Acute hypoxia elicits prefrontal oxygenation asymmetry in young adults.

Significance: Cerebrovascular reactivity can be evaluated by prefrontal cortex (PFC) hemodynamic responses and oxygenation changes secondary to hypoxia using near-infrared spectroscopy (NIRS). However, whether there are hemispheric differences in these NIRS-determined PFC hemodynamic responses and oxygenation changes remains unknown. Aim: This study was performed to determine whether there are differences in the PFC hemodynamic responses and oxygenation changes secondary to hypoxia between the left and right frontal poles (FPL and FPR, respectively). Approach: Fifteen young men participated in the study. During conduction of an isocapnic hypoxia protocol with a 10-min hypoxic phase at partial pressure of end-tidal oxygen (PETO2) of 45 Torr, hemodynamic and oxygenation indices comprising oxygenated hemoglobin (oxy-Hb), deoxygenated Hb (deoxy-Hb), total Hb (total-Hb), and tissue oxygen saturation (StO2) over FPL and FPR were measured by NIRS. The heart rate (HR) was evaluated by electrocardiography. Results: In response to hypoxia, the HR increased, oxy-Hb decreased, deoxy-Hb increased, total-Hb increased above baseline, and StO2 decreased. There was no difference in the change in total-Hb between FPL and FPR. However, there were greater changes in oxy-Hb, deoxy-Hb, and StO2 over FPL than over FPR, indicating that PFC oxygenation asymmetry occurs in response to hypoxia. Moreover, the change in total-Hb over FPL was associated with the increase in HR. Conclusions: NIRS-determined hemodynamic responses and oxygenation changes secondary to hypoxia might not simply reflect the direct effect of hypoxia on cerebral vessels. Although there is no hemispheric difference in the PFC hemodynamic responses to hypoxia as in total-Hb, PFC oxygenation asymmetry occurs in young adults.

Effects of the nitric oxide synthase inhibitor L-NMMA on cerebrovascular and cardiovascular responses to hypoxia and hypercapnia in humans.

Cerebral blood flow is highly sensitive to alterations in the partial pressures of O(2) and CO(2) (P(O(2)) and P(CO(2)), respectively) in the arterial blood. In humans, the extent to which nitric oxide (NO) is involved in this regulation is unclear. We hypothesized that the NO synthase (NOS) inhibitor N(G)-monomethyl-l-arginine (l-NMMA), attenuates the sensitivity of middle cerebral artery blood velocity (V(p)) to isocapnic hypoxia (end-tidal P(O(2)) = 50 Torr) and euoxic hypercapnia (end-tidal P(CO(2)) = +9 Torr above resting values) in 10 volunteers (age, 28.7 +/- 1.3 years; height, 179.2 +/- 2.4 cm; weight, 78.0 +/- 3.7 kg; mean +/- s.e.m.). The techniques of transcranial Doppler ultrasound and dynamic end-tidal forcing were used to measure(V(p)), and control end-tidal P(O(2)) and end-tidal P(CO(2)), respectively. At baseline (isocapnic euoxia), following intravenous administration of l-NMMA, mean arterial blood pressure (MAP) increased (76.3 +/- 7.3 to 86.2 +/- 9.4 mmHg) and heart rate (HR) decreased (59.5 +/- 9.0 to 55.2 +/- 9.5 beats min(-1)) but (V(p)) was unchanged. Hypoxia-induced increases in MAP, HR and were similar with and without l-NMMA (5.0 +/- 0.7 versus 7.1 +/- 1.0 mmHg, 11.5 +/- 1.4 versus 12.4 +/- 1.5 beats min(-1), 6.5 +/- 0.8 versus 6.6 +/- 0.8 cm s(-1) for DeltaMAP, DeltaHR and Delta , respectively). Hypercapnia-induced increases in MAP, HR and (V(p)) were similar with and without l-NMMA (7.4 +/- 3.1 versus 8.1 +/- 2.2 mmHg, 10.4 +/- 4.6 versus 10.0 +/- 4.2 beats min(-1), 16.5 +/- 1.5 versus 17.6 +/- 1.5 cm s(-1) for DeltaMAP, DeltaHR and Delta(V(p)) , respectively) but the sensitivity of the(V(p)) response at the removal of hypercapnia was attenuated with l-NMMA. In young healthy humans, pharmacological blockade of nitric oxide synthesis does not affect the increases in cerebral blood flow with hypoxia and hypercapnia, suggesting that nitric oxide is not required for the cerbrovascular responses to hypoxia and hypercapnia.

