thesis paper

MTBIS: FEMALES HAVE GREATER RISK
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Mild Traumatic Brain Injuries:
Female Athletes are at Greater Risk for Long- Term Impacts
Madison Sestak

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Introduction
Each year millions of people involve themselves in one or more of the 8,000
varieties of indigenous sports or sporting games (CDC). Some of the more common
sports including, American football, hockey, boxing, and soccer are high impact
sports, thus increasing the risk of injury (Marar, Mellvian, Fields & Comstock, 2012).
Concussions or traumatic brain injuries (TBI) are common amongst these particular
contact sports. A TBI can be described as an impairment to the normal functionality
of the brain following a bump, blow or jolt to the head. The symptoms following a
TBI include memory loss, muscle weakness, decrease in muscle functionality, and
vision and speech losses. Moreover, TBIs can be categorized into severe, moderate,
and mild TBIs (CDC). Mild TBIs (mTBIs) are the most common TBIs in sports and
are widely studied (CDC).
While a single mTBI can be dangerous, multiple mTBIs within a certain brain
vulnerability window can have lasting long-term effects, eventually advancing into
neurodegenerative diseases later in life (Mckee et al., 2009). Chronic traumatic
encephalopathy (CTE) is a neurodegenerative disease caused by repetitive mTBIs. It
is most commonly seen in boxing, however has been recently documented in
American football, soccer, hockey, lacrosse and other contact sports where frequent
mTBIs are prevalent (Mckee et al., 2009 and Mckee et al., 2012). Within the last few
years, CTE has began to be acknowledged due to the uproar around its late onset of
detrimental symptoms including, changes in mood and behavior, memory loss,
confusion, disorientation, and impulse control. Distinct brain changes also occur in
this disease, such as abnormal tangles of proteins, neuronal loss, degeneration of
brain tissue, and increased microglial responses. These changes can begin months,
years or even decades after the traumatic incidents (Mckee et al., 2009 and Baugh,
Robbins, Stern, & Mckee, 2014). Despite attempts to provide ample protection for
athletes, high contact sports, such as American football, soccer, and boxing, lack
headgear with the ability to protect the brain. The increased incidences of CTE
among these athletes question the effectiveness of the headgear provided (Bartsch,
Benzel, Miele, & Prakash, 2012).
Sports, such as American football, boxing, and soccer, have established rules

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and regulations on head protection and how the game is played to reduce mTBIs;
however, mTBIs still occur on a regular basis (www.usaboxing.org, www.nfl.com).
Furthermore, in contrast to American football and amateur boxing, soccer headgear
is not required, and while protective headbands have been invented they are rarely
used (Myrick, 2015).
While many of these popular sports are primarily male dominated, female
participants have drastically increased through the years (www.ncaa.org). For
instance, in college NCAA sports, female participation has increased from
approximately 158,000 students in 2002-2003 to 191,000 in 2010-2011 and
continued to increase into the 2013-2014 school year. Additionally, compared to the
1980s, the average female student-athlete population at a NCAA school has
increased by approximately 88 females, where as males have only increased by
about 18 student-athletes. Although, this only accounts for college NCAA athletes,
there is an increase in female participation across all age levels and divisions
(www.ncaa.org). With this growth there has also been an increase of mTBIs in
females (CDC, www.ncaa.org). Despite the increased participation, female athletics
often require less padding and head protection than male sports.
Male and female brains significantly differ, thus having the potential to react
differently in response to head trauma. Observational data have shown that females
often show poorer outcomes in comparison to males later on after repetitive mTBIs.
Despite this, there remains a lack of research on the long-term effects of repetitive
mTBIs in females (Bazarian, Blyth, Mookerjee, He, & McDermott, 2010). Due to the
gender differences in the brain, females are more susceptible to long-term damage
following an mTBI. With this predisposition, head protection for women in high
impact sports should be improved.
Sports and mTBIs
Boxing has always been associated with head trauma. Dating back to the
1920’s, the pathologist Dr. Harrison Stanford Martland first shed light on the lasting
neurological effects of boxing, which he coined “punch drunk” (Martland, 1928).
During the 1920’s, there were few rules for boxing and frequent deaths in the ring

