Pattern Of Sympathetic Activity Research Articles

Noninvasive characterization of peripheral sympathetic activation across sensory stimuli using a peripheral arterial stiffness index.

Introduction: The peripheral arterial stiffness index has been proposed and validated as a noninvasive measure quantifying stimulus intensity based on amplitude changes induced by sympathetic innervation of vascular tone. However, its temporal response characteristics remain unclear, thus hindering continuous and accurate monitoring of the dynamic process of sympathetic activation. This paper presents a study aimed at modeling the transient response of the index across sensory stimuli to characterize the corresponding peripheral sympathetic activation. Methods: The index was measured using a continuous arterial pressure monitor and a pulse oximeter during experiments with local pain and local cooling stimuli designed to elicit different patterns of sympathetic activation. The corresponding response of the index was modeled to clarify its transient response characteristics across stimuli. Results: The constructed transfer function accurately depicted the transient response of the index to local pain and local cooling stimuli (Fit percentage: 78.4% ± 11.00% and 79.92% ± 8.79%). Differences in dead time (1.17 ± 0.67 and 0.99 ± 0.56 s, p = 0.082), peak time (2.89 ± 0.81 and 2.64 ± 0.68 s, p = 0.006), and rise time (1.81 ± 0.50 and 1.65 ± 0.48 s, p = 0.020) revealed different response patterns of the index across stimuli. The index also accurately characterized similar vasomotor velocities at different normalized peak amplitudes (0.19 ± 0.16 and 0.16 ± 0.19 a.u., p = 0.007). Discussion: Our findings flesh out the characterization of peripheral arterial stiffness index responses to different sensory stimuli and demonstrate its validity in characterizing peripheral sympathetic activation. This study valorizes a noninvasive method to characterize peripheral sympathetic activation, with the potential to use this index to continuously and accurately track sympathetic activators.

Differential Control of Blood Flow in Facial and Limb Muscles During Stress

Different patterns of sympathetic activation may be elicited by different stressors (stressor-specificity) and the effects generally depend on the location of the different tissues and organs examined (differential sympathetic activation). In this respect, different vascular control has been reported for cutaneous tissues of the head as compared to limbs’, whereby dilatation rather than constriction is often reported in the facial districts. Whether a different hemodynamic response to stress also concerns skeletal muscles is unclear. The aim of this study was to test the hypothesis that a differential vascular control also concerns head and limb muscles, under stress exposure. Near infrared spectroscopy (NIRS) was used to measure changes in tissue haemoglobin index (THI) and tissue oxygenation index (TOI). From these parameters changes in blood flow can be inferred. One NIRS probe was placed over the masseter muscle and one over the biceps muscle. Cardiac output, HR and ABP were also measured by continuous finger-pulse photoplethysmography. Twelve participants (9 males, 3 females; age 26 ± 3 years) in supine position were subjected to a randomized series of stressors, including cold pressor test (CPT, left hand immersed in 8 deg water for 2 min) and mental arithmetic test (MAT, repeatedly subtracting from 1000 consecutive odd numbers starting from 1). Stress-induced changes in TOI and THI were evaluated by comparing the time average over the last 10 s of stress exposure, with the baseline (10-s interval before stress exposure). Statistical significance (p<0.05) was assessed by Student-t test and Hochberg's Method with Dunn/Sidak alpha correction for multiple comparisons. The masseter TOI exhibited a significant increase during both CPT (from 79.5 ± 2.9 to 81.1 ± 2.2 %) and MAT (from 80.5 ± 3.1 to 82.5 ± 3.6 %), while in the biceps, the TOI significantly decreased (-4.8 ± 4.1%) in CPT and non-significantly increased in MAT (1.5 ± 2.8%). As for blood volume changes, THI exhibited a significant change only in masseter muscle during CPT (+8.7 ± 9.1 %, from baseline). To conclude, simultaneous monitoring of hemodynamic changes by NIRS in facial and limb muscles evidence larger responses of THI and TOI suggesting increased vascular dilatation and blood flow in facial compared to limb muscles. We speculate that this could result from a general strategy aimed at preserving blood flow to the head region, which is characterized by lower perfusion pressure due to hydrostatic gradients, during erect posture.

