INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

CONTROVERSY EXISTS as to whether the metabolic activity of the brain as a whole increases during physical exercise. For example, there appears to be no change in brain O₂ uptake (O₂) during cycling (18, 31), whereas, during vigorous exercise on the treadmill, there is reported to be an increase in brain O₂ (28). Although the cerebral metabolic rate for O₂ has been taken as the variable most closely coupled to metabolic activity of the brain (18), O₂ may not be the most sensitive index for an evaluation of the metabolic activity of the brain. In response to neural activation, regional O₂ increases much less than the increase in cerebral blood flow (7). Also, cerebral oxygenation determined by near-infrared spectroscopy (NIRS) exceeds the increase in O₂ demand in response to motor stimulation (22). Moreover, the increase in regional uptake of glucose surpasses that of O₂ (8), and similar observations have been made for the global value (15). Thus the molar cerebral O₂-to-glucose uptake ratio becomes reduced (15, 16).

During exercise, blood lactate increases progressively with work rate, and lactate may be of importance for brain metabolism (14). Yet, when there is no increase in blood lactate, as during mental activation, no net brain uptake of lactate has been demonstrated (17). Rather, the increase in lactate uptake by the brain becomes apparent during hyperlactemia associated with "stimulation" (in the rat; Ref. 16) and during physical exercise in humans (2).

The hypothesis of this study was that the global brain metabolism would be increased during exercise when glucose and lactate, in addition to O₂, were taken into consideration. Cerebral perfusion was evaluated with transcranial Doppler, and cerebral oxygenation was determined by NIRS. Norepinephrine spillover into the jugular vein was calculated to assess whether exercise is associated with enhanced brain sympathetic activity.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

As approved by the Ethics Committee of Copenhagen (KF 01-369/97), 12 healthy volunteers were studied [2 women, age 23 ± 1 (SE) yr, body wt 80 ± 2 kg, and height 183 ± 2 cm]. Before the main study, the subjects performed an incremental exercise test until exhaustion to determine maximal O₂ (O_{2 max}) on a modified Krogh cycle ergometer (9), and expired air was obtained breath by breath, resulting in a O_{2 max} of 43 ± 2 ml · kg¹ · min¹ (MedGraphics 2001, St. Paul, MN). The work rates corresponding to 30 and 60% of O_{2 max} were calculated from the O₂-work rate relationship. On the day of the main study, the subjects accessed the laboratory after having a light breakfast. In the same semisupine position used in the preliminary study, the subjects cycled at the two work rates for 10 min each. Cannulas were introduced percutaneously into the brachial artery of the nondominant arm (19 gauge) and retrograde into the internal jugular vein (14 gauge) and advanced to its bulb (12). Blood samples were obtained anaerobically at rest and after 4 and 9 min at each work rate. Blood-gas variables (ABL 625, Radiometer, Copenhagen, Denmark) and lactate (Yellow Springs Instruments, Yellow Springs, OH) were determined. For the determination of plasma catecholamines, 5 ml of blood were obtained at rest and at both work rates. Samples were placed in chilled tubes containing 100 µl of EGTA-GSH solution and centrifuged at 600 g for 10 min at 4°C. The plasma was stored at 80°C until analysis. Catecholamines were assayed by HPLC by using a radioenzymatic method (3).

