WINTER 2017

Parkinson’s Disease | Seasonal Affective Disorder | Microglia | Micronutrients and Neural Development | MDMA | Rabies

FEATURING

KEEPING THE
MIND FIT

APHASIA: AN ACQUIRED
LANGUAGE DISORDER

UNDERSTANDING
BRAIN CANCER

THE
GENDERED connect with us!

BRAIN www.greymattersjournal.com
 TABLE OF CONTENTS
featured article

26 THE GENDERED BRAIN

by Annalise Bond, Katalina Gomez, Jack Henry Kotnik, and
Sarah Krawczak | Art by Keaton Weil
Many believe that male and female brains are fundamentally different,
but research suggests we are more alike than we think. Explore the
role of the brain in determining gender, gender-driven behavior, and
the extent to which societal norms and stereotypes are supported by
biological truths.

4 MICRONUTRIENTS AND NEURAL

20 MICROGLIA: DOUBLE-CROSSING THE BRAIN

TELL US WHAT DEVELOPMENT

by Jasmine Shen | Art by Cassandra Chee
by Danielle Sandbach | Art by Keaton Weil

YOU THINK! 9 RABID: THE NEURAL EFFECTS OF RABIES 22 SEASONAL AFFECTIVE DISORDER
by Saahiti Jasti | Art by Anni Hong
by Evan Lester | Art by Keaton Weil

Here at Grey Matters, we are obviously fans of research, and we sense that
38 MDMA: THE PROSOCIAL PILL
our readers are too. That is why we’re requesting your participation in a
short satisfaction survey! The responses to this five-question survey will aid
14 EXPLORING DEEP INTO PARKINSON’S
by Brian Hou | Art by Sarah Beasley
by Kyle Steinbock | Art by Alesca Delmundo

us in our own research evaluating Grey Matters’ effectiveness in achieving

our mission. Please take the survey at the following link:

tinyurl.com/GMsatisfaction

16 APHASIA: AN ACQUIRED 34 UNDERSTANDING BRAIN 42 KEEPING THE MIND FIT

LANGUAGE DISORDER CANCER by Tom Gebert
by Jonathan Lam by Enoch Chung Art by Madeline Kernan
Art by Mara Potter Art by Mara Potter The effects of exercise on physical
What is aphasia? Discover the A look at the pathogenesis of brain health are widely acknowledged, but
troubling implications of damage to cancer and some of the options that what about its effects on mental
the speech and language centers of exist for treating this disease. health? Learn how exercise impacts
the brain. the brain.
THE STAFF ISSUE NOTES EDITOR’S NOTE
ON THE COVER Grey Matters is focused on collaboration between students.
Art by Keaton Weil The leadership team, writers, editors, and artists have worked
together throughout the quarter to create the magazine you
HAVE YOUR SAY hold in your hands today. Each article is a group effort that
If you have questions or comments regarding goes through countless cycles of writing, editing, and design to
this issue, please write a letter to the editor at reach its current quality.
thalamus@uw.edu
Molly Lindstrom Garreck Lenz Chelsea Nelson Rachel Hill
Editor-in-Chief Senior Editor Production Manager Production Manager Issue 8 features a collaboration we are particularly proud of:
Neurobiology | 2017 Biology and Bioethics | 2017 Biology | 2017 English | 2017 LEARN MORE our cover article, “The Gendered Brain.” This article was writ-
Check out our website to read our blog, find out ten by four students at Whitman College in Walla Walla, WA.
how to get involved, and more at We were surprised and thrilled when they expressed interest
greymattersjournal.com in writing for us, and were even more excited with the article
they produced. It is an honor to know that our reach as a jour-
SPECIAL THANKS nal has extended to other parts of the state, and we invite any
Grey Matters Journal is funded, in part, by the interested students to contact us for opportunities to work to-
generous support of the departments of gether. Participation from our members gives Grey Matters its
Keaton Weil Elise Stefanou Eva Grate Pharmacology, Psychology, Physiology & identity, and we want to encourage collaboration with any stu-
Art Director Editing Coordinator Design Director Biophysics, the Neurobiology major, and the dents who share our values of education and outreach.
Neurobiology | 2018 English | 2019 Visual Communication Design | 2018
College of Arts & Sciences at the University of
Washington. I personally want to thank this issue’s hard-working,
open-minded, and patient contributors. Issue 8 truly has been
AUTHORS CORE EDITORS We are especially grateful to those mentors and a collaborative effort, one that reflects the dedicated input of
Annalise Bond Sarah Krawczak Rachel Hill Chelsea Nelson advisors whose encouragement and support each team member. The positive teamwork has created an ide-
Enoch Chung Jonathan Lam Sriram Katipamula Elise Stefanou
make this publication a reality: al working environment, making it a pleasure to produce this
Tom Gebert Evan Lester Molly Lindstrom Sarita Walvekar
Katalina Gomez Danielle Sandbach Dr. Ric Robinson | Biological Structure issue with all those involved. We hope you enjoy reading.
Brian Hou Jasmine Shen
Saahiti Jasti Kyle Steinbock ARTISTS Dr. William Moody | Biology
Jack Henry Kotnik Sarah Beasley Madeline Kernan Dr. Stanley Froehner | Physiology & Biophysics Thank you,
Cassandra Chee Mara Potter
Dr. Sheri Mizumori | Psychology
EDITORS Alesca Delmundo
Anni Hong
Keaton Weil

Faiz Abdur-Rahman Dua Khan

Thank you to the 2015-2016 leadership team for
Aleenah Ansari Anna Kus
Paige Bartlett Cierra LeBlanc GRADUATE STUDENT REVIEWERS their hard work on this issue, especially Alice
Emma Bueren Mat Lee Leah Bakst | Doctoral Student Bosma-Moody, Anmol Hans, and Mara Potter. Molly Lindstrom
Derek Chen Jessica Lo Tim Brown | Doctoral Student
Olga Cherepakhin Nanditha Narasimman Yoni Browning | Doctoral Student Editor-in-Chief
Emma Creegan Aidan O’Connor Stephanie Furrer Bucks, PhD | Post-Doc A special thank you to our Graduate Student
Regan Gong Sharda Raina Emily Conner | Masters Student
Shannon Gu Alison Suh Kelly Duong | Doctoral Student Review Coordinator, whose expertise and
Elyana Heigham Madison Thompson Brady Houston | Doctoral Student dedication ensures that our work is thorough
Randy Huynh Gautham Velchuru Elizabeth Brookshire Madden | Doctoral Student
Sameeha Jilani Jordan Wikman Kanichi Garcia Nakata | Doctoral Student and accurate:
Salina Johnson Ellen Yin Siobhan Pattwell, PhD | Post-Doc
Leah Bakst, PhD | UW Neuroscience
Katie Wagner | Doctoral Student
DESIGNERS
Anni Hong Sameeha Jilani
MICRONUTRIENTS
by Jasmine Shen
art by Cassandra Chee

MICRONUTRIENT DEFICIENCIES AND

AND NEURAL
THE BRAIN
Micronutrient deficiencies affect an estimated two bil-
lion people worldwide—almost 30% of the world’s
population [1]. Although commonly overlooked in

DEVELOPMENT
first world countries, micronutrient deficiencies can
contribute to a wide range of lifelong, irreversible
health consequences, and in some cases, death [2].
Unfortunately, few reliable statistics on micronutrient
deficiencies are available. Though it is difficult to
document the extent and severity of micronutrient
inadequacies when they are a subset of general
mal­
nutrition and undernourishment, their impor-
tance as a major public health issue is undeniable [3].
Micronutrients are the vitamins and minerals needed by
the body in small amounts for good health [4]. They
differ from the second category of nutrients, macronu-
trients (e.g. carbohydrates, lipids, and proteins), which
the body requires in much greater numbers to generate
energy and maintain tissues, among other biological
functions. Both micro- and macronutrients affect the
nervous system throughout the lifespan, but specific
types of micronutrients have been found to have a
higher degree of influence at different phases of devel-
opment. Micronutrients play a critical role in the proper
function of the nervous system, which is one of the
most complex yet fragile systems in the human body.
Thus, deficits in micronutrients can have devastating
impacts [4].

NEURAL TUBE DEVELOPMENT AND

FOLIC ACID
When an embryo begins growing, nutrients help regu-
late nervous system development, and micronutrient
deficiencies can cause abnormalities in the process [5].
The nervous system develops from from a sheet of em-
bryonic cells called the neural plate. The sheet of cells
begins to fold to create the neural tube just three weeks
after conception, before the mother may even know
she is pregnant [6]. Without proper nutrition, the

4 GREY MATTERS | issue 8 GREY MATTERS | issue 8 5

development of the neural tube can be disrupted, lead-
ing to many possible disabilities.
If the front part of the neural tube does not fold and
fuse completely, it will result in a fatal condition known
as anencephaly. A baby with this condition can be born
without parts of its scalp, skull, and brain, and often
does not survive to birth at all. If the back part of the
neural tube does not fuse completely, it results in a con-
dition called spina bifida, characterized by incomplete
closing of the spinal cord membranes and surrounding
vertebrae [6]. Spina bifida causes nerve damage and loss
of muscle function, but the degree of its impact de-
pends on the location of the malformation on the spinal
cord [8]. All of the nerves and muscles located beneath
the malformation are affected, so the higher the malfor-
mation is, the greater the damage. Spina bifida typically
does not affect mental ability, but it can be associated
with Chiari II, a condition in which the lower parts of
the brain, the brain stem and cerebellum, protrude from
the neck and complicate breathing and swallowing [8].
However, these impairments can be avoided if the em-
bryo receives adequate nutrition during development.
One micronutrient that plays a key role in the proper
development of the neural tube is folic acid, also known
as folate. Folic acid is a type of vitamin that is involved
in the synthesis of DNA during cell division [6]. Studies
have shown clear correlations between a lack of folic
acid in the mother’s diet and an increased risk of abnor-
malities in the embryo’s neural tube [7]. Due to the
importance of folic acid so early in a pregnancy, many
food products have been fortified with folic acid.
Fortification is the process of enriching widely con-
sumed foods, like breads and cereals, with necessary
nutrients. In one systematic review of the published lit-
erature, over 100 studies investigating the effects of folic
acid enrichment were identified [9]. The reviewers
found that among these studies, the overall prevalence
of spina bifida in live births was 42.7% more common in
regions with voluntary (non-mandatory) folic acid for-
tification than in regions where fortification was
required [9]. This effect becomes apparent in
6 GREY MATTERS | issue 8
nation-wide changes: for example, before Brazil en-
forced mandatory fortification of its wheat and maize
flours with folic acid and zinc, there were 32% more ba-
bies born with neural tube abnormalities [10].
Although the link between folic acid and neural tube de-
fects is well agreed upon, the mechanism of folic acid’s
action is less clearly defined. Currently, folic acid is
known to play an important role in two major pathways
necessary to cell growth: the synthesis of nucleic acids
in DNA and the modification of the function of DNA
and proteins through gene expression changes [11]. Folic
acid’s presence in these cell growth pathways suggests
that this may be the way in which it affects neural tube
development, but more research is needed to further
understand its function.
PERINATAL STAGE AND IRON
After the formation of the neural tube, the human brain
continues to grow and undergoes many structural and
functional changes [12]. For example, at twenty-two
weeks, the fetus’ brain changes from smooth to wrinkly,
adding grooves that make it resemble an adult brain.
During this time, iron is rapidly accumulated by the fe-
tus and is used for multiple purposes, including brain
cell insulation, production of neurotransmitters, and
energy metabolism [12]. Due to the importance of these
processes, iron deficiencies before birth or shortly
thereafter can have lasting effects.
During brain growth, brain cells themselves also under-
go their own development. One important aspect of
this development is the process of accumulating fat
around the axon for insulation, called myelination,
which allows signals to move quickly from neuron to
neuron [6]. Myelination occurs throughout the brain
and spinal cord, beginning before birth and continuing
until around age thirty [6]. Iron is both directly and in-
directly involved in myelination. It is important for the
synthesis of cholesterol and lipids, both of which make
up the neuron’s insulation [13]. Iron is also required for
oxidative metabolism, a process in which oxygen is used
to make energy from carbohydrates; that is especially
important for the cells involved in myelination, since 11- to 14-year-olds who were previously iron deficient,
neurons require a lot of energy to function [13]. Because but currently of normal iron status scored lower in
of iron’s role in myelination, there is a possible link be- mental and motor functioning tests [19]. There were
tween iron deficiency and under-myelination, which significant differences in math and writing achieve-
can slow neural communication. One study by Beard et ments between adolescents who were iron-deficient as
al. found that rats who experienced iron deficiencies infants and those who were not. Those who had been
immediately after birth exhibited significantly less my- iron-deficient infants were also more likely to repeat a
elination than the control group; effects persisted grade in school and have anxiety, depression, social
beyond the myelination period, suggesting that iron de- problems, and attention problems [19].
ficiencies in this period may have long-lasting effects
[14]. In addition to long-lasting effects, iron can be linked to
a variety of other neurological conditions. In a separate
The link between myelination and iron has not only study, children sixth months to six years of age who had
been studied in rats, but also in humans, although in a iron deficiencies as infants were found to be more likely
different way. It is difficult to directly measure the to develop febrile seizures, a type of seizure associated
amount of iron in a fetal brain, so serum ferritin levels with high body temperature [20]. Additionally, if the
in the umbilical cord are used instead. Ferritin is a pro- mother consumes an iron-deficient diet, it can lead to
tein in the body that stores iron, and thus the level of iron-deficiency anemia, resulting in low birth weight
serum ferritin reflects the level of iron in fetal tissue [15]. and increasing the risk of cerebral palsy in the infant, a
One study by Armony-Sivan et al. found that premature disorder affecting body movement and balance [21].
infants with low serum ferritin concentrations exhibit- Since iron plays multiple roles in the brain, more re-
ed abnormal reflexes at 37 weeks old [16]. Abnormal search is needed to understand the ways in which it
reflexes likely result from under-myelination, signifying specifically affects different re-
the important link between the presence of iron and gions of the nervous system.
proper myelination [16]. Regardless, one thing is
certain: iron is
According to the World Health Organization (WHO),
iron deficiency is the most
frequent micronutrient defi-
ciency in the world [17]. This
is particularly alarming, be-
cause even if the deficiency is
corrected and iron stores are re-
plenished, the effects of iron
deficiency are irreversible. A study
by Tamura et al. conducted on
five-year-old children found that
if they had lower umbilical cord
ferritin concentrations at birth,
they were more likely to experience
difficulties with fine motor skills, lan-
guage skills, and ability to behave [18].
Another study by Lozoff et al. showed that
GREY MATTERS | issue 8 7
critical to the proper development and function of the
brain, and such widespread deficiency has many nega-
tive consequences.
PRENATAL STAGE AND IODINE
Another micronutrient important for brain function is
iodine. Currently, 1.6 billion children are at risk for io-
dine deficiency, 300 million suffer lower mental ability
as a result, and 120,000 every year are born with a con-
dition called congenital hypothyroidism due to lack of
iodine [1]. For this reason, congenital hypothyroidism is
considered the single greatest preventable cause of
brain damage in infants and children. Characteristics
include severe developmental and physical impairments,
as well as other effects [1]. Iodine deficiency is an indi-
rect cause of congenital hypothyroidism since the
thyroid uses iodine to generate important hormones,
Without retinal, people are unable to perceive light [6].
The WHO estimates 250,000-500,000 children develop
blindness due to severe vitamin A deficiency each year
[1]. Children aged four months to six years are the most
susceptible to this deficiency [1]. Even if vitamin A defi-
ciency does not lead directly to blindness, it can cause
other dangerous conditions, such as xerophthalmia [7].
Xerophthalmia is a condition in which the eye cannot
produce tears as a result of dryness caused by a vitamin
A deficiency. When untreated, it leads to blindness
through corneal damage [7]. However, in one random-
ized clinical trial studying 25,000 preschool children, it
was found that periodic vitamin A doses every few
months reduced the incidence of new xerophthalmia
cases [24].
CONCLUSION

and the lack of those hormones causes problems in neu-
rological and skeletal growth [22]. Supplementation
trials in iodine-deficient populations revealed that
mothers who supplemented before conception or
during the early phases of pregnancy had children with
improved mental development [19]. It is important to
note that the effects of iodine deficiency on cognitive
performance during the postnatal stage are not as well
understood as the effects of in-utero deficiency. This is
because children who are iodine deficient do not score
significantly lower on similar standard cognitive tests,
so the effects are not measurable using traditional strat-
egies [23]. Current public health initiatives to combat
such deficiencies include fortifying salt with iodine (cre-
ating “iodized salt”), since salt is a widely consumed and
cheap product [1].
CHILDHOOD AND VITAMIN A
Although much neurological development occurs be-
fore birth, children are still at risk for impaired brain
development and neurological disorders as a result of
malnutrition after birth. For example, vitamin A is a mi-
cronutrient critical to visual development. The eye,
which is directly connected to the central nervous sys-
tem, uses vitamin A to form a molecule, called retinal,
which allows receptors in the eye to respond to light.
The body only requires micronutrients in small amounts,
meaning it is not difficult to supplement diets on a large
scale and drastically reduce the number of micronutri-
ent-related neurological conditions and problems. All
malnutrition-related neurological diseases are prevent-
able with the proper diet, including anencephaly, spina
bifida, congenital hypothyroidism, xerophthalmia, cer-
tain types of blindness, and many more. The world may
still be searching for a cure for AIDS or cancer, but a
way to prevent some neurological conditions—and help
with overall mental and cognitive development—has al-
ready been discovered: increased micronutrient intake.
While controversy exists over the enrichment of foods
or supplementation of vitamins, fortification is an effec-
tive way to ensure we consume the nutrients we may
not otherwise obtain. Hopefully, as more knowledge re-
garding malnutrition’s effect on the nervous system is
acquired, more can be done to decrease the risks of de-
veloping malnutrition-related neurological conditions.
References on page 47.
RABID
by Evan Lester
art by Keaton Weil
THE RABID BRAIN
An attack from a rabid animal may seem chaotic, furi-
ous, or even random, yet only a tiny virus is responsible
for such rage. Rabies enters the body as a small bul-
let-shaped virus, generally found in the saliva that
lingers from a bite. Once inside, the virus begins to rep-
licate and slowly moves through the body until it
reaches an access point on a neuron. The development
of a rabies infection can take months, but if the individ-
ual does not receive treatment before symptoms start,
there is little that can be done to inhibit the virus from
running its course [1].
If rabies evades the immune system and enters the cen-
tral nervous system (CNS), there are two manifestations
of the virus: furious or paralytic rabies [1]. More is
known about furious rabies because its symptoms—fe-
ver, tingling sensations, spasms, and a loss of reality—are
easier to recognize. Paralytic rabies, however, features
far subtler symptoms that are easily mistaken for other
neurological diseases. In both cases, the viruses work in
the same fundamental way: they enter the body through
a bite or scratch and end with the bitten individual’s
death, usually from brain inflammation [1].
By examining how rabies works, the medical communi-
ty has not only gained insight into the immune system,
but also into the nervous system. Tracking rabies by
adding markers to the virus has led to a vast increase in
our understanding of neural pathways [2]. Though the
effects of this disease are terrible, they are uniquely ben-
eficial to research that furthers knowledge about the

