Thad E. Wilson

Autonomic Neural Control of Dynamic Cerebral Autoregulation in Humans

Background—The purpose of the present study was to determine the role of autonomic neural control of dynamic cerebral autoregulation in humans. Methods and Results—We measured arterial pressure and cerebral blood flow (CBF) velocity in 12 healthy subjects (aged 29±6 years) before and after ganglion blockade with trimethaphan. CBF velocity was measured in the middle cerebral artery using transcranial Doppler. The magnitude of spontaneous changes in mean blood pressure and CBF velocity were quantified by spectral analysis. The transfer function gain, phase, and coherence between these variables were estimated to quantify dynamic cerebral autoregulation. After ganglion blockade, systolic and pulse pressure decreased significantly by 13% and 26%, respectively. CBF velocity decreased by 6% (P <0.05). In the very low frequency range (0.02 to 0.07 Hz), mean blood pressure variability decreased significantly (by 82%), while CBF velocity variability persisted. Thus, transfer function gain increased by 81%. In addition, the phase lead of CBF velocity to arterial pressure diminished. These changes in transfer function gain and phase persisted despite restoration of arterial pressure by infusion of phenylephrine and normalization of mean blood pressure variability by oscillatory lower body negative pressure. Conclusions—These data suggest that dynamic cerebral autoregulation is altered by ganglion blockade. We speculate that autonomic neural control of the cerebral circulation is tonically active and likely plays a significant role in the regulation of beat-to-beat CBF in humans.

Effects of passive heating on central blood volume and ventricular dimensions in humans

Mixed findings regarding the effects of whole‐body heat stress on central blood volume have been reported. This study evaluated the hypothesis that heat stress reduces central blood volume and alters blood volume distribution. Ten healthy experimental and seven healthy time control (i.e. non‐heat stressed) subjects participated in this protocol. Changes in regional blood volume during heat stress and time control were estimated using technetium‐99m labelled autologous red blood cells and gamma camera imaging. Whole‐body heating increased internal temperature (> 1.0°C), cutaneous vascular conductance (approximately fivefold), and heart rate (52 ± 2 to 93 ± 4 beats min−1), while reducing central venous pressure (5.5 ± 07 to 0.2 ± 0.6 mmHg) accompanied by minor decreases in mean arterial pressure (all P < 0.05). The heat stress reduced the blood volume of the heart (18 ± 2%), heart plus central vasculature (17 ± 2%), thorax (14 ± 2%), inferior vena cava (23 ± 2%) and liver (23 ± 2%) (all P≤ 0.005 relative to time control subjects). Radionuclide multiple‐gated acquisition assessment revealed that heat stress did not significantly change left ventricular end‐diastolic volume, while ventricular end‐systolic volume was reduced by 24 ± 6% of pre‐heat stress levels (P < 0.001 relative to time control subjects). Thus, heat stress increased left ventricular ejection fraction from 60 ± 1% to 68 ± 2% (P= 0.02). We conclude that heat stress shifts blood volume from thoracic and splanchnic regions presumably to aid in heat dissipation, while simultaneously increasing heart rate and ejection fraction.

Effect of precooling on physical performance in multiple sclerosis

Many individuals with MS experience heat sensitivity that may be associated with transient increases in the frequency of clinical signs and symptoms. Although physical activity may be beneficial for those with MS, induced thermal loads may preclude participation in exercise and other daily activities. This project was designed to evaluate the effects of precooling on physical function. Six thermosensitive MS patients were studied. Participants performed a graded exercise test to determine maximal oxygen uptake (VO2max) on a combined arm-leg ergometer. Thermal load was induced by 30 min of exercise under noncooled and precooled conditions at a workrate corresponding to 60% VO2max. Precooling consisted of 30 min lower body immersion in 16-178C water. Fatigue and 25-ft walk performance were assessed before, immediately after, and 30 min following exercise. No treatment differences in VO2 were observed. Rectal temperature, heart rate, and rating of perceived exertion (RPE) were significantly lower during the precooled exercise trial compared to the noncooled trial. Immediately following exercise, 25-ft walk performance and fatigue scores showed significantly greater deterioration in the noncooled condition. Precooling was effective in preventing gains in core temperature with physical work and may allow heat-sensitive individuals with MS to exercise with greater physical comfort.

