Microglial GLUL loss worsens TBI outcomes by amplifying the arginine-citrulline pathway.

Inflicted Childhood Neurotrauma: New Insight into The Detection, Pathobiology, Prevention, and Treatment of Our Youngest Patients with Traumatic Brain Injury

XV. Steroids

Mechanical impact-induced primary injury after traumatic brain injury (TBI) leads to acute microglial pro-inflammatory activation and consequently mediates neurodegeneration, which is a major secondary brain injury mechanism. However, the detailed pathologic cascades have not been fully elucidated, partially because of the pathologic complexity in animal TBI models. Although there are several in vitro TBI models, none of them closely mimic post-TBI microglial activation. In the present study, we aimed to establish an in vitro TBI model, specifically reconstituting the pro-inflammatory activation and associated neurodegeneration following TBI. We proposed three sets of experiments. First, we established a needle scratch injured neuron-induced microglial activation and neurodegeneration in vitro model of TBI. Second, we compared microglial pro-inflammatory cytokines profiles between the in vitro TBI model and TBI in male mice. Additionally, we validated the role of injured neurons-derived damage-associated molecular patterns in amplifying microglial pro-inflammatory pathways using the in vitro TBI model. Third, we applied the in vitro model for the first time to characterize the cellular metabolic profile of needle scratch injured-neuron-activated microglia, and define the role of metabolic reprogramming in mediating pro-inflammatory microglial activation and mediated neurodegeneration. Our results showed that we successfully established a novel in vitro TBI model, which closely mimics primary neuronal injury-triggered microglial pro-inflammatory activation and mediated neurodegeneration after TBI. This in vitro model provides an advanced and highly translational platform for dissecting interactions in the pathologic processes of neuronal injury-microglial activation-neuronal degeneration cascade, and elucidating the detailed underlying cellular and molecular insights after TBI.SIGNIFICANCE STATEMENT Microglial activation is a key component of acute neuroinflammation that leads to neurodegeneration and long-term neurologic outcome deficits after TBI. However, it is not feasible to truly dissect primary neuronal injury-induced microglia activation, and consequently mediated neurodegeneration in vivo Furthermore, there is currently lacking of in vitro TBI models closely mimicking the TBI primary injury-mediated microglial activation. In this study, we successfully established and validated a novel in vitro TBI model of microglial activation, and for the first time, characterized the cellular metabolic profile of microglia in this model. This novel microglial activation in vitro TBI model will help in elucidating microglial inflammatory activation and consequently associated neurodegeneration after TBI.

Hypothermia in patients with brain injury: the way forward?

Abstracts from The 37^th Annual National Neurotrauma Symposium June 29–July 3, 2019 Pittsburgh, Pennsylvania

Abstracts from The 34(th) Annual National Neurotrauma Symposium June 26-29, 2016 Lexington, Kentucky.

Neurobehavioral symptoms are not uncommon after a traumatic brain injury. However, psychiatric syndromes per se have rarely been studied in patients with such an injury. The purpose of this study was to evaluate the type and extent of psychiatric syndromes in patients with traumatic brain injury. One hundred ninety-six hospitalized adults were studied 1 year after a traumatic brain injury with the use of a two-stage psychiatric diagnostic procedure. Psychiatric diagnoses were made according to ICD-10 criteria on the basis of data from the Schedules for Clinical Assessment in Neuropsychiatry interview. Of 164 patients interviewed, 30 (18.3%) had an ICD-10 diagnosis of a psychiatric illness. Among the 120 patients who were 18-64 years old, 21.7% had a psychiatric illness, compared with 16.4% in a study of the general population. A depressive illness was present in 13.9% of the traumatic brain injury patients, compared with 2.1% of the general population, and panic disorder was present in 9.0%, compared with 0.8% of the general population. In comparison with the general population, a higher proportion of adult patients had developed psychiatric illnesses 1 year after a traumatic brain injury; the rates of depressive episode and panic disorder were significantly higher in the study group. A history of psychiatric illness, an unfavorable global outcome according to the Glasgow Outcome Scale, a lower score on the Mini-Mental State examination, and fewer years of formal education seemed to be important risk factors in the development of a psychiatric illness. Compensation claims, however, were not associated with the rate of psychiatric illness.

