A cautionary tale on the effects of different covariance structures in linear mixed effects modeling of fMRI data.

With the steadily increasing abundance of longitudinal neuroimaging studies with large sample sizes and multiple repeated measures, questions arise regarding the appropriate modeling of variance and covariance. The current study examined the influence of standard classes of variance-covariance structures in linear mixed effects (LME) modeling of fMRI data from patients with pediatric mild traumatic brain injury (pmTBI; N = 181) and healthy controls (N = 162). During two visits, participants performed a cognitive control fMRI paradigm that compared congruent and incongruent stimuli. The hemodynamic response function was parsed into peak and late peak phases. Data were analyzed with a 4-way (GROUP×VISIT×CONGRUENCY×PHASE) LME using AFNI's 3dLME and compound symmetry (CS), autoregressive process of order 1 (AR1), and unstructured (UN) variance-covariance matrices. Voxel-wise results dramatically varied both within the cognitive control network (UN>CS for CONGRUENCY effect) and broader brain regions (CS>UN for GROUP:VISIT) depending on the variance-covariance matrix that was selected. Additional testing indicated that both model fit and estimated standard error were superior for the UN matrix, likely as a result of the modeling of individual terms. In summary, current findings suggest that the interpretation of results from complex designs is highly dependent on the selection of the variance-covariance structure using LME modeling.

Early Blood-Brain Barrier Impairment as a Pathological Hallmark in a Novel Model of Closed-Head Concussive Brain Injury (CBI) in Mice.

Concussion, caused by a rotational acceleration/deceleration injury mild enough to avoid structural brain damage, is insufficiently captured in recent preclinical models, hampering the relation of pathophysiological findings on the cellular level to functional and behavioral deficits. We here describe a novel model of unrestrained, single vs. repetitive concussive brain injury (CBI) in male C56Bl/6j mice. Longitudinal behavioral assessments were conducted for up to seven days afterward, alongside the evaluation of structural cerebral integrity by in vivo magnetic resonance imaging (MRI, 9.4 T), and validated ex vivo by histology. Blood-brain barrier (BBB) integrity was analyzed by means of fluorescent dextran- as well as immunoglobulin G (IgG) extravasation, and neuroinflammatory processes were characterized both in vivo by positron emission tomography (PET) using [18F]DPA-714 and ex vivo using immunohistochemistry. While a single CBI resulted in a defined, subacute neuropsychiatric phenotype, longitudinal cognitive testing revealed a marked decrease in spatial cognition, most pronounced in mice subjected to CBI at high frequency (every 48 h). Functional deficits were correlated to a parallel disruption of the BBB, (R2 = 0.29, p < 0.01), even detectable by a significant increase in hippocampal uptake of [18F]DPA-714, which was not due to activation of microglia, as confirmed immunohistochemically. Featuring a mild but widespread disruption of the BBB without evidence of macroscopic damage, this model induces a characteristic neuro-psychiatric phenotype that correlates to the degree of BBB disruption. Based on these findings, the BBB may function as both a biomarker of CBI severity and as a potential treatment target to improve recovery from concussion.

Comparación de la efectividad entre distintas intervenciones en los síntomas posconmoción en adolescentes y jóvenes: una revisión bibliográfica / Comparison of effectiveness between different interventions in postconcussive symptoms in adolescents and young people: A literature review

Introducción: Actualmente la conmoción cerebral se considera un problema de gran magnitud, siendo los adolescentes y jóvenes la población de riesgo, ya que se encuentran en proceso de maduración. Nuestro objetivo ha sido comparar la eficacia de diferentes intervenciones (ejercicio físico terapéutico, terapia vestibular y descanso) en adolescentes y jóvenes con conmoción cerebral.Desarrollo: Se realizó una búsqueda bibliográfica en las principales bases de datos. Una vez aplicados los criterios de inclusión/exclusión y la escala metodológica Physiotherapy Evidence Database PEDro, fueron revisados seis artículos. Los resultados apoyan la utilización del ejercicio y la terapia vestibular en las etapas iniciales para disminuir los síntomas posconmoción. Según la mayoría de los autores, el ejercicio físico terapéutico y la terapia vestibular reportan mayores beneficios, aunque se necesitaría un protocolo que unificara escalas de valoración, variables de estudio y parámetros de análisis para poder realizar la inferencia en la población diana.Conclusión: Desde el momento del alta hospitalaria del paciente, la aplicación combinada de ejercicio físico y terapia vestibular, podría considerarse como la mejor opción para disminuir los síntomas posconmoción.(AU)

