Cerebral perturbations during exercise in hypoxia

Reduction of aerobic exercise performance observed under hypoxic conditions is mainly attributed to altered muscle metabolism due to impaired O(2) delivery. It has been recently proposed that hypoxia-induced cerebral perturbations may also contribute to exercise performance limitation. A significant reduction in cerebral oxygenation during whole body exercise has been reported in hypoxia compared with normoxia, while changes in cerebral perfusion may depend on the brain region, the level of arterial oxygenation and hyperventilation induced alterations in arterial CO(2). With the use of transcranial magnetic stimulation, inconsistent changes in cortical excitability have been reported in hypoxia, whereas a greater impairment in maximal voluntary activation following a fatiguing exercise has been suggested when arterial O(2) content is reduced. Electromyographic recordings during exercise showed an accelerated rise in central motor drive in hypoxia, probably to compensate for greater muscle contractile fatigue. This accelerated development of muscle fatigue in moderate hypoxia may be responsible for increased inhibitory afferent signals to the central nervous system leading to impaired central drive. In severe hypoxia (arterial O(2) saturation <70-75%), cerebral hypoxia per se may become an important contributor to impaired performance and reduced motor drive during prolonged exercise. This review examines the effects of acute and chronic reduction in arterial O(2) (and CO(2)) on cerebral blood flow and cerebral oxygenation, neuronal function, and central drive to the muscles. Direct and indirect influences of arterial deoxygenation on central command are separated. Methodological concerns as well as future research avenues are also considered.     

Interpretation of near-infrared spectroscopy signals: a study with a newly developed perfused rat brain model.

Using a newly developed perfused rat brain model, we examined direct effects of each change in cerebral blood flow (CBF) and oxygen metabolic rate on cerebral hemoglobin oxygenation to interpret near-infrared spectroscopy signals. Changes in CBF and total hemoglobin (tHb) were in parallel, although tHb showed no change when changes in CBF were small (< or =10%). Increasing CBF caused an increase in oxygenated hemoglobin (HbO(2)) and a decrease in deoxygenated hemoglobin (deoxy-Hb). Decreasing CBF was accompanied by a decrease in HbO(2), whereas changes in direction of deoxy-Hb were various. Cerebral blood congestion caused increases in HbO(2), deoxy-Hb, and tHb. Administration of pentylenetetrazole without increasing the flow rate caused increases in HbO(2) and tHb with a decrease in deoxy-Hb. There were no significant differences in venous oxygen saturation before vs. during seizure. These results suggest that, in activation studies with near-infrared spectroscopy, HbO(2) is the most sensitive indicator of changes in CBF, and the direction of changes in deoxy-Hb is determined by the degree of changes in venous blood oxygenation and volume.     

Nervous control of the cerebrovascular system: doubts and facts.

Increased function of the central neurons results in increased neuronal metabolism and, as a consequence, increased concentration of metabolic end-products (H+, K+, adenosin) results in an increased cerebral blood flow (CBF). There is a general agreement among investigators that products of cerebral tissue metabolism as well as chemical stimuli are key factors that determine the rate of blood flow in the brain. CBF, however, may increase out of proportion to metabolic demands, may increase without significant change in local metabolism, and may increase much faster than the accumulation of the metabolic end-products. Therefore, the 100-year-old metabolic hypothesis of Roy and Sherrington, cannot fully explain the increases of CBF during increased functional activity of the central neurons. The tight coupling of neuronal activity and blood flow in the brain is demonstrated by a large amount of data. Therefore, the likelihood exists that neurogenic stimuli via perivascular nerve endings may act as rapid initiators, to induce a moment-to-moment dynamic adjustment of CBF to the metabolic demands, and further maintenance of these adjusted parameters is ensured by the metabolic and chemical factors. Perivascular nerve endings were identified in the outer smooth muscle layer of the cerebral arteries, arterioles and veins. Their axonterminals contain a large variety of neurotransmitters, often co-localised in synaptic vesicles. Stimulation of the nerves results in a release of transmitters into the narrow neuromuscular synaptic clefts in the cerebrovascular smooth muscle, close to specific receptor sites in the vessel wall. In spite of these facts, however, and in spite of the large number of new experimental evidences, the role of the nervous control of the cerebrovascular system is underestimated both in medical textbooks and in the common medical knowledge since decades. In the last 20 years major advances have been made that make it necessary to revise this false view. The purpose of this review is to facilitate this process at the end of this century, when the importance of the nervous control of the cerebral circulation has been fully appreciated among investigators.     

