Multiple Sclerosis

 

According to the W.H.O. nearly 2.8 million people around the world are affected by Multiple Sclerosis (MS). MS is an autoimmune, neurodegenerative disease that attacks the Central Nervous System (CNS). The pathology for this disease involves demyelination, inflammation, and axonal damage and or loss, followed by a remyelination/repair state that does not return the axons to their original function. Oligodendrocytes are glial cells found within the CNS that myelinate the axons of neurons. Myelin sheath is crucial for quick and speedy signal propagation down the axon. Demyelination refers to the destruction of the myelin sheath, axon insulator, and the degradation of transduction signals, meaning cells are unable to communicate effectively. Alongside this destruction, cellular debris accumulates in the surrounding environment, often resulting in apoptosis on the adjacent cells. Inflammation occurs as a result of T cell and B cell infiltration into the CNS after the Blood Brain Barrier permeabilizes. As these cells begin to attack the myelin sheath, Oligodendrocytes are overstressed, again resulting in further apoptosis, and a reduced ability for remyelination within the brain and spinal cord. Macrophages are also important cells throughout MS progression, contributing to tissue damage and producing reactive oxygen species and chemokines. High levels of macrophages are related to large amounts of demyelination, as they are directly involved in axonal damage. This all leads to cognitive impairments, with common symptoms of patients with MS including, but not limited to walking and coordination impairments, tremor, ataxia, and sensory problems. Most therapeutic options currently for MS patients consist of immunosuppressive medications; usually through B-cell depletion. However, these methods do not stop the disease progression and leave the patient’s body essentially unable to defend itself against infections and viruses because of the immune compensatory behavior of these medications. It’s important for researchers to implore possible cytoprotective therapies for the CNS in order to combat this horrible disease.

In the article titled, “m6A mRNA methylation is essential for oligodendrocyte maturation and CNS myelination,” postdoctoral researcher Vaibhav Patel discusses the importance of N6-methyladenosine (m6A) on the progression of Oligodendrocyte precursor cells (OPc’s) to mature oligodendrocytes (OL’s). They looked at the effects of inactivating the Mettl14 gene, which plays a role in the m6A methyltransferase complex and has been shown, when disrupted, to decrease neurogenesis. They hypothesize these  negative effects may be due to a decrease in m6A. They discovered that through the conditional knockout of the Mettl14 gene, that in vivo “myelin abnormalities and altered oligodendrocyte numbers.” When they later looked at in vitro, OPCs lacking Mettl14 did not properly differentiate into mature oligodendrocytes. Along with the effects the Mettl14 gene deletion had on m6a, they also discovered that, NF155, which is critical to the formation of a paranode, the myelin that surrounds the node, is differentially spliced and disrupted during myelination. Because of this, it’s hypothesized that epigenetic regulation of Mettl14 may be helpful in understanding more about the progression of MS. 

Because of this paper, and similar papers, research into possible gene’s important to myelination have been looked at in the terms of MS. The article titled, “A gene regulatory network approach harmonizes genetic and epigenetic signals and reveals repurposable drug candidates for multiple sclerosis,” looks to implore the genetic risk factors and possible genetic upregulation in MS. Specifically, this paper explores the interplay between genetic risk factors and epigenetic regulation in multiple sclerosis (MS). Using a network model, it integrates GWAS data, DNA methylation profiles, and the human interactome to reconstruct an MS-associated gene regulatory network (GRN). Key findings include GWAS-mQTL colocalizations and enriched cell-type-specific signals in T follicular helper cells. The study identifies potential drug candidates, such as vorinostat and sivelestat, for MS treatment. Like stated before, it’s important to learn more about the disease; whatever front that may be, in order to hypothesize treatment options or further topics to research, something both of these papers seemed to play off of. Genetic regulation has been a key at looking at these demyelinating disorders, whether it be through regulation of transcription factors, or pharmacological activation somewhere in the pathway, this paper, I know, will open doors to further research down the route. 

References.  

World Health Organization. “Multiple Sclerosis.” Www.who.int, World Health Organization, 2023, www.who.int/news-room/fact-sheets/detail/multiple-sclerosis. 