Introduction: Currently, concussion considers a problem of great magnitude, adolescents and young people being the population at risk, since it is in the process of maturation. Our goal has been to compare the effectiveness of different interventions (exercise therapy, vestibular rehabilitation and rest) in adolescents and young people with concussion. Development: A bibliographic search was carried out in the main databases. Once the inclusion / exclusion criteria and the PEDro methodological scale were applied, 6 articles were reviewed. The results support the use of exercise and vestibular rehabilitation in the initial stages to reduce post-concussion symptoms. According to most authors, therapeutic physical exercise and vestibular rehabilitation report greater benefits, although a protocol that unifies assessment scales, study variables and analysis parameters would be needed to be able to make the inference in the target population. Conclusión: From the moment of hospital discharge, the combined application of exercise and vestibular rehabilitation could be the best option to reduce post-concussion symptoms.(AU)

Applying the Common-Sense Self-Regulation Model to Understand Illness Representations of Mild Traumatic Brain Injury in College Students.

OBJECTIVE: The Common Sense Model (CSM) describes cognitive, emotional, and psychosocial factors that influence how health threats are processed and subsequently inform health-related decisions or actions. The purpose of this study was to examine psychosocial factors influencing coherence, or usefulness, of mild traumatic brain injury (mTBI) representations and their relationship to health-related decisions and actions. SETTING: Public university. PARTICIPANTS: There were 458 graduate and undergraduate college students who participated in a web-based survey (mean age = 22 years; SD = 3.6). DESIGN: A mixed-methods design randomized participants into 2 groups to examine perceptions of mTBI across differing injury mechanisms, or causes, by comparing actions recommended to a friend (Other; n = 214) with those generated for self (Self; n = 244). MAIN MEASURES: Seven common injury mechanisms representative of university student mTBI experiences were presented as vignettes (cause). Each vignette included open- and closed-ended questions framed from CSM constructs (identity, consequences, action plans, timeline, and social context). Data were analyzed using a series of chi-square tests and multiple analysis of variance. Post hoc analysis identified differences in the injury vignettes. RESULTS: Students were more likely to identify the injury as mTBI ( = 8.62, P = .035) and recommend immediate healthcare (F1,415 = 316.89, P < .001) for all causes if the injury occurred to a friend as compared with themselves. Action plans also varied by cause, with post hoc analysis revealing a higher likelihood of healthcare seeking for motor vehicle crashes and assault and a lower likelihood for falls while intoxicated. Students were generally more likely to talk to closest confidants than doctors (F8,398 = 33.66, P < .001). CONCLUSION: Cause appears to be a key construct in generating illness representations and associated action plans for seeking care, with lower perceived severity causes (eg, falls) resulting in little to no health-seeking action. In addition, social support appears to be important for college students when making decisions about their health.

Associations of Nightmares and Sleep Disturbance With Neurobehavioral Symptoms Postconcussion.

OBJECTIVE: This study investigates the association of nightmares beyond general sleep disturbance on neurobehavioral symptoms in adults with mild traumatic brain injury (mTBI). DESIGN: Secondary analysis of a concussion cohort study. PARTICIPANTS: One hundred and eleven adults older than 20 years with mTBI were recruited from a specialized concussion treatment center. MAIN MEASURES: Behavioral Assessment Screening Tool, Pittsburgh Sleep Quality Index, and self-report of nightmare frequency in the past 2 weeks. RESULTS: Among adults with mTBI, nightmares accounted for the greatest amount of variability in negative affect (ß = .362, P < .001), anxiety (ß = .332, P < .001), and impulsivity (ß = .270, P < .001) after adjusting for age and sex. Overall sleep disturbance had the strongest association with depression (ß = .493, P < .001), fatigue (ß = .449, P < .001), self-reported executive dysfunction (ß = .376, P < .001), and overall burden from concussive symptoms (ß = .477, P < .001). CONCLUSIONS: Nightmares and sleep disturbance are differentially associated with variance in neurobehavioral symptoms. Nightmares were independently associated with neurobehavioral symptoms representing an excess of normal functioning (eg, anxiety, impulsivity), while general sleep disturbance was associated with neurobehavioral symptoms representing functioning below normal levels (eg, depression, fatigue, self-reported executive dysfunction). Clinical and research implications are discussed.

