Neuroscience - Kenyon 2017 by Sean Bush

NEUROSCIENCE EDITION

SCIENTIFIC KENYON May 2017

kenyon.edu/neuroscience

Current Topics in Neuroscience

Letter from the Professor

The importance of communicating science to the general public. Students who attend Kenyon College receive an excellent education. This is especially true in the sciences in general, and in neuroscience in particular. Over the last two decades my colleagues and I have worked hard to grow and improve the neuroscience program and the astonishing level of success of our graduates tells its own story. Most have gone on to earn advanced degrees in the sciences and medicine and many have returned to visit us as colleagues. We are proud of their achievements and we are confident that you, members of the class of 2017, will continue this legacy of success. Your success, like that of the many scientists that went before you, make possible the medical and technological advances we enjoy as well as the astonishing national wealth of the nation. Yet, even as we celebrate this success, we cannot turn a blind eye to the current political climate that threatens the very science we rely on to improve our lives, our health, and to sustain our national wealth. If we are to continue to support science and make the kinds of investments we need to continue on this path of national success, all of our citizens must learn to embrace science and gain a genuine appreciation of the role it plays in improving their lives. We must not allow science to become a kind of closed society, understood only by those in the inner circle. That is the path to ruin as our fellow citizens, distanced from science by our lack of communication, lose interest in making the kinds of long-term investments that make it all possible. This is why we in the scientific community must get better at communicating science to the general population. No idea is so complicated that it cannot be explained and discussed in ordinary language. Over the last few years you became expert at communicating with other scientists; now you have expanded on those skills and produced a series of articles translating exciting scientific ideas and research into a form that is readable by anyone. This inaugural issue of Scientific Kenyon: The Neuroscience Edition reflects the work you did in your senior seminar. I hope that in your future lives you will continue to share the excitement of scientific research with those around you. Sincerely,

Hewlet G. McFarlane Professor and Chair Department of Neuroscience Kenyon College

Current Topics in Neuroscience

Dr. Hewlet G. McFarlane

& the Class of 2017

Contents 4

Marijuana and the Brain

Tony Amolo

The Recipe for The Perfect Zombie

Blacking Out Versus. Passing Out: What’s the Difference?

Simulating the Brain

The “Bad Student Disease”

Are Two Brains Better Than One? The Microbiome and Autism

Head Strong? Repeated Traumatic Brain Injury and Neurocognitive Degeneration

Kalkidan Aseged Adama Berndt Sean Bush

Dominic Camperchioli Kelsey Hauser

Amelia Loydpierson

ADHD: Parents’ or Physicians’ Problem?

Golf and the Brain: The Power of Motor Skill Learning

Never Gonna Give You Up: The Neuroscience of Social Attachment and Love

Sarah Naguib John O’Brien

Henry Quillian

Disordered Gambling: The Neurobiology of Nature’s Hidden Addiction

Scott Treiman

A N A U J N I I R A A R M B E H T D N A y n o T

MARIJUANA IN OUR LIVES Most people do not think of marijuana as a dangerous drug anymore. Only one study has reported death caused by marijuana1, which sets it apart from

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dangerous substances like alcohol and tobacco. Marijuana addictive properties are low compared to those drugs (Figure 1) 2. Also, evidence from research has shown that it can be used as a treatment for various medical conditions 3. In the United States, 26 states have legalized the MAY 2017

medical use of marijuana and 8 states have legalized its recreational use (Figure 2). Recent surveys have shown that, in states where its possession is still illegal, it is the most used illicit drug 14; 11% of teenagers use marijuana, while over 59% of people between the age of 26 and 34 use it 4. Even so, taken often and regularly, the drug is far from harmless. Although marijuana is rarely lethal and can be therapeutic, its effects on memory may be long-lasting—more so than one might think. MR. X AND MARIJUANA Marijuana—also known as cannabis, or colloquially as weed, pot, ganja, and bud—is a greenish mixture of Cannabis sativa 14. Its major consistent is d-9tetrahydrocannabinol (THC), a molecule in the cannabinoid family. THC is lipid soluble, which means it can easily diffuse around the body. It has a long half-life that can be detected months after ingestion 5. When ingested, it is easily absorbed in the body and can affect different areas of the brain (Figure 3). Mr. X, the subject of a case study in Genen’s article, “Cannabis-Related Disorders,” illustrates several negative manifestations of marijuana use, especially when it comes to some of the immediate, short-term effects of the drug. Though Mr. X was once a successful high school athlete, his reflexes, he now feels, are not as fast as they used to be. Previous studies have shown that short-term cannabis users took longer to complete tasks compared to control 5. In this study, Solowij et al. (2002) showed that the speed of information processing kenyon.edu/neuroscience

was delayed in cannabis users compared to controls 6. When it comes to his mental abilities, the effects are even clearer. Mr. X laments his appalling lifestyle compared to his peers. His lack of motivation and increased sense of social isolation keeps him at home for most of the day. Also, he reported difficulties in concentrating and problems with his short-term memory; though he said he is interested in being more engaged and achieving his goals, he “seems unable to explain why he cannot accomplish what he sets out to do.” Marijuana use appears to have impacted Mr. X’s ability to understand his situation. It is, therefore, important to look at how marijuana functions in the brain to understand how it has affected Mr. X’s cognitive capacity. UNDERSTANDING THE ENDOCANNABINOID SYSTEM THC in marijuana affects memory specifically by altering the normal function

Mr. X is a 19-year-old white male. Though young, this man–a subject reference in a case study by Doctor Lawrence Genen—already has cognition and memory problems, including an inability to pay attention and a difficulty remembering even recent event. X no longer recalls his dreams, and he doesn’t understand why he has trouble meeting girls. He aspires to go to college and get a job but never submits the applications. Biologically, X is an average 19-year-old guy. One habit of his stands out: he smokes WEED. SCIENTIFIC KENYON

of the endocannabinoid system in the body 7 . In humans, the endocannabinoid system plays a significant role in maintaining equilibrium and proper functioning of the nervous system 7. It is also involved in regulating and maintaining our perception of pain, mood, appetite and memory (Figure 3). You can find it throughout the central nervous system, which is composed of the brain and spinal cord, and in the peripheral nervous system— the nerves spread throughout the rest of the body. The system is responsible for producing endocannabinoids, molecules naturally secreted in the brain that bind to the cannabinoid receptors to maintain homeostasis. These receptors—the cannabinoid receptors (CB1) and 8 cannabinoid receptors (CB2) —are sites where endocannabinoids bind to execute their function. These molecules fit into the receptor like a key in a specially-formed lock. They are created by the combined release of glutamate — a chemical molecule that aids communication between neurons, from the metabotropic glutamate

receptors (mGluRs) and depolarization, created by the influx of calcium ions in the post synaptic neuron (Figure 4). The combination of both elements creates a depolarization signal and a chemical signal with a neurotransmitter, glutamate; both of these are reactions that cause the release of endocannabinoids in the neuron. Marijuana interacts with the CB1 receptors specifically, which causes its effect to be widespread, because these receptors are highly expressed in the brain (Figure 3). They are located in the hippocampus, cortex, basal ganglia and hypothalamus (8,7). In the hippocampus, CB1 receptors are expressed in GABAergic neurons, which is important because this type of neuron is the most common type in the brain7. Because the receptors are located all over the brain in these GABAergic neurons, they are able to perform their role as blockers of chemical signals8. The expression of CB1 receptors in various parts of the hippocampus and the function of the hippocampus in memory suggests

Figure 1. Comparing dependence, withdrawal, tolerance, reinforcement and intoxication of cannabis to other drugs.

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Figure 2. Marijuana Legalization Status in the United States

how drugs that bind CB1 receptors can interfere with memory. When they function normally, CB1 receptors influence the formation of new synapses and neuronal growth by activating the mitogen-activated protein (MAPK) kinase activity in the neuron 8, which aids a person’s memory and cognitive function. Studies with Patient Henry Molaison—a patient who had his hippocampus removed—showed memory impairment 11, illustrating the importance of the hippocampus in memory.

HOW THC AFFECTS THE ENDOCANNABINOID SYSTEM As we have just seen, the endocannabinoid system is widespread in the brain and contributes to the proper functioning of our memory. It does so through the activation of the postsynaptic neurons, which releases endocannabinoids that bind to the cannabinoid receptors in the presynaptic neuron 7. This is referred to

Figure 3. Cannabinoid receptors (CB1) are expressed in diffearent regions of the brain. CB1 receptors are expressed in the hippocampus. kenyon.edu/neuroscience

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Figure 4. Retrograde Signaling in the Endocannabinoid system. Activation of glutamate receptors and influx of calcium ions causes the synthesis of endocannabinoids from the postsynaptic neuron. Cannabinoids bind to CB1 receptors to inhibit neurotransmitter release. Figure 5. The structure of THC is like Anandamide, an endocannabinoid produced by the endocannabinoid system.

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as retrograde signaling (Figure 4). As a result, they inhibit and regulate the amount of neurotransmitter released from the presynaptic neuron such as glutamate, GABA 9. THC and endocannabinoids are similar in structure (Figure 5) 15. The THC molecule is like another key that happens to fit the same lock that the endocannabinoids do, and it can open the same “doors” in the brain. In other words, they have a similar binding affinity or strength to CB1 receptors 10 and affect memory by mimicking the function of endocannabinoids in the hippocampus. However, THC does not interact with these systems in the same way. One important difference exists between endocannabinoids and THC; unlike endocannabinoids, which are cleared easily at the synapse, THC is metabolized over the course of several hours. Because THC lasts longer in the body, the endocannabinoid system cannot function properly, and thus, equilibrium is disrupted. Also, when marijuana is ingested, the endocannabinoids do not get a chance to bind with their receptors, because THC competes with them for those coveted spots (Figure 6). THC creates a high because of certain regions it affects. Studies in mice have shown that THC activates the ventral tegmental dopamine neurons in the brain 11. The ventral tegmental area is implicated in the reward circuitry of the brain and activates the nucleus accumbens, which the brain’s main pleasure center. The VTA and nucleus accumbens are regions implicated in drug addiction 11. These findings MAY 2017

may help explain why THC causes addiction—because it activates a chemical “reward”—and an individual to feel ‘high’, or euphoric. Still, the effects of THC depend on the dose level and the personality of the user. It may cause either euphoria, anxiety, relaxation or dysphoria 8 . These processes show how THC in marijuana affects the brain—which led to the symptoms observed in Mr. X. kenyon.edu/neuroscience

DOES CHRONIC MARIJUANA USE CAUSE MORE HARM THAN GOOD? Above, we looked at how marijuana affects the brain the moment after it is ingested. However, research suggests that the effects of marijuana might last even after someone like Mr. X stops using the drug. Dr. Genen uses Mr. X to show the results of chronic use of marijuana over four years. Compared to non-users, heavy marijuana SCIENTIFIC KENYON

“Although marijuana is rarely lethal and can be therapeutic, its effects on memory MAY be long-lasting—more so than one might think”. users had altered brain tissue composition, even when they abstained before testing 12 . Subjects who used marijuana for a minimum of 2 years and abstained for 20 days before testing showed less brain gray matter of the right parahippocampus gyrus, which is important for memory retrieval and encoding in humans (Figure 7). Conversely, another study showed an increase in activity in some areas of the brain. There was increased activation of regions needed for spatial memory, as well as regions not typically used in spatially memory tasks, in marijuana users who have smoked more than 5000 times, compared to non-users 13. In this study, marijuana users showed the more activity in the prefrontal cortex and anterior cingulate, like non-users, but also activation in the basal ganglia, which was unusual (Figure 7). These

studies suggests two things: first, that chronic marijuana use causes a decrease in certain brain regions needed for memory, and second, that the brain tend to compensate for these deficits in other areas and work harder to meet the demand of a specific task. Mr. X fails to realize the effects of marijuana on his brain because other regions act to assist the brain regions inhibited by marijuana, so he is still able to perform the same tasks, even if brain damage has occurred. ARE THESE SYMPTOMS OBSERVED IN MR.X IRREVERSIBLE The question of whether the effects of marijuana are irreversible after cessation is quite unclear and difficult to study. However, a study has shown that cessation of cannabis use did not restore the

Figure 7. Voxel based morphometry and fmri of the brain of mar Uuana users. left- Marijuana users showed a reduction in brain matter in the left parahippocampus gyrus and the left parietal lobule. Right- Marijuana users (top right) showed increased brain activity in the middle frontal and inferior frontal gyrus, left anterior cingulate and right caudate compared to non-users during working memory task.

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Figure 8. Post cessation IQ among former persistent cannabis users. Left. Adolescent onset, who used cannabis weekly before age 18 and Right, Adult Onset, who did not use cannabis weekly before age 18.

normal neuropsychological function among cannabis users 14. The Intelligent Quotient (IQ) of marijuana users who smoked before the age of 18 or who started smoking frequently when they were adults declined even after they stopped using (Figure 8). The limitations in study, however, make it difficult to conclude whether the effects of marijuana are irreversible. For instance, the actual content of the marijuana these users consumed is unknown. The method of intake could also be a factor affecting the results, but the study cannot account for that, because it is difficult to control. Finally, marijuana is often used with other drugs, including alcohol and tobacco 12. A more controlled study will be needed to investigate whether the chronic effects caused by marijuana alone are irreversible. POSITIVE EFFECTS OF MARIJUANA Although long term use of marijuana may harm the brain, it is worth highlighting the positive effects of medical marijuana. Marijuana use has been shown to help control and decrease the symptoms of kenyon.edu/neuroscience

many diseases. As an example, it is used to treat glaucoma, a disease which increases the pressure of the eyeball and causes loss of vision—a previous study showed that marijuana can be used to reduce the pressure of the eyeball 15. Also, marijuana has been used to decrease the seizures in children with epilepsy. Parents reported a reduction in their child’s seizure frequency after cannabis intake 16. Medical marijuana use has also been implicated in preventing cancer from spreading, decreasing progressing of Alzheimer’s disease, treating anxiety and reducing the tremors in Parkinson’s disease. However, the mechanisms by which marijuana produces these diverse effects in these diseases requires further study. Even though marijuana causes several positive effects, it is important to highlight the adverse effects of chronic marijuana use. THE WAY FORWARD The findings regarding the positive and the negative effects of marijuana use on the adolescent brain need to be highlighted to SCIENTIFIC KENYON

the public, and especially to teenagers. Even though marijuana’s health effects depend on the age of the consumer, and the amount and frequency used, it seems logical that policies and preventive measures are set aside for adolescents about the use of marijuana, especially since teenagers might be at increased risk for brain damage. In addition, it’s important to understand the effects of long term marijuana use on the brain and promote research related to marijuanause in our community. As most states in the United States are legalizing marijuana for recreational use, it is likely that the number of people suffering harm, like Mr. X, will rise. A potential solution might be to find healthier ways to use of marijuana. REFERENCES  1.

Hartung B, Kauferstein S, Ritz-Timme S, Daldrup T. Sudden unexpected death under acute influence of cannabis. Forensic Sci Int. 2016;237:e11-e13. doi:10.1016/j.forsciint.2014.02.001. Ramesh D, Schlosburg JE, Wiebelhaus JM, Lichtman AH. Marijuana Dependence: Not Just Smoke and Mirrors. ILAR J. 2011;52(3):295-308. doi:10.1093/ ilar.52.3.295. Grotenhermen F, Müller-Vahl K. The Therapeutic Potential of Cannabis and Cannabinoids. Dtsch Arztebl Int. 2012;109(29-30):495-501. doi:10.3238/ arztebl.2012.0495. Yusoff N, Yuan J, Yang J. A Review of Neuropsychological Status in Cannabis Users. Procedia - Soc Behav Sci. 2013;97:2-11. doi:10.1016/j. sbspro.2013.10.198. Crean RD, Crane NA, Mason BJ. An Evidence Based Review of Acute and Long-Term Effects of Cannabis Use on Executive Cognitive Functions. J Addict Med. 2011;5(1):1-8. doi:10.1097/ ADM.0b013e31820c23fa. Solowij N, Michie PT, Fox AM. Differential

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10.

11.

12.

13.

14.

15.

impairments of selective attention due to frequency and duration of cannabis use. Biol Psychiatry. 1995;37(10):731-739. doi:10.1016/0006-3223(94)00178-6. Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science. 2002;296(5568):678-682. doi:10.1126/ science.1063545. Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu Rev Psychol. 2013;64:21-47. doi:10.1146/annurev-psych-113011-143739. Castillo PE, Younts TJ, Chávez AE, Hashimotodani Y. Endocannabinoid Signaling and Synaptic Function. Neuron. 2012;76(1):70-81. doi:http://dx.doi. org/10.1016/j.neuron.2012.09.020. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215. doi:10.1038/ sj.bjp.0707442. Lupica CR, Riegel AC, Hoffman AF. Marijuana and cannabinoid regulation of brain reward circuits. Br J Pharmacol. 2004;143(2):227-234. doi:10.1038/ sj.bjp.0705931. Matochik JA, Eldreth DA, Cadet J-L, Bolla KI. Altered brain tissue composition in heavy marijuana users. Drug Alcohol Depend. 2005;77(1):23-30. doi:10.1016/j. drugalcdep.2004.06.011. Kanayama G, Rogowska J, Pope HG, Gruber SA, Yurgelun-Todd DA. Spatial working memory in heavy cannabis users: a functional magnetic resonance imaging study. Psychopharmacology (Berl). 2004;176(3-4):239-247. doi:10.1007/ s00213-004-1885-8. Meier MH, Caspi A, Ambler A, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci . 2012;109(40):E2657-E2664. doi:10.1073/ pnas.1206820109. Zhan G-L, Camras CB, Palmberg PF, Toris CB. Effects of Marijuana on Aqueous Humor Dynamics in a Glaucoma Patient. J Glaucoma. 2005;14(2). http://journals.lww. com/glaucomajournal/Fulltext/2005/04000/ MAY 2017

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Effects_of_Marijuana_on_Aqueous_Humor_ Dynamics_in.17.aspx. Porter BE, Jacobson C. Report of a Parent Survey of Cannabidiol-Enriched Cannabis Use in Pediatric Treatment-Resistant Epilepsy. Vol 29.; 2013. doi:10.1016/j. yebeh.2013.08.037.

FURTHER READING AND SOURCES • Budney, Alan, Roger Roffman, Robert Stephens, and Denise Walker. “Marijuana Dependence and Its Treatment.” Addiction Science & Clinical Practice 4.1 (2007): 4-16. • Castillo, Pablo E., Thomas J. Younts, Andrés E. Chávez, and Yuki Hashimotodani. “Endocannabinoid Signaling and Synaptic Function.”Neuron 76.1 (2012): 70-81. • Croxford, J. Ludovic. “Therapeutic Potential of Cannabinoids in CNS Disease.”CNS Drugs 17.3 (2003): 179-202. • Fergusson, David M., and Joseph M. Boden. “Cannabis Use and Later Life Outcomes.” Addiction 103.6 (2008): 969-76. • Gleason, K. A., S. G. Birnbaum, A. Shukla, and S. Ghose. “Susceptibility of the Adolescent Brain to Cannabinoids: Long-term Hippocampal Effects and Relevance to Schizophrenia.” Translational Psychiatry 2.11 (2012) • Gruber, A. J., H. G. Pope, J. I. Hudson, and D. Yurgelun-Todd. “Attributes of Long-term Heavy Cannabis Users: A Casecontrol Study.” Psychological Medicine 33.8 (2003): 1415-422. • Hall, Wayne, and Louisa Degenhardt. “Adverse Health Effects of Non-Medical Cannabis Use.” The Lancet 374.9698 (2009): 1383-391. • Loria, Jennifer Welsh and Kevin. “23 Health Benefits of Marijuana.” Business Insider. Business Insider. • Niyuhire, F., S. A. Varvel, B. R. Martin, and A. H. Lichtman. “Exposure to Marijuana Smoke Impairs Memory Retrieval in Mice.” Journal of Pharmacology and Experimental Therapeutics 322.3 (2007): 1067-075. • Pacher, P. “The Endocannabinoid System as an Emerging Target of Pharmacotherapy.” Pharmacological Reviews 58.3 (2006): 389-462. • Pistis, Marco, Simona Perra, Giuliano kenyon.edu/neuroscience

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Pillolla, Miriam Melis, Anna Lisa Muntoni, and Gian Luigi Gessa. “Adolescent Exposure to Cannabinoids Induces Long-Lasting Changes in the Response to Drugs of Abuse of Rat Midbrain Dopamine Neurons.” Biological Psychiatry 56.2 (2004): 86-94. Rubino, T., E. Zamberletti, and D. Parolaro. “Adolescent Exposure to Cannabis as a Risk Factor for Psychiatric Disorders.” Journal of Psychopharmacology 26.1 (2011): 177-88. Tashkin, Donald P. “Effects of Marijuana Smoking on the Lung.” Annals of the American Thoracic Society 10.3 (2013): 23947. Thames, April D., Zanjbeel Mahmood, Alison C. Burggren, Ahoo Karimian, and Taylor P. Kuhn. “Combined Effects of HIV and Marijuana Use on Neurocognitive Functioning and Immune Status.” AIDS Care 28.5 (2015): 628-32. Tomida, I. “Cannabinoids and Glaucoma.” British Journal of Ophthalmology 88.5 (2004): 708-13. Verrico, Christopher D., Hong Gu, Melanie L. Peterson, Allan R. Sampson, and David A. Lewis. “Repeated Δ 9 -Tetrahydrocannabinol Exposure in Adolescent Monkeys: Persistent Effects Selective for Spatial Working Memory.” American Journal of Psychiatry 171.4 (2014): 416-25.

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"NIDA - Research Report Series - Marijuana Abuse." National Institute on Drug Abuse The Science of Drug Abuse and Addiction. NIDANIH. "How Does Marijuana Produce Its Effects?" How Does Marijuana Produce Its Effects? | National Institute on Drug Abuse (NIDA). "State Marijuana Laws in 2016 Map." Governing Magazine: State and Local Government News for America's Leaders. "22 Awesome Depression Boy Images." Fantasticpixcool. "Addictive Properties of Popular Drugs." Addictive Properties of Popular Drugs | Drug War Facts.

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THE RECIPE FOR THE PERFECT Kalkidan Aseged

The tales of the paranormal have ignited fear and fascination in societies across the globe for centuries. Zombies, in particular, have had a complex heritage in popular culture, originally portrayed to be mindless, soulless creatures controlled by an evil sorceress and now presented as risen bodies of the deceased, hungry for human flesh and brain1. Luckily for us, the likelihood of actually turning into a zombie is small, and the biggest interaction most people will have with these creatures are through popular television shows like The Walking Dead or Michael Jackson’s famous music video, Thriller. In other words, we can bask in the comfort of knowing its only fake. Unfortunately, the same cannot be said for the Periplaneta americana, and Periplaneta australasiae, both species of the tropical cockroach. You see, their lives are plagued by the presence of parasitoid emerald cockroach wasp, also known as the Jewel

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Wasp, and her ability to inject her own concoction of neurotoxic chemicals into the cockroaches, forcing them to serve as live nests and food for the wasp’s offspring. What’s particularly interesting about the venom’s effects is that it does not just paralyze or even kill the cockroach. Instead, it dampens the insect’s motivation to fight back or run away, making it follow the wasps’ commands without resistance, which include being buried alive and eaten from the inside out. Perhaps these stung cockroaches do not acquire a desire to eat brains, however they become zombies nonetheless, as their behaviors and actions are no longer of their own control. Many questions in regards to the relationship between the jewel wasp and the cockroach have arisen, such as how does the wasp control the mind of the cockroach, what is the composition of the venom and how long do these effects last? These are the MAY 2017

questions scientists have been trying to solve for years, and although not all the answers are known, much progress has been made in the understanding of this unique parasitic relationship and more specifically, the zombie making properties of the Jewel Wasp. Phase 1: Thoracic Sting Induces Paralysis The Jewel wasp begins her attack by administering the first of two stings directed towards the cockroach– this one aimed at the thorax or the body of the cockroach. The wasp uses her “stinger” to inject the venom into the first thoracic ganglion (group of nerve cell bodies) of the thorax, which induces temporary paralysis in the cockroach. For the next 2-3 minutes, the cockroach is unable to move, giving the wasp the opportunity to initiate its second sting directed towards the head. Several studies have investigated the mechanism by which the venom induces paralysis in the cockroach5,8. In a normal cockroach there are two motor neurons, the slow coxal depressor motor neuron (Ds) and the fast coxal depressor motor neuron (Df) that help regulate muscle tension to maintain the cockroach’s upright position and allow for the insect to quickly flee from dangerous situations, respectively3. Scientists have found that both Ds and Df activity are blocked in stung cockroaches, meaning that the Ds motor neuron no

Image of Jewel Wasp injecting venom into a cockroach’s head longer maintains muscle tension and the Df motor neuron no longer initiates an escape response in the presence of a dangerous situation (the wasp), resulting in the inability of the insect to move or run away8. The mechanism by which the venom blocks activity in these motor neurons it thought to be through regulation of cholinergic synaptic transmission. When motor neurons, like Ds and Df, are stimulated, they release a neurotransmitter called acetylcholine (ACh) into a synaptic cleft, or a space between the neuron and the muscle it is activating. Once ACh is released, it binds to receptors on the muscle, thereby initiating movement. When venom is injected into the cockroach, however, it acts as a

The wasp targets its first sting towards the first thoracic ganglion of the cockroach. The venom prevents ACh from binding to its receptors on the muscle by binding to the muscle receptors itself. Binding of ACh initiates muscle movement, but if it can no longer bind, the cockroach becomes paralyzed kenyon.edu/neuroscience

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Venom injected into cockroaches inhibits Ds and Df activity temporarily. The longer the line, the higher the frequency/activity cholinergic antagonist. In other words, it prevents acetylcholine from acting on the muscle receptors, by binding to the muscle receptors itself. Since acetylcholine is no longer able to bind to these receptors, the signals from the brain to the muscle are not completed, thereby paralyzing the organism8.