Manuel, Astrid M et al. “A gene regulatory network approach harmonizes genetic and epigenetic signals and reveals repurposable drug candidates for multiple sclerosis.” Human molecular genetics vol. 32,6 (2023): 998-1009. doi:10.1093/hmg/ddac265 

Xu, Huan et al. “m6A mRNA Methylation Is Essential for Oligodendrocyte Maturation and CNS Myelination.” Neuronvol. 105,2 (2020): 293-309.e5. doi:10.1016/j.neuron.2019.12.013

Working Memory and ADHD

    Working memory is short-term memory with instantaneous processing of day-to-day life moments. Because working memory is constantly being updated, it is important to understand how the brain focuses on crucial information and extricates it from irrelevant distractors. Previous research on working memory tends to view it as a single process in the brain. However, Dr.Vogel and his team conducted a research study where they hypothesized that visual working memory has several components that work together to ensure that task-irrelevant distractors aren’t processed into ongoing WM (working memory) representations while task-relevant distractors are. Attention Deficit Hyperactivity Disorder (ADHD) is characterized by inattention and executive dysfunction. According to the article, Your Brain’s GPS Is Glitchy: Why Working Memory Fails and How to Bolster It, recent research has shown that ADHD has strong ties with weak working memory allowing lots of distractors to slip in.

    In Dr.Vogel’s research, the team proposed a complex model of attentional capture for visual working memory consisting of two subcomponents: spatial capture and item-based capture. According to the model, spatial capture refers to a shift in attention to the location of the stimuli. Item-based capture refers to the formation of specific representations of the item in ongoing WM. Using EEG markers such as contralateral delay activity (CDA), distractor positivity (PD), and N2pc, the researchers determined which task distractors were processed into working memory based on their relevancy. As per the results, all incoming stimuli, regardless of relevance, were processed in spatial capture. However, only relevant stimuli were processed in item-based capture as seen by CDA activity and N2pc signals. Irrelevant stimuli triggered suppression mechanisms indicated by the presence of PD signals. The findings showed that visual working memory has an automatic component (spatial attention) and a voluntary component (item-based capture) that work together to ensure that working memory is useful in daily tasks.

    In the article on ADHD, the author discusses how executive functioning, which guides our purposeful efforts in day-to-day life, is often taxing for people with ADHD due to its reliance on working memory. This is because the strength of working memory determines how fast our brains can modify their actions, so the stronger the working memory, the easier it is to conduct intentional tasks. An analogy for working memory is a GPS. When our brain starts a new task, it often refers to its maps (the sensory information stored in working memory), to help form an understanding of the situation. Then, the visual images of non-verbal working memory are combined with verbal working memory as guidance and form our updated interpretation of the task. Like our GPS systems, it is important to process the relevance of information as it is presented to us to alter our plans and achieve maximum results. For those with ADHD, their brains are over-processing machines that cannot distinguish the relevance of the new information or determine what to do with it because too much information is presented all at once.

    Because ADHD is characterized by problems in working memory, it is beneficial to understand Dr.Vogel’s study and discuss its implications for ADHD research. Since Dr.Vogel’s team found two components to the working memory model, potential research studies can try to dissect which component is impaired in those with ADHD. Since an ADHD brain is characterized by overactivity and countless distractors, it can be hypothesized that a potential issue lies within the item-based capture of attentional control, known as the gating mechanism, which determines what distractors are allowed into the ongoing WM representation.

    In conclusion, studying and creating advanced models of working memory can be useful for ADHD research because those models can be used to understand the underlying mechanisms of ADHD.

References: 

 Alexander, Steph. “Your Brain’s GPS Is Glitchy: Why Working Memory Fails and How to Bolster It.” ADDitude, ADDitude, 14 Oct. 2024, www.additudemag.com/working-memory-powers-executive-function/.

