Mads K. Dalsgaard

Brain and central haemodynamics and oxygenation during maximal exercise in humans

During maximal exercise in humans, fatigue is preceded by reductions in systemic and skeletal muscle blood flow, O2 delivery and uptake. Here, we examined whether the uptake of O2 and substrates by the human brain is compromised and whether the fall in stroke volume of the heart underlying the decline in systemic O2 delivery is related to declining venous return. We measured brain and central haemodynamics and oxygenation in healthy males (n= 13 in 2 studies) performing intense cycling exercise (360 ± 10 W; mean ±s.e.m.) to exhaustion starting with either high (H) or normal (control, C) body temperature. Time to exhaustion was shorter in H than in C (5.8 ± 0.2 versus 7.5 ± 0.4 min, P < 0.05), despite heart rate reaching similar maximal values. During the first 90 s of both trials, frontal cortex tissue oxygenation and the arterial–internal jugular venous differences (a‐v diff) for O2 and glucose did not change, whereas middle cerebral artery mean flow velocity (MCA Vmean) and cardiac output increased by ∼22 and ∼115%, respectively. Thereafter, brain extraction of O2, glucose and lactate increased by ∼45, ∼55 and ∼95%, respectively, while frontal cortex tissue oxygenation, MCA Vmean and cardiac output declined ∼40, ∼15 and ∼10%, respectively. At exhaustion in both trials, systemic declined in parallel with a similar fall in stroke volume and central venous pressure; yet the brain uptake of O2, glucose and lactate increased. In conclusion, the reduction in stroke volume, which underlies the fall in systemic O2 delivery and uptake before exhaustion, is partly related to reductions in venous return to the heart. Furthermore, fatigue during maximal exercise, with or without heat stress, in healthy humans is associated with an enhanced rather than impaired brain uptake of O2 and substrates.

Limitations to systemic and locomotor limb muscle oxygen delivery and uptake during maximal exercise in humans.

Reductions in systemic and locomotor limb muscle blood flow and O2 delivery limit aerobic capacity in humans. To examine whether O2 delivery limits both aerobic power and capacity, we first measured systemic haemodynamics, O2 transport and O2 uptake during incremental and constant (372 ± 11 W; 85% of peak power; mean ±s.e.m.) cycling exercise to exhaustion (n= 8) and then measured systemic and leg haemodynamics and during incremental cycling and knee‐extensor exercise in male subjects (n= 10). During incremental cycling, cardiac output and systemic O2 delivery increased linearly to 80% of peak power (r2= 0.998, P < 0.001) and then plateaued in parallel to a decline in stroke volume (SV) and an increase in central venous and mean arterial pressures (P < 0.05). In contrast, heart rate and increased linearly until exhaustion (r2= 0.993; P < 0.001) accompanying a rise in systemic O2 extraction to 84 ± 2%. In the exercising legs, blood flow and O2 delivery levelled off at 73–88% of peak power, blunting leg per unit of work despite increasing O2 extraction. When blood flow increased linearly during one‐legged knee‐extensor exercise, per unit of work was unaltered on fatigue. During constant cycling, , SV, systemic O2 delivery and reached maximal values within ∼5 min, but dropped before exhaustion (P < 0.05) despite increasing or stable central venous and mean arterial pressures. In both types of maximal cycling, the impaired systemic O2 delivery was due to the decline or plateau in because arterial O2 content continued to increase. These results indicate that an inability of the circulatory system to sustain a linear increase in O2 delivery to the locomotor muscles restrains aerobic power. The similar impairment in SV and O2 delivery during incremental and constant load cycling provides evidence for a central limitation to aerobic power and capacity in humans.

A reduced cerebral metabolic ratio in exercise reflects metabolism and not accumulation of lactate within the human brain

