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2.  Vestibular modulation of muscle sympathetic nerve activity during sinusoidal linear acceleration in supine humans 
The utricle and saccular components of the vestibular apparatus preferentially detect linear displacements of the head in the horizontal and vertical planes, respectively. We previously showed that sinusoidal linear acceleration in the horizontal plane of seated humans causes a pronounced modulation of muscle sympathetic nerve activity (MSNA), supporting a significant role for the utricular component of the otolithic organs in the control of blood pressure. Here we tested the hypothesis that the saccule can also play a role in blood pressure regulation by modulating lower limb MSNA. Oligounitary MSNA was recorded via tungsten microelectrodes inserted into the common peroneal nerve in 12 subjects, laying supine on a motorized platform with the head aligned with the longitudinal axis of the body. Slow sinusoidal linear accelerations-decelerations (peak acceleration ±4 mG) were applied in the rostrocaudal axis (which predominantly stimulates the saccule) and in the mediolateral axis (which also engages the utricle) at 0.08 Hz. The modulation of MSNA in the rostrocaudal axis (29.4 ± 3.4%) was similar to that in the mediolateral axis (32.0 ± 3.9%), and comparable to that obtained by stimulation of the utricle alone in seated subjects with the head vertical. We conclude that both the saccular and utricular components of the otolithic organs play a role in the control of arterial pressure during postural challenges.
PMCID: PMC4191191  PMID: 25346657
MSNA; sympathetic; utricle; saccule; vestibulosympathetic reflexes
3.  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.
PMCID: PMC4681770  PMID: 26733786
blood pressure; HRV; MSNA; muscle pain; muscle sympathetic nerve activity
4.  Skin Sympathetic Nerve Activity is Modulated during Slow Sinusoidal Linear Displacements in Supine Humans 
Low-frequency sinusoidal linear acceleration (0.08 Hz, ±4 mG) modulates skin sympathetic nerve activity (SSNA) in seated subjects (head vertical), suggesting that activation of the utricle in the peripheral vestibular labyrinth modulates SSNA. The aim of the current study was to determine whether SSNA is also modulated by input from the saccule. Tungsten microelectrodes were inserted into the common peroneal nerve to record oligounitary SSNA in 8 subjects laying supine on a motorized platform with the head aligned with the longitudinal axis of the body. Slow sinusoidal (0.08 Hz, 100 cycles) linear acceleration-decelerations (peak ±4 mG) were applied rostrocaudally to predominately activate the saccules, or mediolaterally to predominately activate the utricles. Cross-correlation histograms were constructed between the negative-going sympathetic spikes and the positive peaks of the sinusoidal stimuli. Sinusoidal linear acceleration along the rostrocaudal axis or mediolateral axis both resulted in sinusoidal modulation of SSNA (Median, IQR 27.0, 22–33% and 24.8, 17–39%, respectively). This suggests that both otolith organs act on sympathetic outflow to skin and muscle in a similar manner during supine displacements.
PMCID: PMC4754441  PMID: 26909019
SSNA; sympathetic; utricle; saccule; vestibulosympathetic reflexes
5.  Effects of 12 Months Continuous Positive Airway Pressure on Sympathetic Activity Related Brainstem Function and Structure in Obstructive Sleep Apnea 
Muscle sympathetic nerve activity (MSNA) is greatly elevated in patients with obstructive sleep apnea (OSA) during normoxic daytime wakefulness. Increased MSNA is a precursor to hypertension and elevated cardiovascular morbidity and mortality. However, the mechanisms underlying the high MSNA in OSA are not well understood. In this study we used concurrent microneurography and magnetic resonance imaging to explore MSNA-related brainstem activity changes and anatomical changes in 15 control and 15 OSA subjects before and after 6 and 12 months of continuous positive airway pressure (CPAP) treatment. We found that following 6 and 12 months of CPAP treatment, resting MSNA levels were significantly reduced in individuals with OSA. Furthermore, this MSNA reduction was associated with restoration of MSNA-related brainstem activity and structural changes in the medullary raphe, rostral ventrolateral medulla, dorsolateral pons, and ventral midbrain. This restoration occurred after 6 months of CPAP treatment and was maintained following 12 months CPAP. These findings show that continual CPAP treatment is an effective long-term treatment for elevated MSNA likely due to its effects on restoring brainstem structure and function.