8 GREY MATTERS | issue 8 GREY MATTERS | issue 8 9

nervous system. By learning about rabies, we can hope-
fully develop a deeper understanding of our bodies.
HOW IT WORKS
Most people who contract rabies come in contact with
the virus through the saliva of dogs [3]. It may be as long
as a year after the initial entry of the virus before pa-
tients first exhibit symptoms, as the virus cannot impact
the body until reaching a large enough grouping of
nerves [3]. Upon such contact, the first phase of the in-
fection begins; the patient experiences fever, nerve
tingling, and intestinal discomfort [4]. Once the virus
has reached the nerve bundle, the reproduction and
spreading of the virus increases to as much as 10 times
faster than the initial bite [3].
To spread throughout the body, rabies travels in the re-
verse direction of a traditional neural impulse, from the
axon back to the cell body. The virus uses this process,
called retrograde transport, to move inward from nerve
cells associated with muscle movement until it reaches
the central nervous system. At this point, it reaches a
collection of neurons near the spinal cord, called the
dorsal root ganglia, and continues to travel up to the
brain [4]. The interaction with the dorsal root ganglia is
likely responsible for the reported tingling feeling, akin
to pins and needles, around the bite wound. Once in
the CNS, the next phase begins. This phase consists of
spasms, anxiety, fear of water (hydrophobia), and most
notoriously, altered consciousness [4]. Unfortunately,
the CNS offers only a limited immune response because
it is separated from the rest of the body by the blood-
brain barrier, which restricts many immune cells from
entering the brain [5]. While the neurons possess innate
antiviral protections, their protections are simply not
sufficient to fend off rabies [6]. After moving through
the spinal cord, the virus targets neurons in the brain
until it reaches the limbic system, an area commonly
thought to be responsible for basic emotions and drives
[4]. Such targeting of one of the most fundamental ar-
eas of the brain gives rabies the capability to completely
override the core of one’s personality.
10 GREY MATTERS | issue 8
The continued infection of the brain eventually leads to
inflammation, and once enough damage due to inflam-
mation has occurred, the individual enters the final
phase of the virus. If a vaccination has not been deliv-
ered to the patient before symptoms are detected, there
is very little that can be done to stop the virus from run-
ning its course, ending in the patient’s death [3].
PARALYTIC RABIES VS FURIOUS RABIES
Rabies is not always as obvious as its horror movie cli-
ché. Paralytic rabies is a specific manifestation of the
virus that comprises 30% of rabies cases, but it is much
harder to identify and is far less publicly recognized [1].
While furious rabies has been acknowledged for hun-
dreds of years, paralytic rabies was first documented in
1887, but was not identified as rabies until 1930. The
differences between the two manifestations of the virus
are incredibly important in the medical field to ensure
proper treatment occurs [8].
As the name suggests, a person with furious rabies
shows physical signs of agitation and therefore more ac-
tively spreads the disease to others. Paralytic rabies,
however, almost completely immobilizes its victims.
Immobilization can lead the virus to be confused with
Guillain-Barre syndrome, an autoimmune disease.
Difficulties distinguishing between paralytic rabies and
Guillain-Barre syndrome often results in improper
treatment [8].
Despite the subtler symptoms, paralytic rabies is no less
painful than furious rabies. Not only does paralytic ra-
bies keep its patients alive for longer than furious rabies,
but it also involves degradation of the peripheral nerves,
which causes weakness and forces patients to become
bedridden [8]. Furthermore, greater inflammation can
be seen in both the spinal cord and the infection site in
cases of paralytic rabies, causing greater pain for the pa-
tient. Furious rabies also results in inflammation in the
spinal cord, but it occurs to a lesser extent and only ap-
pears in the nerve roots [8].
Currently, the mechanisms behind why these different
manifestations of the virus occur are not fully under-
stood. Previously, researchers believed that paralytic
rabies and furious rabies were completely separate vi-
ruses; however, there is evidence of furious rabies and
paralytic rabies resulting in different individuals from a
single animal’s bite [6]. Such evidence does not com-
pletely rule out the possibility of a spontaneous genetic
mutation occurring in the virus, but analysis of samples
obtained from these patients did not indicate the pres-
ence of a mutation [6]. Interested in the spread of the
rabies virus, Laothamatas et al. examined the brains of
infected dogs for information about the virus. Thirty-
six hours after infection, RNA of paralytic rabies was
primarily found in the thalamus, while in cases of furi-
ous rabies, the RNA of the virus was found in both the
thalamus and the midbrain [9]. After death, however,
GREY MATTERS | issue 8
the entire brain of both furious and paralytic subjects
showed signs of rabies RNA. The absence of paralytic
rabies in the midbrain suggests that its spread is slower
than furious rabies [9]. Additionally, in an MRI exam-
ination of the dogs’ brains, furious rabies showed a
weak immune response, whereas the brains with para-
lytic rabies showed a stronger immune response, and
thus more brain inflammation. This stronger immune
response coupled with the delayed spread of paralytic
rabies led the researchers to theorize that the CNS
could have a more successful immune response in cases
of paralytic rabies [9]. Such a result is consistent with
the greater inflammation of the spinal cord that is
found in paralytic rabies. Ultimately, the difference be-
tween paralytic and furious rabies is still a contested
topic, and no single theory has been fully accepted.
TREATING RABIES
It is both terrifying and rather extraordinary that de-
spite thousands of years of exposure to rabies, humanity
is still powerless against the disease once symptoms are
exhibited. Since the creation of the basic vaccine in 1885,
which simply incites an immune response through ex-
posure to an inactive form of the virus, little
advancement has been made toward an effective treat-
ment proto­­
col. However, in 2004, a new protocol
designed in Milwaukee showed promise when it saved a
15-year-old patient who had begun to exhibit symptoms
of rabies [10]. The new protocol involved placing the pa-
tient in a coma and then administering several different
antivirals. Ideally, the coma reduces brain activity to
slow the spread of the disease while the cocktail of anti-
virals inhibits viral replication and transport. Though
the patient initially exhibited problems walking after
treatment, she could communicate and the hospital
discharged her after 76 days. Today she is alive and
well with a college degree [10]. Success with experimen-
tal treatment options merits excitement, of course, but
in the years since initial success, there have been few
survivors using the same protocol. Of the 25 patients
who received the treatment, there were only three sur-
vivors [11].
11
There has been one documented case of an individual
who exhibited symptoms of rabies and tested positive
for the disease, but survived without intensive care, as
opposed to the Milwaukee experimental treatment [12].
Such survival ultimately indicates the possibility of an
innate or conditioned advantage in certain patients’ im-
mune responses [11]. For example, a Peruvian study in
2010 that examined blood samples from 63 patients
found 11% tested positive for rabies neutralizing anti-
bodies without vaccine administration [13]. The
antibodies indicate these patients had come in contact
with the virus and survived. This could suggest that suc-
cessful cases of the Milwaukee protocol were due to the
existence of antibodies prior to acquiring the virus.
While the Milwaukee protocol seemed promising, it has
not been possible to scientifically confirm its efficacy.
New ideas still abound, one such idea being a preventa-
tive tactic called passive immunization. This immunity
is given through the blood of donors who have been
previously immunized to the virus and have existing an-
tibodies that allow the recipients of the donation to
survive an infection [14]. There are some limitations to
passive immunization, including a lack of potential do-
nors and a risk of infection. Still, vaccinations take time
to generate antibodies, and passive immunization pro-
vides a much faster solution. While this is a preventative
Glycoproteins
Envelope
(membrane)
Figure 1: the anatomy of a virus
12 GREY MATTERS | issue 8
tactic, it may be more affordable and accessible than
regular vaccination [14].
There are few ideas for non-preventative treatment of
rabies. One idea that remains to be tested is induced hy-
pothermia [15]. This would involve cooling the
individual to reduce inflammation in the brain, which is
the ultimate cause of death in rabies patients. However,
no conclusive studies have been able to confirm its
effectiveness.
INFORMATIVE BENEFITS OF RABIES
Rabies spreads quickly through the nervous system and
replicates rapidly, allowing it to be used to track neural
connections throughout the brain [2]. Rabies travels
through neural pathways in the reverse direction, so
adding a tracer to the disease illuminates these path-
ways and allows for an increased understanding of the
connections of particular circuits in the brain. Rabies is
not the only virus that can be used to expand our
knowledge of neural connectivity, but few other viruses
have been used as effectively in the past [2].
In a 1995 study, the tongue muscles of different animals
were injected with rabies and the pathway the virus muscle to the brain, then through other connections nerves, there are few that fully take over the body in the
took to the brain was monitored [2]. As we now expect, between these neurons and another area of the brain way rabies does. It is difficult for us to imagine that our
the virus first went through the neurons connecting the called the hypothalamus. Finally, the virus traveled personalities and thoughts are based entirely in our
from the hypothalamus to the cerebral cortex. brains, and thus even more terrifying to imagine that
Observing rabies’ path allowed the scientists to actually these sacred, almost untouchable parts of ourselves can
see the course of neuronal signals that travel from the be changed by an invisible force. But throughout years
Genetic information brain to the tongue. Using the rabies virus in this way of analyzing the virus, we have been able to discover ex-
(RNA) is held within also enabled scientists to map the connectivity of the vi- traordinary information about neurons and the
sual system in a monkey. Research using rabies has connectivity of the brain. By understanding the effects
facilitated a tremendous number of discoveries about of the virus, we continue to expand on our knowledge
signaling pathways through the nervous system [2]. of neuroscience. Much remains unanswered, but by
While much of this research is relatively recent and breaking down the causes, effects, and process of this
there is still significant progress to be made, it is clear disease, we only stand to gain understanding.
that while deadly, rabies can be a valuable asset to
research. References on page 48.
CONCLUSION
Rabies is terrifying because it is unique; while there are
many neurological diseases and viruses that can damage
GREY MATTERS | issue 8 13

EXPLORING
DEEP INTO
PA R K I N S O N ’ S
by Brian Hou
art by Sarah Beasley
P
arkinson’s disease (PD) is one of the most debil-
itating neurological diseases, affecting about
1%-2% of the population over the age of 65 [1].
PD is characterized as a progressive disorder that causes
slow movements (Bradykinesia) and tremors. People
with PD struggle to complete everyday activities such as
putting on clothes in the morning or eating with silver-
ware [2]. While there is some disagreement about the
causes of PD, the pathophysiology of PD is well under-
stood. The main brain region affected by PD is the
substantia nigra, a crescent-shaped mass of cells located
in the midbrain. One signaling molecule that is highly
concentrated in the substantia nigra, called dopamine,
is critical for the initiation of movement. However, with
the onset of Parkinson’s, the dopaminergic cells die and
dopamine signaling is lost, which affects the control of
movement [3]. Although there are medications that tar-
get the low dopamine concentration in the substantia
nigra, patients who build a tolerance and become resis-
tant to these medications must often choose
experimental treatments such as transcranial direct cur-
rent stimulation (tDCS) and deep brain stimulation
(DBS) [4].
14 GREY MATTERS | issue 8
Unfortunately, PD has no known cure as of yet; howev-
er, several treatment options can help manage the
symptoms of Bradykinesia, rigidity, and tremors. Both
tDCS and DBS involve directing an electrical current to
a specific area of the brain [6, 10]. In tDCS, electrodes
are non-invasively attached to the patient’s head,
whereas in DBS, electrodes are surgically inserted into a
patient’s brain [6, 10]. The tDCS technique is a form of
long-term potentiation that focuses on strengthening
existing neuronal connections by using the brain’s neu-
roplasticity, which is its ability to reorganize itself and
form new connections [5]. Physicians who treat their
patients with tDCS fire continuous electrical signals
within the brain over multiple sessions, which in turn
may bring about improvement in the targeted area’s
overall function [7].
Since its first use in the clinical realm for treating peo-
ple with depression, the use of tDCS has grown
profoundly in the field of neuroscience. Using tDCS,
low current electricity is applied to an area of the brain
through electrodes on the scalp. The electrodes can ei-
ther excite or inhibit neuronal signals in that area,
which will hopefully ameliorate the severe symptoms
associated with Parkinson’s [6]. Anodal stimulation ex-
cites neuronal activity by depolarizing a neuron’s
membrane, while cathodal stimulation inhibits neuro-
nal activity by hyperpolarizing a neuron’s membrane [6].
Although there are no known risks associated with
long-term use of tDCS, patients have often reported
some mild side effects after sessions, such as nausea and
skin irritation on the scalp. Generally, to lessen or pre-
vent skin irritation during treatment, physicians
prepare electrodes with saline solution and apply elec-
trode cream to the patient’s skin [7]. But even these
potential side effects are not severe enough to deter
individuals from the use of tDCS.
While tDCS was first administered in the
19th century, DBS was first introduced in
1987 and is an invasive procedure involv-
ing the implantation of an electrode in two
areas of the brain most commonly affected
by PD, the subthalamic nucleus (STN) and
the globus pallidus internus [8, 9].
These areas are part of the basal
ganglia and are known to produce
inhibitory output to the thalamus,
which can disrupt movement. Both
the STN and globus pallidus nor-
mally receive input from the
substantia nigra. During DBS treat-
ment, the implanted electrode
administers a shock that is thought
to interrupt some of the inhibitory activity in the basal
ganglia, thus facilitating movement [10]. Unlike tDCS,
which is not yet FDA approved, DBS has been approved
and has provided many therapeutic benefits to people
who have PD, Obsessive-Compulsive Disorder, and es-
sential tremors of extremities [7]. However, much like
any treatment, there are always some adverse side ef-
fects. The risk of infection, which is around 8.7%, raises
particular concern given that a foreign object is intro-
duced deep into the brain [11]. Additionally, although
DBS is helpful for some patients, other patients have re-
ported hallucinations or cognitive dysfunction, such as
amnesia and deficits in reasoning capabilities [12].
GREY MATTERS | issue 8
Overall, the effects of DBS and tDCS seem to be specific
to individuals, with the majority of patients reporting
improvements in their overall quality of life [13].
With reports of therapeutic success in the last decade,
public interest in both tDCS and DBS has risen dramat-
ically. The media has already begun to enthusiastically
publish and portray both tDCS and DBS as highly bene-
ficial techniques. About ten times more print media
articles regarding tDCS were published in 2013 com-
pared to 2006 [14]. However, even given this early
enthusiasm, little is known about the
long-term effects of these treatments.
The positive effects of tDCS and DBS
are indeed very encouraging, but it is
wise to be cautiously optimistic until
they are better understood.
Although there may be some poten-
tial undiscovered risks associated
with tDCS and DBS, we should re-
frain from letting the risks
overshadow the incredible medi-
cal advances in therapy that have
occurred in the past several de-
cades. Both tDCS and DBS
increased the quality of life for many patients suffering
from Parkinson’s, allowing them to take control of their
lives again by mitigating their tremors. Furthermore, it
has been shown that tDCS and DBS are promising
treatments for other disorders, meaning the applica-
tions of these therapeutic procedures are not specific to
Parkinson’s [7]. Future research about new uses for
tDCS and DBS can further our understanding of how
these treatments affect the lives of patients who choose
to participate in this advancing frontier.
References on page 48.
15
 INTRODUCTION
No other living species has the complex language abili-
ties of humans [1]. Language is expressive and receptive
in nature; that is, humans can write and speak words to
convey thoughts and emotions, as well as understand
spoken language. Language also shapes the way humans
communicate with others, a basic instinct arising from
AN ACQU
our need for social interaction. Even before the devel-
IRED LAN opment of complex language, our ancestors were
GUAGE D
ISORDE
naturally social creatures who interacted with others on
R a daily basis, a trait passed down through the genera-
tions to create a defining characteristic of humanity [1].
However, damage to the language centers of the brain
can impair or even eliminate the ability to process writ-
ten and spoken words [2]. This situation is frequently
by Jonathan Lam
experienced by stroke survivors who develop aphasia,
art by Mara Potter
an acquired language disorder affecting their ability to
communicate. Approximately one million people in the
United States experience some level of aphasia as a re-
sult of damage to areas of the brain responsible for
language [3]. Aphasia patients are constantly frustrated
by the inability to understand language or speak as well
as they were previously able, and this inability to com-
municate effectively causes a severe decline in their
quality of life, which can be quite difficult [3].
CAUSES OF APHASIA
Aphasia has a variety of causes. The language areas of
the brain can be damaged by tumors, head trauma, in-
fections, and dementia, but aphasia is most commonly
caused by strokes that affect these regions of the brain
[2]. There are two different forms of stroke: ischemic
and hemorrhagic [4]. Ischemic strokes occur when an
artery becomes clogged and interrupts blood flow to the
brain, while hemorrhagic strokes involve the rupturing
of an artery, causing blood to leak into the brain. Both
types of stroke can result in permanent damage in the
form of dead brain cells, caused by insufficient oxygen
supply or the presence of toxic substances within the
blood. The extent of damage is determined by how long
cells are deprived of oxygen or exposed to toxins, as
16 GREY MATTERS | issue 8 GREY MATTERS | issue 8
well as the size of the area affected [4]. Since stroke
damage varies, it is possible that a survivor may not
have permanent brain damage and can recover from
temporary aphasia without treatment [2].
Aphasia occurs in nearly one-third of stroke victims [2].
People with stroke-induced aphasia typically have dam-
age in the language centers, which are most often on
the left side of the brain. In 1861, Paul Broca examined a
patient nicknamed “Tan,” who had lost the capability of
voluntary speech and developed paralysis on the right
side of his body [5]. Upon examining Tan’s brain after
his death, Broca noticed a lesion, or damaged tissue, in
the frontal portion of the left hemisphere. Over the
next two years, Broca saw seven more cases in which
patients could not speak fluently, and all had damage in
the left hemisphere of the brain. Broca thus determined
the common area of the observed lesions must be re-
sponsible for the production of speech and language.
The region was subsequently named Broca’s area, after
its discoverer [5]. Similarly, in 1874, Carl Wernicke en-
countered a patient with speech impairment who could
speak fluently, but could not understand others [6].
When he examined this patient’s brain post-mortem,
Wernicke noticed a lesion in the superior temporal lobe.
The location of this brain lesion eventually became
known as Wernicke’s area, or the left superior temporal
gyrus, and is responsible for comprehension of written
language and speech. Both Broca’s and Wernicke’s areas
are major language centers in the brain, but it is import-
ant to note that they are not the only areas of the brain
involved in language [6]. For example, Broca’s and
Wernicke’s areas are connected by a bundle of nerve fi-
bers called the arcuate fasciculus, which has been
postulated to play a role in short-term memory and rep-
etition, both of which are related to language and
communication [7]. Several other language areas of the
brain have also been identified, and the type and extent
of language impairment depends on which of these ar-
eas have been damaged [6].
17