The Effects of Prenatal Stressors and Predisposition of Schizophrenia

            The argument between social determination and individual autonomy is highly debated in reference to neuropsychological disorders. Decades worth of literature have elucidated that the deficits in structural development responsible for these diseases are prone to environmental influence. That begs the question, are these malformations dependent solely on the infant's environment during child rearing, or could these changes be initiated prior to parturition? What role does their prenatal environment play in the infant's neurostructural development, and subsequently their susceptibility to neural diseases? Dr. Monsheel Sodhi addresses this question in co-authored research exploring how maternal restrictive stress caused a deficit of hippocampal RNA editing. These functional changes resulted in lower signs of behavioral interest among rats, suggesting that prenatal stress contributes to the reduced social interaction of offspring (Bristow et.al, 2021). Prenatal stress may take many forms, in this case, it is the physical entrapment of a pregnant dam within a restrictive space resulting in psychological distress. However, prenatal stress may also stem from intentional biological stressors induced by one’s actions, such as smoking. A 2018 meta-analysis reviewed comparative observational studies with the aim of finding the effects of prenatal maternal tobacco ingestion and to their surprise, “exposure to prenatal smoke increased the risk of schizophrenia by 29%” (Hunter, et.al, 2018). This expansion of research surrounding prenatal stress’s effect on the development of schizophrenia and similar neurophysiological diagnoses is essential for understanding and identifying the structural targets for novel psychopharmacological interventions. 

Dr. Sodhi participated in research investigating the impact of stress on the glutamate system and RNA editing, with the aim of developing a drug targeting the negative symptoms of schizophrenia. In her presentation, she discussed how reduced social withdrawal is associated with glutamatergic systems. Glutamate transmission exhibits a parabolic relationship with cognition and mental abilities, meaning that both reduced and increased activity can damage the neural circuitry. She explained that prenatal stress might lead to deficits in RNA editing which is crucial for the transcription of adenosine deaminase enzymes. These proteins are responsible for purine metabolism, and further down the pathway, the functionality of the glutamatergic AMPA receptor. They conducted experiments measuring the RNA editing of 40 gene targets. After being subjected to prenatal stress, the mutant mice had increased social interaction compared to the wild-type cohort, showing similar behavior as the non-stressed mice. Additionally, mutant male mice had greater synaptic maturation, all of which demonstrate prospective targets for future psychopharmaceuticals. 

Dr. Sodhi's research is centered around the effects of prenatal stress, and while this provides a well-structured understanding of the neurodevelopmental symptoms resulting from restrictive stress, a more comparable example is examined through Hunter et.al.’s Meta-analysis of prenatal tobacco exposure’s risk to the development of schizophrenia. Prenatal exposure to tobacco and nicotine has long-term consequences on neuronal functionality. Once maternally ingested, these substances can cross the placenta and bind to nicotinic acetylcholine receptors in the developing fetal brain. This can lead to reduced functionality of the postnatal dopaminergic system, a symptom strongly correlated with schizophrenia (Stathopoulou, et.al., 2013). Additionally, there is a likelihood of prenatal stress responses in the fetus, as evidenced by analysis of the altered hormone levels in cord blood. This could possibly exacerbate the dysfunctionality of the glutamatergic system, as explained by Dr. Sodhi's research. These effects could partially contribute to the fetus's risk of schizophrenia. As explained in Hunter et.al.’s Meta-analysis, exposure to prenatal smoke increases the risk of schizophrenia, as compared to participants without exposure (Hunter et.al, 2018). 

These disruptions, from both restrictive prenatal stress and prenatal exposure to tobacco and nicotine, can lead to impaired synaptic plasticity in various neurotransmitter systems, such as the glutamatergic and dopaminergic pathways, respectively. It is important to understand the mechanisms behind these two processes so that psychopharmaceuticals can be developed targeting the protein products deficient in these systems. However, further research does need to be accomplished, specifically centered around clarifying the dose-response relationship between the level of prenatal exposure to tobacco or restrictive stress and the chance of schizophrenia. These findings can then work in a concerted manner, with the information being used to inform public health interventions directed toward reducing exposure to these stressors. 

