The neuromodulatory role of dopamine in improved reaction time by acute cardiovascular exercise.

Acute cardiovascular physical exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Here, using positron emission tomography (PET) with [11 C]raclopride, in a multi-experiment study we investigated whether acute exercise releases endogenous dopamine (DA) in the brain. We hypothesized that acute exercise augments the brain DA system, and that RT improvement is correlated with this endogenous DA release. The PET study (Experiment 1: n = 16) demonstrated that acute physical exercise released endogenous DA, and that endogenous DA release was correlated with improvements in RT of the Go/No-Go task. Thereafter, using two electrical muscle stimulation (EMS) studies (Experiments 2 and 3: n = 18 and 22 respectively), we investigated what triggers RT improvement. The EMS studies indicated that EMS with moderate arm cranking improved RT, but RT was not improved following EMS alone or EMS combined with no load arm cranking. The novel mechanistic findings from these experiments are: (1) endogenous DA appears to be an important neuromodulator for RT improvement and (2) RT is only altered when exercise is associated with central signals from higher brain centres. Our findings explain how humans rapidly alter their behaviour using neuromodulatory systems and have significant implications for promotion of cognitive health. KEY POINTS: Acute cardiovascular exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Using the neurochemical specificity of [11 C]raclopride positron emission tomography, we demonstrated that acute supine cycling released endogenous dopamine (DA), and that this release was correlated with improved RT. Additional electrical muscle stimulation studies demonstrated that peripherally driven muscle contractions (i.e. exercise) were insufficient to improve RT. The current study suggests that endogenous DA is an important neuromodulator for RT improvement, and that RT is only altered when exercise is associated with central signals from higher brain centres.

Increase of Glucose Uptake in Human Bone Marrow With Increasing Exercise Intensity.

Human bone marrow is a metabolically active tissue that responds to acute low-intensity exercise by having increased glucose uptake (GU). Here, the authors studied whether bone marrow GU increases more with increased exercise intensities. Femoral bone marrow GU was measured using positron emission tomography and [18F]-fluorodeoxyglucose in six healthy young men during cycling at intensities of 30% (low), 55% (moderate), and 75% (high) of maximal oxygen consumption on three separate days. Bone marrow GU at low was 17.2 µmol·kg-1·min-1 (range 9.0-25.4) and increased significantly (p = .003) at moderate (31.2 µmol·kg-1·min-1, 22.9-39.4) but was not significant from moderate to high (37.4 µmol·kg-1·min-1, 29.0-45.7, p = .26). Furthermore, the ratio between bone and muscle GU decreased from low to moderate exercise intensity (p < .01) but not (p = .99) from moderate to high exercise intensity. In conclusion, these results show that although the increase is not as large as observed in exercising skeletal muscle, GU in femoral bone marrow increases with increasing exercise intensity at least from low- to moderate-intensity effort, which may be important for bone and whole-body metabolic health.

Increasing exercise intensity reduces heterogeneity of glucose uptake in human skeletal muscles.

Proper muscle activation is a key feature of survival in different tasks in daily life as well as sports performance, but can be impaired in elderly and in diseases. Therefore it is also clinically important to better understand the phenomenon that can be elucidated in humans non-invasively by positron emission tomography (PET) with measurements of spatial heterogeneity of glucose uptake within and among muscles during exercise. We studied six healthy young men during 35 minutes of cycling at relative intensities of 30% (low), 55% (moderate), and 75% (high) of maximal oxygen consumption on three separate days. Glucose uptake in the quadriceps femoris muscle group (QF), the main force producing muscle group in recreational cycling, and its four individual muscles, was directly measured using PET and 18F-fluoro-deoxy-glucose. Within-muscle heterogeneity was determined by calculating the coefficient of variance (CV) of glucose uptake in PET image voxels within the muscle of interest, and among-muscles heterogeneity of glucose uptake in QF was expressed as CV of the mean glucose uptake values of its separate muscles. With increasing intensity, within-muscle heterogeneity decreased in the entire QF as well as within its all four individual parts. Among-muscles glucose uptake heterogeneity also decreased with increasing intensity. However, mean glucose uptake was consistently lower and heterogeneity higher in rectus femoris muscle that is known to consist of the highest percentage of fast twitch type II fibers, compared to the other three QF muscles. In conclusion, these results show that in addition to increased contribution of distinct muscle parts, with increases in exercise intensity there is also an enhanced recruitment of muscle fibers within all of the four heads of QF, despite established differences in muscle-part specific fiber type distributions. Glucose uptake heterogeneity may serve as a useful non-invasive tool to elucidate muscle activation in aging and diseased populations.

