Role of Endocannabinoid System in Chronic Pain

Our last speaker Mitchell Roitman discussed the role of dopamine release in the nucleus accumbens (NAc) during cocaine administration. His study analyzed the effects of dopamine release in the NAc shell and core after cocaine administration, to study how each region effects motivated behavior. The NAc core, which is responsible for generating conditioned responses based on associative learning,  was the focus of his study showing that the suppression of cocaine induced dopamine signaling by GLP-1R agonist may decrease the reinforcing properties of cocaine. His research paves the way for a treatment to drug addiction.

In this review, researches evaluated the effects of the endocannabinoid system (ECS) in dopamine signaling within the reward circuits affected by chronic pain, which focuses on the effects of induced dopamine in the NAc shell rather than its core. Both studies evaluate the mesolimbic pathway which plays an important role in the regulation of emotional and cognitive behavior and the effects of dopamine. Dopamine is a catecholamine neurotransmitter that plays a variety of functions in the brain, including reward, aversion, motivation, motor coordination, learning, and hormone secretion. Evidence from past research has indicated that the opioid system, as well as the endocannabinoid system are highly relevant in both pain perception and reward processing. Targeting the ECS has great potential for creating a treatment for chronic pain patients.

Dopamine transmission in the nucleus accumbens (NAS) is increased with natural rewards, such as food or sex, and after administration of addictive drugs. The activation of the dopamine system and amount of dopamine released in response to addictive substances is greater than the effects of a natural reward. Psychostimulant drugs act similar to natural rewards by increasing dopamine release, mainly in the shell, having a short-lived effect that disappears at the end of stimulation, whereas an aversive stimulus induces the elevation of dopamine release in the NAS core and prefrontal cortex. Data has indicated that the mesolimbic reward circuitry is involved in chronic pain. Increased activity in the NAS has been associated with pain. With more research needing to be done, the ECS poses as a promising alternative for opioids in chronic pain treatment. Many studies have shown reports that cannabinoid treatment may improve symptoms of pain, anxiety, depression, and overall quality of life for patients experiencing chronic pain.

With our national opioid crisis still at large, alternative treatments need to be discovered that pose less of a threat to a patient's overall wellbeing when dealing with things such as chronic pain. We have countless military veterans returning home and getting addicted to opioids for pain management whereas with more solid research, the ECS can prove as an amazing alternative.

https://reader.elsevier.com/reader/sd/pii/S1043661819300088?token=D52927CF6937542D006E746BFDE2709608531ABE5B314B0B05A87C28B3FD26426980E9C7D114C1A08E61D32BFAE0E675

Circadian Rhythms: Sleeping and Eating

Circadian clocks are found in nearly all living organisms, and regulate behavioral and physiological processes to be synced up to a specific time in the day. It has been known for a while that the hypothalamus contains a sort of “master clock” that regulates sleep-wake cycles in response to the Earth’s exposure to the sun. This clock runs on a 24-hour schedule. 

In the New York Times article, “When We Eat, or Don’t Eat, May Be Critical to our Health” the author discusses the science behind eating and how time of day plays a role in our overall metabolism. During the daytime, the pancreas produces the most insulin, a hormone that regulates glucose levels in the body. Other organs, such as the gut, also follow this clock, and have optimal times of function in the 24-hour time frame. Humans have evolved greatly since our conception, but a constant that the entire species has had is the rising and setting of the sun at roughly the same schedule forever. There is much evidence suggesting that our blood sugar control is at peak function during the morning, and weakest in the evening. This would then suggest that we should have larger meals earlier in the day and just a light evening meal, for a most advantageous schedule. During late evening, when there isn’t any sunlight, the brain produces melatonin which tells our body to sleep. However, if we are eating late at night, this signal conflicts with the melatonin, and potentially disrupts our sleep patterns. 

Jet lag is a common known phenomenon. We are plagued with fatigue, and our brains feel almost foggy. On a less drastic scale, eating when our bodies aren’t programmed to digest and absorb nutrients from food will work our organs when they aren’t supposed to, which increases the risk of disease, according to Paolo Sassone-Corsi, the director of the Center of Epigenetics and Metabolism at the University of California, Irvine. He goes on to list shift workers as an example of those more susceptible to obesity, heart disease, some cancers, and heart disease. Thought we shouldn’t discount socioeconomic factors as a major cause, studies definitely show that circadian disruption can lead to poor health.   

