Vestibulo-sympathetic responses

Abstract

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. 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.

Fig. 1

Primary connections of the sympathetic and parasympathetic nervous system that control blood flow and blood pressure. Parasympathetic preganglionic neurons (PrG) whose cell bodies are located in the brainstem send axons principally through the vagus nerve to postganglionic neurons (PoG) whose cell bodies are located in ganglia near the heart. Parasympathetic PrG release the neurotransmitter acetylcholine (Ach) onto nicotinic (N) receptors on the cell body and dendrites of parasympathetic PoG. Parasympathetic PoG release acetylcholine onto muscarinic receptors on the surface of autorhythmic (pacemaker) cells in the heart, particularly those in the sinoatrial node. The binding of acetylcholine to these muscarinic receptors induces a decrease in heart rate. Sympathetic PrG whose cell bodies are located in the thoracic and lumbar spinal cord send axons to PoG whose cell bodies are located in prevertebral or paravertebral ganglia. Like parasympathetic PrG, sympathetic PrG release Ach onto nicotinic receptors located on the cell body and dendrites of sympathetic PoG. Sympathetic PoG project to the heart, and release the neurotransmitter norepinephrine (NE) onto β₁ receptors located on the surface of pacemaker cells. The binding of norepinephrine to these receptors induces an increase in heart rate. Sympathetic PoG additionally release norepinephrine onto β₁ receptors located on myocytes in the ventricles of the heart. Binding of neurotransmitter to these receptors induces an increase in contractility of the muscle cells. Furthermore, sympathetic PoG innervate smooth muscle in the walls of blood vessels, primarily arterioles. Norepinephrine released from PoG binds primarily to α receptors on the surface of vascular smooth muscle. Binding of norepinephrine to these receptors causes vasoconstriction, and results in decreased blood flow through the affected vessels. In addition, sympathetic PrG release acetylcholine onto nicotinic receptors on adrenal chromaffin cells. Binding of acetylcholine to these receptors induces the release of epinephrine (E) and some norepinephrine from the chromaffin cells. Epinephrine preferentially binds to β receptors, and elicits an increase in heart rate and ventricular contractility by binding to β₁ receptors in the heart. Epinephrine also binds to β₂ receptors associated with vascular smooth muscle in particular vascular beds, including arterioles in skeletal muscle. Binding of epinephrine to β₂ receptors results in vasodilation. However, when epinephrine levels are high, the hormone binds to α receptors and causes vasoconstriction. Thus, epinephrine can result in an increase or decrease in blood flow to a particular tissue, depending on the amount of the hormone released into the bloodstream.

Fig. 2

Pressures (mm Hg) in the large arteries (red) and veins (blue) when lying supine or standing.

Fig. 3

Average changes in femoral artery (top panel) and vein (middle panel) blood flow during 20°, 40°, and 60° head-up tilts. Bottom trace: instantaneous blood accumulation at each time period, determined by subtraction of percent difference from baseline in venous blood flow from percent difference from baseline in arterial blood flow. Symbols designate changes in blood flow and blood accumulation elicited by 40° and 60° tilt that were significantly different from those resulting from 20° tilt (ANOVA test). Adapted from (331), with permission.

Fig. 4

Section through the head showing the middle and inner ear. The portion of the inner ear containing the vestibular system endorgans is shaded in yellow.

Fig. 5

Effect of increasing mean blood pressure (BP) by injecting an alpha adrenergic agonist on averaged superior mesenteric nerve responses elicited by a train of electrical stimuli delivered to vestibular afferents. Arrows indicate the latency of the stimulus. When blood pressure was normal (98 mmHg, top), stimulation of the vestibular nerve elicited large changes in sympathetic nerve activity. However, when blood pressure was raised modestly (132 mm Hg, bottom), the responses were attenuated. Vertical calibration, 1 μV; time scale, 100 msec. Adapted from (170), with permission.

Fig. 6

Effects of electrical vestibular stimulation (indicated by a bar at the bottom of traces) on arterial blood pressure (top trace) and brachial artery (middle trace) and femoral artery (bottom trace) blood flow. Adapted from (168), with permission.