PMCID: PMC4785184  PMID: 27013952
medullary raphe; dorsolateral pons; sleep disordered breathing; hypertension; rostral ventrolateral medulla
6.  Can loss of muscle spindle afferents explain the ataxic gait in Riley–Day syndrome? 
Brain  2011;134(11):3198-3208.
The Riley–Day syndrome is the most common of the hereditary sensory and autonomic neuropathies (Type III). Among the well-recognized clinical features are reduced pain and temperature sensation, absent deep tendon reflexes and a progressively ataxic gait. To explain the latter we tested the hypothesis that muscle spindles, or their afferents, are absent in hereditary sensory and autonomic neuropathy III by attempting to record from muscle spindle afferents from a nerve supplying the leg in 10 patients. For comparison we also recorded muscle spindles from 15 healthy subjects and from two patients with hereditary sensory and autonomic neuropathy IV, who have profound sensory disturbances but no ataxia. Tungsten microelectrodes were inserted percutaneously into fascicles of the common peroneal nerve at the fibular head. Intraneural stimulation within muscle fascicles evoked twitches at normal stimulus currents (10–30 µA), and deep pain (which often referred) at high intensities (1 mA). Microneurographic recordings from muscle fascicles revealed a complete absence of spontaneously active muscle spindles in patients with hereditary sensory and autonomic neuropathy III; moreover, responses to passive muscle stretch could not be observed. Conversely, muscle spindles appeared normal in patients with hereditary sensory and autonomic neuropathy IV, with mean firing rates of spontaneously active endings being similar to those recorded from healthy controls. Intraneural stimulation within cutaneous fascicles evoked paraesthesiae in the fascicular innervation territory at normal stimulus intensities, but cutaneous pain was never reported during high-intensity stimulation in any of the patients. Microneurographic recordings from cutaneous fascicles revealed the presence of normal large-diameter cutaneous mechanoreceptors in hereditary sensory and autonomic neuropathy III. Our results suggest that the complete absence of functional muscle spindles in these patients explains their loss of deep tendon reflexes. Moreover, we suggest that their ataxic gait is sensory in origin, due to the loss of functional muscle spindles and hence a compromised sensorimotor control of locomotion.
PMCID: PMC3212710  PMID: 22075519
congenital insensitivity to pain; familial dysautonomia; HSAN; microneurography; muscle spindles; peripheral nerve; Riley–Day syndrome
7.  Somatosympathetic Vasoconstrictor Reflexes in Human Spinal Cord Injury: Responses to Innocuous and Noxious Sensory Stimulation below Lesion 
It is known that the sudden increases in blood pressure associated with autonomic dysreflexia in people with spinal cord injury (SCI) are due to a spinally mediated reflex activation of sympathetic vasoconstrictor neurons supplying skeletal muscle and the gut. Apart from visceral inputs, such as those originating from a distended bladder, there is a prevailing opinion that autonomic dysreflexia can be triggered by noxious stimulation below the lesion. However, do noxious inputs really cause an increase in blood pressure in SCI? Using microelectrodes inserted into a peripheral nerve to record sympathetic nerve activity we had previously shown that selective stimulation of small-diameter afferents in muscle or skin, induced by bolus injection of hypertonic saline into the tibialis anterior muscle or the overlying skin, evokes a sustained increase in muscle sympathetic nerve activity and blood pressure and a transient increase in skin sympathetic nerve activity and decrease in skin blood flow in able-bodied subjects. We postulated that these sympathetic responses would be exaggerated in SCI, with a purely noxious stimulus causing long-lasting increases in blood pressure and long-lasting decreases in skin blood flow. Surprisingly, though, we found that intramuscular or subcutaneous injection of hypertonic saline into the leg caused negligible changes in these parameters. Conversely, weak electrical stimulation over the abdominal wall, which in able-bodied subjects is not painful and activates large-diameter cutaneous afferents, caused a marked increase in blood pressure in SCI but not in able-bodied subjects. This suggests that it is activation of large-diameter somatic afferents, not small-diameter afferents, that triggers increases in sympathetic outflow in SCI. Whether the responses to activation of large-diameter afferents reflect plastic changes in the spinal cord in SCI is unknown.
