Treatment of chronic symptoms following mild traumatic brain injury with transcranial LED: a sham run-in pilot study of photobiomodulation therapy.

PRIMARY OBJECTIVE: We evaluated whether photobiomodulation with red/near infrared light applied transcranially via light emitting diodes (LED) was associated with reduced symptoms and improved cognitive functioning in patients with chronic symptoms following mild traumatic brain injury. RESEARCH DESIGN: Participants (3 men, 6 women; 22-61 years-old) underwent a 6-week intervention involving 18 40-minute transcranial LED treatment sessions. METHODS AND PROCEDURES: Reliable change indices were calculated for 10 neuropsychological test scores and 3 self-report questionnaires of subjective cognition, post-concussion symptoms, and depression at baseline and following treatment. Questionnaires were also administered after 2-week sham and at 1-month and 2-month follow-ups. MAIN OUTCOME AND RESULTS: Only 2 participants improved on neuropsychological testing. On questionnaires, 4 reported improved cognition, 5 reported improved post-concussion symptoms, and 3 reported improved depression. Significant improvement in 2 or more domains was reported by 4 participants and mostly maintained at both follow-ups. CONCLUSIONS: Most participants did not improve on neuropsychological testing. A minority self-reported improvement in symptoms, potentially explained by the intervention, psychiatric medication changes, placebo effects, or other factors. Selecting participants with different clinical characteristics, and dosing and delivery system changes, may produce different results. A study design accounting for placebo effects appears warranted in future trials.

Mild Traumatic Brain Injuries and Risk for Affective and Behavioral Disorders.

OBJECTIVES: Recent studies document an association between mild traumatic brain injuries (mTBIs) in children and postinjury psychiatric disorders. However. these studies were subject to limitations in the design, lack of long-term follow-up, and poorly defined psychiatric outcomes. This study determines the incidence and relative risk of postinjury new affective and behavior disorders 4 years after mTBIs. METHODS: A cohort study of mTBI cases and matched comparisons within an integrated health care system. The mTBI group included patients ≤17 years of age, diagnosed with mTBI from 2000 to 2014 (N = 18 917). Comparisons included 2 unexposed patients (N = 37 834) per each mTBI-exposed patient, randomly selected and matched for age, sex, race/ethnicity, and date of medical visit (reference date to mTBI injury). Outcomes included a diagnosis of affective or behavioral disorders in the 4 years after mTBI or the reference date. RESULTS: Adjusted risks for affective disorders were significantly higher across the first 3 years after injury for the mTBI group, especially during the second year, with a 34% increase in risk. Adjusted risks for behavioral disorders were significant at years 2 and 4, with up to a 37% increase in risk. The age group with the highest risk for postinjury affective and behavioral disorders was 10- to 13-year-old patients. CONCLUSIONS: Sustaining an mTBI significantly increased the risks of having a new affective or behavioral disorder up to 4 years after injury. Initial and ongoing screening for affective and behavior disorders following an mTBI can identify persistent conditions that may pose barriers to recovery.

Osteopathic manipulative treatment for concussions and postconcussive syndrome in athletes: a literature review.

CONTEXT: Concussions are the most common type of traumatic brain injury (TBI) and can often occur in athletes. These injuries have many deleterious acute symptoms and can lead to the development of postconcussive syndrome (PCS). Osteopathic manipulative treatment (OMT) is a treatment option that may benefit patients with concussions and PCS. OBJECTIVES: The objective of this review is to determine whether OMT can improve symptoms associated with concussions and PCS in athletes. METHODS: A comprehensive literature review was conducted between August 2021 and March 2022 by two authors (Z.K.L. and K.D.T.) who searched the literature utilizing PubMed, Google Scholar, and Cochrane Library. Articles reviewed included case reports, case studies, randomized control trials, meta-analyses, and peer-reviewed journal articles. Search terms included concussion, postconcussive symptoms, osteopathic manipulative medicine, and manipulation. To be included into this study, articles must have included OMT from an osteopathic physician or manipulative techniques by nonosteopathic providers for patients with a concussion or PCS, and the insulting injury must have occurred in an athletic setting. No disagreements occurred between authors about what studies to include. However, we were prepared to come to a unanimous decision through discussion among the authors. A narrative synthesis was performed. No other data analyses were conducted in this study. RESULTS: Included in this review were nine articles including randomized control trials, retrospective review, case series, longitudinal, retrospective studies, and case reports. The literature shows the positive effects of OMT and manipulative techniques on symptom resolution after a concussion. However, most of the literature is qualitative rather than quantitative in nature, lacking in randomized control trials. CONCLUSIONS: There is a scarcity of high-quality studies evaluating the effectiveness of OMT on concussions and PCS. More research is needed to understand the degree of benefit for this treatment option.