Phase 2: Head Sting Induces Grooming and Zombie-Like Behaviors

Following the thoracic sting and the ensued temporary paralysis, the wasp directs her stinger to the head of the cockroach, where she targets two cerebral ganglia, the subesophageal ganglion (SEG) and the supra esophageal ganglion (SupEG), which are major components of the insect’s brain8. It is crucial that the wasp target the SEG and the

Normal, upright position of a cockroach (top) vs. paralyzed cockroach that is unable to support its own weight (bottom)

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SupEG, so much so that when researchers surgically removed these ganglion from the cranial cavities of cockroaches, the wasp spent a significantly longer time completing the injection to the cockroach’s head7. Furthermore, researchers have hypothesized that the wasp’s stinger even contains specialized “sensory organs” that allow her to discriminate these cerebral ganglion from other brain tissues using mechanoreceptor inputs. However, the complete analyses of these structures are still under investigation7. Once the head sting is completed, the transformation from cockroach to zombie officially begins. The initial effects of the venom induce excessive grooming in the cockroach for about 30 minutes. These grooming behaviors include excessive cleaning of the legs or antennae and rubbing of the head abdomen and wings (Weisel-Eichler et al., 1999). The increased levels of these behaviors are thought to be a result of an influx of dopamine into the cockroach. In the human brain, dopamine is a neurotransmitter with many functions in the central nervous system. Its major roles include maintenance of reward-motivation pathways; for example, many drugs enhance dopamine neuronal activities, and as such are linked with addiction. Dopamine has also been shown to contribute to the regulation of various motor behaviors2. In insects, this neurotransmitter has been associated with the MAY 2017

regulation of rhythmic motor patterns, such as walking, breathing and flying. Studies conducted by Weisel-Eichler et al., (1999) demonstrated similar levels of grooming in cockroaches to cockroaches stung by jewel wasps, once injected with dopamine or a dopamine agonist. Thus, they concluded that the venom circulating in the cockroach’s system induces increased grooming through stimulation of dopamine receptors. The reasons for this behavior are still under speculation. Some theories suggest the enhanced grooming decreases locomotion in the cockroach, diminishing its chances from escaping, while others state it helps rid the organism of any parasite or fungal infections that may be harmful to the wasp’s larvae5. Regardless of the reasons why the venom induces this behavior, this 30 minute time period is crucial for the wasp. As the cockroach is preoccupied with its excessive grooming behaviors, the wasp goes on a hunt for a suitable nest where it will lead the cockroach later on. Once the wasp has returned to the cockroach, the grooming effects of the venom have worn off and have evolved into the more severe and longer lasting euphoric or “zombie-like” phase. At this point, the wasp uses its strong jaws to sever the cockroach’s antennae so that she may taste the hemolymph, the equivalent of insect blood, and measure the levels of

Dopamine induces excessive grooming more than other monoamines, octopamine and serotonin. Dopamine agonist, SKF 82958 also induces grooming in cockroaches. kenyon.edu/neuroscience

SupEG

SEG

circulating toxins in the cockroach9. During this process, the cockroach does not attempt to flee or fight back, and will continue to display these behaviors until its death. It’s important to note that during this time period, the cockroach still has all motor control, in that it is still able to move its legs and wings as well as an unstung cockroach. Yet, it exhibits no motor related behaviors unless guided by the wasp, hence the foundation of the name “zombie cockroach”4. Scientists have attempted to understand how these zombie-like effects occur. It is known that cockroaches contain cerci or wind sensitive hairs on their appendages to detect changes in the environment. These cerci are activated by changes in air pressure or tactile stimuli to their legs or wings, which allow the cockroach to observe its environment and escape from any potential threats. Studies conducted by Gal et al., (2010) demonstrated that the cerci function normally and send the appropriate neuronal signals to the brain in stung cockroaches, but for some reason, these organisms still do not exhibit normal walking or escape related behaviors. As stated previously, the wasp targets two major cerebral ganglions when injecting the cockroach’s head, the SEG and the SupEG. The SEG in particular has been suggested to enhance walking and escape related behaviors in normal or unstung SCIENTIFIC KENYON

Stimulated neuronal activity of the SEG post wind or tactile stimulation in control and stung cockroaches cockroaches4,13. Therefore, scientists have compared SEG neuronal activity levels in stung and unstung cockroaches, to determine if this ganglion’s functions are inhibited by the Jewel Wasp’s venom. To test this, researchers applied either a wind stimulus to the cerci on cockroaches or a tactile stimulus by touching their legs and then compared SEG activity in unstung (control) and stung cockroaches. They found that after applying either stimuli, SEG activity was significantly reduced in stung cockroaches. These results suggested that the venom inhibits the SEG from transmitting signals to the muscles of these cockroaches, resulting in the lack of motivation to walk or run away from the wasp6. Although the specific neurons the venom targets are still unknown, the primary neurons theorized to be affected most are the octopaminergic unpaired median neurons of the SEG. These neurons transcend information from the SEG of the brain to various ganglions throughout the central nervous system of the cockroach, including the SupEG. Recent studies have demonstrated the role of the OA neurons in the initiation of locomotion in various insects, including cockroaches12. In addition, when scientists injected an octopamine like substance (chlordimeform) into previously stung cockroaches, their results showed that levels of spontaneous walking was significantly increased, indicating not only the importance of these neurons in initiating walking behaviors in cockroaches, but also the

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ability of the venom to inhibit these behaviors through modulation of OA neurons12. The inhibition of these OA neurons and potentially other structures of the brain, are what allow the wasp to complete her egg laying process and lead the cockroach to its death. Once the wasp has determined that enough of its venom is circulating in the cockroach from drinking its hemolymph, she guides the insect to its previously determined nest. As the cockroach has all motor ability, it simply walks to the nest, or in its eyes, the tomb, following the lead of the wasp. Once safely inside, the wasp will lay its egg on the leg cuticle of the cockroach and exit the nest. Before she leaves, the wasp will secure the area from harsh weathers and potential predators with rocks and sticks. Once finished, she will leave the cockroach and its newly laid egg for good. Left in the nest, the cockroach is still alive and alert, but unable to escape while under the influence of the venom. Once the larva hatches from the egg, it will penetrate through the cockroach’s leg and continue to feed on its internal organs for several days. It is not until five to six days later when the cockroach finally dies as a result of the larva consuming the majority of its abdomen and internal organs. Once matured, the fully developed wasp will emerge from the nest, ready to embark on its own journey to find a cockroach to “zombify”. MAY 2017

Complete life cycle of the Jewel Wasp, along with the order of events in the zombie-making process of the cockroach Understanding the Behaviors of the Zombie Cockroaches Although the mechanisms behind the effects of the Jewel wasp venom are still under investigation, itâ&#x20AC;&#x2122;s safe to say that one thing is for sure - the ability of the Jewel Wasp to evoke this type of lethargic, or zombielike qualities in her victims is remarkable. Firstly, a unique feature of the Jewel Waspâ&#x20AC;&#x2122;s venom, which differentiates her from other parasitoid wasps, is its ability to induce several behavioral effects in the cockroach. The same venom that is used in the thoracic sting to temporarily paralyze the cockroach

Swimming motion tracks during a one-minute trial period in control (unstung cockroaches) and stung cockroaches. kenyon.edu/neuroscience

stimulates excessive grooming followed by a long lasting lethargic state. Her venom is almost like a magic potion, one that creates many different effects in her victim, making this process not only much easier for her but also more interesting to study. Furthermore, the behavioral effects stimulated by the venom have provided scientists with an increased awareness of the potential complexities of insect behavior. Specifically, the actions of these stung cockroaches are similar to those of animal models exhibiting depression, resulting in a phenomenon called learned This condition arises helplessness5. from a situation in which an animal repeatedly undergoes a traumatic event in which they have no control and are unable to escape. As a result, when given the chance to avoid or escape from a harmful or stressful situation, they fail to do so. Studies conducted by Eisenstein and Carlson, 1997 and Harris and Eisenstein, 1999 have demonstrated the ability of insects to experienced learned helplessness as well. Therefore, it is fascinating that the Jewel SCIENTIFIC KENYON

Wasp’s venom is able to generate similar behavioral responses through manipulation of specific neuronal activities in cockroach’s brain. For example, stung cockroaches have been shown to swim for a significantly shorter time during forced swimming tests (tests in which the animals are placed in water and must swim to stay afloat) than unstung cockroaches, which is demonstrated in depressed mammals when undergoing the same test. Furthermore, the possibility of a faster onset of muscle fatigue contributing to smaller swimming bursts in these stung cockroaches have been ruled out through exams measuring motor neuron activity6. As such, the ideas of “motivation” or even “free will” in these insects have evolved from an absolute impossibility to a potential reality. As a whole, it is clear the relationship between the Jewel Wasp and the cockroach is astonishing and creepy all at the same time. Further analysis of the Jewel Wasp’s ability to accurately sting her victims, the properties of the venom, and its effects on the cockroach are not only important in the development of increased awareness of the world of parasitoid wasps, but also could provide a large understanding of neurotoxins as a whole. Fortunately, the possibility of a wasp’s venom turning us into “zombies” is minute, as there has yet to be a wasp that is able to produce neurotoxins able to penetrate our own blood brain barrier. So, although the Jewel wasp and other parasitoids may be actual threats to their victims, for us, these creatures are nothing more than a scary story.

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Works Cited

[1] Ackermann, H. W., & Gauthier, J. (1991). The ways and nature of the zombi. Journal of American Folklore, 466-494. Chicago [2] Banks, C., & Adams, M. (2012). Biogenic amines in the nervous system of the cockroach, Periplaneta americana following envenomation by the jewel wasp, Ampulex compressa. Toxicon, 59(2), 320-328. [3] Becht, G., Hoyle, G., & Usherwood, P. (1960). Neuromuscular transmission in the coxal muscles of the cockroach. Journal of Insect Physiology, 4(3), 191-201. doi:10.1016/0022-1910(60)90026-3 [4] Fouad, K., Rathmayer, W. & Libersat, F. J Comp Physiol A (1996) 178: 91. doi:10.1007/BF0018959 [5] Gal R, Kaiser M, Haspel G, Libersat F (2014) Sensory Arsenal on the Stinger of the Parasitoid Jewel Wasp and Its Possible Role in Identifying Cockroach Brains. PLOS ONE 9(2): e89683. doi:10.1371/journal.pone.0089683 [6] Gal R, Libersat F (2013) A Wasp Manipulates Neuronal Activity in the Sub-Esophageal Ganglion to Decrease the Drive for Walking in Its Cockroach Prey. PLoS ONE 5(4): e10019. doi:10.1371/journal. pone.0010019 [7] Gal, R., & Libersat, F. (2013). What can parasitoid wasps teach us about decision-making in insects?. Journal of Experimental Biology, 216(4), 4755. doi:10.1242/jeb.073999 [8] Haspel, G., Rosenberg, L. A. and Libersat, F. (2003), Direct injection of venom by a predatory wasp into cockroach brain. J. Neurobiol. 56: 287– 292. doi:10.1002/neu.10238 [9] Libersat, F. J Comp Physiol A (2003) 189: 497. doi: 10.1007/s00359-003-0432-0 [10] Libersat, F., & Gal, R. (2014). Wasp Voodoo Rituals, Venom-Cocktails, and the Zombification of Cockroach Hosts. Integrative and Comparative Biology, 56(4), 1-14. [11] Ram Gal & Frederic Libersat (2012) On predatory wasps and zombie cockroaches, Communicative & Integrative Biology, 3:5, 458-461, DOI: 10.4161/cib.3.5.12472 [12] Rosenberg, L.A., Glusman, J., & Libersat, F. (2007). Octopamine partially restores walking in hypokinetic cockroaches stung by the parasitoid wasp Ampulex compressa. The Journal of Experimental Biology , 210(26), 4411-4417. doi:10.1242/jeb.010488 [13] Weinersmith, K., & Faulkes, Z.F. (2014). Parasitic Manipulation of Hosts’ Phenotype, or How to Make a Zombie—An Introduction to the Symposium. Integrative and Comparative Biology, 54(2), 93-100. doi:10.1093/icb/icu028 [14] Weisel-Eichler, A., Haspel, G., & Libersat, F. (1999). Venom of a parasitoid wasp induces prolonged grooming in the cockroach. Journal of Experimental Biology, 202(1), 957-964.

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Blacking Out versus Passing Out

What’s the Difference? Adama Berndt

The recreational use of alcohol is not a foreign concept in our society and this is especially the case on many college campuses, where people are likely being exposed to alcohol on a weekly basis. A National Survey of Drug Use and Health reported in 2014, that 59% of college-aged students confirmed alcohol use during the past month.18 Alcohol’s status as a legal substance of ubiquitous use might make it that much more shocking to individuals, when they learn that it is also a substance capable of inducing fragmentary, or complete memory loss for a significant period of time. In fact one college survey found that out of 800 participants, 50% reported not being able to remember a night of drinking at least one time in their life.40 Not only can someone be unable to recall certain events, but they are also often unaware that they cannot recall certain events.7 Yet this person is still able to sustain conversation, operate machinery in some cases and otherwise behave as if they were under alcohol’s more normal motor and cognitive impairments.14 Comedian Sarah Hepola even claims that while under the influence of alcohol, she performed a well-received and coherent stand-up show, which she remembers no part of.38 This phenomenon is colloquially referred to as “blacking-out”, and is explicitly defined as “... amnesia for the events of any part of a drinking episode without loss of consciousness”13 . Blackout is tricky, there isn’t yet clear evidence of a genetic kenyon.edu/neuroscience

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Figure 1. Photo of Higinio Salgado on Trial For His Blackout Murder.1 predisposition towards it,18 and the main common drinking habit that leads to blackout, seems to be drinking quickly, evidenced by a rapid increase in blood-alcohol content.8

Blackout in the Lab vs. the Law

In a study unlikely to be approved today, 1970’s psychiatrist D.W. Goodwin illustrated the totality of blackout by subjecting those considered to be frequent drinkers to a bizarre test.7 Over the course of 4 hours, subjects were administered a whopping 18-20 oz. of bourbon, or in common drinking terms, about 12 shots!6 Then they were shown a covered frying-pan, baited with the suggestion of hunger, and the inside of the pan was revealed to contain three dead mice.7 If someone was to trick you in such a decidedly nasty way, it is likely something you would never forget, and yet 30-minutes after seeing the pan’s contents, subjects did not display any recollection of the unsettling event when prompted.7

because he was blackout during the murder.1 Salgado was found intoxicated right next to the deceased, who had taken 17 blunt force injuries to the skull.1 Data from research hints quite clearly at faults with this blackout defense. Those experiencing alcohol amnesia have no problem listing the Ten Commandments, or explaining the penalties of robbing a bank.7 These are both things they likely have learned long ago, but they cannot remember any events that happen during the blackout.7 This suggests two things: first that long-term memory and its retrieval is unaffected by alcohol, meaning a murderer who is blackout, likely knows wrong from right at the time of the murder, even if their decision making is impaired,7 and second that alcohol’s most important ingredient, ethanol, actually prevents the formation of shortterm memories and the subsequent long-term memories that result.15, 23 Therefore, it seems to be a problem that legal defenses today still use blacking out as an unconscious state, although rarely successfully.23 However, even if success rates are not high, attempt rates for blackout defense in cases involving alcohol are reported to be as high as 50%, therefore in the minority of cases where this defense is successful, science is significantly at odds with both legal and common understanding.23 Lawyers have argued that blackout is a state of automatism(absences of mind) lacking criminal intent, which releases some liability from their defendant; some defenses have even used the premise that blackout equates to sleepwalking.24 However, based on an empirical review of 26 scientific studies, nothing about blackout suggests that a person who is blackout is not aware of their actions, and this type of legal defense likely should be considered inadmissible.23 That said, it is not surprising that these misconceptions continue, when at least one popular perception of blackout is an individual falling asleep after drinking too much.

Although blackout is defined as amnesia without loss of consciousness,14 from the perspective of the individual experiencing blackout it is difficult, or impossible to tell the difference. This explains the lack of clarity in the way we culturally describe the phenomenon, with individuals often confusing blacking out and passing out.7 A lack of specific distinction in language between the two can have significant social, and even legal implications when For someone to be unconscious they have to be completely non-receptive and responsive serious events occur during a person’s blackout. to outward stimuli. Perhaps a source for In the 2013 San Diego case of Higinio Salgado, the this confusion, is that people often conflate defense argued unsuccessfully that he could not unconsciousness and sleep as being equivalent and be held fully responsible for the death of his boss, in both textbook blackout and in sleep, a person

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simply cannot remember anything that occurred during this altered state. From the perspective of one who has experienced sleep and separately has experienced blackout, the inability to recall events that occurred during both would feel the same or similar. So if they both feel the same what can we use to explain the difference? Neuroscience! In order to find out what is happening in our brains for both blackout and passing out, we can use known neurological signatures or brain activity to see if there is a difference between the two and hint at why. Unsurprisingly, finding the answers to these questions is complex and laborious, luckily for us, many people have already started the work.

Anatomy of Memory

In order to evaluate the state of blackout from an anatomical perspective, it is helpful to look at other examples of deficits in the brain’s ability to create short term memory. H.M., likely the most famous amnesiac, suffered deficits in memory caused by a physical impairment rather than a chemical one. His full name - Henry Molaison, was only publicly known posthumously.33 He was a severely epileptic patient who underwent a surgery to completely remove his bilateral medial temporal lobes in the 1950’s, this includes brain regions implicated in both short term and long-term memory notably the hippocampi, parahippocampal gyri (Fig. 2), but also the perirhinal and entorhinal neocortical regions.33, 45 The basic premise of this operation was that if epilepsy is caused by overactivity in certain parts of the brain, perhaps removing them will help

the patient dampen this activity and restore normalcy.33 However for H.M., the outcomes of this procedure were not clear cut, no pun intended. Although his epilepsy was indeed gone, and at first he seemed to have normal brain function, it became clear that he was no longer able to form new conscious memories, this condition is called anterograde amnesia and it is also temporarily found in those experiencing alcohol-induced blackout.33 H.M. also lost a few years of already existing memories up to his procedure in a less complete retrograde amnesia. He was able to remember most of his life 10 years before the procedure, and fragmentarily up to 3 years before the procedure, outside of that, any new events were not retained longer than a few minutes.33 Within this period of a few minutes, he could not remember a string of more than 6 digits, regardless of how quickly they were given, suggesting a cap on his immediate memory.33 Since alcohol produces similar anterograde amnesia, we might expect blackout users to have similar difficulty remembering lists21 and ethanol to act on at least some of the same regions of the brain that were lobectomized in H.M. In both cases this is exactly what we see.40 However before H.M. we didn’t think that alcohol had much specific action at all.

Molecular Effects of Alcohol on Memory

In the early 1900’s, the myriad effects of alcohol, both cognitive and motor seemed to suggest that alcohol acted on the brain in a global fashion.41 This idea was bolstered

Figure 2. Coronal transection illustrating the missing lobes in H.M.’s brain post-lobectomy.29 kenyon.edu/neuroscience

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by a few significant considerations; firstly the human brain is made up of 100 billion neurons, neurons being a highly specialized type of cell, that is capable of engaging in the electrochemical communication that helps to govern certain behaviors and functions. Although there are many different sub-types of neurons, neurons like all cells, have a bilayered lipid membrane acting as their cell wall. Ethanol is able to disrupt and breach the lipid membrane of cells, because it is a very small molecule, like water, allowing it to easily diffuse through membranes.41 Therefore ethanol should be able to disrupt neural function in the same way at every neuron, by breaking past neuronal membranes throughout the brain. Although this was a widely taught view, and part of ethanol’s function is its ability to bypass neuronal membranes, it is now more clear that ethanol is not simply gumming up neural cell activity everywhere in the brain in the same way, but that there are actually quite specific mechanisms, by which alcohol can disrupt normal processes in a widespread fashion.41 Rather than just interacting with the membranes of neurons, ethanol also binds to smaller proteins housed within the membrane of neurons.41 You have probably heard of protein that we get from meat, however proteins in the brain are different from many of the proteins found in meat, they are just made out of the same molecular building blocks, hence the blanket term. These proteins which are produced by their respective neurons, work with and respond to chemicals called neurotransmitters, in order to facilitate the electrochemical conditions that determine whether a neuron in the brain fires, or does not.14 When ethanol is in your blood and consequently delivered throughout the brain, it acts on hippocampal neurons selectively because here it can interact with an important protein receptor, NMDA, that is highly expressed in hippocampal neuronal tissue(Fig. 3).16 Ethanol’s impact on short-term memory occurs when it binds at NMDA, mGluR, and GABAA protein receptors in the brain, binding at any of these locations is ultimately antagonistic to NMDA, meaning neural activity facilitated by NMDA decreases(Fig. 4).14,16 In the case of

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Figure 4. Inhibitory action of ethanol at a glutamate synapse, ethanol molecules are represented by purple dots, glutamate dots are green.5

GABAA receptors, ethanol binding activates their normal function to inhibit the activity of neurons, including neuronal membranes housing NMDA and GABAA.28 In the case of mGluR, ethanol binding decreases the release of the neurotransmitter glutamate that normally increases NMDA activity(Fig. 4).5 If disruption of NMDA receptor activity is the basis for ethanol’s disruption of memory, an important question is, what are NMDA receptors doing related to memory, that ethanol stops them from doing? The answer lies in experiments that use electrodes to obtain readings of electrochemical activity from NMDA containing neurons.16,28,30 Researchers found that under normal circumstances, if you electrically stimulate what are known as CA1 neurons in the hippocampus, the signal of these neurons gets stronger, this phenomenon is known as Long Term Potentiation(LTP) and it isn’t limited to CA1 neurons, but wherever there are certain types of NMDA receptors that ethanol interacts with; it is important to note that not all NMDA receptors are inhibited by ethanol and this may explain its selective impacts on certain kinds of memory, but not others(Fig. 5).25, 28 In addition to this, when ethanol is present this electrical signal does not increase after electrical stimulation, and therefore there is significant MAY 2017

inhibition of LTP.28, 30 Describing exactly why LTP is fundamentally important to memory is difficult, but what we can say clearly is that when LTP doesn’t occur, or long-term depression of electrical response(LTD) doesn’t occur,13 we don’t see evidence of memory, which can be defined as a change in behavior resulting from experience.20 For example, a rat simply does not seem to learn a maze when NMDA receptors are deactivated, the mouse does not change its behavior to navigate the maze quicker and LTP is not demonstrated. This electrical signature that we associate with functions of memory is enabled by partial changes at brain sites known as synapses, where neurons meet and exchange chemicals called neurotransmitters. When neurons with NMDA channels are stimulated at the post-synaptic junction (the receiving end of chemical exchange), they induce a chemical domino-effect in the postsynaptic neuron. Ultimately this cascade signals the neuron to do a number things, including attach phosphate groups to another membraneprotein receptor called AMPA (works in concert with NMDA as glutamate binding protein).11 In addition, neurons bolster the strength of connection at synapses, by increasing AMPA receptor expression in the membrane,11 increasing the surface area of the membrane and thus the number of synaptic connections, as well as other general changes to cell morphology that improve the strength of electrical signaling.11 At this point you may be wondering, if ethanol has such strong

Figure 5. Inhibition of NMDA activity by ethanol in inferior colliculus neurons.30 kenyon.edu/neuroscience

impact on encoding of short term-memory, how come it doesn’t seem to strongly affect long-term memory? This is likely because the importance of NMDA is primarily tied to memory encoding or formation, rather than retrieval, or maintenance of memory storage; in addition the task of longterm memory storage is more recently thought to heavily involve cortical structures, some of which were lost in HM, but not all, explaining the partiality of his retrograde amnesia.46

Differentiating Blackout and Sleep States

This is one example of a detailed neurological interaction of ethanol, but it’s action on the brain is not limited to quieting hippocampal cells, ethanol is commonly considered to have a sedative function as well, another reason why blackout and passing out to the point of sleep can often be conflated.34 We have seen that ethanol’s impairment of short-term memory can be fairly complete, even functionally mimicking lobectomy temporarily. If we are to distinguish between ethanol’s amnesic effects and sedative properties then we have to ask, what is the mechanism of ethanol’s impact on normal sleep? People often use alcohol with the goal of aiding in the initiation of sleep.34 However, where high-doses of ethanol, and fall in blood alcohol content(BAC)can promote the start of sleep, at low doses ,and as BAC rises, ethanol actually has a stimulating effect. This means that a glass right before bedtime may be more likely to contribute to insomnia than prevent it and repeated ethanol administration could also have a stimulating effect.34 This stimulation is thought to be primarily locomotor in nature and is attributed to Ethanol’s agonistic function when bound to D2/D3 receptors, which increases their normal activity in the ventral striatum.44 Ethanol also disturbs the normal cycles of electrical brain signatures of sleep. Using a method called electroencephalography(EEG), researchers affixed electrodes to the scalp of sleeping subjects, ultimately finding that we sleep in 90-minute alternating stages termed rapid-eye movement(REM)34 and Non-REM. NREM is further separated into N1-N4 characteristic wave patterns. N1 is the most surface level of sleep, where it is easiest to arouse a sleeping individual, SCIENTIFIC KENYON

Figure 6. Illustration of the complexity of sleep-promoting interactions in A and wake-promoting interactions in B.9

during N2 sleep it becomes slightly more difficult to arouse the sleeper, N3 and N4 both are periods characterized by Delta wave EEG readings, this is termed slow-wave sleep.34 Overall, data on ethanol’s action is somewhat contradictory and harder to relate specifically to the phenomenon of blackout. Ethanol administration appears to have a noted sedative effect when 6 or more drinks are ingested over 6 hours, however, 2-3 hours after BAC falls to 0, sleep disturbance in the second half of the night during NREM or REM is likely.34 Ethanol exposure is also associated with a decrease in the amount of REM sleep. These slightly confusing temporal and dose-dependent effects of alcohol, make more sense when placed in the context of ethanol’s specific actions on both wake-promoting and sleep-promoting systems of the brain. Ethanol initially makes you more likely to sleep first by inhibiting adenosine(AD) neurotransmitter uptake protein channels.36 This leads to increased amounts of inhibitory adenosine interacting with neurons of the Basal forebrain(BF), which has a wakepromoting function. Thus, when the BF is inhibited sleep-promotion is favored. This initial favoring of sleep-promotion causes an imbalance in the cyclical and complex process of sleep homeostasis, that later leads to increased activity of wake promoting systems.36

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We can see in Figure 6. that sleep systems are complicated with many different nuclei playing a role, suggesting the interaction above is unlikely to be ethanol’s sole impact on sleep systems.9 When comparing regular sleep and blackout, the lack of direct physiological signatures to distinguish between the two states is less a problem; people who are sleeping are completely immobilized, those experiencing blackout are often not. Also the fact that sleep is clearly changed significantly in the presence of ethanol and that wakefulness is contextually promoted with ethanol,34 makes it seem less likely that blacking out is an altered state of consciousness comparable to sleep. However the phenomenon of sleepwalking, where people are reported to walk, talk and even engage in criminal behavior, both violent and sexual, blurs the line separating blackout and sleep.4 What if blackout is just a type of sleepwalking? Sleepwalkers have a known propensity towards N3 stage sleep,26 but in the absence of specific EEG studies on blackout patients that can’t remember questions from two minutes ago, it is harder to point to an electrical marker, that would conveniently separate or align the two.10 We can however note that, where scientific studies came out against the use of blackout as a MAY 2017

defense for decreased culpability in legal trial; one study argues that research shows sleepwalkers are not only unable to remember their actions, but unaware of their own behavior and the implications of their behavior at the time of a criminal act.4 In addition, consistent disturbed slow wave sleep activity can be demonstrated in sleepwalking defendants, to verify when someone suffers from a slow wave sleep disorder, therefore they should not be held totally accountable for their actions.4 If blacking out is comparable to sleep, it is not neatly analogous to it, as person who is blackout can recognize their own person and sustain conversation, this uses information that would not be accessible during sleep. Therefore blackout is most likely a different altered state of consciousness, but marked more by impaired short-term memory, rather than motor paralysis and characteristic EEG activity.

Implications of Short Term Memory for the state of Consciousness

One of the defining traits of consciousness seems to be one that is very personal. If I can’t say for sure that during the extended period of my blackout “I was conscious”, then is that really the self-aware experience of consciousness as we know it? However, we also can’t easily recall many of the moments of our childhood, so following this logical train of thought, are we not conscious during those moments also? The difference is that in our early life, the memories are forming at all, events during childhood have the luxury of being forgotten that events while blackout don’t, except perhaps in the case of babies(who may actually have to grow into their consciousnesses). In addition, events that we don’t remember can still affect our behavior, if this is also the case in blackout, the research is less clear. Sweeney, a prominent researcher of alcohol induced blackout, has argued that memory and consciousness are inseparable.21 If we think about the functional capabilities of someone who is blackout, this actually makes a certain amount of sense. If you can’t form new memories, all your responses are based on pre-programmed biology and propensities to a given action based on what kenyon.edu/neuroscience

you have learned so far. So what separates this from a robot that is programmed to act in a certain way based on already given commands? This is a question science doesn’t yet have the clear answer to.2 Even if short-term memory is integral to consciousness as we know it, the fact that those in a state of blackout don’t seem to lose an awareness of the self, implies that there is a neurological basis of that self. So far many signs point to corticothalamic neurons as being important for conscious behaviors, but that is whole other article by itself.47 Since alcohol-induced blackout seems to primarily display inhibition of short-term memory formation, but does not seem to greatly impair self-awareness or previous life lessons found in long-term storage, we are responsible for our actions when we drink. So if you plan on using long island ice-teas to roleplay as Henry Molaison sometime soon, at the very least, please drink slowly.