PMCID: PMC3382416  PMID: 22737131
autonomic dysreflexia; innocuous stimulation; noxious stimulation; spinal cord injury; sympathetic nervous system
8.  Firing Patterns of Muscle Vasoconstrictor Neurons in Respiratory Disease 
Because the cardiovascular system and respiration are so intimately coupled, disturbances in respiratory control often lead to disturbances in cardiovascular control. Obstructive Sleep Apnea (OSA), Chronic Obstructive Pulmonary Disease (COPD), and Bronchiectasis (BE) are all associated with a greatly elevated muscle vasoconstrictor drive (muscle sympathetic nerve activity, MSNA). Indeed, the increase in MSNA is comparable to that seen in congestive heart failure (CHF), in which the increase in MSNA compensates for the reduced cardiac output and thereby assists in maintaining blood pressure. However, in OSA – but not COPD or BE – the increase in MSNA can lead to hypertension. Here, the features of the sympathoexcitation in OSA, COPD, and BE are reviewed in terms of the firing properties of post-ganglionic muscle vasoconstrictor neurons. Compared to healthy subjects with low levels of resting MSNA, single-unit recordings revealed that the augmented MSNA seen in OSA, BE, COPD, and CHF were each associated with an increase in firing probability and mean firing rates of individual neurons. However, unlike patients with heart failure, all patients with respiratory disease exhibited an increase in multiple within-burst firing which, it is argued, reflects an increase in central sympathetic drive. Similar patterns to those seen in OSA, COPD, and BE were seen in healthy subjects during an acute increase in muscle vasoconstrictor drive. These observations emphasize the differences by which the sympathetic nervous system grades its output in health and disease, with an increase in firing probability of active neurons and recruitment of additional neurons being the dominant mechanisms.
PMCID: PMC3358712  PMID: 22654767
bronchiectasis; chronic obstructive pulmonary disease; obstructive sleep apnea; microneurography; single-unit; sympathoexcitation
9.  On the Number of Preganglionic Neurons Driving Human Postganglionic Sympathetic Neurons: A Comparison of Modeling and Empirical Data 
Postganglionic sympathetic axons in awake healthy human subjects, regardless of their identity as muscle vasoconstrictor, cutaneous vasoconstrictor, or sudomotor neurons, discharge with a low firing probability (∼30%), generate low firing rates (∼0.5 Hz) and typically fire only once per cardiac interval. The purpose of the present study was to use modeling of spike trains in an attempt to define the number of preganglionic neurons that drive an individual postganglionic neuron. Artificial spike trains were generated in 1–3 preganglionic neurons converging onto a single postganglionic neuron. Each preganglionic input fired with a mean interval distribution of either 1000, 1500, 2000, 2500, or 3000 ms and the SD varied between 0.5×, 1.0×, and 2.0× the mean interval; the discharge frequency of each preganglionic neuron exhibited positive skewness and kurtosis. Of the 45 patterns examined, the mean discharge properties of the postganglionic neuron could only be explained by it being driven by, on average, two preganglionic neurons firing with a mean interspike interval of 2500 ms and SD of 5000 ms. The mean firing rate resulting from this pattern was 0.22 Hz, comparable to that of spontaneously active muscle vasoconstrictor neurons in healthy subjects (0.40 Hz). Likewise, the distribution of the number of spikes per cardiac interval was similar between the modeled and actual data: 0 spikes (69.5 vs 66.6%), 1 spike (25.6 vs 21.2%), 2 spikes (4.3 vs 6.4%), 3 spikes (0.5 vs 1.7%), and 4 spikes (0.1 vs 0.7%). Although some features of the firing patterns could be explained by the postganglionic neuron being driven by a single preganglionic neuron, none of the emulated firing patterns generated by the firing of three preganglionic neurons matched the discharge of the real neurons. These modeling data indicate that, on average, human postganglionic sympathetic neurons are driven by two preganglionic inputs.