Acute thalamic connectivity precedes chronic post-concussive symptoms in mild traumatic brain injury.

Chronic post-concussive symptoms are common after mild traumatic brain injury (mTBI) and are difficult to predict or treat. Thalamic functional integrity is particularly vulnerable in mTBI and may be related to long-term outcomes but requires further investigation. We compared structural MRI and resting state functional MRI in 108 patients with a Glasgow Coma Scale (GCS) of 13-15 and normal CT, and 76 controls. We examined whether acute changes in thalamic functional connectivity were early markers for persistent symptoms and explored neurochemical associations of our findings using PET data. Of the mTBI cohort, 47% showed incomplete recovery 6 months post-injury. Despite the absence of structural changes, we found acute thalamic hyperconnectivity in mTBI, with specific vulnerabilities of individual thalamic nuclei. Acute fMRI markers differentiated those with chronic post-concussive symptoms, with time- and outcome-dependent relationships in a sub-cohort followed longitudinally. Moreover, emotional and cognitive symptoms were associated with changes in thalamic functional connectivity to known serotonergic and noradrenergic targets, respectively. Our findings suggest that chronic symptoms can have a basis in early thalamic pathophysiology. This may aid identification of patients at risk of chronic post-concussive symptoms following mTBI, provide a basis for development of new therapies and facilitate precision medicine application of these therapies.

Neck Symptoms and Associated Clinical Outcomes in Patients Following Concussion.

OBJECTIVE: To examine the frequency and association of neck pain symptoms in patients with a concussion. STUDY SETTING AND PARTICIPANTS: Three-hundred and thirty-one consecutively enrolled patients aged 9 to 68 years with a diagnosed concussion 1 to 384 days post-injury were enrolled at a concussion clinic from a single integrated healthcare system in Western Pennsylvania between 2019 and 2021. DESIGN: Retrospective cohort analysis of prospectively collected concussion screening tool intake survey responses and clinical outcomes data. The primary outcome was self-reported neck pain or difficulty with neck movement on the Concussion Clinical Profiles Screening (CP Screen) tool, recovery time, and incidence of treatment referral. Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) composite scores, Vestibular/Ocular Motor Screening (VOMS) item scores, type and severity of neck symptoms, mechanism of injury, time from injury to clinic presentation, medical history, and concussion symptom profile were secondary outcomes. RESULTS: Of the 306 consecutively enrolled eligible patients in the registry, 145 (47%) reported neck pain, 68 (22.2%) reported difficulty moving their neck, and 146 (47.7%) reported either symptom. A total of 47 (15.4%) participants reported more severe neck symptoms, and this group took longer to recover (40 ± 27 days) than those not reporting neck symptoms (30 ± 28 days; U = 8316, P < .001). Stepwise logistic regression predicting more severe neck symptoms was significant (Nagelkerke R2 = 0.174, χ 2 = 9.315, P = .316) with older age ( P = .019) and mechanism of injury including motor vehicle collisions (MVCs) ( P = .047) and falls ( P = .044) as risk factors. MVCs and falls were associated with over 4 times and 2 times greater risk, respectively, for reporting more severe neck symptoms. CONCLUSION: Neck pain and stiffness symptoms are common in patients with a concussion following high-energy mechanisms of injury including MVCs or falls from height. These symptoms are associated with prolonged recovery. Providers should evaluate neck symptoms and consider targeted treatment strategies to limit their effects in patients with a concussion.