References

Stathopoulou, A., Beratis, I. N., & Beratis, S. (2013). Prenatal tobacco smoke exposure, risk of schizophrenia, and severity of positive/negative symptoms. Schizophrenia Research, 148(1-3), 105–110.

Harte, E. N., et al. (2021). Prenatal Restraint Stress Alters Hippocampal RNA Editing and Social Interaction Behavior in Adult Offspring: Reversal by Clozapine. bioRxiv.

Hunter, A., Murray, R., Asher, L., & Leonardi-Bee, J. (2020). The Effects of Tobacco Smoking, and Prenatal Tobacco Smoke Exposure, on Risk of Schizophrenia: A Systematic Review and Meta-Analysis. Nicotine & Tobacco Research, 22(1), 3–10.

Understanding the Breathing Circuit

 

    Breathing is an essential mechanism of life, a rhythm that sustains life and it is often unnoticed until we pause to truly feel it, mindful breathing. Breathing is automatically regulated to maintain homeostasis but can also adapt to changes in the body such as behavior and emotional changes ensuring it aligns with the body’s specific needs (Seattle Children’s Hospital, n.d). Breathing rhythm generation is controlled by the preBötzinger complex, a neural network located in the brainstem, and understanding the neural circuits in breathing could serve as a model to understand other neural circuits in the body.

    The research article, Facing the challenge of mammalian neural microcircuits: taking a few breaths may help, Dr. Jordan J. Skach and colleagues describe the complex mechanism underlying respiratory rhythm generation in mammals that is controlled by the preBötzinger Complex found in the brainstem. Despite decades of research, the breathing mechanism is still not well understood. Although breathing seems like a simple well-defined behavior, conventional rhythm generation models such as those involved in pacemakers, inhibition, or bursting are problematic and ignore consequential detail. Dr. Jordan J. Skach and colleagues argue that respiratory rhythm likely emerges from intricate and dynamic molecular, synaptic and neuronal interactions within a diverse neural microcircuit. This idea underlines the challenges in understanding neural control of mammalian behaviors and proposes that neural circuit governing breathing is inimitably accessible and could serve as a model for general strategies to understand other neural microcircuits.

    In the research article, PreBötzinger complex neurons drive respiratory modulation of blood pressure and heart rate, researchers examine how respiratory activity oscillates in phase with heart rate and blood pressure. The use of optogenetic inhibition and excitation as well as neuronal tracing in rats was used to demonstrate that the PreBötzinger complex neurons directly modulate cardiovascular activity. Inhibitory PreBötzinger complex neurons modulate parasympathetic activity which affects heart rate, and excitatory PreBötzinger complex neurons modulate sympathetic vasomotor neuron activity which affects blood pressure. This was found to generate heart rate and blood pressure oscillations in phase with respiration. Findings suggest that the PreBötzinger complex has a broader function in the regulation of these physiological processes. The study highlights the PreBötzinger complex role in cardiorespiratory interactions and its potential implications for cardiovascular diseases where respiratory synchrony of heart rate and blood pressure is disrupted.

    Both research studies highlight the PreBötzinger complex as a central neural hub for regulating physiological rhythms such as cardiovascular and breathing rhythms. Both studies explore the challenges of the PreBötzinger complex function and emphasize the complexity of the role it plays in respiratory rhythms and cardiovascular integration. These studies suggest that the PreBötzinger complex has is a complicated mechanism that could be further studied and serve as a model to understand other neural microcircuits, but when in doubt breathe in…breathe out.

 

Feldman, J. L., & Kam, K. (2014). Facing the challenge of mammalian neural microcircuits: Taking a few breaths may help. The Journal of Physiology, 593(1), 3–23. https://doi.org/10.1113/jphysiol.2014.277632

Menuet, C., Connelly, A. A., Bassi, J. K., Melo, M. R., Le, S., Kamar, J., Kumar, N. N., McDougall, S. J., McMullan, S., & Allen, A. M. (2020). PreBötzinger complex neurons drive respiratory modulation of blood pressure and heart rate. eLife, 9. https://doi.org/10.7554/elife.57288