This relates very well to Dr. Cavanaugh’s research which we saw in class. However, according to Dr. Cavanaugh’s research, chronic circadian misalignment (CCM) results in reduced longevity and can lead to changes in gene expression in Drosophila, the common fruit fly. Drosophila possess a powerful genetic toolkit that can be relatively easily manipulated for scientific purposes. They are extremely useful model organisms because their homeostatic system is functionally conserved with the mammalian one. So his research on Drosophila can be translated over to mammals. CCM can be induced by the altered schedule shift workers are accustomed to, aberrant sleeping patterns, and eating schedules. This has a great effect on cognitive and metabolic activities, which was also summarized by Anahad O’Connor in the aforementioned article. Dr. Cavanaugh and his team of researchers found flies to have approximately a 15% reduction in the average lifespan in both male and female flies when they faced a 4-hour phase delays in their light-dark schedule. CCM also caused large scale changes in general gene expression, which was seen by the upregulation of genes that regulate toxic substances, aging, and oxidative stress, and downregulation of genes that are involved with regulating development, gene expression and biosynthesis. 

The changes that this lab made to the schedules of the Drosophila are consistent with changes that many shift workers and even those with aberrant sleeping and eating patterns already experience. They concluded that CCM can lead to premature organismal decline. Dr. Cavanaugh plans to do further research regarding this subtopic in neuroscience, and we look forward to what he and his team will find.  

Sources:

https://www.nytimes.com/2018/07/24/well/when-we-eat-or-dont-eat-may-be-critical-for-health.html

https://www.dropbox.com/sh/yrruoccwcc8fc6i/AABlCXRgo4CIfDdwrpqwOmHra/(04.16.19)%20-%20Dan%20Cavanaugh?dl=0&preview=boomgarden_cavanaugh_drosophila_jetlag_longevity_gene_expression_BMC_genomics_2019.pdf&subfolder_nav_tracking=1

Reversing Brain Death?

Brain death is just one of the many disorders of consciousness. According to Dr. Joe Vukov of Loyola University of Chicago “someone who is brain dead is in a [irreversible] coma” and also have the following two features: the absence of both brainstem function and spontaneous respiration. Thus being brain dead, is being dead. A common misconception with brain death is that it is the same thing as vegetative state. It is not, a person who is in a vegetative state while they might not be aware or conscious, they exhibit sleep/wake cycles, and typically can breathe on their own. A patient that is in a vegetative state, is not dead.

       In the past there have been many cases dealing with brain death. Unfortunately, all the patients who become brain dead are young, typically ranging from young children to young adults. This is because brain death is not genetic rather from a traumatic incident such as not having access to oxygen for a long period of time. Most of the time the families of these patients don’t accept the death of their loved one and fight the hospital to keep their loved ones alive through a heart-lung machine. This popular ethical debate on the status and treatment of brain death patients may finally be over. Researchers from Yale University School of Medicine, have created a machine, similar to that of a dialysis machine called BrainEx. BrainEx restores function of take in of glucose and oxygen, through the restoration of circulation and oxygen flow in a dead brain. The researchers were then able to restore the cellular function of 32 brain dead pig brains. While the brains were not conscious (having awareness), some level of restoration was made.

While BrainEx doesn’t go to solve or cure brain death, this does provide a possibility for the future. If a person is amidst a traumatic incident maybe BrainEx can restore brain function before a person becomes brain death. Whether or not if that is possible, it still opens the door for the possibility of reversing brain death. If this is the case this would alter the definition of being dead and this would raise more ethical concerns, like whether this is crossing the line of bringing people back from being dead. Given this may rise more ethical questions than solve, it might just be simple as Dr. Joe Vukov suggested, which is to have patient's families well aware of being brain dead means. Providing informational pamphlets with emotional support to patient families can really help in these rare cases of brain death patients.

