Gut microbiome changes and potential treatments

This week's lead article, Changes in gut bacteria found to indicate a concussion; potential treatments, is in the Pathophysiology category.

In this newsletter: Opportunities, Cannabis & Psychedelics, Pathophysiology, Therapies Currently Available, Mental Health, Statistics, and Women’s Health.

This is the first newsletter of our Summer 2023 Concussion Education & Advocacy Internship! For the next six weeks, we will be publishing newsletters every week to give our undergraduate interns opportunities to practice accessible science writing.

We appreciate the Concussion Alliance interns and staff members who created this edition:
Writers: Kat Kresse, Alexander Rosmarino, Hannah Hartmann, Zoe Cronin, Ike Smalley, and Charley Draheim

Editors: Kira Kunzman, Conor Gormally, and Malayka Gormally

Do you find the Concussion Update helpful? If so, forward this to a friend and suggest they subscribe.

Opportunities

Thursday, June 29, 5 pm EST: Free webinar, Concussion Legacy Foundation Presents: New Research on CTE Risk & Prevention, presented by Dr. Dan Daneshvar and Dr. Samantha Register here.

Researchers at Massachusetts General Hospital and Harvard Medical School are offering a free program to help optimize recovery from a recent concussion.

Who can participate?

Ages 18-35 years old
Have a concussion from the previous 10 weeks
English fluency

What does it involve?

Participate in 4 virtual sessions (45 minutes each)
The sessions will take place from the comfort of your own home using secure live-video
Complete 3 sets of questionnaires online through secure link about your emotional functioning and concussion symptoms.

Participants can receive up to $90 for participating in the program and answering questionnaires.

No cost, no medication and no travel. Want to learn more? Email MGHConcussionToolkit@partners.org

Cannabis & Psychedelics

Psychedelics enhance neuroplasticity by activating 5-HT2AR receptors in the brain

A study published in Science explores how psychedelics enhance neuroplasticity and reorganize brain structures. Vargas et al. found that psychedelics, including LSD, MDMA, and psilocybin, remodel the brain and promote growth between neurons by activation of intracellular serotonin 2A receptors (more specifically termed 5-HT2AR receptors) in the cerebral cortex. In a press release by UC Davis Health, lead study author David Olson states that understanding the mechanism of action of 5-HT2AR receptors “gives us deeper mechanistic insight into how the receptor promotes plasticity and allows us to design better drugs” for depression, PTSD, and other neurological disorders. Understanding the role of intracellular activation of the 5-HT2AR by psychedelic drugs opens the door to potential treatments for mental health conditions which are often associated with concussion.

Using molecular and genetic tools, the authors found that the location of the receptor is critical. Engaging 5-HT2AR receptors inside neurons (also known as the intracellular receptors) promotes neuroplasticity, but engaging the same receptor on the surface of nerve cells has no effect on promoting growth. This study also found that though psychedelics can bind to these intracellular receptors, endogenous serotonin (serotonin created in the body) does not. Serotonin doesn't bind because it is polar, meaning the size and charge of the molecules make it too difficult to cross the cell membrane and access the receptors.

Although the study does not directly address traumatic brain injury, a concussion can worsen pre-existing mental health problems or create new mental health issues such as Depression and PTSD; see our Mental Health and PTSD resources.

Pathophysiology

Changes in gut bacteria found to indicate a concussion; potential treatments

A small pilot study published in Brain, Behavior, & Immunity - Health found that athletes experience a decrease in two types of helpful bacteria (Eubacterium rectale and Anaerostipes hadrus) in the gut after sustaining a concussion. Study authors also found that a reduced level of “Eubacterium rectale was associated with serum [blood] inflammatory biomarkers.” Because blood biomarkers degrade in the blood and are also eliminated by the liver and kidney, gut bacteria biomarkers may be a promising alternative diagnostic tool for concussion. Gut bacteria is also an area for researchers to explore to understand better what happens in the body when sustaining a brain injury.