PMCID: PMC3230824  PMID: 22164130
sympathetic nervous system; human; preganglionic neuron; postganglionic neuron; single-unit; microneurography
10.  Vestibulo-Sympathetic Responses 
Comprehensive Physiology  2014;4(2):851-887.
Evidence accumulated over 30 years, from experiments on animals and human subjects, has conclusively demonstrated that inputs from the vestibular otolith organs contribute to the control of blood pressure during movement and changes in posture. This review considers the effects of gravity on the body axis, and the consequences of postural changes on blood distribution in the body. It then separately considers findings collected in experiments on animals and human subjects demonstrating that the vestibular system regulates blood distribution in the body during movement. Vestibulosympathetic reflexes differ from responses triggered by unloading of cardiovascular receptors such as baroreceptors and cardiopulmonary receptors, as they can be elicited before a change in blood distribution occurs in the body. Dissimilarities in the expression of vestibulosympathetic reflexes in humans and animals are also described. In particular, there is evidence from experiments in animals, but not humans, that vestibulosympathetic reflexes are patterned, and differ between body regions. Results from neurophysiological and neuroanatomical studies in animals are discussed that identify the neurons that mediate vestibulosympathetic responses, which include cells in the caudal aspect of the vestibular nucleus complex, interneurons in the lateral medullary reticular formation, and bulbospinal neurons in the rostral ventrolateral medulla (RVLM). Recent findings showing that cognition can modify the gain of vestibulosympathetic responses are also presented, and neural pathways that could mediate adaptive plasticity in the responses are proposed, including connections of the posterior cerebellar vermis with the vestibular nuclei and brainstem nuclei that regulate blood pressure.
PMCID: PMC3999523  PMID: 24715571
11.  Reversal of functional changes in the brain associated with obstructive sleep apnoea following 6 months of CPAP 
NeuroImage : Clinical  2015;7:799-806.
Obstructive sleep apnoea (OSA) is associated with an increase in the number of bursts of muscle sympathetic nerve activity (MSNA), leading to neurogenic hypertension. Continuous positive airway pressure (CPAP) is the most effective and widely used treatment for preventing collapse of the upper airway in OSA. In addition to improving sleep, CPAP decreases daytime MSNA towards control levels. It remains unknown how this restoration of MSNA occurs, in particular whether CPAP treatment results in a simple readjustment in activity of those brain regions responsible for the initial increase in MSNA or whether other brain regions are recruited to over-ride aberrant brain activity. By recording MSNA concurrently with functional Magnetic Resonance Imaging (fMRI), we aimed to assess brain activity associated with each individual subject's patterns of MSNA prior to and following 6 months of CPAP treatment. Spontaneous fluctuations in MSNA were recorded via tungsten microelectrodes inserted into the common peroneal nerve in 13 newly diagnosed patients with OSA before and after 6 months of treatment with CPAP and in 15 healthy control subjects while lying in a 3 T MRI scanner. Blood Oxygen Level Dependent (BOLD) contrast gradient echo, echo-planar images were continuously collected in a 4 s ON, 4 s OFF (200 volumes) sampling protocol. MSNA was significantly elevated in newly diagnosed OSA patients compared to control subjects (55 ± 4 vs 26 ± 2 bursts/min). Fluctuations in BOLD signal intensity in multiple regions covaried with the intensity of the concurrently recorded bursts of MSNA. There was a significant fall in MSNA after 6 months of CPAP (39 ± 2 bursts/min). The reduction in resting MSNA was coupled with significant falls in signal intensity in precuneus bilaterally, the left and right insula, right medial prefrontal cortex, right anterior cingulate cortex, right parahippocampus and the left and right retrosplenial cortices. These data support our contention that functional changes in these suprabulbar sites are, via projections to the brainstem, driving the augmented sympathetic outflow to the muscle vascular bed in untreated OSA.
