A recent global study has highlighted the growing impact of Traumatic Brain Injury (TBI) on the population. This so called “silent epidemic” has grown substantially in recent years, and approximately 70 million people suffer TBI each year.1 While TBI can be catastrophic and receives more attention, mild Traumatic Brain Injury (mTBI), commonly referred to as “concussion”, may be far more prevalent and insidious than TBI. While research is still ongoing, mTBI has already clearly been shown to cause physical, mental and emotional changes. mTBI is also suspected as a cause of several neurodegenerative and deadly diseases including Chronic Traumatic Encephalopathy (CTE), Alzheimer's, Dementia and Parkinson's. These diseases cost the United States billions of dollars every year in treatment and health care spending, in addition to other immeasurable monetary, health and lifestyle costs for patients and their families.2
Because not all people react to and heal from mTBIs the same way, numerous studies have explored the mechanisms through which the brain repairs itself after concussion and mTBI.3 4 5 In April, 2018, a group of scientists working at the National Institutes of Health published a paper in Nature Immunology examining how immune cells promote meningeal vascular repair and remove dead cells after mTBI. Russo et al. (2018) used a mouse model of mTBI and a variety of imaging techniques to view how immune cells interact with the lesions made by mTBI. They found that these immune cells have two major functions: promoting angiogenesis, or the formation of new blood vessels, around the periphery of the lesion, and clearing dead cells from the center of the lesion. Experiment after experiment showed that the combination of these two complementary actions shrunk the size of the lesion to where it almost disappeared in about a week, and replaced the lesion with healthy, functional vasculature. Specifically, within 24 hours of the injury there was a great increase in pro-inflammatory genes in and around the lesion, recruiting peripheral immune cells called neutrophils and monocytes to the area; these inflammatory signals usually faded within a week, when the lesion was normally repaired, suggesting that the immune response is temporally regulated to coincide with the healing process.
At 4 days after mTBI, Russo et al. (2018)6 found large numbers of a certain type of macrophages, Lyve-1+CD206+, that are derived from the non-classical monocytes that migrated to the lesion after the
release of the pro-inflammatory molecules. These Lyve-1+CD206+ macrophages traveled to the edge
of the lesion, where they released an enzyme called Matrix Metalloproteinase MMP-2, which signaled
to nearby endothelial cells to make blood vessels and upregulated Vascular Endothelial Growth Factor,
VEGF, which further promoted angiogenesis.
release of the pro-inflammatory molecules. These Lyve-1+CD206+ macrophages traveled to the edge
of the lesion, where they released an enzyme called Matrix Metalloproteinase MMP-2, which signaled
to nearby endothelial cells to make blood vessels and upregulated Vascular Endothelial Growth Factor,
VEGF, which further promoted angiogenesis.
Around the same time, angiogenesis occurred in the periphery of the lesion, and neutrophils and classical monocytes traveled to the center of the lesion, where they released further pro-inflammatory signals to recruit other immune cells, and participated in the so called “wound-healing” response (removal of dead cells from the core of the lesion and angiogenesis in the periphery). Before new cells and vasculature could replace those killed by the mTBI, the dead cells had to first be removed. The neutrophils and classical monocytes broke down and removed these dead cells, clearing the path for recovery and new growth.
The most interesting finding of the researchers was the effect of a secondary mTBI before complete recovery had occurred. They found that the week of healing could be divided in two stages: a period of rapid influx of immune cells that occurred 24-48 hours after injury, followed by a time of differentiation and proliferation of these cells, along with “wound-healing”. Interestingly, when another mTBI occurred in the first 24-48 hours post-injury (during the recruitment of immune cells phase), the lesion size was increased and peripheral angiogenesis was severely hindered. However, when the second mTBI occurred 4 or more days after the initial trauma, there was no noticeable effect on lesion repair or vascular remodeling. As well, when the second mTBI occurred during the initial inflammatory state, there was an influx of neutrophils in the lesion within 30 minutes, instead of the usual 2-3 hours for neutrophils to invade the the primary mTBI lesion or the lesion if it was re-injured at 4 days. mTBI lesions therefore are clearly temporally sensitive to secondary injuries, and respond with great diversity in terms of how they heal in part based on further injury, and the timing of those injuries.
