Patrice Brassard

Evidence for a release of brain‐derived neurotrophic factor from the brain during exercise

Brain‐derived neurotrophic factor (BDNF) has an important role in regulating maintenance, growth and survival of neurons. However, the main source of circulating BDNF in response to exercise is unknown. To identify whether the brain is a source of BDNF during exercise, eight volunteers rowed for 4 h while simultaneous blood samples were obtained from the radial artery and the internal jugular vein. To further identify putative cerebral region(s) responsible for BDNF release, mouse brains were dissected and analysed for BDNF mRNA expression following treadmill exercise. In humans, a BDNF release from the brain was observed at rest (P < 0.05), and increased two‐ to threefold during exercise (P < 0.05). Both at rest and during exercise, the brain contributed 70–80% of circulating BDNF, while that contribution decreased following 1 h of recovery. In mice, exercise induced a three‐ to fivefold increase in BDNF mRNA expression in the hippocampus and cortex, peaking 2 h after the termination of exercise. These results suggest that the brain is a major but not the sole contributor to circulating BDNF. Moreover, the importance of the cortex and hippocampus as a source for plasma BDNF becomes even more prominent in response to exercise.

Endurance training enhances BDNF release from the human brain

The circulating level of brain-derived neurotrophic factor (BDNF) is reduced in patients with major depression and type-2 diabetes. Because acute exercise increases BDNF production in the hippocampus and cerebral cortex, we hypothesized that endurance training would enhance the release of BDNF from the human brain as detected from arterial and internal jugular venous blood samples. In a randomized controlled study, 12 healthy sedentary males carried out 3 mo of endurance training (n = 7) or served as controls (n = 5). Before and after the intervention, blood samples were obtained at rest and during exercise. At baseline, the training group (58 + or - 106 ng x 100 g(-1) x min(-1), means + or - SD) and the control group (12 + or - 17 ng x 100 g(-1) x min(-1)) had a similar release of BDNF from the brain at rest. Three months of endurance training enhanced the resting release of BDNF to 206 + or - 108 ng x 100 g(-1) x min(-1) (P < 0.05), with no significant change in the control subjects, but there was no training-induced increase in the release of BDNF during exercise. Additionally, eight mice completed a 5-wk treadmill running training protocol that increased the BDNF mRNA expression in the hippocampus (4.5 + or - 1.6 vs. 1.4 + or - 1.1 mRNA/ssDNA; P < 0.05), but not in the cerebral cortex (4.0 + or - 1.4 vs. 4.6 + or - 1.4 mRNA/ssDNA) compared with untrained mice. The increased BDNF expression in the hippocampus and the enhanced release of BDNF from the human brain following training suggest that endurance training promotes brain health.

Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain

Lactate is shuttled between organs, as demonstrated in the Cori cycle. Although the brain releases lactate at rest, during physical exercise there is a cerebral uptake of lactate. Here, we evaluated the cerebral lactate uptake and release in hypoxia, during exercise and when the two interventions were combined. We measured cerebral lactate turnover via a tracer dilution method ([1‐13C]lactate), using arterial to right internal jugular venous differences in 9 healthy individuals (5 males and 4 females), at rest and during 30 min of submaximal exercise in normoxia and hypoxia (Fio2 10%, arterial oxygen saturation 72±10%, mean±sd). Whole‐body lactate turnover increased 3.5‐fold and 9‐fold at two workloads in normoxia and 18‐fold during exercise in hypoxia. Although middle cerebral artery mean flow velocity increased during exercise in hypoxia, calculated cerebral mitochondrial oxygen tension decreased by 13 mmHg (P<0.001). At the same time, cerebral lactate release increased from 0.15 ± 0.1 to 0.8 ± 0.6 mmol min−1 (P<0.05), corresponding to ∼10% of cerebral energy consumption. Concurrently, cerebral lactate uptake was 1.0 ± 0.9 mmol min−1 (P<0.05), of which 57 ± 9% was oxidized, demonstrating that lactate oxidation may account for up to ∼33% of the energy substrate used by the brain. These results support the existence of a cell‐cell lactate shuttle that may involve neurons and astrocytes.— Overgaard, M., Rasmussen, P., Bohm, A. M., Seifert, T., Brassard, P., Zaar, M., Homann, P., Evans, K. A., Nielsen, H. B., Secher, N. H. Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain. FASEB J. 26, 3012–3020 (2012). www.fasebj.org

Phenylephrine decreases frontal lobe oxygenation at rest but not during moderately intense exercise.

