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Background: Mild traumatic brain injury (mTBI) is common in children. Long-term cognitive and behavioral outcomes as well as underlying structural brain alterations following pediatric mTBI have yet to be determined. In addition, the effect of age-at-injury on long-term outcomes is largely unknown. Methods: Children with a history of mTBI (n = 406; M age = 10 years, SD age = 0.63 years) who participated in the Adolescent Brain Cognitive Development (ABCD) study were matched (1:2 ratio) with typically developing children (TDC; n = 812) and orthopedic injury (OI) controls (n = 812). Task-based executive functioning, parent-rated executive functioning and emotion-regulation, and self-reported impulsivity were assessed cross-sectionally. Regression models were used to examine the effect of mTBI on these domains. The effect of age-at-injury was assessed by comparing children with their first mTBI at either 0-3, 4-7, or 8-10 years to the respective matched TDC controls. Fractional anisotropy (FA) and mean diffusivity (MD), both MRI-based measures of white matter microstructure, were compared between children with mTBI and controls. Results: Children with a history of mTBI displayed higher parent-rated executive dysfunction, higher impulsivity, and poorer self-regulation compared to both control groups. At closer investigation, these differences to TDC were only present in one respective age-at-injury group. No alterations were found in task-based executive functioning or white matter microstructure. Conclusions: Findings suggest that everyday executive function, impulsivity, and emotion-regulation are affected years after pediatric mTBI. Outcomes were specific to the age at which the injury occurred, suggesting that functioning is differently affected by pediatric mTBI during vulnerable periods. Groups did not differ in white matter microstructure. [ABSTRACT FROM AUTHOR]

Background: Intimate partner violence (IPV) perpetration is highly prevalent among veterans. Suggested risk factors of IPV perpetration include combat exposure, post-traumatic stress disorder (PTSD), depression, alcohol use, and mild traumatic brain injury (mTBI). While the underlying brain pathophysiological characteristics associated with IPV perpetration remain largely unknown, previous studies have linked aggression and violence to alterations of the limbic system. Here, we investigate whether IPV perpetration is associated with limbic microstructural abnormalities in military veterans. Further, we test the effect of potential risk factors (i.e., PTSD, depression, substance use disorder, mTBI, and war zone-related stress) on the prevalence of IPV perpetration. Methods: Structural and diffusion-weighted magnetic resonance imaging (dMRI) data were acquired from 49 male veterans of the Iraq and Afghanistan wars (Operation Enduring Freedom/Operation Iraqi Freedom; OEF/OIF) of the Translational Research Center for TBI and Stress Disorders (TRACTS) study. IPV perpetration was assessed using the psychological aggression and physical assault sub-scales of the Revised Conflict Tactics Scales (CTS2). Odds ratios were calculated to assess the likelihood of IPV perpetration in veterans with either of the following diagnoses: PTSD, depression, substance use disorder, or mTBI. Fractional anisotropy tissue (FA) measures were calculated for limbic gray matter structures (amygdala-hippocampus complex, cingulate, parahippocampal gyrus, entorhinal cortex). Partial correlations were calculated between IPV perpetration, neuropsychiatric symptoms, and FA. Results: Veterans with a diagnosis of PTSD, depression, substance use disorder, or mTBI had higher odds of perpetrating IPV. Greater war zone-related stress, and symptom severity of PTSD, depression, and mTBI were significantly associated with IPV perpetration. CTS2 (psychological aggression), a measure of IPV perpetration, was associated with higher FA in the right amygdala-hippocampus complex (r  =  0.400, p  =  0.005). Conclusion: Veterans with psychiatric disorders and/or mTBI exhibit higher odds of engaging in IPV perpetration. Further, the more severe the symptoms of PTSD, depression, or TBI, and the greater the war zone-related stress, the greater the frequency of IPV perpetration. Moreover, we report a significant association between psychological aggression against an intimate partner and microstructural alterations in the right amygdala-hippocampus complex. These findings suggest the possibility of a structural brain correlate underlying IPV perpetration that requires further research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Until recently, no disease-specific health-related quality of life (HRQoL) questionnaire existed for pediatric traumatic brain injuries (TBIs). In this revalidation study, the psychometric properties and the validity of the 35-item QOLIBRI-KID/ADO questionnaire in its final German version were examined in 300 children and adolescents. It is the first self-reported TBI-specific tool for measuring pediatric HRQoL in individuals aged between 8 and 17 years. The six-factor model fits the data adequately. The questionnaire's internal consistency was excellent for the total score and satisfactory to excellent for the scale scores. Intraclass correlations indicated good test–retest reliability, and the measure's construct validity was supported by the overlap between the QOLBRI-KID/ADO and the PedsQL, which measures generic HRQoL. The discriminant validity tests showed that older children and girls reported a significantly lower HRQoL than comparison groups, and this was also true of children who were anxious or depressed, or who suffered from post-concussion symptoms, replicating the results of the questionnaire's first developmental study. Our results suggest that the QOLIBRI-KID/ADO is a reliable and valid multidimensional tool that can be used together with the adult version in clinical contexts and research to measure disease-specific HRQoL after pediatric TBI throughout a person's life. This may help improve care, treatment, daily functioning, and HRQoL after TBI. [ABSTRACT FROM AUTHOR]