Wernicke’s Area
Broca’s Area
COMMON TYPES OF APHASIA
There are several types of aphasia that can occur as a re-
sult of damage to the different language centers and the
connections between them. Survivors of strokes that
destroy neurons and neural pathways in Broca’s area
typically speak in a halting manner and use disjointed
phrases that lack appropriate grammar, a condition
known as expressive aphasia [8]. These patients experi-
ence difficulty writing and spelling words, but maintain
language comprehension since Wernicke’s area is unaf-
fected. When a stroke destroys neurons and pathways in
Wernicke’s area, patients experience receptive aphasia.
As a result of this damage, they are unable to compre-
hend written and spoken language, as well as their own
speech. Patients are still able to produce fluent-sound-
ing speech, since Broca’s area remains intact; however,
their language often does not make sense, and may also
18 GREY MATTERS | issue 8
contain nonsense words. Frequently, there is also over-
lap between these two types of aphasia, as patients with
expressive aphasia can experience comprehension prob-
lems, and those with receptive aphasia can exhibit
production impairment [8]. Unfortunately, there are
people who have strokes that affect both Broca’s and
Wernicke’s areas. This results in the most severe form of
aphasia, known as global aphasia, where patients have
extreme impairment in both the production and com-
prehension of speech [9]. These patients are unable to
repeat words spoken to them, and are only able to speak
a few small phrases [9].
Other types of aphasia include anomic aphasia, where a
person cannot identify words for things they wish to re-
call [10]. For example, if a person with anomic aphasia
was given a key, they would be able to correctly identify
the object’s use (to unlock a door), but unable to say the
word “key.” These people speak with appropriate gram-
mar and recognize what to do with an object, but are
unable to identify that object. The cause of anomic
aphasia is thought to be damage to the left parietal lobe.
In a study by Fridriksson et al., researchers examined
patients with left hemisphere damage and noted these
patients had difficulty repeating the speech of others.
This study also linked left parietal lobe damage to an-
other type of aphasia: conduction aphasia. Patients with
conduction aphasia have difficulty repeating speech,
typically as a result of damage to either the arcuate fas-
ciculus or the left parietal lobe. When these individuals
are told to repeat a long phrase, they are unable to do so
since they repeatedly interrupt themselves and forget to
continue. Despite this impairment, people with con-
duction aphasia typically maintain normal speech
function and can answer questions quickly and fluently
[10].
CURRENT TREATMENTS
Since the degree and type of aphasia varies between pa-
tients, treatment is individualized through a CONCLUSION
combination of speech and language therapy [11].
Restoration language treatment works to restore and
improve impaired language abilities, while compensa-
tion treatments target unaffected language abilities in
order to maximize their usage and offset the affected
aspects of language. Augmentative and alternative com-
munication (AAC) utilizes low-tech and high-tech
approaches, such as picture boards and iPads, to teach
alternate methods of communication. AAC frequently
uses pictures, allowing aphasia patients to communi-
cate by selecting a picture that reflects what they want
to express [11]. Constraint-induced therapy (CIT) is a
common type of speech therapy consisting of three
main principles: forced use, constraint, and massed
practice [12]. CIT forces patients to communicate only
by speaking (forced use) and avoid compensatory mech-
anisms such as gesturing and drawing (constraint).
Treatment with CIT occurs for 2–4 hours each day, and
has patients practice speaking words repeatedly in an
attempt to recover lost language faculties [12].
GREY MATTERS | issue 8
Currently, aphasia is treated by behavioral therapy
alone, as there is no FDA-approved drug available to pa-
tients [11]. Scientists have conducted research on
pharmacological treatments that would either speed up
the brain’s ability to recover, strengthen blood flow to
the brain, or replace lost neurotransmitters in damaged
areas [13]. In particular, a study conducted by Berthier et
al. suggests the medication memantine may improve
aphasia symptoms [14]. Patients who received meman-
tine showed significant improvement of symptoms over
a group given a placebo, as measured by the Western
Aphasia Battery, a test that indicates the severity of lan-
guage impairment [14]. The beneficial effects were
sustained in a long-term follow-up, and patients switch-
ing from placebo to memantine also benefitted [15].
Despite the promise of memantine in this study, further
research is still being done to support its use as a clinical
pharmacological treatment. Nevertheless, there is great
interest in whether speech therapy combined with
medication is more beneficial than therapy alone.
About 795,000 Americans have experienced a stroke
within the previous year, and the number of aphasia pa-
tients continues to grow due to the increasing frequency
of strokes [16]. Complete recovery is unlikely for those
with moderate stroke-induced aphasia, which is almost
always chronic and can never be fully resolved [2].
Patients who experience permanent brain damage typi-
cally do not regain the proficiency of communication
they had before their stroke, and unfortunately live out
their lives with some form of language impairment that
affects their communication with others [2]. Given
these chronic, life altering changes in language ability, it
is crucial to continue research focused on aphasia
rehabilitation.
References on page 49.
19

MICROGLIA
DOUBLE-CROSSING
THE BRAIN
by Danielle Sandbach
art by Keaton Weil
N
eurological disorders like Alzheimer’s
Disease (AD) and schizophrenia have per-
plexed scientists for decades. Although these
complex disorders affect patients in different ways, both
share a common trait: the brain’s immune system can
contribute to their debilitating effects. While not per-
fect, the immune system typically helps protect our
brains against foreign pathogens, using small glial cells
called microglia [1]. In general, glial cells support and
maintain signaling abilities of neurons. Microglia are a
subclass of glial cells that provide the first line of de-
fense against pathogens; for most of our lives, microglia
help protect our brains. Along with removing damaged
cells, microglia identify and destroy pathogens that neg-
atively affect interactions between other cells [1].
However, supporting evidence exists that links AD and
schizophrenia to the central nervous system’s microglia
[2]. Studies have cited microglia’s ability to become hy-
peractive and damage their surroundings as a potential
contributor to both disorders [2]. The discovery of this
20 GREY MATTERS | issue 8
in schizophrenic patients, thereby leading to an influx amyloid-β (Aβ), has the ability to bind to and activate
of inflammation that damages the brain. Certain drugs microglia—whose function is to remove such plaques—
that lessen the effects of schizophrenia, like olanzapine leading to further damage due to exaggerated microglial
and risperidone, also decrease microglial activation in production of inflammatory cytokines [1]. This direct
the central nervous system. interaction between mi-
By counteracting microgli- croglia and Aβ suggests
al hyperactivity, the drugs that anti-inflammatory
are able to reduce inflam- drugs could prevent the
mation—MRI studies of gradual loss of brain tissue.
patients using these partic- “Researchers currently hypothesize that Current research shows
ular treatments suggest neuron death occurs as a result of prolonged that targeting our microg-
that use of the drugs may microglial hyperactivity in schizophrenic lia may be successful;
prevent further reduction
of brain tissue [2].
patients, thereby leading to an influx of
inflammation that damages the brain.”
however, due to the already
weakened immune systems
of older patients with AD
Although patients with AD and the tendency for mi-
are affected by microglial hyperactivity similarly to peo- croglia to become more hyperactive as the disease
ple with schizophrenia, the two diseases are very progresses, the use of anti-inflammatory drugs can ac-
different. AD is an irreversible and progressive neuro- tually contribute to further damage [1]. Because of the
degenerative disease, slowly damaging the brain success in younger patients, researchers are asking new
immune dysfunction raises important concerns regard-
causing severe dementia and loss of cognitive skills [1]. questions about when microglial function becomes det-
ing the immune system’s connection to AD and
The disease is characterized by inflammation in the rimental and whether we can try to prevent the
schizophrenia. Learning more about the connections
brain and dysfunction caused by amyloid plaques, a dysfunction before it begins.
between microglia and the immune system may lead to
buildup of proteins folded incorrectly that stick togeth-
newer, more effective ways to treat patients with these
er. A key component of these plaques, the peptide Further research on the connection between microglia
disorders.
and their effects on neurological disorders like schizo-
phrenia and Alzheimer’s Disease—two very different
Before scientists can begin the search for treatments us-
diseases affected by the same kind of cell—could pro-
ing microglial function, more needs to be understood
vide key insights into how the disorders are caused,
about the disorders the cells have been observed to af-
how they progress, and most importantly, how
fect. Schizophrenia is a mental illness characterized by
we can prevent and treat them. Despite uncer-
the DSM-V as including a variety of possible symptoms
tainty regarding the causes of both diseases,
that cause a certain level of social or occupational dys-
more research on immune support for the
function [3]. People with the disorder have a chemical
central nervous system itself will bring us
imbalance of neurotransmitters that may cause “posi-
closer to helping the many people affected by
tive” symptoms, like hallucinations and movement
these debilitating disorders.
issues, and “negative” symptoms that detract from ev-
eryday behavior, such as reduced emotional expression
References on page 50.
or speaking [4]. As schizophrenia progresses, the brain
exhibits several neurological abnormalities—including a
significant loss of grey matter due to cell death [2].
Researchers currently hypothesize that neuron death
occurs as a result of prolonged microglial hyperactivity
GREY MATTERS | issue 8 21
SEASONAL
AFFECTIVE
DISORDER
by Saahiti Jasti
art by Anni Hong
W
hen a person looks out the window and
sees yet another overcast day, the clouds
can cast a shadow over his or her mood.
Everything seems duller, the vibrant aspects of life no-
where in sight. Yet even one ray of sunshine can
suddenly revive them.
Many people who live in Seattle know about and have
experienced the effects of Seasonal Affective Disorder,
or SAD, a recurring depressive disorder that follows a
seasonal pattern. Its effects are most prominent during
fall and winter, when there is limited sunlight. People
who experience this disorder report feelings of sad-
ness and loss of energy, falling into a pattern of
depression that is closely tied to the weather condi-
tions [1]. Although SAD appears to strongly impact a
person at the behavioral level, it originates at the mo-
lecular level and involves what is known as the
biological clock, or circadian rhythm.
22 GREY MATTERS | issue 8
THE BIOLOGICAL CLOCK
Research into the molecular derivation of SAD points to
the mechanism of the biological clock, which takes
place in the suprachiasmatic nuclei (SCN) in the anteri-
or hypothalamus, a region of the brain thought to be
involved in the regulation of sleep [2]. The SCN act as
circadian pacemakers, meaning they orchestrate the
timing of physiological and behavioral changes accord-
ing to the time of day. Circadian pacemakers are
essential to body function, as they control many
rhythms within the brain and in organs such as the liv-
er, kidney, and heart [2]. They regulate hormone levels,
sleep patterns, cell regeneration, and many other criti-
cal processes. Naturally, the biological clock is reset to
line up with a normal 24-hour day when exposed to
light [3]. However, without daylight, the biological clock
is subject to change. How does the presence of daylight
change the function of this clock?
When light enters the eye, one of the first things it in-
teracts with is a protein called melanopsin. The light
detection system through melanopsin is different from
the visual process used to form images and navigate the
world, which involves rods and cones. This difference
comes from the fact that melanopsin is sensitive to blue
light. The protein identifies brightness levels and uses
them to set an internal clock in our cells [3]. In addition
to being reset by the presence of light, the circadian
clock is affected by natural light shifts in the environ-
ment, such as changes in day length due to seasonal
variations [2]. As a result of exposure to natural light
shifts, the circadian rhythm goes through phase-shifts
that either advance or delay the rhythm based on the
GREY MATTERS | issue 8
time of day [4]. Advancing the rhythm would cause an
individual to wake up earlier, and delaying the rhythm
would cause an individual to wake up later. Morning
light advances the rhythm, evening light delays the
rhythm, and light during midday has no effect [4]. As
the seasons change, there is a shift in the circadian
rhythms due to the changes in both the pattern of
morning/midday/evening light and the length of day-
light [5]. In response to these changing sunlight
patterns, several molecular pathways that relay light in-
formation from the retina to the SCN adapt to reflect
the alteration in sunlight, inducing the release of a wide
variety of neurotransmitters [2]. This causes the biologi-
cal clock to be out of sync with its regular schedule,
leading to the neurotransmitter-dependent depressive
symptoms of SAD [5]. Neurotransmitters play a key role
in how the body can become subject to SAD due to their
ability to alter the biological clock.
SEROTONIN
Serotonin is thought to be one of the main neurotrans-
mitters involved in SAD. Serotonin works to advance
the circadian pacemaker during the day and delay it at
night; it also regulates the activity of neurons in the
SCN [2]. Additionally, increased levels of serotonin are
associated with an improvement in mood. Research has
indicated that an alteration in regular serotonin levels
might lead to the inhibition of the pathway that relays
light information from the retina to the SCN [2]. To de-
termine if seasonal shifts could be inducing changes in
serotonin signaling, researchers measured levels of se-
rotonin in the blood collected directly from the jugular
veins of 101 men aged 18-79 [6]. Based on the difference
23

