Social Starvation: The Effect of COVID-19 on Our Brains

Within the first few months of the year 2019, every aspect of our world was flipped upside-down and unkindly accosted by the COVID-19 virus. Due to the grave risk of fatality due to the virus as well as the uncertainty that preceded its emergence, everyone was obligated to stay at home in order to reduce the risk of its spreading. These stay-at-home orders were soon implemented after learning of the fatal effects of the virus. This led to an eruption of sole reliance on digital communication not only for purposes of frivolous socialization but also for school and work. In this world that absolutely requires us to socialize in order to learn and make money, we suddenly simply could not, and reasonably so for the sake of protecting each other’s health. 

However, people are social animals; socialization is a fundamental need. Building strong, healthy relationships with others is imperative for our emotional and mental growth. Clearly, person-to-person interaction is how we can attain this; therefore, many of us were apprehensive of the effects that stay-at-home orders would have on our mental health. After all, we need socialization the same way that we need food. 

But do we truly need socialization in the same way that we need food? Psychologist Scott Barry Kaufman, in his article “Forced Social Isolation Causes Neural Craving Similar to Hunger,” said that if this is truly the case, “then its deprivation should show similar effects on the brain and behavior as the deprivation of other basic needs such as food and sleep.” Kaufman highlights research that shows that we indeed do. 

However, first we should explore how exactly desire for necessities such as food and socialization can affect our behavior in the first place. Dr. Wambura Fobbs recently gave a seminar on a Zoom call hosted by Loyola University Chicago’s Dr. Robert Morrison. There, she presented research completed in her lab wherein they are greatly interested in the implications that striatal dopamine has on obesity and binge-eating disorder. According to Dr. Fobbs, the biological and psychological influences of diet can be observed in the brain. In her lab, they observed mice’s intake of a high-fat diet (HFD) versus chow (bland, unpalatable food) and its effects on their weight. When given the option between HFD and chow, mice will choose HFD, which Dr. Fobbs would have highlighted to show how that choice’s effect causes mice to increasingly gain weight. Mice will choose the tastier food (HFD) to satisfy themselves; they will almost want the tastier food. 

Kaufman explains that when we want something, dopamine transmission increases in the brain reward circuit, which consists of the dopaminergic midbrain and striatum. For example, they are active in response to images of food shown to people who are hungry and images of drugs shown to people who are addicted. 

The author points to Rebecca Saxe et al.’s research in “The need to connect: Acute social isolation causes neural craving responses similar to hunger” wherein forty human adults spent 10 hours (from 9 A.M. to 7 P.M.) in isolation – no access to other humans to interact with, not even digitally. And similarly, participants fasted for 10 hours. Using fMRI, researchers found that there was similar midbrain activity in both those who fasted and those who were isolated: “Midbrain regions showed increased activation to food cues after fasting and to social cues after isolation; these responses were correlated with self-reported craving” (Saxe et al., 2020). (The self-reports made on craving should not be undermined, because the only way we can assess mental health is through self-report) . 

That being said, people’s concerns for mental health deterioration during stay-at-home orders should not be undermined either. The global pandemic has caused a mental health epidemic. As Kaufman and Saxe point out, we need socialization the way we need food, and there is evidence to show: we typically want the tastier option, whatever will satisfy our craving, and if people are presented with the opportunity to socialize, then they will get it. And perhaps this explains why people are collectively having a hard time following stay-at-home orders. The question always remains: How can we make everyone happy? 

References 

Fobbs, Wambura. (2021, December 7). Leveraging neural recording & behavior to better understand how diet impacts cognition [video file]. Retrieved from https://www.dropbox.com/sh/7dgpx2d6hnkj540/AABaeS1V3FrSn2MIb0-jsRyla/(12.07.21)%20-%20Fobbs?dl=0&preview=Fobbs_researchtalk.mp4&subfolder_nav_tracking=1. 

Kaufman, S. B. (2020, May 19). Forced Social Isolation Causes Neural Craving Similar to Hunger. Scientific American Blog Network. Retrieved December 16, 2021, from https://blogs.scientificamerican.com/beautiful-minds/forced-social-isolation-causes-neural-craving-similar-to-hunger/. 

Tomova, L., Wang, K. L., Thompson, T., Matthews, G. A., Takahashi, A., Tye, K. M., & Saxe, R. (2020). Acute social isolation evokes midbrain craving responses similar to hunger. https://doi.org/10.1101/2020.03.25.006643.      

Can Humans Smell Fear?

    Odors are able to connect people in a way other senses don’t. They evoke deep memories and are able to remind us of things we had not thought of in a long time. Odors . It is often joked that people can smell fear on other people but what if it was actually true? In a study done by Akerl et al., women wore under arm pads while they watched a horror movie. Afterwards, the women were asked to smell different pads and were able to identify which pads were worn during the fear inducing trials. The women, quite literally, were able to smell fear. This was once a trait scientists thought animals had and humans lacked. This study sought to disprove that in an interesting way. 

In an  article by Grella et al., it says, “We hypothesized that odor may shift the organization of salient or fearful memories such that when paired with an odor at the time of encoding, they are delayed in the de-contextualization process that occurs across time, and re-trieval may still rely on the HPC, where memories are imbued with contextually rich information, even at remote timepoints. (2021, 150) This is extremely interesting because it possibly shows the way in which the brain responds to odor and fear as a pair. This is also shown In another study done by Sarah Jessen, where infants showed a decreased neural response to fear after smelling their mother’s odor.

Works Cited

Ackerl K, Atzmueller M, Grammer K. The Scent of Fear. Neuro Endocrinol Lett. 2002 

Apr;23(2):79-84. PMID: 12011790.