Control of end-tidal PCO2 reduces middle cerebral artery blood velocity variability: implications for physiological neuroimaging.

Breath-by-breath variability of the end-tidal partial pressure of CO2 (Pet(CO2)) has been shown to be associated with cerebral blood flow (CBF) fluctuations. These fluctuations can impact neuroimaging techniques that depend on cerebrovascular blood flow. We hypothesized that controlling Pet(CO2) would reduce CBF variability. Dynamic end-tidal forcing was used to control Pet(CO2) at 1.5 mm Hg above the resting level and to hold the end-tidal partial pressure of oxygen (Pet(O2)) at the resting level. Peak blood velocity in the middle cerebral artery (MCA) was measured by transcranial Doppler ultrasound (TCD) as an index of CBF. Blood velocity parameters and timing features were determined on each waveform and the variance of these parameters was compared between Normal (air breathing) and Forcing (end-tidal gas control) sessions. The variability of all velocity parameters was significantly reduced in the Forcing session. In particular, the variability of the average velocity over the cardiac cycle was decreased by 18.2% (P < 0.001). For the most part, the variability of the timing parameters was unchanged. Thus, we conclude that controlling Pet(CO2) is effective in reducing CBF variability, which would have important implications for physiologic neuroimaging.

The interaction of central command and the exercise pressor reflex in mediating baroreflex resetting during exercise in humans.

Central command and the exercise pressor reflex can independently reset the carotid baroreflex (CBR) during exercise. The present investigation assessed the interactive relationship between these two neural mechanisms in mediating baroreflex resetting during exercise. Six men performed static leg exercise at 20% maximal voluntary contraction under four conditions: control, no perturbation; neuromuscular blockade (NMB) induced by administration of the neuromuscular blocking agent Norcuron (central command activation); MAST, application of medical antishock trousers inflated to 100 mmHg (exercise pressor reflex activation); and Combo, NMB plus MAST (concomitant central command and exercise pressor reflex activation). With regard to CBR control of heart rate (HR), both NMB and Combo conditions resulted in a further resetting of the carotid-cardiac stimulus-response curve compared to control conditions, suggesting that CBR-HR resetting is predominately mediated by central command. In contrast, it appears that CBR control of blood pressure can be mediated by signals from either central command or the exercise pressor reflex, since both NMB and MAST conditions equally augmented the resetting of the carotid-vasomotor stimulus-response curve. With regard to the regulation of both HR and blood pressure, the extent of CBR resetting was greater during the Combo condition than during overactivation of either central command or the exercise pressor reflex alone. Therefore, we suggest that central command and the exercise pressor reflex interact such that signals from one input facilitate signals from the other, resulting in an enhanced resetting of the baroreflex during exercise.

Effect of five nights of normobaric hypoxia on cardiovascular responses to acute isocapnic hypoxia in humans: relationship to ventilatory chemosensitivity.

The aim of this study was to elucidate (1) the cardiovascular responses to acute isocapnic hypoxia stimuli following five nights of normobaric poikilocapnic hypoxia, and (2) whether the changes in the cardiovascular responses to hypoxia are correlated to the change in acute hypoxic ventilatory (AHVR) chemosensitivity. Twelve male subjects [26.6 +/- 4.1 (SD) years] slept 8-9 h day(-1) overnight for five consecutive days at a simulated altitude of 4300 m (FiO2 = approximately 13.8%). Using the technique of dynamic end-tidal forcing, the AHVR was assessed twice, prior to and immediately after the hypoxic exposure. During each AHVR test, mean arterial blood pressure (MAP) and heart rate (HR) were measured continuously using finger photoplethysmography and an ECG monitor, respectively. Immediately following the exposure, AHVR and MAP sensitivities were increased by 1.80 +/- 1.30 l min(-1) %(-1) (p < 0.01) and 0.69 +/- 0.40 mmHg %(-1) (p < 0.05), respectively, and there were significant correlations between the increases in the AHVR and MAP sensitivities (r = 0.67; p < 0.05). In summary, following five nights of normobaric hypoxia, there is an enhanced MAP response to hypoxic stimuli. The relationship between the enhanced AHVR and MAP sensitivity raises the possibility of a common pathway in the regulation of peripheral chemosensitivity and MAP responses during periods of isocapnic hypoxia.