in the amount of neurotransmitters between arteries
and veins, researchers were able to estimate the
amounts actually produced in the brain itself. They
found that the rate of serotonin turnover (the rate of
depletion and replacement) was lowest in the winter.
Additionally, it was noted that there was a strong cor-
relation between serotonin turnover and the amount of
sunlight present on the day the serotonin was mea-
sured. However, there was minimal association between
serotonin turnover and the amount of sunlight present
on the day before the study, indicating that serotonin
turnover adjusted quickly to the amount of sunlight
present. These results suggest that the amount of sun-
light currently available affects serotonin levels in the
brain [6]. Since it was evident that serotonin levels in-
crease when there is more light available, it is reasonable
that signs of depression, which depend on serotonin,
arise during seasonal shifts when less light is available.
MELATONIN
In addition to serotonin, many other chemicals have
varying effects on the biological clock. Melatonin is a
24 GREY MATTERS | issue 8
hormone secreted by the pineal gland, and is
extremely important for circadian
rhythms. The SCN contains the highest
density of melatonin receptors, so the
effects of melatonin are especially
strong there [2]. Known as the
“darkness hormone,” it is released
at night and accelerates sleep [2].
Since melatonin is secreted at
increased levels in the dark, pro-
duction heightens during seasonal
shifts when the days become
shorter and darker [2]. A group of
researchers from the National
Institute of Mental Health hypothe-
sized that abnormal secretion of the
chemical might contribute to the symptoms
of SAD [7]. The researchers tested this by block-
ing melatonin release using a drug called atenolol. But
in a study of 19 SAD patients, there was no evidence of a
difference between people administered atenolol and
the control group given a placebo drug [7]. Even though
it seems plausible that the melatonin pathway may play
a part in SAD, further research is still being conducted
to establish the relationship.
VITAMIN D
There is abundant evidence suggesting vitamin D cor-
relates with SAD [8]. Since the skin produces vitamin D
after exposure to sunlight, seasonal shifts could alter its
production. During the fall and winter seasons, there is
less sunlight and therefore less vitamin D. Vitamin D
has a number of effects on the central nervous system,
mediated through receptors that are widely distributed
throughout the brain. To test whether vitamin D might
play a role in mood regulation, rats were given a sub-
stance that inhibits the activity of their vitamin D
receptors. Rats, in particular, were used as test subjects
for this study because they have a vitamin D receptor in
their brains that is also found in humans. It has been
proposed that the activation of this variety of receptor is
involved in modulating neuron excitability and other
physiological changes. This study showed that rats
whose vitamin D receptors were inhibited appeared less
active and more anxious than the control group— both
traits indicative of depression [8]. Even with data col-
lected from studies such as this, it is not possible to
confirm that lower vitamin D levels in winter
cause SAD. However, the correlation is apparent
and more studies are working to further verify
the association between vitamin D and SAD.
TREATMENTS
Although many people suffer from the effects of SAD,
studies show that therapy has led to improvement in
67% of SAD patients [1]. Beyond therapy, there are many
treatment options available for those with SAD. For ex-
ample, a treatment called artificial light therapy exposes
patients to a full spectrum light resembling sunlight.
Another treatment is the prescription of SSRIs
(Selective Serotonin Reuptake Inhibitors), which lead to
an increase in serotonin levels. Lastly, prescriptions for
vitamin D are often given to those suffering from SAD,
since low levels of vitamin D have been correlated with
symptoms of depression [1]. Every patient reacts differ-
ently to these treatments, and administration of more
than one is often necessary to combat SAD.
CONCLUSION
Even though many studies point to the association be-
tween depressive episodes and seasonal changes, there
are still unresolved questions. There has been research
into whether patients are predisposed to SAD due to
genetics, their environment, or if they are solely affect-
ed by internal factors such as neurotransmitters and
vitamin levels [6]. However, with the knowledge gained
through current investigations into neurotransmitters
and SCN activity, disruptions in the biological clock
may soon be corrected in order to treat conditions such
as SAD [2]. Hopefully, as more treatments for this disor-
der are developed, the gloomy, overcast skies will no
longer have a hold on the lives of so many.
References on page 50.
GREY MATTERS | issue 8 25
 THE GENDERED BRAIN
by Annalise Bond, Katalina Gomez, Jack Henry Kotnik, and Sarah Krawczak
art by Keaton Weil
T
oday, we live in a society with infinite-
ly complex social guidelines. We fall
in (or out of) line with thousands of
distinct social norms that instruct us on how
to behave in given situations. These norms be-
come deeply rooted in our way of life; as such
they are often difficult to change, and hold the
potential to instigate prejudiced behavior. One
such social norm is gender. Not to be confused
with sex, gender is a spectrum allowing people
to take on an identity based on relative mascu-
linity or femininity. How someone identifies
along that spectrum is not necessarily based on
their biological sex—the male or female repro-
ductive organs they happen to be born with.
Currently, the women’s rights and gender equi-
ty movements suggest that women are treated
differently than men in our society. Inequities
26 GREY MATTERS | issue 8 GREY MATTERS | issue 8
like the gender pay gap, in which women are
paid less than men, are often justified by social-
ly constructed gender roles, such as the
expectation that women maintain the house-
hold while men work to generate income.
These gender roles are reinforced by biological-
ly driven explanations, such as sex-differences
in physical and cognitive capabilities. However,
the extent to which these differences are actu-
ally biologically rooted is uncertain. From a
cognitive standpoint, it is likely that social ex-
pectations of people could change the
development or directly influence the abilities
of a person, an effect called stereotype threat
[1]. Understanding gender is critical to under-
standing a major determinant of the roles,
rights, and power held by individuals in our so-
ciety. Where do these differences come from?
27

STRUCTURE AND FUNCTION
At a fundamental level, differences between
female and male brains are necessary. Sex dif-
ferentiation is a vital part of development, as
the interaction of gonadal hormones with our
tissues drives the development of reproductive
organs and reproductive systems (including
behavior). Indeed, people across the spectrum
develop differently in their physical character-
istics and in their behavior. Since it is so
energetically costly to produce ova, females
produce fewer gametes than males, who invest
little energy in producing large quantities of
sperm. The importance of sex differences does
not stop there, however. Females are addition-
ally tasked with gestation and postnatal
responsibilities such as increasing body fat,
breastfeeding and caring for their young. Due
to the high energetic demands of female re-
production, it makes sense that females are
more selective towards mates with more desirable
behavioral and physical characteristics. Such selectivity
implies there is a spectrum of expressed male and fe-
male characteristics. Viewing the role of sex differ-
entiation from an evolutionary standpoint provides a
possible biological explanation for the origins of a di-
chotomy in brain gender as well as cognitive-behavioral
differences that arise from such structural differences.
In order to understand how differences between brains
might result in functional and behavioral variety, it is
useful to remember the various ways that structure im-
plies function in the biological world. This relationship
is expressed from a cellular level to an organismal level.
At the microbiological scale, proteins are constructed of
long chains of small molecules called amino acids. The
three-dimensional structure of a protein determines
how it will function in cells and tissues. The primary se-
quence of amino acid residues determines the shape of
a protein and whether the protein can be readily modi-
fied by post-translational modifications. Modifying the
residues further affects protein structure. Modifications
to structure can cause a ripple effect as a protein’s speci-
ficity and activity shifts with its new structure. Indeed,
this provides an effective manner of regulating the ac-
tivity of proteins in the body. This simple example
highlights how differences or changes in structure at
the molecular level induce cascading effects on high-
er-level and large-scale functionality.
The same principle is true of structures in the brain.
Brain regions differ in their composition of cells, their
connectivity, and the types of neurotransmitters used,
to name only a few. As with proteins, organizational dif-
ferences between brain regions result in varying
functions of specific regions. To better understand this
relationship in the brain, we can look at the organiza-
tion of certain brain areas, what happens when a
structure is damaged, and the extent to which the struc-
ture of the brain changes throughout life.
Before delving into sex differences, let’s take a look at
different organizational roles in the brain that are well
studied. The brain demonstrates the relationship be-
tween structure and function in its somatotopic
arrangement of sensory and motor cortices. Since the
1930s, human brain mapping research has consistently
demonstrated there are functional regions within the
somatosensory strip, which “map” and correspond to
different body parts. This observation is explained by
the principle that some areas of the body—appendages,
digits, lips, nose, face—require finer motor control or a
greater ability to discern between different sensations,
and thus occupy more neural “real estate.” The regions
of the cortex correlating to these high-demand senses
or precise motor movements will require a greater num-
ber of neurons than less-accurate or precise functions
of the body.
Moreover, noticeable differences exist between struc-
tural organization of the sensorimotor strip when we
compare somatotopic maps across species. Speech, ma-
nipulation of objects, and facial expressions are
incredibly salient to humans, so hands and lips are rep-
resented in larger regions on the human somatotopic
map. By contrast, the rat brain has a disproportionately
large part of its somatosensory cortex dedicated to fa-
cial whiskers, and raccoons over-represent their paws.
These differences highlight how structures that are
more important to a species have greater cortical repre-
sentation. Variations in cortical representation by
means of different receptor densities (i.e., variation in
structure) imply different function or limitations in
function of the corresponding body part.
The notion that structural differences at the cellular lev-
el of neural circuitry can affect overall behavioral
function (e.g., sensory input, motor output) in humans
leads us to question whether more abstract and com-
plex functions are regulated by varying structures and
varying receptor densities. It is likely then, that among
humans, structural differences between individual
brains, such as receptor density variation, might play an
important role in more abstract human aspects like cog-
nition and behavior. This pattern suggests structural
differences between the brains of men and women
could cause the observed behavioral differences that
have been reported.
SEXUAL DIFFERENTIATION IN THE
BRAIN
Cognitive differences between women and men have
been widely studied using spatial reasoning tasks.
Differences seem to exist in patterns of ability rather
than in overall level of intelligence as measured by IQ
tests [2]. Men have been shown to perform better at
certain spatial reasoning tests that focus on object rota-
tion or navigation, whereas women perform better at
spatial reasoning tasks that focus on object location
memory. This finding is significant because it chal-
lenged the previous notion that men excel on all spatial
tasks compared to women. Men were also found to per-
form better on mathematical reasoning and targeting
accuracy, and women were found to have larger color
vocabularies, better verbal memory, and better perfor-
mance on a finger dexterity test [2].
Language processing has also been studied with the ob-
jective of discovering cognitive differences between
men and women. FMRI studies indicate that during
phonological tasks, brain activation in males is localized
to the left inferior frontal gyrus region, commonly
known as Broca’s Area, whereas in females the activa-
tion patterns engage more diffuse neural systems
including both the left and right inferior frontal gyri [3].
This demonstrates variation between sexes in the func-
tional organization of the brain at the level of
phonological processing, which further suggests that
variation in structure arises between men and women
and could underlie behavioral differences.
It is easy to make the assumption that behavioral differ-
ences between men and women likely have underlying
structural differences in the associated neural correlates.
We see a range of cognitive abilities between men and
women across a variety of cognitive functions, so the
next necessary question becomes whether or not these
cognitive differences are actually grounded in structural
differences, and if so, whether these differences are de-
termined by sex or by other influences.
Identifying the relationship between structure and
function can be complicated in an organ like the brain.
Vries and Södersten identify a few particular reasons
why it is so tricky [4]. For example, relating neural cir-
cuitry to function is difficult in the first place. In the
roughly fifty years that advanced techniques have
allowed us to study the electrophysiological and ana-
tomical correlates of behavior, the primary areas of

28 GREY MATTERS | issue 8 GREY MATTERS | issue 8 29

focus have been motor and sensory areas of the brain,
because stimulus elicits a direct response in either
muscle contraction or neuronal firing. Beyond these
regions, processing only gets more complex, less ana-
tomically accessible to study, and further removed from
quantifiable, behavioral responses. This is especially
true in regions critical to “higher level” cognitive pro-
cessing, such as the association cortices and the
hippocampus. There are also structural variations be-
tween brains that can complicate this process, and
observed behavioral differences between men and
women are likely influenced by a host of other environ-
mental factors [4].
In 1959, Phoenix, Goy, Gerrall, and Young published a
paper about the effect of administered testosterone on
tissues mediating behavior [5]. This paper drastically
changed the way behavior was studied and thought
about. It had been recognized for years that gonadal
steroids affect sexual differentiation. Phoenix et al.’s
groundbreaking study proposed that steroids actually
physically change the tissues mediating behavior—in
other words, the brain. Up until this point, it was gener-
ally assumed that hormones themselves were direct
effectors of behavior that acted on peripheral systems
[6]. Since publication of the 1959 paper, Phoenix et al.’s
theory has been expanded and refined, and is now
known as the organizational hypothesis [5]. This hy-
pothesis postulates that during development, hormones
have an irreversible organizational effect on the struc-
ture of the brain, resulting in masculine or feminine
phenotypes. Further, after the brain has been “orga-
nized,” hormones activate or inactivate these already
established pathways later in life, producing sex-specific
behavior.
A series of experiments since 1959 have explored varying
levels of the organizational hypothesis. Of particular in-
terest are recent studies examining hormonal effects on
the hippocampus. The hippocampus is central to coor-
dinating higher cognitive function, and thus could be
implicated in cognitive differences between men and
women. Indeed, MRI scans have shown that women
30 GREY MATTERS | issue 8
tend to have larger hippocampi than men, but a smaller
amygdala, the structure in the limbic system of the
brain that mediates fear and emotional responses [7].
This finding correlates with the presence of estrogen re-
ceptors in the hippocampus, and androgen receptors in
the amygdala [8]. Gould and Woolley performed a study
that showed estrogen stimulates synaptogenesis—the
generation of new connections between neurons—in
the hippocampus of adults, which increases excitability,
suggesting that estrogen has an activational effect on
the hippocampus by physically changing the morpholo-
gy of its neurons [8]. It has been proposed that estrogen
stimulates synaptogenesis through the activation of
neurotrophic factors, such as brain-derived neurotroph-
ic factor (BDNF), which triggers neurogenesis [9].
However, this elucidates another key difference
between the action of male hormones and female hor-
mones. Where estrogen increases BDNF production,
androgen actually has dampening effects on BDNF [10].
In other words, the most basal difference between males
and females, sex hormones, differentially regulate the
neurogenesis and synaptogenesis of various structures
throughout the brain. A hormone specific to females
can activate the development and growth of the hippo-
campus and its synapses, which could in turn
result in behavioral differences. The idea that sex hor-
mones alter the physical structure of the brain is
groundbreaking, and has led to serious advances in our within society have the potential to influence research scores in the past can be explained by environmental
understanding of how male and female brains might methods as well as the portrayal of results. We see this and societal factors, and most likely does not reflect
differentiate. Although these insights are valuable, they occurring in how patterns of observed cognitive differ- lower cognitive ability in females.
cannot on their own explain the variability in structure ences between men and women have been shown to
and behavior between men and women that we see to- change over time, coinciding with changing societal The studies mentioned previously that focus on cogni-
day. How these structural differences actually manifest perceptions of women. A 1995 study published in the tive differences between males and females examine
in behavioral changes is unclear, and we cannot ignore Psychological Bulletin revealed that performance differ- areas in which females and males excel. Although the
other factors that are known to affect behavior, such as ences between males and females on the Scholastic aim of these studies is not to highlight any deficits pres-
social norms and stereotypes. Although biology does Aptitude Test (SAT) and the Differential Aptitude Test ent in cognition of either males or females, there are
impact behavior, it is likely that any biological differenc- (DAT) have been shrinking in recent years [11]. many ways in which people use the existing cognitive
es are grossly exaggerated in their social forms. Additionally, they noted that changes in attitudes to- differences between males and females as an excuse for
ward women over the past several decades have reduced sexist behavior. Early studies employed sexist language
GENDER AND SOCIETY sex differences in cognitive abilities. These finding are to present data implying the differences present in the
A crucial aspect of studying the gendered brain is ac- significant because they are examples of how societal brains of males and females were decisive in determin-
knowledging the potential for societal factors to factors have the potential to influence scientific find- ing roles in society. In a study exploring the sexual
influence research outcomes. Gender inequalities ings. The larger gap between male and female test difference in spatial abilities of pine voles, the authors
GREY MATTERS | issue 8 31
used gendered language to describe their results [12].
Male voles were found to have innately “superior” spa-
tial reasoning ability compared to females, and the
authors made the assumption that this holds true in hu-
mans as well, suggesting a poorly versed knowledge of
the literature of the time. They also broadly assumed
that the same evolutionary mechanisms hypothesized
to drive the differentiation of cognitive abilities in voles
also might have driven human differentiation. The re-
searchers’ generalization of their findings on voles
produced an unnecessarily prejudiced conclusion based
on their experimental evidence. As scientists, it is im-
portant that we maintain neutrality in research and
think carefully about how this research is presented in
order to minimize potential harm that could follow.
Another issue with studying the gendered brain involves
the effects of nature vs. nurture on the formation of
gender and sexuality in an individual. While many stud-
ies haven’t found that gender identity and sexuality are
influenced by upbringing or other environmental
factors, it can be problematic to attribute gender differ-
ences to genetics or conditions in the womb. Genetics
and many other components, such as maternal stress
levels, certain drugs during pregnancy, or birth order,
have an impact on the sexuality of a child [13]. Changes
such as these often occur through a phenomenon called
epigenetics, the process by which the environment af-
fects gene expression and inheritance through processes
such as gene silencing by methylation [14]. This can lead
to heritable changes on the individual level. Thus, it is
critical that the knowledge we gain from studying the
development of gender is not used to alter the identity
of a human being, whether in the womb or after birth.
There are many other serious social implications when
introducing these ideas to the community. The idea of
“normalizing” a person who does not fit the socially con-
structed idea of how a male or female should look or act
is a real concern. There have long been efforts to change
sexuality and gender identities through different con-
version therapies, and identifying parts of the brain that
are different in these individuals is likely to increase
32 GREY MATTERS | issue 8
these movements [15]. It is im-
portant for society to understand that
the differences in brain chemistry do not suggest that
the people who fit our preconceived notions about gen-
der are normal and that those who do not meet these
notions need to be changed or fixed. Rather, these dif-
ferences should be understood as natural occurrences
that do not determine a person’s worth or position in
society.
Indeed, researching the gendered brain can also help re-
inforce these equity-positive ideas. Recently, Joel and
colleagues attempted to debunk the common interpre-
tation of documented sex/gender differences in the
brain as being supportive of sexually dimorphic human
brains (i.e., the binary of “female brain” or “male brain”)
[16]. These researchers believed this definite binary
could only be possible if the brain were also markedly
dimorphic. To investigate whether this dichotomy ex-
ists, Joel and colleagues analyzed over 1,400 different
human brain MRIs. Their findings indicated there was
significant overlap between the distribution of females
and males in terms of all the gray matter, white matter,
and neuronal connections they assessed. In other words,
it was very rare to come across a brain with only “female”
features or only “male” features. Instead, Joel and col-
leagues called most brains unique “mosaics” because
they vary on a “maleness-femaleness” continuum, with
different combinations of “male” or “female” features
[17].
LOOKING AHEAD
Despite the potentially harmful reper-
cussions, researching the gendered brain
holds the potential to have serious benefits. As
we develop a better understanding of differ-
ences between males and females, we gain
insights that help us to improve overall
wellbeing. Consistent differences in brain
chemistry and morphology suggest that mood
disorders such as depression in male and female
brains might be different in nature. Indeed, we
see different levels of the neurotransmitter sero- potential to affect and guide the development of
tonin between male and female brains, which has new treatments.
heavy ties to depression and anxiety [17]. Differences
such as this could help us understand why women see Going forward, we see intrinsic value in studying differ-
higher rates of depression than men, and could mean ences between the male and female brain. This focus in
that treatments targeting these systems could have dif- neuroscience has the potential to change our under-
ferent effects on men and women. A recent study even standing and appreciation of non-binary and LGBTQ
suggested that depression results from decreased avail- individuals. It also has the potential to influence the
ability of brain-derived neurotrophic factor, leading to way we diagnose and treat neurodegenerative disorders
atrophy of neural tissue in the hippocampus and pre- such as depression and anxiety, and how we view sex-
frontal cortex [18]. Degeneration in these areas is specific diseases and even age-related diseases. However,
compounded by chronic stress. Other studies have also we recommend researchers proceed with caution. The
targeted male-specific treatments and disorders, looking scientific community has a history of walking the line
at the possibility of androgen-reversing, age-dependent between what is ethical and what is not. It is critical
epilepsy in men, or examining the relation of BDNF to that we make achieving equity a priority in all of our ex-
hormone-related epilepsy in women [10, 9]. In general, periments and explorations, and that we present our
neurologic research increasingly points towards mal- findings with gender-positive rhetoric.
functions in hormonal systems, such as BDNF, that
differ between men and women. Given that many of References on page 50.
these systems vary significantly between men, women,
and non-binary individuals, it is important that we un-
derstand these differences and how they have the
GREY MATTERS | issue 8 33
 by Enoch Chung
art by Mara Potter
T
he brain is responsible for one’s thoughts,
memories, communication, emotions, and in-
teractions with the world. Consequently,
damage to the brain can have fundamental changes to
one’s life. Brain cancer causes one type of damage that
can result in devastating affects on the brain. Cancer
manipulates the normal function and life cycle of cells.
Normally, the body continuously grows new cells to re-
place old ones, but cancer hijacks this natural process,
preventing the replacement of old cells while still pro-
ducing new cells. This mass of cells eventually creates a
tumor.
Two divisions of cancer exist, classified according to the
manner in which they develop. The first, known as a
primary cancer, is initiated and localized in a single spot,
whereas the second, a metastatic cancer, spreads to oth-
er parts of the body from
the primary cancerous site
[1]. Cancer is also classified
based on its degree of
malignancy, or severity. A
benign tumor is not cancer-
“A vital part of treating cancerous tumors in
ous but can still damage the
the body includes developing and initiating
body by pressing on organs
the least invasive, most beneficial treatment
and vessels. Malignant tu-
for the patient.”
mors grow rapidly and
invade other parts of the brain or body, which makes
them more life-threatening [1]. A malignant tumor is
what we typically consider to be cancerous, and while
dangerous, is treatable in many cases.
UNDERSTANDING
Within the brain, there are various areas that predomi-
nantly processes distinct kinds of information. For
example, the occipital lobe processes visual information
and the hippocampus is involved with memory forma-
BRAIN CANCER
tion. Consequently, a tumor in one region of the brain
may affect a person very differently than a tumor in an-
other region. For instance, a tumor in the occipital lobe
may affect vision, while a tumor in the hippocampus
34 GREY MATTERS | issue 8 GREY MATTERS | issue 8
may cause memory impairments. Since the brain has
specialized regions for certain tasks, a loss of function
may indicate where the brain is experiencing problems,
and in the case of brain cancer, the location of a tumor.
An example of using symptoms to help pinpoint brain
tumors is demonstrated in the case of Professor P, a
neuroscientist who had a tumor on multiple cranial
nerves, including the eighth cranial nerve, responsible
for transmitting sound and balance information from
the inner ear to the brain [2]. Because of this, he experi-
enced impaired balance, hearing difficulty, numbness in
the side of the mouth, and malfunctioning tear ducts.
Based on his symptoms, Professor P. knew he had a tu-
mor that was large enough to affect cranial nerves 5
through 10. An MRI scan confirmed his suspicions, and
doctors performed surgery to remove the tumor. He
survived, but is now deaf and has partial paralysis of the
face, due to necessary cuts the doctor made on the
nerves during surgery [2].
A vital part of treating can-
cerous tumors in the body
includes developing and
initiating the least invasive,
most beneficial treatment
for the patient. One tradi-
tional cancer treatment is
chemotherapy, which in-
volves the use of drugs to
slow the rapid division of
cancer cells. However, because the drugs act on any
cells that divide quickly, they can also harm healthy
cells, such as the cells lining the mouth or intestines, or
the cells that aid in hair growth, often resulting in hair
loss for patients. A major issue for brain cancer patients
in chemotherapy treatment is that the drugs cannot
easily enter the brain. The brain has a natural protec-
tion built in, called the blood-brain barrier, and it works
to keep unwanted and dangerous molecules out of the
brain. Because the chemotherapy drugs cannot pass
through the blood-brain barrier and enter the brain it-
self, they cannot reach the tumor, and thus fail to
effectively combat the brain cancer [3].
35
 there. Thus, the benefits of avoiding the hippocampus
must be weighed against the chance of metastasis.
Recent research suggests the risk of cancer develop-
ment in the hippocampal region untreated by radiation
therapy is low, so sparing the hippocampal region may
produce more benefits and eliminate some of the nega-
tive results of whole-brain radiation therapy [6]. Despite
the risks of impaired development, seizures, and hippo-
campal damage, radiation remains one of the most
effective methods used to combat brain tumors.
resulting from radiotherapy observed in other patients.
However, it is important to remember that there are
many effective treatments, and new ones are continual-
ly being developed in order to decrease the negative
ramifications. Hopefully, with further research, we can
treat brain cancer more efficiently when it arises, and
ensure a better quality of life for survivors.
References on page 51.