Greshko, M. (2019, April 17). Pig brains partially revived hours after death—what it means for people. Retrieved April 23, 2019, from https://www.nationalgeographic.com/science/2019/04/pig-brains-partially-revived-what-it-means-for-medicine-death-ethics/

Circadian Misalignment or Diabetic Misalignment?

The 21st century is a time that has seen immense advancement in almost every facet of life. Mankind is creating things only dreamt of in the past, but our only limit is time. Unfortunately, there are only 24 hours in a day and human life is based on circadian rhythms. Circadian rhythms help facilitate the day-to-day activities such as feeding, sleeping, hormonal release, and it even regulates body temperature based on what time of day it is. Due to the many complexities of life, each day is unique and often there are many fluctuations in this rhythm. Fluctuations can occur from deviating sleeping and eating schedules, night-shift workers, and even cell phone use late at night. The brain's internal clock is known as the Suprachiasmatic Nucleus (SCN). The SCN is involved in coordinating these circadian rhythms to cells in order to adapt to the environment optimally. According to Cavanaugh et al., "to maintain rhythmic oscillations under constant conditions; however, because they oscillate with an intrinsic period that is not exactly 24-h, they must be reset on a daily basis through the process of entrainment in order to remain synchronized to environmental cues." Abrupt changes in these rhythms is known as Chronic Circadian Misalignment (CCM).

To investigate the effect CCM could have on organisms, Dr. Cavanaugh explored this concept with Drosophila melanogaster. Results from his study indicated that CCM caused reduction in life span and overall decline by differentially expressing genes involved in synthetic and developmental pathways. In humans, similar results are shown. In a 2016 study conducted out of Harvard medical school by Scheer, Mistretta, Purvis, and Morris, they investigated the effect of CCM on Glucose tolerance. This study assayed healthy chronic shift workers in two contexts. One group simulated a 12-hour night shift and another group simulated a 12-hour day shift. The researchers attempted to understand the, "postprandial glucose and insulin responses to identical meals given at 8:00 AM and 8:00 PM in both protocols." (Scheer et al., 2016). Results from the study indicated that their postprandial glucose was 6.5% higher in the night eaters. The results demonstrated that pancreatic beta cell function was 18% lower and there was decreased glucose sensitivity. These results are concerning considering the rise in diabetics within the United States. With such hectic schedules, Americans are putting themselves at a higher risk of developing Type 2 diabetes and even becoming closer to obesity.

If someone is unable to change their aberrant circadian rhythms, then maybe they could more fruits and vegetables to combat it? In 2017, a study out of Rice University under Dr. Janet Braam found that vegetables also display some sort of circadian rhythm. According to Dr. Braam, "vegetables increase and decrease certain phytochemicals based on the time of day." This doesn't seem surprising given that vegetables and all plants get their circadian cues directly from their life source, the Sun. So, how does this help humans? According to Dr. Braam's research, the most potent time plants make their most nutrients available is during the middle of the day, when they’re is the most sunlight. Although eating vegetables may not correct CCM, it can for sure help prevent the advent of diseases such as Diabetes.

Making good life choices such as eating healthy could be the start to building better habits. Once better habits are established, an individual will have a better grip on their daily lives. Resulting in potentially developing a rhythmic schedule to correct for CCM. 

Alex C. Boomgarden, Gabriel D. Sagewalker, Aashaka C. Shah, Sarah D. Haider, Heather E. Wheeler, Christine M. Dubowy, & Daniel J. Cavanaugh. (2019, January 07). Chronic circadian misalignment results in reduced longevity and large-scale changes in gene expression in Drosophila. Retrieved from https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-018-5401-7

Douillard, J. (2018, October 12). Reset Your Circadian Rhythms with a Plant-Based Diet. Retrieved from https://lifespa.com/reset-circadian-rhythms-plant-based-diet/

Morris, C. J., Purvis, T. E., Mistretta, J., & Scheer, F. A. (2016, March). Effects of the Internal Circadian System and Circadian Misalignment on Glucose Tolerance in Chronic Shift Workers. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26771705

What Is Death? The Jury Is Still Out

There’s an old saying by Ben Franklin that goes: “in this world nothing can be said to be certain, except death and taxes.” This speaks to the inevitableness of death as a fact of life. Surprisingly, with something as inevitable as death, there is still a lot of talk about when exactly someone is “dead”. These problems concerning the definition of death come up often in cases concerning brain function and brain death.