Thalamic subfield iron accumulation after acute mild traumatic brain injury as a marker of future post-traumatic headache intensity.

OBJECTIVE: To explore alterations in thalamic subfield volume and iron accumulation in individuals with post-traumatic headache (PTH) relative to healthy controls. BACKGROUND: The thalamus plays a pivotal role in the pathomechanism of pain and headache, yet the role of the thalamus in PTH attributed to mild traumatic brain injury (mTBI) remains unclear. METHODS: A total of 107 participants underwent multimodal T1-weighted and T2* brain magnetic resonance imaging. Using a clinic-based observational study, thalamic subfield volume and thalamic iron accumulation were explored in 52 individuals with acute PTH (mean age = 41.3; standard deviation [SD] = 13.5), imaged on average 24 days post mTBI, and compared to 55 healthy controls (mean age = 38.3; SD = 11.7) without history of mTBI or migraine. Symptoms of mTBI and headache characteristics were assessed at baseline (0-59 days post mTBI) (n = 52) and 3 months later (n = 46) using the Symptom Evaluation of the Sports Concussion Assessment Tool (SCAT-5) and a detailed headache history questionnaire. RESULTS: Relative to controls, individuals with acute PTH had significantly less volume in the lateral geniculate nucleus (LGN) (mean volume: PTH = 254.1, SD = 43.4 vs. controls = 278.2, SD = 39.8; p = 0.003) as well as more iron deposition in the left LGN (PTH: T2* signal = 38.6, SD = 6.5 vs. controls: T2* signal = 45.3, SD = 2.3; p = 0.048). Correlations in individuals with PTH revealed a positive relationship between left LGN T2* iron deposition and SCAT-5 symptom severity score at baseline (r = -0.29, p = 0.019) and maximum headache intensity at the 3-month follow-up (r = -0.47, p = 0.002). CONCLUSION: Relative to healthy controls, individuals with acute PTH had less volume and higher iron deposition in the left LGN. Higher iron deposition in the left LGN might reflect mTBI severity and poor headache recovery.

Concussion-related visual memory and reaction time impairment in college athletes improved after osteopathic manipulative medicine: a randomized clinical trial.

CONTEXT: Concussion is an acute, transient disruption in brain function due to head injury. Previous studies suggest osteopathic manipulative medicine (OMM) improved recovery from concussion. OBJECTIVES: The hypothesis was that new-onset impairments (NOI) of neurological functions identified by Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) will improve more so after OMM than after concussion-education. METHODS: College athletes presenting to the outpatient academic healthcare center (AHCC) with concussion due to head injury within the preceding 2 weeks were recruited for this IRB-approved, randomized, single-blinded trial. Consented men and women were randomized into groups receiving two OMM treatments or two concussion-education sessions to control for social effects. Preseason, Baseline, ImPACT was compared to Post-Injury scores to determine NOI. Baseline, Post-Injury, and Post-Interventions ImPACTs were compared by analysis of variance (ANOVA, α≤0.05). Post-Injury correlations and mean changes in King-Devick (KD) scores were analyzed. RESULTS: Post-Injury NOI were found in 77.8% (14/18) men and 85.7% (6/7) women, including ImPACT subscore indices for verbal and visual memory, processing speed (PS), and reaction time (RT). Of those with NOI, mean visual memory recovered by 50.0% following one and by 104.9% (p=0.032) following two OMM treatments in men and by 82.8% (p=0.046) following one treatment in women. Following two interventions, the mean RT in men receiving OMM improved by 0.10 more than education (p=0.0496). The effect sizes of OMM were large (Cohen's d=1.33) on visual memory and small (Cohen's d=0.31) on RT. CONCLUSIONS: The NOI in visual memory and RT following concussion significantly improved in the OMM group compared to the education group. Integrating OMM utilizing physical exam and this treatment was a safe individualized approach in athletes with acute uncomplicated concussions. Further research is warranted to improve the utilization of OMM for individuals with concussion.