Jessen, Sarah. Maternal odor reduces the neural response to fearful faces in human 

infants. Developmental Cognitive Neuroscience. Volume 45. 2020. 100858. 

https://doi.org/10.1016/j.dcn.2020.100858.

Grella, S.L., Fortin, A.H., McKissick, O.P., Leblanc, H., & Ramirez, S. (2020). Odor 

modulates the temporal dynamics of fear memory consolidation. Learning & 

memory, 27 4, 150-163 .

Is it Possible to Smell Your Memories?

 Is it Possible to Smell Your Memories?

Throughout history we have seen the major discoveries and advancements that society has made in science. The topic that sticks out the most is when we dive into the topics of psychology and neuroscience. When we look at the past century, there have been so many new innovations and technologies in terms of studying the brain. We look back at how we analyzed and studied the brain versus the new methods that are completed today. As we learn more and more about the brain, we find deeper connection between the neural networks within the brain and find more about how they work with each other. As we look into Grella’s research, we see that smell and olfaction have a bigger role than we may have originally thought of. Although it is one of the more complex systems in the human body, Grella’s research “Smell Tests Could One Day Reveal Head Trauma and Neurodegenerative Disease” highlighted the importance smell has on memory. It showed the deeper connection that the hippocampus holds with the prefrontal cortex as we will continue to discuss.

In the article "Odor modulates the temporal dynamics of fear memory consolidation”, Grella et al. explains that specific odors can act as a cue to recall memories. Now we know that the hippocampus is the brain structure responsible for memory, but new information from her research shows much more than that. The sense of smell shows how it can be connected with memories and that smelling certain odors can elicit memory retrieval. When talk about retrieval and recall, we can see the difference between this and encoding/storage. Grella points out that although memory is encoded in the hippocampus, it is later stored in the prefrontal cortex. 

Research and previous studies have shown that memories could be associated with certain senses. When we eat something or when smell something distinct, we associate those senses with a certain memory because during that significant event that is stored in your memory, that same sense is stored along with that memory. This is why when we smell or see or taste that specific thing that was encoded with the memory, the memory is then recalled upon. This proves to have both positive and negative aspects. This proves to be a positive aspect when certain senses bring up fond memories of your childhood experiences or just good times in general. However, the opposite may be the case when we look at patients with PTSD. Eliciting a a certain smell or sight can trigger harsh or terrible memories that a patient might be trying to bury away.

It is very interesting to see how far these findings have come and to see what these new studies will take us. We have seen how much we’ve come in the past century, we can only imagine what we will discover in the new future. There is that much more technology to help us find new discoveries that much faster.

Works Cited

Akben, Cantürk, and Hamit Coskun. “Reintroduction of Odor Combined with Cognitive Stimulation Supports Creative Ideation via Memory Retrieval Mechanisms.” Creativity Research Journal, vol. 31, no. 3, July 2019, pp. 309–319. EBSCOhost, doi:10.1080/10400419.2019.1641686.

Engle, Jeremy. “What Smells Trigger Powerful Memories for You?” The New York Times, The New York Times, 24 Nov. 2020, https://www.nytimes.com/2020/11/24/learning/what-smells-trigger-powerful-memories-for-you.html?searchResultPosition=2.

Grella, Stephanie L., et al. “Odor Modulates the Temporal Dynamics of Fear Memory Consolidation.” Psychological and Brain Sciences, 2019, https://doi.org/10.1101/2019.12.19.881615.

Heck, Detlef H et al. “The rhythm of memory: how breathing shapes memory function.” Journal of neurophysiology vol. 122,2 (2019): 563-571. doi:10.1152/jn.00200.2019

Spinal Cord Contusion Research

             The National Spinal Cord Injury Association estimates that 450,000 Americans have a spinal cord injury (AANS). They have also reported that that just over half of this population is made up of young adult (16 to 30 years of age) males and the most common cause for young adult males and females is vehicular collisions (AANS).

One type of spinal cord injury is a spinal cord contusion (or bruise), that is, the crushing of the ventral nerve fibers to the extent that it is severed (Ju et al., 2014). Naturally, the body has evolved an immune response to spinal cord contusions or generally to insults to the CNS. Initially, hemostasis and inflammation occur, and reactive gliosis is triggered. Eventually, an astrocyte scar is formed around the site of injury, functioning as a barrier containing the spread of infection and inflammation-inducing molecules (which would otherwise damage healthy tissue). For the astrocyte scar to form, the proliferation and hypertrophy of astrocytes are triggered, which results in a high concentration of axon-regeneration-inhibiting molecules (Yu & He, 2006). So, the same mechanism that is meant to heal spinal cord contusions also inhibits it. The inhibition of axonal regeneration eventually results in the formation of a cavity in the car and the subsequent collapse of it (Li et al., 2020).

            Due to the body’s flawed response to focal CNS insults, it is not possible to fully heal from contusions to the spinal cord. In a study, Xiaowei Li et al. (2020) investigated a technology that could be used to promote axonal regeneration. The technology that was tested was a nano-hydrogel composite that was developed by Li and their team. The gel was designed to have two main components that distinguish it from previous iterations and allow to promote axonal regeneration; it was designed to have enough rigidity to prevent the collapse of the cavity and to also have sufficient porosity that allows for a microenvironment in which regeneration is possible (Li et al., 2020).

            In a different study, Yi Li et al. (2020) provided evidence that a spinal cord crush injury in mice could be healed without the formation of an astrocyte scar. In depleting the concentration of neonatal microglia in the injury site they found that axonal regeneration is inhibited. This lead them to discover that microglia have 2 crucial roles in the healing of a spinal cord contusion without the formation of an astrocyte scar: “…secrete fibronectin and its binding proteins to form bridges of extracellular matrix…” and “…express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation”(Li et al., 2020).