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or a few days later. Martland associated these deaths with head trauma and bleeding
of the brain (Martland, 1928). Later in life, after the boxer had finished his career, he
would develop a particular gait or a tilt of the head, Parkinsonism symptoms,
tremors, vertigo, and/or deafness (Corsellis, 1989). Mental deterioration was also
seen in these retired boxers, eventually landing them into asylums (Corsellis, 1989).
Today, mTBIs are still closely associated with boxing, however rules and regulation
now require headgear for all amateur boxers. The headgear claims to help protect
against linear and rotational forces on the head as well as reducing the impact,
therefore reducing the probability of an mTBI. Despite this, according to the
American Association of Neurological Surgeons, 90 percent of boxers still suffer
some kind of brain injury while boxing (www.aans.org). Due to the time period that
boxing first started, it is primarily male dominant; therefore the majority of the data
that is collected on head injury is based on males. Although there has been a large
increase in the amount of female boxers, there is little data describing effects in
females after mTBI in boxing (www.usaboxing.org).
Like boxing, American football is another male-dominated sport that has
been around since the late 19th century. This high impact sport has also recently
been closely associated with mTBIs and the long-term impacts of repetitive mTBIs.
Known for its violent clashing, American football is the leading cause of sports-
related mTBIs in the U.S. Additionally, about 53% of football related concussions go
unreported at the high school level (Dompier et al., 2015 and Bartsch et al., 2012).
While it is one of the most watched and loved sports in America, it is also one of the
most dangerous when it comes to head injuries. A typical football player will get hit
in the head over 1,000 times per season (http://www.bloomberg.com). Within the
last decade, similar symptoms to those seen in retired boxers began to appear in
retired football players, including noticeable changes in gait, speech, memory, and
mood. Dr. Bennet Omalu was the first to discover physical evidence of repetitive
mTBIs and chronic traumatic encephalopathy (CTE- a neurodegenerative disease
resulting from repetitive mTBIs) in sports other than boxing. This discovery showed
the expansiveness this disease could have and the need for further research on the
effects of mTBIs (www.protectthebrain.org). Furthermore, while football is still

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extremely male dominated, female participation is growing, specifically in younger
leagues (Bartsch et al., 2012).
Soccer is another sport that has recently gained press for the extent of heads
injuries. Currently, soccer is the most popular sport worldwide with about 265
million players registered to play. It has been reported that for every 1,000 hours of
play, the incidence of mTBI is between 18.8 and 21.5 (Myrick, 2015), making it a
leader amongst other high contact sports for mTBIs. Additionally, soccer has the
highest incidence of mTBIs for females. During a career of 300 games, a soccer
player will sustain approximately 3,000 hits to the head from heading the ball. While
the incidences of head injuries are lower than those of football and boxing, recent
studies have shown long term effects in soccer players resulting in CTE. However,
these results lack female participants (Hales et al., 2014 and Broglio et al., 2003).
Mild Traumatic Brain Injury
The Center for Disease Control and Prevention (CDC) defines a traumatic
brain injury (TBI) as “a disruption in the normal function of the brain that can be
caused by a bump, blow, or jolt to the head or a penetrating head injury.” Symptoms
of a TBI include, a loss of consciousness, retrograde or post-traumatic amnesia,
muscle weakness, decrease in functional movements, vision and speech
impairments, and sensory loss (CDC). Additionally, other symptoms seen
immediately after or at the time of injury are confusion, disorientation, and
decreased ability to think and concentrate. While many will experience bumps,
blows, and jolts to the head, not all will result in a TBI. Furthermore, not all TBIs will
result in identical symptoms or effects. The most common ways in which TBIs occur
are; being struck in the head by an object, penetration of an object into the brain,
and acceleration or deceleration of the body resulting in movement of the brain
causing trauma (CDC).
TBIs can be separated into mild, moderate, and severe, using the Glasgow
Coma Score (GCS). The GCS is a neurological scale, which helps to accurately record
the level of consciousness after a traumatic brain injury (www.trauma.org). It can
be broken up into three sections: (1) eye responses, (2) verbal responses, and (3)