Regional distribution of cerebral blood flow during exercise in dogs

This study was performed to determine whether exercise produces vasodilatation in regions of the brain that are associated with motor functions despite the associated vasoconstrictor effect of hypocapnia. Total and regional cerebral blood flow (CBF) were measured with microspheres in dogs during treadmill exercise of moderate intensity. Flow was also measured at rest after stimulation of ventilation with doxapram. During moderate exercise, total CBF was not changed significantly, but regional flow was increased in structures associated with motor-sensory control; blood flow to motor-sensory cortex, neocerebellar and paleocerebellar cortex, and spinal cord increased 30 +/- 7%, 39 +/- 8%, and 29 +/- 4%, respectively (P less than 0.05). After doxapram, which increased arterial blood pressure and decreased arterial PCO2 to levels similar to those during exercise, total CBF decreased and there was no redistribution of CBF. These results indicate that exercise in conscious dogs increases blood flow in regions of the brain associated with movement despite the associated vasoconstrictor stimulus of arterial hypocapnia. Thus, during exercise, local dilator influences that presumably result from increases in metabolism predominate over a potent constrictor stimulus in regulation of cerebral vascular resistance.     

Cerebral metabolic response to submaximal exercise.

We studied cerebral oxygenation and metabolism during submaximal cycling in 12 subjects. At two work rates, middle cerebral artery blood velocity increased from 62 +/- 3 to 63 +/- 3 and 70 +/- 5 cm/s as did cerebral oxygenation determined by near-infrared spectroscopy. Oxyhemoglobin increased by 10 +/- 3 and 25 +/- 3 micromol/l (P < 0. 01), and there was no significant change in brain norepinephrine spillover. The arterial-to-internal-jugular-venous (a-v) difference for O(2) decreased at low-intensity exercise (from 3.1 +/- 0.1 to 2. 9 +/- 0.1 mmol/l; P < 0.05) and recovered at moderate exercise (to 3. 3 +/- 0.1 mmol/l). The profile for glucose was similar: its a-v difference tended to decrease at low-intensity exercise (from 0.55 +/- 0.05 to 0.50 +/- 0.02 mmol/l) and increased during moderate exercise (to 0.64 +/- 0.04 mmol/l; P < 0.05). Thus the molar ratio (a-v difference, O(2) to glucose) did not change significantly. However, when the a-v difference for lactate (0.02 +/- 0.03 to 0.18 +/- 0.04 mmol/l) was taken into account, the O(2)-to-carbohydrate ratio decreased (from 6.1 +/- 0.4 to 4.7 +/- 0.3; P < 0.05). The enhanced cerebral oxygenation suggests that, during exercise, cerebral blood flow increases in excess of the O(2) demand. Yet it seems that during exercise not all carbohydrate taken up by the brain is oxidized, as brain lactate metabolism appears to lower the balance of O(2)-to-carbohydrate uptake.     

Noninvasive assessment of sympathetic vasoconstriction in human and rodent skeletal muscle using near-infrared spectroscopy and Doppler ultrasound.