References

AANS. (n.d.). Spinal Cord Injury. AANS. Retrieved December 16, 2021, from https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Spinal-Cord-Injury

Ju, G., Wang, J., Wang, Y., & Zhao, X. (2014, April 15). Spinal Cord Contusion. Neural regeneration research. Retrieved December 16, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146247/

Li, X., Zhang, C., Haggerty, A. E., Yan, J., Lan, M., Seu, M., Yang, M., Marlow, M. M., Maldonado-Lasunción, I., Cho, B., Zhou, Z., Chen, L., Martin, R., Nitobe, Y., Yamane, K., You, H., Reddy, S., Quan, D.-P., Oudega, M., & Mao, H.-Q. (2020). The effect of a nanofiber-hydrogel composite on Neural Tissue Repair and regeneration in the contused spinal cord. Biomaterials, 245, 119978. https://doi.org/10.1016/j.biomaterials.2020.119978

Li, Y., He, X., Kawaguchi, R., Zhang, Y., Wang, Q., Monavarfeshani, A., Yang, Z., Chen, B., Shi, Z., Meng, H., Zhou, S., Zhu, J., Jacobi, A., Swarup, V., Popovich, P. G., Geschwind, D. H., & He, Z. (2020). Microglia-organized scar-free spinal cord repair in neonatal mice. Nature, 587(7835), 613–618. https://doi.org/10.1038/s41586-020-2795-6

Yiu, G., & He, Z. (2006). GLIAL inhibition of CNS axon regeneration. Nature Reviews Neuroscience, 7(8), 617–627. https://doi.org/10.1038/nrn1956

 

Memory Traces & Emotion-Induced Trade-Offs in Patients with PTSD

 

        The ultimate true prevalence of psychiatric disorders across the globe remains to be a topic that isn’t to this day fully understood to the same level as other health conditions. The realm of psychiatric health disorders is viewed as a separate and what we know today regarding such topics are not fully representative of their associations to the body themselves. In other words, there is a more complex interconnection between the methods that approach the studies of human health conditions and the insights and what researchers already know about psychiatric disorders. Although extensive research hasn’t been conducted to study all the relationships and how to ultimately alter such disorders to be of benefit to individuals, there has been some remarkable beginning findings. One such study done by Grella et al. examine the stability and flexibility of memories and specifically studied how neuro modulators and dysregulation of systems can lead to maladaptive cognitive and behavioral states. She touches base on how negative memory changes can occur for individuals with PTSD. Many people may have the question as to what the voluntary retrieval aspect of emotional experiences for PTSD are as PTSD seems to rely heavily on involuntary retrieval aspects. In other words, one might ask themselves how exactly do these changes in memory relate to the voluntary aspect as one would assume that it is all involuntary and that is why PTSD happens in the first place. This was further researched in a study done by Steinmetz et al. in which it was studied what the different effects PTSD had on memory for emotional information in specific that in not in any way related to trauma. So, both these studies, further develop way in which to understand how memory is impacted significantly in terms of PTSD and its limitations as to what it doesn’t change to use it in ways that can ultimately help individuals who are experiencing these psychiatric disorders. There is much research to still be done regarding all of this, as it is hard to tell the full impact of what little findings we have to impact these patients dramatically. However, there is some different types of research that has been done that give insight to this information that can lead to further directions with future studies to advance further in these topics.

               In a recent study, “The stability and flexibility of memory traces in psychiatric disease-like states” Grella et al. had given a talk that discussed a bit of her research that she has done. She started off by discussing how memory updating serves an adaptive role at time in ensuring that the most relevant information is accessible in memory and that ultimately tells us that memory is malleable. In other words, memory is always in the work of construction, deconstruction, encoding, or reconsolidation. She touches base on how the pathway that goes from the locus coeruleus to the hippocampus may have a circuit that is important for memory updating and remapping contextual representations. Grella et al. had used a cellular compartmental analysis of temporal in situ hybridization (catfish) to further study the phasic LC activation that drives memory updating. She goes into detail about the phenomenon of being at two places at once that comes from the hippocampus resetting in a way that makes them in a different place which is mediated by norepinephrine. When the system has a high amount or an overactive of the LC, that may lead to cognitive inflexibility but in certain cases where dysregulation is involved, the high tonic signaling eventually reduces the signal to noise ratio. She relates this specific finding to patients who have PTSD who bring up old trauma related representations and memories but have this memory updating impairment where their brain is not able to functionally remap to incorporate safety signals into their life. She talked about the animal models of stress which one of the most common is the foot shock that is used to study PTSD. Using viral technology, more specifically the Tet Tag system where the mice get a virus injection which allows for the cells to be transduced and for genetic material to eventually enter the nucleus. This is because the tTa part of the injection binds to the TRE. The researchers don’t want that binding to happen because they want to tag only one specific memory the animal has experienced. So, an inducible that is named DOX was put into their food and so only those specific memories and those cells associated to them is activated. Now, the aim of one of the experiments that Grella ran was to make negative memories less negative by mediating positive memories which serves as a kind of artificially induced recall. Additionally, they want to see would those effects last even during spontaneous recovery of fear. Results showed that artificial reactivation of hippocampal-mediated positive memories during fear memory reconsolidation does in fact reduce fear enduringly. The conclusions of her study included that hippocampal cells that were active during the encoding of a positive experience are sufficient to interfere with the expression of a fear memory. In addition, the effects seem to be specific to the memory undergoing reconsolidation and appear to also be long-lasting. So, in these ways the original fear memory was altered. These animals were expecting something bad to happen to them and in this case was a foot shock. So, either a foot shock was given which ultimately gave a zero-prediction error. Or, something that fell upon the valence where a positive thing occurred that correlated with the magnitude of the positive prediction error and the decrease freezing of the mice that were observed.