Neural circuits, breathing, behavior and emotion - baertsch lab. Seattle Children’s Hospital. (n.d.). https://www.seattlechildrens.org/research/centers-programs/integrative-brain-research/our-labs/baertsch-lab/identifying-neural-circuits-breathing-emotion/

Ways to Confront Racism in Neuroscience

         Dr. Caitlyn Hudac stresses the importance of community-based neuroscience, and works to explore some of the ways that neuroscientists can better work to support the communities they study. In a 2022 study on the effects of concussions on frustration, Dr. Hudac describes adapting techniques for “typical” EEG nets for Black participants. This was done as Black people have been excluded from EEG studies due to claims that their hair will interfere with the EEG net. In her work, Dr. Hudac confronts this claim, through using traditional EEG nets with Black participants (taking careful note of the net placement, in case settling the net causes the electrodes to shift), and being able to find usable results. Through this research, not only is Dr. Hudac able to help correct a gap in the literature, but also she shows how machines that have been exclusionary can be adapted to be more inclusive.

Another publication that discusses the variety of ways neuroscience excludes Black participants is the article “Neuroscience has to grapple with a long history of racism if it wants to move into the future” by Dr. De-Shaine Murray. This article highlights the variety of ways systematic racism has affected the field of neuroscience, and some of the ways in which we can work together as a field in order to move forward. Dr. Murray discusses the way in which Black participants have been excluded from EEG studies, as well as the fact that fNIRS machines were not made for people with melanated skin, leading to confounding effects in the data. Additionally, Dr. Murray discusses some of the different ways in which systemic racism affects treatment outcomes in Black patients: differing treatment between Black and white autistic patients, higher rates of ALS, glioblastoma, Alzheimer’s and dementia, and stroke among Black populations. 

However, Dr. Murray discusses some of the ways in which we can confront systemic racism in neuroscience and work towards a brighter future. Dr. Murray co-founded the nonprofit group Black in Neuro in 2020 in order to confront some of these assumptions and support other Black researchers. Furthermore, Dr. Murray highlights some of the current statistics for Black professionals in neuroscience fields, and stresses the importance of further representation within the field. Both Dr. Murray and Dr. Hudac are able to help confront systemic issues within the field through spreading awareness and working in order to undo structural barriers. 

References: 

Hudac, C. M., Wallace, J. S., Ward, V. R., Friedman, N. R., Delfin, D., & Newman, S. D. (2022). Dynamic cognitive inhibition in the context of frustration: Increasing racial representation of adolescent athletes using mobile community-engaged EEG methods. Frontiers in Neurology, 13. https://doi.org/10.3389/fneur.2022.918075 

Murray, D.-S. (2023, November 28). Neuroscience has to grapple with a long legacy of racism if it wants to move into the future. STAT. https://www.statnews.com/2023/11/29/racism-in-neuroscience-brain-computer-interfaces-neurotechnology-research/ 

Comparing the "Why birds are smart" research paper to the "Gravity Gives These Birds the Drop on Tough-to-Crack Foods” news article

 The news article, “Gravity Gives These Birds the Drop on Tough-to-Crack Foods” by Priyanka Runwal, shows one way that birds use their brain in a cognitive way. How are birds able to eat foods with hard shells on them? Birds such as gulls, crows, and eagles use the benefits of hard surfaces like rocks and pavements to break their food into pieces with not as much effort as trying to break the seal with their beaks. This news article relates to the “Why birds are smart” by Onur Güntürkün, Roland Pusch, and Jonas Rose research paper that explains the intelligence in birds by comparing their brain structure and function to primates. This article focused on corvids and parrots, similar to Runwal in the sense that birds are capable of assessing the distance they need to be off the ground and type of surface that the food should be impacted by. Supported by gulls being able to assess the size of the clam to the distance that needs to be off the ground and type of ground surface (paved parking lot or mudflat) that would crack open the clam better. They also plan for the future by conserving energy by not having to fly a greater distance up, (I would think this is similar to humans walking on a windy day.) by throwing the heaviest clams closer to the paved parking lot. If they were to crack it open on the mudflat area, they would remain shut. They would need to go higher up for the clam to open. 