Absence of arterial baroreflex modulation of skin sympathetic activity and sweat rate during whole‐body heating in humans

1 Prior findings suggest that baroreflexes are capable of modulating skin blood flow, but the effects of baroreceptor loading/unloading on sweating are less clear. Therefore, this project tested the hypothesis that pharmacologically induced alterations in arterial blood pressure in heated humans would lead to baroreflex‐mediated changes in both skin sympathetic nerve activity (SSNA) and sweat rate. 2 In seven subjects mean arterial blood pressure was lowered (≈8 mmHg) and then raised (≈13 mmHg) by bolus injections of sodium nitroprusside and phenylephrine, respectively. Moreover, in a separate protocol, arterial blood pressure was reduced via steady‐state administration of sodium nitroprusside. In both normothermia and heat‐stress conditions the following responses were monitored: sublingual and mean skin temperatures, heart rate, beat‐by‐beat blood pressure, skin blood flow (laser‐Doppler flowmetry), local sweat rate and SSNA (microneurography from peroneal nerve). 3 Whole‐body heating increased skin and sublingual temperatures, heart rate, cutaneous blood flow, sweat rate and SSNA, but did not change arterial blood pressure. Heart rate was significantly elevated (from 74 ± 3 to 92 ± 4 beats min−1; P < 0.001) during bolus sodium nitroprusside‐induced reductions in blood pressure, and significantly reduced (from 92 ± 4 to 68 ± 4 beats min−1; P < 0.001) during bolus phenylephrine‐induced elevations in blood pressure, thereby demonstrating normal baroreflex function in these subjects. 4 Neither SSNA nor sweat rate was altered by rapid (bolus infusion) or sustained (steady‐state infusion) changes in blood pressure regardless of the thermal condition. 5 These data suggest that SSNA and sweat rate are not modulated by arterial baroreflexes in normothermic or moderately heated individuals.

Effect of whole-body and local heating on cutaneous vasoconstrictor responses in humans

Animal studies suggest that alpha-adrenergic-mediated vasoconstriction is compromised during whole-body heating. The purpose of this study was to identify whether whole-body heating and/or local surface heating reduce cutaneous alpha-adrenergic vasoconstrictor responsiveness in human skin. Protocol I: Six subjects were exposed to neutral skin temperature (i.e., 34 degrees C), whole-body heating, and local heating of forearm skin to increase skin blood flow to the same relative magnitude as that observed during whole-body heating. Protocol II: In eight subjects forearm skin was locally heated to 34, 37, 40, and 42 degrees C. During both protocols, alpha-adrenergic vasoconstrictor responsiveness was assessed by local delivery of norepinephrine (NE) via intradermal microdialysis. Skin blood flow was continuously monitored over each microdialysis membrane via laser-Doppler flowmetry. In protocol I, whole-body and local heating caused similar increases in cutaneous vascular conductance (CVC). The EC50 (log NE dose) of the dose-response curves for both whole body (-4.2 +/- 0.1 M) and local heating (-4.7 +/- 0.4 M) were significantly greater (i.e., high dose required to cause 50% reduction in CVC) relative to neutral skin temperature (- 5.6 +/- 0.0 M; P<0.05 for both). In both local and whole-body heated conditions CVC did not return to pre-heating values even at the highest dose of NE. In protocol II, calculated EC50 for 34, 37, 40, and 42 degrees C local heating was - 5.5 +/- 0.4, -4.6 +/- 0.3, -4.5 +/- 0.3, - 4.2 +/- 0.4 M, respectively. Statistical analyses revealed that the EC50 for 37,40 and 42 degrees C were significantly greater than the EC50 for 34 degrees C. These results indicate that even during administration of high concentrations of NE, alpha-adrenergic vasoconstriction does not fully compensate for local heating and whole-body heating induced vasodilatation in young, healthy subjects. Moreover, these data suggest that elevated local temperatures, above 37 degrees C, and whole-body heating similarly attenuate cutaneous alpha-adrenergic vasoconstriction responsiveness.