Evaluation of individual skeletal muscle activity by glucose uptake during pedaling exercise at different workloads using positron emission tomography.

Skeletal muscle glucose uptake closely reflects muscle activity at exercise intensity levels <55% of maximal oxygen consumption (VO2max). Our purpose was to evaluate individual skeletal muscle activity from glucose uptake in humans during pedaling exercise at different workloads by using [18F]fluorodeoxyglucose (FDG) and positron emission tomography (PET). Twenty healthy male subjects were divided into two groups (7 exercise subjects and 13 control subjects). Exercise subjects were studied during 35 min of pedaling exercise at 40 and 55% VO2max exercise intensities. FDG was injected 10 min after the start of exercise or after 20 min of rest. PET scanning of the whole body was conducted after completion of the exercise or rest period. In exercise subjects, mean FDG uptake [standardized uptake ratio (SUR)] of the iliacus muscle and muscles of the anterior part of the thigh was significantly greater than uptake in muscles of control subjects. At 55% VO2max exercise, SURs of the iliacus muscle and thigh muscles, except for the rectus femoris, increased significantly compared with SURs at 40% VO2max exercise. Our results are the first to clarify that the iliacus muscle, as well as the muscles of the anterior thigh, is the prime muscle used during pedaling exercise. In addition, the iliacus muscle and all muscles in the thigh, except for the rectus femoris, contribute when the workload of the pedaling exercise increases from 40 to 55% VO2max.

Redistribution of whole-body energy metabolism by exercise: a positron emission tomography study.

OBJECTIVE: Our aim was to evaluate changes in glucose metabolism of skeletal muscles and viscera induced by different workloads using (18)F-2-fluoro-2-deoxyglucose ([(18)F]FDG) and three-dimensional positron emission tomography (3-D PET). METHODS: Five male volunteers performed ergometer bicycle exercise for 40 min at 40% and 70% of the maximal O(2) consumption (VO(2max)). [(18)F]FDG was injected 10 min later following the exercise task. Wholebody 3-D PET was performed. Five other male volunteers were studied as a control to compare with the exercise group. The PET image data were analyzed using manually defined regions of interest to quantify the regional metabolic rate of glucose (rMRGlc). Group comparisons were made using analysis of variance, and significant differences (P < 0.05) were determined using Scheffe's test (post hoc analysis). RESULTS: Quantitative analysis demonstrated that rMRGlc increased (P < 0.05) in the skeletal muscles of the thigh at mild or moderate workloads when compared with the resting controls. For visceral organs such as the liver and brain, metabolic reduction was significant (P < 0.05) at mild and/or moderate exercise workload. CONCLUSIONS: The present study demonstrated linear increases or decreases in glucose uptake by skeletal muscles and viscera with mild and moderate exercise workloads, suggesting the presence of homeostatic energy metabolism. This result supports the finding that [(18)F]FDG-PET can be used as an index of organ energy metabolism for moderate exercise workloads (70% VO(2max)). The results of this investigation may contribute to sports medicine and rehabilitation science.

Effect of exercise intensities on free fatty acid uptake in whole-body organs measured with (123)I-BMIPP-SPECT.