References

1. Adams, Andie. “’Blackout Drunk’ Defense Used in Architect Murder Trial.” NBC News San Diego. N.p., 21 Apr. 2014. Web. 13 Nov. 2016. 2. Barba, Gianfranco Dalla. “Memory, Consciousness and the Brain.” Brain and Cognition 42.1 (1999): 20-22. Pubmed. Web. 9 Sept. 2016 3. Carskadon, M.A., & Dement, W.C. (2011). Monitoring and staging human sleep. In M.H. Kryger, T.Roth, & W.C. Dement (Eds.), Principles and practice of sleep medicine, 5th edition, (pp 16-26). St.Louis: Elsevier Saunders 4. Cartwright, Rosalind D., and Christian Guilleminault. “Defending Sleepwalkers with Science and an Illustrative Case.” Journal of Clinical Sleep Medicine (2013): n. pag. Web. 20 Nov. 2016. 5. Clapp, Peter, Ph.D, Sanjiv V. Bhave, Ph.D, and Paula L. Hoffman, Ph.D. “How Adaptation of the Brain to Alcohol Leads to Dependence.” National Institute of Health. NIH, 2009. Web. 6. Eichenbaum, H., G. Schoenbaum, B. Young, and M. Bunsey. “Functional Organization of the Hippocampal Memory System.” Proceedings of the National Academy of Sciences 93.24 (1996): 13500-3507. Web. 16 Sept. 2016. 7. Goodwin, D.W. “Alcohol Amnesia.” Addiction 90.3 (1995): 315-18. Web. 9 Sept. 2016. SCIENTIFIC KENYON

8. Hartzler, Bryan, and Kim Fromme. “Fragmentary Blackouts: Their Etiology and Effect on Alcohol Expectancies.” Alcoholism: Clinical & Experimental Research 27.4 (2003): 628-37. Web. 9. Institute of Medicine (US) Committee on Sleep Medicine and Research; Colten HR, Altevogt BM, editors. Washington (DC): National Academies Press (US); 2006. 10. Kähkönen, Seppo, Juha Wilenius, Vadim V. Nikulin, Marko Ollikainen, and Risto J. Ilmoniemi. “Alcohol Reduces Prefrontal Cortical Excitability in Humans: A Combined TMS and EEG Study.” Neuropsychopharmacology 28.4 (2002): 747-54. Web. 22 Nov. 2016. 11. Kandel, Eric R. “The Molecular Biology of Memory: CAMP, PKA, CRE, CREB-1, CREB-2, and CPEB.” Molecular Brain Mol Brain 5.1 (2012): 14. Web. 12. Kessels, Roy P. C., Hans Kortrijk E., Arie Wester J., and Gudrun Nys M. S. “Confabulation Behavior and False Memories in Korsakoff’s Syndrome: Role of Source Memory and Executive Functioning.” Psychiatry Clin Neurosci Psychiatry and Clinical Neurosciences 62.2 (2008): 220-25. Web. 9 Sept. 2016. 13. Lee, Hamin, Sungwon Roh, and Dai Kim Jin. “Alcohol-Induced Blackout.”International Journal of Environmental Research and Public Health IJERPH 6.11 (2009): 2783-792. Pubmed. Web. 08 Sept. 2016. 14. Lodish, Harvey. “Overview of Neuron Structure and Function - Molecular Cell Biology - NCBI Bookshelf.” National Center for Biotechnology Information. U.S. National Library of Medicine, 01 Jan. 1970. Web. 21 Nov. 2016. 15. Matthews, Douglas B., and Janelle Silvers R. “The Use of Acute Ethanol Administration as a Tool to Investigate Multiple Memory Systems.”Neurobiology of Learning and Memory 82.3 (2004): 299-308. Web. 9 Sept. 2016. 16. Nagy, Jozsef. “Alcohol Related Changes in Regulation of NMDA Receptor Functions.” Current Neuropharmacology CN 6.1 (2008): 39-54. Web. 12 Nov. 2016. 17. Nelson, Elliot C., Andrew Heath C., Kathleen Bucholz K., Pamela Madden A. F., Qiang Fu, Valerie Knopik, Michael Lynskey T., John Whitfield B., Dixie Statham J., and Nicholas Martin G. “Genetic Epidemiology of Alcohol-Induced Blackouts.” Arch Gen Psychiatry Archives of General Psychiatry61.3 (2004): 257. Web. 16 Sept. 2016.

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18. NIAAA. “Alcohol Facts and Statistics | National Institute on Alcohol Abuse and Alcoholism (NIAAA).” U.S National Library of Medicine. U.S. National Library of Medicine, 2013 & 2014. Web. 12 Nov. 2016. 19. Obara, Yoshihito, Ryuki Tsutsui, Takayuki Ishida, and Chiaki Kamei. “Effect of Ethanol on Sleep-Awake State in Sleep-Disturbed Rats.” Biological & Pharmaceutical Bulletin 33.5 (2010): 849-53. Web. 20 Nov. 2016. 20. Okano, H., T. Hirano, and E. Balaban. “Learning and Memory.” Proceedings of the National Academy of Sciences 97.23 (2000): 12403-2404. Web. 21. O’kelley, Erin. “THE ALCOHOL BLACKOUT: A BOOK REVIEW.” (n.d.): n. pag. NCHERM. Web. 22. Perry, Paul J., Tami R. Argo, Mitchell J. Barnett, Jill L. Liesveld, Barry Liskow, Jillian M. Hernan, Michael G. Trnka, and Mary A. Brabson. “The Association of Alcohol-Induced Blackouts and Grayouts to Blood Alcohol Concentrations.” Journal of Forensic Sciences51.4 (2006): 896-99. Web. 13 Nov. 2016. 23. Pressman, Mark R., and David S. Caudill. “Alcohol-Induced Blackout as a Criminal Defense or Mitigating Factor: An Evidence-Based Review and Admissibility as Scientific Evidence.” Journal of Forensic Sciences 58.4 (2013): 932-40. Web. 13 Nov. 2016. 24. Pressman, M. R., M. W. Mahowald, C. H. Schenck, M. A. Cramer Bornemann, D. Banerjee, P. Buchanan, and A. Zadra. “Alcohol, Sleepwalking and Violence: Lack of Reliable Scientific Evidence.” Brain 136.2 (2012): n. pag. Web. 25. Ramachandran, Binu, Saheeb Ahmed, Noman Zafar, and Camin Dean. “Ethanol Inhibits Longterm Potentiation in Hippocampal CA1 Neurons, Irrespective of Lamina and Stimulus Strength, through Neurosteroidogenesis.” Hippocampus 25.1 (2014): 106-18. Web. 23 Sept. 2016. 26. Roehrs, Timothy, and Thomas Roth. “Sleep, Sleepiness, Sleep Disorders and Alcohol Use and Abuse.” Sleep Medicine Reviews 5.4 (2001): 28797. Web. 22 Nov. 2016. 27. Saults, J. Scott, Nelson Cowan, Kenneth Sher J., and Matthew Moreno V. “Differential Effects of Alcohol on Working Memory: Distinguishing Multiple Processes.” Experimental and Clinical Psychopharmacology 15.6 (2007): 576-87. Web. 9 Sept. 2016. MAY 2017

28. Schummers, James, and Michael Browning D. “Evidence for a Role for GABAA and NMDA Receptors in Ethanol Inhibition of Long-term Potentiation.”Molecular Brain Research 94.1-2 (2001): 9-14. Web. 16 Sept. 2016 29. Sherav, Vera. “Patient H.M. Dark Roots and Dubious Ethics: Neuroscience Research Methods.” Alliance for Human Research Protection. N.p., 15 Sept. 2016. Web. 30. Simson, Peter E., Hugh Criswell E., and George Breese R. “Inhibition of NMDA-evoked Electrophysiological Activity by Ethanol in Selected Brain Regions: Evidence for Ethanolsensitive and Ethanol-insensitive NMDA-evoked Responses.” Brain Research 607.1-2 (1993): 9-16. Web. 15 Sept. 2016. 31. Spinetta, Michael J., Martin Woodlee T., Leila Feinberg M., Chris Stroud, Kellan Schallert, Lawrence Cormack K., and Timothy Schallert. “Alcohol-induced Retrograde Memory Impairment in Rats: Prevention by Caffeine.”Psychopharmacology 201.3 (2008): 36171. Web. 9 Sept. 2016. 32. Soto, David, and Juha Silvanto. “Reappraising the Relationship between Working Memory and Conscious Awareness.” Trends in Cognitive Sciences 18.10 (2014): 520-25. Web. 9 Sept. 2016. 33. Squire, Larry R., and John T. Wixted. “The Cognitive Neuroscience of Human Memory Since H.M.” Annu. Rev. Neurosci. Annual Review of Neuroscience 34.1 (2011): 259-88. Web. 13 Nov. 2016. 34. Stein, Michael D., and Peter D. Friedmann. “Disturbed Sleep and Its Relationship to Alcohol Use.” Substance Abuse 26.1 (2006): 1-13. Web. 22 Nov. 2016. 35. Suman, Shubhankar, Santosh Kumar, Prosper N’gouemo, and Kamal Datta. “Increased DNA Double-strand Break Was Associated with Downregulation of Repair and Upregulation of Apoptotic Factors in Rat Hippocampus after Alcohol Exposure.” Alcohol 54 (2016): 45-50. Web. 9 Sept. 2016. 36. Thakkar, Mahesh M., Rishi Sharma, and Pradeep Sahota. “Alcohol Disrupts Sleep Homeostasis.” Alcohol 49.4 (2015): 299-310 Web 37. Wallace, Kelly. “Blackout Drunk: More Common than You Might Think.” CNN. Cable News Network, 7 Aug. 2015. Web. 13 Nov. 2016. 38. Weiner, J. L., C. Valenzuela F., P. Watson L., C. Frazier J., and T. Dunwiddie V. “Elevation of Basal Protein Kinase C Activity Increases kenyon.edu/neuroscience

Ethanol Sensitivity of GABAA Receptors in Rat Hippocampal CA1 Pyramidal Neurons.” Journal of Neurochemistry 68.5 (2002): 1949-959. Web. 24 Sept. 2016. 39. White, Aaron M. “What Happened? Alcohol, Memory Blackouts, and the Brain.” National Center for Biotechnology Information. U.S. National Library of Medicine, 27 July 2003. Web. 09 Sept. 2016. 40. White, Aaron M., David W. Jamieson-Drake, and H. Scott Swartzwelder. “Prevalence and Correlates of Alcohol-Induced Blackouts Among College Students: Results of an E-Mail Survey.” Journal of American College Health 51.3 (2002): 11731. Web. 13 Nov. 2016. 41. White, Aaron M., Douglas Matthews B., and Phillip Best J. “Ethanol, Memory, and Hippocampal Function: A Review of Recent Findings.” Hippocampus10.1 (2000): 88-93. Web. 42. White, Aaron M., and Phillip Best J. “Effects of Ethanol on Hippocampal Place-cell and Interneuron Activity.” Brain Research 876.1-2 (2000): 154-65. Web. 9 Sept. 2016. 43. Zadra A, Desautels A, Petit D. Somnambulism: clinical aspects and pathophysiological hypotheses. Lancet Neurol. 2013;12(3):285-294. PMID: 23415568 www.ncbi.nlm.nih.gov/pubmed/23415568. 44. Hendler, R. A., Ramchandani, V. A., Gilman, J., & Hommer, D. W. (2011). Stimulant and sedative effects of alcohol. In Behavioral neurobiology of alcohol addiction (pp. 489-509). Springer Berlin Heidelberg. 45. Squire, L. R. (2009). The legacy of patient HM for neuroscience. Neuron, 61(1), 6-9.[ADDED] 46. Szapiro, G., Galante, J. M., Barros, D. M., de Stein, M. L., Vianna, M. R., Izquierdo, L. A., ... & Medina, J. H. (2002). Molecular mechanisms of memory retrieval. Neurochemical research, 27(11), 1491-1498. 47. Min, B. K. (2010). A thalamic reticular networking model of consciousness. Theoretical Biology and Medical Modelling, 7(1), 1.

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Computerized display of the neural connections of the human brain. This image is a Diffusion Tensor Image DTI), courtesy of the Human Connectome Project

SIMULATING THE BRAIN Bundles of neurons without a body? A neural circuit without a brain? Does this mean we are in a simulation? Here is how we can uncover the future of automation and healthcare by looking into our own brain. By Sean P. Bush

Self-driving cars, lifelike robots, and augmented reality, these are all futuristic concepts which initially seemed impossible but which are becoming ever more central to our daily lives. These feats of modern magic rely on human advances in technology, yet are primarily based on synthetic programming inspired by the greatest feat in evolution: the human brain. Recently, new ways to model the brain have been developed using biological, mathematical, kenyon.edu/neuroscience

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“Imagine that a human being has been subjected to an operation by an evil scientist. The person’s brain has been removed from the body . . . [has] the illusion that everything is perfectly normal.” -Hilary Putnam and computational methods. These methods all rely on the science which underlies how the brain actually works. How do scientists build a brain and what does it mean for us in the future? Read along as we discuss brain simulations in these three ways and and what this means for the future of the human race.

BRAIN SIMULATIONS What does it mean to simulate a brain? In just thinking of a simulated brain you might imagine an evil laboratory scene from a horror film: in the middle of the laboratory stands a jar filled with bubbling liquid and surrounding a brain bobbing in the fluid. The evil scientist may be inserting electrodes and taking measurements, attempting to prod the brain to life. Returning to reality, we know that such a scene is currently not possible, but let us disregard this momentarily. What if we could grow new brain tissue or even make a computer act like a brain. If we could, how would it know what is real? How would we know if its thoughts are real? How do we

know that we are not just brains in a vat? These types of questions were first posed by René Descartes early in 1641 but have been pondered to this day by modern philosophers such as Hilary Putnam1. In his 1981 book, Reason, Truth and History, Putnam asks that we consider if our brains are in a vat, how would we know? While he concludes that the brain would essentially not be able to tell, he argues that knowing itself must be possible- the brain must either refer to the virtual object of knowledge or the real object. Saving the epistemology for the real philosophers, let us imagine another scenario where we humans are not brains in a jar but are actually creating different brains in a jar. This seems much similar to the world we live in today, but with less of a evil scientist vibe. Today we can grow tissue from just a few cells or interact in vast imaginary worlds on just a pocket device. Maybe each one of us truly is the mad scientist to many other “brains” in the modern world. Still, each of these brains serves a distinct utility for us, serving humans daily to improve our lives.

The human brain is subdivided into many parts which correspond to different neural functions. Diagram courtesy of S. Marc Breedlove & Neil V. Watson

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What if your brain is in a jar?

Illustration courtesy of Christianne Benedict.

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The various parts of a neuron. A chemical signal from another neuron is sensed by the dendrite. This signal propagates down the neuron to the axon where the signal is transmitted to the next neuron. Diagram courtesy of Charles Stangor.

A (VERY BRIEF) INTRODUCTION TO NEUROSCIENCE The brain controls an enormous amount of biological activity: for us humans this means processes like movement and sensation, memory, and automatic functions (like the heart or breathing rate). The brain is actually only part of the central nervous system, which also includes the spinal cord. When a signal is received by the spinal cord it transmits the signal to the brain where it initiates a signal cascade. Information may travel along a certain pathway in a specific area of the brain (such as the visual cortex) where specific information is extracted. Then information may travel elsewhere throughout the brain (such as the motor cortex) in response to the cascade. Eventually the information may be encoded for memory or further processed. The brain works in these particular cascades due to a specialized cell type

called a neuron. Neurons make up a part of the nervous system which helps transduce signals. To do this, a chemical signal from another neuron is sensed by the dendrite of the neuron. This signal propagates down the dendrite, through the neural cell body, and down the axon. It is at the terminal of the axon where the signal is transmitted to the next neuron and the cycle continues. Since neurons have multiple dendrites and axons, the internal environment of the neuron itself and of the transmission points between the neurons can alter the response. This can amplify, modulate, or reduce the signal to the neuronâ&#x20AC;&#x2122;s specification. While neurons are important, the most abundant neural cell is actually termed glia. There are many different variety of glia including myelinating glia (which help neurons singal), microglia (like an immune system for brain), and astrocytes (which transport nutrients).

Model of a synthetic neuron complete with input (dendrite) and output (axon) terminals. This neuron senses neurotransmitter and releases additional neruotransmitter in response. The model illustrates how a neuron can be simulated by biological and chemical components. Image courtsey of Simon et al., 2015.

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THE BIOLOGICAL BRAIN In an age from growing skin grafts to growing entire organs, patients are being exposed to a new era in medicine where physicians and scientists enable personalized healthcare. Since the brain is quite literally the person, whole brain tissue replacement has been notably absent from medicine. However, addition of neural components is possible so that they change the effect that neurons have with one another. Recent research by scientists at the Karolinska Institutet in Sweden has shown that neuron structures can be generated to respond and change the local brain environment2. They specifically use enzymes to break down neural signals (neurotransmitters: glutamate or acetylcholine) and release electrons which are sensed by device. The device can then transmit the signal through an ion pump. This propagates the transmitted signal which delivers the signal to the postsynapse of the next neuron. These researchers believed that this tool had great potential for use in neurological diseases where the neurons ability to release or sense when neurotransmitter is decreased. In a follow-up study the scientists manufactured an electrical and chemical stimulation sensing device that was nearly as small as a single cell3. They call this device a “neural pixel” and tested this technology in mouse hippocampus neurons. The hippocampus is a neural structure highly involved in learning and memory and is known to be a location where seizures start. The scientists manufactured a

Model of a “neural pixel.” The pixel senses neural activity in the hippocampus (stimulated by 4-AP) and releases inhibitory neurotransmitter (chloride) to reduce the seizure response. Image courtesy of Jonsson et al., 2016.

conducting polymer to record the induced signal and began to deliver the neural signal (GABA) with an electronic ion pump. When tested with epileptic activity, the “neural pixel” was able to deliver inhibitory neurotransmitters on the site and decrease the induction of the seizure. In the future, we may see such simulated neurons implanted into human brains. The lead scientist of the group, Agneta Richer-Dahlfors, sees great promise for the technology in human health: “Next, we would like to miniaturize this device to enable implantation into the human body...using such auto-regulated sensing and delivery, or possibly a remote control, new and exciting opportunities for future research and treatment of neurological disorders can be envisioned.”

“At least we can be sure that we ourselves exist, because every time we doubt that, there must exist an ‘I’ that is doing the doubting. So, yes, you may well be a brain in a vat and your experience of the world may be a computer simulation programmed by an evil genius. But, rest assured, at least you’re thinking!” -Laura D’Olimpio kenyon.edu/neuroscience

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MATHEMATICAL MODELS Simulating the brain using individual biological neurons shows great promise for the future in health-care. However, what if we could simulate a neuron on paper with the theories of mathematics. Xiaolin Zhang did just that by treating the neuron like a signal processing device4. By comparing neural start signals (action potentials) to the transmission signal (synaptic vesicle release), Zhang generated several mathematical functions for the neuron. Overall these functions could then be used together as a complete

Systems of neural networks proposed by McCulloch & Pitts, 1944. Networks of these neurons are termed McCollough-Pitts neurons. mathematical model of a neuron. Even with his simplifications, a complete model of a neuron provides insights into how neurons work at a fundamental level. Other cells of the brain have too been modeled mathematically, such as astrocytes or specific sensory neurons5. What if we thought of the brain not as a collection of neurons but as an overall system where information flows between components? That is

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the approach which was taken by Warren McCulloch when he proposed a system of mathematical equations modeled after neurons in the brain6. A neuron receives an input and then acts on the input to other neurons, which in turn refines the response. These neurons may be organized in a variety of ways to provide a number of responses. However, McCulloch assumed many things of his model, including the following: neurons are only all-ornothing, delays can not activate the same response, there is no delay in the neuron, an inhibitory synapse is absolute, and the neural structure does not change. From our understanding of neuroscience, we know that there are caveats to almost all of these assumptions. Still this method became highly popularized in the mathematical community and later became known as a neural network, or “neural net” for short. It was later highly modified by others after its introduction in 1943 and eventually proceeded through many generations of neural networks. The first generation, or McCulloch-Pitts neurons, only had a binary (0 or 1) input and a binary output. Second generation neural networks could have a continuous set of outputs (rather than just binary), but third generation neural networks utilize biologically relevant neurons (also known as spiking neurons) which gather and integrate input to ‘fire’ an output7. This third generation requires similar or less computing power than previous generation neural networks, but is still not completely like true neurons. Improvements can still be made in neural networks to include integration time, the weight/strength of the synapse, the firing potential, and a refractory period to make a more biologically relevant neuron. These neurons may produce neural networks with greater accuracy and capability previous generations of neural networks. Using the basis of neural networks, Kunihiko Fukushima proposed a modified use to mimic the visual organization of MAY 2017

Comparison of Hubel & Wiesel, 1968 neural organization to the visual recognition method proposed by Fukushima, 1980. the brain8. Fukushima primarily based his research off of the visual system organization published by neurophysiologists Hubel and Wiesel9. Specifically, inputs are first processed by S-cells (simple cells), then later by higher order C-cells (complex cells). Other inhibitory cells can decrease the response from the excitatory cells. These cells act in layers to form planes to determine other representations from the input. Fukushima realized that this model may be a similar way our brains utilize

character recognition due to our ability to recognize characters quickly and intuitively. Terming the method neocognitron, Fukushima successfully applied the system to recognizing distorted numerical digits. Later applications and modifications of this method resulted in the development of what is now known as convolutional neural networks. Today they are used in a variety of automated tasks such as bank check verification or document optical character recognition10. Further implementations of convolutional neural networks have allowed things we never would have thought possible, such as the conversion of black and white photos to color11,12. Using convolutional neural networks, these methods process individual parts of figures to understand their base attributes. These networks have learned from previous photos that certain photo parts should be certain colors, and thus if a part of a photo matches what it has learned, it will decide that that photo features should be a certain color. Over an entire image, individual pixels will be colored leading to a grey scale image turned into a vibrant picture. There is also other ongoing research with convolutional neural networks to use them

Comparison of Hubel & Wiesel, 1968 neural organization to the visual recognition method proposed by Fukushima, 1980.

Colorization of Bexley Hall, Kenyon College utilizing code adapted from Zhang, Isola, & Efros, 2016. See the green grass, blue sky, and red-brown building colored from grey scale. kenyon.edu/neuroscience

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Simulated neural components of the C. elegans worm. Image courtesey of the OpenWorm web simulator. in deep learning for object recognition13. Much of this technology is currently being used today to drive self-driving cars and in object recognition for augmented reality.

COMPUTATIONAL CREATIONS We have a wealth of mathematical resources at our disposal which can be used in the context of artificial intelligence and learning. What if we applied these methods to large scales and used computing power to perform these calculations in real time? The OpenWorm project is attempting to do just that to build a virtual and complete Caenorhabditis elegans. C. elegans is a model system in biology, so complete virtualization of it could allow for virtual experiments where we could learn an almost infinite amount about the system. The software, neuroConstruct, is currently being used to empower the OpenWorm project and utilizes conductance-based neuronal network models in 3-D space to more accurately model neurological networks14. The software can be utilized to import physical

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cell morphology and create cell models with positioning in the model. From there, researchers attempted to make the worm move. Scientists implemented new pseudo neurons in the worm to allow it move quickly and propagate signals15. The worm could successfully move forward and backward when they send sinusoidal waves of activation down motor neurons. Other researchers improved the model and attempted to teach it to learn to move forward without their input16. Using the 3D-simulation, they selected 12 neurons which controlled 8 muscle cells. Input was fed from one neuron to the next, which controlled the muscles, and a reward signal was outputted at completion of the circuit. After 100 cycles, they successfully showed that the worm could move forward on its own. While virtualizing a worm is already highly complex, virtualizing a human brain is ever more challenging. The formation of The Human Brain Project allowed a vast amount of neurological and imaging data to be collected for use throughout the brain simulation community17. This data was especially helpful in the creation of the Blue Brain Project, which attempts to simulate an entire brain. The NEURON simulator was used as the basis for modeling in the Blue Brain project as it allows for the creation and simulation of realistic neurons in biological models18. The project utilizes the IBM Blue Gene/L supercomputer platform for their brain simulation19. This computer had previously been utilized to beat human chess players with the brute force of its large processing power (about 360 TFLOPS [floating point operations/ sec]). The system can currently host 100,000 complex neurons or 100 million simple neurons. They estimate that computer power must increase 1,000,000-fold before the human brain (100 billion neurons) can be fully MAY 2017

Comparison of a simulated cortical slice compared to lab measurements. Calcium fluctuations are very similar between the two systems. Images courtesey of the Markram et al., 2015.

Below: Simulated Golgi stain of the virutal neurons simulated, though they speculate that code efficiencies can be utilized to decrease this number. The Blue Brain Project has recently become successful in simulating a part of the rat neocortex20. The researchers compared the simulation to actual neurons and found it similar enough that this system can be utilized for some experiments that would previously have been done in live tissue. The Blue Brain Project is not the only large scale brain simulator. The RIKEN Brain Science Institute used NEST software with the K supercomputer (about 11.28 PFlops) to simulate neural networks21. They demonstrate that the software is capable of simulating 10 neurons and 10 synapses. NEST itself utilizes differential equation neuron models which interact with each other. Other researchers report a working model of part of the human brain (â&#x20AC;&#x153;Spaunâ&#x20AC;? - Semantic Pointer Architecture Unified Network)22. Using a neural architecture of 2.5 million virtual neurons they attempted to process images and move motorized arm in response to the images. Specifically, the system was trained to copy a presented drawing, recognize the image, receive rewards, reproduce lists, and answer basic questions. They report that Spaun does have limitations though, including diminished learning, uncomplete anatomy, and the ability to only recognize digits 0 to 9. kenyon.edu/neuroscience

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TRANSISTORS OF TOMORROW Today we have a vast amount of computational and mathematical power which we can use to simulate lifelike conditions. However, prior to the use of computers for neural simulations, a philosopher, Herber Simon, proposed that brain can be recreated and simulated on a computer so that scientists could better study it23. He demonstrates this with small structured tasks (like algebraic equation solutions). A computer, just like a human, could work out each step of an equation after having learned how to do so. Simon recognized that this method did not illustrate higher order ‘creative’ tasks, but still believed his method can be efficiently utilized in the future. Today we can see that this was the case. Artificial intelligence is now a burgeoning field because people like Herber Simon pushed the boundaries of computers before it was even possible. While we are currently in a technological renaissance of machine intelligence, pioneers such as Elon Musk or Bill Gates warn that we must not let machines become powerful enough to overpower us. Musk is also a supporter of the theory that we are currently in a simulation, as popularized by Nick Bostrom24. Bostrom argues that there are three potential futures for the human civilizations. These futures are based on the fact that technology and simulations have developed dramatically in recent years and that the future will have a great excess of computing power. One can easily see this shift when comparing modern virtual reality gaming to early and low fidelity Atari systems. Bostrom declares that one option is the future death of humanity due to not developing humanity simulations in time. Another option may be that we will develop this technology for running these simulations, but decide not utilize it. The last option is

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that our current reality is a simulation. Bostrom’s equation describing his theory is: fsim= (fpNH)/(fpNH+H). fp is the fraction of human civilizations that can perform simulations, N is the average number of past simulations by fp, H is the average number of people before a simulation, and fsim is the fraction of humans in virtual reality. Since N=f1N1, we can substitute it in the original equation to yield: fsim= (fpf1N1)/ (fpf1N1+1). Since N increasingly becomes greater with increasing computational speed, there is an ever greater chance that we are in a simulation. If we are living in a simulation, Bostom estimates that the number of computer operations necessary to provide this simulation is nearly 1033 to 1036 operations per second, much higher than any supercomputers currently available. What may have caused humans to make a simulation? Bostom theorizes that weaponized technology may be implicated in this. Still, is there any way to tell for sure if we are in a simulation? Pretty powerful people think this is the case, but the choice is still yours to make.

LOOKING EVEN FURTHER TO THE FUTURE The human brain is a highly complex organ which we are still unable to fully understand. However, research in brain stimulation is already yielding advances in modern medicine and automated life. Today we have cars that drive themselves and smart homes which respond to a family’s every need, all developed by looking to the brain to understand computer usage to better serve our needs. Looking beyond our current needs, future humans must use behavorial checks of artificial intelligence to prevent it from overpowering the human race. Still, we must use these machines to improve the lives for all and encourage MAY 2017

innovations in machine intelligence to help accomplish these goals. Going forward, we should continue to look to the human brain to understand its function and of how its organization can be used to further humankind.