Assessment of health-related quality of life (HRQoL) after pediatric traumatic brain injury (TBI) has been limited in children and adolescents due to a lack of disease-specific instruments. To fill this gap, the Quality of Life after Traumatic Brain Injury for Children and Adolescents (QOLIBRI-KID/ADO) Questionnaire was developed for the German-speaking population. Reference values from a comparable general population are essential for comprehending the impact of TBI on health and well-being. This study examines the validity of the German QOLIBRI-KID/ADO in a general pediatric population in Germany and provides reference values for use in clinical practice. Overall, 1997 children and adolescents aged 8–17 years from the general population and 300 from the TBI population participated in this study. The questionnaire was tested for reliability and validity. A measurement invariance (MI) approach was used to assess the comparability of the HRQoL construct between both samples. Reference values were determined by percentile-based stratification according to factors that significantly influenced HRQoL in regression analyses. The QOLIBRI-KID/ADO demonstrated strong psychometric properties. The HRQoL construct was measured largely equivalently in both samples, and reference values could be provided. The QOLIBRI-KID/ADO was considered reliable and valid for assessing HRQoL in a general German-speaking pediatric population, allowing for clinically meaningful comparisons between general and TBI populations. [ABSTRACT FROM AUTHOR]

Background: Post-concussion symptoms (PCS) are a common consequence of pediatric traumatic brain injury (pTBI). They include cognitive, emotional, and physical disturbances. To address the lack of age-adapted instruments assessing PCS after pTBI, this study examines the psychometric properties of the German 17-item post-TBI version of the Postconcussion Symptom Inventory (PCSI-SR8) in children aged 8–12 years. The study also aims to establish reference values based on data from a pediatric general population sample to better estimate the prevalence and clinical relevance of PCS after pTBI in clinical and research settings. Methods: A total of 132 children aged 8–12 years from a post-acute TBI sample and 1,047 from a general population sample were included in the analyses. The questionnaire was translated from English into German and linguistically validated using forward and backward translation and cognitive debriefing to ensure comprehensibility of the developed version. Reliability and validity were examined; descriptive comparisons were made with the results of the English study. Measurement invariance (MI) analyses between TBI and general population samples were conducted prior to establishing reference values. Factors contributing to the total and scale scores of the PCSI-SR8 were identified using regression analyses. Reference values were calculated using percentiles. Results: Most children (TBI: 83%; general population: 79%) rated at least one symptom as “a little” bothersome. The German PCSI-SR8 met the psychometric assumptions in both samples and was comparable to the English version. The four-factor structure comprising physical, emotional, cognitive, and fatigue symptoms could be replicated. The MI assumption was retained. Therefore, reference values could be provided to determine the symptom burden of patients in relation to a comparable general population. Clinical relevance of reported symptoms is indicated by a score of 8, which is one standard deviation above the mean of the general population sample. Conclusion: The German version of the PCSI-SR8 is suitable for assessment of PCS after pTBI. The reference values allow for a more comprehensive evaluation of PCS following pTBI. Future research should focus on validation of the PCSISR8 in more acute phases of TBI, psychometric examination of the pre-post version, and child-proxy comparisons. [ABSTRACT FROM AUTHOR]