Our purpose was to evaluate the effects of exercise intensities on free fatty acid (FFA) uptake in skeletal muscles, myocardium and liver among humans using (123)I-labeled 15-(p-iodophenyl)-3-(R,S)-methyl-pentadecanoic acid ((123)I-BMIPP) and single photon emission computed tomography technique (SPECT). Six untrained male subjects were studied after 35 min of ergometer bicycle exercise at 40, 70 and 80% maximal aerobic power (VO(2max)) One subject was studied as resting control. SPECT scan was done 40 min after (123)I-BMIPP injection. Mean fractional uptake (FU) in quadriceps femoris muscle (QF) were 0.029 +/- 0.001, 0.029 +/- 0.002 and 0.025 +/- 0.002% at 40, 70 and 80% VO(2max), respectively. FU of QF at 40 and 70% VO(2max) were significantly higher than those of 80% VO(2max). Mean FU into myocardium were 0.048 +/- 0.002, 0.052 +/- 0.004 and 0.050 +/- 0.003% and those in liver were 0.033 +/- 0.002, 0.032 +/- 0.002 and 0.034 +/- 0.003% at each loads, respectively. Any significant changes were not suggestive in liver and myocardium after exercise. Mean FU (the mean values of all exercise intensity) at exercise is 2.86, 0.96 and 0.71 times higher than those at rest in QF, myocardium and liver. These results suggest: (1) in skeletal muscles, energy requirements at above lactate threshold at high exercise intensity predominantly depend upon other intramuscular energy substrates, (2) there is possibility of energy compensation by other substrates in myocardium at higher exercise intensity, (3) FFA uptake in liver might decrease after exercise; however, the influence of exercise intensities is not suggested.

Application of positron emission tomography to neuroimaging in sports sciences.

To investigate exercise-induced regional metabolic and perfusion changes in the human brain, various methods are available, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS) and electroencephalography (EEG). In this paper, details of methods of metabolic measurement using PET, [(18)F]fluorodeoxyglucose ([(18)F]FDG) and [(15)O]radio-labelled water ([(15)O]H(2)O) will be explained. Functional neuroimaging in the field of neuroscience was started in the 1970s using an autoradiography technique on experimental animals. The first human functional neuroimaging exercise study was conducted in 1987 using a rough measurement system known as (133)Xe inhalation. Although the data was useful, more detailed and exact functional neuroimaging, especially with respect to spatial resolution, was achieved by positron emission tomography. Early studies measured the cerebral blood flow changes during exercise. Recently, PET was made more applicable to exercise physiology and psychology by the use of the tracer [(18)F]FDG. This technique allowed subjects to be scanned after an exercise task is completed but still obtain data from the exercise itself, which is similar to autoradiography studies. In this report, methodological information is provided with respect to the recommended protocol design, the selection of the scanning mode, how to evaluate the cerebral glucose metabolism and how to interpret the regional brain activity using voxel-by-voxel analysis and regions of interest techniques (ROI). Considering the important role of exercise in health promotion, further efforts in this line of research should be encouraged in order to better understand health behavior. Although the number of research papers is still limited, recent work has indicated that the [(18)F]FDG-PET technique is a useful tool to understand brain activity during exercise.

High intensity exercise decreases global brain glucose uptake in humans.

Physiological activation increases glucose uptake locally in the brain. However, it is not known how high intensity exercise affects regional and global brain glucose uptake. The effect of exercise intensity and exercise capacity on brain glucose uptake was directly measured using positron emission tomography (PET) and [18F]fluoro-deoxy-glucose ([18F]FDG). Fourteen healthy, right-handed men were studied after 35 min of bicycle exercise at exercise intensities corresponding to 30, 55 and 75% of on three separate days. [18F]FDG was injected 10 min after the start of the exercise. Thereafter exercise was continued for another 25 min. PET scanning of the brain was conducted after completion of the exercise. Regional glucose metabolic rate (rGMR) decreased in all measured cortical regions as exercise intensity increased. The mean decrease between the highest and lowest exercise intensity was 32% globally in the brain (38.6+/-4.6 versus 26.1+/-5.0 micromol (100 g)-1 min-1, P<0.001). Lactate availability during exercise tended to correlate negatively with the observed brain glucose uptake. In addition, the decrease in glucose uptake in the dorsal part of the anterior cingulate cortex (37% versus 20%, P<0.05 between 30% and 75% of VO2max) was significantly more pronounced in subjects with higher exercise capacity. These results demonstrate that brain glucose uptake decreases with increase in exercise intensity. Therefore substrates other than glucose, most likely lactate, are utilized by the brain in order to compensate the increased energy needed to maintain neuronal activity during high intensity exercise. Moreover, it seems that exercise training could be related to adaptive metabolic changes locally in the frontal cortical regions.

Skeletal muscle glucose uptake response to exercise in trained and untrained men.