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motor responses. Eye responses are numbered 1-4, the lowest score being one, with
no eye opening and the highest score of four with spontaneous eye opening. Verbal
responses range from 1-5, one being no verbal response; five being the injured is
completely oriented. Motor responses range from 1-6, one showing no motor
responses and six, the injured is able to obey commands. Scores that fall between 13
and 15 can be considered mild traumatic brain injuries (mTBIs), scores ranging
from 9 to 12 constitute as moderate traumatic brain injury, and scores 3 to 9 are
considered severe traumatic brain injury (www.trauma.org and brain injury
alliance).
Although mTBIs and moderate TBIs are not considered to be immediately
life threatening, repetitive or multiple head injuries within a certain window of
brain vulnerability following the original mTBI can result in detrimental long-term
effects in the brain, potentially leading to neurological defects in older age (Dompier
et al., 2015). While mTBIs can occur at any time, anywhere, and with any age group,
sports have become an area of focus because participation in contact sports is
associated with increased risk of mTBIs, specifically multiple mTBIs (Dompier et al.,
2015).
Increases in participation in contact sports such as boxing, football and
soccer, have led to the inevitable increase in head injury. Because sports have
become increasingly competitive through the years, athletes will disregard injuries
in order to continue playing (Dompier et al., 2015). The CDC estimates that sports-
related mTBIs in the U.S. add up to approximately 3.8 million each year (2010).
Sports are one of five of the leading causes of mTBIs seen in emergency
departments (CDC). While these numbers are extremely high, the data does not
account for undiagnosed head injuries that occur regularly in sports. When an
athlete sustains an mTBI and it goes unnoticed, they can be at risk for greater long-
term effects in the future. For instance, a second mTBI within a short period after
the first mTBI may result in second impact syndrome. Second impact syndrome
describes synergistic cognitive and pathological effects after a second mTBI is
sustained within a vulnerability window of the brain following an initial injury (CDC,
Vagnozzi et al., 2010, and Luo et al., 2014). While a single mTBI has been shown to

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significantly impair cognitive function as well as have significant pathological
effects, repetitive mTBIs have been shown to have worse long-term effects. Multiple
head injuries sustained 24 hours apart showed after two months to have impaired
learning and memory abilities. Additionally, repetitive impacts after six months
show prominent pathological alterations including astrogliosis: an abnormal
amount of astrocytes due to neuron destruction and a prominent increase in tau-
protein deposition (Luo et al., 2014). It has also been indicated that there is a
temporary window of brain vulnerability after an initial mTBI. This window spans
from three days after original mTBI up to thirty days post-mTBI. Three days post-
injury displays a significant impairment in cellular energetic metabolism, resulting
in neurons failing to function at optimal levels; recovery of these neurons is slow up
to fifteen days after initial injury. After 15 days, recovery increases more rapidly; by
day 30 the athlete should be at complete recovery. Despite this, every athlete is
different, and therefore could take longer to recover (Vagnozzi et al., 2010). Athletes
returning to play before 30 days after an mTBI could be detrimental if they were to
sustain another injury during that period; leading to localized loss of neuronal
function, resulting in long term abnormal cognitive functions. These repetitive
impacts within the brain vulnerability window contribute to an increase risk of
developing CTE later in life (Mckee et al., 2009 and Mckee et al., 2012).
Pathophysiology of mTBI
After an initial mTBI, the brain goes though a number of physiological
changes. Immediately following the injury, there is a hyperacute (intense) influx of
the excitatory neurotransmitter, glutamate (Xiong, Mahmmod, and Choop, 2013).
Glutamate will in turn bind to the N-methyl-D-aspartate receptor, opening ion
channels, thus resulting in an influx of calcium and sodium and an efflux of
potassium. This influx of calcium can have many detrimental effects on the brain
including; influx to the membrane, causing loss of blood flow in the brain; influx into
the mitochondria leading to the formation of free radicals, energy deficits, and
apoptosis; and inflow into the axon resulting in the phosphorylation and collapse of
neurofilament side arms, causing a loss of structural integrity of the axon. All of
these events in the brain are possible causes for the symptoms seen immediately