MORE TO EXPLORE [1] Putnam, H. Brains in a vat. Reason, truth and history. 21, 1–21 (1981). [2] Simon, D. T. et al. An organic electronic biomimetic neuron enables auto-regulated neuromodulation. Biosensors and Bioelectronics 71, 359–364 (2015). [3] Jonsson, A. et al. Bioelectronic neural pixel: Chemical stimulation and electrical sensing at the same site. Proceedings of the National Academy of Sciences 201604231 (2016). [4] Zhang, X.-l. A Mathematical Model of a Neuron with Synapses based on Physiology. Nature Precedings (2008). [5] Tewari, S. G. & Majumdar, K. K. A mathematical model of the tripartite synapse: Astrocyteinduced synaptic plasticity. Journal of Biological Physics 38, 465–496 (2012). [6] McCulloch, W. S. & Pitts, W. A logical calculus of the ideas immanent in nervous activity. The Bulletin of Mathematical Biophysics 5, 115–133 (1943). [7] Maass, W. Networks of spiking neurons: The third generation of neural network models. Neural Networks 10, 1659–1671 (1997). [8] Fukushima, K. Neocognitron: A self-organizing neural network model for a mechanism of pattern recognition unaffected by shift in position. Biological Cybernetics 36, 193–202 (1980). [9] Hubel, D. H. & Wiesel, T. N. Receptive fields and functional

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architecture of monkey striate cortex. The Journal of Physiology 195, 215–243 (1968). [10] Lecun, Y., Bottou, L., Bengio, Y. & Haffner, P. Gradient-based learning applied to document recognition. Proceedings of the IEEE 86, 2278–2324 (1998). [11] Iizuka, S., Simo-Serra, E. & Ishikawa, H. Let there be Color!: Joint End-to-end Learning of Global and Local Image Priors for Automatic Image Colorization with Simultaneous Classification. ACM Transactions on Graphics (Proc. of SIGGRAPH 2016) 35 (2016). [12] Zhang, R., Isola, P. & Efros, A. A. Colorful Image Colorization 1–25 (2016). [13] Rusk, N., Bengio, Y. & Hinton, G. Deep learning. Nature Methods 13, 35–35 (2015). [14] Gleeson, P., Steuber, V. & Silver, R. A. neuroConstruct: A Tool for Modeling Networks of Neurons in 3D Space. Neuron 54, 219–235 (2007). [15] Palyanov, A., Khayrulin, S., Larson, S. D. & Dibert, A. Towards a virtual C. elegans: a framework for simulation and visualization of the neuromuscular system in a 3D physical environment. In silico biology 11, 137–47 (2011). [16] Demin, A. & Vityaev, E. Learning in a virtual model of the C. elegans nematode for locomotion and chemotaxis. Biologically Inspired Cognitive Architectures 7, 9–14 (2014). [17] Shepherd, G. M. et al. The Human Brain Project: neuroinformatics tools for integrating, searching and modeling multidisciplinary neuroscience data. Trends in neurosciences 21, 460–8 (1998). [18] Hines, M. L. & Carnevale, N. T. The NEURON simulation environment. Neural computation 9, 1179–209 (1997).

Background: Neural simulation image courtesey of Markram et al., 2015.

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[19] Markram, H. The blue brain project. Nature reviews. Neuroscience 7, 153–60 (2006). [20] Markram, H. et al. Reconstruction and Simulation of Neocortical Microcircuitry. Cell 163, 456–492 (2015). [21] Helias, M. et al. Supercomputers Ready for Use as Discovery Machines for Neuroscience. Frontiers in Neuroinformatics 6, 1–12 (2012). [22] Eliasmith, C. et al. A large-scale model of the functioning brain. Science 338, 1202–5 (2012). [23] Simon, H. A. Studying Human Intelligence by Creating Artificial Intelligence: When considered as a physical symbol system, the human brain can be fruitfully studied by computer simulation of its processes. American Scientist 69, 300–309 (1981). [24] Bostrom, N. Are We Living in a Computer Simulation? The Philosophical Quarterly 53, 243–255 (2003).

Background: Neural simulation image courtesey of Markram et al., 2015.

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The “Bad Student Disease”

Could sleep apnea be the underlying cause of poor in-school performance in some students?

Dominic Camperchioli

kenyon.edu/neuroscience

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Put yourself back into your school days, dragging through six hours of classes five days per week. As your mind surely wandered in and out of whatever the teacher was droning on about, you probably looked around and found there was one kid who struggled to stay awake. It seemed like they were always sleeping, or at least nodding in and out of wakefulness. Even if they were punished for this bad behavior, nothing ever seemed to change. And why should they not be punished? If the point of school is to learn, there is no way they can learn if they sleep through class. For some students, this struggle to stay awake is within their control, especially with a concerted effort to get to bed on time to get adequate sleep. For others, it seems they can’t stay awake, regardless of how much sleep they get the night before. In these cases, their daytime sleepiness may be the tip of an enormous iceberg. Sleep apnea is a frequently undiagnosed sleep disorder in which an individual is failing to get the proper amount of oxygen into the blood during sleep, resulting in higher levels of carbon dioxide, which causes the individual to awaken and intake more oxygen to return to homeostatic levels. Waking up during sleep may not sound that bad—it’s something everyone does every now and then—but the waking events can be long, with a few minutes between each successful breath, and in severe cases can sometimes occur hundreds of times per night. Most of the time, those with the disorder have no inclination as to why they are always tired or simply think

they are no more tired than anyone else, and assume they are just worse at controlling it. For those individuals who may be suffering along with their grades due to constant fatigue, testing for sleep apnea may not only allow for treatment to improve their health but also improve their performance academically as well.

What is Obstructive Sleep Apnea?

Obstructive sleep apnea (OSA) occurs when breathing during sleep is physically blocked, usually by a collapse of the airway through excess weight on the neck (usually the case in obese patients) or through blockage in the throat due to inflamed tonsils or adenoids (17). Of the two, OSA is much more prevalent in the general population and even more so among children and teens, where tonsils and adenoids tend to be enlarged more often (12). Although a very accurate number is not known due to factors such as a lack of diagnosis for many people with OSA, some studies estimate that about 3% of children experience sleep apneas (11). This in itself is surprising. Thinking back to my high school days, I remember most classes being about 30 students large. With an incidence of 3%, this means that there was likely about one student with sleep apnea in each of my classes and the thoughts surrounding those memories of students sleeping shift from assumptions of laziness and apathy towards school to sympathy for a perhaps undiagnosed disorder that may be controlling more of the student’s life than they could ever imagine.

Fig 1. Neuronal activity within a sleep deprived (left) vs. well-rested (right) fruit fly brain. Wang et al. 2011, Fig 1b.

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Fig2. Diagram of airway blockage in OSA, compared to a normal open airway. Courtesy of webmd.com

Synaptic Pruning

The effects of poor sleep on the body and mind have been well documented for years and are as broad as they are deep, but in the classroom the cognitive deficit is certainly the most vital. While the exact biological basis for sleep is not yet fully understood, most research is pointing towards the idea of neuronal synaptic pruning as one very important aspect (4, 5, 10). The brain relies heavily on connections between neurons to transmit information from one region to another, allowing us to perform basic functions such as walking and breathing as well as very abstract tasks such

Fig 3. Changes in the net number of synaptic spines after sleep (W1S2), wake (S1W2), or sleep deprivation (W1SD2) From Maret et al., 2012 Fig. 1D kenyon.edu/neuroscience

as talking, playing an instrument, thinking to ourselves, solving a math problem, or recalling the year when the Hundred Yearsâ&#x20AC;&#x2122; War began. These connections, called synapses, are therefore key to the proper functioning of our brains and, in particular, learning. Throughout the day, every time you hear, see, or read something new, a new synapse will form to help engrain that into your memory in case it may be handy information to have in store (5). However, remembering every little detail from each day would be incredibly inefficient, and, just like sorting a filing cabinet filled with every single document you have ever received and throwing out the useless or irrelevant documents, synaptic pruning is the brain going through all of the connections made during the day and eliminating some of the less important ones, recycling their contents for future synapse formation. In species ranging as far down the evolutionary chain as fruit flies, studies have shown that reducing the amount of sleep an individual receives effects how much pruning they are able to accomplish each night. Studies like that of Maret et al. (2012) have yielded plenty of evidence to support this claim. Targeting mice as the model organism, these researchers found distinct differences in the number of synapses immediately after sleeping, right before sleeping, and after being kept awake for an extended period of time. After sleeping, the mice displayed an overall decrease in number of synapses, while after a period of wakefulness or a period of sleep deprivation the mice showed an overall net gain in the number of synapses, but

Fig 4. A standard representation of a sleep cycle. Courtesy of https://en.wikipedia.org/ wiki/Sleep. SCIENTIFIC KENYON

lasting about 90 minutes. Whenever an individual awakens from sleep, they must then start the entire cycle over again, no matter where they left off. For sleep apnea patients, a problem arises here. Once breathing stops during an apneic event, blood concentrations of oxygen will drop. As they drop, the carotid body, which can detect changes in chemical concentrations within the blood, notices the difference indirectly through relative increases in carbon dioxide. It then relays this information to the ventral respiratory column (a cluster of neurons within the brainstem responsible for controlling breathing), which then signals to the diaphragm to increase the rate of respiration, and to the raphe nuclei, which relay information to the rest of the brain controlling circadian rhythms (13). A signal is also sent to the C1 and retrotrapeziod nuclei within the brainstem to wake the individual up so they can try to regain control of their breathing (1). When this happens, the individual loses any progress in their cycle they have had. Often, it is almost as bad as the instances of sleep deprivation in the mice, and it is very likely these individuals are not maintaining synaptic homeostasis through proper pruning.

Fig 5. Brain regions responsible for control of respiration. C1 neurons are located in the ventrolateral medulla, right next to the ventral respiratory group. Image courtesy of StudyBlue. https://classconnection.s3.amazonaws.com/636/ flashcards/1088636/png the exact stage of the sleep cycle during which this process occurs is not yet understood. The ability of sleep to regulate the number of synapses in an organism has been termed the Synaptic Homeostasis Hypothesis (5, 10, 12) and is seen as a main reason why sleep is so important to our daily lives.

The Anatomy & Physiology of Sleep & Respiration

Mammalian sleep relies heavily on cycles, with humans having five stages per cycle and each cycle

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This disruption in sleep and the resultant lack of pruning is damaging to proper brain functioning, including memory and learning, in individuals of all ages, but children and adolescents have much more at stake. During the adolescent window of development, the brain undergoes massive renovations, with the very important thalamocortical pathways maturing. These bridges between the cortex and the thalamus help integrate higher-level processes, such as controlled muscle movement and thinking. The thalamus serves as a central port within the brain, relaying information to both the spinal tracts and subconscious areas, including regulation of sleep. Furthermore, the amount of gray matter, which is representative for the number of synapses within the brain, decreases as it matures into its final form (15). The evidence provided by Maret et al (2012) proves just how important sleep may be for development from childhood through adolescence, given decrease in gray matter and maturation of thalamocortical tracts rely heavily on synaptic pruning and strengthenMAY 2017

Deficits Associated with Sleep Apneas

Fig 6. Changes in levels of carbon dioxide within the blood change the rater of respiration. ing already present synapses. Continuing with this trend, the amount of sleep recommended by the National Sleep Foundation decreases as an individual grows, with 10-13 hours recommended for 3-5 year olds, 9-11 hours recommended for 6-13 year olds, 8-10 for teenagers, and 7-9 for adults (8). For children and adolescents, a lack of sleep may not just deter proper pruning; it may deter proper maturation of the brain as a whole. These changes are exactly what experimental disruptions in breathing during sleep in rats found. By cyclically reducing oxygen concentration in rat sleeping chambers by half throughout the night, the researchers developed a model for chronic oxygen supply disruptions during sleep, representative of a very severe case of OSA. By looking at the rat brains after experimentation, a distinct decrease in dendritic branching in male rats correlated to an apparent decrease in working memory in the treatment group, providing further evidence for cognitive disruption associated with sleep apnea (9).

In a study focusing on children ages 5-9 years old, researchers found that there are differences in neurocognitive functioning between children with OSA and those who do not. Using intelligence tests designed to test neurocognitive function of children and a combination of a sleep questionnaire filled out by parents and a polysomnography to verify sleep apnea, the correlation was well established (6). Taking this connection a step further, an earlier analysis of IQâ&#x20AC;&#x2122;s and ability to pay attention in children between 5 and 10 years old looked simply at the presence of snoring to see if it correlated with neurocognitive dysfunction; the results proved just that. Specifically, the children struggled more to pay attention and their cognitive abilities were lower, but still within the normal range (2). This is part of the problem seen with recognizing a cognitive deficit as resultant of sleep apneaâ&#x20AC;&#x201D;it may not be worse than a normal level of ability, but not nearly as good as the individualâ&#x20AC;&#x2122;s actual potential. It may therefore just seem that the child is on the less intelligent side rather than assuming the child is suffering from OSA. Children who are diagnosed with OSA do tend to see at least some behavioral differences in addition to cognitive ones. It is fairly common for a child with OSA to have ADHDlike behaviors, but there is no correlation to ADHD itself (2). The combination of possible attention, behavioral, and cognitive deficits can inevitably lead to poor performance in the classroom. In fact, the prevalence of OSA among the lowest performing students is up to six times higher than the prevalence of OSA

Fig 7. Synapse thickness increases when awake (W) compared to sleep (S), and increases even more after sleep deprivation (SD). From Bushey et al. 2011, Fig 2G kenyon.edu/neuroscience

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Fig 8. A cartoon of different degrees of airway blockage due to tonsillitis, with each degree being an increasing quarter of the airway covered. www.lessowmd.com/ snoringsleepapnea among all students, with one study finding that 18% of the students within the lowest 10% of the class within an urban public school had OSA, a high number compared to the 3% expected within the general population of children (7). Assuming 3% is accurate as the total percentage of children with OSA, this study implies approximately 60% of children with OSA fall in the bottom ten percent of their class.

Treatments and Outcomes

Luckily, OSA is treatable and there are many techniques by which to do so. Because the issue revolves around a lack of oxygen entering the lungs, it is an easy fix involving physically opening of the airway. Children often develop OSA as a side effect of enlarged tonsils or adenoids, which sometimes covering more than 75% of the airway, so a simple surgical removal suffices as a permanent solution to the problem (6). For others, with age the size of the tonsils will shrink down to a normal, manageable size. Another very effective method for OSA treatment is controlled positive airway pressure (CPAP), a machine that helps to get air into the lungs. Essentially, CPAP forces a small amount of air into the lungs through a mask or nasal cannula. This keeps the airway open enough to allow for proper breathing, just like how softly blowing air into a deflated balloon through a straw would help keep the neck of the balloon open. This is especially effective for patients who have excess weight on their neck that presses the airway closed, and works well for most cases of OSA (3). It is slightly less ideal than other forms of treatment, as it means the patient will then need to have a CPAP machine wherever they travel and wear it every night for the rest of their life. Finally, because of the tendency of OSA to correlate with being overweight or obese, sometimes simple lifestyle changes like diet and exercise are just as effective.

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Importantly, these treatments help reverse affects of OSA, restoring proper brain functioning in most cases. Among the students within the bottom 10% of their class with OSA, those who were treated with adenotonsillectomy had significant scholastic improvement, with 90% of them jumping out of the bottom 10% of their class (7). This is not only beneficial for the students who experience significant improvements, possibly opening up more opportunities for them in the future, but also for teachers and administrators as well, as poor behavior and academic performance usually requires excess work to try to keep the student up to par. Specifically, treatment has been shown to recover the childâ&#x20AC;&#x2122;s ability to pay attention and some cognitive effects relatively quickly (2, 6). However, the long-term effects do remain unclear and likely depend on how soon OSA is recognized and treated (6).

Fig 9. Diagram of a sleep apnea mask and the forced airflow keeping the airway open. www.houstonsleep.net MAY 2017

Conclusions

Ultimately, OSA is a problem among a significant number of children and has potential to effect the individuals in many aspects of their life, both in the short-term and possibly the longterm. It is an issue affecting enough students to warrant some form of action, perhaps by means of increased screening for the disease. While pediatric home sleep apnea testing kits are resting on the brink of being made readily available for commercial use, they are much easier, cheaper, and more accessible than being tested in a sleep lab while also allowing the patient to be in the comfort of their own home (14). A cheaper and even more accessible screening technique could be simple questionnaires sent to parents asking questions about their child’s sleep behaviors, looking for red flags such as snoring and gasping for air. Even this simple step could be enough to catch a number of individuals who may have OSA and direct them to the appropriate specialists. The importance of screening extends beyond treatment, though, simply by shedding light on OSA and raising awareness for it as a possible cause of any deficits, especially among students who nod off during classes. Often, sleep apneas are seen as only diseases of the elderly and overweight, but this idea is nonsense. OSA is not only present within children, but common at a relatively high prevalence. With the potential to influence behavior, attention span, and cognitive abilities, it is no surprise that the rate of occurrence is many times higher among poorly performing students. Furthermore, children are still developing, implying the detriments to proper brain maintenance through processes such as synaptic pruning may pose not only an immediate threat to cognitive functioning but may also alter the final structuring of the brain. These changes may end up being irreversible, with some deficits lasting throughout the individual’s lifetime. Thankfully treatment of the disease through adenotonsillectomy is relatively quick, easy, and effective in preventing future episodes and even CPAP, works phenomenally well. Right now, obstructive sleep apnea weighs down on schoolchildren with the uncontrollable desire to sleep, and leads to suboptimal academic performance, not to mention the psychological damage associated with being viewed as a lazy, apathetic student by teachers kenyon.edu/neuroscience

and peers. With such a large importance placed on doing well during school to have a successful job or to get into a great university, it is shocking that something like OSA is not a bigger deal. As a society, identifying OSA is a problem not only for the present but for the future of the many children with the disease, and making sure teachers and parents are willing to consider obstructive sleep apnea as a possible cause of abnormal behaviors is a vital step in making sure students are able to develop and learn to their full potential.

Works Cited

1. Abbott, S. B., Coates, M. B., Stornetta, R. L., & Guyenet, P. G. (2013). Optogenetic Stimulation of C1 and Retrotrapezoid Nucleus Neurons Causes Sleep State Dependent Cardioprespiratory Stimulation and Arousal in Rats. Hypertension, 61(4), 835–841. https://doi.org/10.1161/HYPERTENSIONAHA.111.00860 2. Blunden, S., Lushington, K., Kennedy, D., Martin, J., & Dawson, D. (2000). Behavior and Neurocognitive Performance in Children Aged 5-10 Years Who Snore Compared to Controls. Journal of Clinical and Experimental Neuropsychology, 22(5), 554–568. https://doi. org/10.1076/1380-3395(200010)22 3. Bradley, T. D., Logan, A. G., Kimoff, R. J., Sériès, F., Morrison, D., Ferguson, K., … Floras, J. S. (2005). Continuous Positive Airway Pressure for Central Sleep Apnea and Heart Failure. New England Journal of Medicine, 353(19), 2025–2033. https://doi. org/10.1056/NEJMoa051001 4. Buchmann, A., Ringli, M., Kurth, S., Schaerer, M., Geiger, A., Jenni, O. G., & Huber, R. (2011). EEG sleep slow-wave activity as a mirror of cortical maturation. Cerebral Cortex, 21(3), 607–615. https://doi. org/10.1093/cercor/bhq129 5. Bushey, D., Tononi, G., & Cirelli, C. (2011). Sleep and Synaptic Homeostasis: Structural Evidence in Drosophila. Science, 332(6037), 1576–1581. https:// doi.org/10.1126/science.1202839 6. Friedman, B.-C., Hendeles-Amita, A., Kominsky, E., Leiberman, A., Friger, M., Tarasiuk, A., & Tal, A. (2003). Adenotonsillectomy Improves Neurocognitive Function in Children with Obstructive Sleep Apnea Syndrome. Sleep, 26(8), 1–7. 7. Gozal, D. (1998). Sleep-Disordered Breathing and School Performance in Children. Pediatrics, 102(3), 616–620. https://doi.org/10.1086/250095 8. Hirshkowitz, M., Whiton, K., Albert, S. M., Alessi, C., Bruni, O., DonCarlos, L., … Adams Hillard, P. J. (2015). National sleep foundation’s sleep time duration recommendations: Methodology and results summary. Sleep Health, 1(1), 40–43. https://doi. org/10.1016/j.sleh.2014.12.010 9. Kheirandish, L., Gozal, D., Pequignot, J. M., SCIENTIFIC KENYON

Pequignot, J., & Row, B. W. (2005). Intermittent hypoxia during development induces long-term alterations in spatial working memory, monoamines, and dendritic branching in rat frontal cortex. Pediatric Research, 58(3), 594–599. https://doi. org/10.1203/01.pdr.0000176915.19287.e2 10. Liston, C., Cichon, J. M., Jeanneteau, F., Jia, Z., Chao, M. V, & Gan, W.-B. (2013). Circadian glucocorticoid oscillations promote learning- dependent synapse formation and maintenance. Natural Neuroscience, 16(6), 698–705. https://doi.org/10.1038/ nn.3387 11. Marcus, C. L., Brooks, L. J., Ward, S. D., Draper, K. A., Gozal, D., Halbower, A. C., … Spruyt, K. (2012). Diagnosis and Management of Childhood Obstructive Sleep Apnea Syndrome abstract. Pediatrics, 130, 714–755. https://doi.org/10.1542/peds.2012-1672 12. Maret, S., Faraguna, U., Nelson, A. B., Cirelli, C., & Tononi, G. (2012). Sleep and wake modulate spine turnover in the adolescent mouse cortex. Natural Neuroscience, 14(11), 1418–1420. https://doi. org/10.1038/nn.2934 13. Nuding, S. C., Segers, L. S., Iceman, K. E., O’Connor, R., Dean, J. B., Bolser, D. C., … Lindsey, B. G. (2015). Functional connectivity in raphé-pontomedullary circuits supports active suppression of breathing during hypocapnic apnea. Journal of Neurophysiology, 114(4), 2162–86. https://doi. org/10.1152/jn.00608.2015 14. Tan, H.-L., Kheirandish-Gozal, L., & Gozal, D. (2015). Pediatric Home Sleep Apnea Testing Slowly Getting Th ere! Chest, 148(6), 1382–1395. https:// doi.org/10.1378/chest.15-1365 15. Tarokh, L., & Carskadon, M. a. (2010). Developmental changes in the human sleep EEG during early adolescence. Sleep, 33(6), 801–809. 16. Wang, G., Grone, B., Colas, D., Appelbaum, L., & Mourrain, P. (2011). Synaptic plasticity in sleep: Learning, homeostasis and disease. Trends in Neurosciences, 34(9), 452–463. https://doi. org/10.1016/j.tins.2011.07.005 17. Zinchuk, A. V., Gentry, M. J., Concato, J., & Yaggi, H. K. (2016). Phenotypes in obstructive sleep apnea: A definition, examples and evolution of approaches. Sleep Medicine Reviews, 1–11. https://doi. org/10.1016/j.smrv.2016.10.002

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Are Two Brains Better Than One? The Microbiome and Autism Kelsey Hauser

The human brain is what makes us, well, human; it is where our

thoughts, hopes, and dreams are created. There is mounting evidence though, of a second brain that seems to be in communication with our central nervous system[6]. Scientists are uncovering the power of this second brain, our microbiome, composed of about 100 trillion microorganisms residing comfortably in our gut. Together, these microbes weigh the same as our actual brain. All together, they encode 3.3 million non-redundant genes, 150 times more than the human genome. While these organisms feed on nutrients we ingest, in return they ferment the carbohydrates from our diets that provide us with about 10%, of our available calories[6].

“We are inhabited by as many as ten thousand bacterial species, these cells outnumber those which we consider our own by ten to one, and weigh, all told, about three pounds-the same as our brain. Together, they are referred to as our microbiome-and they play such a crucial role in our lives that scientists have begun to reconsider what it means to be human.” -Michael Specter, of the New York Times Should we really consider them as another brain? We often associate the brain with neurotransmitters like dopamine and serotonin, with myriad synapses through which electrical impulses are continuously transmitted, with functionally distinct regions and exquisitely specialized cell types. Indeed, all these characteristics and more can also be found in the gut, and furthermore, they are intricately linked to their counterparts in the canonical brain. For example, 95% of all serotonin utilized in the body is produced in the gut[6]. And like the brain located in the skull is a component of the central nervous system, the gut is part of its own specialized nervous system, the enteric nervous system. The ENS, for short, contains neurons that send information to other organs in the body and neurons that deliver signals from other organs, akin to what we call efferent and afferent neurons in the brain, respectively. Yet there are still even more comparisons that can be made. There are numerous cells that provide physical support in the canonical brain, called astroglia. Cells analogous to astroglia exist in the gut too[18].

Intriguingly, these microbes are doing much more than supplementing energy resources. There is now data supporting the idea that the constituents of our gut influence many different aspects of our brains, and our brains can likewise change the composition of our guts[6]. The CNS can affect the microbiome through the release of hormones: for instance, cortisol, which is now known to change bacterial composition, or noradrenaline, which alters bacterial gene expression. Alternatively, bacterial byproducts can themselves act as hormones and signaling molecules. These molecules access the brain through the bloodstream or through a semipermeable membrane of the brain called the area postrema. Microbes have also been shown to affect pathways to the brain[6]. Take, for instance, the division of the nervous system responsible for facilitating “resting and digesting” (the parasympathetic nervous system). One route that the parasympathetic nervous system takes is the vagus nerve, which is a major pathway sending signals from the foregut and colon to the brain. Thus, things that are happening in the gut can be communicated to the brain via this direct pathway[6].

A Short History

The theory that there exists an intricate communication system between the brain and other organs dates back as early as the 1880s[12]. William James and Carl Lange proposed what was called the James-Lange Theory of Emotion. It postulated that we interpret our emotions based on our physiological response. Thus, we might feel anger because

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The Gut-Brain Theory of Autism

we notice our heart rate rising or we might feel anxious because we notice “butterflies” in our stomach[12]. This cohesive view of the brain and gut, though, fell out of favor as Western medicine expanded. Nonetheless, Eastern medicine has continued to recognize the role of the gut in the proper functioning of our brains. In fact, traditional Hindu medical philosophy attributes the digestive system as the most important factor of health. Only recently has the paradigm shifted back to the possibility of the gut-brain connection in Western science and society. We are already acknowledging the connection of the brain and gut, perhaps not fully consciously. Take, for example, the colloquialisms, “trust your gut,” “gut feeling,” “have some guts,” or “hate their guts.” You probably get the picture.

Due to the intimate interaction between gut microbes and the brain, it is intriguing to consider the possible implications of the microbiome to neurological disease. Based on preliminary research, autism, in particular, stands out as at least one condition with a strong connection to the gut. A cardinal feature of autism is deficits in communication, and, importantly, these deficits make it challenging for children to express gastrointestinal pain to physicians. Recently, though, the use of parental reports in research is much more widespread, and parents are more aware of their autistic children’s physical discomfort. In a thoughtprovoking study, the Academy of Pediatrics has reported that gastrointestinal symptoms are present in up to 70% of autism cases[4]. Now that this connection has been established, how are researchers going about digging deeper? One way to explore the effects of the microbiome is to use germ-free (GF) mice[8]. Mice and humans alike acquire much of their microbiome from microorganisms picked up along the birth canal, breast milk, and simply from interactions with the environment in which they live. These GF mice are delivered by sterile Cesarean section. Immediately after birth, they are raised in a sterile environment, virtually eliminating the entirety of their microbiome[8].

Percent composition of bacterial phylum in autistic versus control patients [11] kenyon.edu/neuroscience

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children, Adams et al. found a strong correlation between the number of gastrointestinal symptoms and severity of autism. Additionally, they found concentrations of Bifidobacteria were 45% lower in autistic compared to non-autistic children [1].

A recent study conducted by Desbonnet and his laboratory showed that these GF mice exhibited social deficits and repetitive behaviors akin to those seen in the autistic human population[7]. This implicates the healthy microbiome in developing normal social behavior[7]. Not only did Desbonnet and his team find that mice lacking normal microbe populations have negatively impacted social development, but they further showed that recolonizing these GF mice with microbes from healthy mice can reverse that damage[7]. These findings illustrate potential new and more successful treatments routes for autism.

Evidence for Different Microbiomes

Indeed, several research groups have found significant differences in the microbiomes of people with Autism Spectrum Disorder (ASD) compared to healthy participants[11][1]. One study used a sequencing technique to study microflora present in fecal samples from ASD patients, and their findings are astonishing[11]. Individuals diagnosed with severe autism had significantly higher concentration of the Bacteroidetes phylum of bacteria than either a non-related control group or sibling control group. Conversely, levels of the phylum known as Firmicutes were found to be higher in healthy individuals compared to autistic individuals[11]. Another research group substantiated the results of this laboratory [1]. Using parental reports of 58 autistic children and 39 healthy

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Currently, autism is diagnosed based on the prevalence and severity of a cluster of symptoms based on the Diagnostic and Statistical Manual of Mental Disorders (DSM)[17]. Critics of the DSM and its methodology are growing. The director of the National Institute for Mental Health, Thomas Insel, publically revealed the organization would not use the DSM to steer research funding. He argued the DSM lacks objective laboratory measures and validity[17]. Microbial analyses offer these objective measurements.

Hope for a Better Prognosis

Itâ&#x20AC;&#x2122;s not just diagnostically relevant to target the microflora. Several groups have successfully improved the symptoms of autism by altering populations in the gut. One of the first studies to have an impact on this field was conducted by Sandler and colleagues[15]. They hypothesized that imbalances in the microbiome could allow certain bacteria to over-colonize and produce neurotoxins. These toxins, then, are thought to contribute to autistic symptomology.

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It is important to note that the authors do not recommend antibiotics as a treatment option for autism or any other neurological disease[15]. Vancomycin has the potential to produce vancomycin-resistant enterococcus as well as to negativity impact bacterial composition in certain individuals. Nonetheless, the authors showed improvement in most children of several of the core symptoms associated with the disease[15]. This trial has provided a precedent for further exploration into altering gut bacteria to improve neurological pathologies.