The precise role of the sympathetic nervous system in the regulation of skeletal muscle blood flow during exercise has been challenging to define in humans, partly because of the limited techniques available for measuring blood flow in active muscle. Recent studies using near-infrared (NIR) spectroscopy to measure changes in tissue oxygenation have provided an alternative method to evaluate vasomotor responses in exercising muscle, but this approach has not been fully validated. In this study, we tested the hypothesis that sympathetic activation would evoke parallel changes in tissue oxygenation and blood flow in resting and exercising muscle. We simultaneously measured tissue oxygenation with NIR spectroscopy and blood flow with Doppler ultrasound in skeletal muscle of conscious humans (n = 13) and anesthetized rats (n = 9). In resting forearm of humans, reflex activation of sympathetic nerves with the use of lower body negative pressure produced graded decreases in tissue oxygenation and blood flow that were highly correlated (r = 0.80, P < 0.0001). Similarly, in resting hindlimb of rats, electrical stimulation of sympathetic nerves produced graded decreases in tissue oxygenation and blood flow velocity that were highly correlated (r = 0.93, P < 0.0001). During rhythmic muscle contraction, the decreases in tissue oxygenation and blood flow evoked by sympathetic activation were significantly attenuated (P < 0.05 vs. rest) but remained highly correlated in both humans (r = 0.80, P < 0.006) and rats (r = 0.92, P < 0.0001). These data indicate that, during steady-state metabolic conditions, changes in tissue oxygenation can be used to reliably assess sympathetic vasoconstriction in both resting and exercising skeletal muscle.     

Middle cerebral artery flow velocity and blood flow during exercise and muscle ischemia in humans.

Changes in middle cerebral artery flow velocity (Vmean), measured by transcranial Doppler ultrasound, were used to determine whether increases in mean arterial pressure (MAP) or brain activation enhance cerebral perfusion during exercise. We also evaluated the role of "central command," mechanoreceptors, and/or muscle "metaboreceptors" on cerebral perfusion. Ten healthy subjects performed two levels of dynamic exercise corresponding to a heart rate of 110 (range 89-134) and 148 (129-170) beats/min, respectively, and exhaustive one-legged static knee extension. Measurements were continued during 2-2.5 min of muscle ischemia. MAP increased similarly during static [114 (102-133) mmHg] and heavy dynamic exercise [121 (104-136) mmHg] and increased during muscle ischemia after dynamic exercise. During heavy dynamic exercise, Vmean increased 24% (10-47%; P less than 0.01) over approximately 3 min despite constant arterial carbon dioxide tension. In contrast, static exercise with a higher rate of perceived exertion [18 (13-20) vs. 15 (12-18) units; P less than 0.01] was associated with no significant change in Vmean. Muscle ischemia after exercise was not associated with an elevation in Vmean, and it did not provoke an increase in Vmean after static exercise. Changes in Vmean during exercise were similar to those recorded with the initial slope index of the 133Xe clearance method. The data show that middle cerebral artery mean flow velocity reflects changes in cerebral perfusion during exercise. Furthermore, they support the hypothesis that cerebral perfusion during exercise reflects an increase in brain activation that is independent of MAP, central command, and muscle metaboreceptors but is likely to depend on influence of mechanoreceptors.     

Differential cerebral hypothermia

Differential cerebral hypothermia was induced in these experiments by isolating the cerebral circulation in the halothane-anesthetized goat. The brain was perfused through isolated cerebral branches of the internal maxillary artery using a height-adjusted reservoir system which provided a constant inflow pressure. Cerebral blood flow (CBF) and cerebral O₂ metabolic rate (CMRO₂) were measured continuously as brain temperatures were decreased from 38 to 28, 18 and 8 °C and during rewarming. Arterial blood gases were maintained constant. During hypothermia CBF decreased at brain temperatures of 28 °C and did decrease further at 18 or 8 °C. CMRO₂ decreased linearly from 38 to 8 °C and was 7% control levels at 8 °C. CBF and CMRO₂ returned to control levels upon rewarming. Cerebral lactate metabolism did not change significantly during hypothermia or rewarming. Evoked cortical potentials were abolished at 8 °C but recovered upon rewarming. These results indicate that if adequate brain perfusion is maintained during hypothermia and rewarming, recovery of CBF, metabolism, and brain neural activity can be obtained.     