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following an mTBI. Additionally, following an mTBI, there is an up-regulation of
transcription factors, inflammatory mediators such as microglia, and
neuroprotectant genes, and a down regulation of neurotransmitter receptors.
Despite the neuroprotectants and inflammatory mediators, there is amplified
expression of harmful cytokines, which can induce swelling, damage to the blood
brain barrier, and even cell death. These complex pathways resulting in cell death
and damage after an mTBI can lead to functional deficits immediately following the
mTBI as well as in the future (Xiong, Mahmmod, and Choop, 2013).
While a single mTBI may have detrimental effects on the brain, a second
impact has been shown to lead to further biochemical alterations. If the second
impact occurred within 30 days of the first injury, the brain may experience
amplified levels of free radicals, apoptosis, mitochondrial dysfunction, inflammation,
disturbance of calcium homeostasis and more extensive diffuse axonal injury (Luo
et al., 2014 and Vagnozzi et al., 2010). The cascade of events following a second
mTBI is identical to the first but results in additional neuronal, endothelial and glial
cell death and white matter degeneration. Eventually the increased apoptosis will
result in gradual atrophy in both the gray and white matter. To protect the brain
following repetitive mTBI, ATP is released from the damaged tissue and the
surrounding astrocytes initiate a rapid microglial response toward the injury site.
These microglia cells aid in protection and regeneration of the brain by assisting in
inflammatory responses as well as establishing a small barrier between the
damaged and healthy tissue (Xiong, Mahmmod, and Choop., 2013, Turtzo et al.,
2014, Mckee et al., 2012 and Baugh, Robbins, Stern, & Mckee, 2014) .
Although the involvements of these pathways are confirmed, little is known
about the full mechanism in response to a single mTBI or repetitive mTBIs
immediately or later in the future. Additionally, few studies focus on gender as a
factor, thus it is likely that responses to mTBI differ drastically between males and
females given the various differences between brains. While little is known about
the pathways and any confounding data on gender, there are many studies that
confirm that multiple mTBIs lead to prolonged effects in the future relating to the
atrophy and permanent loss of neurons.

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Chronic Traumatic Encephalopathy
CTE is a neurodegenerative disease following repetitive mild traumatic brain
injury (mTBI). In the early 1900s, CTE was termed “dementia pugilistica” or “punch
drunk” due to its association in boxing, however through the years its prevalence
has expanded into other sports such as American football, hockey, soccer and other
contact sports (Corsellis, 1989).
Symptoms of CTE usually start with decreases in attention span,
concentration, and memory (Millspaugh, 1937). Additionally, some patients will also
experience confusion or disorientation. As the disease progresses, other symptoms
such as poor judgment, lack of insight, and obvious dementia occur. In more severe
cases, patients can experience Parkinsonism symptoms including the slowing of
muscular movements, staggered gait, speech impediments, tremors, vertigo, and
deafness (Millspaugh, 1937). In a more recent study, symptoms that have been
associated with CTE in retired football players include mood disorders (depression,
anxiety, suicidal thoughts or actions), memory loss, paranoia, aggression, irritability,
confusion and hyperreligiosity (Mckee et al., 2009).
In the mid 1900s after Millspaugh (1937) published his work on the rapid
cognitive and functional deterioration of elderly boxers, Corellis, Bruton, and
Freeman-Browne (1973) examined postmortem brains of retired boxers for gross
neuropathological effects. The most common findings included: reduction of brain
weight, ventricle enlargement, reduction of the corpus collosum, neuronal loss, and
scarring of the cerebellar tonsil, which is located under the cerebellar hemisphere
(Corsellis, Bruton & Freeman-Browne 1973, McKee et al., 2009). Other studies have
observed that certain brain regions have a mild yellowish-brown appearance and
evidence of moderate atrophy of the frontal, parietal and temporal lobes, which
correspond to the overall reduction in brain weight. As the disease progresses
increased atrophy in the hippocampus, entorhinal cortex, and amygdala become
present. Collectively, deterioration of all of these regions can account for the
memory loss, behavioral changes, and judgment impairments seen in patients
suffering from CTE (McKee et al., 2009).
While there are not many neuropathological features of CTE, there are