Depletion of gut microbiota is associated with improved neurologic outcome following traumatic brain injury

Salud oral y estetica de la boca, su importancia en la calidad de vida. La enfermedad oral no es una consecuencia inevitable del envejecimiento. Control sistematico y regular. Integracion de la salud oral a la salud general. Formacion de odontologos especialistas, capacitados en la integracion del equipo de salud geriatrica (AU)

You have accessThe ASHA LeaderFeature1 Nov 2010Pediatric Traumatic Brain InjuryWhere Do We Go From Here? Roberta DePompeiCCC-SLP/A Roberta DePompei Google Scholar More articles by this author , CCC-SLP/A https://doi.org/10.1044/leader.FTR2.15132010.16 SectionsAbout ToolsAdd to favorites ShareFacebookTwitterLinked In “She is a beautiful 4-year-old. She was in the hospital for several months and has a severe brain injury. She can’t speak and has difficulty maintaining balance for sitting. She is more like a 2-year-old than a 4-year-old. We know there are many challenges before us in getting all the services she will need throughout her life.” —Jessica’s parents, who found their daughter comatose in her crib at the age of 3 weeks, injured while in the care of her nanny. “I have headaches and can’t concentrate in school. I am a little impatient with my friends, and they don’t call like they used to. Maybe I am just over-stressed with sports and schoolwork?” —Kiesha, 17, a varsity volleyball player, one year after sustaining a concussion when she hit her head on the gym floor and was returned to play in that game against the recommendation of the athletic trainer. “Our son is now 11 and has begun to do poorly in school. We can’t figure out what is bothering him. He was a great student until third grade, but he just can’t keep up anymore. His friends are a little on the wild side and influence him to do bad things. He is physically fine. Maybe he should play sports and get rid of some of this energy.” —Matthew’s parents, discussing academic and behavioral changes in their son, who was hit by a car when he was 8 years old. Matthew was unconscious for 24 hours, hospitalized for three days, and discharged home with no further recommendations. “I served in Iraq. I was injured in a blast and have been home for 11 months. I was discharged and tried working at my old job as a manager at a local pizza shop. But I just could not take the chaos and noise there. I am now enrolled in a local university. Keeping organized for classes, recalling assignments, and listening to lectures is really difficult. Maybe I need counseling for post-traumatic stress disorder. But I was told I only have a minor leg injury and really don’t qualify for any service-related assistance. There doesn’t seem to be anyone here in the community who knows what I should do.” —Marvin, a 21-year-old who was injured in Iraq and now is considering dropping out of college. These quotes—from real families and individuals dealing with traumatic brain injury (TBI)—illustrate the spectrum of traumatic brain injuries and the resulting complexities. The families’ words also convey frustrations that can result from a lack of awareness about TBI and its implications for children, adolescents, and young adults, as brain development continues into their 20s. Some common factors in these experiences are relevant to speech-language pathologists who may be called upon to treat communication difficulties in children and adolescents with TBI: The effects of a TBI in childhood are not fully realized right away and, in fact, new challenges can emerge after the individual has become an adult. The full scope of cognitive-communicative issues that results from a TBI often are not recognized in school and community environments, and sometimes, not even at home. There is a lack of recognition of the full scope of cognitive and communication issues and their impact on lifelong learning and living; as a result, there are significant gaps in the available research, especially with respect to evidence-based methods that are likely to improve outcomes for this population. Considerable information exists based on expert opinion about how practitioners and caregivers can support cognition and communication throughout development, but this information is not widely disseminated. Although professionals often discuss and present on these concerns, positive strides have been made in the past decade and sufficient information exists to guide young TBI patients, their families, and the clinicians who treat them. These advances include increased information about cognitive communication after TBI, research on post-TBI developmental issues, and resources for best practice. Immediate Effects Cognitive communication is the ability to use language and underlying skills such as attention, memory, self-awareness, organization, and problem-solving skills to communicate effectively. Cognitive communication combines thinking skills with language. Language skills may appear to have returned after brain injury, particularly in nonstressful situations. However, when the child most needs to communicate at home, in school, and in the community, the spontaneous and unpredictable nature of communication demands can result in decreased language performance. Changes are most likely to be seen at school under the pressures of time, grades, assignments, the struggle to keep up with curricular requirements, and social pragmatic interactions (DePompei & Blosser, 2003). The entire spectrum of TBI—from mild through severe injuries—can have an effect on cognitive-communication issues and the complex academic learning and social interactions that can be involved. A history of a mild brain injury is considered a significant factor that may preclude an athlete from returning to play and may necessitate academic accommodations. The effects of moderate injuries typically are better understood as causing academic struggles as well as an inability to develop adequate social skills. Individuals with severe injuries uniformly receive specialized accommodations in school and community environments within the special education category of TBI. Strategic learning is essential for success at all educational and social levels and often does not develop properly in students with TBI. Strategic learning, an important function that underlies the brain’s capacity to learn, is the ability to extract important information while inhibiting the unimportant features of that information. When a student is presented with a new learning task, the student’s ability to identify meaningful information, generalize or abstract this information, and