Fig. 7

A: Averaged splanchnic nerve responses to 15° head rotations in vertical planes. The rotations were delivered at 0.2 Hz; in the left diagram the head was rotated in the clockwise direction, and in the right diagram the head rotations were in the counterclockwise direction. During both stimuli, maximal nerve activity occurred during nose-up head rotations. B: Polar diagram of vestibular vector orientations for splanchnic nerve responses to vestibular stimulation. The position of a symbol indicates the direction of tilt that produced maximal sympathetic nerve activity. Abbreviations: CED, contralateral ear down tilt; IED, ipsilateral ear down tilt; ND, nose down tilt; NU, nose up tilt. Adapted from (327), with permission.

Fig. 8

Bode diagrams of responses of the splanchnic nerve to head rotations. The responses whose characteristics are depicted were elicited by performing sinusoidal head rotations in the best plane for producing a response. Different symbols are used to designate responses from each animal. Responses gains were standardized by dividing the gain at each frequency by the average gain across frequencies. Data are plotted with respect to stimulus position. Adapted from (327), with permission.

Fig. 9

The average effects of removal of vestibular inputs on femoral artery (hindlimb; left column) and brachial artery (forelimb; right column) blood flow and vascular resistance during 60° head-up tilts. Blue lines depict average changes in blood flow and vascular resistance prior to vestibular lesions; red lines and green lines respectively show tilt-related changes in blood flow and vascular resistance during the first week and subsequent three weeks after removal of vestibular inputs. Symbols designate post-lesion changes in blood flow and vascular resistance during tilts that were significantly different from those recorded when vestibular inputs were present. Error bars indicate S.E.M. Adapted from (307), with permission.

Fig. 10

Neural regions that generate and modify the gains of vestibulosympathetic reflexes (VSR) and baroreceptor reflexes. Abbreviations: BA, baroreceptor afferent; BP, blood pressure; IML, intermediolateral cell column; IO, inferior olivary nucleus; IX, cerebellar lobule IX, uvula; NTS, nucleus tractus solitaries; PBN, parabrachial nucleus; RF, reticular formation; RVLM: rostral ventrolateral medulla; VA, vestibular afferent; VN, vestibular nucleus complex.

Fig. 11

Cardiac-locked muscle sympathetic bursts are modulated by dynamic vestibular inputs. Experimental records from one subject. Spontaneous muscle sympathetic nerve activity was recorded from the peronei motor fascicle of the common peroneal nerve, and is presented as the filtered neurogram (nerve) and as an RMS-processed signal (RMS nerve). In each panel, the top trace indicates the onset and phase of the sinusoidal modulation when applied (B-D) and the bottom trace records the ECG. Each panel spans a 4 s data period. A, baseline activity; B-D, consecutive sequences obtained during sinusoidal galvanic vestibular stimulation (GVS) at 0.5 Hz. The rectangles illustrate the relationship between the sympathetic burst and the cardiac rhythm (c) and the vestibular rhythm (v). Reproduced from (29), with permission.

Fig. 12

Correlations between muscle sympathetic bursts and cardiac and vestibular rhythms. A, cross-correlation histograms of the relationship between muscle sympathetic nerve activity (MSNA) and the electrocardiogram (ECG; white histogram) and autocorrelogram of the ECG (black histogram). B-C, cross-correlation histograms between ECG and galvanic vestibular stimulation (GVS) and respiration (inspiratory peaks) and GVS. A 0.5 Hz sine wave has been superimposed on the histogram to illustrate the timing of the GVS; it has been inverted for clarity. D-E, cross-correlation histograms of MSNA with respect to the vestibular input (GVS), in white, or to a control sine wave (control), in black. Data in panels A-D are from the same subject represented in Fig. 11; data in panel E were obtained from another subject. 20 ms bins in all panels. n = the numbers of counts comprising the histograms. Reproduced from (29), with permission.

