Davis SL, Wilson TE, White AT, Frohman EM. Thermoregulation in multiple sclerosis. J Appl Physiol 109: 1531-1537. First published July 29, 2010 doi:10.1152/japplphysiol.00460.2010.-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. demyelination; core temperature; sweating; skin blood flow; fatigue MULTIPLE SCLEROSIS (MS) is a disabling progressive neurological disorder affecting ϳ400,000 individuals in the United States. The pathophysiology of MS results in a disruption or loss of axonal myelin in the central nervous system (CNS), leading to the formation of scar tissue (sclerosis). MS is thought to involve a number of autoimmune injury cascades that appear to be dependent on the interaction of complex epigenetic and environmental factors. Immune responses in individuals with MS are skewed toward a proinflammatory state, resulting in inflammation, demyelination, and ultimately loss of axons and disorganization of normal tissue architecture within the CNS (23). Demyelination is associated with corresponding changes in axonal physiology, including a loss of saltatory properties of electrical conduction, reduction in conduction velocity, and a predisposition to conduction block. These pathophysiological mechanisms underlie the myriad of symptoms (Table 1) in individuals with MS and are contingent on the neuroanatomic l...

Near-infrared (NIR) spectroscopy is a noninvasive optical technique that is increasingly used to assess muscle oxygenation during exercise with the assumption that the contribution of skin blood flow to the NIR signal is minor or nonexistent. We tested this assumption in humans by monitoring forearm tissue oxygenation during selective cutaneous vasodilation induced by locally applied heat (n = 6) or indirect whole body heating (i.e., heating subject but not area surrounding NIR probes; n = 8). Neither perturbation has been shown to cause a measurable change in muscle blood flow or metabolism. Local heating (approximately 41 degrees C) caused large increases in the NIR-derived tissue oxygenation signal [before heating = 0.82 +/- 0.89 optical density (OD), after heating = 18.21 +/- 2.44 OD; P < 0.001]. Similarly, whole body heating (increase internal temperature 0.9 degrees C) also caused large increases in the tissue oxygenation signal (before heating = -0.31 +/- 1.47 OD, after heating = 12.48 +/- 1.82 OD; P < 0.001). These increases in the tissue oxygenation signal were closely correlated with increases in skin blood flow during both local heating (mean r = 0.95 +/- 0.02) and whole body heating (mean r = 0.89 +/- 0.04). These data suggest that the contribution of skin blood flow to NIR measurements of tissue oxygenation can be significant, potentially confounding interpretation of the NIR-derived signal during conditions where both skin and muscle blood flows are elevated concomitantly (e.g., high-intensity and/or prolonged exercise).

Whole-body heat stress reduces orthostatic tolerance via a yet to be identified mechanism(s). The reduction in central blood volume that accompanies heat stress may contribute to this phenomenon. The purpose of this study was to test the hypothesis that acute volume expansion prior to the application of an orthostatic challenge attenuates heat stress-induced reductions in orthostatic tolerance. In seven normotensive subjects (age, 40 ± 10 years: mean ± s.d.), orthostatic tolerance was assessed using graded lower-body negative pressure (LBNP) until the onset of symptoms associated with ensuing syncope. Orthostatic tolerance (expressed in cumulative stress index units, CSI) was determined on each of 3 days, with each day having a unique experimental condition: normothermia, whole-body heating, and whole-body heating + acute volume expansion. For the whole-body heating + acute volume expansion experimental day, dextran 40 was rapidly infused prior to LBNP sufficient to return central venous pressure to pre-heat stress values. Whole-body heat stress alone reduced orthostatic tolerance by ∼80% compared to normothermia (938 ± 152 versus 182 ± 57 CSI; mean ± s.e.m., P < 0.001). Acute volume expansion during whole-body heating completely ameliorated the heat stress-induced reduction in orthostatic tolerance (1110 ± 69 CSI, P < 0.001). Although heat stress results in many cardiovascular and neural responses that directionally challenge blood pressure regulation, reduced central blood volume appears to be an underlying mechanism responsible for impaired orthostatic tolerance in the heat-stressed human.

