Download An Investigation into the Effect of Exercise on Cognitive

An Investigation into the Effect of Exercise on Cognitive Functions.
Jessica Coenen
Jonathan Sinclair-Williams
Pass with Merit
Research Paper based on lectures at the
Medlink Conference
at Nottingham University
in December 2012
March 2013
ABSTRACT
In this paper we explore the effect exercise has on the production of a newly found member
of the neurotrophin family, a protein known as BDNF, which is thought to be activated
indirectly by exercise. BDNF is one of several neurotrophic factors that results in neuronal
transmission and plays an important part in regulating growth and preservation of neurones.
Studies using animals have shown additional exercise leads to BDNF production in the
brain and therefore increases the animal’s cognitive functions. The purpose of this
theoretical experiment is to establish a firm relationship between exercise and the BDNF
responses in healthy humans. Firstly we will select 200 healthy adults, and then explore
how different types of exercise effect the production of BDNF and whether this has any long
lasting or substantial effects to individuals’ cognitive functions.
INTRODUCTION
There are many different academic and medical views as to the effects of physical
exercise on the human body (1). Historically there has been a theory that these
effects materialised through the release of endorphins and other neurotransmitters.
(1) However more recent research has extended this theory to include a new
chemical called Brain Derived Neurotrophic Factor (BDNF) and its effect on
cognitive functions (2). This paper explores this development through a desktop
literature review and draws conclusions as to the validity of this new line of
evidence. The aim is to evaluate the effect of exercise on levels of BDNF, and
assess to what extent this has an impact on cognitive functions.
Before looking into how exercise can stimulate the production of Brain-Derived
Neurotrophic Factor (BDNF) and how this can affect the brain, it is first necessary
to consider the other effects of exercise on the brain. Previous investigations have
demonstrated a wide variety of positive benefits as a result of regular exercise:
being physical, neurological and psychological.
Starting with the basics, it is known that during exercise muscles have a high
demand for glucose and oxygen, the heart rate increases to meet this demand, and
the lungs work harder to oxygenate the blood. As a result, over time, the heart
muscle grows in size and the lungs become more efficient, leading to increased
muscular endurance and strength. This can lead to other benefits such as reduced
cholesterol, subsequently reducing the likelihood of an atheroma forming in the
arteries. This illustrates how exercise has many effects leading to an increased life
expectancy and reduced risk of myocardial infarction (heart attack), before even
considering the positive effects of the hormones involved (3).
The hormone somatrophin, commonly known as the growth hormone, is secreted
from the pituitary gland and production increases during exercise (4). This
stimulates protein synthesis and enables muscle growth and increased bone
strength. Another benefit is that it causes the body to use its own fat as fuel as
opposed to glucose. This reduces body fat and helps an individual to maintain a
good physique. In addition to the physical benefits there is an associated
psychological advantage, as the individual is likely to feel better about themselves.
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Another hormone that has physical, alongside neurological effects is endorphin,
which is an endogenous opioid secreted from the pituitary gland during exercise
(5). Firstly this can reduce the feeling of pain by blocking neurotransmitters and
interfering with the transmission of pain impulses to the brain. Secondly endorphins
can give the feeling of euphoria (an exercise ‘high’), which is a positive neurological
effect.
There is also a highly relevant neurotransmitter that can have a similar affect called
serotonin. Serotonin is synthesized in neurons in the brain and is strongly linked to
an individual’s mood as it can promote neuronal plasticity. High levels give an
elevated mood, however low levels can also lead to depression. Regular exercise
releases tryptophan; an amino acid used in synthesis of serotonin. This helps
suggest why aerobic exercise increases levels of serotonin, and hence also affects
mood (6).
Recent studies have provided evidence that exercise also has many effects on
cognitive functions such as memory, the ability to learn, and problem solving due to
chemical reactions. The most important is thought to be BDNF, a member of the
neurotrophin family, and its contribution to neurogenesis, the process by which new
neurons are generated.
BDNF activates a high-affinity cell surface receptor (trkB) that is coupled to
activation of phosphatidylinositol-3-kinase and protein kinase B (Akt). By promoting
neurogenesis, synaptic plasticity and cell survival, BDNF plays a pivotal role in the
development and plasticity of the brain. During development of the cerebral cortex
and the hippocampus, BDNF has been shown to induce the differentiation of neural
stem cells into neurons and promote the survival of newly generated neurons with
many branching dendrite connections at their ends. Increasing the number of
dendrites in the brain means increasing the possibility of new neural pathways,
improving both memory and perception. (7)
DISCUSSION
Multiple mechanisms for the relationship between increased neurogenesis and
improved cognition have been suggested, including computational theories to
demonstrate that new neurons increase memory capacity, reduce interference
between memories, or add information about time to memories. The functional
relevance of adult neurogenesis is uncertain, but there is evidence that
hippocampal adult neurogenesis is important for learning and memory (8).