Background: The Balance Error Scoring System (BESS) is a commonly used method for clinically evaluating balance after traumatic brain injury. The utilization of force plates, characterized by their cost-effectiveness and portability, facilitates the integration of instrumentation into the BESS protocol. Despite the enhanced precision associated with instrumented measures, there remains a need to determine the clinical significance and feasibility of such measures within pediatric cohorts. Objective: To report a comprehensive set of posturographic measures obtained during instrumented BESS and to examine the concurrent validity, reliability, and feasibility of instrumented BESS in the pediatric point of care setting. Methods: Thirty-seven participants (18 female; aged 13.32 ± 3.31 years) performed BESS while standing on a force plate to simultaneously compute stabilometric measures (instrumented BESS). Ellipse area (EA), path length (PL), and sway velocity (VM) were obtained for each of the six BESS positions and compared with the respective BESS scores. Additionally, the effects of sex and age were explored. A second BESS repetition was performed to evaluate the test–retest reliability. Feedback questionnaires were handed out after testing to evaluate the feasibility of the proposed protocol. Results: The BESS total score was 20.81 ± 6.28. While there was no statistically significant age or sex dependency in the BESS results, instrumented posturography demonstrated an age dependency in EA, VM, and PL. The one-leg stance on a soft surface resulted in the highest BESS score (8.38 ± 1.76), EA (218.78 cm2 ± 168.65), PL (4386.91 mm ± 1859.00), and VM (21.93 mm/s ± 9.29). The Spearman's coefficient displayed moderate to high correlations between the EA (rs = 0.429–0.770, p = 0.001–0.009), PL (rs = 0.451–0.809, p = 0.001–0.006), and VM (rs = 0.451–0.809, p = 0.001–0.006) when compared with the BESS scores for all testing positions, except for the one-leg stance on a soft surface. The BESS total score significantly correlated during the first and second repetition (rs = 0.734, p ≤ 0.001), as did errors during the different testing positions (rs = 0.489–0.799, p ≤ 0.001–0.002), except during the two-legged stance on a soft surface. VM and PL correlated significantly in all testing positions (rs = 0.465–0.675, p ≤ 0.001–0.004; (rs = 0.465–0.675, p ≤ 0.001–0.004), as did EA for all positions except for the two-legged stance on a soft surface (rs = 0.392–0.581, p ≤ 0.001–0.016). A total of 92% of participants stated that the instructions for the testing procedure were very well-explained, while 78% of participants enjoyed the balance testing, and 61% of participants could not decide whether the testing was easy or hard to perform. Conclusions: Instrumented posturography may complement clinical assessment in investigating postural control in children and adolescents. While the BESS score only allows for the consideration of a total score approximating postural control, instrumented posturography offers several parameters representing the responsiveness and magnitude of body sway as well as a more differentiated analysis of movement trajectory. Concise instrumented posturography protocols should be developed to augment neuropediatric assessments in cases where a deficiency in postural control is suspected, potentially stemming from disruptions in the processing of visual, proprioceptive, and/or vestibular information. [ABSTRACT FROM AUTHOR]

Background: Post-concussion symptoms (PCS) are a common consequence of pediatric traumatic brain injury (pTBI). They include cognitive, emotional, and physical disturbances. To address the lack of age-adapted instruments assessing PCS after pTBI, this study examines the psychometric properties of the German 17-item post-TBI version of the Postconcussion Symptom Inventory (PCSI-SR8) in children aged 8-12 years. The study also aims to establish reference values based on data from a pediatric general population sample to better estimate the prevalence and clinical relevance of PCS after pTBI in clinical and research settings. Methods: A total of 132 children aged 8-12 years from a post-acute TBI sample and 1,047 from a general population sample were included in the analyses. The questionnaire was translated from English into German and linguistically validated using forward and backward translation and cognitive debriefing to ensure comprehensibility of the developed version. Reliability and validity were examined; descriptive comparisons were made with the results of the English study. Measurement invariance (MI) analyses between TBI and general population samples were conducted prior to establishing reference values. Factors contributing to the total and scale scores of the PCSI-SR8 were identified using regression analyses. Reference values were calculated using percentiles. Results: Most children (TBI: 83%; general population: 79%) rated at least one symptom as "a little" bothersome. The German PCSI-SR8 met the psychometric assumptions in both samples and was comparable to the English version. The four-factor structure comprising physical, emotional, cognitive, and fatigue symptoms could be replicated. The MI assumption was retained. Therefore, reference values could be provided to determine the symptom burden of patients in relation to a comparable general population. Clinical relevance of reported symptoms is indicated by a score of 8, which is one standard deviation above the mean of the general population sample. Conclusion: The German version of the PCSI-SR8 is suitable for assessment of PCS after pTBI. The reference values allow for a more comprehensive evaluation of PCS following pTBI. Future research should focus on validation of the PCSISR8 in more acute phases of TBI, psychometric examination of the pre-post version, and child-proxy comparisons. [ABSTRACT FROM AUTHOR]

Pediatric health-related quality of life (HRQoL) as a measure of subjective wellbeing and functioning has received increasing attention over the past decade. HRQoL in children and adolescents following pediatric traumatic brain injury (pTBI) has been poorly studied, and performing adequate measurements in this population is challenging. This study compares child/adolescent and parent reports of HRQoL following pTBI using the newly developed Quality of Life after Brain Injury in Children and Adolescents (QOLIBRI-KID/ADO) questionnaire. Three hundred dyads of 8–17-year-old children/adolescents and their parents were included in the study. The parent–child agreement, estimated using intraclass correlation coefficients and Cohen's κ, displayed poor to moderate concordance. Approximately two-fifths of parents (39.3%) tended to report lower HRQoL for their children/adolescents on the total QOLIBRI-KID/ADO score. At the same time, about one-fifth (21.3%) reported higher HRQoL Total scores for their children/adolescents. The best agreement for parents rating adolescents (aged 13–17 years) was found in terms of the Total score and the Cognition and Self scale scores. To date, parent-reported HRQoL has been the preferred choice in pediatric research after TBI. However, with a parent–child disagreement of approximately 60%, our results highlight the importance of considering self-reports for children/adolescents capable of answering or completing the HRQoL measures. [ABSTRACT FROM AUTHOR]