Interaction of obesity and proteins associated with the NLRP3 inflammasome following mild traumatic brain injury.

The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome has been associated with worse outcomes from severe traumatic brain injury (TBI). The NLRP3 inflammasome is also strongly associated with other pro-inflammatory conditions, such as obesity. Little is known about the potential effect of mild TBI (mTBI) on the NLRP3 inflammasome and the extent to which modifying factors, such as obesity, may augment the inflammatory response to mTBI. The purpose of this study was to evaluate the association of NLRP3 inflammasome proteins with obese body mass index (BMI ≥ 30) within 24 h of mTBI after presenting to a level 1 trauma center emergency department. This is a secondary analysis of prospectively enrolled patients with mTBI who presented to the emergency department of one U.S. Level 1 trauma center from 2013 to 2018 (n = 243). A series of regression models were built to evaluate the association of NLRP3 proteins obtained from blood plasma within 24 h of injury and BMI as well as the potential interaction effect of higher BMI with NLRP3 proteins (n = 243). A logistic regression model revealed a significant association between IL-18 (p < 0.001) in mTBI patients with obese BMI compared to mTBI patients with non-obese BMI (< 30). Moderation analyses revealed statistically significant interaction effects between apoptotic speck-like protein (ASC), caspase-1, IL-18, IL-1ß and obese BMI which worsened symptom burden, quality of life, and physical function at 2 weeks and 6 months post-injury. Higher acute concentrations of IL-1ß in the overall cohort predicted higher symptoms at 6-months and worse physical function at 2-weeks and 6-months. Higher acute concentrations of IL-18 in the overall cohort predicted worse physical function at 6-months. In this single center mTBI cohort, obese BMI interacted with higher acute concentrations of NLRP3 inflammasome proteins and worsened short- and long-term clinical outcomes.

Modified Mouse Model of Repetitive Mild Traumatic Brain Injury Incorporating Thinned-Skull Window and Fluid Percussion.

Mild traumatic brain injury is a clinically highly heterogeneous neurological disorder. Highly reproducible traumatic brain injury (TBI) animal models with well-defined pathologies are urgently needed for studying the mechanisms of neuropathology after mild TBI and testing therapeutics. Replicating the entire sequelae of TBI in animal models has proven to be a challenge. Therefore, the availability of multiple animal models of TBI is necessary to account for the diverse aspects and severities seen in TBI patients. CHI is one of the most common methods for fabricating rodent models of rmTBI. However, this method is susceptible to many factors, including the impact method used, the thickness and shape of the skull bone, animal apnea, and the type of head support and immobilization utilized. The aim of this protocol is to demonstrate a combination of the thinned-skull window and fluid percussion injury (FPI) methods to produce a precise mouse model of CHI-associated rmTBI. The primary objective of this protocol is to minimize factors that could impact the accuracy and consistency of CHI and FPI modeling, including skull bone thickness, shape, and head support. By utilizing a thinned-skull window method, potential inflammation due to craniotomy and FPI is minimized, resulting in an improved mouse model that replicates the clinical features observed in patients with mild TBI. Results from behavior and histological analysis using hematoxylin and eosin (HE) staining suggest that rmTBI can lead to a cumulative injury that produces changes in both behavior and gross morphology of the brain. Overall, the modified CHI-associated rmTBI presents a useful tool for researchers to explore the underlying mechanisms that contribute to focal and diffuse pathophysiological changes in rmTBI.

The diagnosing and treatment of concussions.

Mild traumatic brain injury, such as concussion, was once considered self-resolving. However, over the past decade, increased understanding of the short- and long-term impact has led to new guidelines for active management. In this review, we summarise recent findings, covering diagnostic criteria, and management for early and persistent symptoms. Many of the postconcussive symptoms can be treated and an individualised approach from a biopsychosocial perspective is recommended. Overall, the new knowledge will significantly impact patient care and future research.