Can mild traumatic brain injury alter cognition chronically? A LIMBIC-CENC multicenter study.

OBJECTIVE: While outcome from mild traumatic brain injury (mTBI) is generally favorable, concern remains over potential negative long-term effects, including impaired cognition. This study examined the link between cognitive performance and remote mTBIs within the Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) multicenter, observational study of Veterans and service members (SMs) with combat exposure. METHOD: Baseline data of the participants passing all cognitive performance validity tests (n = 1,310) were used to conduct a cross-sectional analysis. Using multivariable regression models that adjusted for covariates, including age and estimated preexposure intellectual function, positive mTBI history groups, 1-2 lifetime mTBIs (nonrepetitive, n = 614), and 3 + lifetime mTBIs (repetitive; n = 440) were compared to TBI negative controls (n = 256) on each of the seven cognitive domains computed by averaging Z scores of prespecified component tests. Significance levels were adjusted for multiple comparisons. RESULTS: Neither of the mTBI positive groups differed from the mTBI negative control group on any of the cognitive domains in multivariable analyses. Findings were also consistently negative across sensitivity analyses (e.g., mTBIs as a continuous variable, number of blast-related mTBIs, or years since the first and last mTBI). CONCLUSIONS: Our findings demonstrate that the average veteran or SM who experienced one or more mTBIs does not have postacute objective cognitive deficits due to mTBIs alone. A holistic health care approach including comorbidity assessment is indicated for patients reporting chronic cognitive difficulties after mTBI(s), and strategies for addressing misattribution may be beneficial. Future study is recommended with longitudinal designs to assess within-subjects decline from potential neurodegeneration. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Prophylactic zinc supplementation modulates hippocampal ionic zinc and partially remediates neurological recovery following repetitive mild head injury in mice.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition caused by repetitive mild traumatic brain injury (TBI) that leads to impaired executive functioning, emotional disturbances, and disordered memory, warranting both basic and translational research of potential therapeutic targets. One area of research concerns prophylactic zinc (Zn) supplementation; however, Zn supplementation remains poorly understood. This study explored the effects of Zn supplementation in a mouse model of repetitive mild TBI. Four-week-old male (n = 50) and female (n = 50) C57BL/6J mice consumed tap water or 10 parts per million Zn-supplemented water for eight weeks prior to injury. At 12 weeks of age, mice underwent either five sham procedures or five closed-head injuries spaced apart by 48 h after which they completed behavioral tests. Zinc-supplemented injured mice righted themselves and regained normal ambulatory function as fast as non-injured mice across four out of the five injury days. In contrast, non-supplemented injured mice exhibited impairment in normal ambulation by days 4 and 5. Injury also reduced free, ionic Zn in the dentate gyrus and CA3 region of the hippocampus and Zn supplementation partially remediated this reduction but not to the levels of non-injured mice. There were no structural differences in cortex, hippocampus, striatum, and corpus callosum, suggesting that Zn reduction was not due to macroscopic abnormalities. Overall, these results suggest that Zn may improve short-term and physical neurological recovery, but it may not be sufficient as a single pre-treatment for consequences of repetitive mild TBI such as cognitive impairment. These results further demonstrate the need for additional research documenting the underlying mechanisms of Zn in TBI-related neuropathology.

Mitoquinone supplementation alleviates oxidative stress and pathologic outcomes following repetitive mild traumatic brain injury at a chronic time point.