Questions concerning the definitions of death are raised in the Forbes article titled “What Does ‘Dead’ Mean? The Debate Continues Some 50 Years After Harvard Defined Death.” The article highlights the main questions still surrounding brain death, such as “‘Is death defined in terms of the biological failure of the organism to maintain integrated functioning? Can death be declared on the basis of severe neurological injury even when biological functions remain intact? Is death essentially a social construct that can be defined in different ways, based on human judgment?’ ”. These questions raise a multitude of concerns, not limited to, but including organ transplantation. The concept of when someone is dead is crucial in organ transplantation, as a living person is clearly not capable of donating their vital organs. So, even if someone looks as if they have passed on, if they are technically still alive, their organs are not able to be donated.

The problem extends outside of the scientific community, pervading public thought as well. The Forbes article references how “the inaccurate use of ‘brain death’ has contributed to public misunderstanding of the neurological state.” Many people do not know the differences between distinctions such as a coma, persistent vegetative state, or brain death. This leads to many people misunderstanding crucial facts of what is and is not medically possible for their loved ones. For example, a coma is a state in which a patient is not awake and is also not aware of painful or verbal stimuli. Comas may also be reversible, meaning that the patient can recover. Comas are one of 3 criteria for declaring someone brain dead. An important distinction that leads to the diagnosis of brain death rather than coma is the fact that brain death is irreversible. Permanent vegetative states differ from brain death in that people in PVS do not need respirators to breathe for them. In some cases, PVS patients can show some sense of awareness or recovery of some function.

The problem concerning the definitions surrounding brain death, comas, etc. is in the communication between care providers and families. Care providers use language that is misleading and confusing. On the other end, families of patients are sometimes unsure of the exact reality of the situation they and their loved one is in. This leads to the question of how do we bridge this gap between the scientific community and the confused public. I believe this is best done through bioethicists. Bioethicists fill the crucial gap and allow the information to be relayed in the best way possible. Bioethicists would be able to step in and advise the family on their options and inform them even more clearly on the reality of the predicament they are facing. Bioethicists can also provide a buffer between the family and care providers when it comes to disagreements in care for the individual in question.

Whatever path is taken to accomplish it, it is clear that the area of medicine surrounding neurological states must work to be more compassionate to families, while also maintaining the importance of truth and clarity.

Sources and Links:

Forbes Article “What Does ‘Death’ Mean? The Debate Continues Some 50 Years After Harvard Defined Death.”:

https://www.forbes.com/sites/robinseatonjefferson/2019/01/16/what-does-dead-mean-the-debate-continues-some-50-years-after-harvard-defined-death/#5d5390694a22

Jefferson, Robin Seaton. “What Does ‘Dead’ Mean? The Debate Continues Some 50 Years After Harvard Defined Death.” Forbes, Forbes Magazine, 17 Jan. 2019, www.forbes.com/sites/robinseatonjefferson/2019/01/16/what-does-dead-mean-the-debate-continues-some-50-years-after-harvard-defined-death/#5d5390694a22.

Powell, T. “Brain Death: What Health Professionals Should Know.” American Journal of Critical Care, vol. 23, no. 3, 2014, pp. 263–266., doi:10.4037/ajcc2014721.

The Ongoing Controversy Over the Definition of Death

In Dr. Vukov’s talk about brain death, he first distinguished between disorders of consciousness, such as locked-in state or minimally conscious state, and a vegetative state. I thought it was really interesting that the technique to determine whether or not someone is in a vegetative state is by asking something such as, “Can you imagine playing tennis with me?” and using brain scans to determine whether the brain was actively doing so. This is a quick diagnosis, but the caveat is that doctors must catch the patient while they’re awake in order to ask them, which can be difficult. Brain death is very different from disorders of consciousness and is synonymous with death, particularly in the US. Not only does someone need to be in an irreversible coma to be pronounced brain dead, but they must meet two more requirements: complete absence of brain stem function and absence of spontaneous respiration.