Exercise-induced hippocampal neurogenesis is already well established in rodents
(9), as are scientific experiments to observe a correlation between exercise and
BDNF levels and their affect on cognitive functions. However there have been
limited tests on humans.
In one example scientists monitored how different amounts of running could alter
protein BDNF levels in mice (10). The mice ran for two, four or seven nights. In
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order to measure levels of the protein, a molecule that binds to BDNF was injected.
There was a direct relationship between BDNF levels and the amount of running,
the greater time spent running, the higher the BDNF levels.
In another experiment (11) containing active and sedentary mice, BDNF levels
were measured once again. The increased levels of BDNF in the active mice
illustrated an increase in cognitive functions but only up to a certain point. During
the experiment it was identified that once a certain point of exertion was reached
(commonly described as over exercising) there appeared a reduction in cognitive
benefit. At this point, the linear relationship between BDNF and increased cognitive
functionality also appeared to diminish. A possible explanation causing these
results could have been due to the reduced use of cognitive functions in the over
exercising mice. Their results demonstrate that more sciatic axons had been
regenerated post-injury in the active mice. However, once injected with a
neurotrophin-blocking agent, the results could no longer be noticed. This suggests
that exercise helps to regenerate neurons.
In terms of human testing, short intense bursts of exercise had a noticeable effect
on memory in one experiment (12). A sample of 50-85 years olds containing a
mixture of healthy volunteers and those with memory difficulties, were shown
pictures. One group then had six minutes of intense exercise. An hour later, they
were all asked to recall the pictures. The result being the group that had exercised
saw a noticeable improvement in both healthy volunteers and those with memory
problems. Unfortunately levels of BDNF were not measured in this experiment. By
repeating this experiment in a similar way, but measuring BDNF levels would
enable predictions of how different forms of exercise can strengthen the neuron
connections, influence BDNF production and improve cognitive functions.
In order to carry out any experiment, one of the most important factors to plan is
the sample of volunteers to take part in the trial. In an experiment that is measuring
the effects of exercise it is necessary to use a sample of healthy individuals who
are untrained, i.e. rarely undertake extra curricular exercise beyond normal day to
day activity. This would therefore exclude those who regularly go to the gym and
those who have jobs that demand a significant amount of manual labour, for
example construction workers. This helps to eliminate those who would previously
have increased their levels of BDNF through exercise and possibly already leading
to an increase in their cognitive functions. This sample would allow results to be
noticed more clearly, as a greater increase in exercise would be observed. If the
results of the rodent experiment are directly transferred to humans this would
therefore lead to a higher production in BDNF and hence demonstrate a greater
increase in cognitive functions.
In the sample, it is important that the only significant change to their daily routine is
their new exercise regime. The rest of their daily life should be unchanged for
example not altering their diet or sleeping pattern or encountering any major life
changing events such as moving home or changing job. This would provide
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support that the results are due to an increase in exercise alone and should
eliminate potential results due to other factors such as their diet, stress levels or
environment impacts.
A healthy sample should be used, thereby excluding anyone on prescribed
medication (the contraceptive pill being an exception to this. It has been shown for
example (13) that some medications, such as antidepressant treatments, can have
an effect on BDNF production therefore making it important that this type of
variable does not impact on the sample.
To reduce the possibility of psychological effects, leading to false results the
sample should not be told of the expected benefits or predicted outcomes of the
experiment.
Recent studies (14) have illustrated that at the age of thirty onwards, human nerve
cells in the brain begin to deteriorate, therefore it is possible that little or no
improvement would be observed if the sample was below thirty years of age as
regeneration occurs naturally. This is considered a key trigger point and therefore
the appropriate age range for this trial would be thirty to forty years old to allow
clear results to be observed and to allow for adult neurogenesis to take place. It is
also important to compare the male and female results to see if gender plays a role
in exercise stimulated BDNF production, meaning an equal proportion of male and
female volunteers should be selected.
How the sample is chosen is a key factor in the trial to prevent possible bias. If the
sample is taken from the same work area or, for example, all the volunteers were
found outside of a gym then results might not give a fair representation. To find the
appropriate sample, a short survey could be created to find volunteers that meet
the specified criteria and people targeted in a central point, such as a busy
shopping centre, therefore on a pseudo random basis.
