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.