Sex differences in the extent of acute axonal pathologies after experimental concussion.

Although human females appear be at a higher risk of concussion and suffer worse outcomes than males, underlying mechanisms remain unclear. With increasing recognition that damage to white matter axons is a key pathologic substrate of concussion, we used a clinically relevant swine model of concussion to explore potential sex differences in the extent of axonal pathologies. At 24 h post-injury, female swine displayed a greater number of swollen axonal profiles and more widespread loss of axonal sodium channels than males. Axon degeneration for both sexes appeared to be related to individual axon architecture, reflected by a selective loss of small caliber axons after concussion. However, female brains had a higher percentage of small caliber axons, leading to more extensive axon loss after injury compared to males. Accordingly, sexual dimorphism in axonal size is associated with more extensive axonal pathology in females after concussion, which may contribute to worse outcomes.

Female RNA concussion (FeRNAC) study: assessing hormone profiles and salivary RNA in females with concussion by emergency departments in New Zealand: a study protocol.

BACKGROUND: Females of reproductive age with concussion report a greater number of symptoms that can be more severe and continue for longer than age matched males. Underlying mechanisms for sex differences are not well understood. Short non-coding Ribonucleic Acids (sncRNAs) are candidate salivary biomarkers for concussion and have been studied primarily in male athletes. Female sex hormones influence expression of these biomarkers, and it remains unclear whether a similar pattern of sncRNA expression would be observed in females following concussion. This study aims to evaluate recovery time, the ratio of salivary sncRNAs and symptom severity across different hormone profiles in females presenting to emergency departments (ED) with concussion and, to investigate the presence of low energy availability (LEA) as a potential modifier of concussion symptoms. METHODS: This prospective cohort study recruits participants from New Zealand EDs who are biologically female, of reproductive age (16-50 years) and with a confirmed diagnosis of concussion from an ED healthcare professional. Participants are excluded by ED healthcare professionals from study recruitment as part of initial routine assessment if they have a pre-diagnosed psychiatric condition, neurological condition (i.e., epilepsy, cerebral palsy) or more than three previously diagnosed concussions. Participants provide a saliva sample for measurement of sncRNA's, and online survey responses relating to hormone profile and symptom recovery at 7-day intervals after injury until they report a full return to work/study. The study is being performed in accordance with ethical standards of the Declaration of Helsinki with ethics approval obtained from the Health and Disability Ethics Committee (HDEC #2021 EXP 11655), Auckland University of Technology Ethics Committee (AUTEC #22/110) and locality consent through Wellington hospital research office. DISCUSSION: If saliva samples confirm presence of sncRNAs in females with concussion, it will provide evidence of the potential of saliva sampling as an objective tool to aid in diagnosis of, and confirmation of recovery from, concussion. Findings will determine whether expression of sncRNAs is influenced by steroid hormones in females and may outline the need for sex specific application and interpretation of sncRNAs as a clinical and/or research tool. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12623001129673.

The Evaluation and Management of Concussion to Optimize Safe Recovery.

Concussion is a mild traumatic brain injury causing temporary neurologic dysfunction. Symptoms following concussion are variable and generally are expected to resolve within about 1 month, but some patients experience persistent and prolonged symptoms. An early return to safe, symptom-limited activity is now favored, using targeted rehabilitation and treatments. Accommodations may be needed to facilitate return-to-school and work following concussion. Athletes should not be cleared for a full return to sport until they have recovered from a concussion and completed a return-to-play progression, in addition to returning to work/school fully.

Smart Textile Impact Sensor for e-Helmet to Measure Head Injury.