Although radiotherapy is commonly used in cases of

One of the most commonly used treatments for treat-
ing brain cancer is radiotherapy, which uses radiation to
kill cancer cells. Although this method is not hindered
by the blood-brain barrier, its use is correlated with in-
creased experience of psychiatric disorders such as
anxiety and depression in patients [3]. Radiation is a re-
liable way to treat brain tumors, because its survival
rates are high relative to other treatments. However, be-
cause radiotherapy inhibits cell growth, this method
can damage healthy brain tissue and impair brain devel-
opment in young people. This is especially alarming
because the human brain continues development to at
least age twenty. Impairment from radiotherapy will
prevent the brain from maintaining optimal cognitive
performance as it matures [3]. Radiotherapy also limits
brain cancer, new research is quickly establishing alter-
natives. For example, clinical trials for a drug known as
Gefitinib, an epidermal growth factor receptor (EGFR)
inhibitor, have indicated that it may be effective in
treating EGFR-targetable lung and breast cancers [7].
Growth factors are involved in initiating cell develop-
ment, so using EGFR inhibitors prevents the abnormal
cell growth and division seen in cancer. The Gefitinib
clinical trials involved two patients with lung cancer
that metastasized to the brain. Following drug treat-
ment, researchers found complete regression of the
metastatic brain cancer in both cases. An important rea-
son behind Gefitinib’s effectiveness is that it can pass
through the blood-brain barrier, and is thus able to tar-
get the cancerous cells. Additionally, Gefitinib does not
the ability of the brain to form new neural pathways,
impair brain function (an issue with radiotherapy) be-
which may affect the patient’s capacity to change in re-
cause it does not destroy as much non-cancerous tissue,
sponse to the environment via learning and memory
making it a promising alternative to current treatment
formation [4]. Additionally, studies have shown that ra-
methods [7].
diosurgery—the destruction of certain parts of brain
tissue using radiation—is correlated with an increased
Brain cancer is an interesting and multifaceted disease
likelihood of seizures [5].
comprised of many subtypes. The symptoms of brain
cancer can vary greatly depending on where it de-
Recent research has discovered additional risks of using
velops, and treatments of brain cancer are not
radiotherapy as treatment. Radiation damage to the
perfect. Although they can help the patient
hippocampus is correlated with problems in learning
survive, treatments may have permanent
and memory [6]. Because of this, researchers believe it
adverse effects, such as the
may be advantageous to exclude the hippocampus when
physical repercussions
performing radiotherapy on the brain. However, there
experienced by Profes-
is concern that avoiding radiotherapy use in a specific
sor P. after surgery, or
part of the brain may allow the cancer to metastasize
the neurological deficits

36 GREY MATTERS | issue 8 GREY MATTERS | issue 8 37

 MDMA
THE PROSOCIAL PILL
by Kyle Steinbock
art by Alesca Delmundo
A
mericans spend approximately 100 billion
dollars annually on illicit drugs, including
Methylenedioxymethamphetamine (MDMA),
more commonly known as ecstasy [1]. Often ingested by
young adults for its social and emotional effects, the
substance has been termed a “club drug” due to its prev-
alence in nightclubs and parties. It gained recognition
in the 1970s, and despite its illegalization in the United
States during the mid-1980s, MDMA has continued to
grow in popularity [2].
38 GREY MATTERS | issue 8
MDMA causes the user to have “prosocial” behavior,
which involves the desire to contribute one’s thoughts
and emotions for the benefit of others and society [3].
Self-reports have shown elevated prosocial behavior,
friendliness, insightfulness, and sociability among
MDMA users relative to those who took a placebo.
However, the drug has also been known to amplify
self-reported feelings of anxiety and loneliness [3].
Although that is true, the positive behavioral effects of
MDMA have not only attracted recreational drug en-
thusiasts and party-seekers, but psychiatric researchers
as well. The reputation of self-acceptance and social
connectivity associated with the drug led some psychia-
trists to experiment with using MDMA as a potential
treatment for social anxiety disorders and post-trau-
matic stress disorder in the 1970s [2]. The Drug
Enforcement Agency (DEA) classified MDMA as a
Schedule I controlled substance in 1984, meaning drug
use was prohibited both medicinally and recreationally.
However, medical professionals lobbied for the DEA to
hold a hearing to debate the classification and to sched-
ule MDMA as a Schedule II controlled substance,
allowing for the legal prescription of the drug while still
prohibiting recreational use. Despite the protests from
physicians, the DEA was unwilling to compromise, and
MDMA remains unequivocally banned [2]. The media
covered the story heavily and indirectly advertised the
drug, resulting in an increased awareness that may, in
part, have contributed to further popularization [4].
The psychological and behavioral effects of MDMA have
been well documented. In 2014, Kirkpatrick et al. con-
ducted a psychological experiment
in which human subjects were
given varying doses of MDMA
and tested on their ability to
correctly identify four
emotions (happy, sad, fear-
ful, and angry) according to
computer-generated facial
expressions [3]. Using a sexual climax as delayed but
Morphed Facial Expression Task
(mFER), subjects under the influ-
ence of MDMA consistently
misidentified angry and fearful faces as displaying posi-
tive or neutral emotions. Their perceptions of the happy
faces, however, were unaffected [3]. This finding is cru-
cial to understanding the prosocial effects of the drug.
Misidentifying emotions would impact one’s ability to
communicate in a socially appropriate manner.
Many MDMA users report positive experiences associ-
ated with the drug. After polling one hundred MDMA
users from a randomly selected pool of college under-
graduates, Dr. Peroutka, Dr. Holly Newman, and Hilary
GREY MATTERS | issue 8
Harris collected firsthand accounts of MDMA experi-
ences. 90% percent of the users reported an increased
sense of “closeness,” 20% experienced brief and faint vi-
sual hallucinations, and only 2% of the pool reported
adverse long-term effects including depression, anxiety,
and jaw tightening when anxious [5]. MDMA may also
increase erotic sensation [6]. A European research team
presented subjects with sixteen photographs catego-
rized as sexually neutral, implicit, and explicit using a
sexual arousal task. The subjects were provided with
clickers that lengthened the time that an image would
remain visible. Individuals under the influence of
MDMA pressed the clicker more often in order to
lengthen the time that sexually implicit images were
visible. However, the subjects did not find the sexually
explicit images any more arousing than the placebo
group, and when interviewed, subjects who had used
MDMA in the past reported the drug increased their
erotic pleasure, but not necessarily desire [6]. Other re-
searchers have found similar results on sexual behavior
associated with MDMA. In an inter-
view-based research study, 95%
of males and 100% of females
described their sexual experi-
ence on MDMA as more
sensual than usual [7]. In the
same study, 85% of males and
53% of females described their
more intense [7]. Although the
studies are consistent, research
involving self-reports are subject
to exaggeration and should be accepted with caution.
Although MDMA is known to promote openness and a
desire for interaction, after consuming the drug users
may feel more long-term isolation and anxiety than
before consumption [8]. The phenomenon was demon-
strated in research by McGregor et al. The researchers
gave low, medium, or high doses of MDMA to three
groups of rats over four hours for two consecutive days.
The team then waited ten weeks to perform behavioral
testing in an attempt to understand the long-term
39
social consequences of the drug. After the ten weeks,
the rats were placed in an environment with control
rats and their behavior was monitored. When placed in
this environment for ten minutes, both medium- and
high-dose MDMA treatment groups displayed a de-
crease in the number of social interactions made with
other rats. The medium- and high-does rats also spent
less time engaging in each interaction relative to the
control group. The control rats averaged more than
twice the total time spent in social interactions as com-
pared to the high MDMA treatment group. The research
team then placed individual rats in a white rectangular
box with one side leading to an open field. The open
field test is an experiment used to measure social anxi-
eties in rodents, as they dislike the vulnerability
associated with open spaces. The team measured the
time it took the rats to enter the field and how long they
spent once in the open arena. Taking longer to enter an
open arena and spending less time in the arena was as-
sumed to be a sign of social anxiety. Rats that had been
given MDMA took a significantly longer time to enter
the open field and spent notably less time there. Results
of the experiment demonstrate the relatively long-term
adverse effects of MDMA on behavior. The drugged rats
showed definitive characteristics of social anxiety and
isolationist tendencies even ten weeks post-treat-
ment [8].
The social effects of
MDMA, including the
long-term behav-
ioral changes,
are due to its re-
markable impact
on neurochemistry.
One of these changes is
the release and reuptake
of serotonin, or 5-hy-
droxytryptamine (5-HT) [9].
When a neuron is activated, small pouches of neu-
rotransmitters, or vesicles, release serotonin into a
minute space between two adjacent neurons called the
synaptic cleft. The serotonin molecules interact with
40 GREY MATTERS | issue 8
receptors on the adjacent, or post-synaptic, neuron un-
til they are degraded or reabsorbed into the pre-synaptic
neuron by a serotonin transport protein. When MDMA
is introduced into the system, it acts as an antagonist of
this transport protein, blocking the protein and inhibit-
ing it from pumping serotonin back into the
pre-synaptic neuron. As a result, serotonin occupies the
space in the synaptic cleft for a longer duration and is
more likely to bind to serotonin receptors, triggering
chemical reactions and electrical signals that modify be-
havior [9]. MDMA not only inhibits the reabsorption of
serotonin into the presynaptic cell, it also inhibits its
transportation back into presynaptic vesicles [10].
Ultimately, MDMA reduces the amount of required en-
ergy available to return the serotonin back inside the
vesicles [10]. With serotonin unable to re-enter the pre-
synaptic cell and the serotonergic vesicles, it is subject
to continuous interactions with post-synaptic cells. The
ultimate outcome of this is a sense of elation for users.
MDMA targets neurons throughout the brain in areas
like the prefrontal cortex, striatum, hippocampus, and
amygdala. The prefrontal cortex is associated with so-
cial interaction, planning,
personality, and deci-
sion-making, among several
other functions
Activation of serotonergic
neurons in these regions
would likely explain the
feelings of euphoria and
closeness typical of an
MDMA experience.
When a serotonin recep-
tor is over-stimulated by a
neurotransmitter,
neuron will respond by
decreasing the number of
receptors. This process is vital to
preventing continuous over-stimulation. Chronic
over-simulation due to MDMA may be correlated with
decreased concentrations of serotonin receptors and
transporter-binding interactions [12]. Pharmacological
testing on non-human primates has shown evidence for
long-term decreases in serotonergic receptor levels.
High-performance liquid chromatography is a tech-
nique used to separate and quantify chemical
compounds in a mixture, and Dr. George Ricuarte of
Johns Hopkins used this technique when testing the
long-term effects of MDMA use on serotonin levels in
rhesus and squirrel monkeys. The primates were inject-
ed with MDMA every day for four consecutive days.
When their brains were analyzed, the primates showed
moderate depletion of serotonin marker levels, and lit-
tle to no recovery of serotonin and serotonin reuptake
protein markers 18 months after treatment [12]. This is a
notable conclusion because it provides evidence for ad-
verse long-term effects of MDMA use on the brain’s
serotonin system. Perhaps these results are related to
the long-term behavioral effects seen in rodents. A study
led by Dr. Esther O’Shea of Complutense University of
Madrid found similar results in rats, but also found evi-
dence for serotonin recovery over a 32-week period [13].
The research team administered a single dose of either
MDMA or saline solution (control) to a population of
rats. The rats were killed at 1, 2, 4, 8, and 32 weeks. Their
brains were immediately removed, and serotonin mark-
patients, but only slightly decreases recreational use.
ers were measured using high-performance liquid
This brings up the ethical and political dilemma as to
[11]. chromatography. The measured level of serotonin
whether illegalization is worth the restrictions it places
markers decreased drastically in the rats killed after 1-4
on scientific advancement. Is the substance dangerous
weeks. The rats in the 32-week treatment group showed
enough to warrant the capital and time it takes to police
signs of serotonin recovery, but did not achieve full re-
it? Would a less severe classification permitting clinical
plenishment of serotonin markers [13]. Further research
use help patients with social anxieties feel more con-
is necessary to completely understand the influence of
nected to their peers as it did in Dr. Peroutka’s study, or
MDMA on serotonin and serotonin reuptake protein
would it be conducive to long-term anxiety as was
concentrations.
shown in Dr. McGregor’s study [5, 8]? There may not be
a correct or easy answer to these questions, but further
Despite MDMA’s fascinating effects on the brain and its
research can help us make more educated and evi-
the potential for therapeutic use, it is still classified as a
dence-based decisions regarding the use of MDMA.
Schedule I controlled substance. Due to this restriction,
it is difficult to conduct clinical trials, and illegal to con-
References on page 51.
duct clinical treatments. However, the recreational use
of hallucinogens among teenagers has remained rela-
tively steady, with only a slight decline in recent years
[14]. Illegalization of potentially therapeutic drugs such
as MDMA makes it impossible to clinically treat
GREY MATTERS | issue 8 41