Functional, Metabolic, and Circulatory Changes Associated with Seizure Activity in the Postischemic Brain

Abstract: The present study was undertaken to explore how transient ischemia in rats alters cerebral metabolic capacity and how postischemic metabolism and blood flow are coupled during intense activation. After 6 h of recovery following transient forebrain ischemia 15 min in duration, bicuculline seizures were induced, and brains were frozen in situ after 0.5 or 5 min of seizure discharge. At these times, levels of labile tissue metabolites were measured, whereas the cerebral metabolic rate for oxygen (CMRO₂) and cerebral blood flow (CBF) were measured after 5 min of seizure activity. After 6 h of recovery, and before seizures, animals had a 40–50% reduction in CMRO₂, and CBF. However, because CMRO₂ rose threefold and CBF fivefold during seizures, CMRO₂ and CBF during seizures were similar in control and postischemic rats. Changes in labile metabolites due to the preceding ischemia encompassed an increased phosphocreatine/ creatine ratio, as well as raised glucose and glycogen concentrations. Seizures gave rise to minimal metabolic perturbation, essentially comprising reduced glucose and glycogen contents and raised lactate concentrations. It is concluded that although transient ischemia leads to metabolic depression and a fall in CBF, the metabolic capacity of the tissue is retained, and drug-induced seizures lead to a coupled rise in metabolic rate and blood flow.     

Alterations in cerebral autoregulation and cerebral blood flow velocity during acute hypoxia: rest and exercise

We examined the relationship between changes in cardiorespiratory and cerebrovascular function in 14 healthy volunteers with and without hypoxia [arterial O(2) saturation (Sa(O(2))) approximately 80%] at rest and during 60-70% maximal oxygen uptake steady-state cycling exercise. During all procedures, ventilation, end-tidal gases, heart rate (HR), arterial blood pressure (BP; Finometer) cardiac output (Modelflow), muscle and cerebral oxygenation (near-infrared spectroscopy), and middle cerebral artery blood flow velocity (MCAV; transcranial Doppler ultrasound) were measured continuously. The effect of hypoxia on dynamic cerebral autoregulation was assessed with transfer function gain and phase shift in mean BP and MCAV. At rest, hypoxia resulted in increases in ventilation, progressive hypocapnia, and general sympathoexcitation (i.e., elevated HR and cardiac output); these responses were more marked during hypoxic exercise (P < 0.05 vs. rest) and were also reflected in elevation of the slopes of the linear regressions of ventilation, HR, and cardiac output with Sa(O(2)) (P < 0.05 vs. rest). MCAV was maintained during hypoxic exercise, despite marked hypocapnia (44.1 +/- 2.9 to 36.3 +/- 4.2 Torr; P < 0.05). Conversely, hypoxia both at rest and during exercise decreased cerebral oxygenation compared with muscle. The low-frequency phase between MCAV and mean BP was lowered during hypoxic exercise, indicating impairment in cerebral autoregulation. These data indicate that increases in cerebral neurogenic activity and/or sympathoexcitation during hypoxic exercise can potentially outbalance the hypocapnia-induced lowering of MCAV. Despite maintaining MCAV, such hypoxic exercise can potentially compromise cerebral autoregulation and oxygenation.     

Does cerebral oxygen delivery limit incremental exercise performance?

Previous studies have suggested that a reduction in cerebral oxygen delivery may limit motor drive, particularly in hypoxic conditions, where oxygen transport is impaired. We hypothesized that raising end-tidal Pco(2) (Pet(CO(2))) during incremental exercise would increase cerebral blood flow (CBF) and oxygen delivery, thereby improving peak power output (W(peak)). Amateur cyclists performed two ramped exercise tests (25 W/min) in a counterbalanced order to compare the normal, poikilocapnic response against a clamped condition, in which Pet(CO(2)) was held at 50 Torr throughout exercise. Tests were performed in normoxia (barometric pressure = 630 mmHg, 1,650 m) and hypoxia (barometric pressure = 425 mmHg, 4,875 m) in a hypobaric chamber. An additional trial in hypoxia investigated effects of clamping at a lower Pet(CO(2)) (40 Torr) from ～75 to 100% W(peak) to reduce potential influences of respiratory acidosis and muscle fatigue imposed by clamping Pet(CO(2)) at 50 Torr. Metabolic gases, ventilation, middle cerebral artery CBF velocity (transcranial Doppler), forehead pulse oximetry, and cerebral (prefrontal) and muscle (vastus lateralis) hemoglobin oxygenation (near infrared spectroscopy) were monitored across trials. Clamping Pet(CO(2)) at 50 Torr in both normoxia (n = 9) and hypoxia (n = 11) elevated CBF velocity (～40%) and improved cerebral hemoglobin oxygenation (～15%), but decreased W(peak) (6%) and peak oxygen consumption (11%). Clamping at 40 Torr near maximal effort in hypoxia (n = 6) also improved cerebral oxygenation (～15%), but again limited W(peak) (5%). These findings demonstrate that increasing mass cerebral oxygen delivery via CO(2)-mediated vasodilation does not improve incremental exercise performance, at least when accompanied by respiratory acidosis.     