store it for future use may be impaired. Thus, this student may store details related to less important information and be unable to recall the gist of the new learning task efficiently or successfully. Language and cognitive communicative difficulties are often at the root of these problems and treatment is usually indicated (Blosser & DePompei, 2003; Chapman et al., 1999). Receptive language skills also may be affected and the student may appear not to hear well. In many circumstances, a hearing assessment reveals normal hearing but delayed auditory-processing capacities. The student who may have difficulty processing what is said or written may ask for multiple repetitions, have poor vocabulary recognition, and have difficulty following instructions or remembering what was said. Certain situations such as blast trauma, however, can result in impaired hearing acuity. Therefore, a hearing assessment to rule out or identify a hearing loss should be completed when any receptive language skill is questioned. Long-term Challenges Developmental stages and challenges after TBI can be overlooked because of the erroneous belief that a child who “looks okay” must “be okay.” Therefore, if an educational, behavioral, or social problem emerges several years after an injury, the link between observed problems and a past TBI often is overlooked (Chapman et al., 1999; Yeates & Taylor, 2006; Turkstra et al., 2008). Unlike TBI in an adult, an injury to a child’s brain affects an organ that is still developing. It is often believed that an immature brain may be more plastic or resilient, allowing children to “bounce back” more easily after a TBI. However, recent research demonstrates that the younger a child at the time of injury, the greater the possibility of long-term developmental challenges (Yeates & Taylor, 2006; Turkstra et al., 2008; Babikian & Asarnow, 2009; Hawley et al., 2004). The full impact of an injury to a young brain can become evident over time as the brain fails to mature at the same rate as the child’s physical growth and development. Young children’s cognitive impairments may not be obvious immediately following an injury, but become apparent as the child gets older and faces increasing expectations for new learning and independent, socially appropriate behavior. For example, Chapman, Gamino, and Cook (2009) state that many youths who have experienced a TBI recover to near-normal levels in early-developing, basic cognitive functions such as memory and vocabulary acquisition. However, youths with TBI often are found to have decreased academic and social performance that worsens through adolescence; specific reasons for this performance decline are unclear. Chapman (2006) and Gamino et al. (2009) indicated that TBI in childhood can be followed by a significant decrease in cognitive, social, or behavioral skills at the time of injury and also by a later “stall” (possibly years later) during which failure to develop cognitive, behavioral, or social skills affects learning and the ability to maintain friends and jobs. Figure 1 [PDF] outlines these potential times—immediate and delayed—for loss of learning and social development. Most efforts in rehabilitation focus on the initial dip; few supports are provided for developmental complications—the “stall”—that can occur years later. Given this delay in TBI effects, a student’s cognitive-communication skill development should be followed in the schools and community until high school graduation. These periodic checks are essential to determine if the student’s language learning is sufficient in all developmental stages. The sidebar on p. 18 offers a suggested starting place for following the cognitive-communicative development of these students. Resources and Supports In the past several years, many organizations, materials, and websites have disseminated information about children and TBI. These resources include: Newspapers and magazines. The general public’s interest in pediatric TBI has increased with articles and YouTube videos about concussion and sports injuries. Information about returning military personnel and TBI also has increased public awareness about the cognitive-communicative issues that can alter a person’s ability to perform in school and the community. Journals. Recent issues of Brain Injury Professional, Journal of Head Trauma Rehabilitation, and Neurorehabilitation have focused on pediatrics. National agencies and organizations. ASHA, the Brain Injury Association of America, the National Institute on Disability Rehabilitation Research, and the U.S. Health Resources and Services Administration are advocating for the needs of this population, providing information and materials and offering training opportunities. Websites. See the sidebar on p. 20 for a list of sites that provide significant amounts of information, training, and intervention materials for pediatric TBI. Colleagues. Many professionals share their research and clinical work. Of special interest to SLPs is the website created by the late Mark Ylvisaker, which includes tutorials about underlying processes and methods for analysis, diagnosis, and treatment of cognitive-communicative challenges. National Plan An additional contribution was made by the Sarah Jane Brain Foundation. In January 2009, this foundation brought together 50 researchers, clinicians, and family members and issued a challenge to develop a national plan of care for children, adolescents, and young adults with brain injuries. Within one month, a national Pediatric Acquired Brain Injury Plan (PABI Plan) was created. The PABI Plan outlines seven categories of care for treating brain injuries in children, adolescents, and young adults: Prevention Acute Phase Mild TBI Assessment and Treatment Reintegration and Long-term Care Adult Transition Rural/Telehealth Virtual Center, which provides a family registry and a central location for information and materials about pediatric TBI The extent and scope of the PABI Plan are ambitious, but several benefits have emerged. PABI offers a comprehensive plan that represents best practices and is endorsed by key researchers and clinicians. The major issues and an aggressive plan to address each one are clearly outlined. As a part of the Successful Outcomes plan, each state has a designated lead center that acts as a model and collaborator in the state and communicates with national partners. States can support the plan because each has a stake in the plan’s development, implementation, and benefits. Ideas for funding through federal and state grants are outlined in this document, which can serve to direct and justify