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Creatine Supplementation Enhances Word Association Learning In Young Healthy Adults, But Not Motor Learning Or Forward Digit Span.

Original research project write up.

Date : 13/12/2016

Author Information

Zuzanna

Uploaded by : Zuzanna
Uploaded on : 13/12/2016
Subject : Neuroscience


Abstract


Creatine supplementation has been found to improve cognitive functioning (McMorris et al., 2007 Rae et al., 2003 Hammett, Wall, Edwards & Smith, 2010). Most of previous studies have used subject who are disadvantaged in cognitive functioning or have very low basal creatine levels. The aim of this study has been to investigate to what extent creatine can elevate cognitive functioning in a healthy adults. Involvement of BMI and resting metabolic rate in modulating the effects of creatine have also been investigated. Twenty five subjects were supplemented with 20g of creatine monohydrate or maltodextrin for four days. The performance on words association learning task showed improvement in creatine group. However there were no effects found on motor learning and digit span. These results suggest that simple cognitive functions can be elevated in healthy young adult sample. However creatine may not be effective for more complex cognitive computations.

1.Introduction


Creatine is a dietary supplement widely used during athletic training. It helps athletes to train harder during short intense sessions. During performance, energy demand of the cells is heightened at the site of activity. The athletic advantage of creatine supplementation has been linked to its ability to increase levels of available energy in muscle during training (Graham & Hatton, 1999). In the brain, creatine works on similar principles. The hydrolysis of adenosine triphosphate (ATP), is a major source of energy in an active brain. Phosphocreatine (PCr), synthesized from creatine, donates it s phosphate to adenosine diphosphate (ADP) during activity and resynthesized it into ATP. This process prevents a rapid decrease of ATP in a cell (Rae, Digney, McEwan & Bates, 2003). ATP can be synthesized from phosphocreatine 12 times faster than oxidative phosphorylation of ADP and 70 times faster than synthesis from simple molecules like sugars and amino acids (Wallimann, Wyss, Brdiczka, Nicolay & Eppenberger, 1992). Due to its temporal advantage in ATP synthesis, creatine (Cr) is an important agent in providing energy to cells when their energetic demand changes rapidly.


The fMRI studies confirm that creatine is involved in providing energy in the brain. The BOLD signal is reduced by 16% in V1 during the presentation of visual stimuli in subjects who are supplemented with creatine when compared to placebo control group. Increase in readily available ATP at the site of activation through creatine supplementation, decreases the need for oxygen uptake. The fMRI measure of area activity is dependent on the oxygenation levels in the blood. When the increased metabolic demand at the site of activation is met through increased ATP availability there is less demand for oxygen delivery to the site. Reduced oxygenation levels lead to an observable decrease in the BOLD signal. These results were also coupled with a 26% increase in the backwards digit span in the creatine group. These results show that creatine supplementation does increase an energetic pool potential in an active brain area. Furthermore, this energy increase is couples with an increase in cognitive performance (Hammet, Wall, Edwards & Smith, 2010)


The link between creatine and cognitive performance can be observed in creatine deficiency syndromes. Individuals with inborn errors to in vivo creatine synthesis show some severe cognitive impairments. There are three types metabolic errors by which creatine in the brain can be depleted. AGAT and GAMT deficiencies which cause errors in creatine synthesis and mutations to the SLC6A8 gene cause inefficiency of the creatine transporter (CT1) (Stockler-Ipsiroglu et al., 2014). All three types of creatine deficiency show commonality in intellectual and cognitive impairments. Developmental delays are the hallmark of the disorders followed by seizures and speech impairments. In a review by Comeaux et al. (2013) all up to date reported cases were analyzed for clinical similarities. Developmental delays were displayed in 87% to 58% of patients in three types of the dysfunction. This was followed by seizures displayed in 26% to 67% of patients. Third most commonly shared clinical hallmark found in 21% to 33% of the patients were speech impairments. This implicates that creatine must be an active agent which supports these cognitive functions to some extent.


Going beyond creatine dysfunction, natural variations in creatine in healthy population has been shown to be correlated with variations in cognitive performance. Laakso et al (2003) has reported that lower levels of creatine were associated with poorer performance on the Mini Mental State Examination. This is a measure used for detection and monitoring of progression of dementia. This illustrates that in non-clinical population creatine also influences cognitive performance. However in this study the positive correlation between creatine and cognitive ability was only found in the ApoE e4 allele carriers, which is a factor associated with a higher risk of developing Alzheimer s disease (Evans et al., 1997). This may be related to a metabolic changes associated in the e4 allele carriers in relation to general population. Up to date there is a limited and mixed evidence which investigates the role of creatine as an important agent in cognitive functioning in non-clinical population.


