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

Abstract

During maximal exercise lactate taken up by the human brain contributes to reduce the cerebral metabolic ratio, O(2)/(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 O(2), 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 ((1)H-MRS) was performed after exhaustive exercise to assess lactate levels in the brain (n = 5). Exercise increased the AV(O2) from 3.2 +/- 0.1 at rest to 3.5 +/- 0.2 mM (mean +/-s.e.m.; P < 0.05) and the AV(glc) from 0.6 +/- 0.0 to 0.9 +/- 0.1 mM (P < 0.01). Notably, the AV(lac) 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 (1)H-MRS signal from lactate obtained after exercise was smaller than the estimated detection limit of approximately 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.

Figure 1. Magnetic Resonance Spectroscopy from phantoms (basketballs) with varying lactate concentration for estimation of the detection limit for lactate (Experiment II)

A, spectrum from the phantom containing 10 mm lactate and 10 mm creatine (Cr) in physiological saline. The lactate resonates at 1.33 and 4.11 p.p.m. (where only the two centre peak are seen, *). B, the 1.0–2.0 p.p.m. regions of the spectra from the phantoms containing 0–10 mm lactate, demonstrating that the detection limit for lactate in this set-up is between 0.5 and 1.0 mm, matching the limit found by the Cramér-Rao lower bounds (CRLB) > 20%. Recording conditions in vitro and in vivo were identical. C, the correlation between the true and the measured lactate concentration in the phantoms is fitted by y = 0.9755x+ 0. 1797, r²= 0,9988. A distinction is made between reliable (•) (above the detection limit) and unreliable lactate concentrations (○); see below. Data are means of five measurements with s.e.m. too small to be visible on the graph. The CRLB was calculated by the LCModel quantification program and is the estimated standard deviation expressed as a percentage of the estimated concentration. In all five measurements of the 0.2 mm phantom, CRLB was > 31%. Even though for this phantom the LCModel estimated the lactate concentration consistently to an average of 0.29 mm, the large CRLB (> 20%) by definition renders the detection of lactate at this level unreliable.

Figure 2. Arterial (•) and internal jugular venous (○) concentrations at rest, in response to exhaustive arm and leg exercise and in the recovery (Experiment I)

The time to exhaustion differed and in order to compare between the subjects the exercise data were fitted to 10 min with 5 data points (n = 9); recovery (n = 8). Values represent means ± s.e.m. Different from rest: *P < 0.05; ^†P < 0.01.

Figure 3. Arterio-venous differences over the brain at rest and during exhaustive arm and leg exercise and in the recovery (Experiment I)

Data from exercise are fitted to 10 min as in Fig. 2 (n = 9; recovery, n = 8). Values represent means ± s.e.m. Different from rest: *P < 0.05; ^†P < 0.01. For statistical analysis of AV_O2, data were grouped into 5 time periods and the average for each period calculated. The groups are as follows: rest, exercise at a ‘low’ intensity (first 6 min), exercise at a ‘high’ intensity (last 4 min), the first 5 min, and the remainder of the recovery (Ide et al. 2000). Division of the exercise period and the recovery interval is denoted by dashed lines. Group averages different from rest: ^‡P < 0.05.

Figure 4. The cerebral metabolic ratios of O₂/glucose and O₂/(glucose + 1/2 lactate) at rest and during exhaustive arm and leg exercise and in the recovery (Experiment I)

Data from exercise are fitted to 10 min as in Figs 2 and 3 (n = 9; recovery, n = 8). Values represent means ± s.e.m. Different from rest: *P < 0.05; ^†P < 0.01.

Figure 5. Magnetic Resonance Spectroscopy pre- and postexercise (30 s to 5 min) in a volunteer exercising to exhaustion outside the magnet (Experiment II)

Each of the spectra represents 1 min of averaging. The arrows indicate the position of the lactate doublet centred at 1.33 p.p.m. None of the spectra showed lactate and Cramér-Rao lower bounds were larger than 20% in all spectra. Even if the four postexercise spectra were averaged, lactate was not detectable (not shown). The spectral resolution at rest was 0.06 p.p.m and postexercise 0.06–0.08 p.p.m., and the detection limit for lactate postexercise was 1.5 mm. The metabolites detectable in the spectra are N-acetylaspartate (NAA; 2.02 p.p.m and 2.06 p.p.m), glutamine + glutamate (Glx; 2.05–2.5 p.p.m and 3.65–3.85 p.p.m), total creatine (Cr; 3.03 and 3.9 p.p.m), total choline (Cho; 3.22 p.p.m), and myo-inositol (mI; 3.6 p.p.m). The concentration of metabolites detected in the normal human brain ranges typically from 1 to 10 mm. The broader components of the baseline represent mainly macromolecules and metabolites at lower concentrations that are usually not assigned.