Concussion may cause different types of brain damage which lead to similar symptoms in children, according to research published in eLife. A new way of studying concussions could help inform the development of future treatments.
While most children fully recover after a concussion, some will have lasting symptoms. The findings help explain the complex relationships that exist between symptoms and the damage caused by the injury.
The researchers found that certain combinations of brain damage were associated with specific symptoms such as attention difficulties. Other symptoms, such as sleep problems, occurred in children with multiple types of injuries. For example, damage to areas of the brain that are essential for controlling sleep and wakefulness could cause challenges with sleeping, as could damage to brain regions that control mood.
The brain’s white matter holds clues
To do this, they examined how damage to the brain resulting from concussion affected its structural connection network, known as white matter. They then used statistical modelling techniques to see how these changes related to 19 different symptoms reported by the children or their caregivers.
Analysing symptoms may advance treatment
“Despite decades of research, no new treatment targets and therapies for concussions have been identified in recent years,” said lead author Guido Guberman, a Vanier Scholar and MDCM Candidate at McGill University. “This is likely because damage to the brain caused by concussions, and the symptoms that result from it, can vary widely across individuals. In our study, we wanted to explore the relationships that exist between the symptoms of concussion and the nature of the injury in more detail.”
Guberman and his colleagues analysed data collected from 306 children, aged nine to 10 years old, who had previously had a concussion. The children were all participants in the Adolescent Brain Cognitive Development (ABCD) Study.
“The methods used in our study provide a novel way of conceptualising and studying concussions,” says senior author Maxime Descoteaux, a Professor of Computer Science at Université de Sherbrooke. “Once our results are validated and better understood, they could be used to explore potential new treatment targets for individual patients. More broadly, it would be interesting to see if our methods could also be used to gather new insights on neurological diseases that likewise cause varied symptoms among patients.”
A clinical study from Lund University in Sweden has shown that long-term problems such as dizziness and difficulty focusing after a concussion originate in an injury to the vestibular nerve. The researchers published their findings in the Journal of Neurotrauma.
Concussion resulting from a blow to the head is a hazard in many sports. In American football, where players who have suffered from repeated concussions have developed dementia, severe depression and cognitive impairment.
Concussion usually has only temporary symptoms, but an increasing number of athletes experience long-term problems that make it difficult to work, go to school or play sports. The symptoms are aggravated by activity or impressions and include headaches, depression, anxiety, nausea, difficulty focusing and problems with balance.
“It has been unclear what causes the symptoms, and it is difficult for healthcare professionals to help these athletes. We wanted to investigate this further to find out what really causes the symptoms,” said Professor Niklas Marklund, one of the study’s researchers.
The study included 21 healthy athletes without previous trauma to the head, and 21 athletes who all suffered from sports-related concussions and who had experienced persisting symptoms for more than six months. The researchers used a 7-Tesla MRI, to study the athletes’ brains to understand more about what caused the symptoms. They discovered impaired function of the balance organs in the inner ear of 13 athletes in the group with long-term problems. In the group of healthy athletes three people had similar findings.
“The test results show that the injury is located to the vestibular nerve, which is connected to the semicircular canals in a cavity inside the skull, and which is directly adjacent to the cochlea in the ear. These injuries lead to the inward nerve impulses not working properly, and the brain therefore does not receive important information about body movements and sensory impressions required to maintain a good balance,” said Anna Gard, doctoral student at Lund University and first author of the study.
Concussion often results from the head rotating too fast.
“We have not examined athletes with short-term problems after blows to the head, so we cannot say anything about them. This study applies to athletes with prolonged symptoms after concussion. The rotation of the head that occurs in connection with a concussion could lead to a stretch of the vestibular nerve, which then leads to impaired function. Now that we have more knowledge about where the problems are located, it is easier to find possible therapies that could help these athletes,” concluded Prof Marklund.
More than 70% of patients with traumatic brain injury (TBI) reported at least one problematic symptom at one year of follow-up that was new or worse than before injury according to a study published in the Journal of Neurotrauma. Half of the patients reported three or more such symptoms after a year.