Thermoregulation in multiple sclerosis

Multiple sclerosis (MS) is a progressive neurological disorder that disrupts axonal myelin in the central nervous system. Demyelination produces alterations in saltatory conduction, slowed conduction velocity, and a predisposition to conduction block. An estimated 60-80% of MS patients experience temporary worsening of clinical signs and neurological symptoms with heat exposure. Additionally, MS may produce impaired neural control of autonomic and endocrine functions. This review focuses on five main themes regarding the current understanding of thermoregulatory dysfunction in MS: 1) heat sensitivity; 2) central regulation of body temperature; 3) thermoregulatory effector responses; 4) heat-induced fatigue; and 5) countermeasures to improve or maintain function during thermal stress. Heat sensitivity in MS is related to the detrimental effects of increased temperature on action potential propagation in demyelinated axons, resulting in conduction slowing and/or block, which can be quantitatively characterized using precise measurements of ocular movements. MS lesions can also occur in areas of the brain responsible for the control and regulation of body temperature and thermoregulatory effector responses, resulting in impaired neural control of sudomotor pathways or neural-induced changes in eccrine sweat glands, as evidenced by observations of reduced sweating responses in MS patients. Fatigue during thermal stress is common in MS and results in decreased motor function and increased symptomatology likely due to impairments in central conduction. Although not comprehensive, some evidence exists concerning treatments (cooling, precooling, and pharmacological) for the MS patient to preserve function and decrease symptom worsening during heat stress.

Effect of thermal stress on Frank–Starling relations in humans

The Frank–Starling ‘law of the heart’ is implicated in certain types of orthostatic intolerance in humans. Environmental conditions have the capacity to modulate orthostatic tolerance, where heat stress decreases and cooling increases orthostatic tolerance. The objective of this project was to test the hypothesis that heat stress augments and cooling attenuates orthostatic‐induced decreases in stroke volume (SV) via altering the operating position on a Frank–Starling curve. Pulmonary artery catheters were placed in 11 subjects for measures of pulmonary capillary wedge pressure (PCWP) and SV (thermodilution derived cardiac output/heart rate). Subjects experienced lower‐body negative‐pressure (LBNP) of 0, 15 and 30 mmHg during normothermia, skin‐surface cooling (decrease in mean skin temperature of 4.3 ± 0.4°C (mean ±s.e.m.) via perfusing 16°C water through a tubed‐lined suit), and whole‐body heating (increase in blood temperature of 1.0 ± 0.1°C via perfusing 46°C water through the suit). SV was 123 ± 8, 121 ± 10, 131 ± 7 ml prior to LBNP, during normothermia, skin‐surface cooling, and whole‐body heating, respectfully (P= 0.20). LBNP of 30 mmHg induced greater decreases in SV during heating (−48.7 ± 6.7 ml) compared to normothermia (−33.2 ± 7.4 ml) and to cooling (−10.3 ± 2.9 ml; all P < 0.05). Relating PCWP to SV indicated that cooling values were located on the flatter portion of a Frank–Starling curve because of attenuated decreases in SV per decrease in PCWP. In contrast, heating values were located on the steeper portion of a Frank–Starling curve because of augmented decreases in SV per decrease in PCWP. These data suggest that a Frank–Starling mechanism may contribute to improvements in orthostatic tolerance during cold stress and orthostatic intolerance during heat stress.

Aging affects the cardiovascular responses to cold stress in humans.

Cardiovascular-related mortality peaks during cold winter months, particularly in older adults. Acute physiological responses, such as increases in blood pressure, in response to cold exposure may contribute to these associations. To determine whether the blood pressure-raising effect (pressor response) of non-internal body temperature-reducing cold stress is greater with age, we measured physiological responses to 20 min of superficial skin cooling, via water-perfused suit, in 12 younger [25 +/- 1 (SE) yr old] and 12 older (65 +/- 2 yr old) adults. We found that superficial skin cooling elicited an increase in blood pressure from resting levels (pressor response; P < 0.05) in younger and older adults. However, the magnitude of this pressor response (systolic and mean blood pressure) was more than twofold higher in older adults (P < 0.05 vs. younger adults). The magnitude of the pressor response was similar at peripheral (brachial) and central (estimated in the aorta) measurement sites. Regression analysis revealed that aortic pulse wave velocity, a measure of central arterial stiffness obtained before cooling, was the best predictor of the increased pressor response to superficial skin cooling in older adults, explaining approximately 63% of its variability. These results indicate that there is a greater pressor response to non-internal body temperature-reducing cold stress with age in humans that may be mediated by increased levels of central arterial stiffness.