In the past most of the research conducted exercise with BDNF production in the
brain, has been focused on cardiovascular aerobic exercise, but this experiment
should investigate how both aerobic (15) and anaerobic exercise (16) could provide
benefits.
Four parallel experiments would be set up where 200 adults between the ages of
thirty and forty would take part in a six month study to compare the effect of aerobic
training, anaerobic training or a combination of both, with those who did no
additional exercise regime (the control group). The people in all the groups should
meet the trial selection criteria and then be assigned to one of the groups
randomly. The control group will not be given an additional exercise regime;
however their levels of BDNF will still be measured as part of the trial. The control
group will not be asked to refrain from doing their normal exercise routine. This will
allow researchers to witness how levels of BDNF fluctuate in normal
circumstances, as well as being used to compare to other groups within the trial.
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However due to the fact that they are not doing much, if any exercise, it would not
be expected that their exercise intensity would be high enough for the levels of
BDNF to increase noticeably.
The aerobic group would be asked to do one-hour surplus cardiovascular exercise
a day. This could be either running for one hour, (either on a treadmill or outside) or
cycling for the same amount of time. This should be done at a comfortable intensity
for the individual, at around 60 percent of their maximum heart rate. This takes into
consideration an individual’s own limits and still means that everyone will be at a
similar increased heart rate.
A time period of one hour a day was chosen for the participants within the aerobic
group. The reason being that mice bred to over exercise interestingly showed an
inability to learn, a possible cause for this is the disruption of cognitive function by
the brain or the body becoming preoccupied with exercise. In the experiment the
sample groups should not be over-exerted, ensuring that they still utilize their
cognitive functions. Identifying this tipping point where improvements stop would be
an important outcome of the trial.
The anaerobic group would be given a shorter exercise regime as shorter bursts of
exercise have been shown to have more positive effects on the body. After a time
of above two minutes of an intense burst of anaerobic exercise, the positive effects
on the body do not change or increase. The group would be asked to either sprint
between 100 to 400 metres, depending on their own personal fitness, or do
weightlifting exercises when they could perform high-intensity, fast bursts of
weightlifting with heavy weights, again depending on the own persons limitations.
This will be repeated three times a day, every day to allow an improvement to be
observed.
One group would be asked to do a combination both anaerobic and aerobic
exercise, ensuring that ultimately the group does not over-exert itself to show the
effect of both types of exercise. This group would be given set circuit training
exercises, such as cycling followed by lifting weights or muscle work exercises like
sit-ups or jack knifes. Similar to the aerobic group this sample would be advised to
maintain a comfortable intensity of approximately 60% of their rest heart rate.
In order to link the increased BDNF levels with cognitive functions, the sample
groups would take a variety of intelligence tests. These would be done on an every
other day basis, to allow improvement to be observed over each week. For every
group tests should be undertaken for three weeks prior to the exercise regime
being introduced, providing a baseline for comparison. Throughout the trial levels
of BDNF would be tested taking blood samples at the same time as the intelligence
tests are taken through, once before an exercise regime is started and every 15
minutes whilst the tests are being done.
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It is important to ensure that the intelligence test is not made too difficult, nor too
easy, so a standardised test of an intermediate difficulty should be made. It is hard
to justify “intermediate” as that can vary from person to person. However, it is
essential that the data shows a range of results, to allow results to be compared
from one group to another. Therefore the tests should include a range of
difficulties.
The test must be created so that it is not based on prior knowledge, such as
scientific knowledge. The test should instead assess the sample’s ability at a
variety of problem solving questions. The problem solving could contain a “Sudoku”
which will be a timed round. Although this can be found in almost any newspaper it
has been shown to be one indicator of intelligence alongside brainteasers that will
also be included in this section. Simple maths questions should be incorporated in
order to assess the mental arithmetic and if this is altered by levels of BDNF. Once
again this could be timed and a percentage would be given for number of correct
answers.
Past studies (12) have revealed that exercise has an impact on an individual’s
memory, so the test should contain a memory round to correspond with these
findings. The sample will be asked after an hour to recall as many pictures as
possible, and then results can be plotted against BDNF levels to observe if a
relationship is present.
The final section could be verbal reasoning, where each individual is given several
passages of text and questions relating to that passage. There have been few
previous experiments that have shown how exercise can alter verbal reasoning so
this may not necessarily see any improvement.
