Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation

Abstract

The inverse effects of creatine supplementation and sleep deprivation on high energy phosphates, neural creatine, and cognitive performances suggest that creatine is a suitable candidate for reducing the negative effects of sleep deprivation. With this, the main obstacle is the limited exogenous uptake by the central nervous system (CNS), making creatine only effective over a long-term diet of weeks. Thus far, only repeated dosing of creatine over weeks has been studied, yielding detectable changes in CNS levels. Based on the hypothesis that a high extracellular creatine availability and increased intracellular energy consumption will temporarily increase the central creatine uptake, subjects were orally administered a high single dose of creatinemonohydrate (0.35 g/kg) while performing cognitive tests during sleep deprivation. Two consecutive ³¹P-MRS scans, ¹H-MRS, and cognitive tests were performed each at evening baseline, 3, 5.5, and 7.5 h after single dose creatine (0.35 g/kg) or placebo during sub-total 21 h sleep deprivation (SD). Our results show that creatine induces changes in PCr/Pi, ATP, tCr/tNAA, prevents a drop in pH level, and improves cognitive performance and processing speed. These outcomes suggest that a high single dose of creatine can partially reverse metabolic alterations and fatigue-related cognitive deterioration.

Figure 1

(A) Study design. Subjects were administered creatine at 8:30 p.m. in one session and placebo in another, spaced at least five days in random order. Seven participants completed the verum and eight the placebo as the first condition. Cognitive and metabolic parameters were acquired in four runs, baseline starting at 6 p.m., the other at 0 a.m., 2 a.m., and 4 a.m. Each session took 1 h:35 min and comprised two ³¹P-MRS-, three ¹H-MRS measurements, followed by fatigue scores, psychomotor vigilance tests (PVT), and other cognitive tasks (Cog.Test). (B) Positioning of three single voxel ¹H-MR-spectroscopy (PRESS) voxels (left, red) and two 8 × 8 ³¹P-MRS CSI grids (right, white) in coronal, transversal and sagittal view. Isotropic voxel size was (25 mm)³ except for the frontal PRESS-voxel of double volume. Exemplary spectra are given with some signals assigned. Signals exploited in this study were of ³¹P-MRS Pi at ≈5 ppm, PCr set at 0 ppm and the ATP-β-signal at − 16.3 ppm, of ¹H-MRS the CH₃-signal at 3.2 ppm, and the CH₂-signal at 3.92 ppm of creatine (total creatine, tCr), N-acetyl-aspartate (NAA) at 2.0 ppm and signals of glutamate (Glu) at 2.35 (C3, C4-protons) and glutamine or glutamate (Glx) at 3.75 ppm (C2-proton).

Figure 2

Plots of ¹H and ³¹P spectra over time, including processed signal, fit (in green), baseline and residual of left parietal voxel (PRESS), and from one CSI voxel (R5C4) located in the middle grid.

Figure 3

Time courses of selected metabolic parameters during sleep deprivation after oral administration of creatine (red solid lines) or placebo (black dashed lines). Shown are tCr/tNAA of the voxel located in the left medial parietal region, and averages of Pi/³¹P, ATP-ß/³¹P and pH levels of the middle and upper grid voxels. ³¹P represents the total phosphorus signal, including PCr, Pi, ATP-ß, PE, and TCho. Arrows indicate administration of creatine or placebo at 8:30 p.m. Asterisks (*) represent significant changes versus baseline after creatine, and (+) after placebo administration (p ≤ 0.005) that survived the Bonferroni correction. Bars denote standard errors (SE).

Figure 4

Changes in cognitive performance and metabolites versus baseline (6 p.m.) during sleep deprivation under placebo (grey) and creatine (red) when pooled at all 3 timepoints (0 p.m., 2 a.m., 4 a.m.). Shown are changes in cognitive tasks (Language, Logic, Numeric), forward digit span (SPAN), word memory tasks (WMT), psychomotor vigilance test (PVT, reaction speed) and selected metabolic parameters of tCr/tNAA from the left medial parietal region, of PCr/Pi, Pi/³¹P and pH level from the averaged middle.-, and ATP-ß/³¹P from the averaged upper grid. Significance levels are presented by *p₄₃ < 0.005, **p₄₃ < 0.0005 and ***p₄₃ < 0.00005. Bars represent standard errors (SE).

Figure 5

Baseline (6 p.m.) related changes in cognitive performance, speed in processing time and metabolic parameters after oral administration of creatine versus placebo when pooled at 3 points (0 p.m., 2 a.m., 4 a.m.). Creatine administration led to significant improvements in word memory task (WMT), speed in processing time in WMT, language, logic, and numeric tasks, and induced declines in ATP-ß/³¹P, Pi/³¹P, and increase in PCr/³¹P. Significance levels are color coded and indicated by arrows onto axial brain slices in radiological orientation.

Figure 6

Time course of percentual changes from baseline of PCr/³¹P, ATP-ß/³¹P and PCr/ATP in selected voxels from left hemisphere at 0 a.m., 2 a.m. and 4 a.m. versus baseline 6 p.m. after creatine (red lines) and placebo (black lines).