Whether sympathetic activity influences cerebral blood flow (CBF) and oxygenation remains controversial. The influence of sympathetic activity on CBF and oxygenation was evaluated by the effect of phenylephrine on middle cerebral artery (MCA) mean flow velocity (Vmean) and the near-infrared spectroscopy-derived frontal lobe oxygenation (ScO2) at rest and during exercise. At rest, nine healthy male subjects received bolus injections of phenylephrine (0.1, 0.25, and 0.4 mg), and changes in mean arterial pressure (MAP), MCA Vmean, internal jugular venous O2 saturation (SjvO2), ScO2), and arterial PCO2 (PaCO2) were measured and the cerebral metabolic rate for O2 (CMRO2) was calculated. In randomized order, a bolus of saline or 0.3 mg of phenylephrine was then injected during semisupine cycling, eliciting a low (approximately 110 beats/min) or a high (approximately 150 beats/min) heart rate. At rest, MAP and MCA Vmean increased approximately 20% (P<0.001) and approximately 10% (P<0.001 for 0.25 mg of phenylephrine and P<0.05 for 0.4 mg of phenylephrine), respectively. ScO2 then decreased approximately 7% (P<0.001). Phenylephrine had no effect on SjvO2, PaCO2, or CMRO2. MAP increased after the administration of phenylephrine during low-intensity exercise (approximately 15%), but this was attenuated (approximately 10%) during high-intensity exercise (P<0.001). The reduction in ScO2 after administration of phenylephrine was attenuated during low-intensity exercise (-5%, P<0.001) and abolished during high-intensity exercise (-3%, P=not significant), where PaCO2 decreased 7% (P<0.05) and CMRO2 increased 17% (P<0.05). These results suggest that the administration of phenylephrine reduced ScO2 but that the increased cerebral metabolism needed for moderately intense exercise eliminated that effect.

High-intensity interval exercise and cerebrovascular health: curiosity, cause, and consequence

Exercise is a uniquely effective and pluripotent medicine against several noncommunicable diseases of westernised lifestyles, including protection against neurodegenerative disorders. High-intensity interval exercise training (HIT) is emerging as an effective alternative to current health-related exercise guidelines. Compared with traditional moderate-intensity continuous exercise training, HIT confers equivalent if not indeed superior metabolic, cardiac, and systemic vascular adaptation. Consequently, HIT is being promoted as a more time-efficient and practical approach to optimize health thereby reducing the burden of disease associated with physical inactivity. However, no studies to date have examined the impact of HIT on the cerebrovasculature and corresponding implications for cognitive function. This review critiques the implications of HIT for cerebrovascular function, with a focus on the mechanisms and translational impact for patient health and well-being. It also introduces similarly novel interventions currently under investigation as alternative means of accelerating exercise-induced cerebrovascular adaptation. We highlight a need for studies of the mechanisms and thereby also the optimal dose-response strategies to guide exercise prescription, and for studies to explore alternative approaches to optimize exercise outcomes in brain-related health and disease prevention. From a clinical perspective, interventions that selectively target the aging brain have the potential to prevent stroke and associated neurovascular diseases.

Central and Peripheral Blood Flow During Exercise With a Continuous-Flow Left Ventricular Assist DeviceClinical Perspective

Background— End-stage heart failure is associated with impaired cardiac output (CO) and organ blood flow. We determined whether CO and peripheral perfusion are maintained during exercise in patients with an axial-flow left ventricular assist device (LVAD) and whether an increase in LVAD pump speed with work rate would increase organ blood flow. Methods and Results— Invasively determined CO and leg blood flow and Doppler-determined cerebral perfusion were measured during 2 incremental cycle exercise tests on the same day in 8 patients provided with a HeartMate II LVAD. In random order, patients exercised both with a constant (≈9775 rpm) and with an increasing pump speed (+400 rpm per exercise stage). At 60 W, the elevation in CO was more pronounced with increased pump speed (8.7±0.6 versus 8.1±1.1 L · min−1; mean±SD; P=0.05), but at maximal exercise increases in CO (from 7.0±0.9 to 13.6±2.5 L · min−1; P<0.01) and leg blood flow [0.7 (0.5 to 0.8) to 4.4 (3.9 to 4.8) L · min−1 per leg; median (range); P<0.001] were similar with both pumping modes. Normally, middle cerebral artery mean flow velocity increases from ≈50 to ≈65 cm · s−1 during exercise, but in LVAD patients with a constant pump speed it was low at rest (39±14 cm · s−1) and remained unchanged during exercise, whereas in patients with increasing pump speed, it increased by 5.2±2.8 cm · s−1 at 60 W (P<0.01). Conclusions— With maximal exercise, the axial-flow LVAD supports near-normal increments in cardiac output and leg perfusion, but cerebral perfusion is poor. Increased pump speed augments cerebral perfusion during exercise.