Figure from [15]. Communication and behavior improvements of autistic children during vancomycin treatment.

Participants in the experiment were placed on an eight-week oral vancomycin treatment. Vancomycin is an antibiotic that targets Grampositive bacteria and is commonly used for suspected cases of MRSA, a potentially deadly infection. Gram-positive bacteria do not possess an outer membrane like Gram-negative bacteria, which makes them more susceptible to antibiotics. Due to ethical considerations, only children diagnosed with autism were allowed to participate. Shockingly, 8 of the 11 children showed short-term improvements in both behavior and communication rated by both a clinical psychologist and physician, although these effects seemed to dissipate after several months. Nonetheless, Sandler and his team demonstrated a clear connection between the gut and brain in autism[15]. Whether there is a causative relationship or not, digestive symptomology has largely been ignored in both the diagnosis and treatment of neurological disease up until very recently. Clearly, more attention need be devoted to gut health. kenyon.edu/neuroscience

As an alternative route to antibiotics, a movement to treat autism with probiotics is gaining support[2]. A study published in 2013 produced a mouse model of this neurological disease by modeling a maternal immune activation response in pregnant mice, which is hypothesized to be a possible cause of autism in humans[12]. These mice also have reduced gut wall integrity due to altered microbe populations. When their diets were subsequently supplemented with Bacteroides fragilis, a bacterial species normally present in the gut, the autistic-like symptoms were ameliorated[12]. Beyond probiotics, there is growing desire to employ fecal transplants to treat autism[2]. Fecal transplants are exactly what they sound like: fecal microflora are taken from a healthy donor and transplanted into another person. This then replaces species that may be absent in the receiving individual[2]. Such transplants are currently only approved to treat the potentially deadly C. dificile infection, but offlabel and even at-home procedures have found traction in a population that is impatient with the slow process of FDA clinical trials[3]. Finally, some parents and clinicians have looked simply to changes in diet to help children with autism[2]. Common diets include those with unprocessed, fermented, and gluten-free foods SCIENTIFIC KENYON

to foster the growth of bacteria with a diet closer to that of ancestral humans[2]. A ketogenic diet, also being investigated as a treatment for many cancers, is similarly promising for improving autism symptoms[10]. Ketogenic diets are low in carbohydrates. In effect, this puts your body into a state of ketosis, making your body an efficient fat burner[16]. That diet can affect the microflora is easy enough to believe, but the precise mechanisms involved are revealing. Endotoxin, also referred to as lipopolysaccharide, composes the bacterial wall of gram-negative bacteria[9]. The condition that occurs when there are abnormally high levels of circulating endotoxin is known as endotoxemia and has been linked to severe cases of autism[9]. One experiment found an interesting effect of diet on endotoxemia[14]. When participants were placed on a Western-style diet containing high trans-fat and low quantities of protein for just four weeks, blood endotoxin concentrations rose an incredible 71%. Comparatively, when on a prudent-style diet (low fat and high protein contents), endotoxin levels dropped 31% in the same amount of time[14].

Looking Towards the Future

It is not just autism that has been linked to perturbations in the microbiome: neurological disorders ranging from schizophrenia, depression, Alzheimer’s, and even to multiple sclerosis have also been connected to alterations in gut communities[6]. Moreover, anxiety and stress are associated with microbiome imbalance[6]. Perhaps we should all take the phrase “you are what you eat” more seriously, for our physical, mental, and emotional health. The health of the microbiome must be taken into consideration as diagnostics and treatments for neurological disorders continue to evolve. It is likely that it is neither solely the brain nor the gut responsible for all characteristics we recognize as autism, but rather a combination of perturbations in both. We need not neglect the

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brain or the gut in treating autism and related neurological disorders. Current treatment options for many neuropsychiatric disorders are relatively lacking[2]. In particular, managing autism typically involves utilizing several types of behavioral therapies to develop skills[2]. There are no medications that have been developed to even treat the characteristic symptoms of autism. Rather, the available drugs only work to improve daily functioning for some individuals[2]. Perhaps, though, we are treating the wrong thing; just because autism manifests as neurological symptoms, does not preclude the possibility that the real problem lies in the gut. For, as Hippocrates so aptly stated, “All disease begins in the gut.”

MAY 2017

References

[1] Adams, J. B., Johansen, L. J., Powell, L. D., Quig, D., & Rubin, R. A. (2011). Gastrointestinal flora and gastrointestinal status in children with autism– comparisons to typical children and correlation with autism severity. BMC gastroenterology, 11(1), 1. [2] Autism Spectrum Disorder (ASD): Treatment. (2015, August 12). Retrieved November 29, 2016, from Centers for Disease Control and Prevention, http://www.cdc.gov/ ncbddd/autism/treatment.html. [3] Bakken, J. S., Borody, T., Brandt, L. J., Brill, J. V., Demarco, D. C., Franzos, M. A., ... & Moore, T. A. (2011). Treating Clostridium difficile infection with fecal microbiota transplantation. Clinical Gastroenterology and Hepatology,9(12), 1044-1049. [4] Benach, J. L., Li, E., & McGovern, M. M. (2012). A microbial association with autism. MBio, 3(1), e00019-12. [5] Bravo, J. A., Forsythe, P., Chew, M. V., Escaravage, E., Savignac, H. M., Dinan, T. G., ... & Cryan, J. F. (2011). Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences, 108(38), 16050-16055. [6] Collins, S. M., Surette, M., & Bercik, P. (2012). The interplay between the intestinal microbiota and the brain. Nature Reviews Microbiology, 10(11), 735-742. [7] Desbonnet, L., Clarke, G., Shanahan, F., Dinan, T. G., & Cryan, J. F. (2014). Microbiota is essential for social development in the mouse. Molecular psychiatry, 19(2), 146. [8] Dinan, T. G., & Cryan, J. F. (2013). Melancholic microbes: a link between gut microbiota and depression?. Neurogastroenterology & Motility, 25(9), 713-719. [9] Emanuele, E., Orsi, P., Boso, M., Broglia, D., Brondino, N., Barale, F., & Politi, P. (2010). Lowgrade endotoxemia in patients with severe autism. Neuroscience letters, 471(3), 162-165. [10] Evangeliou, A., Vlachonikolis, I., Mihailidou, H., Spilioti, M., Skarpalezou, A., Makaronas, N., & Sbyrakis, S. (2003). Application of a ketogenic diet in children with autistic behavior: pilot study. Journal of child neurology, 18(2), 113-118. [11] Finegold, Sydney M., Scot E. Dowd, Viktoria Gontcharova, Chengxu Liu, Kathleen E. Henley, Randall D. Wolcott, Eunseog Youn et al. “Pyrosequencing study of fecal microflora of autistic and control children.”Anaerobe 16, no. 4 (2010): 444-453. kenyon.edu/neuroscience

[12] Gilbert, J. A., Krajmalnik-Brown, R., Porazinska, D. L., Weiss, S. J., & Knight, R. (2013). Toward effective probiotics for autism and other neurodevelopmental disorders. Cell, 155(7), 1446-1448. [13] Mayer, E. A. (2011). Gut feelings: the emerging biology of gut–brain communication. Nature Reviews Neuroscience, 12(8), 453-466. [14] Pendyala, S., Walker, J. M., & Holt, P. R. (2012). A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology, 142(5), 11001101. [15] Sandler, R. H., Finegold, S. M., Bolte, E. R., Buchanan, C. P., Maxwell, A. P., Väisänen, M. L., & Wexler, H. M. (2000). Short-term benefit from oral vancomycin treatment of regressive-onset autism. Journal of child neurology,15(7), 429-435. [16] Veech, R. L. (2004). The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism.Prostaglandins, leukotrienes and essential fatty acids, 70(3), 309-319. [17] Watters, E. (2013, June 03). The Problem With Psychiatry, the ‘DSM,’ and the Way We Study Mental Illness. Retrieved November 25, 2016, from https://psmag.com/the-problem-with-psychiatrythe-dsm-and-the-way-we-study-mental-illness8e9a80ca94ed#.8pwvtt7ap. [18] Adaes, S. (2015) The Brain-Gut Axis, Part 1-A Paradigm Shift in Neuroscience. (n.d) Retrieved December 14, 2016, from http://brainblogger. com/2015/08/18/the-brain-gut-axis-part-1-a-paradigmshift-in-neuroscience/.

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Head Strong?

Repeated Traumatic Brain Injury and Neurocognitive Degeneration Amelia Loydpierson

On May 2nd, 2012, former NFL linebacker Junior Seau

took his life [1]. With a single gunshot to the chest, the 30-year old football legend was added to a devastatingly long list of prematurely deceased professional football players with similar stories. Time after time, the illusory perception of football as unrelated to the neurocognitive detriment obtained though this sport is disproved.

Seau, like many others, played football the majority of his life. Playing at the collegiate level for the University of Southern California and then professionally for the San Diego Chargers, the Miami Dolphins, and the New England to Junior Sean experienced countless (likely on the order of 10 thousand) blows to head throughout his career [1]. While Sean was never diagnosed with or treated for any concussive brain injury, video review of his playing along with neurological autopsy findings suggest that he likely sustained a number of concussive end subconcussive brain injuries. In the years following Seau’s retirement from the NFL, he experienced dramatic behavioral changes including “withdrawal, heavy alcohol consumption, reckless business and financial decisions, and gambling”. He was also reported to have become uncharacteristically violent and aggressive”, with at least one incident resulting in arrest for domestic violence. Upon his death, which was preceded by months (maybe years) of unrelenting cognitive chaos and despair, Seau’s brain was donated to science and extensively examined. Like many before him, it was the cumulative neurological damage kenyon.edu/neuroscience

acquired by repeated mild traumatic brain injuries, clinically termed Chronic Traumatic Encephalopathy (CTE), which ultimately ended his life [1].

Chronic

Traumatic Encephalopathy (CTE) is a progressive neurodegenerative disease that develops as a consequence of repeated traumatic brain injury (rTBI) [8] . CTE is clinically characterized by mood impairments, altered behaviors, cognitive dysfunction, and motor disruptions. Mood impairments are often exhibited through depression and irritability, while behavioral changes often include increased levels of aggression and impulsivity [16]. Further, cognitive function is altered by memory impairments, dementia, diminished attention, and compromised executive function and decision-making. Finally, parkinsonian-like motor symptoms, including slurred or slowed speech as well as general muscle weakness, are also often present in CTE cases [16].

There

is approximately 1.6 to 3.8 million sports-related concussions reported every year in the United States [9]. However, this number is likely only a portion of those that actually SCIENTIFIC KENYON

recovery mechanisms but also leads to an accumulation of neural pathology that may not result in clinical symptoms until a large, unrecoverable amount of damage has been done [4].

Beyond Football

With

Former Steelers player, Mike Webster (1952-2002) occur as many such head traumas go undiagnosed [9]. It is often easy to conceive the neurocognitive detriment that more severe blunt force traumas to the head (such as in concussions) cause, but it is much less recognized that even milder subconcussive head injuries, such as those obtained during any average football game, can cause just as severe damage to the brain. It is even conceivable that such injuries can actually cause more severe downstream neurocognitive effects as these types of injuries are likely to occur far more frequently (i.e. several times per football practice or game). While the brain might be able to implement ‘built-in’ recovery mechanisms after a singular mild head trauma, the repetitive nature of these traumas experienced by many athletes not only interferes with the brain’s natural

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one of the highest concussion rates of all sports and the large number of celebrity-focused CTE case studies in former professional football players, it must be noted that chronic traumatic encephalopathy is not specific to the game of football [9]. In fact, almost a century ago, the condition was initially observed in former boxers and termed ‘punch-drunk syndrome’ [4]. As clinical reports and autopsy findings provided a growing awareness of the distinct neurodegenerative pathology, the disease became known as dementia pugilistica until 2002, when a Nigerian pathologist, Dr. Bennett Omalu, observed the condition in former Steelers player, Mike Webster, refining and defining the disease we now refer to as chronic traumatic encephalopathy [4]. In the United States, CTE is most commonly observed (aside from in football) in boxers, wrestlers, hockey players, soccer players, and in other individuals exposed to high-impact sports [11]. Interestingly, military personnel or war veterans have also been recognized as a high-risk cohort for developing CTE as proximal exposure to bomb-blasts can cause traumatic brain injuries from the primary pressure waves and biomechanical force to the brain. In 2011, CTE was confirmed upon autopsy in an Iraqi war veteran who had been diagnosed with post-traumatic stress disorder (PTSD) and later committed suicide at the age of 27 [10]. This case, MAY 2017

along with several before him, lead to the notion of PTSD in war veterans as belonging to the CTE spectrum of disease. We now know that while PTSD is a mental health issue suffered by many war veterans, the etiology behind its clinical symptoms (i.e. insomnia, anxiety, depression, etc.), in many cases may be explained by neurological pathology associated with CTE [10].

The Brain Upon Impact

Concussive

and subconcussive brain injury results from rapid rotational and translational accelerations and decelerations as well as impact decelerations, exerting significant forces on the brain tissues [2]. The brain is encased by several protective layers, referred to as the meninges, as well as by cerebral spinal fluid directly surrounding the brain [4]. While these layers do serve as protection for the brain, it is not

Diagram of neuron Blue= axon always enough. Put simply, we were not manufactured to endure repeated head trauma. However, in many cases, additional layers of protection for the skull (and brain) can be provided by simply wearing a helmet. The football helmets used today have drastically reduced head injury compared to older helmet models [6]. Despite this, current helmet models do not appear to vary greatly in their effectiveness, as no one manufacturer or design appears advantageous in preventing concussion [6] . Given the current technological and manufacturing resources, it is possible that helmets may have reached their protective or efficacious potential. That is not to say that helmet to do not help reduce the force that the brain feels, but they ultimately cannot protect the brain from the skull.

One

Biomechanical forces of concussions kenyon.edu/neuroscience

of the most fundamental and immediate consequences of biomechanical force to the head is injury to the axons of neurons and the surrounding myelin [15]. Axons are vital components of cellular function and disruption to their structural integrity results in an impaired ability to transport cargo from one end of the cell to the other and to communicate SCIENTIFIC KENYON

with neighboring cells. In 2012, a team of researchers examined an in vitro axon model that introduces external air pressure in order to simulate TBI and consequently examined the dynamic stretch injury of axons [15]. Specifically, these researchers investigated a vital structure found within the axon, collectively termed microtubules. In neurons, microtubules are critical to the maintenance of neuronal structure as well as intracellular transport. Due to their relatively stiff and stable tubelike composition within cells, they particularly vulnerable to impact-related stress. Physical strain to axons can cause the microtubules within them to break, disrupting the cytoskeletal structure of the axon as well as molecular transport within the axon [15]. Unsurprisingly, these microtubule breaks are associated with axonal undulations that resulted from TBI. A more recent method of assessing axonal integrity in vivo, diffusion tensor imaging (DTI), has shown that even mild traumatic brain injury (mTBI) can result in some degree of axonal damage [5]. In a 2007 study of individuals with varying degrees of TBI, the degree of damage to axons was further associated with reduced cognitive function [5].

Additionally,

in response to neuronal damage, such as the diffuse axonal injury discussed above, a neuroinflammatory response is mediated through the activation of resident immune cells referred to as microglia, whose job is to help repair and/or clear damaged cells from the network [12]. Activated microglia and chronic neuroinflammation is a common hallmark observed in several neurodegenerative diseases, such as Alzheimerâ&#x20AC;&#x2122;s disease, Parkinsonâ&#x20AC;&#x2122;s disease, prion diseases, etc. and has been associated with neuronal

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degeneration and axonal abnormalities [12] . However, under such pathological conditions, it remains unclear whether microglial activity is actually harmful or helpful to neurological conditions. While it is possible that overactive microglia are simple a result of injury, it is also possible that their chronic activity further contributes to the neurological damage. The activation of microglia has been studied using positron emission tomography (PET) techniques and demonstrated increased microglial activation in some cases up to 17 years following a traumatic brain injury [12]. Interestingly, the site of this inflammatory response appeared independent of specific site of injury on the brain and was most severe in subcortical regions [12]. If even a single TBI can trigger pathologically chronic microglial activity, imagine the neurological detriment to the brain when an individual obtains tens or even hundreds of these throughout a professional football career for example.

Pathological Hallmarks

The

combined effect of persistent neuroinflammation and recurring

kenyon.edu/neuroscience

axonal damage can ultimately lead to the presentation of insoluble protein aggregations that are more specifically associated with the neurodegenerative nature of this disease [4]. Autopsy findings have shown that the most prominent proteinopathy of observed in CTE is related to the aggregation of tau proteins, which are directly associated with the stabilization of microtubules within neurons [13]. As a result of the destabilized microtubules within axons, tau proteins become over phosphorylated and form obstructive neurofibrillary tangles (NFTs), ultimately contributing to larger scale neurodegeneration [4].

Additionally, more than 80% of confirmed

CTE cases also possess inclusion bodies (i.e. protein aggregates) composed of transactive response (TAR) DNAbinding of 43-kDa (TDP-43) [2, 7]. TDP43 is a widely expressed protein in many tissues that, under certain conditions, may migrate from the nucleus to the cytoplasm of neurons, where they form pathological inclusion bodies and impair neuronal health [7].

Finally, amyloid-Î˛ is an additional protein

that has been shown to form pathological SCIENTIFIC KENYON

aggregates in CTE. TBI and axonal injury creates an environment in which higher concentrations of Aβ protein may be produced, leading to the formation of Aβ plaques or deposits. Aβ is more controversially associated with CTE as they only appear in a fraction (between one-third and one-half) of confirmed CTE cases [4, 12, 13]. t remains unclear whether these protein aggregates cause neurodegeneration or result from other neurodegenerative mechanisms. More than likely, these tangles, plaques, and inclusion bodies both result from axonal injury and further impair neural function and communication by ‘mucking’ up neuronal networks and causing cell death. While the mechanisms underlying the formation and clearance of these pathological aggregations continues to elude researchers and medical doctors, their presence and distribution in the brain has become an important diagnostic tool that can be examined and researched in individuals upon autopsy. The most affected regions of the brain are generally subcortical structures such as the brainstem and thalamus, specifically regions within the cortico-striato-pallido-thallamic loops [2].

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This neural pathway has been implicated in relaying/connecting information from different areas of the brain via various feedback mechanisms, which allow the brain to regulate and modulate activity during both physical and cognitive tasks. The core regions initially, consistently, and increasingly affected include these limbic regions of the medial temporal lobe, with particularly high rates in the pons, midbrain, thalamus, and basal ganglia [2, 5, 12]. These regions are broadly implicated in processes involving memory, emotion, homeostatic regulation (e.g. sleep), and movement [12]. The various patterns of such pathological distribution (primarily tau pathology) and the associated symptomology are outlined in the table below.

The Challenge

Diagnosing CTE

ne of the major limitations faced in both diagnosing and studying this disease is the high level of similarity (both clinically and pathologically) and between CTE and other psychological and neurodegenerative disorders [14]. While the presence of insoluble protein deposits irrefutably disrupts neuronal function and contributes to cell death, none of the proteins mentioned above are specific to CTE. For example, tau and amyloid-β pathology are also the two neurologically defining characteristics of Alzheimer’s disease (AD), while TDP43 is the primary pathological hallmark found in amyotrophic lateral sclerosis (ALS) [7, 13] . However, patient history reports and autopsy findings have demonstrated a clear MAY 2017

CTE Progression

Clinical Presentation

Neuropathological Distribution (patterns of fibrillary protein pathology)

• Headaches • Impaired concentration/attention

• Minor ventricular enlargement • Protein deposition in subcortical structures (i.e. primarily thc brainstem) • Limbic medial temporal lobe pathology (limited to the amygdala)

Stage 2

• Depression • Impulsivity • Short-term memory loss

• Atrophy in Locus Ceruleus and Substantia Nigra • Protein deposition found in all limbic medial temporal lobe areas [amygdala and medial temporal lobe (MTL); hippocampus, entorhinal cortex, parahippocampal gyrus)], and in parts of thc frontal cortex including anterior cingulate gyrus (ACG)

Stage 3

• Impaired executive • Protein deposition found in additional cortifunction and cognitive cal regions • Cortical atrophy function • Pathology in posterior cingulate gyrus (PCG), • Aggression lateral temporal lobe (LTL), and parietal lobe • Motor dysfunction

Stage 4

• Dementia • Impaired communication • High probability of comorbidity

Stage 1

neuropathological distinction between CTE and other neurodegenerative conditions, as more obvious distinctions lie in the distribution patterns of the proteinopathies within the brain rather than the composition of the pathologies themselves [2]. For example, several studies have found distinct differences in the signal pattern distribution between CTE and Alzheimer’s disease (AD) primarily within the subcortical areas (dorsal midbrain) and the amygdala, in which significant pathology accumulation was only seen in the CTE brains, whereas cortical regions showed high levels of protein aggregations in both AD and CTE cases [2]. kenyon.edu/neuroscience

• Protein deposition throughout the cortical, subcortical, and limbic medial temporal lobe structures, as well as in the white matter areas • Significant cortical atrophy

additional challenge to studying CTE has been the high degree of variability or heterogeneity amongst cases. First of all, it must be noted that not all individuals that experience

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repeated head trauma develop CTE. The reason for this is similar to the reason that not all people that regularly smoke develop lung cancer. We are all genetically unique and thus have genetic predispositions to developing certain conditions. For example, perhaps one individual may naturally have greater levels of tau protein expression to begin with (making aggregation more likely), while another may have increased levels of proteins that break down tau and tau aggregates (which could reduce the impact of such pathology). Further, there are often high levels of comorbidity in individuals that develop CTE [8, 10, 12]. While misdiagnosis could account for some of these reports, it is also possible that individuals already genetically susceptible to protein aggregating neurodegenerative conditions are also further susceptible to developing CTE [13] . Thorough analysis of both clinical symptoms, patient and family disease and injury history can help overcome the diagnostic challenge with CTE, allowing doctors to determine the presence of CTE and the possibility of comorbid conditions.

New Directions

the majority of our knowledge on CTE neuropathology comes from histopathological examination of the brain upon autopsy, as there remains no definitive measure of clinical CTE diagnosis [4]. While autopsy reports have contributed valuable and distinguishing information regarding chronic traumatic encephalopathy, more recent research

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has attempted to develop methods for diagnosing and studying CTE in vivo [2,5]. Various neuroimaging techniques, such as DTI and PET, have been implemented in this pursuit, but no such technique has reliably demonstrated diagnostic value [2, 5]. As this promising research continues, other approaches to better understanding this condition involves the creation of a CTE mouse model [11]. Mice have been used extensively within the field of neuroscience research and provide a less variable, simplified model of specific diseases and disorders. In 2014, a novel mouse model of CTE was examined and was able to demonstrate many of the clinical symptoms associated with CTE [11]. However, traumatic brain injury, clinical CTE symptomology, and CTE neuropathology have yet to be recapitulated in a mouse model. The focus of these new directions in CTE research is ultimately largely related to the development of a treatment for this neurodegenerative condition. However, at the same time, a greater emphasis on the prevention of traumatic brain injuries is needed [9]. In a large majority of cases, the development MAY 2017

References

of CTE could have been largely, if not entirely, prevented. As awareness of this devastating disease increases, it is my hope that reforms continue to be made in how sports are played and how concussions are diagnosed and treated. This is not to belittle the progress that has been made. Many researchers and even football programs have decided to avoid tackle football until kids are older (~14 years old) as TBI on the developing brain may be particularly detrimental to later neurocognitive health [3]. However, more research is still needed to provide the concrete evidence necessary to elicit drastic reforms. Further applied progress was recently made when the NFL, after many years of denial, acknowledged the link between CTE and football [6]. The NFL has attempted to make changes when it comes to player safety and concussions, such as altering tackling methods, improving safety equipment, and enforcing proper concussion recovery protocol, but it remains to be seen if these relatively minor modifications are enough to save lives.

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1. Azad, T. D., Li, A., Pendharkar, A. V., Veeravagu, A., & Grant, G. A. (2016). Junior Seau: an illustrative case of chronic traumatic encephalopathy and update on chronic sportsrelated head injury. World neurosurgery, 86, 515-e11. 2. Barrio, J. R., Small, G. W., Wong, K. P., Huang, S. C., Liu, J., Merrill, D. A., ... & Kepe, V. (2015). In vivo characterization of chronic traumatic encephalopathy using [F-18] FDDNP PET brain imaging. Proceedings of the National Academy of Sciences, 112(16), E2039-E2047. 3. Gregory, S. (2016, April 19). CDC to Investigate When Kids Should Start Playing Football. Retrieved from http://time. com/4298317/cdc-to-investigate-when-kidsshould-start-playing-football/ 4. Hay, J., Johnson, V. E., Smith, D. H., & Stewart, W. (2016). Chronic traumatic encephalopathy: the neuropathological legacy of traumatic brain injury. Annual Review of Pathology: Mechanisms of Disease, 11, 21-45. 5. Kraus, M. F., Susmaras, T., Caughlin, B. P., Walker, C. J., Sweeney, J. A., & Little, D. M. (2007). White matter integrity and cognition in chronic traumatic brain injury: a diffusion tensor imaging study. Brain, 130(10), 2508-2519. 6. Martin, J. (2016, March 16). NFL acknowledges CTE link with football. Now what? Retrieved from http://www.cnn. com/2016/03/15/health/nfl-cte-link/ ... 7. McKee, A. C., Gavett, B. E., Stern, R. A., Nowinski, C. J., Cantu, R. C., Kowall, N. W., ... & Morin, P. (2010). TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. Journal of Neuropathology & Experimental Neurology, 69(9), 918-929. 8. McKee, A. C., Stein, T. D., Nowinski, C. J., Stern, R. A., Daneshvar, D. H., Alvarez, V. E., ... & Riley, D. O. (2013). The spectrum of disease in chronic traumatic encephalopathy. Brain, 136(1), 43-64. 9. Moran, R., & Covassin, T. (2015). An Examination of Concussion Injury Rates in Various Models of Football Helmets in NCAA Football Athletes. Journal of Sports Science, 3, 29-34. SCIENTIFIC KENYON

10. Omalu, B., Hammers, J. L., Bailes, J., Hamilton, R. L., Kamboh, M. I., Webster, G., & Fitzsimmons, R. P. (2011). Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurgical focus, 31(5), E3. 11. Petraglia, A. L., Plog, B. A., Dayawansa, S., Chen, M., Dashnaw, M. L., Czerniecka, K., ... & Deane, R. (2014). The spectrum of neurobehavioral sequelae after repetitive mild traumatic brain injury: a novel mouse model of chronic traumatic encephalopathy. Journal of neurotrauma, 31(13), 12111224. 12. Ramlackhansingh, A. F., Brooks, D. J., Greenwood, R. J., Bose, S. K., Turkheimer, F. E., Kinnunen, K. M., ... & Sharp, D. J. (2011). Inflammation after trauma: microglial activation and traumatic brain injury. Annals of neurology, 70(3), 374383. 13. Schmidt, M., Zhukareva, V., Newell,

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K., Lee, V., & Trojanowski, J. (2001). Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimerâ&#x20AC;&#x2122;s disease. Acta neuropathologica, 101(5), 518-524. 14. Stein, T. D., Montenigro, P. H., Alvarez, V. E., Xia, W., Crary, J. F., Tripodis, Y., ... & Kubilus, C. A. (2015). Betaamyloid deposition in chronic traumatic encephalopathy. Acta neuropathologica, 130(1), 21-34. 15. Tang-Schomer, M. D., Johnson, V. E., Baas, P. W., Stewart, W., & Smith, D. H. (2012). Partial interruption of axonal transport due to microtubule breakage accounts for the formation of periodic varicosities after traumatic axonal injury. Experimental neurology, 233(1), 364-372. 16. Tateno, A., Jorge, R. E., & Robinson, R. G. (2003). Clinical correlates of aggressive behavior after traumatic brain injury. The Journal of Neuropsychiatry and Clinical Neurosciences, 15(2), 155-160.

MAY 2017

ADHD: Parents’ or Physicians’ Problem? Sarah Naguib

Following the summer 2016 Olympics, Simone Biles’ name appeared all over the news; however, the coverage was not only for her achievements on her floor exercises, but it was also because of her exposed diagnosis of Attention Deficit Hyperactivity Disorder (ADHD). A group of Russians hacked the World Doping Agency’s confidential information on several American athletes—including Biles—and released their medical information. Their claim? That Biles was using stimulants— methylphenidate, to be exact—to enhance her performance as a gymnast.

the child just needs more discipline or maybe the parents don’t spend enough time with their children at home. While these scenarios are sometimes accurate, it is unfair to place blame on the parents of all children who are hyperactive and lack focus. It could truly be that their child is missing a diagnosis of ADHD.

