015. * Correspondence: Miss. Sophie Kobuch, Western Sydney University, Medicine, Penrith, NSW, 2751, Australia, kobuchso@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Sophie Kobuch Rachael Brown Azharuddin Fazalbhoy Vaughan G Macefield Google Sophie Kobuch Rachael Brown Azharuddin Fazalbhoy Vaughan G Macefield Google Scholar Sophie Kobuch Rachael Brown Azharuddin Fazalbhoy Vaughan G Macefield PubMed Sophie Kobuch Rachael Brown Azharuddin Fazalbhoy Vaughan G Macefield Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Features and timing of the response of single neurons to novelty in the substantia nigra

Substantia nigra neurons are known to play a key role in normal cognitive processes and disease states. While animal models and neuroimaging studies link dopamine neurons to novelty detection, this has not been demonstrated electrophysiologically in humans. We used single neuron extracellular recordings in awake human subjects undergoing surgery for Parkinson disease to characterize the features and timing of this response in the substantia nigra. We recorded 49 neurons in the substantia nigra. Using an auditory oddball task, we showed that they fired more rapidly following novel sounds than repetitive tones. The response was biphasic with peaks at approximately 250ms, comparable to that described in primate studies, and a second peak at 500ms. This response was primarily driven by slower firing neurons as firing rate was inversely correlated to novelty response. Our data provide human validation of the purported role of dopamine neurons in novelty detection and suggest modifications to proposed models of novelty detection circuitry.

Reconstructing integration in sympathetic ganglia

This talk introduces a symposium focusing on current efforts to dissect nicotinic and non-nicotinic mechanisms of synaptic transmission in autonomic ganglia and their integrative consequences in health and disease. We begin with a general theory of ganglionic integration. This framework incorporates basic features of synaptic divergence and convergence that operate in most paravertebral sympathetic ganglia. The goal is to reconstruct the integrative properties of ganglia from the bottom up beginning with nicotinic synapses and using information from the literature describing natural patterns of activity observed in experimental animals and in awake human subjects.

Polyvinylidene fluoride film based nasal sensor to monitor human respiration pattern: An initial clinical study

Design and development of a piezoelectric polyvinylidene fluoride (PVDF) thin film based nasal sensor to monitor human respiration pattern (RP) from each nostril simultaneously is presented in this paper. Thin film based PVDF nasal sensor is designed in a cantilever beam configuration. Two cantilevers are mounted on a spectacle frame in such a way that the air flow from each nostril impinges on this sensor causing bending of the cantilever beams. Voltage signal produced due to air flow induced dynamic piezoelectric effect produce a respective RP. A group of 23 healthy awake human subjects are studied. The RP in terms of respiratory rate (RR) and Respiratory air-flow changes/alterations obtained from the developed PVDF nasal sensor are compared with RP obtained from respiratory inductance plethysmograph (RIP) device. The mean RR of the developed nasal sensor (19.65±4.1) and the RIP (19.57±4.1) are found to be almost same (difference not significant, p>0.05) with the correlation coefficient 0.96, p<0.0001. It was observed that any change/alterations in the pattern of RIP is followed by same amount of change/alterations in the pattern of PVDF nasal sensor with k=0.815 indicating strong agreement between the PVDF nasal sensor and RIP respiratory air-flow pattern. The developed sensor is simple in design, non-invasive, patient friendly and hence shows promising routine clinical usage. The preliminary result shows that this new method can have various applications in respiratory monitoring and diagnosis.

Cardiorespiratory coupling of sympathetic outflow in humans: a comparison of respiratory and cardiac modulation of sympathetic nerve activity to skin and muscle