Joan Machamer, from the University of Washington, Harborview Medical Center, and colleagues representing the TRACK-TBI Investigators, compared the frequency and persistence of symptoms in patients with TBI to two control groups: patients with orthopedic trauma and friend controls. The groups were evaluated at 2 weeks, and 3, 6, and 12 months after injury.
Physical symptoms such as headache, fatigue, and dizziness tended to occur earlier, according to the researchers, with cognitive symptoms becoming dominant later. While physical symptoms declined noticeably over time, cognitive symptoms remained more constant over time.
“Clinicians should inquire about symptoms in patients who have had a TBI, reassure them that experiencing symptoms is common, and direct them to seek treatment for symptoms that are disrupting their lives,” the researchers said.
Commenting on the study, David L. Brody, MD, PhD, Editor-in-Chief of Journal of Neurotrauma noted that is remarkable for several reasons. “First, it is among the largest studies of its type, with over 2,000 participants. Second, it confirms what many of us who practice brain injury medicine have observed for many years– a wide variety of symptoms can be very persistent and very troubling to our patients even after so-called ‘mild’ TBI. Third, the investigators used the right controls; people with orthopedic injury as well as friends of the patients with TBI. Symptoms in patients with TBI were substantially more common and more severe than in both control groups.”
Traumatic brain injury can lead to long-term visual impairment, which researchers have found is caused by a dramatic drop in the number of neurons in the visual cortex. Their findings were published in Communications Biology.
Traumatic brain injury (TBI) is associated with mechanical brain damage and a wide range of neuronal abnormalities. Injuries to the posterior occipital cortex are common in humans, and can result in visual impairment. Up to 75% of current or former soldiers live with permanent visual dysfunction or cortical blindness.
The human brain possesses surprising neuroplasticity, which allows other areas of the brain to take over the functions of a damaged area.
Such neuroplasticity is also characteristic of the sensory areas of the visual cortex, which is final component of the visual pathway, responsible for receiving and processing visual impressions. The primary visual cortex (V1) is reached by the nerve fibres of the optic radiation, which carry nerve impulses from the retinas of both eyes.
Until now, scientists knew little about the effects of TBI on long-term visual circuit function. Using mice, a team of researchers examined how neurons respond to visual stimuli two weeks and three months after mild injury to the primary visual cortex (V1). V1 neurons normally show sensitivity to different features of a visual stimulus, such as colour or direction of movement. The preprocessed data is transmitted to subsequent areas of the visual cortex. This study showed that although the primary visual cortex remained largely intact after the brain injury, there was a 35% reduction in the number of neurons. This loss largely affected inhibitory neurons rather than excitatory neurons, which inhibit or stimulate action in the target cells, respectively.
After TBI, fewer than half of the isolated neurons were sensitive to visual stimuli (32% at two weeks after injury; 49% at three months after the event), compared with 90% of V1 cells in the control group. Up to a threefold decrease in neuronal activity was seen after the brain injury, and the cells themselves had worse spatial orientation. The overall results mean that even minor, superficial brain injuries cause long-term impairment in the way visual stimuli are perceived, persisting several months after the event.
Such a deeper understanding of the functional impairments in damaged visual cortex could provide a basis for developing circuit-level therapies for visual cortex damage.
A new study adds to the growing body of evidence that decisions regarding moderate-to-severe traumatic brain injury (TBI) should not be made too soon after the injury, as a good prognosis can still emerge.
Researchers followed 484 patients with moderate-to-severe TBI and found that among the patients in a vegetative state, one quarter “regained orientation” — awareness of who, when and where they were — within 12 months of their injury.
“Withdrawal of life-sustaining treatment based on early prediction of poor outcome accounts for most deaths in patients hospitalised with severe TBI,” said senior author Geoffrey Manley, MD, PhD, noting that 64 of the 92 fatalities in the study occurred within two weeks of injury. Dr Manley is professor and vice chair of neurological surgery at UCSF and chief of neurosurgery at Zuckerberg San Francisco General Hospital.
“TBI is a life-changing event that can produce significant, lasting disability, and there are cases when it is very clear early on that a patient will not recover,” he said. “But results from this study show a significant proportion of our participants experienced major improvements in life functioning, with many regaining independence between two weeks and 12 months after injury.”