This document is a corrigendum for an article titled "Psychometric evaluation and reference values for the German Postconcussion Symptom Inventory (PCSI-SR8) in children aged 8-12 years." The corrigendum acknowledges errors in Table 5 and Supplementary Table S2 of the original article, as well as misspellings in the Funding statement. The corrected tables and funding statement are provided, and the authors apologize for the errors. The corrigendum does not affect the scientific conclusions of the original article. [Extracted from the article]

Background: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are common in Veterans and linked to behavioral disturbances, increased risk of cognitive decline, and Alzheimer's disease. Objective: We studied the synergistic effects of PTSD and TBI on behavioral, cognitive, and neuroimaging measures in Vietnam war Veterans. Methods: Data were acquired at baseline and after about one-year from male Veterans categorized into: PTSD, TBI, PTSD+TBI, and Veteran controls without PTSD or TBI. We applied manual tractography to examine white matter microstructure of three fiber tracts: uncinate fasciculus (N = 91), cingulum (N = 87), and inferior longitudinal fasciculus (N = 95). ANCOVAs were used to compare Veterans' baseline behavioral and cognitive functioning (N = 285), white matter microstructure, amyloid-β (N = 230), and tau PET (N = 120). Additional ANCOVAs examined scores' differences from baseline to follow-up. Results: Veterans with PTSD and PTSD+TBI, but not Veterans with TBI only, exhibited poorer behavioral and cognitive functioning at baseline than controls. The groups did not differ in baseline white matter, amyloid-β, or tau, nor in behavioral and cognitive functioning, and tau accumulation change. Progression of white matter abnormalities of the uncinate fasciculus in Veterans with PTSD compared to controls was observed; analyses in TBI and PTSD+TBI were not run due to insufficient sample size. Conclusions: PTSD and PTSD+TBI negatively affect behavioral and cognitive functioning, while TBI does not contribute independently. Whether progressive decline in uncinate fasciculus microstructure in Veterans with PTSD might account for cognitive decline should be further studied. Findings did not support an association between PTSD, TBI, and Alzheimer's disease pathology based on amyloid and tau PET. [ABSTRACT FROM AUTHOR]

The subjective impact of the consequences of pediatric traumatic brain injury (pTBI) on different life dimensions should be assessed multidimensionally and as sensitively as possible using a disease-specific health-related quality of life (HRQoL) instrument. The development and psychometrics of the first such self-report questionnaire for children and adolescents after TBI are reported here. Focus group interviews with children, adolescents, and their parents, cognitive debriefing, item pool generation and reduction using Delphi expert panels were performed. The resulting version was psychometrically tested on 300 individuals aged 8–17 years. After item reduction based on factor analyses, differential item functioning, reliability, and validity were investigated. The final 35 items were associated with six scales (Cognition, Self, Daily Life and Autonomy, Social Relationships, Emotions, Physical Problems). Internal consistency and construct validity were satisfactory. Health-related Quality of life (HRQoL) was significantly lower in older and in female participants, as well as those with cognitive disabilities, anxiety, depression and post-concussion symptoms, than in comparative groups. The new QOLIBRI-KID/ADO is a comprehensive, multidimensional, reliable, and valid instrument, comparable in content and items to the QOLIBRI adult version. Therefore, disease-specific HRQoL can now be measured across the lifespan and may support the amelioration of treatment, care, rehabilitation, and daily life of children and adolescents after TBI. [ABSTRACT FROM AUTHOR]

In the field of pediatric traumatic brain injury (TBI), relationships between pre-injury and injury-related characteristics and post-TBI outcomes (functional recovery, post-concussion depression, anxiety) and their impact on disease-specific health-related quality of life (HRQoL) are under-investigated. Here, a multidimensional conceptual model was tested using a structural equation model (SEM). The final SEM evaluates the associations between these four latent variables. We retrospectively investigated 152 children (8–12 years) and 148 adolescents (13–17 years) after TBI at the recruiting clinics or online. The final SEM displayed a fair goodness-of-fit (SRMR = 0.09, RMSEA = 0.08 with 90% CI [0.068, 0.085], GFI = 0.87, CFI = 0.83), explaining 39% of the variance across the four latent variables and 45% of the variance in HRQoL in particular. The relationships between pre-injury and post-injury outcomes and between post-injury outcomes and TBI-specific HRQoL were moderately strong. Especially, pre-injury characteristics (children's age, sensory, cognitive, or physical impairments, neurological and chronic diseases, and parental education) may aggravate post-injury outcomes, which in turn may influence TBI-specific HRQoL negatively. Thus, the SEM comprises potential risk factors for developing negative post-injury outcomes, impacting TBI-specific HRQoL. Our findings may assist healthcare providers and parents in the management, therapy, rehabilitation, and care of pediatric individuals after TBI. [ABSTRACT FROM AUTHOR]