KEEPING
THE MIND
FIT
by Tom Gebert
art by Madeline Kernan
INTRODUCTION
As I left the doctor’s office last week, my doctor wrote a
brief note summarizing the visit. Along with the usual
administrative jargon, one prescription stood out:
“Exercise thirty minutes a day for… ever.” Those were his
words verbatim. Forever? That seemed like a hefty pre-
scription. But consistent exercise may be the only
recommendation which doctors might unequivocally
endorse. When we look to justify exercise, we usually
think of the benefits to our hearts, our lungs, our pre-
cious-yet-abused American arteries, and possibly our
muscles if we are aiming to impress. Rarely do we con-
sider the benefits of exercise that exist in the brain.
However, the evidence supporting neurological benefits
of exercise is proving to be just as robust as the evidence
for its cardiovascular benefits. Beyond simply determin-
ing that these neurological benefits exist, researchers
have made significant strides in elucidating the mech-
anistic links between exercise and the brain.
42 GREY MATTERS | issue 8
DEFINING THE COGNITIVE BENEFITS
OF EXERCISE
Before jumping into the “how” or “why,” we must un-
derstand the “what:” what are the effects of exercise on
cognition? A simple study conducted by researchers at
Stanford University answers this question nicely [1].
Researchers recruited 144 community members and
tested their memory to establish a baseline. Once base-
lines were established, the researchers split the group in
two. When tested a second time, one group showed a
significantly larger improvement in memory when
To test working memory, researchers used a standard
test called an “n-back test.” In this test, participants
watched a screen and were randomly presented with
numbers between 0 and 9. After multiple presentations,
they were then asked to identify whether the current
number matched the number seen n numbers ago, where n
could be either 1 or 2.
compared to the other. The only difference? The group
showing improvement had ridden a stationary bicycle
for 15 minutes between the trials while the control
group merely sat and waited for the same 15 minutes [1].
As reputable as Stanford may be, there is the possibility
that this study was a fluke. Perhaps the effects only hold
true for the 144 desk-ridden, Silicon Valley start-up
nerds that were recruited by the researchers. But this
study isn’t an exception. A recent meta-analysis found
79 individual research studies that documented imme-
diate cognitive benefits following exercise [2]. The
benefits they found were small, but significant
nonetheless.
Extending beyond acute effects, investigators also
demonstrated cognitive benefits associated with exer-
cise over a longer period of time. Data from a
longitudinal study at the University of Minnesota found
that individuals who were physically active in their
twenties showed better verbal memory and faster psy-
chomotor speed 25 years later [3]. More specifically,
consistent exercise was correlated with better memori-
zation and recall of a list of words, and faster matching
of symbolic representations to their corresponding
numbers [3]. Likewise, a similar study in Finland found
that low levels of physical activity in midlife are associ-
ated with a higher risk of dementia at older ages [4].
Whether short or long-term, the cognitive benefits of
exercise are supported by a substantial base of evidence.
However, none of the studies mentioned above answer
the question of “how?” How does exercise improve our
cognitive abilities? The answer to this question lies
within the hippocampus, which is a brain region in-
volved in memory formation as well as many additional
cognitive functions, ranging from navigation to the
connection of pieces of our environment into a logical
concept. Given that memory and cognition are im-
proved with exercise, it isn’t surprising that the
hippocampus is affected. One molecule in parti-
cular shows a relation to exercise’s effect on the
hippocampus.
GREY MATTERS | issue 8
BDNF
The key component in the relationship between exer-
cise and the hippocampus is an increased concentration
of a growth-promoting molecule in the hippocampus
called Brain Derived Neurotrophic Factor (BDNF). Many
studies over the past decade have noted an increased
concentration of BDNF in the brain and blood during
and after exercise, some documenting up to threefold
increases [5].
In order to understand the significance of this, it is im-
portant to understand the possible implications of
BDNF, especially in the hippocampus. BDNF is the most
widely expressed neurotrophin—a protein that pro-
motes neuron growth and connectivity—in the human
brain [6]. It is the crème de la crème of neurotrophins,
involved in a wide range of processes, from cell survival
and maturation to the production and strengthening of
connections between neurons.
While the cellular processes have important roles in
cognition, learning, and memory, perhaps the most
compelling evidence of the influence of BDNF comes
from studies directly focused on cognition itself.
Increased levels of BDNF in the blood and brain have
been associated with improved verbal, spatial, and epi-
sodic memory [5]. All of these processes involve the
hippocampus; therefore, BDNF has also been associated
with improved hippocampal functioning and increased
hippocampal size [13]. Overall, BDNF’s association with
improved cognitive functioning is a widely-accepted
phenomenon.
MECHANISM LINKING EXERCISE AND
BDNF
Until recently, the puzzle of how BDNF affects the brain
remained unsolved. Scientists knew that BDNF was as-
sociated with increased cognitive function through a
variety of means and that exercise increased hippocam-
pal BDNF levels, yet the exact molecular mechanisms
leading to this increase was unclear. Recent work at
Harvard has helped to complete the puzzle.
43
The beginning of the connection between exercise and
BDNF involves a small signaling molecule with a large
name: peroxisome proliferator-activated receptor coactiva-
tor 1 (PGC1-α). During exercise, the concentration of
PGC1-α is increased in muscles. PGC1-α causes muscles
to release a molecule called irisin into the bloodstream
[15]. In 2013, the Spiegelman lab at Harvard University
was able to show an analogous pathway also occurred in
the neurons of the hippocampus during exercise. So,
due to increased expression within the hippocampus,
elevated secretion by muscle, or a combination of both,
irisin levels in the hippocampus rise during exercise [15].
The next step in this pathway is the key connection be-
tween exercise and brain function.
The cause of increased PGC1-α expression is still
unknown, but researchers hypothesize that it is
initiated by metabolic cues with the primary purpose
of inducing processes necessary to sustain elevated
metabolic activity [14]. In essence, this would mean
that when a cell senses high levels of exertion, PGC1-α
is synthesized in higher amounts in order to ramp up
processes like sugar breakdown.
Spiegelman and other Harvard researchers showed a
positive effect of irisin on the synthesis of BDNF in the
hippocampus [15]. By increasing the levels of irisin cir-
culating in the blood of mice, Spiegelman found a
subsequent increase in the expression of BDNF in the
hippocampus. Furthermore, when researchers reduced
irisin levels, the mice showed significantly depressed
levels of BDNF. Clearly, irisin plays a vital role in posi-
tively regulating the expression of BDNF. With this
work, a pathway between exercise and improved cogni-
tion was clear: when we exercise, our muscle cells
synthesize an augmented level of PGC1-α. Increased
PGC1-α causes our muscles to release an increased
amount of irisin into the bloodstream. Irisin then posi-
tively influences the expression of BDNF in the
hippocampus, and BDNF promotes a variety of cellular
44 GREY MATTERS | issue 8
and neuronal processes associated with cognition [15].
While lengthy and intricate, this pathway convincingly
connects exercise and cognition.
EXPLAINING THE SHORT-TERM
BENEFITS
While the aforementioned pathway is a plausible expla-
nation of the long-term cognitive benefits of exercise,
the time required for this process is likely too long to
explain the acute cognitive benefits experienced after a
bout of moderate exercise. The process induced by
BDNF may take hours or even days, yet our brains expe-
rience cognitive benefits nearly immediately after
exercise. The more immediate benefits are likely attrib-
utable to other factors. One such factor may be a state
of arousal. During exercise, the levels of adrenaline and
norepinephrine circulating in the blood increase, acti-
vating the sympathetic nervous system, which
heightens alertness and reactivity. Extreme increases in
these levels cause a phenomenon known as the “fight-
or-flight” response, which facilitates many cognitive
processes [16]. It is important to realize that the rela-
tionship between arousal and performance or cognition
exists upon an inverted U-shaped curve, meaning that
while some degree of arousal can enhance our cognitive
processes, too much or too little can be detrimental.
Since exercise induces arousal, this suggests that the re-
lationship between exercise and cognition may work
around a similar sweet spot [17].
Alternatively, some have suggested the improved cogni-
tion immediately following exercise may be due to an
increased amount of oxygen being delivered to the
brain. As we all have experienced, our heart rate in-
creases when we exercise. This increases the amount of
blood flowing to our brains, thus increasing oxygen and
nutrient availability. The hypothesis is that since oxy-
gen supports the neural and metabolic activity
underlying cognition, increasing oxygen delivery
would thereby increase cognitive ability. A 2015 study
supported this hypothesis by showing a positive correla-
tion between exercise, blood flow to the brain, and
cognitive performance [18].
LEARN MORE ABOUT BDNF
At the cellular level, the most rudimentary function of
BDNF is its promotion of cell survival. When applied to a
dish containing embryonic neural stem cells—the pre-
cursors to neurons—BDNF promotes survival and
development into adult neurons [7, 8]. Furthermore,
when researchers directly infused BDNF into the hippo-
campus of living rats, they found a subsequent increase
in the number of adult-born neurons [9]. Neurogenesis,
or the creation of new neurons, is rare in adulthood, but
recent work has confirmed that it does occur in the hip-
pocampus and that it may be a vital component of
learning and memory [10].
Beyond neurogenesis, BDNF also plays a role in synapse
formation and maturation. Upon application of BDNF,
the number of both excitatory and inhibitory synapses
between cultured hippocampal neurons increases. BDNF
increases the expression of various proteins necessary
for synapse formation, vesicle release, and neurotrans-
mitter synthesis [11]. This suggests that BDNF increases
BEYOND COGNITION
Beyond the benefits to memory, exercise also shows
marked benefits in our mood, affect, and the symptoms
of many mental health disorders. To explain these ef-
fects, researchers focused on other molecules generated
during exercise. Namely, endorphins—our body’s self-
made painkillers—and endocannabinoids, which are
molecules involved in a system best known for its role
in the marijuana high.
The endorphin hypothesis began in the late 1980s when
researchers noted a large increase in the concentration
of one particular endorphin in the blood of male volun-
teers during exercise [19]. At this point, endorphins had
already been characterized as endogenous opioid anal-
gesics. Because of this, researchers hypothesized that
endorphins were the link between exercise and
GREY MATTERS | issue 8
the ability of hippocampal neurons to communicate with
their neighbors via neurochemical connections, a vital
component of association learning and cognition.
Finally, work using living neurons isolated in a dish sug-
gests that BDNF enhances long-term potentiation
(LTP)—the process through which one neuron increases
its ability to excite another. In slices of rat hippocampus,
BDNF increased the efficiency of presynaptic neu-
rotransmitter release during high frequency stimulation,
elevating the extent of long-term potentiation [12]. In
the presence of BDNF, a lower frequency or a shorter
duration of the same frequency could elicit the same
amount of LTP as compared to trials not involving BDNF.
In other words, BDNF lessened the amount of stimula-
tion needed to induce LTP. In insect and animal models
ranging from bees to primates, LTP is a vital component
of memory formation and cognition. Facilitating LTP is
therefore likely to also aid the higher order cognitive
processes that LTP supports.
improved mood. While the endorphin hypothesis was
well received and highly distributed by the popular
press, scientists now criticize it as overly simplistic and
flawed [20]. One glaring issue with the hypothesis is
that all of the human studies measured an increase in
endorphin concentration in the blood, but none have
shown an increased concentration in the brain. Since
endorphins are relatively large molecules that cannot
cross the blood-brain barrier, increased blood concen-
trations are likely due to increased peripheral release,
which is independent of the effects on mood [20].
However, more recent studies suggest that aerobic exer-
cise may activate the endocannabinoid system, which
could underlie the effects seen on mood [21]. Unlike en-
dorphins, endocannabinoids are able to cross the
blood-brain barrier. Given this, endocannabinoids may
45
be a more promising connection between exercise and
mood. In 2015, a research group in Germany used mice
to test the endocannabinoid hypothesis [22]. Mice that
were given an exercise wheel showed elevated levels of
endocannabinoids in both the fluid surrounding the
brain (CSF) and the blood. Additionally, these mice
showed fewer anxiety-related behaviors. However, when
the mice were injected with an endocannabinoid block-
er before exercising, there was no reduction in anxiety
behaviors [22]. Given this study and others like it, endo-
cannabinoids, rather than endorphins, may be the
mediator between exercise and mood improvements.
Beyond hypotheses involving hormones, some research-
ers have also proposed hypotheses involving neural
activation to account for the observed effects of exercise
on mood. The “cross-stressor adaptation hypothesis”
is one such example. Under this model, researchers
believe that exercise excites the hypothalamic-pitu-
itary-adrenal axis, which is responsible for the stress
46 GREY MATTERS | issue 8
responses. Over time, the nervous system adapts to the
exercise-induced stress, making it less sensitive to stress
in everyday situations. Researchers suggest that this ad-
aptation may then carry over into our everyday lives,
improving our mood and making us better able to cope
with stress and anxiety [23].
CONCLUSION
In examining the relationship between exercise and our
brains, we are reminded of the power of our conscious
decisions over our bodies. We often overlook this aspect
of the bidirectional relationship between brain and be-
havior. We have no trouble understanding that the
activity in our brains can directly influence our behav-
ior, but behavior influencing the activity of our brains is
less intuitive. If we ingest a hallucinogenic drug, it is
easy to say that the behavior of ingestion in this case
had the power to influence our brain activity, but when
we run a couple of laps around the track, we don’t often
think in this way. Studies like those cited here remind
us of the importance of how we live and what we do.