Traumatic brain injury (TBI) is a major cause of disability and death. Mild TBI (mTBI) constitutes ~75% of all TBI cases. Repeated exposure to mTBI (rmTBI), leads to the exacerbation of the symptoms compared to single mTBI. To date, there is no FDA-approved drug for TBI or rmTBI. This research aims to investigate possible rmTBI neurotherapy by targeting TBI pathology-related mechanisms. Oxidative stress is partly responsible for TBI/rmTBI neuropathologic outcomes. Thus, targeting oxidative stress may ameliorate TBI/rmTBI consequences. In this study, we hypothesized that mitoquinone (MitoQ), a mitochondria-targeted antioxidant, would ameliorate TBI/rmTBI associated pathologic features by mitigating rmTBI-induced oxidative stress. To model rmTBI, C57BL/6 mice were subjected to three concussive head injuries. MitoQ (5 mg/kg) was administered intraperitoneally to rmTBI+MitoQ mice twice per week over one month. Behavioral and cognitive outcomes were assessed, 30 days following the first head injury, using a battery of behavioral tests. Immunofluorescence was used to assess neuroinflammation and neuronal integrity. Also, qRT-PCR was used to evaluate the expression levels of antioxidant enzymes. Our findings indicated that MitoQ alleviated fine motor function and learning impairments caused by rmTBI. Mechanistically, MitoQ reduced astrocytosis, microgliosis, dendritic and axonal shearing, and increased the expression of antioxidant enzymes. MitoQ administration following rmTBI may represent an efficient approach to ameliorate rmTBI neurological and cellular outcomes with no observable side effects.

Fatigue After Traumatic Brain Injury: A Systematic Review.

OBJECTIVE: To provide a systematic review of published interventions for posttraumatic brain injury fatigue (PTBIF). METHODS: PubMed and OneSearch were systematically searched for PTBIF interventions published between January 1, 1989, and March 31, 2019. Search results were evaluated for inclusion based on an abstract and full-text review. Inclusion criteria were (1) an investigation of an intervention, (2) participant sample including individuals with traumatic brain injury (TBI), (3) report of fatigue outcome data among individuals with TBI, and (4) articles available in English, Spanish, French, German, Afrikaans, or Dutch. A risk of bias assessment was conducted on all included publications. RESULTS: The search resulted in 2343 publications, with 37 meeting inclusion criteria for this review. Categories of PTBIF interventions were pharmacological ( n = 13), psychological ( n = 9), exercise-based ( n = 4), complementary alternative medicine ( n = 5), electrotherapeutic ( n = 3), and multimodal ( n = 3). Only methylphenidate, modafinil, and cognitive behavioral therapy interventions included multiple cohorts. Pharmacological and psychological interventions represented the groups with the lowest risk of bias. CONCLUSIONS: This review includes 37 studies, with 21 studies published after 2014. Methylphenidate and melatonin were the only pharmacological agents found to reduce fatigue in randomized controlled trials. Creatine given to children prospectively at onset of injury reduced fatigue at follow-up. Walking and water aerobics were effective exercise interventions in isolated randomized controlled studies. One multimodal study of children after concussion was more effective at reducing fatigue and postconcussion symptoms than community standard of care. Other interventions had equivocal results. Overall, more work remains to understand and develop treatments for PTBIF.

Prevalence of depression and anxiety disorders following mild traumatic brain injury.

BACKGROUND: Previous studies have identified an association between traumatic brain injuries and the development of psychiatric disorders in general. However, these studies were subject to limitations that demonstrate the need for a study of a large, clearly defined mild traumatic brain injury (mTBI) population within an integrated healthcare system. OBJECTIVE: To determine the prevalence and relative risk of postinjury affective disorders over 4 years following mTBI. DESIGN: Cohort study of mTBI cases and matched controls, over a 4-year period. SETTING: An integrated healthcare delivery system in California. PATIENTS: A total of 9428 adult health plan members diagnosed with mTBI from 2000-2007 and enrolled in the year before injury, during which no TBI was ascertained. Control participants included 18,856 individuals selected based on the following criteria: Two unexposed health plan members per each mTBI-exposed patient were randomly selected and individually matched for age, gender, race/ethnicity, and medical comorbidities. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: A diagnosis of affective disorder (depressive, anxiety, and adjustment disorders) in the 4 years after mTBI or the reference date, determined according to the International Classification of Diseases, Ninth Revision, Clinical Modification as well as the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. RESULTS: Affective disorders were most prominent during the first 12 months with 23% following mTBI and 14% in the control group. Four-year aggregate adjusted odds ratios for having an affective disorder following mTBI were 1.2 (95% CI: 1.1, 1.2; p < .001) and 1.5 (95% CI: 1.5, 1.6; p < .001) for patients with and without prior affective disorders, respectively. CONCLUSION: mTBI was associated with a significantly increased risk of having subsequent affective disorders. Screening for and addressing affective disorders at earlier stages following the injury is an important step to avoid persisting conditions that may pose a barrier to full recovery.