Differential sympathetic outflow to adipose depots is required for visceral fat loss in response to calorie restriction

The sympathetic nervous system (SNS) regulates energy homeostasis in part by governing fatty acid liberation from adipose tissue. We first examined whether SNS activity toward discrete adipose depots changes in response to a weight loss diet in mice. We found that SNS activity toward each adipose depot is unique in timing, pattern of activation, and habituation with the most dramatic contrast between visceral and subcutaneous adipose depots. Sympathetic drive toward visceral epididymal adipose is more than doubled early in weight loss and then suppressed later in the diet when weight loss plateaued. Coincident with the decline in SNS activity toward visceral adipose is an increase in activity toward subcutaneous depots indicating a switch in lipolytic sources. In response to calorie restriction, SNS activity toward retroperitoneal and brown adipose depots is unaffected. Finally, pharmacological blockage of sympathetic activity on adipose tissue using the β3-adrenergic receptor antagonist, SR59230a, suppressed loss of visceral adipose mass in response to diet. These findings indicate that SNS activity toward discrete adipose depots is dynamic and potentially hierarchical. This pattern of sympathetic activation is required for energy liberation and loss of adipose tissue in response to calorie-restricted diet.

Hyperoxia blunts counterregulation in humans and differential control of the sympathetic nervous system

Wehrwein and colleagues recently reported that the counterregulatory response to insulin-induced hypoglycaemia was reduced significantly during hyperoxia in normal human volunteers (Wehrwein et al. 2010). Specifically, they showed that the increased plasma concentrations of growth hormone, glucagon, adrenaline, cortisol and noradrenaline that occur under the conditions of hyperinsulinaemic hypoglycaemia were suppressed during hyperoxia. The study provides support for the hypothesis that oxygen tension can modulate glucose homeostasis. Studies in animals, such as those cited by Wehrwein et al. as well as those that demonstrate that hypoxia activates adrenomedullary sympathetic nerve activity and adrenal catecholamine release (Biesold et al. 1989), provide additional support. In the subsequent discussion of the potential mechanisms and limitations of their findings, the authors seem to hold the view that the sympathetic outflow operates in a uniform manner. They propose that the suppression of the release of glucagon, adrenaline and noradrenaline may be associated with the observations made by Seals et al. (1991) that hyperoxia suppresses muscle sympathetic activity and by others that muscle sympathetic nerve activity is elevated during hypoglycaemia in man (Fagius et al. 1986). They imply that hyperoxia may induce generalised sympathoinhibition and so suppress the counterregulatory responses. However, recent studies in rats suggest that hypersinsulinaemia per se activates muscle sympathetic activity selectively (Bardgett et al. 2010). Furthermore, we have recently shown that neuroglucoprivation activates a subpopulation of spinally projecting neurones in the rostral ventrolateral medulla (RVLM) (Verberne & Sartor, 2010). The properties of the neurones that were activated by depriving the brain of glucose were fundamentally different from those that are classically regarded as presympathetic vasomotor neurones (Guyenet, 2006). Presympathetic vasomotor neurones are profoundly inhibited by activation of the baroreceptors. In contrast, the neurones that were activated by neuroglucoprivation were baroinsensitive and lacked cardiac rhythm. Wehrwein and colleagues speculated that in experiments by others in which carotid chemoreceptors were denervated, carotid sinus baroreceptors may have also been impaired. While they dismissed these concerns, our studies confirm that RVLM neurones that control adrenomedullary adrenaline secretion are not under arterial baroreceptor control. Taken together, these observations add to an expanding body of evidence that supports the view that the sympathetic outflow to the periphery is differentially controlled (Morrison, 2001). Goldstein, in a recent review, also emphasised that viewing the ‘sympathoadrenal’ system as an integral whole is erroneous (Goldstein, 2010). In summary, Wehrwein and colleagues demonstrate that hyperoxia modulates the counterregulatory response to hypoglycaemia. The underlying mechanism remains unclear and merits further investigation in animal experiments. However, the interpretation of their findings would be enhanced by consideration of the modern view that the sympathetic nervous system operates differentially to orchestrate specific patterns of sympathetic activity that are associated with homeostatic reflexes.

Altered pattern of sympathetic activity with the ovarian cycle in female smokers

Smoking increases cardiovascular risk in young women and eliminates the protective effect of the premenopausal state. Increased sympathetic nervous system (SNS) activity is associated with increased cardiovascular risk. One potential mechanism by which smoking increases risk is through chronic SNS activation. It has been reported that premenopausal women have high SNS activity during the midluteal (ML) phase, which falls to low levels during the early follicular (EF) phase. We tested the hypothesis that smoking disrupts this fall in SNS activity during the EF phase. We measured blood pressure and muscle sympathetic nerve activity (MSNA) using microneurography in 11 premenopausal female smokers and 11 age-matched nonsmoking controls at two separate times during the ovarian cycle: ML phase (8-10 days after the luteinizing hormone surge) and EF phase (days 1-4 of the menstrual cycle). The change in MSNA from the EF phase to the ML phase was significantly different between the smoking and nonsmoking groups (P = 0.036). Whereas there was a significant decrease in MSNA from the ML phase to the EF phase among nonsmoking controls (22.7 +/- 3.3 vs. 17.9 +/- 2.8 bursts/min, P = 0.012), MSNA remained elevated during the EF phase in smokers (22.5 +/- 3.8 vs. 26.8 +/- 4.0 bursts/min, P = 0.28). Surprisingly, mean arterial pressure (MAP) was significantly lower during the ML phase than in the EF phase in both nonsmokers (P = 0.0080) and smokers (P = 0.0094). We conclude that smoking disrupts the ovarian pattern of SNS activity by preventing the normal fall in MSNA during the EF phase of the ovarian cycle. Such chronic alterations may contribute to the pathogenesis of cardiovascular risk in young smoking females.