The research article “Why birds are smart”, they look into the intelligence capacity of birds. NCL (nidopallium caudolaterale) is a part of the avian brain that functions similarly to the PFC (prefrontal cortex) in mammals. The NCL is involved in working memory, aspects of cognition. Working memory in birds looks like the process of birds figuring out the distance to drop the object and what type of surface to drop it on. The research uses evidence to support their statement about brain size not having anything to do with knowledge but the number of associative pallial neurons having to do with birds' knowledge. Ravens, similarly to the birds talked about in Runwal’s article, plan for the future and remember what methods for cracking shells work and which methods don’t work. The memory stored in the hippocampus is supported by Runwal discussing birds not being able to crack shells when they are young and it is a skill that is learned from practice. Gulls when they are young peck at the clams, instead of dropping them. They learn as adults to drop the clams as it’s more fast and efficient than pecking at the clam. 

Güntürkün, O., Pusch, R., & Rose, J. (2024). Why birds are smart. Trends in Cognitive Sciences, 28(3), 197-209.

Runwal, P. (2020, February 12). Gravity Gives These Birds the Drop on Tough-to-Crack Foods. Audubon. https://www.audubon.org/news/gravity-gives-these-birds-drop-tough-crack-foods

A Comparison of Polarization in Social Groups and Social Media

 Within recent years the common habit of scrolling on one’s phone has become included in the American daily routine. Despite negative connotations that may hover over this habit of individuals interactions with social media do enhance knowledge of current events. Although the definition of current events is not limited and can vary from observing a sports team, stock market or simple life updates of those we socialize with. Despite the reasoning, social media does create an environment that helps aid in understanding what’s going on around us. In fact, this is one of the most intriguing segments of social media. Social media has been able to curate a said environment that is applicable to our own personal ideals, in other words the algorithm developed based off our own interaction with social media and technology. As referenced in The New York Times article, What if You Knew What You Were Missing on Social Media? “Most social media platforms algorithms use your behavior to narrow in on the posts you are shown”. The algorithms developed on our behalf grant guidance of the virality of content we consume through media as it factors in one’s interests and behavior. Therefore, depending on your behavior and interactions with social media that includes sharing, liking and clicking your algorithm will begin to predict preferences that will display content within your feed curated to your viewpoints and interests. How the algorithm creates this distinctive separation of what should be both included and excluded is like the categorization method observed in the article, Social groups and polarization of aesthetic values from symmetry and complexity. The premise of this study provides a focus on determining the preferences of individuals for visual aesthetics. Data collected on individuals being observed within the study is used to divide the individuals into islands, another way to specifically separate individuals based on visual aesthetic preferences. This study conducted its experiment by showing a set of images with varying intensities of symmetry and complexity, both aspects of visual aesthetics specifically being tested, and had the participant rank each photo from one to ten according to one’s likeability of each visual display.  Like how individuals were specifically isolated into islands, where membership was strictly dependent on the data per individual. Social media segregates individuals into their own islands, creating realms for those who have shared preferences. Have you ever seen someone you know like or comment on the same post or perhaps read the same article that showed on their feed. This may have been a result of the algorithm developing a feed based off data. When this separation occurs, the algorithm has then created what’s known as a filter bubble. Which is a means of the algorithm limiting an individual’s exposure due to its enhancement of including material adhering to the user's personal preferences. This strongly encourages polarization as it limits what a user may view, since the algorithm will keep excluding what does not relate to previous preferences and behavior. Yet, the difference between the two examples of distinction between both articles is that the individuals within the study were granted access to all of the information and visuals. While those who engage on social media platforms are limited to viewing the entirety of what is available for viewing, since the algorithm will exclude nearly anything that does not express similarities to previous interactions. This results in echo chambers, where individuals are only exposed to information that simply reinforces their current opinions, beliefs and interests. Due to this situation amplifying polarization it hones the concept of islands as found in the article pertaining to polarization of aesthetic values. 

Sources Referenced: https://www.nytimes.com/2023/08/17/opinion/social-media-algorithm-choice.html?searchResultPosition=5