            It first became very important to define death following the development of the first ventilator in the 1930s and then the first successful organ transplant in 1967 because it opened up the possibility of acting quickly to preserve the organs of donors who were just pronounced dead. Also, cardiac death and brain death could now be separate; however, without a ventilator one would follow the other. In the United States, death is pronounced if either the Cardiopulmonary Standard or the Neurological Standard is met. A problem with the Cardiopulmonary Standard is that we currently cannot determine when someone’s cardiopulmonary systems have stopped. Being “close enough” is no longer acceptable in a world where there is the possibility of organ transplantation. A problem with the Neurological Standard is that although most organs are harvested from neurologically dead individuals, certain individuals who meet the criteria for brain death raise questions about whether or not this criterion actually captures death (for example, Johi McMath). These problems raise ethical issues because doctors want to continue transplanting organs, but doctors do not want to prematurely pronounce someone brain dead solely for their organs. Also, it is important for healthcare officials to respect patients’ and families’ wishes at the end of life, but it’s unreasonable to waste resources, especially on someone who is already dead.

            In “When is dead really dead?” by Katharina Busl, a neurologist specializing in neurocritical care, Dr. Busl agrees with Dr. Vukov that up until the 1930s when ventilators were created and the 1950s when pacemakers were developed, “death” was simply defined when the heart stopped beating and breathing ceased, and death is much trickier to define today. However, there is not a machine that could revive a patient with irreversible brain damage, which introduced the concept of “brain death,” which has been legally adopted in the U.S. and many other parts of the world. She agrees with Dr. Vukov that brain death is difficult to imagine and is a less visible form of death because the patient’s heart continues to beat (typically from machines) and the body is still warm to touch. However, on April 17, 2019, Nature published a study that has made brain death an even more controversial topic. The study examined pig brains in which the scientists took the brains of pigs that had been slaughtered and “connected them to a machine that pumped an artificial blood-like nutritional fluid through the brains” for four hours after the slaughtering and measured brain cell activity. The scientists discovered that even four hours after death, blood circulation and certain brain cell functions could be restored. This research suggests that our brains may have “a better capacity to heal than is currently know.” However, Dr. Busl believes that although this is scientific news because it is an experiment that has never been done before, scientists have known for a long time that death is a continuum so it is not groundbreaking. Dr. Busl believes this research does not demonstrate that these brain cells that were able to function after death were a part of a cell network that lead to higher brain function that make humans distinct from other animals, such as consciousness and awareness. Also, the research does not show how these brains will function for a long period after restoration but rather an immediate restoration of some cell function. Hooking up patients to artificial blood and oxygen supplies could maintain living body parts or cells, but like Dr. Vukrov discussed, it is unethical to waste resources on doing so when the person will remain in an irreversible coma. Dr. Vukrov believes that it may be best to stop worrying about giving a black and white definition of death in terms of brain death because scientists still do not really know the difference between death and brain death.

An angiogram of a brain with blood flow (left) and without blood flow (right), as would be examined in a brain dead patient.

Works Cited:

Busl, Katharina. “When Is Dead Really Dead?” EarthSky, 28 Apr. 2019, earthsky.org/human-world/study-death-pig-brains-activity-4-hours-later.

Picture Works Cited:

“Understanding Brain Death.” Finger Lakes Donor Recovery Network, www.donorrecovery.org/learn/understanding-brain-death/.

A Matter of Life and Death

Life is filled with uncertainty: as Christopher Bullok famously said, “‘Tis impossible to be sure of anything but Death and Taxes.” Death may be losing its place on the list of certainties, as a group of primarily Yale based researchers managed to partially restore function to the brains of pigs who had 

been dead for hours.

According to Simon Makin in his article Brain Restoration SystemExplores Hazy Territory between Being Dead or Alive, the researchers were compelled by the use of neural cell cultures harvested from animals in labs. They wondered if they couldn’t do the same thing in an intact bran that is commonly done in a dish. The team used a system they call “BrainEx” to protect and oxygenate the tissue, and even hours after death the cells treated returned to a state resembling life, even showing immune responses. It should be noted that there was no activity in the brains as BrainEx included neural activity blockers to prevent spontaneous firing. It is unclear if the brains themselves could return to an active state had these blockers not been used.