Probiotic treatment may help manage gut microbiome stability. According to the study, “thinking about a post-concussion clinical treatment, novel preventive and therapeutic strategies, including nutritional diets, microbiota manipulations with probiotics or prebiotics, or strengthening the enteric barrier could be applied to modulate the intestinal microbiota and ultimately improve both cognitive and functional TBI health outcomes.” There is some precedence for this idea; for example, in a 2011 study, the bacteria Lactobacillus was given in supplement form to patients who suffered severe TBI, resulting in a shorter time spent in intensive care.

The study by Sirena Soriano et al. examined 33 American Football players throughout the 2019 season at three different times: mid-season, after the last game, and resting during the off-season in 2020. Four players experienced a concussion; additional samples were taken after their concussion. Sonia Villapol, Ph.D., a neuroscientist at Houston Methodist and lead author of the study, says, “The gut bacteria can be a good diagnostic tool for detecting both long-term and short-term inflammation, which may produce various symptoms such as depression, abdominal pain, and vomiting.” Villapol believes NCAA Division I football teams have the money to perform these microbiome analyses and serum analyses to diagnose when a player has inflammation.

Problems with the digestive system after concussion have been linked to the injury’s physiological effects, but researchers have been unsure as to why. Nausea and vomiting early after a concussion are symptoms recognized by the CDC, as is feeling sick to your stomach. Reduced appetite can occur early after the concussion, according to the Cleveland Clinic. These symptoms may have relevance to the connection known as the brain-gut axis, which connects the body’s central nervous system (related to the brain and spine) to the enteric nervous system (related to the gut). This link is bi-directional, and changes in mood, stress, and anxiety in the brain affect the body’s digestive system. Changes in the digestive system can influence emotions, energy, and stress levels within the brain.

During a concussion, the brain experiences significant increases in inflammation, throwing this connection off balance. “The gastrointestinal and metabolic disruptions that often accompany brain trauma can be explained by the bidirectional link between the central nervous system (CNS) and the enteric nervous system (e.g., the brain-gut axis).” As the brain tries to heal after a head injury, its effects from inflammation cascade down to the gut. Research has shown a strong correlation between gut changes and severe TBI, but less evidence exists with concussions. Studies on mice in the mid-2010s found evidence of gut bacteria changes in mice who sustained a concussion; however, this is the first study to find definitive proof of this phenomenon from a concussion in humans.

While changes in gut bacteria show promising signs of being a body biomarker for a brain injury, the researchers only looked at a small sample of male football athletes aged 18-23. In the future, tests must be conducted on those of different ages, backgrounds, and genders to become more conclusive.

Therapies Currently Available

Aerobic exercise as a possible treatment for persistent post-concussion symptoms

In a study published in BMC Neurology, researchers found sub-symptom threshold aerobic exercise (SSTAE) to be a safe and feasible intervention to include in a future randomized control trial (RCT) for reducing persistent post-concussion symptoms (PPCS) and exercise intolerance. There is a significant body of research on SSTAE interventions for concussion patients in the acute and sub-acute phases, but this is the first research we are aware of that plans to examine the effectiveness of SSTAE for persistent symptoms.

According to researchers, up to 46% of people who experience a mild traumatic brain injury (mTBI) will experience persistent post-concussion symptoms (PPCS) after their injury. These ongoing symptoms impact patients’ quality of life and include a variety of physical, emotional, and cognitive difficulties. Research has also found that limiting exercise for prolonged periods of time after mTBI may increase PPCS. The metabolic and physiological impacts of a concussion can lead to autonomic dysfunction and disruption to cerebral blood flow–resulting in a wide range of symptoms, including headaches, dizziness, anxiety, fatigue, and memory changes. Increasing cerebral blood flow through exercise may be a way to mitigate some of these symptoms while speeding up the healing process.

To explore the feasibility of a future RCT, the researchers used a controlled, single-blinded parallel-group study focusing on adults aged 18-60. Participants had received a concussion within the last 3-24 months and struggled with PPCS and exercise intolerance. The intervention group received SSTAE for 12 weeks, measured by the Buffalo Concussion Treadmill Test (BCTT). The SSTAE aerobic exercise plan allows patients to exercise safely at a rate of 80-90% of the symptom threshold. Valaas et al. utilized a numerical rating scale to measure symptom aggravation during exercise or following the days after to create safe and individualized treatment plans for participants.