Some creatine supplementation studies have shown that Cr can have advantageous effects on cognitive performance. Rae, Digney, McEwan and Bates (2003) found enhancement in intelligence and working memory in 45 adults following 6 week 5g creatine supplementation. Subjects supplemented with creatine have shown a significant increase in general cognitive ability measured by Raven s Advanced Matrices. This is a non-verbal measure of general cognitive ability (Carpenter, Just & Shell, 1990). Subjects receiving creatine have also shown a greater increase in backward digit span than the placebo group. Furthermore, in a study conducted by McMorris, Mielcarz, Harris, Swain and Howard (2007) creatine supplementation for 1 week increased verbal and spatial long term memory, as measured by forward recall. There was also an improved long term memory (LTM) performance. In the task assessing LTM subjects were presented with 10 photos of individuals with occupation written underneath, 1 hour later there was a recognition test. However in the same study there was no significant difference between the groups on backward recall and random number generation. There is further evidence against creatine potential cognitive enhancing properties. Rawson et al. (2008) involved subjects in a long term (6 weeks) creatine or placebo supplementation. There was no difference found between the groups in reaction times, logistical reasoning, memory search and immediate and delayed code substitution. The evidence supporting creatine having a potential to increase cognitive performance is not conclusive.


The discrepancies in evidence of creatine as a potential cognitive enhancer can to some extent be attributed to the difference in the study designs. The studies vary in what cognitive tests are used and in the characteristics of the subjects. In Rawson et al. (2008) the null results could possibly be due to a low daily creatine dose, 0.03g for every kilogram of body weight. Based on the body weight range, the daily dose ranged from 1.8g to 2.62g. On the other hand, the positive results found in a Rae et al., (2003) may be restricted to the vegetarian population used in this study. Although the advantage on cognitive tests in the creatine group in vegetarian individuals is a supporting evidence for involvement of Cr in cognitive processing, it does not inform if such advantage can be observed in a general population. Vegetarian individuals have been confirmed to have lower plasma creatine levels which has been linked to their dietary restrictions ( Delanghe, Slypere, Buyzere, Robbercht, Wieme & Vermeulen, 1989). Pan and Takahashi (2007) have demonstrated that lower Phosphocreatine/ATP ratios shows the biggest increase in creatine levels following a 7 day supplementation. Therefore in vegetarians the creatine increase might be much bigger due to lower basal levels. In a population without dietary restrictions the energy potential gains may not be as high due to the higher basal creatine levels.


McMorris et al., (2007) found mixed results for different cognitive tests in their study have also used a specific population of elderly subjects (mean age = 76.4). It is well established finding that increasing age shows a linear relationship with declining cognitive abilities (Park, O Connell & Thomson, 2003).Therefore elderly individuals are already disadvantages in their cognitive performance. So far there is no information in the literature about how creatine supplementation affects cognitive processing efficiency in healthy young individuals with no pre-existing disadvantages in basal creatine levels of cognitive performance. The only study investigating such sample has most likely used creatine dosage too low to significantly increase cerebral creatine levels. Dechent et al (1999) reported that 20g daily 7 day supplementation does significantly increase creatine levels in the brain. It is unknown if the very low dosage used in Rawson et al,(2007) study has created any cerebral creatine increase. However it must be noted that the maximum dose was 2.62 grams per week, which is considerably smaller in comparison to 20g per day. Sufficient dose is an important part of the creatine supplementation investigation. Although most of the creatine is turned into creatinine and secreted in urine, overloading with larger doses may be necessary for sufficient amount to pass through the brain blood barrier (Delaghe et al. 1989).


This study will also explore any potential relationships between body composition, cognitive performance and creatine. It is of interest if particularly BMI, resting metabolic rate and muscle percentage are a modulating factor in the amount of cognitive performance advantage supplied by creatine. Overweight and obese adults (BMI above 25) show a significantly lower cognitive performance than subjects with a normal range BMI (18.5 24.9). Body mass index is has been associated with cerebral metabolism. Volkow et al., (2009) found a significant negative correlation between BMI and baseline cerebral metabolism. Higher BMI was associated with lower metabolism. However this relationship was restricted to prefrontal regions and cingulate gyrus. In the same study BMI was also directly correlated with the performance on three out of four WAIS subtests. Because low BMI is associated with cerebral metabolism it may possibly interact with creatine produce variations in cognitive performance gains in individuals with different BMI s.


The aim of this study is to investigate if creatine supplementation in healthy young adults can enhance cognitive performance. Because up to date evidence is not conclusive this study is aimed to provide further evidence which could clarify how creatine affects healthy young adults. This is also a first study which investigates BMI as a possible modulating factor in the effects of creatine. The cognitive functions of interest are learning in verbal and motor domains. These aspects of cognition have not yet been assessed under creatine supplementation. Forward digit span will also be used to be able to draw direct comparisons to previous findings.


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