Sports-Related Brain Injury and Neurodegeneration in Athletes.

Sports deserve a special place in human life to impart healthy and refreshing wellbeing. However, sports activities, especially contact sports, renders athlete vulnerable to brain injuries. Athletes participating in a contact sport like boxing, rugby, American football, wrestling, and basketball are exposed to traumatic brain injuries (TBI) or concussions. The acute and chronic nature of these heterogeneous injuries provides a spectrum of dysfunctions that alters the neuronal, musculoskeletal, and behavioral responses of an athlete. Many sports-related brain injuries go unreported, but these head impacts trigger neurometabolic disruptions that contribute to long-term neuronal impairment. The pathophysiology of post-concussion and its underlying mechanisms are undergoing intense research. It also shed light on chronic disorders like Parkinson's disease, Alzheimer's disease, and dementia. In this review, we examined post-concussion neurobehavioral changes, tools for early detection of signs, and their impact on the athlete. Further, we discussed the role of nutritional supplements in ameliorating neuropsychiatric diseases in athletes.

An interdisciplinary approach to the screening, diagnosis, and treatment of OEF/OIF Veterans with mild traumatic brain injury.

OBJECTIVE: To implement an Integrated TBI Screening Clinic (ITSC) during the mandatory TBI evaluation process at the Department of Veterans Affairs. Referral outcomes were examined regarding Veterans who were determined to need a full neuropsychological evaluation versus those for whom mental health treatment was clinically indicated. Correlations among cognitive measures, posttraumatic stress disorder (PTSD), anxiety, depression, and insomnia symptoms were also examined. METHOD: This study was a retrospective chart review study that included 138 Veterans seen between 2011 and 2014 in a post-deployment primary care clinic. Descriptive statistics and correlations were completed using the: screening Module of the Neuropsychological Assessment Battery (S-NAB), PTSD Checklist-Military version (PCL-M), Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and Insomnia Severity Index (ISI). RESULTS: 19.8% of Veterans required a referral for a full neuropsychological exam and 72.7% were referred for additional mental health services (with some Veterans being referred to both). Significant correlations were found among higher PTSD, depression, anxiety symptoms, with poorer attention and memory (all p < .05). Only PTSD was significantly correlated with poorer executive functioning (r = 0.19, p < .05). CONCLUSION: Integration of a multidisciplinary neuropsychological screening exam during a primary care visit with OEF/OIF Veterans may assist in better delineating symptoms.