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extensive microscopic effects. Some microscopic effects occurring on the cellular
level include neuronal loss, tau protein deposition, beta-amyloid deposition, gliosis,
changes in white matter and other abnormalities (Mckee et al., 2009, Mckee et al.,
2012). Despite these abnormalities, CTE is primarily characterized by extensive
deposition of tau protein tangles, also called neurofibrillary tangles (NFTs) (Mckee
et al., 2009, Mckee et al., 2012, Baugh, Robbins, Stern, & Mckee, 2014).
Tau Protein in CTE and Brain Injury
Tau protein is a microtubule-associated protein (MAP) found in the brain.
When the brain is injured, tau forms tangles disrupting the normal function of the
brain. Tau protein is a consequence of differential splicing of a single gene located
on chromosome 17, designated to the MAP tau. This MAP protein is a highly soluble
phosphoprotein and predominantly found in neurons, specifically axons. Under
biological conditions, tau controls dynamic behavior, assembly, stability, and spatial
organization of microtubules (Medina & Avila, 2014). Microtubules are important
for the structure and stability of the brain as well as transportation of vesicles. Tau
stabilizes microtubules by interacting with tubulin, thus stimulating the tubulin
assembly into microtubules. Tau is distinguished by its binding domains, which are
positively charged allowing them to bind to the negatively charged microtubules.
Additionally, tau has 79 Threonine and Serine phosphorylation sites, in which 30
have been reported as filled (Billingsley & Kincaid, 1997).
After an mTBI, normal tau will disconnect from tubulin, thus exposing
multiple phosphate binding sites (Medina & Avila 2014). Once phosphate binds to
the open sites the hyperphosphorylated tau (pTau) will be unable to bind to the
tubules. Due to the insolubility and the increased size of the new pTau, it will
relocate to the soma of the neuron. This translocation occurs due to the increased
size of the pTau, which is too large to function appropriately in the axon. The
accumulation of the pTau leads to the development of tau oligomers, consisting of
more than one monomer units of the pTau bound together. The oligomers
eventually build up, developing NFTs. The maturation of the NFT leads to large pTau
aggregates, which ultimately disrupts the normal function of the brain (Medina &
Avila 2014, Billingsley & Kincaid, 1997).

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Hyperphosphorylated tau aggregates in the brain are one of the major
distinguishing factors in the diagnosis of CTE. Mckee et al. (2013) examined 85,
primarily male, post-mortem brains with histories of repetitive traumatic brain
injury. To determine whether the subject had CTE, they needed to fit into one of the
four following categories: (i) distinguishable hyperphospholated tau protein (p-tau)
tangles (ii) irregular distribution of the tangles (iii) p-tau dense in medial temporal
lobes, dispersed throughout cortex, brainstem, and spinal cord (iv) widespread p-
tau pathology, major neuronal loss and gliosis (change in glia cells in response to
CNS damage), stiffening of the hippocampus. These categories also determine the
progress of the disease (Baugh et al., 2014 and Mckee et al., 2013). While the extent
of pTau in the brain determines the stages of severity for CTE, there are other
indications of this disease.
Gliosis in CTE and Brain Injury
While pTau tangles are the primary indicator of CTE, gliosis serves as an
additional defining characteristic. Gliosis is a change in glia cells in response to CNS
damage, for instance, when there has been a focal contusion, the microglial cells will
migrate towards the inflicted area to heal it (Baugh et al., 2014). Glial cells are cells
that assist in the formation of myelin, provide protection and support for neurons,
and preserve homeostasis in the central nervous system (CNS). Subsets of glia cells
are microglial cells. These cells are found in the brain and spinal cord and assist in
immune defense in the CNS. There are two types of microglial cells: M1 and M2. M1
cells aid in inflammatory responses, where as M2 act as anti-inflammatories, and
facilitates in repair and regeneration.
It has been shown that within a week, post mTBI there is a maximum
response of M1 cells to the injured area, and levels remain elevated for about
fourteen days (Turtzo et al., 2014). Conversely, M2 microglia showed a maximum
response at five days, then rapidly decreased. After an mTBI, M1 and M2 microglia
work together fluctuating back and forth, thus immediately after the mTBI there is
an influx of M2 microglia, but are then gradually replaced with M1 microglia. The
severity of an mTBI has also been shown to correlate with the number of M1
microglial cells, concluding that the presence of M1 microglia exacerbates the effects

