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Randomized Controlled Trial
, 35 (4), 1773-80

Creatine Supplementation Enhances Corticomotor Excitability and Cognitive Performance During Oxygen Deprivation

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Randomized Controlled Trial

Creatine Supplementation Enhances Corticomotor Excitability and Cognitive Performance During Oxygen Deprivation

Clare E Turner et al. J Neurosci.

Abstract

Impairment or interruption of oxygen supply compromises brain function and plays a role in neurological and neurodegenerative conditions. Creatine is a naturally occurring compound involved in the buffering, transport, and regulation of cellular energy, with the potential to replenish cellular adenosine triphosphate without oxygen. Creatine is also neuroprotective in vitro against anoxic/hypoxic damage. Dietary creatine supplementation has been associated with improved symptoms in neurological disorders defined by impaired neural energy provision. Here we investigate, for the first time in humans, the utility of creatine as a dietary supplement to protect against energetic insult. The aim of this study was to assess the influence of oral creatine supplementation on the neurophysiological and neuropsychological function of healthy young adults during acute oxygen deprivation. Fifteen healthy adults were supplemented with creatine and placebo treatments for 7 d, which increased brain creatine on average by 9.2%. A hypoxic gas mixture (10% oxygen) was administered for 90 min, causing global oxygen deficit and impairing a range of neuropsychological processes. Hypoxia-induced decrements in cognitive performance, specifically attentional capacity, were restored when participants were creatine supplemented, and corticomotor excitability increased. A neuromodulatory effect of creatine via increased energy availability is presumed to be a contributing factor of the restoration, perhaps by supporting the maintenance of appropriate neuronal membrane potentials. Dietary creatine monohydrate supplementation augments neural creatine, increases corticomotor excitability, and prevents the decline in attention that occurs during severe oxygen deficit. This is the first demonstration of creatine's utility as a neuroprotective supplement when cellular energy provision is compromised.

Keywords: cognition; corticomotor excitability; creatine; dietary supplementation; hypoxia; neural metabolism.

Figures

Figure 1.
Figure 1.
Experimental workflow and procedures. Fifteen healthy participants were recruited to participate in the study. A familiarization session was conducted to collect the baseline neuropsychological assessment (Cognitive Tests) and introduce the participant to the hypoxia intervention (Hypoxia). Participants were then randomized into an initial supplementation regime (CrM or PLA), and supplementation was conducted for 7 d, with a 5 week washout period. Experimental sessions were conducted 24 h after supplementation, involving the collection of neuroimaging, neurophysiological, and neuropsychological data. Structural MRI was used to position an MRS volume of interest (voxel) over the hand knob of the primary motor cortex. The location was verified with functional MRI. The red–yellow contrast shows areas of increased activation during a functional finger-tapping task (Z > 2.3, p < 0.05). Spectroscopy data were acquired and corrected for the proportion of tissue types using neural tissue segmentation and transformed to absolute quantities using a brain-mimicking phantom containing a range of known physiological Cr concentrations. Neurophysiological data, as assessed via TMS and PNS, were recorded using surface EMG at baseline and during the hypoxia intervention to measure central and peripheral excitability levels, respectively. The hypoxia intervention was conducted for 90 min using a gas mixture with a fraction of inspired oxygen (FiO2) of 0.1 and delivered via a one-way valve face-mask system. Cardiovascular measures [arterial oxygen saturation (SpO2), heart rate (HR), and blood pressure (BP)] were monitored throughout to assess autonomic system regulation to the hypoxic intervention.
Figure 2.
Figure 2.
Neural creatine concentration after supplementation. a, Mean Cr concentration detected in the sensorimotor cortex increased after 1 week of dietary CrM supplementation (black bars) compared to PLA (white bars). Data were recorded using 1H MRS, transformed to an absolute quantity (in millimoles per liter) and corrected for the proportion of gray and white matter present in the volume of interest. Bars show the mean ± SEM. *p < 0.05. b, Amplitude of the Cr + PCr peaks from 1H MRS. An example spectra acquired at 3 T from the sensorimotor cortex of one participant is shown. Resonances at 3.069 and 3.960 ppm represent the primary and secondary Cr + PCr peaks, respectively.
Figure 3.
Figure 3.
Autonomic regulation during hypoxia. Arterial oxygen saturation (SpO2) was reduced by 19% during hypoxia. A compensatory 12% increase, on average, in heart rate (HR) occurred, with no changes in blood pressure (BP) detected. Gray shading represents wash-in stabilization period followed by 80 min of hypoxia for CrM (black circles) and PLA (white circles) treatments. Data are mean ± SD; n = 12 (n = 11 for BP). **p < 0.01 for 0 min versus subsequent observations.
Figure 4.
Figure 4.
Changes in cognitive domain scores with hypoxia. Hypoxia degraded performance significantly in four neurocognitive domains with PLA (white bars), but these decrements were lessened or prevented with CrM (black bars). Standard scores are raw scores relative to an age-matched normative data set of healthy individuals. Bars show the mean ± SEM. *p < 0.05; †p ≥ 0.05 and <0.1.
Figure 5.
Figure 5.
Corticomotor excitability and correlations with cognition during hypoxia. a, Stimulus–response curves for CrM and PLA treatments during normoxic (circles) and hypoxic (triangles) conditions. Data are mean ± SD; n = 13. b, Compared to normoxia, corticomotor excitability increased during hypoxia with CrM (black fill), but not PLA (white fill). Bars show the mean ± SEM; n = 13. *p < 0.05; ** p < 0.01. c, Correlations between the change in corticomotor excitability and the change in cognitive performance from baseline. Decreases in cognitive performance were prevalent in most variables with PLA. Bold type highlights statistically significant correlations.

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