Systemic Elevation of n-3 Polyunsaturated Fatty Acids (n-3-PUFA) Is Associated with Protection against Visual, Motor, and Emotional Deficits in Mice following Closed-Head Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration leading to various pathological complications such as motor and sensory (visual) deficits, cognitive impairment, and depression. N-3 polyunsaturated fatty acid (n-3 PUFA) containing lipids are known to be anti-inflammatory, whereas the sphingolipid, ceramide (Cer), is an inducer of neuroinflammation and degeneration. Using Fat1+-transgenic mice that contain elevated levels of systemic n-3 PUFA, we tested whether they are resistant to mild TBI-mediated sensory-motor and emotional deficits by subjecting Fat1-transgenic mice and their WT littermates to focal cranial air blast (50 psi) or sham blast (0 psi, control). We observed that visual function in WT mice was reduced significantly following TBI but not in Fat1+-blast animals. We also found Fat1+-blast mice were resistant to the decline in motor functions, depression, and fear-producing effects of blast, as well as the reduction in the area of oculomotor nucleus and increase in activated microglia in the optic tract in brain sections seen following blast in WT mice. Lipid and gene expression analyses confirmed an elevated level of the n-3 PUFA eicosapentaenoic acid (EPA) in the plasma and brain, blocking of TBI-mediated increase of Cer in the brain, and decrease in TBI-mediated induction of Cer biosynthetic and inflammatory gene expression in the brain of the Fat1+ mice. Our results demonstrate that suppression of ceramide biosynthesis and inflammatory factors in Fat1+-transgenic mice is associated with significant protection against the visual, motor, and emotional deficits caused by mild TBI. This study suggests that n-3 PUFA (especially, EPA) has a promising therapeutic role in preventing neurodegeneration after TBI.

Factors Associated with the Development of Persistent Pain after mTBI.

BACKGROUND: Persistent pain after mild traumatic brain injury (mTBI) is widely experienced, yet little is known about who is at risk for experiencing persistent pain after their injury. AIMS: The purpose of this study was to 1) determine if there are factors associated with later experiencing persistent pain after mTBI and 2) examine if there are symptom patterns associated with the experience of persistent pain. DESIGN: Secondary analysis was conducted using de-identified data from an NIH-funded longitudinal study.SettingsParticipants were enrolled in the emergency department. PARTICIPANTS: Participants were aged 21 to 92 and all had experienced mTBI. METHODS: We examined baseline characteristics, symptoms, and injury related variables associated with the endorsement of persistent pain among those with mTBI (N = 183) from baseline to 6 months post-injury. In order to identify a persistent pain phenotype, exploratory factor analysis was used to determine which symptoms co-occur with persistent pain. RESULTS: Persistent pain was found in 78% of those with mTBI. Those with lower overall health status at day 7 and at 1-month following injury had greater odds of developing persistent pain. Those with higher levels of general health status and physical function health status at day 7 and 1 month, and those with higher levels of overall health related status at 1 month had significantly lesser odds of persistent pain at 6 months. Factor analysis revealed that persistent pain and co-occurring symptoms (anxiety, depression, dizziness, nausea and vomiting, sleep disturbance, poor memory, poor concentration, longer to think and light sensitivity) loaded on one factor, indicating that these symptoms are associated. CONCLUSIONS: Those at increased risk for persistent pain should be screened beginning early in the recovery trajectory to reduce their risk of developing persistent pain. Identification of a phenotype offers potential for recognition of symptoms that cluster with persistent pain, improving the ability to treat patients more holistically, and develop interventions to support recovery from injury.

Early Stage Longitudinal Subcortical Volumetric Changes following Mild Traumatic Brain Injury.

Objective: To investigate early brain volumetric changes from acute to 6 months following mild traumatic brain injury (mTBI) in deep gray matter regions and their association with patient 6-month outcome.Methods: Fifty-six patients with mTBI underwent MRI and behavioral evaluation at acute (<10 days) and approximately 1 and 6 months post injury. Regional volume changes were investigated in key gray matter regions: thalamus, hippocampus, putamen, caudate, pallidum, and amygdala, and compared with volumes from 34 healthy control subjects. In patients with mTBI, we further assessed associations between longitudinal regional volume changes with patient outcome measures at 6 months including post-concussive symptoms, cognitive performance, and overall satisfaction with life.Results: Reduction in thalamic and hippocampal volumes was observed at 1 month among patients with mTBI. Such volume reduction persisted in the thalamus until 6 months. Changes in thalamic volumes also correlated with multiple symptom and functional outcome measures in patients at 6 months.Conclusion: Our results indicate that the thalamus may be differentially affected among patients with mTBI, resulting in both structural and functional deficits with subsequent post-concussive sequelae and may serve as a biomarker for the assessment of efficacy of novel therapeutic interventions.