Photo of Simone Biles taken from www.teamusa.org Methylphenidate is one of the most commonly used drugs to treat symptoms of ADHD. Biles decided to go public with her diagnosis of ADHD and tweeted to her viewers that “having ADHD, and taking medicine for it, is nothing to be ashamed of[,] nothing I am afraid to let people know.” Other famous Olympians, such as Michael Phelps, as well as celebrities such as Justin Timberlake and Jamie Oliver also have publicized their diagnoses of ADHD. With its increase in media presence, ADHD is becoming somewhat a normal part of American culture. The increase in diagnosis, however, is unaccompanied with an increase in understanding of what this disorder is about. What the consequences are of such a movement, however, are striking. When Simone Biles came out with her statements on Twitter and in numerous interviews about her pride as a gymnast with ADHD, it caused uproar. The confidence that she exuded gave other children with the same diagnosis an increased sense of self as well as the desire to work past their disorder in order to achieve their dreams, just as Biles did. Additionally, it dissolves the stigma that is often associated with the disorder. On first glance, it is easy to judge a child’s erratic and uncooperative behavior as the fault of poor parenting. Perhaps

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While the recent nationwide discussion of ADHD can be perceived as positive, there are also several issues with the movement. First, ADHD’s presence in the media gives the general public a false sense of knowledge about the disorder. Parents can take the little information that they are exposed to from the Internet, radio or TV and use it to self-diagnose their children. With the rise in accessible information comes great responsibility for physicians and teachers to educate parents on the truth about ADHD, before any conclusions can be drawn about a child. Second, an ADHD diagnosis is now considered almost normal. While this is good because it gives hope to children with the diagnosis, statements like Biles’ potentially lowers the reality of an ADHD diagnosis. It is becoming more commonplace for children to be taking medications than not. Long-term administration of any medication could have some seriously deleterious effects on anyone, which will be explored later. Although no one knows exactly what causes ADHD, there are many hypotheses in the field. There are also several myths circulating the general population as to what predisposes someone to ADHD. If a mother’s pregnancy is particularly stressful or if she smokes or drinks, there are hypotheses that these may increase the risk for the child to develop ADHD. Many parents also believe that a diet high in sugar for their children may cause ADHD symptoms, although there is no evidence to back up these claims (regardless, a diet high in sugar for children is probably not the best). Additionally, spending too much time on the computer, playing video games or watching TV does not necessarily MAY 2017

Statistics

• ADHD is the most commonly diagnosed mental illness in the United States for children between the ages of 4 and 17 • Approximately 11% of children in the US have received a diagnosis of ADHD at some point in their lives • Males are 4 times more likely to be diagnosed with ADHD than females • About 65% of people diagnosed with ADHD also have another comorbid disorder such as: Obsessive Compulsive Disorder, Anxiety,Depression, Tourette’s Syndrome, Mood disorders cause ADHD, but there are studies that show that kids who spend extended periods of time in front of a screen have more difficulty concentrating than those who don’t. Ultimately, while the cause of ADHD has not been elucidated, it is definite that genetics do play a role in ADHD. For a complete diagnosis of ADHD, physicians are required to match their patient’s symptoms with the guidelines present in the Diagnostic and Statistics Manual Volume V (also known as DSM V)1. Despite the existence of diagnosis criteria for ADHD in DSM V, there is no objective test physicians can use to diagnose a patient. What results, then, is variability in the interpretation of symptoms from doctor to doctor. This variation was studied by giving a group of 1,000 child psychiatrists, therapists and social workers four vignettes of case studies of children15. Only one of the four vignettes actually had a patient that met all the requirements for ADHD, as according to the most recent DSM. The other three vignettes were children with similar symptoms,

1. 2. 3. 4. 5.

but ultimately did not fit the requirements for ADHD diagnosis—perhaps, they had a comorbid disorder. Ultimately, results from the study showed that 17% of professionals reported a false positive diagnosis of ADHD— that is, they falsely gave patients in vignettes 2-4 a diagnosis of ADHD when the patient file did not meet all the requirements present in the DSM. Interestingly enough, there was also a 7% false negative diagnosis among these professionals. Additionally, males were twice as likely to be given an incorrect diagnosis of ADHD than females, indicating some sort of a predisposed gender bias toward males. This study illuminates that not only is the disorder being over-diagnosed, but ADHD is also being misdiagnosed on the whole. Perhaps, the lack of education that the average parent has concerning ADHD is spilling over into the medical professional population as well. The first step to getting an ADHD diagnosis is initiated by either the parents themselves or a teacher/school counselor who makes a recommendation to the parents that a doctor sees the child. It should be the job of general practitioners to refer their patients to a

DSM Criteria for ADHD Diagnosis: In order to receive a diagnosis for ADHD, patients must fulfill the following criteria:

6 symptoms of inattention and 6 symptoms of hyperactivity Symptoms must be onset after the age of 7 Impairment must be present in at least two settings Impairments must be clinically significant Symptoms cannot be accounted for/by another disorder

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they are qualified to make a diagnosis for ADHD, the disorder is still being misdiagnosed, as seen in the aforementioned study. Why, then, does this discrepancy exist? Making a correct diagnosis of ADHD takes timeâ&#x20AC;&#x201D;more than just one visit to a general practitioner. It is not fair to assume that the diagnosis will be made correctly on first glance, Study with 1,000 child psychiatrists and professionals blindly diagnosing because other mental ADHD. Vignette 1 contains true diagnosis according to DSM. Table shows disorders in children rates of over-diagnosis. manifest themselves psychiatrist or a psychologist, who is a licensed with many of the same symptoms seen in professional and is trained to make a proper ADHD. According to the DSM, symptoms diagnosis. Instead, what often happens is that must be present in multiple settings for a pediatricians themselves are the ones making period of at last 6 months. Additionally, said diagnoses and writing prescriptions. In note that the DSM states that a diagnosis Australia, a study was done asking general should not be made before the age of 71: this practitioners what their perceived role would makes sense considering that preschoolers be in the diagnosis process of ADHD patients and early elementary school students do not should be15. The consensus among over thirty have the attention span, often, to sit down general practitioners was that psychiatrists, as for long periods of time. This, however, does more trained professionals, should be responsible not mean that every child under the age of for being the primary care providers for ADHD 7 has ADHD. How is it, then, that ADHD patients. Ultimately, however, despite the fact is considered the most commonly diagnosed that general practitioners do not believe that mental disorder in children from the ages of 4 to 17? Additionally, because ADHD is a true neurodevelopmental disorder10, it makes sense that the prevalence of diagnosis should be fairly consistent. Unfortunately, this is not the case (see map above).

Rate of diagnosis of ADHD per state, taken from www.cdc.gov

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Consequently, the rate of diagnosis of ADHD has gone up significantly in the last few decades. Before 1970, the diagnosis was relatively rare among school age children and pretty much nonexistent into adulthood8. However, between 1980 and 2007, the CDC has reported an eight-fold increase of prevalence in ADHD diagnosis in the United States17. Interestingly enough, MAY 2017

Did you know?

The Role of Gender & Culture in ADHD Diagnosis11 The National Health Interview Survey wanted to point out that the prevalence of ADHD varies greatly between races and ethnicities, which could correlate directly with a particular culture’s view of the disorder. Historically, there has been a higher prevalence of ADHD among African American children than white children and a higher prevalence of ADHD among white children than Hispanic children. The study was conducted using the 2001 National Center for Health Statistics annual survey. One child per family, younger than 19 years of age, was selected randomly. Information from the child’s file concerning basic health status, health care services that are available for the family, and behavior of the child was all collected, with parental consent. Additionally, the parents filled out a Strengths and Difficulties Questionnaire as a supplement. Questions addressed emotional symptoms, conduct problems, hyperactive behavior, peer relationships and pro-social behavior. The study was divided into 51% male, 64% white, 16% Hispanic, 15% black and 5% other. If a child received a score of 7 or higher within the hyperactivity questions, had difficulties in emotion/ concentration/behavior for a period of at least 6 months, and parents found that these difficulties extended into every aspect of the child’s life, then the child is characterized as having ADHD. In females, there were no statistically significant differences by age, race, income, parental level of education, socioeconomic status or residence location. However, in male subjects, Hispanic children had fewer symptoms according to the Strengths and Difficulties Questionnaire (3.06% of Hispanic males). African American males as well as white males had significantly greater prevalence of ADHD than the other race category, too (5.65% African American males and 4.33% white males). There was a false positive rate of 8% and false negative of 26%. Different cultures interpret ADHD in different ways. For example, if it is not socially acceptable for Hispanics to have ADHD, this could contribute to the fact that there is a lesser percentage of children being diagnosed with ADHD via the Strengths and Difficulties Questionnaire (because the survey is being conducted by parents). On the other hand, if ADHD is more widely accepted into white communities, it could be that parents are more likely to color their answering of the Strengths and Difficulties Questionnaire to reflect their open mind if their child were to be given a diagnosis of ADHD. Could it be, then, that depending on the environment in which the child is raised affects whether or not he/she will be accurately diagnosed of ADHD? diagnosis rates of ADHD around the world have seen similar increases in prevalence over the years. It is difficult to tell what the source of this increased diagnosis could be. Some hypothesize that as time has progressed, there has been a greater focus placed on mental health in addition to physical health. Thus, people begin to take mental health more seriously than in the past, which could have reduced the existing stigma associated kenyon.edu/neuroscience

with mental disorders4. Others think that the extremely high expectations placed on kids to succeed in school, starting from a young age, could contribute to this increased diagnosis6. The pressure placed on children by their parents—in addition to the extraordinarily high cultural or societal standards—to get good grades, practice instruments, play a sport, be involved in leadership and extracurricular opportunities has the potential to have some serious consequences on both a child’s mental SCIENTIFIC KENYON

ADHD are methylphenidate (Ritalin) and amphetamine (Adderall).

and physical health. Additionally, it could be that the school system in many countries has shifted to limit the amount of playtime that children getâ&#x20AC;&#x201D;instead their recess and breaks are limited to perhaps only one per day8. Logically speaking, children have a lot of energy as it is, and likely require a certain amount of time to run around in order to maximize their productivity and concentration. While there is no cure for ADHD, treatments do exist to reduce the severity of the hyperactivity and impulsivity symptoms and lessen the effect of the disorder on the childâ&#x20AC;&#x2122;s everyday life. In other countries, psychotherapy is used as the first line of defense against ADHD symptoms3: In European countries, for example, only about 0.3% of children diagnosed with ADHD are being treated pharmacologically15. Instead, a greater emphasis on behavioral and educational therapy is used for several months, before any prescription is written. This is completely the opposite case in the United States, where at least half of the children who receive a diagnosis for ADHD are currently being administered stimulants9. The most common medications prescribed for

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In the United States, at least half of the children who have received an ADHD diagnosis are regularly being administered stimulants in order to treat their symptoms. In 2011 alone, 50 million prescriptions for Adderall and other stimulants were filled18. Additionally, as the number of prescriptions rises, so will the rates of recreational and non-medical uses for these drugs. Adderall and Ritalin are being abused on college campuses on a regular basis13. Although stimulants are incredibly effective at reducing the severity of ADHD symptoms, it is unclear what the long-term consequences will be for patients who take stimulants for an extended period of time. Likely, once a child begins taking medication at a young age, he or she will continue to use the prescription into adulthood14. Scientists have found that heavy use of Adderall, one of the most common drugs to treat ADHD, can have some substantial side-effects, ranging

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How do stimulants work5?

Stimulants work by increasing the amount of dopamine in the brain. Dopamine is a neurotransmitter that is heavily implicated in ADHD because of its involvement in locomotion, attention and the reward-motivation systems. Deficits in the dopamine system can yield huge consequences—the most wellknown being Parkinson’s disease—but also ADHD and ADD. While no one ultimately knows the cause of ADHD, the improvements seen from stimulant treatment in ADHD patients is profound. Stimulants reduce self-stimulation, which is defined as the hyperactivity aspect in kids with ADHD—the inability to sit still and the seeming requirement for constant motion. Some studies have found that there are reduced levels of dopamine in people with ADHD when compared to those without the diagnosis. Other studies, however, have found that dopamine levels are the same in both populations, and hypothesize that dopamine is simply being metabolized at a faster rate in ADHD patients. The reuptake of dopamine into the synapse is regulated by Dopamine Transporters (DATs). DATs prevent dopamine from binding to its receptors. Several stimulants on the market, such as both methylphenidate and amphetamines, target DATs. The extremely high efficacy of these drugs implicates DAT in the mechanism of ADHD. from more minor ones such as difficulty sleeping and irritability to the more severe: depression, paranoia, anxiety, hallucinations, panic attacks and heart disease. Because most ADHD patients receive their diagnosis at a young age, their mental and physical health lies in the hands of their parents7. It is the responsibility of physicians to educate parents on the long-term consequences of continual stimulant treatment. It is also essential for the United States to invest more time and money into psychotherapy as a first option for treating ADHD so that perhaps not as many children will be taking stimulants consistently. In Europe, less than 1% of children being diagnosed with ADHD take stimulants on a regular basis—instead, Europeans rely on behavioral and educational therapy (and, in some cases, changes in diet) in order to see a reduction of ADHD symptoms. kenyon.edu/neuroscience

Genetic studies were able to locate the gene DAT615R that is involved in the production of DAT16. Through various molecular experiments, researchers were able to find the DAT615C gene, as well, which turns out to be a single nucleotide polymorphism (SNP) of the gene—a change in a single base pair within a DNA sequence. Changing DAT615R to DAT615C turns out to have serious consequences. DAT615C causes proteins to be recycled constitutively—without any sort of regulation. Interestingly, however, the mutation doesn’t cause any change in the amount of dopamine secreted from one cell to another, which ultimately supports the hypothesis that ADHD is a result of a problem with dopamine metabolism, rather than with the amount of dopamine present in the system.

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Studies with PET scans were also done in both ADHD and control populations to measure blood flow in certain regions of the brain as well as localize specific neurotransmitters— such as Dopamine19. PET scans are a powerful and non-invasive way to gaining a greater insight into the neurobiology of any disease. Through a technique known as nuclear medicine imaging, DAT occupancy was measured through the use of specific molecules that bind directly to DAT. The most significant result in this study was the increased DAT binding in the striatum of the brains of ADHD patients in comparison to the control population. The striatum is heavily involved in the reward system in the brain, and it also affects the basal ganglia12. The basal ganglia is a movement control center in the brain, and the circuit between the striatum and the basal ganglia—with regard to dopamine—is heavily involved in the motor/action planning pathways as well as motivation and reinforcement. In a patient with ADHD, the motor/action-planning pathway is overactive, which contributes to the hyperactivity symptoms. Therefore, the increase in DAT binding in the striatum of ADHD patients makes perfect sense; with an increase in activity in the striatum, no

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wonder self-stimulation is seen in the ADHD population. The hope of this article is to illuminate some of the issues that exist within the world of mental health regarding ADHD. With such large levels of misdiagnosis, there is a need for consistent re-testing that should occur for the physicians who are giving these diagnoses, perhaps one that occurs every 3-5 years, or one that occurs every time a new edition of the DSM is published. The gender and cultural biases that exist are also issues that need to be addressed within the medical community. Perhaps, upon diagnosis, doctors should remain blind to the gender, race, ethnicity, socioeconomic status etc. of the child when assessing if symptoms match the requirements in DSM. Additionally, I believe that parents should be required to have their children see two physicians before any prescription is written. Requiring that two physicians confer a diagnosis might prevent any doctor-shopping that could be occurring in order for parents to receive the diagnosis that they desire for their children. In general, the United States should place a greater emphasis on psychotherapy before stimulant treatment. An extensive education for parents of the consequences of long-term stimulant treatment should also be necessary once the prescription is about to be written. Ultimately, as the world shifts to be more open-minded toward mental health, there is still a greater need for the general public to be educated as the culture changes.

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For Further Reading... 1. ADHD. (2016). Retrieved October 3, 2016 from http://www.apa.org/topis/adhd 2. Batzle, C., Weyandt, L., Janusis, G., and DeVietti, T. Potential impact of ADHD with stimulant medication label on teacher expectations. Journal of Attention Disorders, 20(10), 1-10. 3. Bruchmiller, K., Marragaf, J., & Schneider, S. (2012, February). Is ADHD diagnosed in accord with diagnostic criteria? Overdiagnosis and influence of client gender on diagnosis. Journal of Consulting and Clinical Psychology, 80(1), 128-138. Retrieved October 3, 2016, from http://psychnet.apa.org/journals/ ccp/80/1/128 4. Collingwood, J. (2016). ADHD and Gender. Psych Central. Retrieved October 3, 2016, from http:// psychcentral.com/lib/adhd-and-gender 5. Cuffe, S., Moore, C., and McKeown, R. Prevalence and correlates of ADHD symptoms in the National Health Interview Survey. Journal of Attention Disorders, 9(2), 392-401. 6. Elkins, R., Carpenter, A., Pincus, D., & Comer, J. (2010, November). Child Behavior Checklist Attention Problems Scale can Distinguish between ADHD and GAD-related Inattention. PsychEXTRA Dataset, 1-6. 7. Fararone, S., Sergeant, J., Gillberg, C., & Biederman, J. (2003, June). The worldwide prevalence of ADHD: Is it an American condition? World Psychiatry, 2(2), Retrieved October 3, 2016 from http://www.ncbi.nlm. nih.gov/omc/articles/PMC1525089/. 8. Franke, B., Neale, B., and Faraone, S. Genome-wide association studies with ADHD. Human Genetics, 126(1), 13-50. 9. Gillberg, C., Melander, H., Von Knorring, A., Janols, L., Thernlund, G., Haggelof, B., & Kopp, S. (1997, September). Long-term stimulant treatment of children with attention-deficit hyperactivity disorder symptoms. A randomized, double-blind, placebo-controlled trial. General Psychiatry, 54(9), 857-864. Retrieved October3, 2016, from http://www.ncbi.nlm.nih.gov/ pubmed/9294377 10. Hart, H., Radua, J., Nakao, T., Mataix-Cols, D., and Rubia, K. Meta-analysis of Functional Magnetic Resonance Imaging Studies of Inhibition and Attention in Attention-deficit/Hyperactivity Disorder: Exploring Task-Specific, Stimulant Medication, and Age Effects. JAMA Psychiatry, 70(2), 185-198. 11. Jensen, P., Martin, D., & Cantwell, D. (1997, kenyon.edu/neuroscience

August). Comorbidity in ADHD: Implications for Research, Practice, DSM-V. Journal of American Academy of Child Adolescent Psychiatry, 36(8), 1065-1079. Retrieved October 3, 2016 from http://researchgate.net/profile/Peter_ Jensen/publication/1396794_Comorbidity/V/ links/00b495183d6897773d000000.pdf 12. Jensen, P., Kettle, L., Roper, M., Sloan, M., Dulcan, M., Hoven, C., Bird, H., Bauermeister, J., and Payne, J. Are stimulants overprescribed? Treatments of ADHD in four communities. Journal of American Academy of Child & Adolescent Psychiatry, 38(7), 797-804. 13. Lesch, K., Timmesfeld, N., Renner, T., Halperin, R., Roser, C., Nguyen, T., Craig, D., Romanos, J., Heine, M., Meyer, J., Freitag, C., Warnke, A., Romanos, M., Schafter, H., and Walitza, S. Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. Journal of Neural Transmission, 115(11), 15731585. 14. Lou, H., Rosa, P., Pyrds, O., Karrebaek, H., Lunding, J., Cumming, P., & Gjedde, A. (2007). ADHD: Increased dopamine receptor availability linked to attention deficit and low neonatal cerebral blood flow. Developmental Medicine & Child Neurology, 46(3), 179-183. 15. Okie, S. (2006). ADHD in Adults. New England Journal of Medicine, 354(25), 2637-2641. 16. Shaw, K., Wagner, I., Eastwood, H., and Mitchell, G. A qualitative study of Australian GPsâ&#x20AC;&#x2122; attitudes and practices in the diagnosis and management of attentiondeficit/hyperactivity disorder (ADHD). Oxford Journal of Family Practice, 20(2), 129-134. 17. Tripp, G., & Wickens, J. (2009). Neurobiology of ADHD. Neuropharmacology, 57, 579-589. Retrieved October 3, 2016, from http://www.researchgate. net/profile/Jeff_Wickens/publication/26691291_ Neurobiology 18. Young, S. and Amarasinghe, M. Practitioner review: non-pharmacological treatments of ADHD: a lifespan approach. Journal of Childhood Psychology and Psychiatry, 51(2), 116-133. 19. Zimmer, L. Position emission tomography neuroimaging for a better understanding of the biology of ADHD. Neuropharmacology, 57(7-8), 601-607.

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Golf and the Brain: The Power of Motor Skill Learning erm l Pa s; ld o rn

separates great player s fro “What mt r b a i s n a p y t o i l he w i er and ab h c goo u m e q o s uili t o bri d on n um e ”– si A

John O’Brien

The importance of mental discipline and focus in golf has been emphasized since its earliest beginnings. It is a game that combines athleticism, strategy, and clutch performance in the most unpredictable of ways. In the 1913 U.S. Open, a twenty-year old amateur named Francis Ouimet outlasted two outstanding professionals to capture the title in a three-way playoff.

In the 1991 PGA Championship, John Daly was the 9th alternate selected to fill the final spot in the tournament. He rallied to win his first Major tournament that weekend, and he remains a fan favorite today. However, Ouimet was not born into a wealthy family, an early stereotyped “necessity” for golf excellence, yet he learned the game of golf working as a caddy. Additionally, John Daly did not exactly fit the stereotypical mold of a professional golfer, often seen on live TV smoking cigarettes and drinking while on the course (Figure 1). These two men, in addition to countless other individuals throughout the sport’s history, defied the odds in a game that has baffled men and women of all ages for centuries. If golf is a game that demands the utmost focus and discipline, what is it about the mental fortitude of professional golfers that contributes to their exceptional performance? The advancing field of neuroscience can aid in the search for new insights into golf and all its complexities. What is unique about the neural activity of professionals that allows them to stay focused in clutch moments? Can increases in brain matter occur as a result of motor learning, even in later years? How can this information to beat that annoying relative this weekend? Efforts in answering questions such as these have uncovered valuable information regarding motor control, mentality, and learning in the context of golf. This information can be utilized by many, even those not involved in professional golf, such as researchers, physicians, physical and occupational therapists, etc.

Teeing off

In order to understand the changes induced by motor learning, the importance of learning must first be established. The human brain exhibits experience-dependent plasticity, giving it the remarkable ability to alter its dimensions and connections based on neuronal

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Figure 1. As legends such as Jack Nicklaus (top) begun to show their age, golf was looking for its next set of stars. While Daly (bottom) quickly became a fan favorite for his booming swing and on-course antics, he was not exactly the poster boy the Professional Golfers Association (PGA) was looking for.

activity12, 14. Everyone’s brain is structurally unique due to the differences in life experiences. Frequent, and rapid, exposure to certain stimuli over time strengthens the circuits in the brain responsible for processing the stimuli. These circuits make up various signal transduction networks that are involved in detecting stimuli, such as a scent or a sound, transmitting that signal to the brain, and deciding how to react appropriately. Over time, neuronal connections are altered in order to provide for the most efficient signal transduction network (Figure 2). Another method of enhancing signal transduction is through myelin, the

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protective membrane surrounding axons throughout the nervous system. Myelin allows for faster transmission of electrical signals between neurons by preventing signal loss during propagation along the axon (Figure 3). This phenomenon of neuronal plasticity allows for brain development and/or alterations throughout life in response to encountered stimuli. This is the basis on which humans, and many other organisms, undergo advances in learning and memory.

Figure 2. Images of random perigranular neurons stained with GFP, a molecular marker for expression at 45 and 90 days post injection (DPI) 13. Notice the increase in axon length and diameter from 45 to 90 DPI, in addition to the clustering of axons. Also notice the refinement, also called pruning, of weak connections by observing the reduction in axons; compare the clustered dendrites of the top right neuron at 90 DPI to the top right neuron at 45 DPI

Myelin and Motor Learning

Figure 3. Depiction of peripheral nervous system (PNS) neuron (Top). Illustration of myelination in the PNS via Schwann cells. As the signal moves along the axon via a process called saltatory conduction (the signal â&#x20AC;&#x153;jumpsâ&#x20AC;? between the nodes), depolarization occurs only at nodes of Ranvier, minimizing disturbances in ion concentrations (Bottom).

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In a recent study, scientists were able to effectively prevent new myelination in mice by inactivating myelin regulatory factor (MyRF), a transcription factor that promotes the expression of genes involved in the production of myelin. Prior to the inactivation of new myelin formation, the mice were trained on a standard running wheel. Mutant mice with no new myelination did not adjust very well when a different, unevenly spaced running wheel was introduced (Figure 4). The increased activity of circuits formed during the acquisition of novel motor skills may be involved in stimulating myelination in order to stabilize the newly formed circuits. Additionally, learning a new motor task has been shown to increase the clustering of dendrites, thereby increasing the strength of the synapses, the point of communication between neurons. (Recall from Figure 2 the neuronal changMAY 2017

es that occurred). Within 1 hour of learning a new motor task, synapse formation begins. This formation is rapid, but quite stable. After formation, the spines are selectively eliminated, leaving behind the newly- formed and stable synapses23. From current research, it appears evident that myelination, in addition to other methods of neuronal enhancement/ stabilization, are crucial for successful motor learning8. This can be further evidence by another recent study that found an increased learning rate in rats correlated with higher myelin staining density in the area of motor cortex responsible for their learned skill21. It is important to note that all of this research controlled for gross motor movement. That is, the studies included control groups that exerted some form of physical activity, but it was not something new or complex. Controlling for gross motor movement vs. new motor activity allowed the researchers to show that learning-induced changes are mostly seen during a novel motor task. The importance of discussing myelination, and other changes occurring at the cellular level during learning, is to ensure both an understanding of and appreciation for neuroplasticity. It allows humans to make necessary environmental changes, presented with new and novel tasks each and every day that

Figure 5. Brain with labeled lobes, in addition to the vPMC and POJ (in bold), which have been shown to be structurally altered in novel motor tasks 3 kenyon.edu/neuroscience

Figure 4. Differences between the standard wheel (A), and the complex wheel (B, D). WT mice showed higher average speed, distance, and greater rhythm than unmyelinated mice once exposed to the complex wheel.14

require some form of myelination and/or neural refinement in order to adjust accordingly.