               In the research done by Grella et al., it only touched based on the memory changes that occurred in patients with PTSD and didn’t really talk about and control participants. This was incorporated in the study done by Steinmetz el al. in which a trauma-exposed control group that didn’t have PTSD was involved so there could be comparisons that could be made. The researchers in this study tried to find the effect of PTSD on memory for emotional information that is not in any way related to the trauma. PTSD is currently only defined by the cognitive changes that take place in the involuntary memory following a traumatic incident. We already know that there is not much of information about the voluntary retrieval aspect of emotional experiences, and this is what the researchers wanted to study more of. To do this, researchers had participants that were separated into three different groups which consisted of participants either currently having PTSD, experiencing trauma but did not have any current diagnosis of PTSD, or had neither or. These individuals were then shown visual scenes in which they included an item that was either positive, negative, or neutral on a neutral background and then around forty-five minutes later, they had to do a recognition memory test for the items and backgrounds separately. When there seemed to be a big difference in the item and background memory for emotional scenes, there seemed to be an emotion-induced memory trade-off. One of the main findings out of all of this was that individuals who have PTSD were more likely to remember positive and negative items rather than neutral. One of the main things that this study included that is not often considered is looking at individuals with trauma-exposed control group that don’t have PTSD to show the differences in both the emotional and cognitive processing that takes place. So, in other words in delved into the realm of how extreme or repeated stress without PTSD alone can cause certain changes in memory. Overall, participants with PTSD did have a larger memory trade-off when compared to trauma-exposed controls and this was because of the item-background difference between both the emotional and neutral items that caused this decrease for the trauma-exposed controls. This all shows that the emotional memory trade-off at least may be explained by the experience of trauma and the presence of PTSD. Grella had ended her talk with some future aims and one was to see develop novel memory modulation strategies that target these circuits to alleviate some of the dysregulations and to ultimately restore cognitive abilities. Using this aim and the research she had found that were presented from her talk, this research of memory trade-off can be studied further with in terms of its circuits in comparison to the control group that can lead to later on a unifying concept of psychiatric disorder to help individuals effectively.

References:

Grella, Stephanie. (2021, November). The stability and flexibility of memory traces in psychiatric disease-like states. Talk presented at Loyola University Chicago, Chicago, IL.

Mickley Steinmetz, K. R., Scott, L. A., Smith, D., & Kensinger, E. A. (1AD, January 1). The effects of trauma exposure and posttraumatic stress disorder (PTSD) on the emotion-induced memory trade-off. Frontiers. Retrieved December 16, 2021, from https://www.frontiersin.org/articles/10.3389/fnint.2012.00034/full

The evolutionary sense of olfaction and its role in strengthening fear memories

            Previous research on olfaction has established it as an ancient evolutionary sense but has still yet to determine the extent to which it can influence human behavior. In the article “An Evolutionarily Threat-Relevant Odor Strengthens Human Fear Memory”, researchers Taylor et al. investigated whether threat-related predator odors would contextually enhance the formation of human fear memory associations. Notably, the authors made a distinction between odor acting as a powerful cue for triggering recall of fear memories vs. the ability of odor to act as contextual modulators of fear memory formation. Another key difference was that many other studies exposed the experimental animals to odors at the same time as fear memory formation which establishes odors as direct cues for the learned associations. However, in this study the researchers sought to set odor as a simple background context to investigate how odors may actually affect fear learning. In the study, Taylor et al. found that participants who learned to associate the visual stimuli with the electric shock given the predator odor context eventually showed stronger fear responses to the same visual stimuli compared to the participants who learned these associations in an aversiveness-matched control odor context. Even after extinction training, this effect generalized to testing in other odor contexts. The authors also noted a separate secondary experiment that indicated a “​​possible biological mechanism for this effect may be increased cortisol levels in a predator odor context” (Taylor et al., 2020). This suggests that the innate olfactory processes do play an important role in human fear learning. Applications of the research can be extended to partly explaining the maladaptive persistence of human fear memory, like for example, in post-traumatic stress disorders.

            This contemporary article’s findings relate to another research study on the same topic presented in class. In the article “Odor modulates the temporal dynamics of fear memory consolidation”, researchers Grella et al., sought to determine how odor is a particularly evocative cue for intense remote memory recall. The authors also considered instances such as post-traumatic stress disorders where there is intense remote memory recall which can occur even years after trauma. Here, the authors hypothesized that “odor may shift the organization of salient or fearful memories such that when paired with an odor at the time of encoding, they are delayed in the de-contextualization process that occurs across time, and retrieval may still rely on the HPC, where memories are imbued with contextually rich information, even at remote time points” (Grella et al., 2021). Their results demonstrated that odor did indeed shift the organization of fear memories at the systems level.

References

Grella, Stephanie L., et al. “Odor Modulates the Temporal Dynamics of Fear Memory Consolidation.”      

Learning & Memory, Cold Spring Harbor Lab, 1 Jan. 1970, http://learnmem.cshlp.org/content/27/4/150.full. 

Taylor, Jessica E., et al. “An Evolutionarily Threat-Relevant Odor Strengthens Human Fear Memory.” Frontiers, Frontiers, 1 Jan. 1AD, https://www.frontiersin.org/articles/10.3389/fnins.2020.00255/full. 

How We Decide What We Decide

How We Decide What We Decide

    We make decisions thousands of times a day. Most of the time, we never stop to wonder how we came to this decision, what influences our decision-making, or where the decision is actually being processed within our brains. Many scientific studies have researched where in the brain there is activation when a decision is being made or thought about. These findings have greatly revealed answers to actions in the brain that affect the majority of everyone’s day.