The relationship between muscle sympathetic nerve activity (MSNA) and diastolic blood pressure has been used to describe two sites for arterial baroreflex control of MSNA. By determining both the likelihood of occurrence for sympathetic bursts and the area of each burst for a given diastolic blood pressure, both a 'gating' and an 'area' control site has been described in normothermic humans. Assessing the effect of heat stress on these mechanisms will improve the understanding of baroreflex control of arterial blood pressure under this thermal condition. Therefore, the purpose of this study was to test the hypothesis that heat stress enhances arterial baroreflex control of burst gating and area. In 10 normotensive subjects (age, 32 ± 2 years; mean ± S.E.M.), MSNA (peroneal) was assessed using standard microneurographic techniques. Five minute periods of data were examined during normothermic and whole-body heating conditions. The burst incidence (i.e. number of sympathetic bursts per 100 cardiac cycles) and the area of each burst were determined for each cardiac cycle and were placed into 3 mmHg intervals of diastolic blood pressure. During normotheric conditions, there was a moderate, negative relationship between burst incidence and diastolic blood pressure (slope = -2.49 ± 0.38; r 2 = 0.73 ± 0.06; mean ± S.E.M.), while area per burst relative to diastolic blood pressure exhibited a less strong relationship (slope = -1.13 ± 0.46; r 2 = 0.45 ± 0.09). During whole-body heating there was an increase in the slope of the relationship between burst incidence and diastolic blood pressure (slope = -4.69 ± 0.44; r 2 = 0.84 ± 0.03) compared to normothermia (P < 0.05), while the relationship between area per burst and diastolic blood pressure was unchanged (slope = -0.92 ± 0.29; r 2 = 0.41 ± 0.08) (P = 0.50). The primary finding of this investigation is that, at rest, whole-body heating enhanced arterial baroreflex control of MSNA through increased sensitivity of a 'gating' mechanism, as indicated by an increase in the slope of the relationship between burst incidence and diastolic blood pressure. This occurrence is likely to afford protection against potential decreases in arterial blood pressure in an effort to preserve orthostatic tolerance during heat stress.

CG. Cerebrovascular responsiveness to steady-state changes in end-tidal CO2 during passive heat stress. J Appl Physiol 104: 976-981, 2008. First published January 24, 2008 doi:10.1152/japplphysiol.01040.2007.-This study tested the hypothesis that passive heat stress alters cerebrovascular responsiveness to steady-state changes in end-tidal CO2 (PETCO 2 ). Nine healthy subjects (4 men and 5 women), each dressed in a water-perfused suit, underwent normoxic hypocapnic hyperventilation (decrease PETCO 2 ϳ20 Torr) and normoxic hypercapnic (increase in PETCO 2 ϳ9 Torr) challenges under normothermic and passive heat stress conditions. The slope of the relationship between calculated cerebrovascular conductance (CBVC; middle cerebral artery blood velocity/mean arterial blood pressure) and PETCO 2 was used to evaluate cerebrovascular CO2 responsiveness. Passive heat stress increased core temperature (1.1 Ϯ 0.2°C, P Ͻ 0.001) and reduced middle cerebral artery blood velocity by 8 Ϯ 8 cm/s (P ϭ 0.01), reduced CBVC by 0.09 Ϯ 0.09 CBVC units (P ϭ 0.02), and decreased PETCO 2 by 3 Ϯ 4 Torr (P ϭ 0.07), while mean arterial blood pressure was well maintained (P ϭ 0.36). The slope of the CBVC-PET CO 2 relationship to the hypocapnic challenge was not different between normothermia and heat stress conditions (0.009 Ϯ 0.006 vs. 0.009 Ϯ 0.004 CBVC units/Torr, P ϭ 0.63). Similarly, in response to the hypercapnic challenge, the slope of the CBVC-PETCO 2 relationship was not different between normothermia and heat stress conditions (0.028 Ϯ 0.020 vs. 0.023 Ϯ 0.008 CBVC units/Torr, P ϭ 0.31). These results indicate that cerebrovascular CO2 responsiveness, to the prescribed steady-state changes in PETCO 2 , is unchanged during passive heat stress. brain blood flow; hyperthermia; hypocapnia; hypercapnia ORTHOSTATIC TOLERANCE IS REDUCED under heat stress, relative to normothermic, conditions (1,8,19,40,41). Although mechanisms responsible for reduced orthostatic tolerance during heat stress are unclear, they are likely associated with factors that directly or indirectly affect cerebral perfusion pressure, cerebral blood flow, and thus cerebral oxygenation (20, 24,38). Cerebral perfusion is very sensitive to changes in arterial carbon dioxide tension (Pa CO 2 ), such that increases in Pa CO 2 increase cerebral perfusion, whereas decreases in Pa CO 2 decrease cerebral perfusion (16, 36). Previously, our laboratory identified decreases in end-tidal carbon dioxide (PET CO 2 ; surrogate of Pa CO 2 ) of ϳ2 Torr in response to whole body passive heat stress, as well as significant reductions in cerebral perfusion and cerebral vascular conductance (40,41). Decreased cerebral perfusion would theoretically reduce the functional reserve by which cerebral blood flow can decrease further, before the onset of syncopal symptoms.It is unlikely that the relatively small decrease in PET CO 2 (i.e., ϳ2 Torr) in response to passive heat stress is the sole mechanism leading to the observed reduction in cerebral perfusion. However, this assumption is based on ca...