Stress and thermoregulation: Different sympathetic responses and different effects on experimental pain

Stress and thermoregulation both activate the sympathetic nervous system (SNS) but might differently affect pain. Studies investigating possible interactions in patients are problematic because of the high prevalence of SNS disturbances in patients. We therefore analyzed the influence of these different sympathetic challenges on experimentally-induced pain in healthy subjects. SNS was activated in two different ways: by mental stress (Stroop task, mental arithmetic task), and by thermoregulatory stimulation using a water-perfused thermal suit (7 °C, 32 °C, or 50 °C). Attentional effects of the mental stress tasks were controlled by using easy control tasks. Both, stress and thermoregulatory stimuli, robustly activated SNS parameters. However, the patterns of activation were different. While stress co-activated heart rate, blood pressure, peripheral vasoconstriction and sweating, thermal stimulation either increased blood pressure (cold) or heart rate and sweating (warm). Only stress was able to induce a significant reduction of pain. The control tasks neither activated the SNS nor altered pain perception. Our results suggest that (1) different patterns of sympathetic activation can be recorded after stress and thermoregulatory challenges and (2) that only stress is able to interfere with sensation of experimental pain. Whether SNS activation is causally responsible for analgesia needs to be further investigated.

Neural mechanisms and management of obesity-related hypertension

The sympathetic nervous system is activated in human obesity and in the analogous experimental obesity produced by overfeeding. The causes remain uncertain and may be multiple. The consequences include hypertension, probably attributable to activation of the sympathetic outflow to the kidneys, and, more disputed, insulin resistance. The pattern of sympathetic activation in normal-weight and obesity-related hypertension differs in terms of the firing characteristics of individual sympathetic fibers (increased rate of nerve firing in normal-weight hypertensives, increased number of active fibers firing at a normal rate in obesity-hypertension) and the sympathetic outflows involved. The underlying mechanisms and the adverse consequences of the two modes of sympathetic activation may differ. Should antihypertensive drug therapy in obesity-hypertension specifically target the existing neural pathophysiology? Such an approach can be advocated on theoretical grounds. Perhaps more important is the requirement that chosen antihypertensives do not cause weight gain or insulin resistance.

Landmarks in understanding the central nervous control of the cardiovascular system

In this Paton Lecture I have tried to trace the key experiments that have developed ideas on how the brain regulates the cardiovascular system. It is a personal view and inevitably, owing to constraints on space and time, I have not been able to cover areas such as the nucleus tractus solitarius and cardiac vagal neurones, although I acknowledge that some may consider the story is incomplete without them. Starting with the crucial discovery of vasomotor nerves and 'vasomotor tone', the patterns of activity in sympathetic nerves which led to the important idea of central oscillating networks of neurones are described. I discuss how this knowledge has informed current controversies on the origin of vasomotor activity in presympathetic neurones in the ventral medulla, which identify intrinsic pacemaker activity or synaptic input from multiple oscillators as prime mechanisms. I present an emerging view that the role of other regions of the brain, in particular supramedullary sites, has been underplayed. These regions are pivotal for the non-uniform distribution of cardiac output that is unique to each reflex and behavioural state. I discuss the most recent evidence for 'central command' neurones that offers a plausible explanation for how these patterns of sympathetic activity are achieved. Finally, I stress the importance of these current ideas to the understanding of pathological changes in sympathetic activity in cardiovascular diseases such as hypertension or congestive heart failure.

Psychological, autonomic and neuroendocrine responses to acute stressors in the combined dexamethasone/CRH test: a study in healthy subjects

The combined dexamethasone/CRH test (DEX/CRH test) is reported to produce augmented ACTH and cortisol responses in various psychiatric disorders as well as in some non-psychiatric conditions. To examine whether stress affects the outcome of DEX/CRH test, two stress groups in a repeated measures design were compared to an age-matched control group with regard to the psychological, autonomic and neuroendocrine responses after the combined dexamethasone and CRH challenge. Cold pressor (4°C, total 10 min) produced stronger subjective distress than mental arithmetic (15 min). Cold exposure, but not the mental test, elevated systolic and diastolic blood pressure, whereas the mental test increased pulse rate and skin conductance level more markedly than cold exposure. Neither stressor produced a significantly enhanced response of ACTH and cortisol in DEX/CRH test, and there was no correlation between psychological and neuroendocrine responses. These findings suggest that different stressors induce different patterns of sympathetic activation and that acute stress is unlikely to affect the results of DEX/CRH test.