This study has, as one might expect, sparked enormous ethical debate. Before addressing the matter of bringing back the dead, it might be wise to look at bringing back the living. Dr. Joe Vukov, an ethicist Loyola University, has been attempting to parse the nature of death for some time. His focus has been primarily on people who are in a minimally conscious state, where a patient has exhibited some response to the world around them, even if it is only slight. This is different from a vegetative state where the patient is completely unaware of their surroundings. Patients in either state are often unable to breath on their own and always unable to eat, but patients in a minimally conscious state are more likely to recover then those in a vegetative state, causing enormous controversy of when it is okay to pull the plug

In Dr. Vukov’s paper When Does Consciousness Matter? Lessons from the Minimally Conscious State, he suggests that the moral fabric of when it is okay to let a person go who is unable to autonomously maintain life can be roughly assessed by their probability of regaining consciousness. This makes a lot of sense, it obviously is not okay to murder someone who is simply sleeping, but if they have been unconscious for years and may never return it seems more justifiable to let them go.

But what does this have to do with mostly dead pigs? Well, if it is possible to return a brain from dead to inactive or partially active, it will become extremely important to understand what it means for a thing to have consciousness. Currently, complete lack of brain activity is classified as death, and it will likely remain that way, so if the science stops here there is not much more to discuss. But if it is possible to regain partial brain activity with the BrainEx method, the ethics of consciousness will quite literally become a matter of life and death.

Joseph Vukov (2018) When Does Consciousness Matter? Lessons From the Minimally Conscious State, AJOB Neuroscience, 9:1,5-15, DOI: 10.1080/21507740.2018.1428237

Simon Makin (2019) “Brain Restoration System Explores Hazy Territory between Being Dead or Alive,” Scientific American https://www.scientificamerican.com/article/brain-restoration-system-explores-hazy-territory-between-being-dead-or-alive/

Auditory Signals Translated to Speech

Auditory Signals Translated to Speech
In his article “Morphological and physiological development of auditory synapses”, Dr. Wei-Ming Yu observed the functions of auditory synapses throughout their development. The ribbon synapse is associated with fast, precise, and sustained signaling and the endbulb of Held is associated with precise timing for interaural sound localization (speech perception). In his presentation, “Genetic dissection of the Auditory Neural Circuits”, Dr. Yu took these observations further by drawing on their genetic origins. He found that the c-Maf transcription factor plays a role in the development of the firing properties of primary auditory neurons, especially during their differentiation. He discovered this in mice by using cell-type-specific gene knockout to remove the c-Maf gene and then used auditory brainstem response recordings which recalled electrical signals in the brain. He discovered that c-Maf mutants, or those lacking the gene, have high hearing impairments, leading to delayed auditory responses. This provides evidence that c-Maf is essential for the transmission of sound information to the central nervous system. Understanding how auditory synapses develop is important in order to recognize their roles in speech perception and formation.
Audition and speech are closely related in that the process of translating audition to coherent speech requires brain signals. When speech comes fluidly to many of us, it is easy to take the process for granted. Many people suffer from speech impediments due to injuries such as stroke as well as other neurodegenerative disorders like amyotrophic lateral sclerosis, or ALS. In an article from The New York Times, researchers are discovering ways to directly decode the brains signals into speech using a virtual prosthetic voice. The developing system uses motor commands to create speech that suits the individual’s actual speaking flow. Although the system had only been tested on people with normal speech, scientists decided to test its functionality on patients who had surgery for epilepsy. These patients, since they tend to not do well with medications, frequently prefer to have brain surgery done. Before doing so, doctors must locate the spot in the patient’s brain that serves as the origin for seizures by identifying electrical storms with electrodes placed in the brain. These electrodes are placed in locations of the brain that are responsible for auditory signaling as well as movement. Since this process can take a long time, studies are often conducted on the patients at the same time. Researchers kept track of the electrodes as they recorded the firing patterns from the motor cortex. They then correlated the patterns to the patients’ facial movements and translated them into speech. Researchers found that through decoding brain signaling associated with speech, they could make more natural sounding and accurate speech simulations. With future research, scientists hope to provide individuals with speech impairments a more natural and efficient way to communicate and interact with the world.
“Scientists Create Speech from Brain Signals” https://www.nytimes.com/2019/04/24/health/artificial-speech-brain-injury.html “Morphological and physiological development of auditory synapses” & “Genetic Dissections of the Auditory Neural Circuits”, Dr. Wei-Ming Yu