Valaas et al. conclude, “This RCT will contribute to increased knowledge about the effect of SSTAE on persistent PPCS and exercise intolerance after mTBI.” This nested feasibility study shows us that SSTAE is a safe and feasible treatment option for those struggling with PPCS. However, future studies will need to be done to further test the efficacy of SSTAE on PPCS.

Mental Health

Civilians exposed to a blast demonstrate more PCS/PTSD symptoms and reduced white matter connectivity

A study published in BMC Psychiatry found that civilians who had been directly or indirectly exposed to explosive blasts exhibited greater post-concussion syndrome (PCS) and post-traumatic stress disorder (PTSD) symptoms and had reduced white matter (WM) connectivity compared to unexposed civilians. R. Saar-Ashkenazy et al. discuss their two-phase observational study that examines the relationship between blast exposure level, PCS/PTSD symptomatology, cognitive functioning, and white matter connectivity in 305 Beer-Sheva civilians of various blast exposure levels. Rocket attacks–explosions–had previously exposed residential areas in this Israel city to blast impacts. The researchers add that their study “highlights the complexity in differential diagnosis between the two disorders [PCS and PTSD] and may suggest that they are not distinct symptom clusters.”

Over two years, researchers at Soroka University Medical Center in Israel enrolled 289 civilians of different exposure levels (frequency, proximity, direct vs. indirect) to recent blast explosions into Phase 1 of their study, administering questionnaires to gauge exposure levels, demographics, and severity of PCS and PTSD symptoms. Participants who had been directly exposed to a blast had been in a building in “open sightline” to the blast and thus experienced the full blast, while indirectly exposed participants had been in a building obstructed by other buildings from experiencing the full blast. They wished to test whether the severity of PCS and PTSD symptoms is associated with the level of exposure. From participant questionnaires, the authors found that symptom severity is comparable for both direct and indirect exposure groups, although direct exposure participants reported feeling more in danger. Female sex, history of head trauma, and time passed since blast exposure were risk factors for both PCS and PTSD symptoms while being unmarried and feeling scared were risk factors for PCS.

In Phase 2 of their study, they recruited 46 of the previous 289 exposed individuals and 16 new unexposed control participants and administered cognitive and neuroimaging testing to test whether blast exposure was correlated with cognitive ability and white matter connectivity. Compared to unexposed civilians, direct and indirect exposure participants reported greater symptom severity than unexposed participants. In neuroimaging tests, direct exposure participants had reduced WM connectivity compared to indirect exposure and unexposed participants, although cognitive abilities were comparable for all three groups. This suggests that the subjective emotional response is greater for those with direct exposure, but the overall symptom severity for exposed individuals does not depend on the level of exposure. Additionally, exposure to a blast is significantly associated with symptoms of both PCS and PTSD; direct exposure is associated with damage to various white matter tracts in the brain.

The researchers include, “Following our hypothesis, WM connectivity was modulated by exposure to the impact site, with specific WM diffusion alterations occurring in direct-exposed civilians solely… Unlike our hypothesis, these WM diffusion alterations did not correlate with clinical symptoms or with cognitive abilities.”

The authors believe their findings demonstrate that “even if they are not clinically diagnosed, civilians who are directly exposed to explosion blast suffer from mental and WM neuro-anatomical changes and should thus be considered a population at risk for the future development of PTSD and/or PCS.” However, they acknowledge that their study is retrospective and does not draw any causal conclusions. Additionally, future prospective studies with repeated objective and subjective tests may demonstrate how symptomatology can change over time, which may “allow the establishment of biomarkers that would help guide diagnosis and prevention.”