There are different types of decisions that can be made. One of those types of decisions is a value decision. A value decision takes information about the choices available and quantifies which option would provide the maximum positive outcome. Different styles of decision making has the potential to be coded in the brain using different processes or even different parts of the brain entirely. A group of researchers in San Diego looked into this area of neuroscience, to better understand this specific type of decision making and what areas of the brain are associated with this process.  Reinforcement learning is the behavior that was used to optimize the value decision making in mice and the corresponding brain activity linked to those tasks were recorded and analyzed by the researchers. 

The results of this study went on to be discovered as finding a large quantity of brain activity in the cerebrum but more specifically the retrosplenial cortex within the cerebrum. These findings create the inference that value information is stored and potentially coded in this area of the mouse’s brain, and can open the door to future studies that look into how brain injuries of this area affect value decision-making, or how the different areas involved in different types of decision making code and process information differently, and how that affects the outcomes of each type of decision making. Current research furthering these results, by the same researchers is working to shift the findings into compatible AI programs to detect patterns of processing networks and codes.

Thorsten Kant and Fang Wang similarly studied decision-making, but more specifically inference-based decision-making. While this is a different type of decision making than what the Hattori and Komiyama study analyzed, understanding multiple types of decision-making allows for the differences and understanding of all types of decision-making in the brain. This study again took a specific type of decision making and optimized it into a recordable behavior that is associated with activating brain activity. The results of this study pointed towards a different area of the brain working to process and code decision-making when it is inference-based. The orbitofrontal cortex (OFC) lit up with activity when intentional behaviors produce these types of decision making ideas in a participant’s head. These results led to inferences that the OFC is central across many species in the process of coding inference-based decision making.

If future research continues following the paths of all forms of decision-making, soon it could be known why the brain has created such specific paths for each form and how each pathway is best fit for decision-making. The understanding of how other species' brains conduct these behaviors also can lead us to better understand the human brian and how similar or dissimilar it is to other species typically studied in neuroscience. Once we can pinpoint individual directions of decision-making pathways, focus can shift to how best to amplify those pathways when they are faced with obstacles, like mental illness, physical injury, or a cognitive disability. The opportunity to change lives by understanding our brain and why it works the way it does, is a motivation that hopefully future researchers keep deciding to pursue.

References:

Wang, F., & Kahnt, T. (2021). Neural circuits for inference-based decision-making. Current Opinion in Behavioral Sciences, 41, 10–14. https://doi.org/10.1016/j.cobeha.2021.02.004 

Hattori, R., & Komiyama, T. (2021). Context-dependent persistency as a coding mechanism for robust and widely distributed value coding. Neuron. https://doi.org/10.1016/j.neuron.2021.11.001 

Can TMR be an Effective Treatment for Reducing Pain for People with Post-Mastectomy Pain Syndrome

    Post-surgical pain can lead to phantom limb pain, residual limb pain, or even Post-mastectomy pain syndrome (PMPS). PMPS can be defined as chronic pain that persists after breast surgery in the post-surgical area and area surrounding it. Typically after breast surgery, patients may experience PMPS. Patients expressing Post-mastectomy pain syndrome typically show effects after procedures such as mastectomy and reduction mammoplasty. People suffering from PMPS tend to be diagnosed infrequently and have limited treatment options including, opioid medications which tend to be ineffective. In, "Trigger point injection for post-mastectomy pain: a simple intervention with high rate of long-term relief," Khoury et al. analyzed the effects of trigger point injections in individuals experiencing PMPS that underwent either a mastectomy or mammoplasty with/or without reconstruction. Previous research has been shown linking PMPS after breast surgeries to the formation of neuromas, specifically in the T4 and T5 cutaneous intercostal nerve branches. A neuroma can cause chronic pain and is the blunt and benign end of damaged nerve tissue. These researchers wanted to use injections of bupivacaine and dexamethasone to reduce pain in people with PMPS. The chest wall contains the T4 and T5 intercostal nerve branches where it is common for people with PMPS to experience pain in this region. These researchers predicted that trigger points, or focal points of the radiating pain, can be located through clinicals and can be used for injections sites to help relieve pain. In the article, "Targeted Muscle Reinnervation Treats Neuroma and Phantom Pain in Major Limb Amputees" by Dumanian et al. they studied how the Targeted Muscle Reinnervation (TMR) technique can reduce pain in people with phantom limb pain and residual limb pain. Treatment for these types of pain includes nerve ablations and neurotoxin injections which have been ineffective in some cases. TMR allows surgeons to remove neuromas and connect the residual nerve to an adjacent motor neuron. The TMR technique was originally made for TMR prosthesis control, but studies have shown it to be effective for postamputation pain. TMR could be a potential treatment to reduce pain in people with PMPS that underwent a mastectomy or reduction mammoplasty.

    In the study done by Dumanian and his colleagues, twenty-eight amputee participants underwent a randomized clinical trial splitting the group up into participants that receive TMR and participants that receive standard neuroma surgery to analyze which technique is the most effective to treat phantom limb pain. Participants rated their pain on two pain scales including the NRS and PROMIS scale. MRI scans were completed on patients to record any potential complications after the operation. Through the researchers' results, TMR showed evidence for decreasing phantom limb pain (PLP) in participants. There was also evidence showing a positive trend for participants that underwent TMR with residual limb pain compared to those who had standard neuroma surgery. The applications of TMR have been shown to improve PLP and can potentially be effective for PMPS. TMR being used to treat postamputation pain can lead to experimenting TMR as treatment for other chronic pain like PMPS that is associated with the formation of neuromas.