Differential responses to CO2 and sympathetic stimulation in the cerebral and femoral circulations in humans.

The relative importance of CO2 and sympathetic stimulation in the regulation of cerebral and peripheral vasculatures has not been previously studied in humans. We investigated the effect of sympathetic activation, produced by isometric handgrip (HG) exercise, on cerebral and femoral vasculatures during periods of isocapnia and hypercapnia. In 14 healthy males (28.1 +/- 3.7 (mean +/- S.D.) years), we measured flow velocity (VP; transcranial Doppler ultrasound) in the middle cerebral artery during euoxic isocapnia (ISO, +1 mmHg above rest) and two levels of euoxic hypercapnia (HC5, end-tidal P(CO(2)), P(ET,CO2), = +5 mmHg above ISO; HC10, P(ET,CO2) = +10 above ISO). Each P(ET,CO2) level was maintained for 10 min using the dynamic end-tidal forcing technique, during which increases in sympathetic activity were elicited by a 2-min HG at 30% of maximal voluntary contraction. Femoral blood flow (FBF; Doppler ultrasound), muscle sympathetic nerve activity (MSNA; microneurography) and mean arterial pressure (MAP; Portapres) were also measured. Hypercapnia increased VP and FBF by 5.0 and 0.6% mmHg-1, respectively, and MSNA by 20-220%. Isometric HG increased MSNA by 50% and MAP by 20%, with no differences between ISO, HC5 and HC10. During the ISO HG there was an increase in cerebral vascular resistance (CVR; 20 +/- 11%), while VP remained unchanged. During HC5 and HC10 HG, VP increased (13% and 14%, respectively), but CVR was unchanged. In contrast, HG-induced sympathetic stimulation increased femoral vascular resistance (FVR) during ISO, HC5 and HC10 (17-41%), while there was a general decrease in FBF below ISO. The HG-induced increases in MSNA were associated with increases in FVR in all conditions (r = 0.76-0.87), whereas increases in MSNA were associated with increases in CVR only during ISO (r = 0.91). In summary, in the absence of hypercapnia, HG exercise caused cerebral vasoconstriction, myogenically and/or neurally, which was reflected by increases in CVR and a maintained VP. In contrast, HG increased FVR during conditions of ISO, HC5 and HC10. Therefore, the cerebral circulation is more responsive to alterations in PCO2, and less responsive to sympathetic stimulation than the femoral circulation.

Protocol to measure acute cerebrovascular and ventilatory responses to isocapnic hypoxia in humans.

This study describes a protocol to determine acute cerebrovascular and ventilatory (AHVR) responses to hypoxia. Thirteen subjects undertook a protocol twice, 5 days apart. The protocol started with 8 min of eucapnic euoxia (end-tidal P(CO2) (PET(CO2)= 1.5 Torr) above rest; end-tidal P(O2) (PET(O2)) = 88 Torr) followed by six descending 90 s hypoxic steps (PET(O2) = 75.2, 64.0, 57.0, 52.0, 48.2, 45.0 Torr). Then, PET(O2) was elevated to 300 Torr for 10 min while PET(O2) remained at eucapnia (5 min) then raised by 7.5 Torr (5 min). Peak blood flow velocity in the middle cerebral artery (MCA) and regional cerebral oxygen saturation (Sr(O2)) were measured with transcranial Doppler ultrasound and near-infrared spectroscopy, respectively, and indices of acute hypoxic sensitivity were calculated (AHR(CBF) and AHRSr(O2)). Values for AHR(CBF), AHRSr(O2) and AHVR were 0.43 cm s(-1) % desaturation(-1), 0.80% % desaturation(-1) and 1.24l min(-1) % desaturation(-1), respectively. Coefficients of variation for AHR(CBF), AHRSr(O2) and AHVR were small (range = 8.0-15.2%). This protocol appears suitable to quantify cerebrovascular and ventilatory responses to acute isocapnic hypoxia.

Resting fluctuations in arterial carbon dioxide induce significant low frequency variations in BOLD signal.