Concussions, a prevalent public health concern in the United States, often result from mild traumatic brain injuries (mTBI), notably in sports such as American football. There is limited exploration of smart-textile-based sensors for measuring the head impacts associated with concussions in sports and recreational activities. In this paper, we describe the development and construction of a smart textile impact sensor (STIS) and validate STIS functionality under high magnitude impacts. This STIS can be inserted into helmet cushioning to determine head impact force. The designed 2 × 2 STIS matrix is composed of a number of material layered structures, with a sensing surface made of semiconducting polymer composite (SPC). The SPC dimension was modified in the design iteration to increase sensor range, responsiveness, and linearity. This was to be applicable in high impact situations. A microcontroller board with a biasing circuit was used to interface the STIS and read the sensor's response. A pendulum test setup was constructed to evaluate various STISs with impact forces. A camera and Tracker software were used to monitor the pendulum swing. The impact forces were calculated by measuring the pendulum bob's velocity and acceleration. The performance of the various STISs was measured in terms of voltage due to impact force, with forces varying from 180 to 722 N. Through data analysis, the threshold impact forces in the linear range were determined. Through an analysis of linear regression, the sensors' sensitivity was assessed. Also, a simplified model was developed to measure the force distribution in the 2 × 2 STIS areas from the measured voltages. The results showed that improving the SPC thickness could obtain improved sensor behavior. However, for impacts that exceeded the threshold, the suggested sensor did not respond by reflecting the actual impact forces, but it gave helpful information about the impact distribution on the sensor regardless of the accurate expected linear response. Results showed that the proposed STIS performs satisfactorily within a range and has the potential to be used in the development of an e-helmet with a large STIS matrix that could cover the whole head within the e-helmet. This work also encourages future research, especially on the structure of the sensor that could withstand impacts which in turn could improve the overall range and performance and would accurately measure the impact in concussion-causing impact ranges.

Central auditory processing and self-perception questionnaire after acoustically controlled auditory training in individuals with mild traumatic brain injury. / Processamento auditivo central e questionário de autopercepção pós-treinamento auditivo acusticamente controlado em indivíduos com traumatismo cranioencefálico leve.

PURPOSE: To correlate behavioral assessment results of central auditory processing and the self-perception questionnaire after acoustically controlled auditory training. METHODS: The study assessed 10 individuals with a mean age of 44.5 years who had suffered mild traumatic brain injury. They underwent behavioral assessment of central auditory processing and answered the Formal Auditory Training self-perception questionnaire after the therapeutic intervention - whose questions address auditory perception, understanding orders, request to repeat statements, occurrence of misunderstandings, attention span, auditory performance in noisy environments, telephone communication, and self-esteem. Patients were asked to indicate the frequency with which the listed behaviors occurred. RESULTS: Figure-ground, sequential memory for sounds, and temporal processing correlated with improvement in following instructions, fewer requests to repeat statements, increased attention span, improved communication, and understanding on the phone and when watching TV. CONCLUSION: Auditory closure, figure-ground, and temporal processing had improved in the assessment after the acoustically controlled auditory training, and there were fewer auditory behavior complaints.

OBJETIVO: Correlacionar os resultados da avaliação comportamental do processamento auditivo central e do questionário de autopercepção após o treinamento auditivo acusticamente controlado. MÉTODO: Foram avaliados dez indivíduos com média de idade de 44,5 anos, que sofreram traumatismo cranioencefálico de grau leve. Os indivíduos foram submetidos a avaliação comportamental do processamento auditivo central e também responderam ao questionário de autopercepção "Treinamento Auditivo Formal" após a intervenção terapêutica. O questionário foi composto por questões referentes a percepção auditiva, compreensão de ordens, solicitação de repetição de enunciados, ocorrência mal-entendidos, tempo de atenção, desempenho auditivo em ambiente ruidoso, comunicação ao telefone e autoestima e os pacientes foram solicitados a assinalar a frequência de ocorrência dos comportamentos listados. RESULTADOS: As habilidades auditivas de figura-fundo e memória para sons em sequência e processamento temporal correlacionaram-se com melhora para seguir instruções, diminuição das solicitações de repetições e aumento do tempo de atenção e melhora da comunicação e da compreensão ao telefone e para assistir TV. CONCLUSÃO: Observou-se adequação das habilidades auditivas de fechamento auditivo, figura fundo, e processamento temporal na avaliação pós-treinamento auditivo acusticamente controlado, além de redução das queixas quanto ao comportamento auditivo.

A Comprehensive and Broad Approach to Resting-State Functional Connectivity in Adult Patients with Mild Traumatic Brain Injury.