The patients in the study were enrolled by the brain injury research initiative TRACK-TBI, of which Dr Manley is the principal investigator. All patients were 17 and older and had presented to hospitals with level 1 trauma centers within 24 hours of injury. Their exams met criteria for either moderate TBI or severe TBI. The causes were falls, assault and primarily crashes involving a motor vehicle.
The patients, whose average ages were 35 in the severe TBI group (78 percent males) and 38 in the moderate TBI group (80 percent males), were assessed using the Glasgow Outcomes Scale Extended (GOSE), which ranges from 1 for death to 8 for “upper good recovery” and resumption of normal life. Impairment was also categorised with the Disability Rating Scale (DRS).
At two weeks post-injury, 93 percent of the severe TBI group and 79 percent of the moderate TBI group had moderate-to-severe disability, according to the DRS, and 80 percent had GOSE scores from 2 to 3, meaning they required assistance in basic everyday functioning.
But by 12 months, half of the severe TBI group and three-quarters of the moderate TBI group had GOSE scores of at least 4, indicating they could function independently at home for at least eight hours per day. Moreover, 19 percent of the severe TBI group had no disability, according to the DRS, and a further 14 percent had only mild injury, the researchers noted.
Most surprising were the findings for the 62 surviving patients who had been in a vegetative state. By the 12-month mark all patients had recovered consciousness and 1 in 4 had regained orientation. All but one survivor in this group recovered at least basic communication ability.
“These patients made the cut for favorable outcome,” said co-first author, Joseph Giacino, PhD, of Spaulding Rehabilitation Hospital, Massachusetts General Hospital and Harvard Medical School. “Their GOSE scores were 4 or higher, which meant they could be at home unsupervised for at least eight hours a day, since they were able to take care of basic needs, such as eating and toileting.”
In prior work, a significant percentage of patients with grave impairments had been shown to achieve favorable functionality after many months or years. This study coincided with the recommendation in 2018 from the American Academy of Neurology that in the first 28 days after injury, clinicians should refrain from telling families that a patient’s prognosis is beyond hope.
“While a substantial proportion of patients die or suffer lasting disability, our study adds to growing evidence that severe acute impairment does not portend uniformly poor long-term outcome,” said Manley, who is also affiliated with the UCSF Weill Institute for Neurosciences. “Even those patients in a vegetative state – an outcome viewed as dire – may improve, since this is a dynamic condition that evolves over the first year.”
A study found that CT scans for concussion patients provide crucial information on their risk for long-term impairment and their potential to make a complete recovery, and points to the need for more follow-up.
In the UC San Francisco-led study, researchers examined CT scans of 1935 patients, aged 17 and over, whose neurological exams met criteria for concussion, or mild traumatic brain injury (TBI). Outcomes for moderate and severe TBI have been linked to CT imaging features, but this may be the first time this link has been identified in patients with concussion. This contradicts previous research which had found no prognostic significance of specific types of CT abnormalities.
“Radiologists who routinely read trauma scans know intuitively that patterns of intracranial injury on CT are not random,” said first author Esther Yuh, MD, PhD, of the UCSF Department of Radiology and Biomedical Imaging. “We showed there are patterns of injury, that some of these are associated with worse outcome than others, and that they provide a window into mechanisms of injury that is reproducible across large studies.”
The study was published online in JAMA Neurology.
“Although concussions are referred to as mild traumatic brain injuries, there is nothing mild about some concussions,” explained senior author Geoffrey Manley, MD, PhD, professor and vice chair of neurological surgery at UCSF and chief of neurosurgery at Zuckerberg San Francisco General Hospital. “Patients with concussion may suffer from prolonged headache, poor sleep and impaired concentration, and they are at higher risk of self-medicating with drugs and alcohol. Concussion can also contribute to depression and anxiety, and increase the risk for suicide. We need to view concussion not as an event but as a disease requiring physician follow-up after a patient is discharged from the hospital.”
The participants were enrolled by the brain injury research initiative TRACK-TBI, of which Manley is the principal investigator. To enrich the number of so-called complicated concussions, the researchers drew exclusively from patients who had been seen at hospitals with level 1 trauma centres. This meant 37 percent of study participants had a positive CT, significantly more than the 9 percent of positive CTs from patients in US emergency departments.