future research initiatives. Finally, any organization or agency can use part of this plan to implement its own programs for this population. Successful Treatment The four children and young adults with TBI introduced in the beginning of this article—Jessica, Kiesha, Matthew, and Marvin—were each referred to SLPs who helped them develop cognitive-communicative skills that support them in school and in the community. Jessicareceives multiple therapies in school and has an Individualized Education Program (IEP) that addresses her cognitive-communication challenges. Her SLP reports that she now uses an augmentative and alternative communication device to communicate essential feelings and needs. Kieshawas referred to a neurologist who diagnosed mild seizure activity and prescribed medication. She receives social-pragmatic language intervention from her SLP, and qualifies for services on a 504 plan (for students who need accommodations, but not specialized instruction). She is considering attending a two-year college this fall. Supports to help her achieve success should be provided by the college’s accessibility office and its speech and hearing center. Matthewwas identified for a full assessment and was found to have cognitive-communication challenges based in problems with attention, memory, organization, and expressive language. His IEP includes placement in a regular-education classroom. Marvinwas identified as having cognitive-communication problems with memory, organization, and planning. He is continuing his education at the university with classroom accommodations and supports from the speech and hearing center. These youngsters received appropriate services, in part because evidence-based information is now available, agencies now advocate for this population and provide well-designed educational materials, and more research is available for professionals who are helping them overcome the short- and long-term effects of TBI. Cognitive-Communicative Checklist This list can be used to monitor the cognitive-communicative and language skills of a child with TBI. This list is not all-inclusive and should be modified according to the needs of an individual student. These indications can appear immediately after a TBI or years later, and need to be monitored throughout the student’s academic career. Receptive skills: Can the child understand what is said or written? Becomes confused by lots of spoken or written information Needs information repeated Does not follow conversations Recalls instructions inconsistently Has difficulty understanding spoken words Recalls or understands what has been read with difficulty Expressive skills: Can the child express ideas? Uses limited vocabulary Does not use new vocabulary Uses rude or immature language Retells the same story repeatedly Talks about unrelated topics Talks quickly or non-stop Cognitive-communication skills: Can the child produce and use organized language? Has difficulty expressing thoughts Becomes easily sidetracked Rambles in conversation or writing Provides short answers to questions Leaves out details in a response Loses topic focus and drops out of conversations Loses interest in TV or a movie Does not catch jokes or puns Takes what is said literally Has difficulty with reasoning or idea analysis Needs extra time to understand Isn’t sure how to use new words in conversation or writing Online Resources The following websites offer information on TBI for clinicians, parents, students, teachers, athletic coaches, and others who work with children and young adults: ASHA BrainLine Brain Injury Association of America Brain Injury Partners: Navigating the School System Centers for Disease Control and Prevention Defense and Veteran Brain Injury Center Exceptional Educational Services Lash & Associates Publishing/Training, Inc. LEARNet, Brain Injury Association of New York State Project BRAIN The Sarah Jane Brain Project Academy of Neurologic Communication Disorders and Sciences: Evidence-Based TBI Practice Guidelines References Babikian T., & Asarnow R. (2009). Neurocognitive outcomes and recovery after pediatric TBI: Meta-analysis of the literature.Neuropsychology, 23(3), 283–296. Google Scholar Blosser J. L., & DePompei R. (2003). Pediatric traumatic brain injury: Proactive intervention. New York: Delmar. Google Scholar Chapman S. B. (2006). Neurocognitive stall: A paradox in long term recovery from pediatric brain injury.Brain Injury Professional, 3(4), 10–13. Google Scholar Chapman S. B., Gamino J. F., Cook L. G., Hanten G., Li X., & Levin H. S. (2009).Impaired discourse gist and working memory in children after brain injury.Brain and Language, 97, 178–188. Google Scholar Chapman S. B., Nasits J., Challas J. D., & Billinger A. P. (1999). Long-term recovery in pediatric head injury: Overcoming the hurdles.Advances in Speech Language Pathology, 191, 19–30. Google Scholar DePompei R., & Blosser J. (2003). Communication: How communication changes over time. Wake Forest, NC: LA Publishing/Training. Google Scholar Gamino J. F., Chapman S.B., & Cook L. G. (2009). Strategic learning in youth with traumatic brain injury: Evidence for stall in higher-order cognition.Topics in Language Disorders, 24(3), 1–12. Google Scholar Hawley C., Ward A. B., Magnay A., & Mychalkiw W. (2004). Return to school after brain injury.Archives of Disease in Childhood, 89, 136–142. Google Scholar Turkstra L. S., Williams W. H., Tonks J., & Frampton I. (2008). Measuring social cognition in adolescents: Implications for students with TBI returning to school.NeuroRehabilitation, 23(6), 501–509. CrossrefMedlineGoogle Scholar Yeates K. O., & Taylor G. H. (2006). Behavior problems in school and their educational correlates among children with traumatic brain injury.Exceptionality, 14(3), 141–154. Google Scholar Author Notes Roberta DePompei, CCC-SLP/A, is a distinguished professor and director of the School of Speech-Language Pathology and Audiology at the University of Akron. She is a former co-chair of the Brain Injury Association of America’s Task Force for Children and Adolescents. Her research interests include TBI and resultant cognitive-communication disorders. Contact her at [email protected]. Advertising Disclaimer | Advertise With Us Advertising Disclaimer | Advertise With Us Additional Resources FiguresSourcesRelatedDetails Volume 15Issue 13November 2010 Get Permissions Add to your Mendeley library History Published in print: Nov 1, 2010 Metrics Downloaded 3,053 times Topicsasha-topicsleader_do_tagleader-topicsasha-article-typesCopyright & Permissions© 2010 American Speech-Language-Hearing AssociationLoading ...