Modulation of Vascular Function by Diet and Exercise

Clinical research is conducted in free living individuals who are always subject to the influences on vascular function and the major cardiovascular regulators of their lifestyle. The purpose of this paper is to review some lifestyle influences on cardiovascular function, particularly the sympathetic nervous system and endothelially mediated vasodilatation. There are highly differentiated sympathetic responses to feeding, and to acute exercise. Over a longer period obesity has a typical pattern of sympathetic activity. Reduced dietary salt intake elicits profound localised increases in sympathetic activity to the kidney. Marine oil supplementation attenuates the sympathetic responses to psychological stress and improves endothelially mediated vasodilatation in hypercholesterolaemics. Exercise training reduces total noradrenaline spillover, the major beds affected being the renal and skeletal muscle. These examples illustrate the dynamic nature of vascular dilatation and that, like the sympathetic nervous system, it is modulated by short, medium and long term influences. In both cases there is regulation both at a local and systemic level. Habitual, and recent, lifestyle can exert important cardiovascular effects which must be taken into account in clinical and epidemiological research.

Differential development of vascular and cardiac hypertrophy in genetic hypertension. Relation to sympathetic function.

We compared blood pressure, hindquarter vascular resistance properties, left ventricular weight, and norepinephrine kinetics, in spontaneously hypertensive rats (SHR) and weight-matched normotensive Wistar-Kyoto (WKY) rats at 4, 9, 14, 20, 30, and 50 weeks of age. At 4 weeks, systolic and mean blood pressure measurements were the same in both strains, but the vascular resistance of the fully dilated hindquarter bed was significantly higher in SHR than in WKY rats, with a much larger difference during maximum constriction. Plots of resistance at maximum dilatation and at maximum constriction against body weight suggest that a component of the increase in vascular muscle mass in SHR occurred in the neonatal period preceding hypertension followed by a later component related to the rise in blood pressure. By contrast, left ventricular hypertrophy was minimal at 4 weeks and most of its development paralleled the rise in blood pressure. Sympathetic activity, assessed by norepinephrine fractional rate constant, was higher in SHR than in WKY rats in the left ventricle and kidney through most of the period between 4 and 50 weeks, but was similar in both strains in the muscle bed. This pattern of sympathetic activity will accentuate hypertension once cardiac and vascular hypertrophy are fully established. In all regions, norepinephrine tissue concentration was higher in young SHR and could potentiate the trophic effects of growth factors in early vascular hypertrophy. We suggest that the initial (primary) component of vascular hypertrophy precedes the rise in blood pressure and may be critical in the pathogenesis of hypertension. Possible reasons for the short delay in the rise in blood pressure in young SHR, once the vascular "amplifier" has been established, include high vascularity, immaturity of smooth muscle, and delay in the development of left ventricular hypertrophy.

CUTANEOUS PATTERNS OF SYMPATHETIC ACTIVITY IN CLINICAL ABNORMALITIES OF THE MUSCULOSKELETAL SYSTEM.

1. These studies on 130 patients have been concerned with topographical patterns of sudomotor activity associated with known musculoskeletal disturbances, myofascial stresses and pain syndromes. 2. The method employed for measuring sudomotor activity, as an indicator of regional variations in sympathetic activity, was that of recording the electrical resistance of the skin (ESR). Radiographic, electromyographic and palpatory examinations, as well as other conventional clinical methods, were used in the evaluation of the musculoskeletal disturbances. 3. The observations frequently showed the presence of regional and segmental patterns of low electrical skin resistance (LRA) in areas of referred pain and dermatomes segmentally related to the musculoskeletal disturbances or myofascial stresses. 4. These patterns of altered electrical skin resistance appear to reflect enduring changes in the patterns of sympathetic activity associated with musculoskeletal disturbances of clinical origin. 5. These studies suggest that the patterns of aberrant areas of sudomotor and vasomotor activity, which we have previously described in apparently normal subjects, may reflect subclinical and asymptomatic sources of afferent bombardment, over selected dorsal roots, or of direct irritation of nerve fibers or ganglion cells. That is, the altered patterns of sympathetic activity appear to be either reflex manifestations of changes in sensory input arising in nerve endings and receptors in the musculoskeletal tessues or the effects of direct insults to nerve fibers (or ganglion cells) or a combination of both.