Sleep Dependent Changes of Lactate Concentration in Human Brain

Abstract

Lactate is an important cellular metabolite that is present at high concentrations in the brain, both within cells and in the extracellular space between cells. Small animal studies demonstrated high extracellular concentrations of lactate during wakefulness with reductions during sleep and/or anesthesia with a recent study suggesting the glymphatic activity as the mechanism for the reduction of lactate concentrations. We have recently developed a rigorous non-invasive imaging approach combining simultaneous magnetic resonance spectroscopy (MRS) and polysomnography (PSG) measurements, and here, we present the first in-vivo evaluation of brain lactate levels during sleep-wake cycles in young healthy humans. First, we collected single voxel proton MRS (1H-MRS) data at the posterior cingulate with high temporal resolution (every 7.5 sec), and simultaneously recorded PSG data while temporally registering with 1H-MRS time-series. Second, we evaluated PSG data in 30 s epochs, and classified into four stages Wake (W), Non-REM sleep stage 1 (N1), Non-REM sleep stage 2 (N2), and Non-REM sleep stage 3 (N3). Third, we determined lactate signal intensity from each 7.5-s spectrum, normalized to corresponding water signal, and averaged over 30-s for each PSG epoch. In examinations of nine healthy participants (four females, five males; mean age 24.2 ({+/-}2; SD) years; age range: 21-27 years) undergoing up to 3-hour simultaneous MRS/PSG recordings, we observed a group mean reduction of [4.9 {+/-} 4.9] % in N1, [10.4 {+/-} 5.2] % in N2, and [24.0 {+/-} 5.8] % in N3 when compared to W. Our finding is consistent with more than 70 years of invasive lactate measurements from small animal studies. In addition, reduced brain lactate was accompanied by a significant reduction the apparent diffusion coefficient of brain lactate. Taken together, these findings are consistent with the loss of lactate from the extracellular space during sleep while suggesting lactate metabolism is altered and/or lactate clearance via glymphatic exchange is increased during sleep. Significance StatementThis study describes a non-invasive magnetic resonance spectroscopy/polysomnography technique that allows rigorous measurement of brain metabolite levels together with simultaneous characterization of brain arousal state as either wakeful or one of the several sleep states. The results provide the first in-vivo demonstration of reductions in brain lactate concentration and diffusivity during sleep versus wakefulness in young healthy human brain. These findings are consistent with invasive small-animal studies showing the loss of extracellular lactate during sleep, and support the notion of altered lactate metabolism and/or increased glymphatic activity in sleeping human brain.