The proximal segment of the middle cerebral artery (MCA) was insonated (Multidop X, DWL, Sipplingen, Germany) through the posterior temporal "window." Once the optimal signal-to-noise ratio was obtained, the probe was covered with adhesive ultrasonic gel (Tensive, Parker Laboratories, Orange, NJ) and secured with a headband. The MCA mean blood velocity (V_mean) was computed as the time average of continuously sampled maximal frequency shifts for each heart beat and averaged for each minute. Such determination of MCA is made with a coefficient of variation of ~5% at rest, 12% during vigorous exercise such as rowing (25), and ~5% during cycling (24). Mean arterial pressure was obtained from the catheter in the brachial artery and was integrated by a monitor that also calculated heart rate (HR) from a two-lead electrocardiogram (8000, Simonsen & Weel, Copenhagen, Denmark). Cerebral oxygenation was measured by NIRS (NIRO 500, Hamamatsu Photonics, Hamamatsu, Japan). The optodes on the forehead were placed 4.5 cm apart, covered with black rubber for light shielding, and fixed against the skin by adhesive tape. The NIRO 500 uses wavelengths of 775, 825, 850, and 905 nm to calculate the concentration changes (C) of oxyhemoglobin (HbO₂) and deoxyhemoglobin and cytochrome oxidases by applying the Lambert-Beer law: C = OD/( · L · B), where OD is the attenuation of light expressed as changes in optical density,  is the extinction coefficient of the chromophore (mM/cm), L is the distance between the point of light entry and point of light exit (cm), and B is a path length factor that takes into account the scattering of light in the tissue (4.0). Measurements were obtained every 5 s, and the near-infrared signal was stored on hard disk for off-line analysis.

Norepinephrine spillover from the brain was calculated as NE_spill = ([NE]_v  [NE]_a + C_NE [NE]_a) CBF (1  Hct), where [NE]_v and [NE]_a are the venous and arterial concentrations of NE, respectively, and C_NE is the fractional clearance of NE from the cerebral circulation and is estimated as ([NE]_a  [NE]_v)/[NE]_a, CBF is cerebral blood flow, and Hct is hematocrit. For this calculation, the jugular venous flow was regarded as remaining constant (17). Data are means ± SE. The Friedman test was used to determine whether significant changes occurred among circumstances, and such changes were located with Wilcoxon's matched-pairs sign test by rank. A P value of <0.05 was considered statistically significant.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Mean arterial pressure and HR increased with exercise intensity from a rest value of 97 ± 3 to 101 ± 3 and 111 ± 4 mmHg during the two levels of exercise and from 63 ± 3 to 95 ± 2 and 134 ± 4 beats/min, respectively (Fig. 1). During exercise, MCA V_mean increased from 62 ± 3 to 63 ± 3 and 70 ± 5 cm/s as did the change in oxygenated Hb (HbO₂) by 10 ± 3 and 25 ± 3 µmol/l. Also, the change in deoxyhemoglobin and thus the change in total Hb increased during exercise (to 2 ± 1 and 5 ± 1 µmol/l and to 12 ± 3 and 30 ± 3 µmol/l, respectively) (Fig. 2).

View larger version (11K): [in this window] [in a new window]   Fig. 1.   Data (means ± SE) are shown for middle cerebral artery (MCA) mean blood velocity (Vmean), change in oxygenated hemoglobin (HbO2) determined by near-infrared spectroscopy, mean arterial pressure (MAP), and heart rate (HR) at rest and during cycling at 30 and 60% of maximal O2 uptake (O2 max). * P < 0.05,  P < 0.01 compared with rest. n = 10 Subjects for MCA Vmean, MAP, and HR during cycling at 30% O2 max, n = 7 subjects for HbO2, otherwise n = 12 subjects.

View larger version (17K): [in this window] [in a new window]   Fig. 2.   Representative data are shown for concentration changes in deoxygenated Hb (Hb), oxygenated Hb (HbO2), and total Hb (Hbtotal) for 1 subject during 10 min at rest, during 2 levels of cycling, and for 10 min of recovery. HbO2 increased in proportion to work rate and reached a maximal level during first few minutes of recovery.

The arterial O₂ content increased during exercise, whereas the arterial glucose decreased (Table 1). The arterial epinephrine concentration did not change significantly during exercise, whereas the norepinephrine concentration increased. Neither the arteriovenous (a-v) difference of epinephrine nor that of norepinephrine changed during exercise. Thus the norepinephrine spillover did not change significantly, and there was no significant change in the arterial CO₂ tension. During 30% exercise, the arterial lactate accumulation did not change significantly, but it increased during 60% exercise. Accordingly, the arterial pH did not change during 30% exercise, but it decreased at the higher work rate.

