Browsing by Author "Macefield, Vaughan G."

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Founder mutation in IKBKAP gene causes vestibular impairment in familial dysautonomia
(2018) Macefield, Vaughan G.
Objective: To assess vestibular function in patients with familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy – caused by a mutation in the IKBKAP gene (c.2204 + 6 T > C) – and characterized by marked gait ataxia. Methods: Cervical and vestibular evoked myogenic potentials (cVEMPs and oVEMPs) were recorded from the sternocleidomastoid (SCM) and extraocular muscles in 14 homozygous patients, 2 heterozygous patients, and 15 healthy controls during percussion of the forehead. Results: cVEMP and oVEMP amplitudes were significantly lower, and peak latencies significantly delayed, in the FD patients. There were no differences in overall EMG during attempted maximal voluntary contractions of the SCM muscle, suggesting intact efferent function. The two heterozygotes with a minor haplotype missense (R696P) mutation in exon 19 of the IKBKAP gene had cVEMP responses less affected than the homozygous. Conclusions: The founder mutation in the IKBKAP gene affects the development of vestibular afferent pathways, leading to attenuated cVEMPs. Significance: Vestibular abnormalities may contribute to the gait ataxia in FD.
The metaboreflex does not contribute to the increase in muscle sympathetic nerve activity to contracting muscle during static exercise in humans
(2018-01-08) Macefield, Vaughan G.
Abstract: Both central command and metaboreflex inputs from contracting muscles increase muscle sympathetic nerve activity (MSNA) to non-contracting muscle during sustainedisometric exercise. We recently showed that MSNA to contracting muscle also increases in an intensity-dependent manner, although whether this can be sustained by the metaboreflex is unknown. MSNA was recorded from the left common peroneal nerve and individual spikes of MSNA extracted from the nerve signal. Eleven subjects performed a series of 4 min dorsiflexions of the left ankle at 10% of maximum voluntary contraction under three conditions: without ischaemia, with 6 min of post-exercise ischaemia, and with ischaemia during and after exercise;these were repeated in the right leg. Compared with pre-contraction values, MSNA to the contracting muscles increased and plateaued in the first minute of contraction (50±18vs.34±10 spikes min−1,P=0.01), returned to pre-contraction levels within 1 min of the contraction ending and was not influenced by ischaemia during or after contraction. Conversely, MSNA to the non-contracting muscles was not different from pre-contraction levels in the first minute of contraction (34±9vs.32±5 spikes min−1,P=0.48), whereas it increased each minute and was significantly greater by the second minute (44±8 spikes min−1,P=0.01).Ischaemia augmented the MSNA response to contraction (63±25 spikes min−1after 4 min,P<0.05) and post-exercise ischaemia (63±27 spikes min−1after 6 min,P<0.01) for the non-contracting muscles only. These findings support our conclusion that the metaboreflex is not expressed in the contracting muscle during sustained static exercise.
Muscle sympathetic nerve activity and hemodynamic responses to venous distension: does sex play a role?
(2019) Macefield, Vaughan G.
Peripheral venous distension mechanically stimulates type III/IV sensory fibers in veins and evokes pressor and sympathoexcitatory reflex responses in humans. As young women have reduced venous compliance and impaired sympathetic transduction, we tested the hypothesis that pressor and sympathoexcitatory responses to venous distension may be attenuated in women compared with men. Mean arterial pressure (photoplethysmography), heart rate (HR), stroke volume (SV; Modelflow), cardiac output (CO = HR x SV), muscle sympathetic nerve activity (MSNA), femoral artery blood flow, and femoral artery conductance (Doppler ultrasound) were quantified in eight men (27 ± 4 yr) and nine women (28 ± 4 yr) before [control (CON)], during (INF), and immediately after (post- INF) a local infusion of saline [5% of the total forearm volume (30 ml/min); the infusion time was 2 ± 1 and 1 ± 1 min (P = 0.0001) for men and women, respectively] through a retrograde catheter inserted into an antecubital vein, to which venous drainage and arterial supply had been occluded. Mean arterial pressure increased during and after infusion in both groups (vs. the CON group, P < 0.05), but women showed a smaller pressor response in the post-INF period (Δ+7.2 ± 2.0 vs. Δ +18.3 ± 3.9 mmHg in men, P = 0.019). MSNA increased and femoral artery conductance decreased similarly in both groups (vs. the CON group, P<0.05) at post-INF. Although HR changes were similar, increases in SV (Δ +20.4 ± 8.6 vs. Δ +2.6 ± 2.7 ml, P = 0.05) and CO (Δ +0.84 ± 0.17 vs. Δ +0.34 ± 0.10 l/min, P = 0.024) were greater in men compared with women. Therefore, venous distension evokes a smaller pressor response in young women due to attenuated cardiac adjustments rather than reduced venous compliance or sympathetic transduction. NEW & NOTEWORTHY We found that the pressor response to venous distension was attenuated in young women compared with age-matched men. This was due to attenuated cardiac adjustments rather than reduced venous compliance, sympathetic activation, or impaired transduction and vascular control. Collectively, these findings suggest that an attenuated venous distension reflex could be involved in orthostatic intolerance in young women.
Muscle sympathetic nerve activity peaks in the first trimester in healthy pregnancy: a longitudinal case study
(2017-07-03) Macefield, Vaughan G.