This research is important public health information, and highlights the dangers of experiencing a secondary head injury
soon after the first, with likely complications and prolonged recoveries. As there are an estimated 1.6-3.8
million sports-related concussions in America alone7, the data Russo and colleagues discovered can
be very influential in creating changes to policy and the so called “return to play” protocols that
either allow or prohibit an athlete from re-entering a match in which they sustained a possible
head injury or concussion. As well, by understanding the molecular mechanisms that occur when
mTBI lesions heal, doctors can better treat concussions and hope to prevent Post-Concussion
Syndrome8, where symptoms linger for months to years after the initial mTBI. Because an
estimated 13% of Americans who sustain an mTBI develop Post-Concussion Syndrome, and a
recent study found that in some cases this syndrome can result in permanent symptoms9, there
is a pressing need for the medical community to further research these mTBIs and what can
be done to promote and accelerate healing.
soon after the first, with likely complications and prolonged recoveries. As there are an estimated 1.6-3.8
million sports-related concussions in America alone7, the data Russo and colleagues discovered can
be very influential in creating changes to policy and the so called “return to play” protocols that
either allow or prohibit an athlete from re-entering a match in which they sustained a possible
head injury or concussion. As well, by understanding the molecular mechanisms that occur when
mTBI lesions heal, doctors can better treat concussions and hope to prevent Post-Concussion
Syndrome8, where symptoms linger for months to years after the initial mTBI. Because an
estimated 13% of Americans who sustain an mTBI develop Post-Concussion Syndrome, and a
recent study found that in some cases this syndrome can result in permanent symptoms9, there
is a pressing need for the medical community to further research these mTBIs and what can
be done to promote and accelerate healing.
Although this article was extremely informative and shows how lesions repair after mTBI in mice,
there are still important questions to be answered. One of the most important questions is if
environmental factors affect recovery. Until very recently, “return to play” guidelines included rest,
avoiding sensory-stimulating environments (bright lights and loud noises) and not exercising until
symptoms subside. However, some doctors have recently started advising brief specific types of aerobic
exercise (like indoor stationary biking) while still symptomatic, which new research shows may in fact
be more beneficial and promote repair. Researchers could perform a similar experiment, after the
primary mTBI, by dividing the mice and placing them in different environments, some of which involved
controlled aerobic exercise, some of which contained bright lights and loud noises, and some of which
would have a combination of both. They could again examine the lesions and see if environmental
factors can play a role in recovery, and if so, which are most beneficial. This would be extremely
informative, and could change mTBI recovery protocol drastically.
there are still important questions to be answered. One of the most important questions is if
environmental factors affect recovery. Until very recently, “return to play” guidelines included rest,
avoiding sensory-stimulating environments (bright lights and loud noises) and not exercising until
symptoms subside. However, some doctors have recently started advising brief specific types of aerobic
exercise (like indoor stationary biking) while still symptomatic, which new research shows may in fact
be more beneficial and promote repair. Researchers could perform a similar experiment, after the
primary mTBI, by dividing the mice and placing them in different environments, some of which involved
controlled aerobic exercise, some of which contained bright lights and loud noises, and some of which
would have a combination of both. They could again examine the lesions and see if environmental
factors can play a role in recovery, and if so, which are most beneficial. This would be extremely
informative, and could change mTBI recovery protocol drastically.
________________________________________
Shrime, M., Rubiano, A., Rosenfeld, J., Park, K. (2018). “Estimating the Global Incidence of Traumatic
Brain Injury”. Journal of Neurosurgery, (2018).
2. Mayo Clinic description of symptoms and diseases that can result from TBI and mTBI:
https://www.mayoclinic.org/diseases-conditions/traumatic-brain-injury/symptoms-causes/syc-20378557
3. Heidi Losoi, Noah D. Silverberg, Minna Wäljas, Senni Turunen, Eija Rosti-Otajärvi, Mika Helminen,
Teemu M. Luoto, Juhani Julkunen, Juha Öhman, and Grant L. Iverson.Journal of Neurotrauma.
Apr 2016.
4. Hellstrøm T, Kaufmann T, Andelic N, Soberg HL, Sigurdardottir S, Helseth E, Andreassen OA and
Westlye LT (2017) Predicting Outcome 12 Months after Mild Traumatic Brain Injury in Patients Admitted
to a Neurosurgery Service. Front. Neurol. 8:125.
5. Dikmen, Sureyya, Joan Machamer, and Nancy Temkin. “Mild Traumatic Brain Injury: Longitudinal
Study of Cognition, Functional Status, and Post-Traumatic Symptoms.” Journal of Neurotrauma 34.8
(2017): 1524–1530. PMC. Web. 25 Sept. 2018.
6. Russo, M., Latour, L., McGavern, D. “Distinct Myeloid Cell Subsets Promote Meningeal Remodeling
and Vascular Repair after Mild Traumatic Brain Injury”. Nature Immunology (2018).
7. Statistics about sports-related concussions/mTBI: http://www.protectthebrain.org/Brain-Injury-
Research/What-is-a-Concussion-.aspx
8. Statistics about the percentage of people who experience Post-Concussion Syndrome:
https://www.statista.com/statistics/705230/rate-of-post-concussion-syndrome-by-year-in-us/
9. Hiploylee, Carmen et al. “Longitudinal Study of Postconcussion Syndrome: Not Everyone Recovers.”
Journal of Neurotrauma 34.8 (2017): 1511–1523. PMC. Web. 25 Sept. 2018.
No comments:
Post a Comment