The internal jugular venous O₂ saturation increased during 30% exercise but was not significantly different from rest during 60% exercise (Table 1). Thus during 30% exercise, the a-v difference for O₂ decreased and then recovered. The a-v difference for glucose followed a similar pattern; i.e., it tended to decrease at 30% exercise and increased during 60% exercise. As a result, the molar ratio of O₂ to glucose a-v difference did not change significantly. The a-v difference for lactate did not change during 30% exercise, but it increased at the higher work rate. When the a-v difference of lactate was taken into account, the ratio of O₂ to carbohydrate (glucose + lactate/2) a-v difference decreased (~ 30%).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

In contrast to an evaluation based on the O₂ (18, 31) or glucose uptake (10), with an evaluation also taking lactate into consideration, the substrate uptake of the brain appears to increase in response to exercise. Thus the sum of the a-v difference for glucose plus one-half of that for lactate increased ~30%, and, for the brain, the molar ratio of the a-v difference of O₂ to that of carbohydrate decreased from the resting level of ~6 to 4.7. Furthermore, as evidenced by MCA V_mean determined by transcranial Doppler, cerebral perfusion was enhanced, and cerebral oxygenation determined by NIRS supported that flow increased to a larger extent than that corresponding to the metabolic O₂ demand.

It is not generally accepted that physical exercise causes neuronal activation. Yet, as determined by positron-emission tomography during foot movement and after cycling, it seems that hyperventilation activates the superolateral primary cortex (6). Also, low-intensity cycling (HR ~100 beats/min) activates the left insular cortex (30), and even handgrip exercise with a rubber ball is able to stimulate the sensorimotor cortex (21).

It has been argued that the increase in MCA V_mean might be caused by a decrease in the diameter of the insonated artery, despite an unchanged cerebral blood flow (18). Also, with the use of the integrated Doppler signal rather than V_mean, it has been argued that, during exercise, the change in flow is overestimated by a factor of 3 (26). Yet, when subjects can keep their head motionless, as during the release of an occluding cuff around a leg, these two expressions of flow velocity are similar (1). Thus it is not certain if such an intensity-weighted signal is affected by a head movement-related artifact during exercise. We used norepinephrine spillover to evaluate whether brain sympathetic activity would become elevated during exercise and in turn cause constriction of the MCA. In the present study, MCA V_mean increased by 14% during 60% exercise, even though cerebral norepinephrine spillover did not change significantly. Furthermore, an increase in cerebral blood flow was supported by the NIRS-determined cerebral oxygenation during exercise. As observed during a motor task (finger opposition) in the study of Hirth et al. (11), the changes in HbO₂ were paralleled by changes in MCA V_mean. In confirmation of evaluations based on the regional O₂ and cerebral blood flow by positron-emission tomography (8) and functional magnetic resonance (22), in response to cerebral activation the increase in flow is larger than the O₂ demand. Alternatively, it could be argued that the increase in O₂ balance for the brain could reflect a reduced cerebral metabolic rate, but we noted an increase in carbohydrate uptake by the brain during exercise. Also, it may be argued that cerebral hyperoxygenation would be caused by an increase in hematocrit without an alteration in flow. In the present study, the arterial hematocrit increased from 43 to 44 and 46% during the two levels of cycling in reflection of muscle edema (4, 27) rather than of recruitment of red blood cells from the spleen (20). Yet MCA V_mean and cerebral oxygenation appear to follow each other during exercise. Thus during cycling with ₁-blockade, the increase in MCA V_mean is lowered, and the trend is similar in cerebral oxygenation determined by NIRS, although hematocrit was not affected by the blockade (Table 2). Only when exercise induces arterial desaturation, as during rowing, is it associated with a similar cerebral desaturation (19).

Uptake of lactate by neurons (5) and astrocytes (29) is sensitive to the pH gradient, as is peripheral tissue, including skeletal muscle (13). In the present study, there was only a small reduction in arterial pH (from 7.41 to 7.38). At this level of pH, more than 99% of lactate will be dissociated (the acidic dissociation constant for lactic acid is 3.9), and the undissociated form would be increased only from 0.6 to 2.8 pM. Therefore, the results suggest that cerebral perfusion increases in excess of the increases in the global cerebral metabolic activity during the brain activation associated with exercise and that lactate supplements glucose as energy fuel for the brain when the plasma lactate level is elevated.