Cerebral non‐oxidative carbohydrate consumption in humans driven by adrenaline

During brain activation, the decrease in the ratio between cerebral oxygen and carbohydrate uptake (6 O2/(glucose +1/2 lactate); the oxygen–carbohydrate index, OCI) is attenuated by the non‐selective β‐adrenergic receptor antagonist propranolol, whereas OCI remains unaffected by the β1‐adrenergic receptor antagonist metroprolol. These observations suggest involvement of a β2‐adrenergic mechanism in non‐oxidative metabolism for the brain. Therefore, we evaluated the effect of adrenaline (0.08 μg kg−1 min−1i.v. for 15 min) and noradrenaline (0.5, 0.1 and 0.15 μg kg−1 min−1i.v. for 20 min) on the arterial to internal jugular venous concentration differences (a‐v diff) of O2, glucose and lactate in healthy humans. Adrenaline (n= 10) increased the arterial concentrations of O2, glucose and lactate (P < 0.05) and also increased the a‐v diff for glucose from 0.6 ± 0.1 to 0.8 ± 0.2 mm (mean ±s.d.; P < 0.05). The a‐v diff for lactate shifted from a net cerebral release to an uptake and OCI was lowered from 5.1 ± 1.5 to 3.6 ± 0.4 (P < 0.05) indicating an 8‐fold increase in the rate of non‐oxidative carbohydrate uptake during adrenaline infusion (P < 0.01). Conversely, noradrenaline (n= 8) did not affect the OCI despite an increase in the a‐v diff for glucose (P < 0.05). These results support that non‐oxidative carbohydrate consumption for the brain is driven by a β2‐adrenergic mechanism, giving neurons an abundant provision of energy when plasma adrenaline increases.

Why is the neural control of cerebral autoregulation so controversial

Cerebral autoregulation refers to the mechanisms that act to keep cerebral blood flow (CBF) constant during changes in blood pressure. The mechanisms of cerebral autoregulation, especially in humans, are poorly understood but are undoubtedly multifactorial and likely reflect many redundant pathways that potentially differ between species. Whether sympathetic nervous activity influences CBF and/or cerebral autoregulation in humans remains controversial. Following a brief introduction to cerebral autoregulation, this review highlights the likely reasons behind the controversy of the neural control of cerebral autoregulation. Finally, suggestions are provided for further studies to improve the understanding of the neural control of CBF regulation.

Cerebral oxygenation and metabolism during exercise following three months of endurance training in healthy overweight males

Endurance training improves muscular and cardiovascular fitness, but the effect on cerebral oxygenation and metabolism remains unknown. We hypothesized that 3 mo of endurance training would reduce cerebral carbohydrate uptake with maintained cerebral oxygenation during submaximal exercise. Healthy overweight males were included in a randomized, controlled study (training: n = 10; control: n = 7). Arterial and internal jugular venous catheterization was used to determine concentration differences for oxygen, glucose, and lactate across the brain and the oxygen-carbohydrate index [molar uptake of oxygen/(glucose + (1/2) lactate); OCI], changes in mitochondrial oxygen tension (DeltaP(Mito)O(2)) and the cerebral metabolic rate of oxygen (CMRO(2)) were calculated. For all subjects, resting OCI was higher at the 3-mo follow-up (6.3 +/- 1.3 compared with 4.7 +/- 0.9 at baseline, mean +/- SD; P < 0.05) and coincided with a lower plasma epinephrine concentration (P < 0.05). Cerebral adaptations to endurance training manifested when exercising at 70% of maximal oxygen uptake (approximately 211 W). Before training, both OCI (3.9 +/- 0.9) and DeltaP(Mito)O(2) (-22 mmHg) decreased (P < 0.05), whereas CMRO(2) increased by 79 +/- 53 micromol x 100 x g(-1) min(-1) (P < 0.05). At the 3-mo follow-up, OCI (4.9 +/- 1.0) and DeltaP(Mito)O(2) (-7 +/- 13 mmHg) did not decrease significantly from rest and when compared with values before training (P < 0.05), CMRO(2) did not increase. This study demonstrates that endurance training attenuates the cerebral metabolic response to submaximal exercise, as reflected in a lower carbohydrate uptake and maintained cerebral oxygenation.

Central and Peripheral Blood Flow During Exercise With a Continuous-Flow Left Ventricular Assist Device Constant Versus Increasing Pump Speed: A Pilot Study

Background— End-stage heart failure is associated with impaired cardiac output (CO) and organ blood flow. We determined whether CO and peripheral perfusion are maintained during exercise in patients with an axial-flow left ventricular assist device (LVAD) and whether an increase in LVAD pump speed with work rate would increase organ blood flow. Methods and Results— Invasively determined CO and leg blood flow and Doppler-determined cerebral perfusion were measured during 2 incremental cycle exercise tests on the same day in 8 patients provided with a HeartMate II LVAD. In random order, patients exercised both with a constant (≈9775 rpm) and with an increasing pump speed (+400 rpm per exercise stage). At 60 W, the elevation in CO was more pronounced with increased pump speed (8.7±0.6 versus 8.1±1.1 L · min−1; mean±SD; P=0.05), but at maximal exercise increases in CO (from 7.0±0.9 to 13.6±2.5 L · min−1; P<0.01) and leg blood flow [0.7 (0.5 to 0.8) to 4.4 (3.9 to 4.8) L · min−1 per leg; median (range); P<0.001] were similar with both pumping modes. Normally, middle cerebral artery mean flow velocity increases from ≈50 to ≈65 cm · s−1 during exercise, but in LVAD patients with a constant pump speed it was low at rest (39±14 cm · s−1) and remained unchanged during exercise, whereas in patients with increasing pump speed, it increased by 5.2±2.8 cm · s−1 at 60 W (P<0.01). Conclusions— With maximal exercise, the axial-flow LVAD supports near-normal increments in cardiac output and leg perfusion, but cerebral perfusion is poor. Increased pump speed augments cerebral perfusion during exercise.