PURPOSE: Endurance training enhances skeletal muscle glucose uptake at rest, but the responses to different exercise intensities are unknown. In the present study, we tested whether glucose uptake is enhanced in trained men during low-, moderate-, and high-intensity exercise as compared with untrained men. METHODS: Seven trained and untrained men were studied without any dietary manipulation during bicycle exercise at relative intensities of 30%, 55%, and 75% of maximal oxygen consumption ([OV0312]O(2max)) on three separate days. Glucose uptake in the quadriceps femoris muscle was directly measured using positron emission tomography (PET) and 18F-fluoro-deoxy-glucose ([18F]FDG). [18F]FDG was injected 10 min after the start of the exercise. Thereafter exercise was continued for another 25 min. PET scanning was conducted immediately after completion of the exercise. The measured glucose uptake values reflect the situation during exercise due to chemical characteristics of the [18F]FDG. RESULTS: Muscle glucose uptake increased from 30% to 55% [OV0312]O(2max) intensity exercise similarly in both groups (P < 0.05). However, from 55% to 75% [OV0312]O(2max) intensity exercise, only athletes were able to further enhance glucose uptake. Furthermore, at highest intensity, glucose uptake was significantly higher in trained than in untrained men (236.6 +/- 29.6 vs 176.3 +/- 22.4 micromol.kg-1.min-1, P < 0.05). There were no differences in plasma glucose, insulin, or lactate in any time point at 75% [OV0312]O(2max) intensity between groups. CONCLUSIONS: These results show that skeletal muscle glucose uptake is higher in trained than in untrained men at high relative exercise intensity, although at lower relative exercise intensities no differences are observed. Thus, endurance training improves the capacity of contraction-induced glucose uptake in skeletal muscle.

FDG-PET imaging of lower extremity muscular activity during level walking.

We analyzed muscular activity of the lower extremities during level walking using positron emission tomography (PET) with (18)F-fluorodeoxyglucose ((18)F-FDG). We examined 17 healthy male subjects; 11 were assigned to a walking group and 6 to a resting group. After (18)F-FDG injection, the walking group subjects walked at a free speed for 15 min. A whole-body image was then obtained by a PET camera, and the standardized uptake ratio (SUR) was computed for each muscle. The SUR for each muscle of the walking group was compared with that for the corresponding muscles in the resting group. The level of muscular activity of all the muscles we examined were higher during level walking than when resting. The activity of the lower leg muscles was higher than that of the thigh muscles during level walking. The muscular activity of the soleus was highest among all the muscles examined. Among the gluteal muscles, the muscular activity of the gluteus minimus was higher than that of the gluteus maximus and gluteus medius. The concurrent validity of measuring muscular activity of the lower extremity during level walking by the PET method using (18)F-FDG was demonstrated.

Myocardial and skeletal muscle glucose uptake during exercise in humans.

The purpose of this study was to investigate the effects of exercise on myocardial glucose uptake and whether the pattern of glucose uptake is the same as in skeletal muscle. Glucose uptake was measured using positron emission tomography (PET) and 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG). Twelve healthy men were studied during rest, while 14 subjects were studied after 35 min of bicycle exercise corresponding to 30, 55 and 75 % of maximal oxygen consumption (*VO2,max)) on three separate days. [(18)F]FDG was injected 10 min after the start of exercise and exercise continued for a further 25 min. Myocardial and skeletal muscle PET scanning was commenced directly after the completion of the exercise bout. As compared to the resting state, exercise doubled myocardial glucose uptake at the 30 % (P = 0.056) and 55 % intensity levels (P < 0.05), while at the 75 % intensity level glucose uptake was reduced significantly compared to the lower exercise intensities. There was no significant difference between the highest intensity level and the resting state (P = 0.18). At rest and during low-intensity exercise, myocardial glucose uptake was inversely associated with circulating levels of free fatty acids. However, during higher exercise intensities when plasma lactate concentrations increased significantly, this association disappeared. In contrast to myocardial responses, skeletal muscle glucose uptake rose in parallel with exercise intensity from rest to 30 % and then 55 % *VO2,max) (P < 0.001) and tended to increase further at the intensity of 75 % *VO2,max) (P = 0.065). In conclusion, these results demonstrate that myocardial glucose uptake is increased during mild- and moderate-intensity exercise, but is decreased during high-intensity exercise. This finding suggests that the increased myocardial energy that is needed during high-intensity exercise is supplied by substrates other than glucose.