An improvement may be shown from week to week as each individual attempts
similar questions and are more used to the style of question for any of the sections.
The control group should show a similar trend if that is the case, which will then
demonstrate if the improvement is due to practice or BDNF levels.
In the test each section must be done and assessed separately, as opposed to
having an overall score. Once results are plotted on a graph it would become clear
if a relationship is present between BDNF levels and each one of the cognitive
functions assessed by the different tests.
These different tests would allow for results to show whether the BDNF protein is
specific to what type of ‘intelligence’ or cognitive function it improves. It would be
clear whether it is different to every person, whether it helps them improve in
subjects or areas that they already excel in, or whether it allows improvements of
the weaker areas of their brain.
Simply establishing certainty that exercise improves intelligence would motivate
and drive some groups of the population to introduce the required exercise regime
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into their lives. They will achieve the benefits without any direct medical
intervention and the government could promote the findings in a positive way to
target other sectors of the population that otherwise would not normally consider
taking the time or making the effort to exercise to the required amount.
However not everyone would be so motivated or indeed be able to do sufficient
physical exercise for example disabled people, even knowing and understanding
the payback they would receive. The challenge therefore would be to capture the
benefits that increased BDNF gives in a way of ‘indirect exercise' that could reach
the whole of society irrespective of motivation or capability.
The creation of a drug or other medication containing a synthesised BDNF that
provides just the right amount of additional BDNF required to have the desired
effect would enable all parts of the population to benefit. Whilst the creation of such
a drug would be complex, work has already begun to find a drug to normalise
excessive levels of protein synthesis in the brain. (17) This could be used to partly
control autistic-like behaviours, and this could be built upon.
Building on studies (18) where mice were genetically engineered to create nerve
cell proteins that respond to light, laser treatments could be developed to stimulate
the production of hormones such as phosphatidylinositol-3-kinase and protein
kinase B (Akt) which are coupled to the activation of BDNF thereby stimulating the
brain in a 'indirect exercise' way that it produces required proteins without the
patient even moving.
CONCLUSION
It has already been shown that aerobic exercise can reinforce these neural
connections by increasing the number of dendrite connections between neurons.
This means it is expected that the group taking part in this type of exercise would
show the greatest improvement in the intelligence tests and have the highest levels
of BDNF produced whereas it is expected that the exercise intensity of the control
group would not be high enough for the levels of BDNF to increase noticeably.
It could be possible that if BDNF does increase the cognitive functions that there is
a certain amount of time that the supposed greater intelligence might last for. It
could be the case that the amount of exercise and therefore the amount of BDNF
produced is directly proportional to the length of time that the improved cognitive
function is maintained, [Figure 1] and the 15 minute testing will help to identify this.
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Figure One:
Another trend that could appear from the results would be that there is a limit to
individual cognitive functions, so after a certain amount of time and a certain
amount of exercise, each individual reaches a plateau where they cannot improve
any more, regardless of the amount of exercise they do. [Figure 2]
Figure 2:
These ideas of a plateau and a limitation to the cognitive function of individual’s
links back to the rodent experiments where the mice that were bred to overexercise actually showed an inability to function as well. This could lead to the
trends shown in Figure 3, or possibly Figure 4, where there is a noticeable peak in
the cognitive functions and a specific amount of exercise would produce the best
results.
Figure 3:
Figure 4:
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It would therefore be important to measure the long-term effects that BDNF has on
cognitive functions. This would lead to further experiments into finding the optimum
levels of exercise for the peak levels of BDNF and whether excessive exercise
does in fact cause a downfall in intelligence.
Development of 'indirect exercise' methods to deliver BDNF through an artificial
protein or one produced through laser stimulus as described above could lead to
'exercise on prescription' where mental illnesses or psychological disorders could
be in part treated with either physical or 'indirect' exercise or a combination of both.
It has already been established that exercise improves behavioural problems; such
as ADHD (19) and in mental illnesses such as Alzheimer’s BDNF improves
cognition (20) so the potential application is extensive. However a potential
downside to the development of the perhaps easier methods of indirect exercise
could be less people doing physical exercise and so a downside could be all the
known issues associated with lack of exercise.
The supplementary benefits to people undertaking more physical exercise, beyond
cognitive improvements, such as obesity reduction would be most welcome, as
would the fall in ailments and illnesses associated with this. However for those
people so motivated, these benefits have been achieved for decades previously.
The moral conundrum is where the application of the new science goes further and
the proven improved intelligence is desired in different ways, such as providing
unborn or newborn babies with the developed drug to produce 'super human
intelligence'.
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