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of an mTBI (Turtzo et al., 2014, Wang et al., 2013 and Hu et al., 2012). If M1 levels
are increased in the brain, there will be increased inflammation, resulting in;
potential loss of blood flow to various regions of the brain, neuronal loss, and
apoptosis. In CTE, gliosis is typically seen in the cortex, the outer layer of the
cerebrum, and found in conjunction with neuronal loss. Since mTBIs do not
constitute as localized penetration of the brain, the damage from the impact will be
on the outside of the brain in the cortex region. This is due to the brain hitting the
inner wall of the skull. Microglial cells will migrate to the injured regions, resulting
in the atrophy seen in the cortex with CTE (Baugh, Robbins, Stern, & Mckee, 2014).
While the dynamic behavior of microglia cells post mTBI may aid in the process of
reconstruction and healing, it can also lead to additional neuronal death resulting in
worse long term effects.
Head Protection in Sports
Although it is known that mTBIs cause various damaging cascades of events
in the brain, they are currently inevitable in high contact sports. In knowing this,
through the years athletics have become more aware of the risks and now require
various styles of protective headgear. Additionally, rules and regulations have been
set to reduce the risk of blows to head; resulting in mTBIs.
Football is a multi-billion dollar industry and the biggest sport in the United
States, with thousands of kids starting each year (http://biggestglobalsports.com).
With the rise in concern for head injuries the National Football League (NFL) has
instilled rules and regulations, as well as gear requirements in order to reduce the
risk of concussions. The NFL first made helmets mandatory in 1943, three years
after Riddell came out with a plastic helmet, which were stronger, lighter and longer
lasting than the prior leather ones (http://www.riddell.com). With this, the
technology in these helmets continues to evolve and grow in order to best protect
athletes from head injuries. Today there are committees designated to determine
the rules regarding helmets. The National Operating Committee on Standards for
Athletic Equipment (NOCSAE) governs various sports and the use and
protectiveness of helmets worn. Additionally, these NOCSAE helmets are ranked on

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a Summation of Tests for the Analysis of Risk (STAR) scale developed at Virginia
Tech. All NOCSAE helmets were tested based on linear forces (straight on collision)
then ranked from one to five on how well it reduced the risk of brain injury. While
Virginia Tech declares no helmet is “concussion-proof”, they believe the helmets
that fall into the “5” STAR category will greatly reduce the risk of head injury. In
addition to the requirement for a helmet, the NFL recently made new rules and
regulations that protect the athletes from serious head injuries. One rule that was
instilled was prohibiting a player to take shots above the waist, preventing helmet-
first hits. Another rule that was introduced is the play has to immediately stop when
a player loses his helmet. Furthermore, more strict return-to-play guidelines for
athletes who sustained a concussion were put into place (www.nfl.com). While
many of these rules will decreases the opportunity to get a hit to the head, and
helmets help lessen the blow, the risk of mTBI is still extremely high.
Boxing is another major contact sport that has high risk of mTBIs. While
professional boxers are not required to wear headgear, amateur boxers are. In
boxing all headgear must be approved by USA boxing or AIBA (International boxing
Association) for competition use (www.usaboxing.org). The objective for headgear
is that the padding will protect the athlete from significant blows to the head,
therefore reducing the risk of head injury or concussions. Moreover, in the addition
to headgear boxing has instilled rules and regulations regarding hits to the head.
One being; a hit to the back of the head is illegal, if an athlete intentionally hits the
opponent on the back of the head the fight will be stopped and the boxer would have
to forfeit and lose the fight. The same rules apply for hitting another boxer in the
head with their own head. Additionally, boxers are required to have a pre and post
fight medical exams with the medical doctor on site. In this exam they are able to
crudely check for signs and symptoms of a concussion (www.usaboxing.org).
Although precautions such as rule changes and head protection have shown to
decrease the risk of mTBIs, the primary objective of boxing is nevertheless to hit an
opponent’s critical areas (the head and chest), thus causing mTBIs to be inevitable.
Soccer, also a leading contender for mTBIs, in addition to the leading sport
for concussions in females, does not require any type of head protection. While