Carbon dioxide is a potent cerebral vasodilator. We have identified a significant source of low-frequency variation in blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) signal at 3 T arising from spontaneous fluctuations in arterial carbon dioxide level in volunteers at rest. Fluctuations in the partial pressure of end-tidal carbon dioxide (Pet(CO(2))) of +/-1.1 mm Hg in the frequency range 0-0.05 Hz were observed in a cohort of nine volunteers. Correlating with these fluctuations were significant generalized grey and white matter BOLD signal fluctuations. We observed a mean (+/-standard error) regression coefficient across the group of 0.110 +/- 0.033% BOLD signal change per mm Hg CO(2) for grey matter and 0.049 +/- 0.022% per mm Hg in white matter. Pet(CO(2))-related BOLD signal fluctuations showed regional differences across the grey matter, suggesting variability of the responsiveness to carbon dioxide at rest. Functional magnetic resonance imaging (fMRI) results were corroborated by transcranial Doppler (TCD) ultrasound measurements of the middle cerebral artery (MCA) blood velocity in a cohort of four volunteers. Significant Pet(CO(2))-correlated fluctuations in MCA blood velocity were observed with a lag of 6.3 +/- 1.2 s (mean +/- standard error) with respect to Pet(CO(2)) changes. This haemodynamic lag was adopted in the analysis of the BOLD signal. Doppler ultrasound suggests that a component of low-frequency BOLD signal fluctuations is mediated by CO(2)-induced changes in cerebral blood flow (CBF). These fluctuations are a source of physiological noise and a potentially important confounding factor in fMRI paradigms that modify breathing. However, they can also be used for mapping regional vascular responsiveness to CO(2).

Effects of five consecutive nocturnal hypoxic exposures on the cerebrovascular responses to acute hypoxia and hypercapnia in humans.

The effects of discontinuous hypoxia on cerebrovascular regulation in humans are unknown. We hypothesized that five nocturnal hypoxic exposures (8 h/day) at a simulated altitude of 4,300 m (inspired O2 fraction = approximately 13.8%) would elicit cerebrovascular responses that are similar to those that have been reported during chronic altitude exposures. Twelve male subjects (26.6 +/- 4.1 yr, mean +/- SD) volunteered for this study. The technique of end-tidal forcing was used to examine cerebral blood flow (CBF) and regional cerebral O2 saturation (Sr(O2)) responses to acute variations in O2 and CO2 twice before, immediately after, and 5 days after the overnight hypoxic exposures. Transcranial Doppler ultrasound was used to assess CBF, and near-infrared spectroscopy was used to assess Sr(O2). Throughout the nocturnal hypoxic exposures, end-tidal Pco2 decreased (P < 0.001) whereas arterial O2 saturation increased (P < 0.001) compared with overnight normoxic control measurements. Symptoms associated with altitude illness were significantly greater than control values on the first night (P < 0.001) and second night (P < 0.01) of nocturnal hypoxia. Immediately after the nocturnal hypoxic intervention, the sensitivity of CBF to acute variations in O2 and CO2 increased 116% (P < 0.01) and 33% (P < 0.05), respectively, compared with control values. Sr(O2) was highly correlated with arterial O2 saturation (R2 = 0.94 +/- 0.04). These results show that discontinuous hypoxia elicits increases in the sensitivity of CBF to acute variations in O2 and CO2, which are similar to those observed during chronic hypoxia.

Effects of five nights of normobaric hypoxia on the ventilatory responses to acute hypoxia and hypercapnia.

This study examined the effects of five nights of normobaric hypoxia on ventilatory responses to acute isocapnic hypoxia (AHVR) and hyperoxic hypercapnia (AHCVR). Twelve male subjects (26.6 +/- 4.1 years, standard deviation (S.D.)) slept 8-9 h per day overnight for 5 consecutive days at a simulated altitude of 4,300 m (FiO2= approximately 13.8%). Using the technique of dynamic end-tidal forcing, the AHVR and AHCVR were assessed twice prior to, immediately after, and 5 days following the hypoxic exposure. Immediately following the exposure, AHVR was increased by 1.6 +/- 1.3 L min(-1) %(-1) (P<0.01) when compared with control values. Likewise, after the exposure, ventilation in hyperoxia was increased (P<0.001) and was associated with both an increase in the slope (1.5 +/- 1.4 L min(-1) Torr(-1); P<0.05) and decrease in the intercept (-2.7 +/- 4.3 Torr; P<0.05) of the AHCVR. These results show that five nights of hypoxia can elicit similar perturbations, in both AHVR and AHCVR, as have been reported during more chronic altitude exposures.