    The article, "Trigger point injection for post-mastectomy pain: a simple intervention with high rate of long-term relief," by Khoury et al. uses trigger point injections to help relieve pain in individuals with PMPS. These researchers had fifty-two women who underwent mammoplasty with or without reconstruction and mastectomy to participate in this experiment and proceeded to inject them with a combination mixture of bupivacaine and dexamethasone to reduce pain in individuals with PMPS. This combination of drugs has been known to help improve pain caused by neuromas. These researchers used trigger points to localize the point of injection. Khoury et al.'s results support that trigger point injections can lead to pain reduction in individuals with PMPS. Trigger point injection is a non-invasive technique that is safe and effective in treating PMPS. But this research is limited and without a long period of data collection researchers don't know how long pain reduction could last. Some people also require multiple injections to maintain pain regulation. TMR might be an effective one-time treatment to help manage and reduce pain in people with PMPS. Although TMR has been used to reduce PLP, it might potentially be useful for PMPS management.

    It is apparent in both studies that people suffering from chronic pain due to PMPS live uncomfortable lives. Khoury et al. research emphasizes the need for better treatment for PMPS and uses trigger injection points to help create a more effective treatment. This research is beneficial for people who underwent breast surgery and want a variety of treatment options to help with potential pain symptoms after their procedure. These injections have limitations including the need of multiple injections over a persistent time period and possible research may find results showing that this method might be proven to be ineffective after a person's immune system builds tolerance to the injection. The Dumanian et al. stud talks about how TMR could be effective in reducing PLP. TMR works to target neuromas that also play a factor in PMPS which might be beneficial for future studies as another treatment option for people with PMPS.

Works Cited

Dumanian GA, Potter BK, Mioton LM, Ko JH, Cheesborough JE, Souza JM, Ertl WJ, Tintle SM, Nanos GP, Valerio IL, Kuiken TA, Apkarian AV, Porter K, Jordan SW. Targeted Muscle Reinnervation Treats Neuroma and Phantom Pain in Major Limb Amputees: A Randomized Clinical Trial. Ann Surg. 2019 Aug;270(2):238-246. doi: 10.1097/SLA.0000000000003088. PMID: 30371518.

Khoury, A.L., Keane, H., Varghese, F. et al. Trigger point injection for post-mastectomy pain: a simple intervention with high rate of long-term relief. npj Breast Cancer 7, 123 (2021). https://doi.org/10.1038/s41523-021-00321-w

Hyaluronic Acid Hydrogel: The Future Key to Tissue Repair and Regeneration

Alexandra G. Brist

Dr. Robert Morrison

NEUR 300-001

15 December, 2021

Hyaluronic Acid Hydrogel: The Future Key to Tissue Repair and Regeneration

“The effect of a nanofiber-hydrogel composite on neural tissue repair and regeneration in the contused spinal cord,” a research paper penned by Li et al., focused on “an injectable nanofiber-hydrogel composite” that was investigated to learn whether it is capable of strengthening and potentially healing an “injury to the spinal cord [that] causes long-lasting loss of nervous tissue” (Li et al., 2020). Hyaluronic acid (HA) hydrogel, which was the hydrogel of focus in this study, was used in the place of a contused spinal cord segment by replacing the lumen of the injury that had previously collapsed. The damaged tissue either caused pain or a loss of feeling and functionality in the participants of the study. It was noted that HA hydrogel was utilized in this study because it is especially compatible with the spinal cord and surrounding tissue and is “naturally distributed throughout the central nervous system” (Li et al., 2020). 

This study in particular included the study of HA hydrogel in rats and it was noted early on that “none of the rats required treatment for pain or distress” (Li et al., 2020). It is clear that the researchers were keeping in mind the wellbeing of the animals and holding high ethical standards. Compared to control groups, the researchers revealed that the HA hydrogel succeeded in bettering the innervation within damaged spinal cord segments. Specifically, the researchers explained that improvements were seen “28 days after treatment” and any contused spinal cord segments that were studied had a “higher immature neuron presence” and were noticeably wider, larger, and denser. (Li et al., 2020). 

Some questions to be asked about this procedure, in general, revolve around the costs related to this new science and how safe it is expected to be for patients, especially in the long term. What will the out-of-pocket cost look like for patients, and how much will insurance cover? Will it be accessible to all patients that suffer from spinal cord or nearby tissue injuries? How might this procedure and potential risks change with human patients compared to this study that utilizes rats? With the ability to degrade easily, how long will the HA hydrogel last and improve loss of feeling or pain in these injuries? Will patients need to undergo routine procedures to maintain improved pain levels and feeling in these segments? Were any adverse or allergic reactions recorded in this experiment? How might the reactions differ in humans compared to rats?

It has been recorded that adverse reactions do occur in some patients that are given IV contrast injections including elements like iodine, a naturally-occurring halogen needed to make proper thyroid hormones and regulate the body’s metabolism. Iodine, like hyaluronic acid, is found in the body naturally. Patients that are unable to tolerate IV contrast are given substitutes if they need a CT scan or MRI. Should an adverse reaction occur with HA hydrogel, is there an alternative measure that can be taken or another hydrogel that has been closely studied enough that may be used in place of HA? Are patch tests and other allergy exams run before inserting HA hydrogel in the damaged sections of spinal cords and tissues of patients? If not, they should certainly be done so as not to cause extra complications throughout the procedure. The NIH reports research from Italy that states “delayed immune mediated adverse effects to hyaluronic acid” are not uncommon and can produce other “non-allergic, local side effects” like “slight edema, ecchymoses, hypercorrection, and bluish discoloration” and “other more serious long terms symptoms” like “tender granulomas, edema, and indurated nodules…suggesting an allergic mechanism” (Bitterman-Deutsch, 2015). As HA hydrogel continues to be used in various new procedures like bone and cartilage tissue engineering, maintaining robust procedures for keeping patients safe will be integral to the success of this work. 