Orthostatic challenge does not alter skin sympathetic nerve activity in heat-stressed humans.

Perturbations that load or unload baroreceptors do not alter skin sympathetic nerve activity (SSNA) in normothermic individuals. However, in pronounced heat-stressed individuals, when a significant component of the SSNA signal is sudomotor and possibly vasodilator in origin, the effects of baroreceptor unloading via an orthostatic stress on SSNA remain unclear. The purpose of the present study was to test the hypothesis that low and moderate levels of orthostatic stress via lower body negative pressure (LBNP) alter SSNA in pronounced heat-stressed individuals. In both normothermic and heat-stressed conditions, progressive LBNP at -3, -6, -9, -12, -15, -18, -21 and -40 mm Hg were applied to 11 subjects for 2 min per stage. Whole-body heating increased sublingual temperature by 0.7+/-0.1 degrees C, heart rate by 28+/-2.1 bpm, SSNA by 259+/-76 %, forearm skin blood flow by 631+/-142% and forearm sweat rate to 0.68+/-0.14 mg/cm(2)/min (all p<0.005), but did not change mean arterial blood pressure (MAP) (p>0.05). LBNP did not change total SSNA in normothermic or heat-stressed conditions (both p>0.05), although skin blood flow and sweat rate decreased during moderate levels of LBNP while heat stressed. These data suggest that in pronounced heat-stressed individuals, when a significant component of the SSNA signal contains sudomotor and possibly cutaneous active vasodilator activities, low and moderate levels of baroreceptor unloading via LBNP do not alter total SSNA. This observation, coupled with reductions in skin blood flow and sweating during moderate levels of LBNP, suggests that integrated SSNA should not be used as an indicator of baroreflex modulation of the cutaneous vasculature or sweat rate in heat-stressed subjects.

Effects of heat and cold stress on central vascular pressure relationships during orthostasis in humans

Central venous pressure (CVP) provides information regarding right ventricular filling pressure, but is often assumed to reflect left ventricular filling pressure. It remains unknown whether this assumption is correct during thermal challenges when CVP is elevated during skin‐surface cooling or reduced during whole‐body heating. The primary objective of this study was to test the hypothesis that changes in CVP reflect those in left ventricular filling pressure, as expressed by pulmonary capillary wedge pressure (PCWP), during lower‐body negative pressure (LBNP) while subjects are normothermic, during skin‐surface cooling, and during whole‐body heating. In 11 subjects, skin‐surface cooling was imposed by perfusing 16°C water through a water‐perfused suit worn by each subject, while heat stress was imposed by perfusing 47°C water through the suit sufficient to increase internal temperature 0.95 ± 0.07°C (mean ±s.e.m.). While normothermic, CVP was 6.3 ± 0.2 mmHg and PCWP was 9.5 ± 0.3 mmHg. These pressures increased during skin‐surface cooling (7.8 ± 0.2 and 11.1 ± 0.3 mmHg, respectively; P < 0.05) and decreased during whole‐body heating (3.6 ± 0.1 and 6.5 ± 0.2 mmHg, respectively; P < 0.05). The decrease in CVP with LBNP was correlated with the reduction in PCWP during normothermia (r= 0.93), skin‐surface cooling (r= 0.91), and whole‐body heating (r= 0.81; all P < 0.001). When these three thermal conditions were combined, the overall r value between CVP and PCWP was 0.92. These data suggest that in the assessed thermal conditions, CVP appropriately tracks left ventricular filling pressure as indexed by PCWP. The correlation between these values provides confidence for the use of CVP in studies assessing ventricular preload during thermal and combined thermal and orthostatic perturbations.