Partial blockade of skeletal muscle somatosensory afferents attenuates baroreflex resetting during exercise in humans.

During exercise, the carotid baroreflex is reset to operate around the higher arterial pressures evoked by physical exertion. The purpose of this investigation was to evaluate the contribution of somatosensory input from the exercise pressor reflex to this resetting during exercise. Nine subjects performed seven minutes of dynamic cycling at 30% of maximal work load and three minutes of static one-legged contraction at 25% maximal voluntary contraction before (control) and after partial blockade of skeletal muscle afferents with epidural anaesthesia. Carotid baroreflex function was assessed by applying rapid pulses of hyper- and hypotensive stimuli to the neck via a customised collar. Using a logistic model, heart rate (HR) and mean arterial pressure (MAP) responses to carotid sinus stimulation were used to develop reflex function stimulus-response curves. Compared with rest, control dynamic and static exercise reset carotid baroreflex-HR and carotid baroreflex-MAP curves vertically upward on the response arm and laterally rightward to higher operating pressures. Inhibition of exercise pressor reflex input by epidural anaesthesia attenuated the bi-directional resetting of the carotid baroreflex-MAP curve during both exercise protocols. In contrast, the effect of epidural anaesthesia on the resetting of the carotid baroreflex-HR curve was negligible during dynamic cycling whereas it relocated the curve in a laterally leftward direction during static contraction. The data suggest that afferent input from skeletal muscle is requisite for the complete resetting of the carotid baroreflex during exercise. However, this neural input appears to modify baroreflex control of blood pressure to a greater extent than heart rate.

Middle cerebral artery blood velocity during intense static exercise is dominated by a Valsalva maneuver.

Lifting of a heavy weight may lead to "blackout" and occasionally also to cerebral hemorrhage, indicating pronounced consequences for the blood flow through the brain. We hypothesized that especially strenuous respiratory straining (a Valsalva-like maneuver) associated with intense static exercise would lead to a precipitous rise in mean arterial and central venous pressures and, in turn, influence the middle cerebral artery blood velocity (MCA V(mean)) as a noninvasive indicator of changes in cerebral blood flow. In 10 healthy subjects, MCA V(mean) was evaluated in response to maximal static two-legged exercise performed either with a concomitantly performed Valsalva maneuver or with continued ventilation and also during a Valsalva maneuver without associated exercise (n = 6). During static two-legged exercise, the largest rise for mean arterial pressure and MCA V(mean) was established at the onset of exercise performed with a Valsalva-like maneuver (by 42 +/- 5 mmHg and 31 +/- 3% vs. 22 +/- 6 mmHg and 25 +/- 6% with continued ventilation; P < 0.05). Profound reductions in MCA V(mean) were observed both after exercise with continued ventilation (-29 +/- 4% together with a reduction in the arterial CO(2) tension by -5 +/- 1 Torr) and during the maintained Valsalva maneuver (-21 +/- 3% together with an elevation in central venous pressure to 40 +/- 7 mmHg). Responses to performance of the Valsalva maneuver with and without exercise were similar, reflecting the deterministic importance of the Valsalva maneuver for the central and cerebral hemodynamic response to intense static exercise. Continued ventilation during intense static exercise may limit the initial rise in arterial pressure and may in turn reduce the risk of hemorrhage. On the other hand, blackout during and after intense static exercise may reflect a reduction in cerebral blood flow due to expiratory straining and/or hyperventilation.

Relationship between middle cerebral artery blood velocity and end-tidal PCO2 in the hypocapnic-hypercapnic range in humans.

This study examined the relationship between cerebral blood flow (CBF) and end-tidal PCO2 (PETCO2) in humans. We used transcranial Doppler ultrasound to determine middle cerebral artery peak blood velocity responses to 14 levels of PETCO2 in a range of 22 to 50 Torr with a constant end-tidal PO2 (100 Torr) in eight subjects. PETCO2 and end-tidal PO2 were controlled by using the technique of dynamic end-tidal forcing combined with controlled hyperventilation. Two protocols were conducted in which PETCO2 was changed by 2 Torr every 2 min from hypocapnia to hypercapnia (protocol I) and vice-versa (protocol D). Over the range of PETCO2 studied, the sensitivity of peak blood velocity to changes in PETCO2 (CBF-PETCO2 sensitivity) was nonlinear with a greater sensitivity in hypercapnia (4.7 and 4.0%/Torr, protocols I and D, respectively) compared with hypocapnia (2.5 and 2.2%/Torr). Furthermore, there was evidence of hysteresis in the CBF-PETCO2 sensitivity; for a given PETCO2, there was greater sensitivity during protocol I compared with protocol D. In conclusion, CBF-PETCO2 sensitivity varies depending on the level of PETCO2 and the protocol that is used. The mechanisms underlying these responses require further investigation.