The most common patterns of injury, affecting more than half of CT-positive patients, were combinations of subarachnoid haemorrhage (SAH), subdural haematoma (SDH), and/or contusion, which may be caused by injuries such as falls from standing. About 7 percent had intraventricular haemorrhage (IVH) or petechial haemorrhage, caused by head rotation as in some sporting, scooter and automobile accidents; and 5 percent had epidural haematoma (EDH), often seen in sports injuries such as being hit with a baseball.
Average age of the patients was 41 and 66 percent were male. They were followed-up at two weeks, and at three-, six- and 12 months following injury. Patients in the SAH/SDH/contusion group failed to make a complete recovery at 12 months post-injury and had a range of outcome impairments, from mild to more severe.
Patients in the IVH/petechial haemorrhage group tended toward more severe impairments, in the lower-moderate disability range, a level potentially affecting multiple areas of function, such as employment, social and leisure activities, up to 12 months post-injury. Patients with EDH fared significantly better and demonstrated complete recovery by their six-month assessment.
Results from CENTER-TBI, a parallel brain injury research group that had enrolled 2594 participants at European trauma centres. validated the findings. “The confirmation of the findings in an independent cohort confirms the fidelity of our results,” said Manley, adding that patients with EDH were one exception, with incomplete recovery lingering for months longer than those patients followed by TRACK-TBI. However, more severe outcomes were not seen at any point in either study.
The researchers noted that even among concussion patients with positive CT scans, only 39 percent get follow-up care, which should be routine. They also cautioned that their findings are not a call for increased CT use, which has radiation dose concerns and is restricted to known or suspected concussions.
Indeed, a recently approved rapid hand-held blood test may reduce the amount of CT scans. Manley found this test was more sensitive than CT in detecting concussion. The blood test measures biomarkers associated with TBI, which were nearly 52 times higher in MRI-identified concussion patients than in healthy participants.
In addition to challenging the belief that CT features in concussion are not relevant, the researchers are also challenging the idea that concussion is “what the patient brings to the injury,” said Manley, who is also affiliated with the UCSF Weill Institute for Neurosciences. “In moderate and severe TBI, it is anecdotally taught that outcome is determined by ‘what the injury brings to the patient,’ while concussion is determined by baseline characteristics like age, sex and years of education. While the study confirms the importance of these characteristics, we show that in some concussion cases, poor outcomes are also attributed to ‘what the injury brings to the patient.'”
Journal information: Yuh EL et al., Pathological computed tomography features associated with adverse outcomes after mild traumatic brain injury, JAMA Neurology, July 19, 2021.
New research has identified a sex-specific window of opportunity to treat traumatic brain injuries (TBIs), which scientists are exploiting in a project to create a sex-targeted drug delivery for TBI.
The study, a collaboration of The University of Texas Health Science Center at Houston (UTHealth) and Arizona State University will be used to help design nanoparticle delivery systems targeting both sexes for treatment of TBI.
“Under normal circumstances, most drugs, even when encapsulated within nanoparticles, do not reach the brain at an effective concentration due to the presence of the blood-brain barrier. However, after a TBI this barrier is compromised, allowing us a window of opportunity to deliver those drugs to the brain where they can have a better chance of exerting a therapeutic effect,” said Rachael Sirianni, PhD, associate professor of neurosurgery at McGovern Medical School at UTHealth. Dr Sirianni’s collaborator and co-lead investigator on this grant, Sarah Stabenfeldt, PhD, was the first to demonstrate that the window of opportunity created in the blood-brain barrier differed between men and women, and it was this key finding that led them to apply for funding.
TBI results from blows to the head, and in the most severe form of TBI, the entirety of the brain is affected by a diffuse type of injury and swelling. The body responds with an acute response to the injury, followed by a chronic phase as it tries to heal.
“In this second phase, a variety of abnormal processes create additional injury that go well beyond the original physical damage to the brain,” Dr Sirianni said.
Normally, the blood vessels maintain a very carefully controlled blood-brain barrier to prevent the entry of harmful substances. However, during this second phase of healing following a TBI, those blood vessels are compromised, possibly allowing substances to seep in.