Health-related quality of life (HRQOL) is an important indicator for recovery after pediatric TBI. To date, there are a few questionnaires available for assessing generic HRQOL in children and adolescents, but there are not yet any TBI-specific measures of HRQOL that are applicable to pediatric populations. The aim of the present study was to examine psychometric characteristics of the newly developed Quality of Life After Brain Injury Scale for Kids and Adolescents (QOLIBRI-KID/ADO) questionnaire capturing TBI-specific HRQOL in children and adolescents using an item response theory (IRT) framework. Children (8–12 years; n = 152) and adolescents (13–17 years; n = 148) participated in the study. The final version of the QOLIBRI-KID/ADO, comprising 35 items forming 6 scales, was investigated using the partial credit model (PCM). A scale-wise examination for unidimensionality, monotonicity, item infit and outfit, person homogeneity, and local independency was conducted. The questionnaire widely fulfilled the predefined assumptions, with a few restrictions. The newly developed QOLIBRI-KID/ADO instrument shows at least satisfactory psychometric properties according to the results of both classical test theoretical and IRT analyses. Further evidence of its applicability should be explored in the ongoing validation study by performing multidimensional IRT analyses. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) in military populations can cause disruptions in brain structure and function, along with cognitive and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) can detect alterations in white matter (WM) microstructure, but few studies have examined brain asymmetry. Examining asymmetry in large samples may increase sensitivity to detect heterogeneous areas of WM alteration in mild TBI. Through the Enhancing Neuroimaging Genetics Through Meta‐Analysis Military‐Relevant Brain Injury working group, we conducted a mega‐analysis of neuroimaging and clinical data from 16 cohorts of Active Duty Service Members and Veterans (n = 2598). dMRI data were processed together along with harmonized demographic, injury, psychiatric, and cognitive measures. Fractional anisotropy in the cingulum showed greater asymmetry in individuals with deployment‐related TBI, driven by greater left lateralization in TBI. Results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness, and were driven primarily by individuals whose worst TBI occurred before age 40. Alterations in the cingulum were also associated with slower processing speed and poorer set shifting. The results indicate an enhancement of the natural left laterality of the cingulum, possibly due to vulnerability of the nondominant hemisphere or compensatory mechanisms in the dominant hemisphere. The cingulum is one of the last WM tracts to mature, reaching peak FA around 42 years old. This effect was primarily detected in individuals whose worst injury occurred before age 40, suggesting that the protracted development of the cingulum may lead to increased vulnerability to insults, such as TBI. [ABSTRACT FROM AUTHOR]

The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) assesses post-concussion symptoms (PCS) after traumatic brain injury (TBI). The current study examines the applicability of self-report and proxy versions of the German RPQ in adolescents (13–17 years) after TBI. We investigated reliability and validity on the total and scale score level. Construct validity was investigated by correlations with the Post-Concussion Symptoms Inventory (PCSI-SR13), Generalized Anxiety Disorder Scale 7 (GAD-7), and Patient Health Questionnaire 9 (PHQ-9) and by hypothesis testing regarding individuals' characteristics. Intraclass correlation coefficients (ICC) assessed adolescent–proxy agreement. In total, 148 adolescents after TBI and 147 proxies completed the RPQ. Cronbach's α (0.81–0.91) and McDonald's ω (0.84–0.95) indicated good internal consistency. The three-factor structure outperformed the unidimensional model. The RPQ was strongly correlated with the PCSI-SR13 (self-report: r = 0.80; proxy: r = 0.75) and moderately–strongly with GAD-7 and PHQ-9 (self-report: r = 0.36, r = 0.35; proxy: r = 0.53, r = 0.62). Adolescent–proxy agreement was fair (ICC [2,1] = 0.44, CI95% [0.41, 0.47]). Overall, both self-report and proxy assessment forms of the German RPQ are suitable for application in adolescents after TBI. As proxy ratings tend to underestimate PCS, self-reports are preferable for evaluations. Only if a patient is unable to answer, a proxy should be used as a surrogate. [ABSTRACT FROM AUTHOR]

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age‐related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non‐negative matrix factorization (NMF) is a data‐driven approach that detects covarying patterns (components) within high‐dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self‐reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta‐Analysis) Military Brain Injury working group. Regressions were used to examine TBI‐ and mTBI‐related associations in NMF‐derived components while adjusting for age, sex, post‐traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age‐dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age‐dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans. [ABSTRACT FROM AUTHOR]