Abstracts fromThe 32^nd AnnualNational Neurotrauma SymposiumJune 29–July 2, 2014San Francisco, California

Neuropsychiatric Complications of Traumatic Brain Injury: A Critical Review of the Literature (A Report by the ANPA Committee on Research)

XIII. Antiseizure Prophylaxis

Defense and Veterans Brain Injury Center: The First 25 Years

Background:Neurological dysfunction is a common complication of traumatic brain injury (TBI), and early treatments are critical for the long-term prognosis. This study aimed to investigate whether hypidone hydrochloride (YL-0919) improves neurological function impairment in mice with TBI.Methods:TBI was induced in adult male C57BL/6J mice using the controlled cortical impact (CCI) method. First, the modified neurological severity score (mNSS), rotarod test, and Morris water maze (MWM) test were conducted to assess the impact of YL-0919 on neurological function in mice with TBI. Next, immunofluorescence and laser speckle contrast imaging were utilized to measure the number and activation of microglia and cerebral blood flow (CBF) after TBI. Enzyme-linked immunosorbent assay (ELISA) was employed to assess the inflammatory factors. Finally, Western blotting was performed to measure the expression of proteins. Golgi–Cox staining was utilized to investigate the structure of pyramidal neurons.Results:YL-0919 significantly alleviated neurological dysfunction in TBI+YL-0919 mice compared with TBI+Vehicle mice, increased the time spent on the rotarod (F = 1.297, P <0.05), and partially relieved cognitive dysfunction in TBI mice (for mNSS, F = 5.540, P <0.01; for MWM test, F = 30.78, P <0.05). Additionally, YL-0919 effectively inhibited the proliferation and activation of microglia (both P <0.01), promoted the recovery of CBF around the brain injury site and inhibited the expression of tumor necrosis factor-α (F = 9.142, P <0.05) and IL-1β (F = 4.662, P <0.05), and increased the concentration of IL-4 (F = 5.172, P <0.05). Furthermore, continuous gavage of YL-0919 (2.5 mg/kg) for seven days effectively increased the protein expression of brain-derived neurotrophic factor (BDNF), promoted the phosphorylation of mammalian target of rapamycin (mTOR), increased postsynaptic density protein 95 (PSD95) and synapsin1 levels, and increased the neuronal dendritic complexity and the dendritic spine density around the brain injury site (all P <0.05).Conclusions:Our findings indicated that YL-0919 can ameliorate neurological dysfunction in mice after TBI through the suppression of inflammation and the stimulation of the BDNF-mTOR signaling pathway. These findings provide an insightful perspective on the potential pharmacological mechanism involved in the neuroprotective effect of YL-0919.