•Obstructive sleep apnoea increases muscle sympathetic nerve activity (MSNA).•fMRI was used to identify brain sites temporally coupled to the increase in MSNA.•Augmented BOLD signal intensity occurred in several cortical and subcortical sites.•These changes were reversed following 6 months of CPAP, which reduced the MSNA.
PMCID: PMC4459270  PMID: 26082888
Hypertension; Muscle sympathetic nerve activity; Obstructive sleep apnoea
12.  Baroreflex modulation of muscle sympathetic nerve activity at rest does not differ between morning and afternoon 
The incidence of cardiovascular events is significantly higher in the morning than other times of day. This has previously been associated with poor blood pressure control via the cardiac baroreflex. However, it is not known whether diurnal variation exists in vascular sympathetic baroreflex function, in which blood pressure is regulated via muscle sympathetic nerve activity (MSNA). The aim of this study was to compare vascular sympathetic baroreflex sensitivity (BRS) in the same participants between the morning and afternoon. In 10 participants (mean age 22 ± 2.9 years), continuous measurements of blood pressure, heart rate and MSNA were made during 10 min of rest in the morning (between 0900 and 1000 h) and afternoon (between 1400 and 1500 h). Spontaneous vascular sympathetic BRS was quantified by plotting MSNA burst incidence against diastolic pressure (vascular sympathetic BRSinc), and by plotting total MSNA against diastolic pressure (vascular sympathetic BRStotal). Significant vascular sympathetic BRSinc and vascular sympathetic BRStotal slopes were obtained for 10 participants at both times of day. There was no significant difference in vascular sympathetic BRSinc between morning (−2.2 ± 0.6% bursts/mmHg) and afternoon (−2.5 ± 0.2% bursts/mmHg; P = 0.68) sessions. Similarly, vascular sympathetic BRStotal did not differ significantly between the morning (−3.0±0.5 AU/beat/mmHg) and afternoon (−2.9 ± 0.4 AU/beat/mmHg; P = 0.89). It is concluded that in healthy, young individuals baroreflex modulation of MSNA at rest does not differ between the morning and afternoon. The results indicate that recording MSNA at different times of the day is a valid means of assessing sympathetic function.
PMCID: PMC4557114  PMID: 26388723
muscle sympathetic nerve activity; blood pressure; baroreflex sensitivity; diurnal variation; circadian
13.  Functional and structural changes in the brain associated with the increase in muscle sympathetic nerve activity in obstructive sleep apnoea 
NeuroImage : Clinical  2014;6:275-283.
Muscle sympathetic nerve activity (MSNA) is greatly elevated in patients with obstructive sleep apnoea (OSA) during daytime wakefulness, leading to hypertension, but the underlying mechanisms are poorly understood. By recording MSNA concurrently with functional Magnetic Resonance Imaging (fMRI) of the brain we aimed to identify the central processes responsible for the sympathoexcitation. Spontaneous fluctuations in MSNA were recorded via tungsten microelectrodes inserted percutaneously into the common peroneal nerve in 17 OSA patients and 15 healthy controls lying in a 3 T MRI scanner. Blood Oxygen Level Dependent (BOLD) contrast gradient echo, echo-planar images were continuously collected in a 4 s ON, 4 s OFF (200 volumes) sampling protocol. Fluctuations in BOLD signal intensity covaried with the intensity of the concurrently recorded bursts of MSNA. In both groups there was a positive correlation between MSNA and signal intensity in the left and right insulae, dorsolateral prefrontal cortex (dlPFC), dorsal precuneus, sensorimotor cortex and posterior temporal cortex, and the right mid-cingulate cortex and hypothalamus. In OSA the left and right dlPFC, medial PFC (mPFC), dorsal precuneus, anterior cingulate cortex, retrosplenial cortex and caudate nucleus showed augmented signal changes compared with controls, while the right hippocampus/parahippocampus signal intensity decreased in controls but did not change in the OSA subjects. In addition, there were significant increases in grey matter volume in the left mid-insula, the right insula, left and right primary motor cortices, left premotor cortex, left hippocampus and within the brainstem and cerebellum, and significant decreases in the mPFC, occipital lobe, right posterior cingulate cortex, left cerebellar cortex and the left and right amygdala in OSA, but there was no overlap between these structural changes and the functional changes in OSA. These data suggest that the elevated muscle vasoconstrictor drive in OSA may result from functional changes within these brain regions, which are known to be directly or indirectly involved in the modulation of sympathetic outflow via the brainstem. That there was no overlap in the structural and functional changes suggests that asphyxic damage due to repeated episodes of nocturnal obstructive apnoea is not the main cause of the sympathoexcitation.