Background: Repetitive head impacts (RHI) from contact sports have been associated with cognitive and neuropsychiatric disorders. However, not all individuals exposed to RHI develop such disorders. This may be explained by the reserve hypothesis. It remains unclear if the reserve hypothesis accounts for the heterogenous symptom presentation in RHI-exposed individuals. Moreover, optimal measurement of reserve in this population is unclear and likely unique from non-athlete populations.Objective: We examined the association between metrics of reserve and cognitive and neuropsychiatric functioning in 89 symptomatic former National Football League players.Methods: Individual-level proxies (e.g., education) defined reserve. We additionally quantified reserve as remaining residual variance in 1) episodic memory and 2) executive functioning performance, after accounting for demographics and brain pathology. Associations between reserve metrics and cognitive and neuropsychiatric functioning were examined.Results: Higher reading ability was associated with better attention/information processing (β=0.25; 95% CI, 0.05-0.46), episodic memory (β=0.27; 95% CI, 0.06-0.48), semantic and phonemic fluency (β=0.24; 95% CI, 0.02-0.46; β=0.38; 95% CI, 0.17-0.59), and behavioral regulation (β=-0.26; 95% CI, -0.48, -0.03) performance. There were no effects for other individual-level proxies. Residual episodic memory variance was associated with better attention/information processing (β=0.45; 95% CI, 0.25, 0.65), executive functioning (β=0.36; 95% CI, 0.15, 0.57), and semantic fluency (β=0.38; 95% CI, 0.17, 0.59) performance. Residual executive functioning variance was associated with better attention/information processing (β=0.44; 95% CI, 0.24, 0.64) and episodic memory (β=0.37; 95% CI, 0.16, 0.58) performance.Conclusion: Traditional reserve proxies (e.g., years of education, occupational attainment) have limitations and may be unsuitable for use in elite athlete samples. Alternative approaches of reserve quantification may prove more suitable for this population. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major cause of disability worldwide, but the heterogeneous nature of TBI with respect to injury severity and health comorbidities make patient outcome difficult to predict. Injury severity accounts for only some of this variance, and a wide range of preinjury, injury‐related, and postinjury factors may influence outcome, such as sex, socioeconomic status, injury mechanism, and social support. Neuroimaging research in this area has generally been limited by insufficient sample sizes. Additionally, development of reliable biomarkers of mild TBI or repeated subconcussive impacts has been slow, likely due, in part, to subtle effects of injury and the aforementioned variability. The ENIGMA Consortium has established a framework for global collaboration that has resulted in the largest‐ever neuroimaging studies of multiple psychiatric and neurological disorders. Here we describe the organization, recent progress, and future goals of the Brain Injury working group. [ABSTRACT FROM AUTHOR]

Characterizing cortical plasticity becomes increasingly important for identifying compensatory mechanisms and structural reserve in the ageing population. While cortical thickness (CT) largely contributed to systems neuroscience, it incompletely informs about the underlying neuroplastic pathophysiology. In turn, microstructural characteristics may correspond to atrophy mechanisms in a more sensitive way. Fractional anisotropy, a diffusion tensor imaging (DTI) measure, is inversely related to cortical histologic complexity. Axial diffusivity and radial diffusivity are assumed to be linked to the density of structures oriented perpendicular and parallel to the cortical surface, respectively. We hypothesized (1) that cortical DTI will reveal microstructural correlates for hemispheric specialization, particularly in the language and motor systems, and (2) that lateralization of cortical DTI parameters will show an age effect, paralleling age‐related changes in activation, especially in the prefrontal cortex. We analysed data from healthy younger and older adult participants (N = 91). DTI and CT data were extracted from regions of the Destrieux atlas. Diffusion measures showed lateralization in specialized motor, language, visual, auditory and inferior parietal cortices. Age‐dependent increased lateralization for DTI measures was observed in the prefrontal, angular, superior temporal and lateral occipital cortex. CT did not show any age‐dependent alterations in lateralization. Our observations argue that cortical DTI can capture microstructural properties associated with functional specialization, resembling findings from histology. Age effects on diffusion measures in the integrative prefrontal and parietal areas may shed novel light on the atrophy‐related plasticity in healthy ageing. [ABSTRACT FROM AUTHOR]