The association of concussion history and symptom presentation in combat sport athletes.

OBJECTIVE: The purpose of this study was to describe the concussion-related symptoms reported among combat sport athletes with and without a history of concussion, and a history of neck injury. DESIGN: Cross-sectional survey. SETTING: Data were collected using an online survey instrument. PARTICIPANTS: Three hundred and nine adult combat sport athletes. MAIN OUTCOME MEASURES: Self-reported 12-month concussion history and neck injury history and a 22-item symptom checklist. RESULTS: A history of concussion was reported by 19.1% of athletes, a history of neck injury was reported by 23.0%, and 13.6% reported both injuries. Neck pain was the most frequently reported symptom. Athletes with a history of injury had significantly greater proportions of 'high' total symptoms and symptom severity scores compared with athletes with no history of injury. Athletes with a history of concussion had 2.35 times higher odds of reporting 'high' total symptoms and symptoms severity scores. CONCLUSION: Athletes with a history of concussion or neck injury have greater odds of presenting with higher symptom scores. The presence of high total symptom scores and high symptom severity scores may indicate a need for further investigation into domains commonly associated with concussion.

Impaired Glutamate Receptor Function Underlies Early Activity Loss of Ipsilesional Motor Cortex after Closed-Head Mild Traumatic Brain Injury.

Although mild traumatic brain injury (mTBI) accounts for the majority of TBI patients, the effects and cellular and molecular mechanisms of mTBI on cortical neural circuits are still not well understood. Given the transient and non-specific functional deficits after mTBI, it is important to understand whether mTBI causes functional deficits of the brain and the underlying mechanism, particularly during the early stage after injury. Here, we used in vivo optogenetic motor mapping to determine longitudinal changes in cortical motor map and in vitro calcium imaging to study how changes in cortical excitability and calcium signals may contribute to the motor deficits in a closed-head mTBI model. In channelrhodopsin 2 (ChR2)-expressing transgenic mice, we recorded electromyograms (EMGs) from bicep muscles induced by scanning blue laser on the motor cortex. There were significant decreases in the size and response amplitude of motor maps of the injured cortex at 2 h post-mTBI, but an increase in motor map size of the contralateral cortex in 12 h post-mTBI, both of which recovered to baseline level in 24 h. Calcium imaging of cortical slices prepared from green fluorescent calmodulin proteins-expressing transgenic mice showed a lower amplitude, but longer duration, of calcium transients of the injured cortex in 2 h post-mTBI. Blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or N-methyl-d-aspartate receptors resulted in smaller amplitude of calcium transients, suggesting impaired function of both receptor types. Imaging of calcium transients evoked by glutamate uncaging revealed reduced response amplitudes and longer duration in 2, 12, and 24 h after mTBI. Higher percentages of neurons of the injured cortex had a longer latency period after uncaging than that of the uninjured neurons. The results suggest that impaired glutamate neurotransmission contributes to functional deficits of the motor cortex in vivo, which supports enhancing glutamate neurotransmission as a potential therapeutic approach for the treatment of mTBI.

Long Chain Omega-3 Fatty Acid Intervention in Ageing Adults at Risk of Dementia Following Repeated Head Trauma. Low-level Support or an Opportunity for an Unanswered Question?

Emerging evidence of brain injury on risk of neurodegenerative diseases such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) have resulted in interest in therapeutic potential of omega-3 fatty acids (n-3FA). We conducted a systematic review of n-3FA therapeutic efficacy for ageing adults at risk of AD/CTE following a history of repeated head trauma. Databases for articles between 1980-June 2020 were examined for studies reporting on n-3 FAs in adults (≥ 45 years) with a history of repeated brain injury. Following an initial screen of 175 articles, 12 studies were considered but were eventually rejected, as they did not meet inclusion criteria. Our review could find no evidence to support, or disprove, effectiveness of n-3FA intervention in older adults with a history of head trauma. With animal studies showing neuro-restorative potential of n-3FA following brain injury, this review highlights the urgent need for human research in this area.