During maximal exercise lactate taken up by the human brain contributes to reduce the cerebral metabolic ratio, O2/(glucose + 1/2 lactate), but it is not known whether the lactate is metabolized or if it accumulates in a distribution volume. In one experiment the cerebral arterio‐venous differences (AV) for O2, glucose (glc) and lactate (lac) were evaluated in nine healthy subjects at rest and during and after exercise to exhaustion. The cerebrospinal fluid (CSF) was drained through a lumbar puncture immediately after exercise, while control values were obtained from six other healthy young subjects. In a second experiment magnetic resonance spectroscopy (1H‐MRS) was performed after exhaustive exercise to assess lactate levels in the brain (n = 5). Exercise increased the AVO2 from 3.2 ± 0.1 at rest to 3.5 ± 0.2 mm (mean ±s.e.m.; P < 0.05) and the AVglc from 0.6 ± 0.0 to 0.9 ± 0.1 mm (P < 0.01). Notably, the AVlac increased from 0.0 ± 0.0 to 1.3 ± 0.2 mm at the point of exhaustion (P < 0.01). Thus, maximal exercise reduced the cerebral metabolic ratio from 6.0 ± 0.3 to 2.8 ± 0.2 (P < 0.05) and it remained low during the early recovery. Despite this, the CSF concentration of lactate postexercise (1.2 ± 0.1 mm; n= 7) was not different from baseline (1.4 ± 0.1 mm; n= 6). Also, the 1H‐MRS signal from lactate obtained after exercise was smaller than the estimated detection limit of ∼1.5 mm. The finding that an increase in lactate could not be detected in the CSF or within the brain rules out accumulation in a distribution volume and indicates that the lactate taken up by the brain is metabolized.

Fuelling cerebral activity in exercising man

The metabolic response to brain activation in exercise might be expressed as the cerebral metabolic ratio (MR; uptake O2/glucose + 1/2 lactate). At rest, brain energy is provided by a balanced oxidation of glucose as MR is close to 6, but activation provokes a ‘surplus’ uptake of glucose relative to that of O2. Whereas MR remains stable during light exercise, it is reduced by 30% to 40% when exercise becomes demanding. The MR integrates metabolism in brain areas stimulated by sensory input from skeletal muscle, the mental effort to exercise and control of exercising limbs. The MR decreases during prolonged exhaustive exercise where blood lactate remains low, but when vigorous exercise raises blood lactate, the brain takes up lactate in an amount similar to that of glucose. This lactate taken up by the brain is oxidised as it does not accumulate within the brain and such pronounced brain uptake of substrate occurs independently of plasma hormones. The ‘surplus’ of glucose equivalents taken up by the activated brain may reach ~ 10 mmol, that is, an amount compatible with the global glycogen level. It is suggested that a low MR predicts shortage of energy that ultimately limits motor activation and reflects a biologic background for ‘central fatigue’.

The intent to exercise influences the cerebral O2/carbohydrate uptake ratio in humans

During and after maximal exercise there is a 15–30 % decrease in the metabolic uptake ratio (O2/[glucose +1/2lactate]) 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 O2, 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 O2 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’.

Cerebral ammonia uptake and accumulation during prolonged exercise in humans

We evaluated whether peripheral ammonia production during prolonged exercise enhances the uptake and subsequent accumulation of ammonia within the brain. Two studies determined the cerebral uptake of ammonia (arterial and jugular venous blood sampling combined with Kety–Schmidt‐determined cerebral blood flow; n= 5) and the ammonia concentration in the cerebrospinal fluid (CSF; n= 8) at rest and immediately following prolonged exercise either with or without glucose supplementation. There was a net balance of ammonia across the brain at rest and at 30 min of exercise, whereas 3 h of exercise elicited an uptake of 3.7 ± 1.3 μmol min−1 (mean ±s.e.m.) in the placebo trial and 2.5 ± 1.0 μmol min−1 in the glucose trial (P < 0.05 compared to rest, not different across trials). At rest, CSF ammonia was below the detection limit of 2 μm in all subjects, but it increased to 5.3 ± 1.1 μm following exercise with glucose, and further to 16.1 ± 3.3 μm after the placebo trial (P < 0.05). Correlations were established between both the cerebral uptake (r2= 0.87; P < 0.05) and the CSF concentration (r2= 0.72; P < 0.05) and the arterial ammonia level and, in addition, a weaker correlation (r2= 0.37; P < 0.05) was established between perceived exertion and CSF ammonia at the end of exercise. The results let us suggest that during prolonged exercise the cerebral uptake and accumulation of ammonia may provoke fatigue, e.g. by affecting neurotransmitter metabolism.

The brain at work: A cerebral metabolic manifestation of central fatigue?