BACKGROUND AND PURPOSE: Several recent works using resting-state fMRI suggest possible alterations of resting-state functional connectivity after mild traumatic brain injury. However, the literature is plagued by various analysis approaches and small study cohorts, resulting in an inconsistent array of reported findings. In this study, we aimed to investigate differences in whole-brain resting-state functional connectivity between adult patients with mild traumatic brain injury within 1 month of injury and healthy control subjects using several comprehensive resting-state functional connectivity measurement methods and analyses. MATERIALS AND METHODS: A total of 123 subjects (72 patients with mild traumatic brain injury and 51 healthy controls) were included. A standard fMRI preprocessing pipeline was used. ROI/seed-based analyses were conducted using 4 standard brain parcellation methods, and the independent component analysis method was applied to measure resting-state functional connectivity. The fractional amplitude of low-frequency fluctuations was also measured. Group comparisons were performed on all measurements with appropriate whole-brain multilevel statistical analysis and correction. RESULTS: There were no significant differences in age, sex, education, and hand preference between groups as well as no significant correlation between all measurements and these potential confounders. We found that each resting-state functional connectivity measurement revealed various regions or connections that were different between groups. However, after we corrected for multiple comparisons, the results showed no statistically significant differences between groups in terms of resting-state functional connectivity across methods and analyses. CONCLUSIONS: Although previous studies point to multiple regions and networks as possible mild traumatic brain injury biomarkers, this study shows that the effect of mild injury on brain resting-state functional connectivity has not survived after rigorous statistical correction. A further study using subject-level connectivity analyses may be necessary due to both subtle and variable effects of mild traumatic brain injury on brain functional connectivity across individuals.

Perturbations in risk/reward decision making and frontal cortical catecholamine regulation induced by mild traumatic brain injury.

Mild traumatic brain injury (mTBI) disrupts cognitive processes that influence risk taking behavior. Little is known regarding the effects of repetitive mild injury (rmTBI) or whether these outcomes are sex specific. Risk/reward decision making is mediated by the prefrontal cortex (PFC), which is densely innervated by catecholaminergic fibers. Aberrant PFC catecholamine activity has been documented following TBI and may underlie TBI-induced risky behavior. The present study characterized the effects of rmTBI on risk/reward decision making behavior and catecholamine transmitter regulatory proteins within the PFC. Rats were exposed to sham, single (smTBI), or three closed-head controlled cortical impact (CH-CCI) injuries and assessed for injury-induced effects on risk/reward decision making using a probabilistic discounting task (PDT). In the first week post-final surgery, mTBI increased risky choice preference. By the fourth week, males exhibited increased latencies to make risky choices following rmTBI, demonstrating a delayed effect on processing speed. When levels of tyrosine hydroxylase (TH) and the norepinephrine reuptake transporter (NET) were measured within subregions of the PFC, females exhibited dramatic increases of TH levels within the orbitofrontal cortex (OFC) following smTBI. However, both males and females demonstrated reduced levels of OFC NET following rmTBI. These results indicate the OFC is susceptible to catecholamine instability after rmTBI and suggests that not all areas of the PFC contribute equally to TBI-induced imbalances. Overall, the CH-CCI model of rmTBI has revealed time-dependent and sex-specific changes in risk/reward decision making and catecholamine regulation following repetitive mild head injuries.

A Siamese Convolutional Neural Network for Identifying Mild Traumatic Brain Injury and Predicting Recovery.

Timely diagnosis of mild traumatic brain injury (mTBI) remains challenging due to the rapid recovery of acute symptoms and the absence of evidence of injury in static neuroimaging scans. Furthermore, while longitudinal tracking of mTBI is essential in understanding how the diseases progresses/regresses over time for enhancing personalized patient care, a standardized approach for this purpose is not yet available. Recent functional neuroimaging studies have provided evidence of brain function alterations following mTBI, suggesting mTBI-detection models can be built based on these changes. Most of these models, however, rely on manual feature engineering, but the optimal set of features for detecting mTBI may be unknown. Data-driven approaches, on the other hand, may uncover hidden relationships in an automated manner, making them suitable for the problem of mTBI detection. This paper presents a data-driven framework based on Siamese Convolutional Neural Network (SCNN) to detect mTBI and to monitor the recovery state from mTBI over time. The proposed framework is tested on the cortical images of Thy1-GCaMP6s mice, obtained via widefield calcium imaging, acquired in a longitudinal study. Results show that the proposed model achieves a classification accuracy of 96.5%. To track the state of the injured brain over time, a reference distance map is constructed, which together with the SCNN model, are employed to assess the recovery state in subsequent sessions after injury, revealing that the recovery progress varies among subjects. The promising results of this work suggest that a similar approach could be potentially applicable for monitoring recovery from mTBI, in humans.