How to Still Do Well on Finals if you can't Sleep 8 Hours Every Night

        Circadian Rhythms exert a powerful, invisible force that coordinates the day-to-day activities of our body, and addition to our sleep cycle, these subconscious rhythms regulate everything from blood pressure and body temperature to stress and alertness. The body's internal clock functions by a timed molecular feedback loop in the Suprachismatic Nucleus, where Clock genes express Clock proteins, inhibiting the genes until the proteins are degraded, allowing more Clock proteins to be synthesized and so on. The whole process takes a little under 24 hours, and persists even in the absence of light cues. However, light plays a crucial role in synchronizing the clock, effectively aligning biological rhythms to the day/night cycle of the environment. The problem arises when the lights don't go out when the body expects them to -- whether it's jet lag, going out with friends, or staying up late studying for that final you need a really good grade on, a whole mess of things go wrong when we mess with our circadian rhythm.

       Dr. Cavanaugh's research on circadian disruption in fruit flies (Drosophila) revealed that exposing flies to long periods of circadian misalignment lead to a nearly 15% reduction in lifespan in both males and females. The advantage using Drosophila as an experimental model is the comprehensive genetic toolkit that scientists have developed for it over the last half a century. By using whole-body RNA-sequencing techniques, Dr. Cavanaugh was able to analyze the differences in gene expression between normal and circadian-misaligned flies, which revealed upregulation in genes involved in oxidative stress, immune response, and aging. It is no surprise that a genetically coordinated system like the suprachiasmatic circadian clock has harmful genetic effects when it becomes misaligned. The question then becomes how these effects play out in humans, and more importantly, how much sleep I can miss during finals before I endure lasting, permanent consequences to my health and my exam scores.

A 2017 Harvard study by Andrew Phillips et al. sought the answer to the latter, investigating how "irregular sleep/wake patterns are associated with poorer academic performance." By establishing a scale that measured how consistently 61 Harvard undergrads got their snooze on, the researchers were able to come up with a Sleep Regularity Index (SRI) that measured the likelihood of a student being awake/asleep at the same point of the day 24 hours apart. In other words, someone who went to bed and woke up at the same time every day would be at a 100, with lower scores indicating greater irregularity in sleep schedule. The researchers found a 1:1 correlation between SRI and GPA, with every point lower SRI correlating to a .01 drop in GPA. The gap between the most regular sleepers and the most irregular represented a .40 point gap, not overwhelming, but still significant. More interestingly, they found no significant correlation between the amount of sleep and GPA, rather it was the regularity of sleep onset that was the biggest predictor of GPA. However, this doesn't mean you should sleep 3 hours a night at the same time every night, but those who sleep naturally less are not at so great a disadvantage.

From this data, I surmise that I should adjust my approach to sleeping during this finals week. It is clear that sleep plays a big role in academic performance, but personally I have trouble falling asleep, so 8 hours a night is rarely feasible, and 6 is usually the norm. If, as the Harvard study claims, consistency is more important than quantity, then it is not the length of my sleep that matters as much as when I fall asleep. I suspect that the innate pattern circadian rhythm itself is not as important as preventing its disruption. As with studying and exercise, consistency is key.