In “The Application of Hyaluronic Acid-Based Hydrogels in Bone and Cartilage Tissue Engineering” authored by Li. et al. (a different Li than the original paper), a research team from China discusses the advantages and disadvantages of HA hydrogel usage and recent applications in medicine, specifically in the Department of Orthopedic Surgery in Changchun, China. The researchers reflect that overall, hyaluronic acid hydrogels “have many advantages, such as promoting cell adhesion and proliferation and wound healing” and “they also demonstrate sufficient biological activity for stimulating a microenvironment for cell survival” (Li. et al., 2019).  However, the disadvantages of using HA hydrogel include the requirement of “...further modification and…a poor degradation rate and insufficient mechanical performance” (Li et al., 2019). These disadvantages connect with the earlier notion that it may be worthwhile to experiment with other hydrogels that can be used in the place of HA that may require less alteration to be used in these experiments.

A major application of these HA-based hydrogels is that they can be used to help treat injuries due to cartilage tissue engineering (CTE) and bone tissue engineering (BTE) (Li et al., 2019). Due to disadvantages such as a “hydrophilic nature and lack of mechanical integrity, HA requires chemical modification and cross-linking to alter it for use in BTE and CTE applications”, potentially leading to greater costs for the procedure, extended preparatory time, and overconsumption of resources (Li et al., 2019). Despite these issues, HA hydrogel is preferred in these procedures because it allows for the most extensive, efficient “cell migration and proliferation” (Li et al., 2019). It is clear that the future holds a lot of promise for HA hydrogel in helping patients gain back feeling and lessen pain in contused spinal cord segments and injured tissues.

References 

Bitterman-Deutsch, O., Kogan, L., & Nasser, F. (2015, March 30). Delayed immune mediated adverse effects to hyaluronic acid fillers: Report of five cases and review of the literature. Dermatology reports. Retrieved December 16, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387334/.

Li, H. et al., (2019, December 20). The Application of Hyaluronic Acid-Based Hydrogels in Bone and Cartilage Tissue Engineering. Retrieved December 10, 2021, from https://www.hindawi.com/journals/amse/2019/3027303/.

Li, X. et al., (2020, March 16). The effect of a nanofiber-hydrogel composite on neural tissue repair and regeneration in the contused spinal cord. Retrieved December 10, 2021, from https://www.sciencedirect.com/science/article/pii/S0142961220302246?via=ihub.

Non-traditional Developing PTSD Treatments

 Post traumatic stress disorder is a mental health condition that is characterized by a dysfunctional norepinephrine (NE) system, which prohibits an individual's ability to successfully integrate new information to past traumatic memories. Common treatments that are currently offered for PTSD patients are: cognitive processing therapy, prolonged exposure therapy, eye movement desensitization and reprocessing, stress inoculation training, or pharmacological  options such as SSRIs and SNRIs. Patient feedback from previously mentioned modes of treatment have revealed that even after a patient undergoes psychotherapy their PTSD remains a chronic illness. Oftentimes when a patient experiences PTSD their symptoms may run comorbid with depression and other mental illnesses as well. Due to the fact that each patient’s neuroanatomy responds differently to medications, each case of PTSD is treated uniquely. Which prompts the need for further neuroscience and psychology research to develop novel approaches for PTSD treatments. A few non-traditional developments that are in the works is bilateral phasic activation of the locus coeruleus that resets spatial memories and the reviewal of psychedelic assisted psychotherapy. 

Within the recent publication of, “Locus Coeruleus Phasic, But Not Tonic, Activation Initiates Global Remapping in a Familiar Environment” conducted by Grella et al., researchers proposed a network reset and potential memory updating by unilateral glutamate locus coeruleus (LC) activation. The neural networks reviewed in this study were of lab rats that were conditioned to an open field in (Environment A). The rats momentarily returned to the colony for 20 minutes and were reintroduced to Environment A (A/A) or taken to Environment B (A/B). Before placement in the “B” environment, the rats were given clonidine infusions and produced the familiar “A” environment map in the dentate gyrus (DG). The immediate early gene (IEG) data collected for DG, CA1, and CA3 was reviewed within both groups of rats. The ipsilateral phasic activation paired with glutamate activated the LC and reset the familiar A/A spatial map in the DGS. Researchers then closely reviewed the pyramidal cells of CA1 and CA3, which revealed a bilateral phasic activation paired with glutamate activates the LC to generate a global reset. Researchers conclude that the LC episodic memory signal is underlined by a failure to switch between memory encoding and memory retrieval of new space maps in DGS, CA1, and CA3. These research findings reveal a deeper understanding of the mechanisms in PTSD and the development of future treatments that interfere a traumatic memory with a positive one, during memory reconsolidation in efforts to reduce fear. 

In a separate study by Krediet et al., “Reviewing the Potential of Psychedelics for the Treatment of PTSD,” researchers examined the redevelopment of psychedelics in psychotherapy. A population of PTSD patients can not tolerate the re-experience of traumatic memories during therapy, which causes high nonresponse rates and treatment dropout. The substance-assisted psychotherapy approach uses MDMA or ketamine as a means to catalyze psychotherapy. Substance-assisted psychotherapy reduces the fear response of anxiety-provoking trauma and increases a patient's interpersonal trust with their therapist. Ketamine possesses antidepressant properties and acts through the glutamatergic signaling pathway that was similarly previewed by Grella et al. The glutamate system is essential  in the reconsolidation of memory as well as the extinction of learning. When ketamine is administered at the beginning of a mindfulness-based cognitive therapy session in doses of 0.5 mg/kg over a period of 40 minutes, patients experienced enhanced levels of fear extinction. MDMA was also reviewed in this study and is capable of decreasing the overactive amygdala activity in PTSD patients. According to researchers, patients who experienced 2-3 sessions of MDMA-assisted psychotherapy with doses ranging from 75-125 mg show sustained reductions in PTSD symptoms in follow up non-drug psychotherapy sessions. These long-term treatment effects persisted over a 3.5-year period that demonstrated higher effect size and lower dropout rates than FDA approved treatments for paroxetine and sertraline. Concerns for neurotoxicity and abuse liability are curbed from the medically supervised component of substance-assisted psychotherapy. Although MDMA and ketamine hold promise for use within a substance-assisted psychotherapy framework, further clinical trials must be explored. One may also take note that monitored prescription of MDMA or ketamine in controlled dosages cannot be compared to excessive use from unknown sources. 