Central fatigue refers to circumstances in which strength appears to be limited by the ability of the central nervous system to recruit motoneurons. Central fatigue manifests when the effort to contract skeletal muscles is intense and, thus, is aggravated when exercise is performed under stress, whereas it becomes attenuated following training. Central fatigue has not been explained, but the cerebral metabolic response to intense exercise, as to other modalities of cerebral activation, is a reduction in its “metabolic ratio” (MR), i.e., the brains uptake of oxygen relative to that of carbohydrate. At rest the MR is close to 6 but during intense whole‐body exercise it decreases to less than 3, with the uptake of lactate becoming as important as that of glucose. It remains debated what underlies this apparent inability of the brain to oxidize the carbohydrate taken up, but it may approach ∼10 mmol glucose equivalents. In the case of exercise, a concomitant uptake of ammonium for formation of amino acids may account for only ∼10% of this “extra” carbohydrate taken up. Also, accumulation of intermediates in metabolic pathways and compartmentalization of metabolism between astrocytes and neurons are avenues that have to be explored. Depletion of glycogen stores and subsequent supercompensation during periods of low neuronal activity may not only play a role but also link brain metabolism to its function.

The CSF and arterial to internal jugular venous hormonal differences during exercise in humans.

Strenuous exercise increases the cerebral uptake of carbohydrate out of proportion to that of oxygen, but it is unknown whether such enhanced carbohydrate uptake is influenced by the marked endocrine response to exercise. During exhaustive exercise this study evaluated the a–v differences across the brain (a–v diff) of hormones that could influence its carbohydrate uptake (n= 9). In addition, neuroendocrine activity and a potential uptake of hormones via the cerebrospinal fluid (CSF) were assessed by lumbar puncture postexercise and at rest (n= 6). Exercise increased the arterial concentration of noradrenaline and adrenaline, but there was no cerebral uptake. However, following exercise CSF noradrenaline was 1.4 (0.73–5.5) nmol l−1, and higher than at rest, 0.3 (0.19–1.84) nmol l−1 (P < 0.05), whereas adrenaline could not be detected. Exercise increased both the arterial concentration of NH4+ and its a–v diff, which increased from 1 (–12 to 5) to 17 (5–41) μmol l−1 (P < 0.05), while the CSF NH4+ was reduced to 7 (0–10) versus 11 (7–16) μmol l−1 (P < 0.05). There was no release from, or accumulation in the brain of interleukin (IL)‐6, tumour necrosis factor (TNF‐α), heatshock protein (HSP72), insulin, or insulin‐like growth factor (IGF)‐I. The findings indicate that for maximal exercise, the concentration of noradrenaline is increased within the brain, whereas blood borne hormones and cytokines are seemingly unimportant. The results support the notion that the exercise‐induced changes in brain metabolism are controlled by factors intrinsic to the brain.

Cerebral metabolism is influenced by muscle ischaemia during exercise in humans.

Maximal exercise reduces the cerebral metabolic ratio (O2/(glucose + 1/2lactate)) to < 4 from a resting value close to 6, and only part of this decrease is explained by the ‘intent’ to exercise. This study evaluated whether sensory stimulation of brain by muscle ischaemia would reduce the cerebral metabolic ratio. In 10 healthy human subjects the cerebral arterial‐venous differences (a‐v differences) for O2, glucose and lactate were assessed before, during and after three bouts of 10 min cycling with equal workload: (1) control exercise at light intensity, (2) exercise that elicited a high rating of perceived exertion due to a 100 mmHg thigh cuff, and (3) exercise followed by 5 min of post‐exercise muscle ischaemia that increased blood pressure by ∼ 20%. Control exercise did not significantly affect the a‐v differences. However, during the recovery from exercise with thigh cuffs the cerebral metabolic ratio decreased from a resting value of 5.4 ± 0.2 to 4.0 ± 0.4 (mean ±s.e.m.. P < 0.05) as a discrete lactate efflux from the brain at rest shifted to a slight uptake. Also, following post‐exercise muscle ischaemia, the cerebral metabolic ratio decreased to 4.5 ± 0.3 (P < 0.05). The results support the hypothesis that during exercise, cerebral metabolism is influenced both by the mental effort to exercise and by sensory input from skeletal muscles.

Dynamic blood pressure control and middle cerebral artery mean blood velocity variability at rest and during exercise in humans

Aims:  Cardiac failure and ischaemic heart disease patients receive standard of care cardiac β1‐adrenergic blockade medication. Such medication reduces cardiac output and cerebral blood flow. It is unknown whether the β1‐adrenergic blockade‐induced reduction of cardiac output in the presence of an exercise‐induced reduction in cardiac–arterial baroreflex gain affects cerebral blood flow variability. This study evaluated the influence of cardiac output variability on beat‐to‐beat middle cerebral artery mean blood velocity (MCA Vmean) during exercise with and without cardiac β1‐adrenergic blockade.