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many people don’t think soccer is overtly physical, when a player heads the ball,
their head is colliding with a hard blunt object moving at around 70mph (Broglio et
al., 2003). In efforts to reduce this impact, new head protecting headbands were
introduced. These headbands are designed to disperse the impact and direct it away
from the brain (http://www.unequal.com/technology). It has been shown that these
headbands significantly reduce the ball-to-head impact, thus reducing the
probability of an mTBI (Broglio et al., 2003). However, use of these headbands is
only encouraged and is not required, so very few soccer players actually wear them.
With this data and the increased rates of mTBIs, head protection in soccer should be
required for all athletes.
While sports such as football, boxing, and soccer have requirements and
various types of equipment to reduce head injury, there still is a large chance of
receiving an mTBI. It has been shown that while football helmets do reduce impact
to the head, leather helmets from the 20th century were shown to be more effective
or on par with the plastic helmets seen today (Bartsch et al., 2012). Though most
helmets lower the force of linear impacts (straight on), rotational impacts (impacts
to the side of the head) are difficult to reduce, primarily because the entire head will
swivel around the neck increasing the risk of internal brain damage. This is the
same issue with boxing headgear, which has a greater risk of rotational impacts.
Another problem with boxing is professional fighters and fighters in the Olympics
are not required to wear headgear. While this greatly increases the boxer’s vision in
the ring it leaves the head and brain exposed, leading to a greater risk of head injury
(www.usaboxing.org). Additionally, as stated above, the protective headband in
soccer is not required therefore most players do not wear them; increasing the risk
of mTBIs. Even with protective headgear, these high contact sports continue to
remain in the top five leading causes of mTBI (CDC). This evidence supports the
argument for the lack of effectiveness for the various types of head protection.
Although head protection is seen in these various sports, head protection is
more prominent in male athletics. For instance, in lacrosse, males wear helmets
where as females only wear protective goggles. Many people would agree with this
notion since male lacrosse is more aggressive, however females are still able to

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receive hits to the head by colliding with other players, falling, or in some cases
getting hit with the ball. The same goes with female football. While they still wear
helmets, they wear far less padding then the men do (www.ncaa.org). Although male
sports may be more aggressive, females have a greater risk for long-term effects
after sustaining an mTBI. Therefore, where females often have less protection they
should actually have more.
Gender differences in response to an mTBI
There are various studies supporting the notion that protecting against
sports related head injuries should take into account gender differences. Many
factors contribute to long and short-term effects after an mTBI, gender being the
most controversial because multiple studies currently show significant
improvements in female animals after an mTBI in comparison to male animals
(Bazarian et al., 2010). These studies suggest estrogen acts as a neuroprotectant.
However, there have also been multiple observational studies in humans that have
reported females having poorer outcomes recovering from mTBIs than males. One
study conducted by Bazarian et al. (2010) measured post-concussive symptoms in
1425 patients 3 months after the initial emergency room visit. Unlike other studies,
this experiment attempted to control confounding factors that may misperceive the
relationship between outcome and gender. The results of this study indicated that
women have a significantly higher risk of poorer outcomes after mTBI, compared to
males. Despite these results there may be other factors that contribute to the
results, which differ from the animal studies. One result that may differ is that
females may be more likely to report symptoms of mTBIs than males. Furthermore,
Bazarian et al. (2010) hypothesized that the significant difference may be due to
major physiological and hormonal differences such as menstruation. Females who
are menstruating will experience changes in their estrogen and progesterone levels.
Alterations in these hormones may contribute to the poor outcomes seen, if
estrogen is low at the time of injury, the female may experience a worse mTBI based
on a lack of neuroprotectants (hormones) in the brain. In animals these hormones
may not be affected since they are highly controlled experiments (Bazarian, Blyth,