Brain Restoration System

According to WedMD, brain death is defined as complete loss of function, which is different than a vegetative state. “The vegetative state is a clinical condition of complete unawareness of the self and the environment, accompanied by sleep-wake cycles, with either complete or partial preservation of hypothalamic and brainstem autonomic functions.” Complete loss of brain function can be caused by traumatic brain injury or even stroke. Professor Joseph Vukov presented a lecture on brain death. This lecture was based on understanding the definition of “death” and the benefits that can be used after the incident. Legally, a dead individual can be described as either irreversible cessation of circulatory and respiratory functions or irreversible cessation of all functions of the entire brain, including the brain stem.

According to US National Library of Medicine, the concepts and practices relating to death are influenced by our values and social practices. These definitions are what constitutes death but also questions of grieving, medical treatment, estate planning, organ donation, and a myriad of other legal and ethical issues. Dr. Vukov, explained that brain dead patients may look like they are breathing because of being attached to a ventilator. As an outsider, this may seem like the patient is still alive with medical equipment attached. Recovery from vegetative state is quite unlikely after 12 months and is rare in a non-traumatic injury. Case study presented by Dr. Vukov explained how a woman who was brain dead in a coma underwent puberty because of the medical equipment attached to her. The patient went through all hormonal change’s medical assistance. However, through the eyes of her family she was considered alive. Dr. Vukov explains that in order to fix this debate individuals must be aware of the terms legally. Understanding the concept of brain dead, and how certain organs can be used for organ donations. This is virtually a medical misunderstanding, because patients who are brain dead cannot function on their own such as breathing but may presumably look like they are. Today, this debate is still a rising issue. The article below talks about cell cultures and functionality of the brain after being death. However, there are many legal and medical issues with working dead objects. Both researchers describe how being educated in brain death can also be beneficial to others such as organ donations or other clinical work.

The article recognizes the cultivation of cell cultures to study the internal functionality of the brain after death. While utilizing a series of instruments to sustain and trick the brain into believing it is alive, the scientists at BrainEx have come up with a revolutionary method of digging into many things regarding the brain. This could propose the cures for various neurological disorders, diseases which attack the brain, etc. The only way to do so is to approach the brain and its activity before and during. Typically, case studies on Alzheimer’s and other diseases take place in the late stages of contracting it. The benefits reside on the ability to see where in the brain, proteins or other chemicals may attack. This tests ethic related motives and produces the issue on whether or not the brain is fully conscious during these procedures. However, there is no proof that there was any electrical activity justifying the brain being in a cognitive state. This may be possible due to the fact that there are neural activity blockers which may be hindering the brain’s ability to increase electrical activity. It is thought that this would maximize cellular recovery. Having an increased rate of electrical activity in the brain could potentially trigger neuron damage through excitotoxicity. These tests have currently been done on deceased pigs. Since this has worked, it is plausible to believe that utilizing this on a human with an active brain would work. This revolutionary marvel in the medical field is the key to solving so many issues faced in the world of neurological and pathological disorders. This research team contacted Institutional Animal Care and Use Committee at Yale, were told that the study “was not subject to animal welfare-protection guidelines. This is because the pigs were defined as already dead.” However, with more research the team would like to understand how long brains can be sustained this way. If the brains can be obtained for this long period then the team can change their direction to revive electrical function which would then, however, be in an ethical dilemma.

Farahany does question if “we can ever get EEG recovery?  What would be the limits and limitations if this could be tested on animals or humans. Such research can be first used in rodents by removing the chemicals that block electrical activity. Minimizing any risk of pain or distress would be appropriate, however the problem is that Farahany thinks of this as tissue research and it's no longer just clearly dead, but it’s just not alive either.

References

Rubin, R. (2014, January 03). What 'Brain-Dead' Means. Retrieved from

https://www.webmd.com/brain/news/20140103/brain-dead-faq#1

Medical Aspects of the Persistent Vegetative State | NEJM. (n.d.). Retrieved from

https://www.nejm.org/doi/full/10.1056/NEJM199405263302107

Makin, S. (2019, April 19). Brain Restoration System Explores Hazy Territory between

Being Dead or Alive. Retrieved from

https://www.scientificamerican.com/article/brain-restoration-system-explores-

hazy-territory-between-being-dead-or-alive/

Vukov, Joseph. Loyola University Chicago Neuroscience Seminar. 2 April. 2019,

Chicago, Loyola University Chicago.