What is the central question of this study?Muscle sympathetic nerve activity (MSNA) is well known to be modulated by the arterial baroreceptors and respiration, but what are the magnitudes of cardiac and respiratory modulation of skin sympathetic nerve activity (SSNA), which primarily subserves thermoregulation?What is the main finding and what is its importance?Using direct microelectrode recordings of MSNA and SSNA in awake humans, we show that the magnitude of respiratory modulation of SSNA is identical to that of MSNA, the primary difference between the two sources of sympathetic outflow being the greater cardiac modulation of MSNA. This emphasises the role of the baroreceptors in entraining sympathetic outflow to muscle. It is well known that microelectrode recordings of skin sympathetic nerve activity (SSNA) in awake human subjects reveal spontaneous bursts of activity with no overt modulation by changes in blood pressure or respiration, in contrast to the clear cardiac and respiratory modulation of muscle sympathetic nerve activity (MSNA). However, cross-correlation analysis has revealed that, like individual muscle vasoconstrictor neurones, the firing of individual cutaneous vasoconstrictor neurones is temporally coupled to both the cardiac and respiratory rhythms during cold-induced cutaneous vasoconstriction, and the same is true of single sudomotor neurones during heat-induced sweating. Here, we used cross-correlation analysis to determine whether SSNA exhibits cardiac and respiratory modulation in thermoneutral conditions and to compare respiratory and cardiac modulation of SSNA with that of MSNA. Oligounitary recordings of spontaneous SSNA (n = 20) and MSNA (n = 18) were obtained during quiet, unrestrained breathing. Respiration was recorded by a strain-gauge transducer around the chest and ECG recorded by surface electrodes. Respiratory and cardiac modulation of SSNA and MSNA were quantified by fitting polynomial equations to the cross-correlation histograms constructed between the sympathetic spikes and respiration or ECG. The amplitude of the respiratory modulation (52.5 ± 3.4%) of SSNA was not significantly different from the amplitude of the cardiac modulation (46.6 ± 3.2%). Both were comparable to the respiratory modulation of MSNA (47.7 ± 4.2%), while cardiac modulation of MSNA was significantly higher (89.8 ± 1.5%). We conclude that SSNA and MSNA share similar levels of respiratory modulation, the primary difference between the two sources of sympathetic outflow being the marked cardiac modulation of MSNA provided by the baroreceptors.

The vestibular system does not modulate fusimotor drive to muscle spindles in contracting leg muscles of seated subjects

We previously showed that sinusoidal galvanic vestibular stimulation (GVS) does not modulate the firing of spontaneously active muscle spindles in relaxed human leg muscles. However, given that there is little, if any, fusimotor drive to relaxed human muscles, we tested the hypothesis that vestibular modulation of muscle spindles becomes apparent during volitional contractions at levels that engage the fusimotor system. Unitary recordings were made from 28 muscle spindle afferents via tungsten microelectrodes inserted percutaneously into the common peroneal nerve of seated awake human subjects. Twenty-one of the spindle afferents were spontaneously active at rest and each increased its firing rate during a weak static contraction; seven were silent at rest and were recruited during the contraction. Sinusoidal bipolar binaural galvanic vestibular stimulation (±2mA, 100 cycles) was applied to the mastoid processes at 0.8Hz. This continuous stimulation produced a sustained illusion of "rocking in a boat" or "swinging in a hammock" but no entrainment of EMG. Despite these robust vestibular illusions, none of the fusimotor-driven muscle spindles exhibited phase-locked modulation of firing during sinusoidal GVS. We conclude that this dynamic vestibular input was not sufficient to modulate the firing of fusimotor neurones recruited during a voluntary steady-state contraction, arguing against a significant role of the vestibular system in adjusting the sensitivity of muscle spindles via fusimotor neurones.

The effect of inhaled menthol on upper airway resistance in humans: A randomized controlled crossover study

Menthol (l-menthol) is a naturally-occurring cold receptor agonist commonly used to provide symptomatic relief for upper airway congestion. Menthol can also reduce the sensation of dyspnea. It is unclear whether the physiological action of menthol in dyspnea reduction is through its cold receptor agonist effect or whether associated mechanical changes occur in the upper airway. To determine whether menthol inhalation alters upper airway resistance in humans. A randomized, sham-controlled, single-blinded crossover study of inhaled menthol on upper airway resistance during semirecumbent quiet breathing in healthy subjects was conducted. Ten healthy participants (eight female) with a mean (± SD) age of 21±1.6 years completed the study. Nasal resistance before testing was similar on both occasions. No differences were found in respiratory frequency (mean ± SEM) (menthol 17.0±1.1 cmH2O⁄L⁄s; sham 16.9±0.9 cmH2O⁄L⁄s), minute ventilation (menthol 7.7±0.5 cmH2O⁄L⁄s; sham 7.9±0.5 cmH2O⁄L⁄s) or total inspiratory time⁄total breath time (menthol 0.4±0.1 cmH2O⁄L⁄s; sham 0.4±0.1 cmH2O⁄L⁄s). The upper airway resistance was similar during menthol (3.47±0.32 cmH2O⁄L⁄s) and sham (3.27±0.28 cmH2O⁄L⁄s) (P=0.33) inhalation. Inhalation of menthol does not alter upper airway resistance in awake human subjects.