Background and Objectives: Exposure to repetitive head impacts (RHI) is linked to the development of chronic traumatic encephalopathy (CTE), which can only be diagnosed at post-mortem. The presence of a cavum septum pellucidum (CSP) is a common finding in post-mortem studies of confirmed CTE and in neuroimaging studies of individuals exposed to RHI. This study examines CSP in living former American football players, investigating its association with RHI exposure, traumatic encephalopathy syndrome (TES) diagnosis, and provisional levels of certainty for CTE pathology., Methods: Data from the DIAGNOSE CTE Research Project were used to compare the presence and ratio of CSP in former American football players (n = 175), consisting of former college (n = 58) and former professional players (n = 117), and asymptomatic unexposed controls without RHI exposure (n = 55). We further evaluated potential associations between CSP measures and cumulative head impact index (CHII) measures (frequency, linear acceleration, and rotational force), a TES diagnosis (yes/no), and a provisional level of certainty for CTE pathology (suggestive, possible, and probable)., Results: Former American football players exhibited a higher CSP presence and ratio than unexposed asymptomatic controls. Among player subgroups, professional players showed a greater CSP ratio than former college players and unexposed asymptomatic controls. Among all football players, CHII rotational forces correlated with an increased CSP ratio. No significant associations were found between CSP measures and diagnosis of TES or provisional levels of certainty for CTE pathology., Discussion: This study confirms previous findings, highlighting a greater prevalence of CSP and a greater CSP ratio in former American football players compared with unexposed asymptomatic controls. In addition, former professional players showed a greater CSP ratio than college players. Moreover, the relationship between estimates of CHII rotational forces and CSP measures suggests that cumulative frequency and strength of rotational forces experienced in football are associated with CSP. However, CSP does not directly correlate with TES diagnosis or provisional levels of certainty for CTE, indicating that it may be a consequence of RHI associated with rotational forces. Further research, especially longitudinal studies, is needed for confirmation and to explore changes over time., Competing Interests: C.H. Adler consulted for Avion, CND Life Sciences, Jazz, and PreCon Health; LJB is Editor-in-Chief of the Journal of Neuro-Ophthalmology and is a paid consultant to Biogen (Cambridge, MA, USA); C. Bernick receives research support from the Ultimate Fighting Championship, Top Rank promotions, Haymon Boxing, Las Vegas Raiders, and Professional Bull Riders. He is a paid consultant for Aurora Concussion Therapy Systems, Inc. (St. Paul, MN); A.P. Lin consulted for Agios, BioMarin, and Moncton MRI. He is a co-founder of BrainSpec, Inc; J.L. Cummings has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren Therapeutics, Biogen, Biohaven, Cassava, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, Prothena, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI pharmaceutical, assessment, and investment companies; E.M. Reiman is a compensated scientific advisor for Alkahest, Alzheon, Aural Analytics, Denali, Green Valley, Retromer Therapeutics, and Vaxxinity and is a cofounder of ALZPath; R.A. Stern is a paid consultant to Biogen (Cambridge, MA, USA) and Lundbeck (Copenhagen, Denmark). He is a member of the Board of Directors of King-Devick Technologies, Inc. (Chicago, IL, USA), and he receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. (Lutz, FL, USA). He has been a member of the Medical Science Committee for the National Collegiate Athletic Association Student-Athlete Concussion Injury Litigation; I.K. Koerte receives funding for a collaborative project from Abbott Inc. She receives royalties for book chapters. Her spouse is an employee at Siemens AG and a stockholder of Siemens AG and Siemens Healthineers. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Importance: Exposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role., Objective: To investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associated neurodegeneration., Design, Setting, and Participants: This cross-sectional study was part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project, a 7-year multicenter study consisting of 4 US study sites. Data were collected from September 2016 to February 2020 and analyses were performed between May 2021 and October 2023. After controlling for magnetic resonance image (MRI) and processing quality, former American football players and unexposed asymptomatic control participants were included in analyses., Exposure: Prior exposure to RHI while participating in American football was estimated using the 3 cumulative head impact indices (CHII-G, linear acceleration; CHII-R, rotational acceleration; and CHII, number of head impacts)., Main Outcomes and Measures: Individual PVS volume was calculated in the white matter of structural MRI. Cognitive impairment was based on neuropsychological assessment. Linear regression models were used to assess associations of PVS volume with neuropsychological assessments in former American football players. All analyses were adjusted for confounders associated with PVS volume., Results: Analyses included 224 participants (median [IQR] age, 57 [51-65] years), with 170 male former football players (114 former professional athletes, 56 former collegiate athletes) and 54 male unexposed control participants. Former football players had larger PVS volume compared with the unexposed group (mean difference, 0.28 [95% CI, 0.00-0.56]; P = .05). Within the football group, PVS volume was associated with higher CHII-R (β = 2.71 × 10-8 [95% CI, 0.50 × 10-8 to 4.93 × 10-8]; P = .03) and CHII-G (β = 2.24 × 10-6 [95% CI, 0.35 × 10-6 to 4.13 × 10-6]; P = .03). Larger PVS volume was also associated with worse performance on cognitive functioning in former American football players (β = -0.74 [95% CI, -1.35 to -0.13]; P = .04)., Conclusions and Relevance: These findings suggest that impaired perivascular brain clearance, as indicated by larger PVS volume, may contribute to the association observed between RHI exposure and neurodegeneration.