Motor-Induced Structural Changes

In addition to the myelination and dendritic remodeling mentioned above, motor learning can also induce changes in brain structure and size. After golf novices completed 40 hours of vPMC practice, researchers found gray matter increases in areas such as the ventral premotor cortex (vPMC) associated with mental imagery and movement observation, and the parietal-occipital junction (POJ), associated with the control and correction of visually

Figure 6. Correlation of gray matter percent increase in parietal-occipital junction and training intensity (TI). Filled dots represent participants that passed a golf entrance exam, a license to play on golf courses in Switzerland, within the time frame 3 SCIENTIFIC KENYON

during mental imagery of pre shot routines among expert and novice female golfers16. Pre shot routines are crucial in allowing players to align themselves properly, visualize their shot, and whatever remaining quirks/superstitions that can promote a performance mental state. When rehearsing their pre-shot routines in the scanner, it was shown that expert golfers have reduced overall brain activation compared to novice golfers (Figure 7). Figure 7. Brain activations from Milton’s experiment 15. (a) and (b) contrast two This suggests that expert different skilled golfers that most closely matched the average novice (a) or expert golfers have defined neu(b) brain. (c) highlights the activation of the limbic system (green arrow) and basal ral networks that incorganglia (red arrow) in novice golfers. (d) highlights the activation of the premotor porate visual information cortex in expert golfers. into complex and effective guided arm movements3 (Figure 5). Intermovements, whereas novice golfers still can’t estingly, they also suggested a correlation find their focus. The ability to focus on the between training intensity, meaning how task at hand (the golf shot), tuning out harmlong it took each subject to complete the ful stimuli throughout, is vital to anyone‚Äôs forty hours of golf practice and percentage success, especially at higher levels of competiincrease in POJ volume (Figure 6). tion. The activations seen in the expert golfers are mostly restricted to the premotor cortex, Anatomical Differences specifically cortical areas associated with visuospatial tasks. Another study took a similar between Experts and Novices approach, as they compared fMRI data beThe weekend golfer will often wonder what tween various skilled golfers17. However, they makes Tiger Woods so special and them so instead asked the participants to mentally reblah at golf. To help answer this poor soul’s hearse their normal golf swing. By effectively question, it would be beneficial to discuss controlling the experimental design, the reanatomical differences found among difsearchers were able to activate areas that were ferent skill levels. In golf, a player’s skill is responsible for the golf swing, not just gross measured by their handicap, which is calcumotor movements. Their study found that lated using previous rounds’ scores, course as golfers increased in skill level, it resulted ratings, and other factors. Essentially, the in decreased activation of the supplementalower the handicap (HCP), the higher the ry motor area and cerebellum (Figure 8). The skill; a zero HCP is more skilled than a 5 cerebellum is involved in motor execution and HCP. Many recent studies have found that error correction, thus its decreased activity is golfers with lower handicaps have different supported by the results. More experienced brain activations and organizations than golfers will have more automated swings, with less skilled golfers16, 17. One such study less error correction occurring. Their finding used fMRI analysis to observe activations

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of the decreased supplementary motor area activation is curious, as it has been shown to be involved in the performance of self-initiated tasks, particularly those that have been extensively overlearned6. Essentially, the cerebellum should see reduced activation during novel motor learning, but increased activation as it becomes a more automatic response17. Furthermore, there were few differences observed in golfers with handicaps between 0-14, indicating that after the initial training period (800-3,000 practice hours), little reorganization occurs. This suggests that the early period in learning is crucial for skill development, marked by visible structural changes as they advance in skill. These findings help illustrate the differences between brain structures and activations among skilled and novice golfers, suggesting that an organized neural network dedicated to execution of the golf swing is critical for increased performance. Additionally, it was shown that loose training protocols were sufficient in inducing neural changes as a result of motor learning. While the rate at which one practices a skill may correlate with greater structural change, casual practice of a novel motor task can still inflict positive neural changes6. This information can be useful for novices that are looking to develop their golf skills. If the initial skill acquisition phase is the most important, then it would be wise to ensure proper teaching and training when learning the game of golf. Whether it’s taking lessons from a professional, or playing with a friend that has experience, proper instruction is vital for maximum development. Those that are unfortunate to have a little “hiccup” in their swing after years of getting used to it (for further information, simply YouTube Charles Barkley playing golf), this can still be useful information. Learning a new golf swing, one with more flow and efficiency, will invoke changes in the brain due to the learning (or significant altering, in this case) of a motor task. kenyon.edu/neuroscience

Figure 8. Fused functional imaging results16. Notice the decrease in activations as handicap decreases, especially in the supplementary motor area (highlighted by the green crosshairs)

Attentional Focus

Many other forms of research, especially sports performance, has also targeted golf in recent years. Since golf is such a mental and strategic game, researchers investigated how to maximize a golfer’s attention span. Many tips and tricks offered by professionals involve manipulating the extremities in one way or another, whether it’s altering the club or the person. However, humans have a limited attention span, and there’s only so many things one could keep in their mind while trying to execute their shot. Thus, scientists designed experiments that could test various levels of focus throughout a golf swing. There are three different kinds of attentional focus (Figure 9). In a study involving only skilled golfers, the distal external focus of attention was found to be the most effective, under both neutral and stressful conditions, followed by proximal external, and then internal focus subjects that performed the worst. Results from the study suggest that skilled golfers should use a distal external focus of attention while performing, especially during times of heightened anxiety, such as competition1. Another study using SCIENTIFIC KENYON

too many internal rules as a result, increasing attentional load19.

Beyond Golf: Archers, Music, and More

Additionally, the results from scientific studies involving golf are not limited to coaches and Figure 9. Various forms of attentional focus, with points of emphasis marked by a red arrow. An internal focus would have the golfer concentrating on his wrist players. Studies involving motion. A proximal external focus has the golfer fixate on part of the club. A distal motor control and neural external focus has the golfer focusing on the trajectory of the ball. reorganization can provide useful information only novice golfers found the proximal exterfor neurorehabilitation. For example, a renal focus of attention to be the most effective, cent study found that visual-spatial perfollowed by distal external and then internal 22 formance could be significantly improved focus . Given the disparity in these results, it in stroke patients following golf training, seems reasonable to conclude that different as compared to a group that met only soforms of focus may suit different players better. cially with no physical activity10. For those A distal external focus requires less cognitive that arenâ&#x20AC;&#x2122;t fans of golf, donâ&#x20AC;&#x2122;t lose hope. A demands, easing the attentional workload, but study conducted on various skilled archers also requires more automation in the swing, found similar results compared to Ross et which will better suit the more skilled golfer. al. (2012), in that more skilled archers had The variation in the effects of these different more organized neural networks11. As disforms of focus are still not yet fully understood, cussed in the myelination studies, neural but it is proposed that an internal focus causes

Table 1. Various studies that target different varieties of motor learning and skill expertise 6

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Table 2. The Neuroscientists’ Guide to Golf

changes occur during novel motor learning; the exposure to any new motor task can induce structural changes (Table 1).

The Neuroscientists’ Guide to Golf

A guide has been included recapping only a mere handful of the information that research has gathered on the science involved with golf (Table 2). Even if one doesn’t have the slightest interest in golf, it still provides for an efficient and unique means of studying motor learning and the many positive effects it can have on the nervous system. Its applications can span throughout many other sports and activities. The cognitive defects that can be seen in an aging brain are the result of synaptic changes, receptor dysfunction, signaling deficits, and metabolic decline13. Novel motor skill learning can help combat this by increasing myelination and signal efficacy. Motor skill learning in sports and music resulted in increased spatial cognitive performance compared to an educational learning group, emphasizing the importance of extracurricular activities in schools18. Physical exercise has been shown kenyon.edu/neuroscience

to decrease hyperactivity of the prefrontal cortex in later years, thus providing for faster response times in those with physically active lifestyles2. Furthermore, a study that analyzed data from over 300,000 Swedish golfers found that not only did golfers exhibit a 40% decreased mortality rate than non-golfers, but that golfers with the lowest handicaps had the lowest mortality rates7. Whether it’s hitting the links, playing chess, or knitting, the benefits of novel motor activities are endless. As Nike says it, “just do it.”

References

1. Bell, J. J., & Hardy, J. (2009). Effects of attentional focus on skilled performance in golf. Journal of Applied Sport Psychology, 21(2), 163-177. 2. Berchicci, M., Lucci, G., & Di Russo, F. (2013). Benefits of physical exercise on the aging brain: the role of the prefrontal cortex. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 68(11), 1337-1341. 3. Bezzola, L., Mérillat, S., Gaser, C., & Jäncke, L. (2011). Training-induced neural plasticity in golf novices. The Journal of Neuroscience, 31(35), 12444-12448. 4. Boecker, H., Dagher, A., Ceballos-Baumann, A., SCIENTIFIC KENYON

et al (1998). Role of the human rostral supplementary motor area and the basal ganglia in motor sequence control: investigations with H2 15O PET. Journal of Neuroscience, 79 (1070-1080) 5. Carless, D., & Douglas, K. (2004). A golf programme for people with severe and enduring mental health problems. Journal of Public Mental Health, 3(4), 26–39. 6. Chang, Y. (2015). Reorganization and plastic changes of the human brain associated with skill learning and expertise. Neural Implementations of Expertise, 58. 7. Farahmand, B., Broman, G., De Faire, U., Vågerö, D., & Ahlbom, A. (2009). Golf: a game of life and death–reduced mortality in Swedish golf players. Scandinavian journal of medicine & science in sports, 19(3), 419-424. 8. Fu, M., Yu, X., Lu, J., & Zuo, Y. (2012). Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo. Nature, 483(7387), 92-95. 9. Jäncke, L., Koeneke, S., Hoppe, A., Rominger, C., & Hänggi, J. (2009). The architecture of the golfer’s brain. PloS one, 4(3), e4785. 10. Jansen, P., & Schachten. (2016). Cogniț ie, creier, comportament: The improvement of visual-spatial performance after golf training in patients with stroke: a pilot study Asociația de Ș tiinț e Cognitive din Româ nia. 11. Kim, Wojong, Yongmin Chang, Jingu Kim, Jeehye Seo, Kwangmin Ryu, . Brain Activity Among Elite, Expert, and Novice Archers at the Moment of Optimal Aiming.” Cognitive And Behavioral Neurology 27.4 (2014): 173-82. 12. Kleim, J. A., Barbay, S., Cooper, N. R., Hogg, T. M., Reidel, C. N., Remple, M. S., & Nudo, R. J. (2002). Motor learning-dependent synaptogenesis is localized to functionally reorganized motor cortex. Neurobiology of learning and memory, 77(1), 63-77. 13. Luiten, P., Nyakas, C., Eisel, U., & Van der Zee, E. (2013). Aging of the Brain. In Neuroscience in the 21st Century (pp. 2239-2272). Springer New York. 14. Mizrahi A (2007) Dendritic development and plasticity of adult-born neurons in the mouse olfactory bulb. Nat Neuroscience 10:444–452. 15. McKenzie, I. A., Ohayon, D., Li, H., De Faria, J. P., Emery, B., Tohyama, K., & Richardson,

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W. D. (2014). Motor skill learning requires active central myelination. Science, 346(6207), 318322. 16. Milton, J., Solodkin, A., Hluštík, P., & Small, S. L. (2007). The mind of expert motor performance is cool and focused. Neuroimage, 35(2), 804-813. 17. Ross, J. S., Tkach, J., Ruggieri, P. M., Lieber, M., & Lapresto, E. (2003). The mind’s eye: functional MR imaging evaluation of golf motor imagery.American Journal of Neuroradiology, 24(6), 1036-1044. 18. Pietsch, S., & Jansen, P. (2012). Different mental rotation performance in students of music, sport and education. Learning and Individual Differences, 22(1), 159-163. 19. Poolton, J. M., Maxwell, J. P., Masters, R. S. W., & Raab, M. (2006). Benefits of an external focus of attention: Common coding or conscious processing?. Journal of sports sciences, 24(1), 89-99. 20. Sampaio-Baptista, C., Khrapitchev, A. A., Foxley, S., Schlagheck, T., Scholz, J., Jbabdi, S., ... & Kleim, J. (2013). Motor skill learning induces changes in white matter microstructure and myelination. The Journal of Neuroscience, 33(50), 19499-19503. 21. Thill, E. E., & Cury, F. (2000). Learning to play golf under different goal conditions: Their effects on irrelevant thoughts and on subsequent control strategies. European Journal of Social Psychology. 22. Wulf, G., McNevin, N. H., Fuchs, T., Ritter, F., & Toole, T. (2000). Attentional focus in complex skill learning. Research quarterly for exercise and sport, 71(3), 229239. 23. Xu, T., Yu, X., Perlik, A. J., Tobin, W. F., Zweig, J. A., Tennant, K., ... & Zuo, Y. (2009). Rapid formation and selective stabilization of synapses for enduring motor memories. Nature, 462(7275), 915-919.

MAY 2017

Never Gonna Give You Up: The Neuroscience of Social Attachment and Love Henry Q uil li a n As a species, humans rely heavily on social interactions during daily interactions and over the course of our lives. The ability to form lasting connections with other humans is extremely beneficial for many aspects of our nature from the day we are born to our deathbeds. As newborn infants we rely on others to care for us, due to our helpless nature, and similarly we rely on others to care for us as we age and lose the functioning we once had. kenyon.edu/neuroscience

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Furthermore, for most people’s adult lives, lasting connections with friends and romantic interests create an advantageous network that increases access to support and resources to fulfill one’s needs. The phenomenon of these lasting relationships is generally referred to as social attachment (i.e. the forming of long-term social bonds that are preserved for beneficiary purposes). Immediately after birth, social attachment begins occurring between a child and their mother as a mechanism to ensure that nurturing attention will be given to the child while it is still vulnerable Of course, the emotional byproduct of social attachment is what is commonly referred to as “love.” While many may consider love to be an ephemeral feeling that could not be explained by science, research into the neuroscience of social attachment and love has started to give us a peek at possible biological bases for this phenomenon.

Social Attachment and Monogomy:

We’re no strangers to love, but most do not realize the evolutionary importance of love and social attachment in their many different forms, especially romantic love. As discussed above, maternal love is obviously important for the basic caring for a child, but it has also been proposed that romantic love has been selectively chosen for in evolution as well [6]. Creating a lasting monogamous relationship between mates is an effective method of maintaining the involvement of the father during the development of offspring when the efforts of the mother may not be enough. This would explain why monogamous behaviors are seen primarily in mammals where the involvement of both parents is needed for effectively raising offspring [9]. Whether the natural state of humans is to be monogamous for their entire life span, though assumed by many to be the case, is debated within this academic field. Divorce rates in Western societies are at an astounding 50% [7], which brings the cultural idea of life-long monogamy being the norm into question. Furthermore, it has been found that there is a dramatic increase in the rate of divorce after the fourth year of marriage in

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Pair bonded prairie voles and their pups

humans, leading to the “four-year itch” theory that proposes that humans naturally form social attachments with their partners for the amount of time when offspring are most vulnerable: four years [5]. The same research found that this period was extended for those that had subsequent children within that initial window, which makes sense, as more time would be needed to care for those younger children. It very well may be that the base nature of humans is to practice “serial-monogomy,” but that we have normalized lifelong monogamy due to the development of culture. An animal that does exhibit behaviors of true life-long monogamy is the prairie vole, though few would like to admit that they are more likely to commit infidelity than a rodent. After mating, the prairie vole forms life-long social attachments with mates for their entire life, a behavior commonly referred to as pair bonding. Pair-bonded voles share their nest, care for their offspring together, selectively mate with each other, and show aggression towards unfamiliar voles (especially the males). These are heavily researched alongside the closely related, non-monogamous meadow and montane species of voles in an effort to understand social attachment at a biological level. For example, there has been found to be less sexual dimorphism (i.e. difference in physical characteristics) in the prairie vole than in the non- monogamous voles, a trend seen in other pair-bonding species indicating that sexual dimorphism may be linked to monogamous behaviors.

MAY 2017

The Neurochemicals of Social Attachment

In order to understand the neurological basis of social attachment, as seen in the pair-bonding behavior of prairie voles but not the non-monogamous behavior of the other voles, researchers have primarily investigated the roles different neurochemicals, the messengers between cells in the brain. This is done by observing the densities of the receptors for these neurochemicals in different parts of the brain, stimulating or blocking these receptors using drugs, and/ or affecting the number of receptors themselves, and then comparing these results to the behaviors seen in the voles. Through these methods, it has been found that the three main neurochemicals responsible for social attachment are dopamine, oxytocin, and vasopressin.

Distribution of oxytocin (top) and vasopressin (bottom) receptors in prairie and non-monogamous montane voles [15]

Dopamine is known to play a strong role in the reward and motivation systems in the brain and has two main receptors in these areas of the brains of voles that have identified as key players in social attachment and its associated behaviors: the D1 receptor and the D2 receptor. Activation of the D2 receptor by dopamine and other chemicals very similar in structure has been seen to lead to

the pair-bonding behavior seen in prairie voles [1], whereas blocking of this receptor causes unconditional suppression of pair-bonding behavior [17]. Furthermore, it has been found that prairie voles, in comparison to non-monogamous voles, have a higher density of these receptors in the areas of the brain thought to be responsible for social attachment [15]. D1 receptors have been shown to have the opposite effects when activated, decreasing pair-bonding behavior and increasing aggressivity, or blocked, increasing pair-bonding behavior and decreasing aggressivity [1]. Similarly, D1 receptors exist at lower densities in prairie voles, in comparison to non- monogamous voles, for the same social attachment areas of the brain [15]. Interestingly, D1 receptor density has been shown to increase in prairie voles after pair-bonding, accompanied by in increase in aggressivity towards unfamiliar voles [1]. This increase in D1 density may be a way to establish long-term monogamy in the voles by decreasing the likelihood of pair bonding after the first time.

Distribution of D1 (top) and D2 (bottom) receptors in prairie and non-monogamous meadow voles [15] kenyon.edu/neuroscience

Vasopressin is a chemical that serves a number of functions in the body such as regulating water retention and controlling blood vessel constriction, but is also seen to play in important role in social attachSCIENTIFIC KENYON

ment. Administration of this neurochemical has been found to induce pair bonding in prairie voles, even when they have never mated, and blocking of the receptor irrevocably prevents pair bonding from occurring [4]. This seems to be related to the dense distribution of vasopressin receptors in a brain area known as the ventral pallidum, an area known to play a role in the regulation of motivation and emotions. When the gene for the regulation of these receptors in the prairie vole was transferred into non- monogamous voles by researchers, they found that these voles exhibited the pair bonding and paternal care behaviors of the prairie voles and that the receptor density pattern in the ventral pallidum resembled that of prairie voles [10]. Researchers have also found that the density of these receptors is correlated with activity during and after mating in other areas of the brain known to be involved in sociosexual behavior and reward [11]. Oxytocin is a chemical that is known to be involved in bodily functions such as childbirth, production of milk, and reduction of stress, but like vasopressin it also plays an important role in the neurological aspects of social attachment. Oxytocin receptors important for this function have been located to the nucleus accumbens (NAcc) [12], an area known to be involved in reward and

Activation in the brain for maternal and romantic love [2].

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motivation, as well as in the medial prefrontal cortex (mPFC), which directly interacts with the reward and motivation pathways in the NAcc [15]. As seen with Vasopressin receptors, the activation of oxytocin receptors through administration of oxytocin to sexually naiĂ&#x192;Ă ve prairie voles has been shown to induce pair-bonding behaviors, while blocking of the receptors inhibits this behavior [4]. Evidence exists that oxytocin is important in social attachment in humans as well. Levels of oxytocin in the blood have been found to increase when performing trust based tasks, which makes sense since trust building is a key aspect of successful social attachment in humans.

Signals of Social Attachment in Humans

Research on social attachment has not only been done with these voles, but with humans as well. Using functional magnetic resonance imaging (fMRI), researchers can analyze the activation the brain to images of loved ones versus strangers to observe what areas selectively respond to those who we are socially attached to. Researchers have also used fMRI to observe regional homogeneity, which is essentially the level of synchronization in areas of the brain, as well as the functional connectivity within the brain to tell if social attachment affects the strength of connections within and between areas of the brain. These techniques allows us to compare the differences in brain activity between different types of love, as well as the changes that the brain may undergo when one is in love. Activation in the brain when viewing one that is loved is generally seen to in areas similar to those found to be important in vole pair-bonding. Activation in the reward and motivation systems is widespread in the brain when viewing a loved one [17]. More specifically, the striatum (S), middle insula (I), and dorsal anterior cingulate cortex (aC) are all parts of the reward and motivations pathways and are shown to selectively activate to both romantic and maternal love [2]. This is comparable MAY 2017

Deactivation in the brain for maternal and romantic love [2].

to the importance of receptors in these pathways seen in voles, and indicates that similar mechanisms may be at play for social attachment. Furthermore, there are activity overlapped with areas rich in oxytocin and vasopressin receptors in humans, such as the substantia nigra, the globus pallidus, and the nucleus of meynert, further emphasizing this connection in the research that has been done. The deactivation seen in brain caused by viewing those who they socially attached to is similarly interesting to look at. Researchers have found that there is deactivation in the amygdala (A), which is a center in the brain that is known to control fear responses [17]. This indicates that social attachment may create a calming effect for our nervous systems, and could possibly be correlated to release of oxytocin into the body, reducing stress. Deactivation has also been seen in areas such as the lateral prefrontal cortex (LPF), the medial prefrontal cortex (mp), and the temporal poles (tp) [2]. These areas are known to be involved in the experience of negative emotion and judgment [10], meaning that the way that we view the ones we love may be impaired due to our social attachment to them. This could have beneficial evolutionary effects by allowing dampening negative emotions towards and judgment of a partner raiskenyon.edu/neuroscience

ing your children to increase the cooperation between parents to ensure offspring survival. This could also have implications as to not being able to properly perceive dangerous flaws in the ones we are socially attached to. Looking at the functionality within and between areas of the brain, there have been interesting results discovered that show how the brain actually changes while socially attached to a romantic partner. The regional homogeneity of the left dorsal anterior cingulate cortex has been found to be greater for those in romantic relationships, and is actually positively correlated to the length of time in love and negatively correlated to the time since a break up with a loved one [16]. This makes sense because, as mentioned earlier, the dorsal anterior cingulate cortex is activated when viewing a loved one. Furthermore, decreases in regional homogeneity have been found in the caudate nuclei for those who were in a romantic relationship that had recently ended [16], showing that the termination of social attachment may affect the brain as much as the initiation of it. Furthermore, functional connectivity has been seen to be increased in the reward, motivation, and emotion regulation networks as well as the social cognition networks for those in romantic relationships [16], meaning these networks have SCIENTIFIC KENYON

greater connectivity within their active areas of the brain when one is in a relationship. This increase in functional connectivity is positively correlated to how long one has been in a relationship and negatively correlated to the time since one has been out of a relationship [16], further emphasizing how social attachment can actually change the way a brain works.

Conclusion

In 1993, musical artist Haddaway asked the quintessential question: What is love? It can be seen through the research discussed here that social attachment and love are not just vague expressions of the soul, the existence of which is a whole other debate, but rather that they can be seen to be directly affected by and to directly affect the neural systems in the brain. Despite this, it is clear that there is much more research to be done understand the direct mechanism of social attachment and the perceived emotion of love. As there is increased discussion about the “institution of marriage” and the increasing rates of divorce in Western society, continuing this research will be important in answering questions beyond citing personal beliefs and anecdotes on the subject.

Literature Cited

1. Aragona, B., Liu, Y., Yu, Y. J., Curtis, J. T., Detwiler, J., Insel, T., & Wang, Z. (2006). Nucleus accumbens dopamine differentially mediates the formation and maintenance of monogamous pair bonds. Nature Neuroscience, 9(1), 133-139. doi:10.1038/nn1613 2. Bartels, A., & Zeki, S. (2004). The neural correlates of maternal and romantic love. NeuroImage, 21(3), 11551166. doi:10.1016/j.neuroimage.2003.11.003 3. Chai, H., Chen, W., Xu, Y., Hu, J., Xu, S., Zhang, J., & Wang, W. (2014). Mismatch Negativity Tells You How Much You Automatically Miss Your Lover’s Love. Translational Neuroscience, 5(1), 72-77. doi:10.2478/s13380014-0208-8 4. Cho, M., DeVris, A. C., Williams, J. R., & Carter, C. S. (1999). The Effects of Oxytocin and Vasopressin on Partner Preferences in Male and Female Prairie Voles (Microtus ochrogaster). Behavioral Neuroscience, 113(5), 1071-1079. doi:10.1037/0735- 7044.113.5.1071 5. Fisher, H. E. (1992). Anatomy of love: The natural history of monogamy, adultery, and divorce. New York: Norton. 6. Fisher, H. E. (1998). Lust, attraction, and attachment

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in mammalian reproduction. Human Nature, 9(1), 23-52. doi:10.1007/s12110-998-1010-5 7. Kalmijn, M. (2007). Explaining cross-national differences in marriage, cohabitation, and divorce in Europe, 1990‚Äì2000. Population Studies, 61(3), 243-263. doi:10.1080/00324720701571806 8. KeÃÅri, S, and Kiss, I. (2011). Oxytocin response in a trust game and habituation of arousal. Physiology & Behavior, 102(2), 221-224. doi:10.1016/j.physbeh.2010.11.011 9. Kleiman, D. G. (1977). Monogamy in Mammals. The Quarterly Review of Biology, 52(1), 39-69. doi:10.1086/409721 10. Lim, M., Wang, Z., OlazaÃÅba, D., Ren, X., Terwilliger, E., & Young, L. (2004). Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene. Nature, 429(6993), 754-757. doi:10.1038/ nature02539 11. Lim, M. M., & Young, L. J. (2004). Vasopressin-dependent neural circuits underlying pair bond formation in the monogamous prairie vole. Neuroscience, 125(1), 35-45. doi:10.1016/j.neuroscience.2003.12.008 12. Liu, Y., & Wang, Z. X. (2003). NUCLEUS ACCUMBENS OXYTOCIN AND DOPAMINE INTERACT TO REGULATE PAIR BOND FORMATION IN FEMALE PRAIRIE VOLES. Neuroscience, 121(3), 537544. doi:10.1016/S0306-4522(03)00555-4 13. Murray, E. A., & Wise, S. P. (2010). Interactions between orbital prefrontal cortex and amygdala: Advanced cognition, learned responses and instinctive behaviors. Current Opinion in Neurobiology, 20(2), 212-220. doi:10.1016/j.conb.2010.02.001 14. Shapiro, L. E., Leonard, C. M., Sessions, C. E., Dewsbury, D. A., & Insel, T. R. (1991). Comparative neuroanatomy of the sexually dimorphic hypothalamus in monogamous and polygamous voles. Brain Research, 541(2), 232-240. doi:10.1016/0006-8993(91)91023-T 15. Smeltzer, M., Curtis, J. T., Aragona, B., & Wang, Z. (2006). Dopamine, oxytocin, and vasopressin receptor binding in the medial prefrontal cortex of monogamous and promiscuous voles. Neuroscience Letters, 394(2), 146-151. doi:10.1016/j.neulet.2005.10.019 16. Song, H., Zou, Z., Kou, J., Liu, Y., Yang, L., Zilverstand, A., . . . Zhang, X. (2015). Love- related changes in the brain: A resting-state functional magnetic resonance imaging study. Frontiers in Human Neuroscience, 9, 1-13. doi:10.3389/fnhum.2015.00071 17. Xu, X., Aron, A., Brown, L., Cao, G., Feng, T., & Weng, X. (2011). Reward and motivation systems: A brain mapping study of early-stage intense romantic love in Chinese participants. Human Brian Mapping, 32, 249-257. doi:10.1002/hbm.21017 MAY 2017

Disordered Gambling: THE NEUROBIOLOGY OF NATUREâ&#x20AC;&#x2122;S HIDDEN ADDICTION Scott Treiman Many people have seen or are familiar with the physical signs of addiction: the slurred speech of an alcoholic, the needle marks of a drug abuser, the distinct odor of a smoker after a pack of cigarettes, or the sometimes present abnormal physique of a person with an eating disorder. In order to treat these addictions, pharmacological agents are usually recommended. However, in the case of a gambling problem, the outward physical manifestations of the disease are nonexistent.

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either win or lose their wager. Although excessive risk can lead to dangerous behavior, some risk is necessary when approaching a living food source or when encountering a mate. Consequently, although gambling has only been present for a few thousand years, gambling behaviors may continue to persist because its core elements of chance and risk promoted survival for early humans [38]. Figure 1: Gambling has been practiced for thousands of years by many early civilizations. The painter Exekias depicted the Greek heroes Achilles and Ajax playing a board game with dice on this amphora (two-handled jar) (Image: GJCL Classical Art History).