Statistics

Concussions from car crashes found to result in more symptoms and more severe mood-related symptoms than sports concussions

A study published in Applied Neuropsychology-Adult by Eric J. Shumski et al. found that young adults who received concussions from motor vehicle crashes experienced more total symptoms and more severe affective symptoms than young adults with sports-related concussion (SRC) but generally performed similarly on balance and cognitive tests. Affective symptoms involve “feeling more emotional, irritability, sadness, and nervous or anxious.” According to the authors, these differences might be due to more significant psychological trauma after a motor vehicle-related concussion. Shumski et al. note that “medical practitioners should be aware that different mechanisms experience different outcomes which may influence their recovery timeline.”

The study compares forty-three 18-to-30-year-olds who received a SRC to 26 who received a motor-vehicle-related concussion (MVC). The authors examined differences in total symptoms, symptom severity, and specific symptom clusters–including migraines, disorientation, lethargy, affective symptoms, balance, and neurocognitive performance.

Previous studies comparing the symptom profiles of different concussion injury mechanisms have focused chiefly on adolescents, not young adults. Studying young adults specifically is relevant as they might be less physiologically vulnerable than adolescents to the effects of concussions and may have different post-injury coping strategies and receive different recovery guidance. Additionally, both motor vehicle crashes and sports are leading causes of concussions in undergraduate students, according to a separate study. Most research on concussions focuses specifically on SRCs, and the authors hope to contribute to more focus on non-SRCs. Assessing differences in post-concussion symptoms between injury mechanisms may help determine if different velocities or mechanisms of injury significantly contribute to disparities in post-concussion symptoms and whether those differences are due to psychological factors such as trauma or neurological reasons. Regardless, the authors find that affective distress may be a key symptom among MVC patients.

Participants self-reported their symptoms and symptom severity on established concussion symptom assessments. Neurocognitive ability was measured with a commonly used digital exam known as the CNS Vital Signs, and balance was tested using the Balance Error Scoring System, an established set of balance tests.

The study included exclusively young adults, so it cannot be generalized to other populations, and it possibly had too few participants to reliably detect a difference in neurocognitive performance between the groups. Additionally, the study did not track secondary injuries besides concussions, which could have influenced either group to feel more stressed or perform differently on the cognitive and balance tests.

Women’s Health

Preseason concussion rates in women's gymnastics surpass all NCAA sports by 50%

Women's gymnastics has the highest preseason concussion rate among all NCAA sports, 50% higher than that of football players. In a Michigan News press release, lead study author Steven Broglio from the University of Michigan Concussion Center stated, “Everybody worries about football, ice hockey, and men’s and women’s soccer, but gymnastics is out there by themselves with a preseason injury risk that we didn’t expect to see.” This surprising finding challenges the notion that women's gymnastics is a low concussion-risk sport and highlights the need to prioritize the health and safety of gymnasts, particularly in the preseason. Concussion rates dropped during the regular season, with women gymnasts experiencing concussions at half the frequency of preseason levels. The study findings were presented June 2nd at the American College of Sports Medicine Annual Meeting and World Congress.

The study's findings shed light on the importance of optimizing performance healthily and safely across all sports. While concussion rates for other NCAA sports aligned with expectations, the results in women's gymnastics call for further investigation and potential modifications to training activities during the preseason. By identifying the preseason concussion concern, this study provides valuable insights that may lead to targeted treatment recommendations to facilitate an optimal recovery environment for gymnasts.

The researchers examined sport-related concussion rates during the preseason practice period and regular season from 2013-14 through 2018-19. The researchers found that approximately nine gymnasts per 10,000 athletes experienced a concussion during the preseason, compared to roughly six football players per 10,000 athletes. The preseason sessions only involved practices, while the regular season included training and competition. However, the study has revealed that concussion rates drop significantly during the regular season, with women gymnasts experiencing concussions at only half the frequency compared to preseason levels.

Broglio emphasized that the high preseason concussion risk in women's gymnastics was unexpected and previously unidentified. He highlighted the need to improve gymnasts' health and safety and investigate the preseason activities that may contribute to the increased risk. As demonstrated by a recent study co-authored by Broglio, the lack of concussion research on female athletes further emphasizes the need to address the deficits in the literature and gain a deeper understanding of the factors influencing outcomes in women's sports.