Fig. 13

Variation in relative contributions of cardiac and vestibular rhythms over time. Cross-correlation histograms of the relationship between muscle sympathetic nerve activity (MSNA) and galvanic vestibular stimulation (GVS; white histogram) and the electrocardiogram (ECG, black histogram) after dividing the data into four consecutive 30 s segments, each composed of 15 cycles of GVS (0.5 Hz). The relative influences of the cardiac and vestibular rhythms changed during the course of stimulation. The muscle sympathetic nerve activity (MSNA)—ECG cross-correlograms have been compressed vertically to better illustrate these temporal relationships: 100 spikes is represented by one division on the vertical scale for these data. 20 ms bins in all panels. n = the numbers of counts comprising the histograms. Same subject as in Fig. 11 and Fig 12A-C. Reproduced from (29), with permission.

Fig. 14

Cross-correlation histograms between muscle sympathetic nerve activity (MSNA) and sinusoidal galvanic vestibular stimulation (sGVS) in one subject. The thick curve superimposed on the histograms is the smoothed polynomial that was fitted to the data. The sinusoid above represents the galvanic stimulus, delivered at 0.08, 0.13 and 0.18 Hz. Each cross-correlation histogram shows a large peak of modulation (primary peak), associated with the positive peak of the sinusoid, and a smaller peak (secondary peak). The secondary peak was largest at 0.08 Hz and smallest at 0.18 Hz. Reproduced from (133), with permission.

Fig. 15

Bilateral recordings of muscle sympathetic nerve activity, together with ECG, blood pressure and respiration, during sinusoidal galvanic vestibular stimulation (GVS) at 0.08 Hz in one subject. Overall, sympathetic outflow was similar between the two sides, but close inspection revealed subtle differences. In the expanded sections, the sympathetic bursts have been shifted back 1.25 s in time to account for peripheral conduction delays, allowing those bursts aligned with the cardiac cycle (‘c’) or vestibular stimulus (‘v’) to be identified. Reproduced from (93), with permission.

Fig. 16

Modulation indices of primary peak of skin sympathetic nerve activity (SSNA) during sinusoidal galvanic vestibular stimulation (sGVS) at different frequencies as a function of whether or not subjects reported nausea. It is evident that modulation indices were higher in those subjects who reported nausea. Reproduced from (132), with permission.

Fig. 17

Mean and 95% confidence interval of mean of low frequency/high frequency (LF/HF ratio of heart rate variability during active change in posture, as follows: 5 min supine rest, 5 min back-unsupported sitting, and 5 min upright stance. Data from seven persons with unilateral vestibular failure and seven healthy age/sex matched volunteers at A: day 1, and B: week 2. From (158); used with permission.

Fig. 18

Head-down neck flexion posture first used by Essandoh et al (95). A: The subject is prone, with neck slightly extended and the chin resting comfortably on a soft-padded support at the edge of the table. This represents the head-up posture B: chin support is removed, and subject’s head is lowered to maximally flex the neck. This represents the head-down neck flexion (HDNF) posture.

Fig. 19

Recordings of muscle and skin sympathetic nerve activity in two subjects, during baseline and head-down neck flexion (HDNF) conditions. Muscle sympathetic nerve activity was increased during HDNF, whereas skin sympathetic nerve activity was unchanged during HDNF. From (239); used with permission.

Fig. 20

Hemodynamic, respiratory, and autonomic modulations during off-vertical axis rotation (OVAR) at 60°/s. A, Phase of respiratory cycle; B, RR interval; C, diastolic blood pressure; D, change in MSNA; E, changes in the naso-occipital and interaural components of the gravity vector over each cycle of OVAR. Inserts on top indicate the direction of rotation and the position of the head at various phases of the OVAR cycle. Data are the means ± SE from 10 consecutive cycles of rotation in seven subjects (LSD, left side down; NU, nose-up; RSD, right side down; ND, nose down). From (167); used with permission.

Fig. 21

Muscle sympathetic nerve activity (MSNA) during earth vertical axis rotation (EVAR) at 60°/s (A) and off-vertical axis rotation (OVAR) at 24°/s (B) 60°/s (C) and 110°/s (D). The axis of rotation was tilted 15° during OVAR, resulting in a peak acceleration of 0.26g along the interaural axis. Upper tracings, MSNA; Lower tracings, signal from the chair holding the subject. The vertical breaks indicate 360° of rotation and, in B-D, the nose-up position. Inserts over the vertical breaks show the nose-up position of the subject and the axis or rotation. Calibrations are for MSNA voltage and time. From (167); used with permission.