For generations, the only suggested treatment for this “impulse control problem” has been cognitive-behavioral therapy, as no FDAapproved medication exists [1] [29]. Nevertheless, recent studies have demonstrated that gambling problems have neurobiological underpinnings, which suggest that treating this disorder is far more complex than using behavioral therapy for an “impulse control problem.” Gambling is defined as risking something with the hopes of attaining something of higher value [32]. Throughout human history, gambling has been practiced in some form by almost all civilizations (Figure 1). Game boards and dice have been excavated from the early civilizations of Ur (2000 BC), Crete (1800 BC), Egypt (1600 BC), and India (1000 BC) [1]. These behaviors may have evolved due to the elements of chance and risk in gambling. Chance is present in gambling since an element of unpredictability exists, and inclinations for activities involving chance are related to noveltyseeking behaviors. Although stability was necessary for early humans, novelty-seeking behaviors were likely to produce a more nutritionally diverse diet and therefore increase the odds of survival [38]. Similarly, the element of risk is present in gambling, as gamblers

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Gambling has emerged as a socially acceptable and lucrative form of entertainment. In the United States, 76.9% of the population has reported gambling at least once in the past year [40]. While gambling remains a leisurely activity for most people, others have difficulties distancing themselves from it. Among gamblers, about 5% develop disordered gambling, which occurs when gambling becomes excessive and detrimental to the person [3] [32]. In order to receive a diagnosis of disordered gambling, a person must meet 4 out of 9 criteria in the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) (Figure 2) [28]. A gambling disorder was previously classified

Figure 2: The nine criteria on the DSM-V for assessing a gambling problem. If a person fulfills the criteria for four of the nine questions, then the person will be diagnosed with disordered gambling [23]. MAY 2017

Figure 3: While many resources like the sign above are available for disordered gamblers, treatment is almost always given in the form of counseling sessions, as drugs are only prescribed in clinical trials (Image: Kansas Responsible Gambling Alliance).

in DSM-IV in the “Impulse Control Disorders Not Elsewhere Classified” section [30]. Since gambling was classified as a problem stemming from a behavioral impulse, the recommended treatment for gambling problems has been cognitive-behavioral therapy [29] (Figure 3). Additionally, many gamblers were thought to partake in gambling as a “thrill-seeking” behavior, which further led researchers to believe that a gambling disorder could be treated by behavioral therapies. However, sensation-seeking behavior was shown to not be a significant predictor of disordered gambling, and further research was necessary on the etiology of these gambling problems[27]. One reason why the impulse disorder classification has fallen out of favor is due to the now recognized cognitive distortions in gamblers. Although statistical theory clearly predicts that gamblers will lose over time, gamblers often believe that they can “beat the system”. One example of this phenomenon is the gambler’s fallacy, which is the idea that preceding events influence the chances of a kenyon.edu/neuroscience

subsequent event occurring [1]. Other cognitive distortions have also been identified, such as overconfidence in perceived gambling skills, as some disordered gamblers think that they will win because they are better at the game than the average player [11]. Gamblers also often suffer from recall bias, as they tend to recall their wins to a greater extent than their losses [24] . Furthermore, some gamblers suffer from the false belief that superstitious behaviors can affect the outcomes of events[15]. In addition to the cognitive impairments of gambling, the behaviors of disordered gamblers are similar to behaviors of individuals with substance-abuse addictions. An addiction can be defined as having three core elements: (1) a craving state before engaging in the substance or behavior; (2) impaired control over this substance or behavior, and (3) continued engagement with this substance or behavior in spite of negative consequences [30]. Disordered gambling, like other substance-abuse addictions, can lead to periods of withdrawal where gamblers SCIENTIFIC KENYON

develop intensive cravings to continue playing even when they are away from games [18] . Additionally, gamblers suffer from repeated unsuccessful attempts to cease their behavior, adverse emotional states in absence of the stimulus, and inability to resist despite severe negative consequences, all hallmarks of substance-abuse addictions[10].

Neurochemical

Hypothesized Function

Findings in Disordered Gamblers

Serotonin

Learning, Memory, and Impulse Control

Elevated serotonin receptor sensitivity and â&#x20AC;&#x153;highâ&#x20AC;? feeling after administration of serotonin agonist

Dopamine

Reward-Based Learning and Reinforcement

Greater dopamine correlated with severity of gambling symptoms

Norepinephrine

Excitement and Arousal

Increased levels of norepinephrine and metabolites

Pleasure and Cravings

Opioid antagonists currently most efficacious treatment as gamblers have dysregulated opioid release

Opoids

Preliminary findings show However, underlying these Cognition, Memory, treatment with glutamatergic Glutamate addictive disorders are Compulsiveness drugs improves cognition in molecular and cellular gamblers mechanisms that contribute Table 1: Neurochemicals that have been implicated in disordered gambling. All of to these behaviors. Substance the resulting neurotransmitter systems have been modulated, but no current treatabusers have dysregulated ment has been found for the disease [26]. neurotransmitter systems, the neurobiology of disordered gambling altered reward brain circuits, and shared genetic [4] is by comparing the neurotransmitter vulnerabilities . Consequently, treatment for systems of gamblers to controls. Since these these substance-abuse addictions involves neurotransmitter systems are responsible using drugs that can help correct these for regulating many behaviors associated physiological abnormalities, while research with disorderly gambling (Table 1), it was seeks to determine the genetic components of hypothesized that chronic gamblers may the addiction. have dysregulation in these neurotransmitter systems. Three neurotransmitter systems Since treatment for substance-abuse addictions that have been extensively analyzed are the is based upon understanding the neurobiology serotonergic, dopaminergic, and opioidergic of the disorder, researchers hypothesized systems. that there may be genetic and molecular components to gambling disorders because Serotonergic System: of the overlapping behaviors associated with Serotonin is a neurotransmitter found other addictions. Additionally, the recognition throughout the central nervous system of cognitive impairment combined with (brain and spinal cord) that is responsible for impulsivity has further strengthened the idea regulating learning, memory, and impulse that behavioral therapy is not a sufficient control [20]. Since impulsivity is a common approach to combating this disorder. characteristic of gamblers, it was suggested Consequently, researchers have begun to that gamblers might have dysregulated analyze possible neurochemical, anatomical, serotonergic systems (Figure 4). Researchers and genetic differences between disordered assessed possible neurotransmitter gamblers and non-addicted individuals in dysfunction by comparing serotonin receptor hopes of finding pharmacological agents to sensitivity between disordered gamblers combat gambling addictions. and the normal population by administering prolactin, an agonist of serotonin. Neurochemical Differences: Agonists bind to the same receptor as the One way researchers are currently studying

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slot machine and found that greater dopamine release correlated with severity of gambling symptoms These results, (Figure 5) [16]. combined with the interesting relationship between disordered gambling and Parkinson’s diseases, support the concept that an altered dopaminergic system may contribute to severity of gambling problems.

Opioidergic System:

The opioidergic system is another neurotransmitter system that was predicted to contribute to abnormal Figure 4: A graphic of a serotonin neuron and the resulting receptors. behaviors seen in gambling Serotonin binds to these receptors on the postsynaptic cell. This binddisorders. This neurotransmitter ing regulates the release of other neurotransmitters, which in turn system regulates pleasures and cause behaviors such as impulse control (Image: National Institute on urges through modulation of Drug Abuse) dopamine neurons, and since neurotransmitter to elicit a similar response disordered gamblers often feel a heightened (while antagonists block the receptor to stop the sense of euphoria after winning, researchers response), so prolactin is a molecule that mimics hypothesized that gamblers would have the effects of serotonin by binding to serotonin an altered opioidergic system [12]. One receptors. After prolactin administration, experiment gave gamblers and controls disordered gamblers felt a “high” feeling similar an amphetamine to stimulate endogenous to the one that they felt while gambling. opioid release. Disordered gamblers had Additionally, disordered gamblers showed an an attenuated endogenous opioid release, elevated prolactin response in comparison to controls, suggesting that chronic gamblers have a dysregulated serotonergic system [26].

Dopaminergic System:

Another neurotransmitter system that was hypothesized to be associated with gambling was the dopaminergic system. This neurotransmitter system is similar to the serotonergic system at the molecular level; however, the dopaminergic system plays a crucial role in reward learning and reinforcement [9]. Several studies have examined the dopaminergic system in disordered gambler using Positron Emission Tomography (PET) scanning, which can measure the dopamine release in different regions of the brain. Researchers measured changes in dopamine levels of gamblers and healthy controls as they played an online kenyon.edu/neuroscience

Figure 5: Dopamine release during gambling. Subject partook in an online gambling activity, and the weighted fMRI scans show significant increases of dopamine release in the ventral striatum, which is a major component of the brain’s reward system. Greater amounts of dopamine release were correlated with more severe gambling symptoms [16]. SCIENTIFIC KENYON

Parkinsonâ&#x20AC;&#x2122;s Disease and Disordered Gambling Parkinsonâ&#x20AC;&#x2122;s disease (PD) is a debilitating neurodegenerative disorder primarily caused by a loss of dopaminergic neurons in the nigrostriatal pathway [30]. This loss of dopaminergic neurons leads to reduced dopamine levels in the striatum; consequently, L-DOPA (which is converted into dopamine) and dopamine agonists are used to restore dopamine levels. Interestingly, when doctors began prescribing these pharmacological agents to PD patients, they found that several patients developed gambling disorders [8]. Luckily, this effect was reversible, as gambling problems almost completely subsided after patients were treated with a non-dopamine agonist [8]. Nevertheless, when these PD subjects who had been treated for a gambling disorder were compared to PD controls, those with a gambling disorder had dysfunctional activation of dopamine receptors in the striatum [35]. Researchers are using these results to further investigate the effects of an altered dopaminergic system, as disordered gamblers with PD also have impairment in controlling and modifying negative behavior outside of gambling [37]. These behaviors also correspond to dysfunction from the ventral striatum, so researchers are actively searching for new drugs that target this brain region. However, although the connection between disordered gambling and PG has helped pinpoint a location responsible for these adverse effects, no therapies that alleviate the negative behaviors outside of gambling have specifically helped PD patients with a gambling addiction [37]. suggesting that addicted gamblers have a dysregulated endorphin system [25]. The above examples are just three of many neurochemical systems that are altered in disordered gamblers. Differences in neurotransmitter release in the norepinephrine, glutamatergic, and endocannabinoid system have also been observed in comparing gamblers with the rest of the population [33] [13] . Nevertheless, manipulating one of these systems through the use of pharmacological agent has not yet led to a reliably effective treatment (see Pharmacological Drugs).

Anatomical Differences:

In addition to neurochemical changes, disordered gamblers have anatomical disparities compared with controls. One

abnormality in disordered gamblers is reduced white matter integrity in brain regions associated with the limbic system [17] . White matter consists of myelinated axons that transmit messages across the brain, so its integrity is a measurement of brain circuitry function. This lower integrity in limbic areas suggests that disordered gamblers have altered emotions, drives, and long-term memory, as the limbic system is hypothesized to have a role in all of these behaviors [19]. Lower white matter integrity is also commonly seen in substance-use addictions such as alcoholism [16]. In addition to differences in white matter integrity, disordered gamblers have volumetric abnormalities of the brain. The hippocampus, involved in the control emotion and memory, and the amygdala,

Figure 6: Volumetric differences in brain regions for disordered gamblers and controls. Disordered gamblers (brain in the middle) had reduced lower right amygdala and left hippocampal volumes compared to controls (left and right)[34].

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predicted to regulate emotions and decisionmaking, are smaller in disordered gamblers (Figure 6) [34]. These anatomical differences are also observed in individuals with substanceabuse addictions, as stimulant users show similar volumetric reductions in the same brain regions [22].

Genetics:

Researchers have also recently begun to explore possible genetic predispositions of disordered gamblers. Since several neurotransmitters systems for disordered gamblers are dysregulated, researchers are examining polymorphisms in genes that encode molecules associated with these neurotransmitter systems. Several genes responsible for dopamine, serotonin, and norepinephrine metabolism are distinct for disordered gamblers, suggesting that these genes play an additive role in determining the risk of becoming a disordered gambler [7]. As gene sequencing techniques improved, researchers have had the opportunity to perform genome-wide associated studies. These experiments involved identifying single-nucleotide polymorphisms (SNP), which are variations in one base pair of a DNA sequence. The entire genome of disordered gamblers has been compared with the rest of the population, but to date, no single SNP has been found to be universally distinct amongst gamblers. However, genes encoding for physical stress and dopamine, such as Metallothionein 1X, are significantly different for most gamblers [21]. Additionally, neurologic pathways of gamblers vs. nongamblers were compared, and researchers found that gamblers possessed genes that had previously been linked to substance abuse addictions [21]. The differences in neurotransmitter systems, brain physiology, and genetics of gamblers demonstrate that disordered gambling has neurobiological underpinnings that are similar to other addictions. These findings have also made disordered gambling a kenyon.edu/neuroscience

â&#x20AC;&#x153;hidden addiction,â&#x20AC;? since the underlying genetic and physiological factors associated with the addiction are present without any macroscopic physical manifestations. Since cognitive-behavioral therapy is not the only method of treatment for drug users or alcoholics, the same should be true for disordered gambling. Consequently, over the last few years, researchers have begun to search for the molecular mechanisms underlying the disorder as well as possible pharmacological therapeutics.

Current Research: Rat Gambling Task:

One way researchers search for novel therapeutics is through development of animal models. While several animal models have been utilized in substance-abuse addictions, using an animal to model a behavioral addiction is significantly more challenging. Recently, however, researchers have attempted to model gambling addictions using a rat in a paradigm called the rat gambling task (rGT). The rGT is based on the Iowa Gambling Task (IGT), which is given to humans in an attempt to assess poor decision-making [39]. In this task, subjects choose cards from one of four decks, which either lead to winning or losing money. Two of the decks lead to bigger possible winnings but

Figure 7: A comparison of the Iowa Gambling Task (IGT) (A) and the Rat Gambling Task (rGT) (B). In both experimental setups, subjects can choose two options with a greater yet less frequent reward, or two options with a lower reward that lead to a higher net gain over time [36]. SCIENTIFIC KENYON

result in a net loss over time (disadvantageous decks), while the other two decks give smaller immediate winnings but lead to a net gain over time (advantageous decks) [5]. Healthy individuals can quickly learn to choose the advantageous decks after a few trials, while disordered gamblers perform significantly worse compared with controls and consistently choose the disadvantageous decks [5]. The rGT utilizes a similar paradigm as the IGT, with a food reward substituted for winning and a timeout period substituted for losing money (Figure 7). After exposure to the consequences associated with each option, most rats are able to learn to choose feeding holes that give a smaller yet more stable food reward. However, some rats consistently choose the disadvantageous options, and this population is often used to represent the disordered gambling population[36]. A more common way to conduct rGT studies is to take a population of normal decision-making rats and inject them with a neurochemical associated with a neurotransmitter system thought to be involved in addictive behavior. Premature responses, measured by impulsivity, and decision-making are then measured in an attempt to determine if modulation of these neurotransmitter systems can cause changes in the behaviors that are most commonly altered in disordered gamblers. Several experiments have tested if agonists or antagonists of an individual neurotransmitter system can cause a change in impulsivity or decision-making. Most of these pharmacological agents have not led to changes in behavior, as neurochemicals that affect the endocannabinoid and serotonergic system did not alter impulsivity or decisionHowever, when researchers making [13] [2]. administered agonists of the dopaminergic and noradrenergic systems, correct decisionmaking decreased [2]. The dopamine and norepinephrine systems are both involved with the transmission of catecholamine molecules. These organic molecules function as neurotransmitters and are involved in decisionmaking, so it is possible that the additive

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effects of dopamine and norepinephrine antagonists cause decreased catecholamine neurotransmission and consequently poorer decision-making. While these results are promising, an inherent disadvantage to the rGT is that rats may not be suffering from a gambling problem but rather a decision-making deficit applicable to many disorders. Therefore, to increase the validity of the rGT as it pertains to modeling a gambling addiction, it is critical that rats have the specific cognitive deficits observed in disordered gamblers. One possible way to enhance this validity might be to conduct an experiment where rats first performed a different cognitive task. Rats who performed equally well on this cognitive task would then be tested with the rGT, and only then could differences in performance on the rGT be attributed to gambling-like cognitive deficits. Nevertheless, while the above results are not completely applicable to the gambling population, these findings highlight a likely reality of disordered gambling: it is a complicated addiction caused by multiple altered neurotransmitter systems.

Pharmacological Drugs:

Although no drugs are currently FDAapproved for treatment of gambling disorders, many clinical trials have been tried or are currently under investigation. Agonists or antagonists of serotonin, glutamate, dopamine, norepinephrine, and opioids have all been prescribed to disordered gambling patients. However, similar to substance-abuse addictions, the results have been largely mixed, and no drug has been demonstrated to work for all disordered gamblers [6]. Analogous to these addictions, disordered gambling could be a disorder where individuals are given drugs sequentially until clinical success is obtained. Nevertheless, manipulation of the opioidergic system has led to the most substantial rates of improvements for gamblers in comparison to other neurochemical systems, as the opioid antagonist naltrexone successfully reduced gambling symptoms in 55% of individuals. This result has led current research to most actively MAY 2017

focus on this system, as other opioidergic antagonists such as nalmefene are now being tested in clinical trials [6]. The results have largely been mixed, but they nevertheless demonstrate that a dysregulated endorphin system might have a more substantial role in disordered gambling than previously thought.

The Future of Disordered Gambling:

In addition to the adverse consequences associated with gambling, disordered gamblers must also deal with the negative stigma associated with the disease. When social attitudes of university students were assessed, disordered gamblers were found to be significantly more negatively stigmatized than the normal population or cancer patients who had no control over their situation [14]. While the negative stigmas may never completely subside, knowledge that disordered gambling is an addictive disease with some uncontrollable neurobiological factors will hopefully reduce the negative social attitudes towards individuals with the disorder.

physiological, and neurochemical similarities with substance-abuse disorders, research on the mechanisms of the disorder may in turn help with other addictions. Unlike other addictions, however, the absence of a physical stimulus in disordered gambling allows researchers to study the addiction without having to account for the biological effects of the substance. This intriguing feature of disordered gambling may allow researchers to explore the same changes in brain circuitry observed in alcoholism and disordered gambling but without having to worry about how alcohol potentially altered these circuits. Nevertheless, the understanding that neurobiological factors contribute to the disease will hopefully accelerate research in psychopharmacology and produce an effective therapy that works for a greater percentage of disordered gamblers. As advances are made in neuroscience, it is possible that one day a pharmacological agent will be developed that completely erases the negative behaviors of disordered gambling. While this drug may help a person socially and financially, its elimination of a unique behavior may have profound implications on the notion of free will. If we can begin to treat suboptimal behaviors such as disordered gambling with medications, then we might reduce

Disordered gambling was for years classified as an impulse control disorder until the neurobiological underpinnings of the disease revealed that disordered gambling resembles many substance-abuse addictions. In the newly published DSM-5, disordered gambling was moved from “impulse control disorder” section to the “behavioral addiction” section [28] . Even with this recognition, understanding and treatment for the disorder are well behind other addictions. In all likelihood, the treatment will consist of some combination of pharmacological agents and behavioral therapy. Comorbidities must be assessed, and external factors, such as exposure to gambling activities, familial support, and financial situation may also worsen or help alleviate the disease. Figure 8: If we developed drugs that could eliminate the behaviors Due

the

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genetic,

that we viewed as suboptimal, would it lead to the equivalent of a gambler having only one possible hand to play? (Image: QuoteSaga) SCIENTIFIC KENYON

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the free will that allows gamblers to make these wrong decisions. This situation could theoretically progress to a point where any suboptimal decision is considered abnormal, and medication could be administered to immediately induce the “optimal” behavior (Figure 8). However, if this “optimal” behavior is the only option, then free will could subside. Even though researchers are nowhere near designing drugs that have this type of effect on behaviors, current medications may act on free will to a lesser extent. Although reducing these perceived adverse behaviors unquestionably helps people in many aspects of life, a tradeoff may also exist in the form of less free will as neuroscience attempts to create an “optimal” behavior. Works Cited

1. Ashley LL, Boehlke KK (2012) Pathological Gambling: A General Overview. J Psychoactive Drugs 44:27–37. 2. Baarendse PJJ, Winstanley CA, Vanderschuren LJMJ (2013) Simultaneous blockade of dopamine and noradrenaline reuptake promotes disadvantageous decision making in a rat gambling task. Psychopharmacology (Berl) 225:719–731. 3. Becona E (1996) Prevalence surveys of problem and pathological gambling in Europe: The cases of Germany, Holland and Spain. J Gambl Stud 12:179–192. 4. Blanco C, García-Anaya M, Wall M, de los Cobos JCP, Swierad E, Wang S, Petry NM (2015) Should pathological gambling and obesity be considered addictive disorders? A factor analytic study in a nationally representative sample. Drug Alcohol Depend 150:129–134. 5. Buelow MT, Suhr JA (2009) Construct validity of the Iowa gambling task. Neuropsychol Rev 19:102–114. 6. Bullock, S. A., & Potenza MN (2012) Pathological gambling: Neuropsychopharmacology and treatment. Curr Psychopharmacol 1:67–85. 7. Comings DE, Gade-Andavolu R, Gonzalez N, Wu S, Muhleman D, Chen C, Koh P, Farwell K, Blake H, Dietz G, MacMurray JP, Lesieur HR, Rugle LJ, Rosenthal RJ (2001) The additive effect of neurotransmitter genes in pathological gambling. Clin Genet 60:107–116. 8. Dodd ML, Klos KJ, Bower JH, Geda YE, Josephs KA, Ahlskog JE (2006) Pathological gambling caused by drugs Used to Treat Parkinson Disease. Arch Neurol 62. 9. Dreher J, Kohn P, Kolachana B, Weinberger DR, Berman KF, Faith K (2009) Variation in dopamine genes influences responsivity of the human reward system. Proc Natl Acad Sci 106:617–622. 10. El-Guebaly N, Mudry T, Zohar J, Tavares H, Potenza MN (2012) Compulsive features in behavioural addictions: The case of pathological gambling. Addiction 107:1726–1734.

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11. Goodie AS (2005) The role of perceived control and overconfidence in pathological gambling. J Gambl Stud 21:481–502. 12. Grant JE, Brewer JA, Potenza MN (2006) The neurobiology of substance and behavioral addictions. CNS Spectr 11:924–930. 13. Gueye AB, Trigo JM, Vemuri K V., Makriyannis A, Le Foll B (2016) Effects of various cannabinoid ligands on choice behaviour in a rat model of gambling. Behav Pharmacol 27:258–269. 14. Horch JD, Hodgins DC (2000) Public Stigma of Disordered Gambling: Social Distance, Dangerousness, and Familiarity. Rockloff Schof J Soc Clin Psychol 27:505–528. 15. Johansson A, Grant JE, Kim SW, Odlaug BL, G??testam KG (2009) Risk factors for problematic gambling: A critical literature review. J Gambl Stud 25:67–92. 16. Joutsa J, Johansson J, Niemelä S, Ollikainen A, Hirvonen MM, Piepponen P, Arponen E, Alho H, Voon V, Rinne JO, Hietala J, Kaasinen V (2012) Mesolimbic dopamine release is linked to symptom severity in pathological gambling. Neuroimage 60:1992–1999. 17. Joutsa J, Saunavaara J, Parkkola R, Niemelä S, Kaasinen V (2011) Extensive abnormality of brain white matter integrity in pathological gambling. Psychiatry Res - Neuroimaging 194:340–346. 18. Kaptsis D, King DL, Delfabbro PH, Gradisar M (2016) Withdrawal symptoms in internet gaming disorder: A systematic review. Clin Psychol Rev 43:58–66. 19. Kotter R, Meyer N (1992) The limbic system: a review of its empirical foundation.[Review]. Behav Brain Res 52:105–127. 20. Leiser SC, Li Y, Pehrson AL, Dale E, Smagin G, Sanchez C (2015) Serotonergic Regulation of Prefrontal Cortical Circuitries Involved in Cognitive Processing: A Review of Individual 5-HT Receptor Mechanisms and Concerted Effects of 5-HT Receptors Exemplified by the Multimodal Antidepressant Vortioxetine. ACS Chem Neurosci 6:970–986. 21. Lind PA, Zhu G, Montgomery GW, Madden PAF, Heath AC, Martin NG, Slutske WS (2013) Genome-wide association study of a quantitative disordered gambling trait. Addict Biol 18:511–522. 22. Makris N, Gasic GP, Seidman LJ, Goldstein JM, Gastfriend DR, Elman I, Albaugh MD, Hodge SM, Ziegler DA, Sheahan FS, Caviness VS, Tsuang MT, Kennedy DN, Hyman SE, Rosen BR, Breiter HC (2004) Decreased absolute amygdala volume in cocaine addicts. Neuron 44:729–740. 23. McCready, J., Jimenez-Murcia, S., Turner, N., Petry, N., Grant, J., Winters, K., ... & Chapman, H. (2013). Diagnosis of Gambling Disorder: Comparison of DSM-IV and DSM-V. 24. McCusker CG, Gettings B (1997) Automaticity of cognitive biases in addictive behaviours: further evidence with gamblers. Br J Clin Psychol 36 ( Pt 4):543– MAY 2017

554. 25. Mick I, Myers J, Ramos AC, Stokes PR, Erritzoe D, Colasanti A, Gunn RN, Rabiner EA, Searle GE, Waldman AD, Parkin MC, Brailsford AD, Galduróz JC, BowdenJones H, Clark L, Nutt DJ, Lingford-Hughes AR (2015) Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers. Neuropsychopharmacology:1–9. 26. Pallanti S, Bernardi S, Quercioli L, DeCaria C, Hollander E (2006) Serotonin dysfunction in pathological gamblers: increased prolactin response to oral m-CPP versus placebo. CNS Spectr 11:956–964. 27. Parke A, Griffiths M, Irwing P (2004) Personality traits in Pathological Gambling: Sensation Seeking, Deferment of Gratification and Competitiveness as Risk Factors. Addict Res Theory 12:201–212. 28. Petry NM, Blanco C, Auriacombe M, Borges G, Bucholz K, Crowley TJ, Grant BF, Hasin DS, O’Brien C (2014) An Overview of and Rationale for Changes Proposed for Pathological Gambling in DSM-5. J Gambl Stud 30:493– 502. 29. Pettorruso M, De Risio L, Martinotti G, Di Nicola M, Ruggeri F, Conte G, Di Giannantonio M, Janiri L (2014) Targeting the glutamatergic system to treat pathological gambling: Current evidence and future perspectives. Biomed Res Int 2014. 30. Poletti M, Bonuccelli U (2013) Acute and chronic cognitive effects of levodopa and dopamine agonists on patients with Parkinson’s disease: a review. Ther Adv Psychopharmacol 3:101–113. 31. Potenza, M. (2006). Should addictive disorders include non-substance related conditions? Addiction 101: 142151. 32. Potenza MN (2008) The neurobiology of pathological gambling and drug addiction: an overview and new findings. Philos Trans R Soc Lond B Biol Sci 363:3181– 3189. 33. Potenza MN (2013) Neurobiology of gambling behaviors. Curr Opin Neurobiol 23:660–667. 34. Rahman AS, Xu J, Potenza MN (2014) Hippocampal and amygdalar volumetric differences in pathological gambling: a preliminary study of the associations with the behavioral inhibition system. Neuropsychopharmacology 39:738–745. 35. Ray NJ, Miyasaki JM, Zurowski M, Ko JH, Cho SS, Pellecchia G, Antonelli F, Houle S, Lang AE, Strafella AP (2012) Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson’s patients with medicationinduced pathological gambling: A [11C] FLB-457 and PET study. Neurobiol Dis 48:519–525. 36. Rivalan M, Ahmed SH, Dellu-Hagedorn F (2009) Risk-prone individuals prefer the wrong options on a rat version of the Iowa Gambling Task. Biol Psychiatry 66:743–749. 37. Santangelo G, Barone P, Trojano L, Vitale C (2013) Pathological gambling in Parkinson’s disease. A comprehensive review. Park Relat Disord 19:645–653. kenyon.edu/neuroscience

38. Spinella, M (2003) Evolutionary Mismatch, Neural Reward Circuits, and Pathological Gambling. Int J Neurosci 113:503–512. 39. Van Den Bos R, Davies W, Dellu-Hagedorn F, Goudriaan AE, Granon S, Homberg J, Rivalan M, Swendsen J, Adriani W (2013) Cross-species approaches to pathological gambling: A review targeting sex differences, adolescent vulnerability and ecological validity of research tools. Neurosci Biobehav Rev 37:2454–2471. 40. Welte JW, Barnes GM, Tidwell MCO, Hoffman JH, Wieczorek WF (2014) Gambling and problem gambling in the united states: Changes between 1999 and 2013. J Gambl Stud 31:695–715.

Images Figure 1: “Achilles and Ajax Playing a Game” (2016) Retrieved from GJCL Classical Art History Figure 2: McCready, J., Jimenez-Murcia, S., Turner, N., Petry, N., Grant, J., Winters, K., ... & Chapman, H. (2013). Diagnosis of Gambling Disorder: Comparison of DSM-IV and DSM-V. Figure 3: “Gambling Help” (2016) Retrieved from Kansas Responsible Gambling Alliance Figure 4: “Seretonin Rceptor” (2016). Retrieved from National Institute of Drug Abuse Figure 5: Joutsa J, Johansson J, Niemelä S, Ollikainen A, Hirvonen MM, Piepponen P, Arponen E, Alho H, Voon V, Rinne JO, Hietala J, Kaasinen V (2012) Mesolimbic dopamine release is linked to symptom severity in pathological gambling. Neuroimage 60:1992–1999. Figure 6: Rahman AS, Xu J, Potenza MN (2014) Hippocampal and amygdalar volumetric differences in pathological gambling: a preliminary study of the associations with the behavioral inhibition system. Neuropsychopharmacology 39:738–745. Figure 7: Rivalan M, Ahmed SH, Dellu-Hagedorn F (2009) Risk-prone individuals prefer the wrong options on a rat version of the Iowa Gambling Task. Biol Psychiatry 66:743–749. Figure 8: “Life is like a game of cards. The hand you are dealt is determinism; the way you play is free will ~Jawaharlal Nehru” (2016). Retrieved from QuoteSaga.

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