A Proposed Mechanism for Visual Vertigo: Post-Concussion Patients Have Higher Gain From Visual Input Into Subcortical Gaze Stabilization.

Purpose: Post-concussion syndrome (PCS) is commonly associated with dizziness and visual motion sensitivity. This case-control study set out to explore altered motion processing in PCS by measuring gaze stabilization as a reflection of the capacity of the brain to integrate motion, and it aimed to uncover mechanisms of injury where invasive subcortical recordings are not feasible. Methods: A total of 554 eye movements were analyzed in 10 PCS patients and nine healthy controls across 171 trials. Optokinetic and vestibulo-ocular reflexes were recorded using a head-mounted eye tracker while participants were exposed to visual, vestibular, and visuo-vestibular motion stimulations in the roll plane. Torsional and vergence eye movements were analyzed in terms of slow-phase velocities, gain, nystagmus frequency, and sensory-specific contributions toward gaze stabilization. Results: Participants expressed eye-movement responses consistent with expected gaze stabilization; slow phases were fastest for visuo-vestibular trials and slowest for visual stimulations (P < 0.001) and increased with stimulus acceleration (P < 0.001). Concussed patients demonstrated increased gain from visual input to gaze stabilization (P = 0.005), faster slow phases (P = 0.013), earlier nystagmus beats (P = 0.003), and higher relative visual influence over the gaze-stabilizing response (P = 0.001), presenting robust effect sizes despite the limited population size. Conclusions: The enhanced neural responsiveness to visual motion in PCS, combined with semi-intact visuo-vestibular integration, presented a subcortical hierarchy for altered gaze stabilization. Drawing on comparable animal trials, findings suggest that concussed patients may suffer from diffuse injuries to inhibiting pathways for optokinetic information, likely early in the visuo-vestibular hierarchy of sensorimotor integration. These findings offer context for common but elusive symptoms, presenting a neurological explanation for motion sensitivity and visual vertigo in PCS.

Applicability and clinical utility of the German rivermead post-concussion symptoms questionnaire in proxies of children after traumatic brain injury: an instrument validation study.

BACKGROUND: The German Rivermead Post-Concussion Symptoms Questionnaire (RPQ) can be used to assess post-concussion symptoms (PCS) after traumatic brain injury (TBI) in adults, adolescents, and children. METHODS: In this study, we examined the psychometric properties of the German RPQ proxy version (N = 146) for children (8-12 years) after TBI at the item, total and scale score level. Construct validity was analyzed using rank correlations with the proxy-assessed Post-Concussion Symptoms Inventory (PCSI-P), the Patient Health Questionnaire 9 (PHQ-9), and the Generalized Anxiety Disorder Scale 7 (GAD-7). Furthermore, sensitivity testing was performed concerning subjects' sociodemographic and injury-related characteristics. Differential item functioning (DIF) was analyzed to assess the comparability of RPQ proxy ratings for children with those for adolescents. RESULTS: Good internal consistency was demonstrated regarding Cronbach's α (0.81-0.90) and McDonald's ω (0.84-0.92). The factorial validity of a three-factor model was superior to the original one-factor model. Proxy ratings of the RPQ total and scale scores were strongly correlated with the PCSI-P (ϱ = 0.50-0.69), as well as moderately to strongly correlated with the PHQ-9 (ϱ = 0.49-0.65) and the GAD-7 (ϱ = 0.44-0.64). The DIF analysis revealed no relevant differences between the child and adolescent proxy versions. CONCLUSIONS: The German RPQ proxy is a psychometrically reliable and valid instrument for assessing PCS in children after TBI. Therefore, RPQ self- and proxy-ratings can be used to assess PCS in childhood as well as along the lifespan of an individual after TBI.