•Obstructive sleep apnea increases muscle sympathetic nerve activity (MSNA).•fMRI was used to identify brain sites temporally coupled to the increase in MSNA.•Augmented BOLD signal intensity occurred in several cortical and subcortical sites.•The elevated MSNA in OSA may result from functional changes within these sites.
PMCID: PMC4215471  PMID: 25379440
fMRI; Microneurography; Muscle sympathetic nerve activity; Obstructive sleep apnoea
14.  Disturbances in affective touch in hereditary sensory & autonomic neuropathy type III 
Hereditary sensory and autonomic neuropathy type III (HSAN III, Riley–Day syndrome, Familial Dysautomia) is characterised by elevated thermal thresholds and an indifference to pain. Using microelectrode recordings we recently showed that these patients possess no functional stretch-sensitive mechanoreceptors in their muscles (muscle spindles), a feature that may explain their lack of stretch reflexes and ataxic gait, yet patients have apparently normal low-threshold cutaneous mechanoreceptors. The density of C-fibres in the skin is markedly reduced in patients with HSAN III, but it is not known whether the C-tactile afferents, a distinct type of low-threshold C fibre present in hairy skin that is sensitive to gentle stroking and has been implicated in the coding of pleasant touch are specifically affected in HSAN III patients. We addressed the relationship between C-tactile afferent function and pleasant touch perception in 15 patients with HSAN III and 15 age-matched control subjects. A soft make-up brush was used to apply stroking stimuli to the forearm and lateral aspect of the leg at five velocities: 0.3, 1, 3, 10 and 30 cm/s. As demonstrated previously, the control subjects rated the slowest and highest velocities as less pleasant than those applied at 1–10 cm/s, which fits with the optimal velocities for exciting C-tactile afferents. Conversely, for the patients, ratings of pleasantness did not fit the profile for C-tactile afferents. Patients either rated the higher velocities as more pleasant than the slow velocities, with the slowest velocities being rated unpleasant, or rated all velocities equally pleasant. We interpret this to reflect absent or reduced C-tactile afferent density in the skin of patients with HSAN III, who are likely using tactile cues (i.e. myelinated afferents) to rate pleasantness of stroking or are attributing pleasantness to this type of stimulus irrespective of velocity.
•C-tactile afferents in hairy skin are believed to mediate affective touch.•They are sensitive to slow brushing stimuli, which are perceived as pleasant.•It is not known whether C-tactile afferents are affected in HSAN III.•Ratings of pleasantness were reduced in 15 HSAN III patients compared to controls.•We suggest that the density of C-tactile afferents is reduced in HSAN III.
PMCID: PMC4078239  PMID: 24726998
Affective touch; CT afferents; Pleasant touch; Tactile sensation
15.  Effect of contraction intensity on sympathetic nerve activity to active human skeletal muscle 
The effect of contraction intensity on muscle sympathetic nerve activity (MSNA) to active human limbs has not been established. To address this, MSNA was recorded from the left peroneal nerve during and after dorsiflexion contractions sustained for 2 min by the left leg at ~10, 25, and 40% MVC. To explore the involvement of the muscle metaboreflex, limb ischemia was imposed midway during three additional contractions and maintained during recovery. Compared with total MSNA at rest (11.5 ± 4.1 mv.min−1), MSNA in the active leg increased significantly at the low (21.9 ± 13.6 mv.min−1), medium (30.5 ± 20.8 mv.min−1), and high (50.0 ± 24.5 mv.min−1) intensities. This intensity-dependent effect was more strongly associated with increases in MSNA burst amplitude than burst frequency. Total MSNA then returned to resting levels within the first minute of recovery. Limb ischemia had no significant influence on the intensity-dependent rise in MSNA or its decline during recovery in the active leg. These findings reveal intensity-dependent increases in total MSNA and burst amplitude to contracting human skeletal muscle that do not appear to involve the muscle metaboreflex.