Objective and methods: Muscle sympathetic nerve activity and baroreflex sensitivity were examined at rest before, during (weeks 6, 11, 17, 22, 25, 33 and 36) and after a normotensive pregnancy. Results: Muscle sympathetic nerve activity is elevated during pregnancy with a large peak in the first trimester (D17 bursts/min) and a secondary peak in the third trimester (D11 bursts/min). Cardiac baroreflex sensitivity peaked in the first trimester (10 vs. 6 ms/mmHg prepregnancy), whereas sympathetic baroreflex sensitivity was greater throughout. Interpretation: The increase in sympathetic outflow early in pregnancy cannot be explained by a reduction in baroreflex sensitivity, while the secondary increase in burst frequency in the third trimester may, in part, be explained by the elevated heart rate.
Muscle sympathetic nerve activity-coupled changes in brain activity during sustained muscle pain
(2018-02-07) Macefield, Vaughan G.
Introduction: Long-lasting experimental muscle pain elicits divergent muscle sympathetic responses, with some individuals exhibiting a persistent increase in muscle sympathetic nerve activity (MSNA), and others a decrease. These divergent responses are thought to result from sustained functional changes in specific brain regions that modulate the cardiovascular responses to pain. Aim: The aim of this study was to investigate brain regions that are functionally coupled to the generation of an MSNA burst at rest and to determine their behavior during tonic muscle pain. Methods: Functional magnetic resonance imaging of the brain was performed concurrently with microelectrode recording of MSNA from the common peroneal nerve during a 40 min infusion of hypertonic saline into the ipsilateral tibialis anterior muscle of 37 healthy human subjects. Results: At rest, blood oxygen level-dependent signal intensity coupled to bursts of MSNA increased in the rostral ventrolateral medulla, insula, dorsolateral prefrontal cortex, posterior cingulate cortex, and precuneus and decreased in the region of the midbrain periaqueductal gray. During pain, MSNA-coupled signal intensity was greater in the region of the nucleus tractus solitarius, midbrain periaqueductal gray, dorsolateral prefrontal, medial prefrontal, and anterior cingulate cortices, than at rest. Conversely, MSNA-coupled signal intensity decreased during pain in parts of the prefrontal cortex. Conclusions: These results suggest that multiple brain regions are recruited in a burst-to-burst manner, and the magnitude of these signal changes is correlated to the overall change in MSNA amplitude during tonic muscle pain.
The relationship between thalamic GABA content and resting cortical rhythm in neuropathic pain
(2018-01) Macefield, Vaughan G.
Abstract: Recurrent thalamocortical connections are integral to the generation of brain rhythms and it is thought that the inhibitory action of the thalamic reticular nucleus is critical in setting these rhythms. Our work and others’ has suggested that chronic pain that develops following nerve injury, that is, neuropathic pain, results from altered thalamocortical rhythm, although whether thisdysrhythmia is associated with thalamic inhibitory function remains unknown. In this investigation,we used electroencephalography and magnetic resonance spectroscopy to investigate cortical power and thalamic GABAergic concentration in 20 patients with neuropathic pain and 20pain-free controls. First, we found thalamocortical dysrhythmia in chronic orofacial neuropathic pain; patients displayed greater power than controls over the 4–25 Hz frequency range, most marked in the theta and low alpha bands. Furthermore, sensorimotor cortex displayed a strong positive correlation between cortical power and pain intensity. Interestingly, we found no difference in thalamic GABA concentration between pain subjects and control subjects. However, we demonstrated significant linear relationships between thalamic GABA concentration and enhanced cortical power in pain subjects but not controls. Whilst the difference in relationship between thalamic GABA concentration and resting brain rhythm between chronic pain and control subjects does not prove a cause and effect link, it is consistent with a role for thalamic inhibitory neuro-transmitter release, possibly from the thalamic reticular nucleus, in altered brain rhythms in individuals with chronic neuropathic pain.
Vestibular Modulation of Sympathetic Nerve Activity to Muscle and Skin in Humans
(2017-07-26) Macefield, Vaughan G.
Abstract: We review the existence of vestibulosympathetic reflexes in humans. While several methods to activate the human vestibular apparatus have been used, galvanic vestibular stimulation (GVS) is a means of selectively modulating vestibular afferent activity via electrodes over the mastoid processes, causing robust vestibular illusions of side-to-side movement. Sinusoidal GVS (sGVS) causes partial entrainment of sympathetic outflow to muscle and skin. Modulation of muscle sympathetic nerve activity (MSNA) from vestibular inputs competes with baroreceptor inputs, with stronger temporal coupling to the vestibular stimulus being observed at frequencies remote from the cardiac frequency; “super entrainment” was observed in some individuals. Low-frequency (<0.2 Hz) sGVS revealed two peaks of modulation per cycle, with bilateral recordings of MSNA or skin sympathetic nerve activity, providing evidence of lateralization of sympathetic outflow during vestibular stimulation. However, it should be noted that GVS influences the firing of afferents from the entire vestibular apparatus, including the semicircular canals. To identify the specific source of vestibular input responsible for the generation of vestibulosympathetic reflexes, we used low-frequency (<0.2 Hz) sinusoidal linear acceleration of seated or supine subjects to, respectively, target the utricular or saccular components of the otoliths. While others had discounted the semicircular canals, we showed that the contributions of the utricle and saccule to the vestibular modulation of MSNA are very similar. Moreover, that modulation of MSNA occurs at accelerations well below levels at which subjects are able to perceive any motion indicates that, like vestibulospinal control of posture, the vestibular system contributes to the control of blood pressure through potent reflexes in humans.