The preview of these two recent research studies conducted by Grella et al., and Krediet et al. demonstrate new non-traditional frameworks that deserve to be further explored for the future of PTSD treatments.  

Works Cited 

Grella, Stephanie L., et al. “Locus Coeruleus Phasic, But Not Tonic, Activation Initiates Global Remapping in a Familiar Environment.” The Journal of Neuroscience, vol. 39, no. 3, 2019, pp. 445-455, https://doi.org/10.1523/JNEUROSCI.1956-18.2018  

Krediet, Erwin, et al. “Reviewing the Potential of Psychedelics for the Treatment of PTSD.” The International Journal of Neuropsychopharmacology, vol. 23, no. 6, Oxford University Press, 2020, pp. 385–400, https://doi.org/10.1093/ijnp/pyaa018.

Treating PTSD with Virtual Reality coupled with Odor Emittance

 Treating PTSD with Virtual Reality coupled with Odor Emittance

Post-Traumatic Stress Disorder (PTSD) is a disorder that individuals can develop after experiencing dangerous, fearful, and life-changing events. Individuals can experience varying levels of PTSD and the effects can differ from one individual to another. Many studies attempt to identify and explain the long-lasting effects of PTSD and how it alters the physiology of the brain. Other studies are focused on finding ways to eliminate or reduce the effects of PTSD. These treatments may include Cognitive Processing Therapy (CPT), Prolonged Exposure Therapy (PE), medication, etc. (Bhandari, 2020). Researchers are actively proposing new treatments ideas that may be more accessible and reliable. Within the past few years, there have been recent studies that explore the topic of virtual reality (VR) and how sensory programming may support those with PTSD and aid in rehabilitation. VR works by targeting the visual and auditory senses to display a rendered reality within a headset. For the treatment of PTSD, VR can render past events that aid in modifying behaviors and emotions that can lead to better visualization of their traumatic events. With this more detailed understanding of their trauma, the individuals suffering can better communicate their trauma and receive the proper care.

The recounting of memories can be unpredictable and unreliable. It has been shown that odor assists in memory recall both negatively and positively. In the study, "Odor modulates the temporal dynamics of fear memory consolidation," (Grella et. al, 2020), researchers questioned the reasoning for why some memories, mainly those related to PTSD or fear, are less schematized and retain more detail. They hypothesized that odor was the cause and that odors can trigger the reorganization of fear-related memories during the encoding process. Researchers found that there is a correlation between odor and the re-organization of fear-related memories. This shows us that odor can trigger not only memories in general but can specifically target memories related to fear and PTSD events. In another study, it is shown that various odors can trigger positive memories that aid in the “decrease negative mood states, disrupt cravings, and reduce physiological indices of stress, including systemic markers of inflammation” (Herz, 2016). In Herz’s study, “The Role of Odor-Evoked Memory in Psychological and Physiological Health”, she compiles multiple different studies that show how “odors can be harnessed to induce emotional and physiological responses that can improve human health and wellbeing” (Herz, 2016).

In a study done by Mary P. Aiken and Mike J. Berry, they reviewed the effects that odor has on memory recollection and the sensory overtake that virtual reality can cause. The study is called “Posttraumatic stress disorder: possibilities for olfaction and virtual reality exposure therapy”, in this, they do not directly provide results for how VR can improve symptoms related to PTSD but rather speculates on an odor coupled therapy with VR. The study mentions the “role of sensory stimulation in VR has highlighted olfactory stimulation as a potentially powerful yet underutilized therapeutic tool”, suggesting the unidentified roles of olfactory stimulation. The study then provides an experimental design that shows the progression of virtual reality and odor stimulation as it relates to technology. Through these experiments and future studies, the role of modern technology such as virtual reality could be greatly beneficial in therapies. This is especially beneficial as it relates to PTSD and its long-lasting effects on psychological and physiological beings.

Works Cited

Aiken, Mary P., and Mike J. Berry. “Posttraumatic Stress Disorder: Possibilities for Olfaction and Virtual Reality Exposure Therapy - Virtual Reality.” SpringerLink, Springer London, 11 Feb. 2015, https://link.springer.com/article/10.1007/s10055-015-0260-x#citeas.

Grella, Stephanie L., et al. “Odor Modulates the Temporal Dynamics of Fear Memory Consolidation.” BioRxiv, Cold Spring Harbor Laboratory, 1 Jan. 2019, https://www.biorxiv.org/content/10.1101/2019.12.19.881615v1.full.

Herz, Rachel S. “The Role of Odor-Evoked Memory in Psychological and Physiological Health.” Brain sciences vol. 6,3 22. 19 Jul. 2016, doi:10.3390/brainsci6030022

“How Virtual Reality Therapy Impacts Veterans.” Bradley University Online, 5 Apr. 2019, https://onlinedegrees.bradley.edu/blog/how-virtual-reality-therapy-impacts-veterans-with-ptsd/.

“6 Common Treatments for PTSD (Post-Traumatic Stress Disorder).” Edited by Smitha Bhandari, WebMD, WebMD, 21 Jan. 2020, https://www.webmd.com/mental-health/what-are-treatments-for-posttraumatic-stress-disorder.