PMCID: PMC4042086  PMID: 24917823
muscle; contraction; metaboreflex; sympathetic; ischemia
Hereditary sensory and autonomic neuropathy type III features a marked ataxic gait that progressively worsens over time. We assessed whether proprioceptive disturbances can explain the ataxia. Proprioception at the knee joint was assessed using passive joint angle matching in 18 patients and 14 age-matched controls; 5 patients with cerebellar ataxia were also studied. Ataxia was quantified using the Brief Ataxia Rating Score, which ranged from 7 to 26/30. Neuropathy patients performed poorly in judging joint position: mean absolute error was 8.7±1.0° and the range was very wide (2.8–18.1°); conversely, absolute error was only 2.7±0.3° (1.6–5.5°) in the controls and 3.0±0.2° (2.1–3.4°) in the cerebellar patients. This error was positively correlated to the degree of ataxia in the neuropathy patients but not the cerebellar patients, suggesting that poor proprioceptive acuity at the knee joint is a major contributor to the ataxic gait associated with hereditary sensory and autonomic neuropathy type III.
PMCID: PMC3694996  PMID: 23681701
congenital insensitivity to pain; familial dysautonomia; joint sense; hereditary sensory & autonomic neuropathy; muscle spindles; proprioception; Riley-Day syndrome
17.  Skin sympathetic nerve activity in humans during exposure to emotionally-charged images: sex differences 
While it is known that anxiety or emotional arousal affects skin sympathetic nerve activity (SSNA), the galvanic skin response (GSR) is the most widely used parameter to infer increases in SSNA during stress or emotional studies. We recently showed that SSNA provides a more sensitive measure of emotional state than effector-organ responses. The aim of the present study was to assess whether there are gender differences in the responses of SSNA and other physiological parameters such as blood pressure, heart rate, skin blood flow and sweat release, while subjects viewed neutral or emotionally-charged images from the International Affective Picture System (IAPS). Changes in SSNA were assessed using microneurography in 20 subjects (10 male and 10 female). Blocks of positively-charged (erotica) or negatively-charge images (mutilation) were presented in a quasi-random fashion, following a block of neutral images, with each block containing 15 images and lasting 2 min. Images of both erotica and mutilation caused significant increases in SSNA, with increases being greater for males viewing erotica and greater for females viewing mutilation. The increases in SSNA were often coupled with sweat release and cutaneous vasoconstriction; however, these markers were not significantly different than those produced by viewing neutral images and were not always consistent with the SSNA increases. We conclude that SSNA increases with both positively-charged and negatively-charged emotional images, yet sex differences are present.
PMCID: PMC3958733  PMID: 24678303
skin sympathetic nerve activity; emotional processing; sex differences; sweat release; microneurography
18.  Functional Imaging of the Human Brainstem during Somatosensory Input and Autonomic Output 
Over the past half a century, many investigations in experimental animal have explored the functional roles of specific regions in the brainstem. Despite the accumulation of a considerable body of knowledge in, primarily, anesthetized preparations, relatively few studies have explored brainstem function in awake humans. It is important that human brainstem function is explored given that many neurological conditions, from obstructive sleep apnea, chronic pain, and hypertension, likely involve significant changes in the processing of information within the brainstem. Recent advances in the collection and processing of magnetic resonance images have resulted in the possibility of exploring brainstem activity changes in awake healthy individuals and in those with various clinical conditions. We and others have begun to explore changes in brainstem activity in humans during a number of challenges, including cutaneous and muscle pain, as well as during maneuvers that evoke increases in sympathetic nerve activity. More recently we have successfully recorded sympathetic nerve activity concurrently with functional magnetic resonance imaging of the brainstem, which will allow us, for the first time to explore brainstem sites directly responsible for conditions such as hypertension. Since many pathophysiological conditions no doubt involve changes in brainstem function and structure, defining these changes will likely result in a greater ability to develop more effective treatment regimens.