Effects of hyperthermia on cerebral blood flow and metabolism during prolonged exercise in humans.

The development of hyperthermia during prolonged exercise in humans is associated with various changes in the brain, but it is not known whether the cerebral metabolism or the global cerebral blood flow (gCBF) is affected. Eight endurance-trained subjects completed two exercise bouts on a cycle ergometer. The gCBF and cerebral metabolic rates of oxygen, glucose, and lactate were determined with the Kety-Schmidt technique after 15 min of exercise when core temperature was similar across trials, and at the end of exercise, either when subjects remained normothermic (core temperature = 37.9 degrees C; control) or when severe hyperthermia had developed (core temperature = 39.5 degrees C; hyperthermia). The gCBF was similar after 15 min in the two trials, and it remained stable throughout control. In contrast, during hyperthermia gCBF decreased by 18% and was therefore lower in hyperthermia compared with control at the end of exercise (43 +/- 4 vs. 51 +/- 4 ml. 100 g(-1). min(-1); P < 0.05). Concomitant with the reduction in gCBF, there was a proportionally larger increase in the arteriovenous differences for oxygen and glucose, and the cerebral metabolic rate was therefore higher at the end of the hyperthermic trial compared with control. The hyperthermia-induced lowering of gCBF did not alter cerebral lactate release. The hyperthermia-induced reduction in exercise cerebral blood flow seems to relate to a concomitant 18% lowering of arterial carbon dioxide tension, whereas the higher cerebral metabolic rate of oxygen may be ascribed to a Q(10) (temperature) effect and/or the level of cerebral neuronal activity associated with increased exertion.     

Hyperthermia and fatigue.

The present review addresses mechanisms of importance for hyperthermia-induced fatigue during short intense activities and prolonged exercise in the heat. Inferior performance during physical activities with intensities that elicit maximal oxygen uptake is to a large extent related to perturbation of the cardiovascular function, which eventually reduces arterial oxygen delivery to the exercising muscles. Accordingly, aerobic energy turnover is impaired and anaerobic metabolism provokes peripheral fatigue. In contrast, metabolic disturbances of muscle homeostasis are less important during prolonged exercise in the heat, because increased oxygen extraction compensates for the reduction in systemic blood flow. The decrease in endurance seems to involve changes in the function of the central nervous system (CNS) that lead to fatigue. The CNS fatigue appears to be influenced by neurotransmitter activity of the dopaminergic system, but may primarily relate to inhibitory signals from the hypothalamus arising secondary to an increase in brain temperature. Fatigue is an integrated phenomenon, and psychological factors, including the anticipation of fatigue, should not be neglected and the interaction between central and peripheral physiological factors also needs to be considered.     

Effects of acute hypoxia on cerebral and muscle oxygenation during incremental exercise.