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Mookerjee, He, and McDermott., 2010).
While it has been shown in mouse models of brain injury that males have a
greater long-term effect after mTBIs, these results contradict the effects seen in
observational studies with humans. There are various reasons as to why a mouse
model may not be an adequate model for understanding the effects seen after an
mTBI. One reason being that mouse brains may differ from humans more than we
expected and have slight differences in response to mTBIs (Xiong, Mahmood, &
Chopp., 2013). Additionally, mouse studies avoid confounding variables, such as
hormone fluxes, whereas it is nearly impossible to avoid all confounding variables in
observational studies in humans.
In addition to hormones, microglial cells also play an important role in
neuroprotection and destruction after mTBIs. However, there are major differences
in the levels of microglial cells present in males and females. In mice, aged females
have a significantly greater amount of microglia than age-matched males.
Furthermore, younger males have more microglia than younger females. When
females hit puberty the amount of microglia cells rises significantly, however when
males hit puberty microglia cell count decreases (Mouton et al., 2002). Microglia
also show strong relationships with sex steroids such as estrogen and progesterone,
by expressing receptors for both in a highly dynamic manor. Therefore, estrogen
and progesterone are able to switch microglia from M1 to M2 (Habib & Beyer,
2015). With increased or decreased amounts of hormones, such as during various
stages of the menstrual cycle or when a female is on birth control, the dynamic
fluctuation of microglia cells may be hindered causing a potential rise in the risks
following an mTBI.
Conclusion
Long-term risks including neurodegenerative diseases such as CTE are
potential threats for both male and female athletes. However, currently there is only
data on male subjects. While this may be due to the fact that the subjects are older
and 20 years ago male athletes were far more dominant that females, more
attention needs to be paid to female athletes and their brains. It has been shown

17
that females have poorer cognitive function outcomes following repetitive mTBIs
than males (Bazarian, Blyth, Mookerjee, He, and McDermott., 2010). However,
studies in mice show the opposite. Due to highly controlled experiments mice
studies may not account for the random fluctuations in hormones that humans have,
in addition to whether the female is menstruating or not. These are factors that
could skew results to favor males.
Although females have shown to display neuroprotectant features with
hormones such as progesterone and estrogen, they may be at risk due to their levels
of microglia cells. Microglia cells aid in inflammatory (M1) and anti-inflammatory
(M2) responses. Women have been shown to have an increase in microglia cell
production when they hit puberty (Mouton et al., 2002). Since microglia cells are
able to shift dynamically with the levels of estrogen and progesterone, there is a
potential that these sex steroids may decrease levels of M2 and increase levels of
M1, causing increased inflammation, thus leading to detrimental brain damage. This
shift in M1 and M2 cells needs to be examined more thoroughly in the future to
determine the type of microglia cells females express compared to males, providing
insight to the mechanism behind mTBIs in females and possible treatments for the
future.
Another reason as to why females may be at greater risk for long-term effects
is through a comparison to Alzheimer’s disease (AD). AD and CTE are both
neurodegenerative diseases resulting in cognitive and behavioral changes. While
AD’s defining characteristic is increased abnormal beta-amyloid protein, pTau is
also used to diagnose AD. Females are seen to get AD at a much higher frequency
than males (2:1). Additionally, studies have shown that hormones may play an
important role in the metabolism of the beta-amyloid protein, which may also be the
case with the increase in tau, resulting in poor cognitive effects in the future (Viña,
2010). With this, if females are already at risk for neurodegenerative diseases
accompanied with pTau, the addition of multiple mTBIs throughout their lifetime
may increase the risk of diseases such as CTE, later on. Furthermore, females
typically live longer than males, which is found to be a potential factor for why more
women develop AD (Viña, 2010). Therefore, the longer a female lives the more

18
prone she is to see the major long-term consequences associated with mTBIs.
Further research on AD should be conducted on why females are at a greater risk.
The more information that is known about AD may unlock key mechanisms or
processes in other neurodegenerative diseases such as, CTE, aiding in the
improvements of treatments and cures.
There are many theories as to why females may have worse long term effects
in comparison to males. Despite these theories and the data showing poorer
outcomes later in life, females still lack the necessary protective headgear in
athletics. Today the major focus of sports are males, however, it should be females.
While males tend to be more aggressive and may sustain more mTBIs throughout
their career, neurodegenerative diseases, such as CTE, do not have a specific
number of mTBIs needed (Mckee et al., 2009). With this, although females may not
sustain as many blows to the head, they are still in danger of the detrimental effects
later on. Extensive research needs to be done on females and the effects in humans
following repetitive mTBIs. Moreover, additional attention needs to be paid to
female athletes and their head protection in order to fully defend against mTBIs in
the future.

19
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