One of the numerous differences between female and male patients is varying levels and cycles of sex hormones such as oestrogen, progesterone, and testosterone. While these levels already differ in healthy people, additional hormone disruption for both sexes can result from a brain injury.
Dr Sirianni explained that this work is extremely important as presently TBIs have no effective treatment options. Current treatments for TBI vary widely based on injury severity and range from daily cognitive therapy sessions to radical surgery such as bilateral decompressive craniectomies.
“The goal of this research is to develop different nanoparticle delivery systems that can target the unique physiological state of males versus females following a TBI. Through this research, we hope to develop an optimum distribution system for these drugs to be delivered to the brain and can hopefully find an effective treatment plan for TBIs,” Sirianni said.
Drugs that previously perceived as unsafe or ineffective when given systemically can instead be targeted directly to the injury microenvironment through nanoparticle delivery systems.
“With these nanoparticle systems, we’re looking at how we can revisit a drug that showed promise in preclinical studies or clinical trials but then failed,” Stabenfeldt said.
A new study has uncovered insights into white matter changes that occur during chronic traumatic encephalopathy (CTE), a progressive brain disease associated with repetitive head impacts. This discovery may help in identifying new targets for therapies.
CTE been diagnosed after death in the brains of American football players and other contact sport athletes as well as members of the armed services. The disease has been identified as causing impulsivity, explosivity, depression, memory impairment and executive dysfunction.
Though much prior research focused on repetitive head trauma leading to the development of abnormal tau, this study focused on white matter changes, particularly the oligodendrocytes which myelinate nerve sheaths. The results have been published online [PDF] in the journal Acta Neuropathologica.
“Research to date has focused on the deposition of abnormal tau in the gray matter in CTE. This study shows that the white matter undergoes important alterations as well. There is loss of oligodendrocytes and alteration of oligodendrocyte subtypes in CTE that might provide new targets for prevention and therapies,” explained corresponding author Ann McKee, MD, chief of neuropathology at VA Boston Healthcare, director of the BU CTE Center.
Dr McKee and her team isolated cellular nuclei from the postmortem dorsolateral frontal white matter in eight cases of CTE and eight matched controls. They conducted single-nucleus RNA-seq (snRNA-seq) with these nuclei, revealing transcriptomic, cell-type-specific differences between the CTE and control cases. In doing so, they discovered that the white matter in CTE had fewer oligodendrocytes and the oligodendroglial subtypes were altered compared to control tissue.
Since previous studies have largely focused on the CTE-specific tau lesion located in the cortex in the brain, these findings are particularly informative as they explain a number of features of the disease. “In comparison, the cellular death process occurring in white matter oligodendrocytes in CTE appears to be separate from the accumulation of hyperphosphorylated tau,” she said. “We know that the behavioural and mood changes that occur in CTE are not explained by tau deposition. This study suggests that white matter alterations are also important features of the disease, and future studies will determine whether these white matter changes play a role in the production of behavioral or mood symptoms in CTE, such as explosivity, violence, impulsivity, and depression.”
Journal information: Chancellor, K. B., et al. (2021) Altered oligodendroglia and astroglia in chronic traumatic Encephalopathy. Acta Neuropathologica. doi.org/10.1007/s00401-021-02322-2.
New research has found that 78% of women prisoners in Scotland have a history of significant head injury – most of which occurred in the context of years of domestic abuse.
The University of Glasgow-led study also found 66% of women prisoners had suffered repeat head injuries for many years. The majority of the study participants were from the most deprived 20% of the population. One US study of male prisoners found 63.7% of at least one traumatic brain injury, and 32.5% had experienced multiple such injuries.
Of those with a history of head injury, the most common cause (89%) of repeat head injury was domestic violence. Only five women had experienced a single incident of moderate-severe head injury. Of those with a history of significant head injury, a first head injury before the age of 15 was reported by 69% of women.
For the study, researchers interviewed around a quarter of women in Scottish prisons, 109 women in total, between 2018 and 2019. They were assessed for a history of head injury, including its causes, a history of abuse, as well as for disability and mental and physical health conditions.
Of the 78% with a history of significant head injury, 40% also had an associated disability. Previous research has reported that many women in prison have a history of head injury, but none looked at disability.