The goal of this study was to access antioxidant status and markers of oxidative damage in elite alpine ski racers during routine training. Subjects included 12 members of the U.S. Men's Alpine Ski Team attending a 10-day summer training camp. Blood draws were collected at rest and after exercise: (a) prior to training, (b) following 2 days of dry land training, and (c) after 4 days of on-snow skiing. Seven measures of antioxidant status were determined using colorimetric and HPLC methods (Trolox equivalent antioxidant capacity, uric oxidase, alpha-tocopherol, total glutathione, cytosolic glutathione peroxidase, and superoxide dismutase). Oxidative stress was assessed using 2 markers of lipid oxidation (malondialdehyde and lipid hydroperoxides) and 2 markers of protein oxidation (carbonylated total proteins and carbonylated hemoglobin). The results of this study suggest that antioxidant status of elite alpine skiers may decline over a period of intense training. However, elevations in markers of oxidative stress were not evident.

Skin sympathetic nerve activity (SSNA) exhibits low- and high-frequency spectral components in normothermic subjects. However, spectral characteristics of SSNA in heat-stressed subjects are unknown. Because the main components of the integrated SSNA during heat stress (sudomotor/vasodilator activities) are different from those during normothermia and cooling (vasoconstrictor activity), we hypothesize that spectral characteristics of SSNA in heat-stressed subjects will be different from those in subjects subjected to normothermia or cooling. In 17 healthy subjects, SSNA, electrocardiogram, arterial blood pressure (via Finapres), respiratory activity, and skin blood flow were recorded during normothermia and heat stress. In 7 of the 17 subjects, these variables were also recorded during cooling. Spectral characteristics of integrated SSNA, R-R interval, beat-by-beat mean blood pressure, skin blood flow variability, and respiratory excursions were assessed. Heat stress and cooling significantly increased total SSNA. SSNA spectral power in the low-frequency (0.03-0.15 Hz), high-frequency (0.15-0.45 Hz), and very-high-frequency (0.45-2.5 Hz) regions was significantly elevated by heat stress and cooling. Interestingly, heat stress caused a greater relative increase of SSNA spectral power within the 0.45- to 2.5-Hz region than in the other spectral ranges; cooling did not show this effect. Differences in the SSNA spectral distribution between normothermia/cooling and heat stress may reflect different characteristics of central modulation of vasoconstrictor and sudomotor/vasodilator activities.

In the late 19(th) century, Wilhelm Uhthoff reported on a series of patients with acute optic neuritis who manifested similar recurrent, stereotyped visual symptoms that were of paroxysmal onset, short in duration, and reversible. These 'Uhthoff's phenomena', which are a feature of multiple sclerosis (MS) and other demyelinating diseases, can be triggered by factors including the perimenstrual period, exercise, infection, fever, exposure to high ambient temperatures, and psychological stress. Here, we characterize the clinical, pathophysiological and neurotherapeutic challenges associated with Uhthoff's phenomena, and discuss the differentiation of these events from other paroxysmal, acute or subacute changes in functional capabilities and neurological symptoms in MS. For instance, whereas MS exacerbations are contingent on immune dysregulation, Uhthoff's phenomena are predicated on ion channel modifications, in conjunction with thermoregulatory derangements that transiently alter the conduction properties of demyelinated axons. An understanding of these pathophysiological underpinnings of Uhthoff's phenomena is germane to their recognition and timely treatment.