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. 2018 Dec 5;38(49):10552-10565.
doi: 10.1523/JNEUROSCI.0865-18.2018. Epub 2018 Oct 3.

Phosphocreatine Levels in the Left Thalamus Decline during Wakefulness and Increase after a Nap

Ali Gordji-Nejad  1 , Andreas Matusch  2 , Shumei Li  2 , Tina Kroll  2 , Simone Beer  2 , David Elmenhorst  2   3 , Andreas Bauer  2   4
Affiliations

Phosphocreatine Levels in the Left Thalamus Decline during Wakefulness and Increase after a Nap

Ali Gordji-Nejad et al. J Neurosci. .

Abstract

Scientists have hypothesized that the availability of phosphocreatine (PCr) and its ratio to inorganic phosphate (Pi) in cerebral tissue form a substrate of wakefulness. It follows then, according to this hypothesis, that the exhaustion of PCr and the decline in the ratio of PCr to Pi form a substrate of fatigue. We used 31P-magnetic resonance spectroscopy (31P-MRS) to investigate quantitative levels of PCr, the γ-signal of ATP, and Pi in 30 healthy humans (18 female) in the morning, in the afternoon, and while napping (n = 15) versus awake controls (n = 10). Levels of PCr (2.40 mM at 9 A.M.) decreased by 7.0 ± 0.8% (p = 7.1 × 10-6, t = -5.5) in the left thalamus between 9 A.M. and 5 P.M. Inversely, Pi (0.74 mM at 9 A.M.) increased by 17.1 ± 5% (p = 0.005, t = 3.1) and pH levels dropped by 0.14 ± 0.07 (p = 0.002; t = 3.6). Following a 20 min nap after 5 P.M., local PCr, Pi, and pH were restored to morning levels. We did not find respective significant changes in the contralateral thalamus or in other investigated brain regions. Left hemispheric PCr was signficantly lower than right hemispheric PCr only at 5 P.M. in the thalamus and at all conditions in the temporal region. Thus, cerebral daytime-related and sleep-related molecular changes are accessible in vivo Prominent changes were identified in the thalamus. This region is heavily relied on for a series of energy-consuming tasks, such as the relay of sensory information to the cortex. Furthermore, our data confirm that lateralization of brain function is regionally dynamic and includes PCr.SIGNIFICANCE STATEMENT The metabolites phosphocreatine (PCr) and inorganic phosphate (Pi) are assumed to inversely reflect the cellular energy load. This study detected a diurnal decrease of intracellular PCr and a nap-associated reincrease in the left thalamus. Pi behaved inversely. This outcome corroborates the role of the thalamus as a region of high energy consumption in agreement with its function as a gateway that relays and modulates information flow. Conversely to the dynamic lateralization of thalamic PCr, a constantly significant lateralization was observed in other regions. Increasing fatigue over the course of the day may also be a matter of cerebral energy supply. Comparatively fast restoration of that supply may be part of the biological basis for the recreational value of "power napping."

Keywords: 31P magnetic resonance spectroscopy; inorganic phosphate; pH; phosphocreatine; thalamus.

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Figures

Figure 1.
Figure 1.
A, Study design. Top, Subjects were measured in two sessions, one in the morning at 9 A.M. and one in the afternoon at 5 P.M. of the same day. After the afternoon 5 P.M. scan at wake state, 15 subjects remained positioned in the scanner and were further measured while napping. Each measurement lasted 20 min. Bottom, 10 controls underwent the same protocol but stayed awake during the second and third scan of the 5 P.M. session. B, 31P spectrum of the left thalamic voxel (R5, C5) after postprocessing with Tarquin. The upper black line represents residuals after fitting. The green and red lines are the fitted and modeled linear combination of monomolecular basic spectra. C, Sagittal view with the grid placed parallel to and 2 mm under the anterior commissure–posterior commissure plane. D, Axial 2D flash image in radiological orientation (left hemisphere at the right image side) overlaid with the CSI grid of 8 × 8 voxels. E, Comparison of PCr levels in the left (R5C5) and right (R5C4) thalamus voxel. In the morning the intraindividual left–right percentage difference averaged −1.9%, rising in the afternoon to highly significant −6.7%. Error bars denote SEM.
Figure 2.
Figure 2.
A–D, Plots of the courses of PCr (A), Pi (B), metabolic ratio Pi/PCr (C), and pH level (D) in the left thalamus 15.6 ml voxel throughout the four conditions assessed. Dotted lines represent the control group that did not nap. Note the inverse course of Pi and Pi/PCr versus PCr and pH, respectively.
Figure 3.
Figure 3.
A, Voxelwise concentrations of PCr, Pi, and γ-ATP at 9 A.M. B, Localization of the observed significant changes between conditions within the CSI grid overlaid onto an axial MRI.
Figure 4.
Figure 4.
Illustration of voxels displaying significant left–right hemispheric differences of PCr, Pi/PCr, and ATP level throughout 16 voxels at 9 A.M. and 5 P.M. for all subjects, while napping (Nap1, Nap2) for napping subjects, and while awake for wake controls (Wake1, Wake2).
Figure 5.
Figure 5.
A, Scatter plots of individual changes of PCr and Pi in the left thalamus throughout four conditions for both subjects who napped (black circles) and controls (red circles). B, Individual changes of PCr and Pi/PCr in nap versus wake at 5 P.M. plotted as a function of changes in awake state in the course of the day (5 P.M. vs 9 A.M.). Red triangles represent the respective changes within the control group that stayed awake during all four scans and black diamonds the group that napped. Note the vertical shift between the test and control cluster of data points.
Figure 6.
Figure 6.
31P-MRS signal saturation studies of PCr, γ-ATP, and Pi, of relaxation times (T1), and of relaxation rates (1/T1): A, Comparison of saturation curves in vivo in four subjects with those of best matching phantom preparations containing all 2.5 mM PCr, 3.5 mM ATP, and 1.0 mM Pi and 8 μM Gd for PCr, 0.1 μM Gd for ATP, and 14 μM Gd for Pi. B–D, Relaxation rate (1/T1) of PCr, γ-ATP, and Pi in solutions with different concentrations of Mg2+ (1–10 mM), Gd (0.07–25 μM) and agarose (0.07–0.6%). E, Calibration lines for PCr (diamond), ATP (circle) and Pi (triangle) signal covering the concentration range 1–6.4 mM measured at TR = 3000 ms (filled symbols) and at saturated level with TR = 20 000 ms (open symbols). The in vivo PCr, γ-ATP and Pi level in the thalamus region at 9 AM corresponded to a concentration of 2.40, 2.91 and 0.8 mM (n = 30), respectively. Error bars indicate SEM. F, 31P spectrum of the R5, C5 voxel of a phantom containing 2.5 mM PCr, 3.5 mM ATP, 1.0 mM Pi and 0.44% agarose placed inside a human skull.
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