Olfactory function after mild traumatic brain injury in children-a longitudinal case control study.

The prevalence of posttraumatic olfactory dysfunction in children after mild traumatic brain injury ranges from 3 to 58%, with potential factors influencing this variation, including traumatic brain injury severity and assessment methods. This prospective longitudinal study examines the association between mild traumatic brain injury and olfactory dysfunction in children. Seventy-five pediatric patients with mild traumatic brain injury and an age-matched healthy control group were enrolled. Olfactory function was assessed using the Sniffin' Sticks battery, which focuses on olfactory threshold and odor identification. The study found that children with mild traumatic brain injury had impaired olfactory function compared with healthy controls, particularly in olfactory threshold scores. The prevalence of olfactory dysfunction in the patient group was 33% and persisted for 1 yr. No significant association was found between traumatic brain injury symptoms (e.g. amnesia, loss of consciousness) and olfactory dysfunction. The study highlights the importance of assessing olfactory function in children after mild traumatic brain injury, given its potential impact on daily life. Although most olfactory dysfunction appears transient, long-term follow-up is essential to fully understand the recovery process. The findings add valuable insights to the limited literature on this topic and urge the inclusion of olfactory assessments in the management of pediatric mild traumatic brain injury.

White Matter Alterations in Military Service Members With Remote Mild Traumatic Brain Injury.

Importance: Mild traumatic brain injury (mTBI) is the signature injury experienced by military service members and is associated with poor neuropsychiatric outcomes. Yet, there is a lack of reliable clinical tools for mTBI diagnosis and prognosis. Objective: To examine the white matter microstructure and neuropsychiatric outcomes of service members with a remote history of mTBI (ie, mTBI that occurred over 2 years ago) using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). Design, Setting, and Participants: This case-control study examined 98 male service members enrolled in a study at the National Intrepid Center of Excellence. Eligible participants were active duty status or able to enroll in the Defense Enrollment Eligibility Reporting system, ages 18 to 60 years, and had a remote history of mTBI; controls were matched by age. Exposures: Remote history of mTBI. Main Outcomes and Measures: White matter microstructure was assessed using a region-of-interest approach of skeletonized diffusion images, including DTI (fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity) and NODDI (orientation dispersion index [ODI], isotropic volume fraction, intra-cellular volume fraction). Neuropsychiatric outcomes associated with posttraumatic stress disorder (PTSD) and postconcussion syndrome were assessed. Results: A total of 65 male patients with a remote history of mTBI (mean [SD] age, 40.5 [5.0] years) and 33 age-matched male controls (mean [SD] age, 38.9 [5.6] years) were included in analysis. Compared with the control cohort, the 65 service members with mTBI presented with significantly more severe PTSD-like symptoms (mean [SD] PTSD CheckList-Civilian [PCL-C] version scores: control, 19.0 [3.8] vs mTBI, 41.2 [11.6]; P < .001). DTI and NODDI metrics were altered in the mTBI group compared with the control, including intra-cellular volume fraction of the right cortico-spinal tract (ß = -0.029, Cohen d = 0.66; P < .001), ODI of the left posterior thalamic radiation (ß = -0.006, Cohen d = 0.55; P < .001), and ODI of the left uncinate fasciculus (ß = 0.013, Cohen d = 0.61; P < .001). In service members with mTBI, fractional anisotropy of the left uncinate fasciculus was associated with postconcussion syndrome (ß = 5.4 × 10-3; P = .003), isotropic volume fraction of the genu of the corpus callosum with PCL-C (ß = 4.3 × 10-4; P = .01), and ODI of the left fornix and stria terminalis with PCL-C avoidance scores (ß = 1.2 × 10-3; P = .02). Conclusions and Relevance: In this case-control study of military-related mTBI, the results suggest that advanced magnetic resonance imaging techniques using NODDI can reveal white matter microstructural alterations associated with neuropsychiatric symptoms in the chronic phase of mTBI. Diffusion trends observed throughout widespread white matter regions-of-interest may reflect mechanisms of neurodegeneration as well as postinjury tissue scarring and reorganization.