Cerebral oxygenation during exercise in patients with terminal lung disease.

STUDY OBJECTIVES: In patients with terminal lung disease who were exercising, we assessed whether improved arterial O2 saturation with an increased fraction of inspired oxygen (FIO2) affects cerebral oxygenation. DESIGN: Randomized, crossover. PATIENTS AND METHODS: The cerebral changes in oxyhemoglobin (DeltaHbO2) and changes in deoxyhemoglobin (DeltaHb) levels were evaluated using near-infrared spectrophotometry and the middle cerebral artery (MCA) mean velocity (V(mean)) was determined by transcranial Doppler ultrasonography in 13 patients with terminal lung disease (New York Heart Association class III-IV). Patients were allocated to an FIO2 of either 0.21 or 0.35 during incremental exercise with 15 min between trials. RESULTS: Peak exercise intensity (mean [+/- SE], 26 +/- 4 W) reduced the arterial O2 pressure (at rest, 64 +/- 3 mm Hg; during exercise, 56 +/- 3 mm Hg) and the arterial oxygen saturation (SaO2) [at rest, 92 +/- 2%; 87 +/- 2%; p < 0.05], while the arterial CO2 pressure was not significantly affected. The MCA V(mean) increased from 49 +/- 5 to 63 +/- 7 cm/s (p < 0.05) as did the DeltaHb, while the DeltaHbO2 remained unaffected by exercise. With an elevated FIO2, the SaO2 level (at rest, 95.8 +/- 0.7%; during exercise, 96.0 +/- 1.0%) and arterial O2 pressure (at rest, 102 +/- 11 mm Hg; during exercise, 100 +/- 8 mm Hg) were not significantly affected by exercise, and the levels of blood oxygenation remained higher than the values established at normoxia (p < 0.05). The MCA V(mean) increased to a level similar to that achieved during control exercise (ie, to 70 +/- 11 cm/s). In contrast to control exercise, DeltaHb decreased while DeltaHbO2 increased during exercise with 35% O2 (p < 0.05). CONCLUSION: An O2-enriched atmosphere enabled patients with terminal lung disease to maintain arterial O2 saturation during exercise. An exercise-induced increase in cerebral perfusion was not affected by hyperoxia, whereby the enhanced availability of oxygenated hemoglobin increases cerebral oxygenation. The clinical implication of the study is that during physical activity patients with terminal lung disease are recommended to use an elevated FIO2 to protect cerebral oxygenation.

The intent to exercise influences the cerebral O(2)/carbohydrate uptake ratio in humans.

During and after maximal exercise there is a 15-30 % decrease in the metabolic uptake ratio (O(2)/[glucose + 1/2 lactate]) and a net lactate uptake by the human brain. This study evaluated if this cerebral metabolic uptake ratio is influenced by the intent to exercise, and whether a change could be explained by substrates other than glucose and lactate. The arterial-internal jugular venous differences (a-v difference) for O(2), glucose and lactate as well as for glutamate, glutamine, alanine, glycerol and free fatty acids were evaluated in 10 healthy human subjects in response to cycling. However, the a-v difference for the amino acids and glycerol did not change significantly, and there was only a minimal increase in the a-v difference for free fatty acids after maximal exercise. After maximal exercise the metabolic uptake ratio of the brain decreased from 6.1 +/- 0.5 (mean +/- S.E.M.) at rest to 3.7 +/- 0.2 in the first minutes of the recovery (P < 0.01). Submaximal exercise did not change the uptake ratio significantly. Yet, in a second experiment, when submaximal exercise required a maximal effort due to partial neuromuscular blockade, the ratio decreased and remained low (4.9 +/- 0.2) in the early recovery (n = 10; P < 0.05). The results indicate that glucose and lactate uptake by the brain are increased out of proportion to O(2) when the brain is activated by exhaustive exercise, and that such metabolic changes are influenced by the will to exercise. We speculate that the uptake ratio for the brain may serve as a metabolic indicator of 'central fatigue'.