To determine if fatigue at maximal aerobic power output was associated with a critical decrease in cerebral oxygenation, 13 male cyclists performed incremental maximal exercise tests (25 W/min ramp) under normoxic (Norm: 21% Fi(O2)) and acute hypoxic (Hypox: 12% Fi(O2)) conditions. Near-infrared spectroscopy (NIRS) was used to monitor concentration (microM) changes of oxy- and deoxyhemoglobin (Delta[O2Hb], Delta[HHb]) in the left vastus lateralis muscle and frontal cerebral cortex. Changes in total Hb were calculated (Delta[THb] = Delta[O2Hb] + Delta[HHb]) and used as an index of change in regional blood volume. Repeated-measures ANOVA were performed across treatments and work rates (alpha = 0.05). During Norm, cerebral oxygenation rose between 25 and 75% peak power output {Power(peak); increased (inc) Delta[O2Hb], inc. Delta[HHb], inc. Delta[THb]}, but fell from 75 to 100% Power(peak) {decreased (dec) Delta[O2Hb], inc. Delta[HHb], no change Delta[THb]}. In contrast, during Hypox, cerebral oxygenation dropped progressively across all work rates (dec. Delta[O2Hb], inc. Delta[HHb]), whereas Delta[THb] again rose up to 75% Power(peak) and remained constant thereafter. Changes in cerebral oxygenation during Hypox were larger than Norm. In muscle, oxygenation decreased progressively throughout exercise in both Norm and Hypox (dec. Delta[O2Hb], inc. Delta [HHb], inc. Delta[THb]), although Delta[O2Hb] was unchanged between 75 and 100% Power peak. Changes in muscle oxygenation were also greater in Hypox compared with Norm. On the basis of these findings, it is unlikely that changes in cerebral oxygenation limit incremental exercise performance in normoxia, yet it is possible that such changes play a more pivotal role in hypoxia.     

Stroke volume decline during prolonged exercise is influenced by the increase in heart rate.

This study determined whether the decline in stroke volume (SV) during prolonged exercise is related to an increase in heart rate (HR) and/or an increase in cutaneous blood flow (CBF). Seven active men cycled for 60 min at approximately 57% peak O2 uptake in a neutral environment (i.e., 27 degrees C, <40% relative humidity). They received a placebo control (CON) or a small oral dose (i.e., approximately 7 mg) of the beta1-adrenoceptor blocker atenolol (BB) at the onset of exercise. At 15 min, HR and SV were similar during CON and BB. From 15 to 55 min during CON, a 13% decline in SV was associated with an 11% increase in HR and not with an increase in CBF. CBF increased mainly from 5 to 15 min and remained stable from 20 to 60 min of exercise in both treatments. However, from 15 to 55 min during BB, when the increase in HR was prevented by atenolol, the decline in SV was also prevented, despite a normal CBF response (i.e., similar to CON). Cardiac output was similar in both treatments and stable throughout the exercise bouts. We conclude that during prolonged exercise in a neutral environment the decline in SV is related to the increase in HR and is not affected by CBF.     

Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease.

The brain is critically dependent on a continuous supply of blood to function. Therefore, the cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the energy needs of its cellular constituents. The regulation of cerebral blood flow (CBF) during brain activity involves the coordinated interaction of neurons, glia, and vascular cells. Thus, whereas neurons and glia generate the signals initiating the vasodilation, endothelial cells, pericytes, and smooth muscle cells act in concert to transduce these signals into carefully orchestrated vascular changes that lead to CBF increases focused to the activated area and temporally linked to the period of activation. Neurovascular coupling is disrupted in pathological conditions, such as hypertension, Alzheimer disease, and ischemic stroke. Consequently, CBF is no longer matched to the metabolic requirements of the tissue. This cerebrovascular dysregulation is mediated in large part by the deleterious action of reactive oxygen species on cerebral blood vessels. A major source of cerebral vascular radicals in models of hypertension and Alzheimer disease is the enzyme NADPH oxidase. These findings, collectively, highlight the importance of neurovascular coupling to the health of the normal brain and suggest a therapeutic target for improving brain function in pathologies associated with cerebrovascular dysfunction.     