PMCID: PMC3775150  PMID: 24062670
trigeminal nuclei; dorsal column nuclei; pain; sympathetic nerve activity; rostral ventrolateral medulla
19.  Autonomic markers of emotional processing: skin sympathetic nerve activity in humans during exposure to emotionally charged images 
The sympathetic innervation of the skin primarily subserves thermoregulation, but the system has also been commandeered as a means of expressing emotion. While it is known that the level of skin sympathetic nerve activity (SSNA) is affected by anxiety, the majority of emotional studies have utilized the galvanic skin response as a means of inferring increases in SSNA. The purpose of the present study was to characterize the changes in SSNA when showing subjects neutral or emotionally charged images from the International Affective Picture System (IAPS). SSNA was recorded via tungsten microelectrodes inserted into cutaneous fascicles of the common peroneal nerve in ten subjects. Neutral images, positively charged images (erotica) or negatively charged images (mutilation) were presented in blocks of fifteen images of a specific type, each block lasting 2 min. Images of erotica or mutilation were presented in a quasi-random fashion, each block following a block of neutral images. Both images of erotica or images of mutilation caused significant increases in SSNA, but the increases in SSNA were greater for mutilation. The increases in SSNA were often coupled with sweat release and cutaneous vasoconstriction; however, these markers were not always consistent with the SSNA increases. We conclude that SSNA, comprising cutaneous vasoconstrictor and sudomotor activity, increases with both positively charged and negatively charged emotional images. Measurement of SSNA provides a more comprehensive assessment of sympathetic outflow to the skin than does the use of sweat release alone as a marker of emotional processing.
PMCID: PMC3461643  PMID: 23060818
skin sympathetic nerve activity; emotionally charged images; microneurography; sweat release; skin blood flow
20.  Modulation of Human Muscle Spindle Discharge by Arterial Pulsations - Functional Effects and Consequences 
PLoS ONE  2012;7(4):e35091.
Arterial pulsations are known to modulate muscle spindle firing; however, the physiological significance of such synchronised modulation has not been investigated. Unitary recordings were made from 75 human muscle spindle afferents innervating the pretibial muscles. The modulation of muscle spindle discharge by arterial pulsations was evaluated by R-wave triggered averaging and power spectral analysis. We describe various effects arterial pulsations may have on muscle spindle afferent discharge. Afferents could be “driven” by arterial pulsations, e.g., showing no other spontaneous activity than spikes generated with cardiac rhythmicity. Among afferents showing ongoing discharge that was not primarily related to cardiac rhythmicity we illustrate several mechanisms by which individual spikes may become phase-locked. However, in the majority of afferents the discharge rate was modulated by the pulse wave without spikes being phase locked. Then we assessed whether these influences changed in two physiological conditions in which a sustained increase in muscle sympathetic nerve activity was observed without activation of fusimotor neurones: a maximal inspiratory breath-hold, which causes a fall in systolic pressure, and acute muscle pain, which causes an increase in systolic pressure. The majority of primary muscle spindle afferents displayed pulse-wave modulation, but neither apnoea nor pain had any significant effect on the strength of this modulation, suggesting that the physiological noise injected by the arterial pulsations is robust and relatively insensitive to fluctuations in blood pressure. Within the afferent population there was a similar number of muscle spindles that were inhibited and that were excited by the arterial pulse wave, indicating that after signal integration at the population level, arterial pulsations of opposite polarity would cancel each other out. We speculate that with close-to-threshold stimuli the arterial pulsations may serve as an endogenous noise source that may synchronise the sporadic discharge within the afferent population and thus facilitate the detection of weak stimuli.
PMCID: PMC3328488  PMID: 22529975

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