Those with a history of significant head injury were three times more likely to have violent criminal behaviour, and also spent three times longer in prison.
Nearly all participants (95%) reported a history of abuse, with over half reporting sexual abuse in childhood and 46% reporting sexual abuse in adulthood. Physical abuse in childhood was reported by 39%, while 81% of participants reported physical abuse in adulthood.
Alcohol or drug misuse history was common, with substantially higher rates in the group who reported significant head injuries. Almost all, 92%, complained of mental health difficulties, with anxiety and depression the most commonly reported. Although the participants had 12 years of education on average, schooling was often disrupted by exclusion or truanting and many required special schooling or support.
Professor Tom McMillan, Professor of Clinical Neuropsychology at the University of Glasgow and lead author of the study, said: “It is already recognised that women in prison are vulnerable because of histories of abuse and substance misuse. However, this research shows that a history of significant head injury is also a vulnerability and needs to be included when considering mental health needs and in developing criminal justice policy given the relationships with associated disabilities, abuse and violent crime’’.
“Our findings suggest that interventions to reduce mental health morbidity, and assessment and management of risk of violent offending should include history of significant head injury. There is a need to recognise these vulnerabilities at an early stage, including at the first contact with the criminal justice system, to assess these women and provide long term support.”
Common persistent effects of significant head injury include impairments in information processing and emotional changes associated with impulsivity, irritability and egocentricity. These effects can impair judgement and self-control, increase the risk of offending. Significant head injury can also impair the maturation of the developing brain if occurring before adulthood.
The characteristics of significant head injury in women in prison differ from women with significant head injury in the general population. Domestic violence was the most common cause of these injuries in women in prison, whereas in the general population falls are most common. In addition head injury occurred repeatedly in around two-thirds of women in prison with significant head injury, whereas single incident head injury from an accident is more common in the general population.
Journal information: Tom M McMillan et al. Associations between significant head injury and persisting disability and violent crime in women in prison in Scotland, UK: a cross-sectional study, The Lancet Psychiatry (2021). DOI: 10.1016/S2215-0366(21)00082-1
In high school American football, girls are at nearly double the risk of concussion compared to boys, according to a new study. Girls are also less likely to be removed from play and take longer to recover from the injury than their male counterparts.
Researchers at the University of Pennsylvania and Michigan State University along with Prof Willie Stewart, Honorary Professor at the University of Glasgow reviewed three years of injury data for a population of around 40 000 female high school American footballers in the Michigan High School Athletic Association, comparing them to a similar number of their male counterparts.
They found that, as seen in previous studies, the risk of sports related concussion among female footballers was 1.88 times higher than among males. The researchers also identified several sex-associated differences in sports concussion mechanism and management. This provides new insight into this kind of injury in this demographic.
Male footballers tended to be injured in collisions with another player and were 1.5 times more likely than females to be removed from play on the day of injury. Female footballers were most often injured from impacts involving equipment, such as the ball or a goalpost, and also took on two days longer on average to recover from injury and return to play. A recent study however showed no differences for concussion recovery time among male and female college athletes, but there could be differences depending on the type of sport.
These sex-associated differences among teenage athletes in mechanism of injury and in management and outcomes of concussion raise the question of whether sports should consider the adoption of sex specific approaches to both participation and concussion management.
Lead author Dr Abigail Bretzin, postdoctoral fellow and certified athletic trainer at the University of Pennsylvania, said: “This is the first study to look in this detail at sex-associated differences in concussion management and outcomes in teenage footballers. Our findings add to research showing that female athletes are at increased concussion risk compared to male athletes, and highlight the importance of sex-specific research in this field.”
Senior author Prof Stewart, said: “Given we know the importance of immediate removal from play for any athlete with suspected concussion, it is notable that “if in doubt, sit them out” appears more likely to happen for boys than girls. This, together with the finding that mechanism of injury appears different between boys and girls, suggests that there might be value in sex-specific approaches to concussion education and management in this age group.”
Journal information: Abigail C. Bretzin et al. Association of Sex With Adolescent Soccer Concussion Incidence and Characteristics, JAMA Network Open (2021). DOI: 10.1001/jamanetworkopen.2021.8191