Dissociation of AMPK activity and ACCbeta phosphorylation in human muscle during prolonged exercise

During prolonged, low intensity exercise, the type of substrate utilized varies with time. If 5' AMP-activated protein kinase (AMPK) regulates muscle metabolism during exercise, signaling through AMPK would be expected to change in concordance with changes in substrate utilization. Six healthy, young males cycled (approximately 45% VO(2peak)) until exhaustion (approximately 3.5h). During exercise, leg glucose uptake and rate of glycogenolysis gradually decreased whereas free fatty acid uptake gradually increased. In the thigh muscle, the alpha AMPK subunits became progressively more phosphorylated on Thr(172) during exercise eliciting a parallel increase in alpha2 but not alpha1 AMPK activity. In contrast, after 1h of exercise, Ser(221) phosphorylation of acetyl-CoA carboxylase-beta (ACCbeta) peaked at 1h of exercise and returned to resting levels at exhaustion. Protein expression of alpha2 AMPK, alpha1 AMPK or ACCbeta did not change with time. These data suggest that AMPK signaling is not a key regulatory system of muscle substrate combustion during prolonged exercise and that marked activation of AMPK via phosphorylation is not sufficient to maintain an elevated ACCbeta Ser(221) phosphorylation during prolonged exercise.     

Skin blood flow influences near-infrared spectroscopy-derived measurements of tissue oxygenation during heat stress.

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).     

The thermodynamics of thinking: connections between neural activity,energy metabolism and blood flow

Several current functional neuroimaging methods are sensitive to cerebral metabolism and cerebral blood flow (CBF) rather than the underlying neural activity itself. Empirically, the connections between metabolism, flow and neural activity are complex and somewhat counterintuitive: CBF and glycolysis increase more than seems to be needed to provide oxygen and pyruvate for oxidative metabolism, and the oxygen extraction fraction is relatively low in the brain and decreases when oxygen metabolism increases. This work lays a foundation for the idea that this unexpected pattern of physiological changes is consistent with basic thermodynamic considerations related to metabolism. In the context of this thermodynamic framework, the apparent mismatches in metabolic rates and CBF are related to preserving the entropy change of oxidative metabolism, specifically the O₂/CO₂ ratio in the mitochondria. However, the mechanism supporting this CBF response is likely not owing to feedback from a hypothetical O₂ sensor in tissue, but rather is consistent with feed-forward control by signals from both excitatory and inhibitory neural activity. Quantitative predictions of the thermodynamic framework, based on models of O₂ and CO₂ transport and possible neural drivers of CBF control, are in good agreement with a wide range of experimental data, including responses to neural activation, hypercapnia, hypoxia and high-altitude acclimatization.This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.     

Hemodynamic responses to heat stress in the resting and exercising human leg: insight into the effect of temperature on skeletal muscle blood flow

Heat stress increases limb blood flow and cardiac output (Q) in humans, presumably in sole response to an augmented thermoregulatory demand of the skin circulation. Here we tested the hypothesis that local hyperthermia also increases skeletal muscle blood flow at rest and during exercise. Hemodynamics, blood and tissue oxygenation, and muscle, skin, and core temperatures were measured at rest and during exercise in 11 males across four conditions of progressive whole body heat stress and at rest during isolated leg heat stress. During whole body heat stress, leg blood flow (LBF), Q, and leg (LVC) and systemic vascular conductance increased gradually with elevations in muscle temperature both at rest and during exercise (r(2) = 0.86-0.99; P < 0.05). Enhanced LBF and LVC were accompanied by reductions in leg arteriovenous oxygen (a-vO(2)) difference and increases in deep femoral venous O(2) content and quadriceps tissue oxygenation, reflecting elevations in muscle and skin perfusion. The increase in LVC occurred despite an augmented plasma norepinephrine (P < 0.05) and was associated with elevations in muscle temperature (r(2) = 0.85; P = 0.001) and arterial plasma ATP (r(2) = 0.87; P < 0.001). Isolated leg heat stress accounted for one-half of the increase in LBF with severe whole body heat stress. Our findings suggest that local hyperthermia also induces vasodilatation of the skeletal muscle microvasculature, thereby contributing to heat stress and exercise hyperemia. The increased limb muscle vasodilatation in these conditions of elevated muscle sympathetic vasoconstrictor activity is closely related to the rise in arterial plasma ATP and local tissue temperature.