Our mental abilities and cognitive capacities seem to
dictate much of our daily lives, but so too do our daily
lives influence our mental abilities and cognitive
capacities.
While the mental benefits of exercise are well docu-
mented in the scientific community, exercise still
certainly receives more acclaim due to its cardiovascular
and metabolic benefits. Although it would be futile to
argue the significance of one kind of benefit over the
other, the two may provide differing degrees of motiva-
tion for different people. So when my doctor tells me to
“exercise 30 minutes a day for…ever” in order to keep my
body fit, perhaps he should mention the potential to
keep my mind fit as well.
References on page 52.
REFERENCES
Functioning. Annual Review of Nutrition, 23(1): 41-58. doi:
MICRO N U TRIEN TS AN D N EU RAL 10.1146/annurev.nutr.23.020102.075739
DEVELO PMEN T 13. Connor, J.R., & Menizes S.L. (1996). Relationship of iron to
oligodendrocytes and myelination. Glia, 17(2): 83-89.
by Jasmine Shen, art by Cassandra Chee
PAGE 4
14. Beard. J.L, Wiesinger J.A., & Connor J.R. (2003). Pre- and
postweaning iron deficiency alters myelination in Sprague-
1. Committee on Micronutrient Deficiencies, Board on
Dawley rats. Developmental Neuroscience, 25(5): 308-315.
International Health, Food and Nutrition Board. (1998).
doi: 73507
Prevention of Micronutrient Deficiencies: Tools for
15. Fleming, R.E. (2002). Cord serum ferritin levels, fetal iron
Policymakers and Public Health Workers. Washington
status, and neurodevelopmental outcomes: Correlations
D.C.: National Academies Press.
and confounding variables. The Journal of Pediatrics
2. Bailey, R.L., West Jr. K.P., & Black R.E. (2015). The
140(2): 145-148. doi: 10.1067/mpd.2002.121931
Epidemiology of Global Micronutrient Deficiencies.
16. Armony-Sivan R., Eidelman A.I., Lanir A., Sredni D., &
Annals of Nutrition and Metabolism 66(2). doi:
Yehuda S. (2004). Iron status and neurobehavioral develop-
10.1159/000371618
ment of premature infants. Journal of Perinatology 24(12):
3. Mark, H.E., Houghton, L.A., Gibson, R.S., Monterrosa E.,
757-762. doi: 10.1038/sj.jp.7211178
and Kraemer K. (2016). Estimating dietary micronutrient
17. World Health Organization. Neurological disorders associ-
supply and the prevalence of inadequate intakes from na-
ated with malnutrition. Retrieved from http://www.who.
tional Food Balance Sheets in the South Asia region. Asia
int/mental_health/neurology/chapter_3_b_neuro_disor-
Pacific Journal of Clinical Nutrition 25(2): 368-376.
ders_public_h_challenges.pdf
4. National Institute of Health. (2015, February). Spina Bifida
18. Tamura, T., Goldenberg, R.L., Hou, J., Johnston, K.E.,
Fact Sheet. Retrieved from http://www.ninds.nih.gov/dis-
Cliver, S.P., Ramey, S.L., & Nelson K.G. (2002). Cord serum
orders/spina_bifida/detail_spina_bifida.htm
ferritin concentrations and mental and psychomotor de-
5. Georgieff, M.K. (2007). Nutrition and the developing brain:
velopment of children at five years of age. Journal of
nutrient priorities and measurement. The American
Pediatrics 120(2): 16-170. doi: 10.1067/mpd.2002.120688
Journal of Clinical Nutrition 85(2): 614S-620S.
19. Lozoff, B., Jimenez, E., Hagen, J., Mollen, E., & Wolf, A.W.
6. Bear, M.F., Connors, B.W., & Paradiso M.A. (2016).
(2000). Poorer behavioral and developmental outcome
Neuroscience: Exploring the Brain. Philadelphia, PA:
more than 10 years after treatment for iron deficiency in
Wolters Kluwer.
infancy. Pediatrics 105(4): E51.
7. An Introduction to Nutrition. (2012). Unnamed Publisher.
20. Sreenivasa, B., Kumar, G. V., & Manjunatha, B. (2015). Study
8. Blencowe, H., Cousens, S., Bernadette, M., & Lawn, J.
of Role of Iron Deficiency Anaemia in Febrile Seizures in
(2010). Folic acid to reduce neonatal mortality from neural
Children in a Tertiary Care Centre. Journal Of Nepal
tube disorders. International Journal of Epidemiology
Paediatric Society, 35(2), 148-151. doi:10.3126/jnps.
39(1): i110-i121. doi: 10.1093/ije/dyq028
v35i2.12845
9. Christianson A., Howson C.P., & Modell B. (2006). March
21. Black, R.E., et al. (2013). Maternal and child undernutrition
of Dimes Global Report on Birth Defects: The Hidden Toll
and overweight in low-income and middle-income coun-
of Dying and Disabled Children. March of Dimes Birth
tries. The Lancet 382(9890): 427-451. doi: 10.1016/
Defects Foundation.
S0140-6736(13)60937-X
10. Pacheo Santos, L.M., Reyes Lecca, R.C., Cortez-Escalante,
22. Dunn, J.T. (1992). Iodine Deficiency—The Next Target for
J.J., Sanchez, M.N., & Rodrigues, H.G. (2016). Prevention of
Elimination? The New England Journal of Medicine 326:
neural tube defects by the fortification of flour with folic
267-268. doi: 10.1056/NEJM199201233260411
acid: a population-based retrospective study in Brazil.
23. Black, M.M. (2003). Micronutrient Deficiencies and
Bulletin Of the World Health Organization, 94(1), 22-29.
Cognitive Functioning. Journal of Nutrition 133(11):
doi: 10.2471/BLT.14.151365
3927S-3931S.
11. Binder, A.M., & Michels, K. B. (2013). The casual effect of
24. Djunadedi, E., Sommer, A., Pandiji, A., et al. (1988). Impact
red blood cell folate on genome-wide methylation in cord
of Vitamin A Supplementation on Xerophthalmia. Arch
blood: a Mendelian randomization approach. BMC
Opthalmol 106(2): 218-222. doi 10.1001/
Bioinformatics, 12(1), 1-21. doi: 10.1186/1471-2105-14-353
archopht.1988.01060130228033
12. Beard, J.L, & Connor, J.R. (2003). Iron Status and Neural
GREY MATTERS | issue 8 47
REFERENCES
RA BID
by Evan Lester, art by Keaton Weil
PAGE 9
1. Rabies: Fact Sheet. (2016). Retrieved April 6, 2016, from
http://www.who.int.offcampus.lib.washington.edu/media-
centre/factsheets/fs099/en/
2. Nassi, J. J., Cepko, C. L., Born, R. T., & Beier, K. T. (2015).
Neuroanatomy goes viral!Front. Neuroanat. Frontiers in
Neuroanatomy, 9.
3. Greene, C. E. (2006). Infectious diseases of the dog and cat
(3rd ed.). Elsevier.
4. Ludlow, M., Kortekaas, J., Herden, C., Hoffmann, B., Tappe,
D., Trebst, C., . . . Osterhaus, A. D. (2015). Neurotropic virus
infections as the cause of immediate and delayed neuropa-
thology. Acta Neuropathologica Acta Neuropathol, 131(2),
159-184.
5. Engelhardt, B., & Coisne, C. (2011). Fluids and barriers of
the CNS establish immune privilege by confining immune
surveillance to a two-walled castle moat surrounding the
CNS castle. Fluids Barriers CNS Fluids and Barriers of the
CNS,8(1), 4. doi:10.1186/2045-8118-8-4
6. Mitrabhakdi, E., Shuangshoti, S., Wannakrairot, P., Lewis,
R. A., Susuki, K., Laothamatas, J., & Hemachudha, T. (2005).
Difference in neuropathogenetic mechanisms in human
furious and paralytic rabies. Journal of the Neurological
Sciences, 238(1-2), 3-10. doi:10.1016/j.jns.2005.05.004
7. Ménager, P., Roux, P., Mégret, F., Bourgeois, J., Sourd, A. L.,
Danckaert, A., . . . Lafon, M. (2009). Toll-Like Receptor 3
(TLR3) Plays a Major Role in the Formation of Rabies Virus
Negri Bodies. PLoS Pathog PLoS Pathogens, 5(2).
doi:10.1371/journal.ppat.1000315
8. Hemachudha, T., Wacharapluesadee, S., Mitrabhakdi, E.,
Wilde, H., Morimoto, K., & Lewis, A. R. (2005).
Pathophysiology of human paralytic rabies. Journal of
NeuroVirology, 11(1), 93-100.
9. Laothamatas, J., Wacharapluesadee, S., Lumlertdacha, B.,
Ampawong, S., Tepsumethanon, V., Shuangshoti, S., & ...
Hemachudha, T. (2008). Furious and paralytic rabies of ca-
nine origin: Neuroimaging with virological and cytokine
studies. Journal Of Neurovirology, 14(2), 119-129.
doi:10.1080/13550280701883857
10. Aramburo, A., Willoughby, R. E., Bollen, A. W., Glaser, C.
A., Hsieh, C. J., Davis, S. L., . . . Roy-Burman, A. (2011).
Failure of the Milwaukee Protocol in a Child With Rabies.
Clinical Infectious Diseases, 53(6), 572-574. doi:10.1093/cid/
48 GREY MATTERS | issue 8
cir483
11. Willoughby, R. E., Tieves, K. S., Hoffman, G. M., Ghanayem,
N. S., Amlie-Lefond, C. M., Schwabe, M. J., . . . Rupprecht,
C. E. (2005). Survival after Treatment of Rabies with
Induction of Coma. New England Journal of Medicine N
Engl J Med, 352(24), 2508-2514. doi:10.1056/nejmoa050382
12. Frederick A. Zeiler and Alan C. Jackson (2016). Critical
Appraisal of the Milwaukee Protocol for Rabies: This
Failed Approach Should Be Abandoned. Canadian Journal
of Neurological Sciences / Journal Canadien des Sciences
Neurologiques, 43, pp 44-51. doi:10.1017/cjn.2015.331.
13. Gilbert, A. T., Petersen, B. W., Recuenco, S., Niezgoda, M.,
Gomez, J., Laguna-Torres, V. A., & Rupprecht, C. (2012).
Evidence of Rabies Virus Exposure among Humans in the
Peruvian Amazon. American Journal of Tropical Medicine
and Hygiene, 87(2), 206-215. doi:10.4269/
ajtmh.2012.11-0689
14. Both, L., Banyard, A. C., Dolleweerd, C. V., Horton, D. L.,
Ma, J. K., & Fooks, A. R. (2012). Passive immunity in the
prevention of rabies. The Lancet Infectious Diseases, 12(5),
397-407. doi:10.1016/s1473-3099(11)70340-1
15. Jackson, A. C. (2013). Current and future approaches to the
therapy of human rabies. Antiviral Research, 99(1), 61-67.
doi:10.1016/j.antiviral.2013.01.003
EXP LORI NG DEEP I NTO
PA RK I NS ON’S
by Brian Hou, art by Sarah Beasley
PAGE 14
1. Liu, C., Li, C., Lee, P., & Sun, Y. (2016). Variations in
Incidence and Prevalence of Parkinson’s Disease in
Taiwan: A Population-Based Nationwide Study.
Parkinson’s Disease, 2016, 1-8. doi:10.1155/2016/8756359
2. Berardelli, A. (2001). Pathophysiology of bradykinesia in
Parkinson’s disease. Brain, 124(11), 2131-2146. doi:10.1093/
brain/124.11.2131
3. Gröger, A., Kolb, R., Schäfer, R., & Klose, U. (2014).
Dopamine Reduction in the Substantia Nigra of
Parkinson’s Disease Patients Confirmed by In Vivo
Magnetic Resonance Spectroscopic Imaging. PLoS ONE,
9(1). doi:10.1371/journal.pone.0084081
4. Brunoni, A. R., Nitsche, M. A., Bolognini, N., Bikson, M.,
Wagner, T., Merabet, L., . . . Fregni, F. (2012). Clinical re-
search with transcranial direct current stimulation (tDCS):
Challenges and future directions. Brain Stimulation, 5(3),
175-195. doi:10.1016/j.brs.2011.03.002
REFERENCES
5. Eriksson PS, Perfilieva E, Björk-Eriksson T, et al.:
Neurogenesis in the adult human hippocampus. Nat Med APH ASIA: AN AC Q UIR ED
1998; 4:1313–1317 CrossRef, Medline LAN GU AGE DISO R D ER
6. Tortella, G., Casati, R., Aparicio, L., Mantovani, A., Senco,
by Jonathan Lam, art by Mara Potter
N., Urso, G., Brunoni, A. (n.d.) March 22, 2015. Transcranial
PAGE 16
Direct Current Stimulation in Psychiatric Disorders.
1. Fitch WT. Unity and Diversity in Human Language. (2011).
5(1):88-102. doi: 10.5498/wjp.v5.i1.88.
Philosophical Transactions of the Royal Society of London.
7. Manenti, R., Brambilla, M., Benussi, A., Rosini, S., Cobelli,
Series B, Biological Sciences. 366: 376-388.
C., Ferrari, C., Cotelli, M. (2016). Mild cognitive impair-
2. Pedersen PM, Jorgensen HS, Nakayama H, Raaschou HO,
ment in Parkinson’s disease is improved by transcranial
and Olsen TS. Aphasia in Acute Stroke: Incidence,
direct current stimulation combined with physical therapy.
Determinants, and Recovery. (1995). Annals of Neurology.
Movement Disorders Mov Disord. doi:10.1002/mds.26561
38: 659-666.
8. Yokoi, Y., & Sumiyoshi, T. (2015). Application of transcrani-
3. “Stroke.” American Speech-Language-Hearing Association.
al direct current stimulation to psychiatric disorders:
Web. <http://www.asha.org/public/speech/disorders/
Trends and perspectives. Neuropsychiatr Electrophysiol
Stroke>
Neuropsychiatric Electrophysiology, 1(1). doi:10.1186/
4. Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ,
s40810-015-0012-x
Culebras A, Elkind M, George MG, Hamdan, AD, and
9. Okun, M. (n.d.). Deep-Brain Stimulation for Parkinson’s
Higashida RT et. al. An Updated Definition of Stroke for
Disease — NEJM. Retrieved April 10, 2016, 2012; 367:1529-
the 21st Century. (2013). Stroke. 44: 2064-2089.
1538 DOI: 10.1056/NEJMct1208070
5. Finger S. Pioneers of Neurology: Paul Broca (1824-1880).
10. Martinez-Ramirez, D., Hu, W., Bona, A. R., Okun, M. S., &
(2004). Journal of Neurology. 251: 769-770.
Shukla, A. W. (2015). Update on deep brain stimulation in
6. Dewitt I and Rauschecker JP. Wernicke’s Area Revisited:
Parkinson’s disease. Transl Neurodegener Translational
Parallel Streams and Word Processing. (2013). Brain
Neurodegeneration, 4(1). doi:10.1186/s40035-015-0034-0
Language. 127: 181-191.
11. Gorgulho, A., Juillard, C., Uslan, D. Z., Tajik, K., Aurasteh,
7. Bernal B, Ardila A. The Role of the Arcuate Fasciculus in
P., Behnke, E., . . . Salles, A. A. (2009). Infection following
Conduction Aphasia. (2009). Brain: A Journal of Neurology.
deep brain stimulator implantation performed in the con-
132: 2309-2316.
ventional versus magnetic resonance imaging–equipped
8. Dick F, Bates E, Wulfeck B, Utman J, Dronker N, and
operating room. Journal of Neurosurgery, 110(2), 239-246.
Gernsbacher MA. Language Deficits, Localization, and
doi:10.3171/2008.6.17603
Grammar: Evidence for a Distributive Model of Language
12. Pinsker, M., Amtage, F., Berger, M., Nikkhah, G., & Elst, L.
Breakdown in Aphasic Patients and Neurologically Intact
T. (2013). Psychiatric Side-Effects of Bilateral Deep Brain
Individuals. (2001). Psychological Review. 108: 759-788.
Stimulation for Movement Disorders. Stereotactic and
9. Scarpa M, Colombo A, Sorgato P, De Renzi E. The inci-
Functional Neurosurgery, 47-51.
dence of aphasia and global aphasia in left brain-damaged
doi:10.1007/978-3-7091-1482-7_8
patients. (1987). Cortex. 23: 331-336.
13. Haan, S. D., Rietveld, E., Stokhof, M., & Denys, D. (2015,
10. Fridriksson J, Kjartansson O, Morgan PS, Hjaltason H,
August 19). Effects of Deep Brain Stimulation on the Lived
Magnusdottir S, Bonilha L, and Rorden C. Impaired
Experience of Obsessive-Compulsive Disorder Patients: In-
Speech Repetition and Left Parietal Lobe Damage. (2010).
Depth Interviews with 18 Patients. PLoS ONE, 10(8).
Journal of Neuroscience. 30: 11057-11061.
doi:10.1371/journal.pone.0135524
11. “Aphasia: Treatment.” American Speech-Language-
14. Dubljević, V., Saigle, V., & Racine, E. (2014). The Rising
Hearing Association. Web. <http://www.asha.org/
Tide of tDCS in the Media and Academic Literature.
PRPSpecificTopic.
Neuron, 82(4), 731-736. doi:10.1016/j.neuron.2014.05.003
aspx?folderid=8589934663&section=Treatment>
12. Woldag H, Voigt N, Bley M, and Hummelsheim H.
Constraint-Induced Aphasia Therapy in the Acute Stage:
What is the Key Factor for Efficacy? A Randomized
Controlled Study. (2016). Neurorehabilitation and Neural
Repair. Epub.
GREY MATTERS | issue 8 49
REFERENCES
13. Bakheit AMO. Drug Treatment of Poststroke Aphasia.
(2014). Expert Review of Neurotherapeutics. 2: 211-217.
14. Berthier ML, Green C, Pablo Lara J, Higueras C, Barbancho
M, Davila G, and Pulvermuller F. Memantine and
Constraint-Induced Aphasia Therapy in Chronic
Poststroke Aphasia. (2009). Annals of Neurology. 65:
577-585.
15. Barbancho MA, Berthier ML, Navas-Sanchez P, Davila G,
Green-Heredia C, Garcia-Alberca JM, Ruiz-Cruces R,
Lopez-Gonzalez MV, Dawid-Milner MS, Pulvermuller F,
Pablo Lara J. Bilateral Brain Reorganization with
Memantine and Constraint-Induced Aphasia Therapy in
Chronic Post-Stroke Aphasia: An ERP Study. (2015). Brain
and Language. 145-146: 1-10.
16. “Heart Disease and Stroke Statistics – At-a-Glance.”
American Stroke Association. Web. <https://www.heart.
org/idc/groups/ahamah-public/@wcm/@sop/@smd/docu-
ments/downloadable/ucm_470704.pdf>
MI C R O G LI A : D OU B L E- C R OSSIN G
TH E BR A I N
by Danielle Sandbach, art by Keaton Weil
PAGE 20
1. Solito, E., & Sastre, M. (2012). Microglia Function in
Alzheimer’s Disease. Frontiers in Pharmacology, 3, 14.
http://doi.org/10.3389/fphar.2012.00014
2. Monji, A., Kato, T. and Kanba, S. (2009), Cytokines and
schizophrenia: Microglia hypothesis of schizophrenia.
Psychiatry and Clinical Neurosciences, 63: 257–265. doi:
10.1111/j.1440-1819.2009.01945.x
3. American Psychiatric Association. (2013). Diagnostic and
statistical manual of mental disorders (5th ed.). Arlington,
VA: American Psychiatric Publishing.
4. McGlashan, T.H, & Fenton, W.S. (1992). The Positive-
Negative Distinction in Schizophrenia: Review of Natural
History Validators. Arch Gen Psychiatry; 49(1): 63-72.
doi:10.1001/archpsyc.1992.01820010063008
S EA S O N AL A F F EC TI V E D I SOR D ER
by Saahiti Jasti, art by Anni Hong
PAGE 22
1. Partonen, T., & Lönnqvist, J. (1998). Seasonal affective dis-
order. The Lancet, 352(9137), 1369-1374. doi:10.1016/
s0140-6736(98)01015-0
50 GREY MATTERS | issue 8
2. Reghunandanan, V., & Reghunandanan, R. (2006).
Neurotransmitters of the suprachiasmatic nuclei. Journal
of Circadian Rhythms, 4, 2. http://doi.
org/10.1186/1740-3391-4-2
3. Genetic Science Learning Center. (2016, March 1) The
Time of Our Lives. Retrieved November 16, 2016,
from http://learn.genetics.utah.edu/content/basics/
clockgenes/
4. Lee, Tatiana M.C, Carl A. Blashko, Henry L. Janzen, John G.
Patterson, and Chetwyn C.H Chan. “Pathophysiological
Mechanism of Seasonal Affective Disorder.”
Pathophysiological Mechanism of Seasonal Affective
Disorder. Journal of Affective Disorders, Oct. 1997. Web. 24
Apr. 2016.
5. “Seasonal Affective Disorder (SAD).” Mental Health
America. N.p., 2016. Web. 9 May 2016.
6. Lambert, G., Reid, C., Kaye, D., Jennings, G., & Esler, M.
(2002). Effect of sunlight and season on serotonin turnover
in the brain. The Lancet, 360(9348), 1840-1842. doi:10.1016/
s0140-6736(02)11737-5
7. Rosenthal, N. E., Sack, D. A., Jacobsen, F. M., James, S. P.,
Parry, B. L., Arendt, J., . . . Wehr, T. A. (1986). Melatonin in
seasonal affective disorder and phototherapy. Journal of
Neural Transmission. Supplementum, 21, 257-267.
8. Berk, Michael, Kerrie M. Sanders, Julie A. Pasco, Felice N.
Jacka, Lana J. Williams, Amanda L. Hayles, and Seetal
Dodd. “Vitamin D Deficiency May Play a Role in
Depression.” Medical Hypotheses 69.6 (2007): 1316-319.
Web.
THE G ENDERED B RA I N
by Annalise Bond, Katalina Gomez, Jack Henry Kotnik, and
Sarah Krawczak, art by Keaton Weil
PAGE 26
1. Steele, C.M., & Aronson, J. (1995). Stereotype threat and the
intellectual test performance of African Americans. Journal
of personality and social psychology, 69(5), 797.
2. Hall, J.A.Y., & Kimura, D. (1995). Sexual orientation and
performance on sexually dimorphic motor tasks. Archives
of Sexual Behavior, 24(4), 395-407.
3. Shaywitz, B.A., Shaywitz, S.E., Pugh, K.R., Constable, T.R.,
Skudlarski, P., Fulbright, R.K.,…Gore, J.C. (1995). Sex differ-
ences in the functional organization of the brain for
language. Nature, 373, 607-609.
4. de Vries, G.J., & Södersten, P. (2009). Sex differences in the
brain: the relation between structure and function.
Hormones and behavior, 55(5), 589-596.
5. Phoenix, C.H., Goy, R.W., Gerall, A.A., & Young, W.C.
(1959). Organizing action of prenatally administered tes-
tosterone propionate on the tissues mediating mating
behavior in the female guinea pig 1. Endocrinology, 65(3),
369-382.
6. Wallen, K. (2009). The Organizational Hypothesis:
Reflections on the 50th anniversary of the publication of
Phoenix, Goy, Gerall, and Young (1959). Hormones and
Behavior, 55(5), 561-565.
7. Cosgrove, K.P., Mazure, C.M., & Staley, J.K. (2007). Evolving
knowledge of sex differences in brain structure, function,
and chemistry. Biological psychiatry, 62(8), 847-855.
8. Gould, E., Woolley, C.S., Frankfurt, M., & McEwen, B.S.
(1990). Gonadal steroids regulate dendritic spine density in
hippocampal pyramidal cells in adulthood. The Journal of
Neuroscience, 10(4), 1286-1291.
9. Scharfman, H.E., Mercurio, T.C., Goodman, J.H., Wilson,
M.A., & MacLusky, N.J. (2003). Hippocampal excitability
increases during the estrous cycle in the rat: a potential
role for brain-derived neurotrophic factor. The Journal of
neuroscience, 23(37), 11641-11652.
10. Atwi, S., McMahon, D., Scharfman, H., & MacLusky, N.J.
(2016). Androgen modulation of hippocampal structure
and function. The Neuroscientist, 22(1), 46-60.
11. Voyer, D., Voyer, S., & Bryden, M.P. (1995). Magnitude of
sex differences in spatial abilities: a meta-analysis and con-
sideration of critical variables. Psychological bulletin, 117(2),
250.
12. Gaulin, S.J., & FitzGerald, R.W. (1986). Sex differences in
spatial ability: an evolutionary hypothesis and test.
American Naturalist, 74-88.
13. Swaab, D.F. (2007). Sexual differentiation of the brain and
behavior. Best practice & research clinical endocrinology &
metabolism, 21(3), 431-444.
14. Holliday, R. (2006). Epigenetics: a historical overview.
Epigenetics, 1(2), 76-80.
15. Haldeman, D.C. (1991). Sexual orientation conversion ther-
apy for gay men and lesbians: A scientific examination.
Homosexuality: Research implications for public policy,
149, 160.
16. Joel, D. (2011). Male or female? Brains are intersex.
Frontiers in integrative neuroscience, 5(57.10), 3389.
17. Cosgrove, K.P., Mazure, C.M., & Staley, J.K. (2007).
Evolving knowledge of sex differences in brain structure,
function, and chemistry. Biological psychiatry 62(8),
847-855.
18. Duman, R.S., & Li, N. (2012). A neurotrophic hypothesis of
GREY MATTERS | issue 8
REFERENCES
depression: role of synaptogenesis in the actions of NMDA
receptor antagonists. Philosophical Transactions of the
Royal Society of London B: Biological Sciences, 367(1601),
2475-2484.
U N DERSTAN D ING B R AIN C ANC ER
by Enoch Chung, art by Mara Potter
PAGE 34
1. Primer of Brain Tumors - American Brain Tumor
Association. (n.d.). Retrieved April 12, 2016, from http://
www.abta.org/secure/about-brain-tumors-a-primer.pdf
2. Pinel, J. P. (2011). Chapter 5. In Biopsychology (8th ed.). San
Francisco, CA: Perason.
3. Bran, M., Ladea, M., Stanculescu, D., & Purnichi, T. (2016).
Psychiatric comorbidities in patients with brain tumors af-
ter radiotherapy – An intermediate report. European
Psychiatry, 33S242. doi:10.1016/j.eurpsy.2016.01.487
4. Simpson, G. K., Koh, E.-S., Whiting, D., Wright, K. M.,
Simpson, T., Firth, R., … Younan, K. (2015). Frequency, clin-
ical correlates, and ratings of behavioral changes in
primary brain tumor patients: a preliminary investigation.
Neuro-Oncology, 5, 78. http://doi.org/10.3389/
fonc.2015.00078
5. Jairam, V., Chiang, V., & Yu, J. (2015). Prognostic Factors for
Seizures After First Radiosurgical Treatment in Patients
With Brain Metastases. International Journal Of Radiation
Oncology, Biology, Physics, 93(3), E100. doi:10.1016/j.
ijrobp.2015.07.802
6. Hong, A. M., Suo, C., Valenzuela, M., Haydu, L. E.,
Jacobsen, K. D., Reisse, C. H., & Fogarty, G. (2014). Low in-
cidence of melanoma brain metastasis in the hippocampus.
Radiotherapy & Oncology, 111(1), 59-62. doi:10.1016/j.
radonc.2014.01.012
7. Chonan, M., Narita, N., & Tominaga, T. (2016). Total re-
gression of brain metastases in non-small cell lung cancer
patients harboring EGFR mutations treated with gefitinib
without radiotherapy: two case reports. BMC Research
Notes, 91-4. doi:10.1186/s13104-015-1834-0
MDMA: TH E PR O SO C IAL PIL L
by Kyle Steinbock, art by Alesca Delmundo
PAGE 38
1. Zobeck, T. (2014, March 7). How Much Do Americans
Really Spend on Drugs Each Year? Retrieved May 10, 2016,
from https://www.whitehouse.gov/blog/2014/03/07/
51
REFERENCES
how-much-do-americans-really-spend-drugs-each-year
2. Rosenbaum, M., & Doblin, R. (1999). Why MDMA Should
Not Have Been Made Illegal. Retrieved April 18, 2016, from
http://www.psychedelic-library.org/rosenbaum.htm
3. Kirkpatrick, M. G., Lee, R., Wardle, M. C., Jacob, S., & De
Wit, H. (2014). Effect of MDMA and Intranasal Oxytocin
on Social and Emotional Processing. Journal of
Neuropharmacology, 39, 1654-1663. Retrieved April 2, 2016,
from http://www.nature.com/npp/journal/v39/n7/pdf/np-
p201412a.pdf
4. Beck, J. (1986). MDMA: The popularization and resultant
implications of a recently controlled psychoactive sub-
stance. Contemporary Drug Problems, 23-63. Retrieved
April 11, 2016, from http://heinonline.org/HOL/
Page?handle=hein.journals/
condp13&div=9&g_sent=1&collection=journals#
5. Peroutka, S. J., Newman, H., & Harris, H. (1988). Subjective
Effects of 3, 4- Methylenedioxymethamphetamine in
Recreational Users. Neuropsychopharmacology, 1(4), 273-
277. Retrieved April 26, 2016, from http://www.ncbi.nlm.
nih.gov/pubmed/2908020Antonio R. Damasio.
“Impairment of Social and Moral Behavior Related to Early
Damage in Human Prefrontal Cortex.” Nature
Neuroscience 2 (1999): 1032-037. Nature.com. 9 Sept. 1999.
Web. 16 Apr. 2016
6. Yasmin, S., Cédric, H. M., Katrin, P. H., Bosch, O. G.,
Bilderbeck, A. C., Rogers, R. D., . . . Liechti, M. E. (2015).
Effects of methylphenidate and MDMA on appraisal of
erotic stimuli and intimate relationships. European
Neuropsychopharmacology, 25(1), 17-25. doi:10.1016/j.
euroneuro.2014.11.020
7. Zemishlany, Z., Aizenberg, D., & Weizman, A. (2001).
Subjective effects of MDMA (“Ecstasy”) on sexual function.
European Psychiatry, 16(2), 127-130. doi:10.1016/
S0924-9338(01)00550-8
8. McGregor, I. S., Clemens, K. J., Van der Plasse, G., Li, K. M.,
Hunt, G. E., Chen, F., & Lawrence, A. J. (2003). Increased
Anxiety 3 Months after Brief Exposure to MDMA (‘Ecstasy’)
in Rats: Association with Altered 5-HT Transporter and
Receptor Density. Neuropsychopharmacology, 28, 1472-
1484. doi:10.1038/sj.npp.1300185
9. Gary, R., & Stephen, W. C. (1992). The molecular mecha-
nism of “ecstasy” [3,4-methylenedioxy- methamphetamine
(MDMA)]: Serotonin transporters are targets for MDMA-
induced serotonin release. Proceedings of the National
Academy of Sciences of the United States of America, 89(5),
1817-1821. doi:10.1073/pnas.89.5.181
10. Rudnick, G., & Wall, S. C. (n.d.). The molecular mechanism
52 GREY MATTERS | issue 8
of “ecstasy” [3,4-methylenedioxy- methamphetamine
(MDMA)]: Serotonin transporters are targets for MDMA-
induced serotonin release. Proceedings of the National
Academy of Sciences of the United States of America, 89(5),
1817-1821. Retrieved May 1, 2016, from http://www.ncbi.
nlm.nih.gov/pmc/articles/PMC48544/
11. Anderson, Steven W., Antoine Bechara, Hanna Damasio,
Daniel Tranel, and Antonio R. Damasio. “Impairment of
Social and Moral Behavior Related to Early Damage in
Human Prefrontal Cortex.” Nature Neuroscience 2 (1999):
1032-037. Nature.com. 9 Sept. 1999. Web. 16 Apr. 2016
12. Ricaurte, G. A., Martello, A. L., Katz, J. L., & Martello, M. B.
(1992). Lasting Effects of (±)-3
,4-Methylenedioxymethamphetamine (MDMA) on Central
Serotonergic Neurons in Nonhuman Primates:
Neurochemical Observations. Journal of Pharmacology
and Experimental Therapeutics, 261(2). Retrieved April 11,
2016, from http://jpet.aspetjournals.org/content/261/2/616.
full.pdf
13. O’Shea, E., Orio, L., Escobedo, I., Sanchez, V., Camerero, J.,
Richard Green, A., & Isabel Colado, M. (2006, July).
MDMA-induced neurotoxicity: Long-term effects on
5-HTbiosynthesis and the influence of ambient tempera-
ture. British Journal of Pharmacology, 148(6), 778-785.
doi:10.1038/sj.bjp.0706783
14. Johnson, L. D., O’Malley, P. M., Miech, R. A., Bachman, J.
G., & John, S. E. (2016, February). [2015 Overview Key
Findings on Adolescent Drug Use. Retrieved September 1,
2016, from http://www.monitoringthefuture.org/pubs/
monographs/mtf-overview2015.pdf
K EEPI NG T HE MI ND FIT
by Tom Gebert, art by Madeline Kernan
PAGE 42
1. Hogan CL, Mata J, Carstensen LL. (2013). Exercise holds
immediate benefits for affect and cognition in younger and
older adults. Psychology and Aging 28:587-594
2. Chang, Y. K., Labban, J. D., Gapin, J. I., & Etnier, J. L. (2012).
The effects of acute exercise on cognitive performance: a
meta-analysis. Brain research, 1453, 87-101.
3. Zhu, N., Jacobs, D. R., Schreiner, P. J., Yaffe, K., Bryan, N.,
Launer, L. J., & Bouchard, C. (2014). Cardiorespiratory fit-
ness and cognitive function in middle age The CARDIA
Study. Neurology, 82(15), 1339-1346.
4. Tolppanen, A. M., Solomon, A., Kulmala, J., Kåreholt, I.,
Ngandu, T., Rusanen, M., & Kivipelto, M. (2015).
REFERENCES
Leisure-time physical activity from mid-to late life, body International journal of sports medicine, 15(4), 172-176.
mass index, and risk of dementia. Alzheimer’s & Dementia, 17. Tomporowski, P. D. (2003). Effects of acute bouts of exer-
11(4), 434-443. cise on cognition. Acta psychologica, 112(3), 297-324.
5. Szuhany, K. L., Bugatti, M., & Otto, M. W. (2015). A me- 18. Guiney H, Lucas SJ, Cotter JD & Machado L (2015).
ta-analytic review of the effects of exercise on Evidence cerebral blood-flow regulation mediates exer-
brain-derived neurotrophic factor. Journal of psychiatric cise-cognition links in healthy young adults.
research, 60, 56-64. Neuropsychology 29, 1–9
6. Park, H., & Poo, M. M. (2013). Neurotrophin regulation of 19. Schwarz, L., & Kindermann, W. (1992). Changes in β-en-
neural circuit development and function. Nature Reviews dorphin levels in response to aerobic and anaerobic
Neuroscience, 14(1), 7-23. exercise. Sports Medicine, 13(1), 25-36.
7. Ahmed, S., Reynolds, B. A. & Weiss, S. BDNF enhances the 20. Dietrich, A., & McDaniel, W. F. (2004). Endocannabinoids
differentiation but not the survival of CNS stem cell-de- and exercise. British Journal of Sports Medicine, 38(5),
rived neuronal precursors.
J. Neurosci. 15, 5765–5778 (1995) 536-541.
8. Shetty, A. K. & Turner, D. A. In vitro survival and differenti- 21. Sparling PB, Giuffrida A, Piomelli D, et al. Exercise acti-
ation of neurons derived from epidermal growth vates the endocannabinoid system. Neuroreport, 2003;14,
factor-responsive postnatal hippocampal stem cells: induc- 2209–11.
ing effects of brain-derived neurotrophic factor. J. 22. Fuss, J., Steinle, J., Bindila, L., Auer, M. K., Kirchherr, H.,
Neurobiol. 35, 395–425 (1998). Lutz, B., & Gass, P. (2015). A runner’s high depends on can-
9. Scharfman, H. et al. Increased neurogenesis and the ecto- nabinoid receptors in mice. Proceedings of the National
pic granule cells after intrahippocampal BDNF infusion in Academy of Sciences, 112(42), 13105-13108.
adult rats. Exp. Neurol. 192, 348–356 (2005). 23. Sothmann M. S. (2006). The cross-stressor adaptation hy-
10. Kempermann, G., & Gage, F. H. (2000, January). pothesis and exercise training, in Psychobiology of Physical
Neurogenesis in the adult hippocampus. In Neural Activity, eds Acevedo E. O., Ekkekakis P., editors.
Transplantation in Neurodegenerative Disease: Current (Champaign, IL: Human Kinetics; ), 149–160
Status and New Directions: Novartis Foundation
Symposium 231 (pp. 220-241). John Wiley & Sons, Ltd.
11. Vicario-Abejon, C., Owens, D., McKay, R. & Segal, M. Role
of neurotrophins in central synapse formation and stabili-
zation. Nature Rev. Neurosci. 3, 965–974 (2002).
12. Figurov, A., Pozzo-Miller, L. D., Olafsson, P., Wang, T. & Lu,
B. Regulation of synaptic responses to high- frequency
stimulation & LTP by neurotrophins in the hippocampus.
Nature 381, 706–709 (1996).
13. Erickson KI, Miller DL, Roecklein KA. The aging hippo-
campus: interactions between exercise, depression, and
BDNF. The Neuroscientist : a review journal bringing neu-
robiology, neurology and psychiatry. 2012; 18:82–97.
14. Handschin, C., & Spiegelman, B. M. (2006). Peroxisome
proliferator-activated receptor γ coactivator 1 coactivators,
energy homeostasis, and metabolism. Endocrine reviews,
27(7), 728-735.
15. Wrann, C. D., White, J. P., Salogiannnis, J., Laznik-
Bogoslavski, D., Wu, J., Ma, D., & Spiegelman, B. M. (2013).
Exercise induces hippocampal BDNF through a PGC-1α/
FNDC5 pathway. Cell metabolism, 18(5), 649-659.
16. Chmura, J., Nazar, K., & Kaciuba-Uściłko, H. (1994). Choice
reaction time during graded exercise in relation to blood
lactate and plasma catecholamine thresholds.
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