Intimate partner violence (IPV) is a significant, global public health concern. Women, individuals with historically underrepresented identities, and disabilities are at high risk for IPV and tend to experience severe injuries. There has been growing concern about the risk of exposure to IPV-related head trauma, resulting in IPV-related brain injury (IPV-BI), and its health consequences. Past work suggests that a significant proportion of women exposed to IPV experience IPV-BI, likely representing a distinct phenotype compared with BI of other etiologies. An IPV-BI often co-occurs with psychological trauma and mental health complaints, leading to unique issues related to identifying, prognosticating, and managing IPV-BI outcomes. The goal of this review is to identify important gaps in research and clinical practice in IPV-BI and suggest potential solutions to address them. We summarize IPV research in five key priority areas: (1) unique considerations for IPV-BI study design; (2) understanding non-fatal strangulation as a form of BI; (3) identifying objective biomarkers of IPV-BI; (4) consideration of the chronicity, cumulative and late effects of IPV-BI; and (5) BI as a risk factor for IPV engagement. Our review concludes with a call to action to help investigators develop ecologically valid research studies addressing the identified clinical-research knowledge gaps and strategies to improve care in individuals exposed to IPV-BI. By reducing the current gaps and answering these calls to action, we will approach IPV-BI in a trauma-informed manner, ultimately improving outcomes and quality of life for those impacted by IPV-BI.

Background and Objectives: Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players., Methods: The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested., Results: Approximately 36.7% of NFL players had diagnosed SA compared with 30% of the former college football players and 16.7% of the controls. Former NFL players and college football players also had higher ESS scores compared with the controls. Years of football play was not associated with any of the sleep metrics. Among the former NFL players, diagnosed SA was associated with worse Executive Function and Psychomotor Speed factor scores, greater BDI-II scores, and higher flortaucipir PET standard uptake value ratios, independent of age, race, body mass index, and APOE ε4 gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup., Discussion: Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health., Competing Interests: The authors report no relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Exposure to repetitive head impacts (RHIs) in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE) which currently can be diagnosed only at postmortem. American football players are at higher risk of developing CTE given their exposure to RHIs. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at postmortem in living individuals using structural magnetic resonance imaging (MRI). MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 58 age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each Traumatic Encephalopathy Syndrome (TES) diagnosis core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula temporal pole and superior frontal gyrus. Post-hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe age-by-group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggest that MRI morphometrics detects abnormalities in individuals with a history of RHI exposure that resemble the anatomic distribution of pathological findings from postmortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggests that brain morphometry must be complemented by other types of measures to characterize individuals with RHIs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health., Methods: Participants underwent clinical interviews, MRI, and lumbar puncture as part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Structural equation modeling tested direct and indirect effects between log-transformed total fluid-attenuated inversion recovery (FLAIR) lesion volumes (TLV) and the revised Framingham stroke risk profile (rFSRP), MRI-derived global metrics of cortical thickness and fractional anisotropy (FA), and CSF levels of amyloid β 1-42 , p-tau 181 , soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light. Covariates included age, race, education, body mass index, APOE ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI., Results: In 180 former football players (mean age = 57.2, 36% Black), higher log(TLV) had direct associations with the following: higher rFSRP score (B = 0.26, 95% CI 0.07-0.40), higher p-tau 181 (B = 0.17, 95% CI 0.01-0.43), lower FA (B = -0.28, 95% CI -0.42 to -0.13), and reduced cortical thickness (B = -0.25, 95% CI -0.45 to -0.08). In 60 asymptomatic unexposed men (mean age = 59.3, 40% Black), there were no direct effects on log(TLV) (rFSRP: B = -0.03, 95% CI -0.48 to 0.57; p-tau 181 : B = -0.30, 95% CI -1.14 to 0.37; FA: B = -0.07, 95% CI -0.48 to 0.42; or cortical thickness: B = -0.28, 95% CI -0.64 to 0.10). The former football players showed stronger associations between log(TLV) and rFSRP (1,069% difference in estimates), p-tau 181 (158%), and FA (287%) than the unexposed men., Discussion: Risk factors and biological correlates of WMH differed between former American football players and asymptomatic unexposed men. In addition to vascular health, p-tau 181 and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.

Background:  Arterial spin labeling (ASL) is a magnetic resonance imaging (MRI)-based technique using labeled blood-water of the brain-feeding arteries as an endogenous tracer to derive information about brain perfusion. It enables the assessment of cerebral blood flow (CBF)., Method:  This review aims to provide a methodological and technical overview of ASL techniques, and to give examples of clinical use cases for various diseases affecting the central nervous system (CNS). There is a special focus on recent developments including super-selective ASL (ssASL) and time-resolved ASL-based magnetic resonance angiography (MRA) and on diseases commonly not leading to characteristic alterations on conventional structural MRI (e. g., concussion or migraine)., Results:  ASL-derived CBF may represent a clinically relevant parameter in various pathologies such as cerebrovascular diseases, neoplasms, or neurodegenerative diseases. Furthermore, ASL has also been used to investigate CBF in mild traumatic brain injury or migraine, potentially leading to the establishment of imaging-based biomarkers. Recent advances made possible the acquisition of ssASL by selective labeling of single brain-feeding arteries, enabling spatial perfusion territory mapping dependent on blood flow of a specific preselected artery. Furthermore, ASL-based MRA has been introduced, providing time-resolved delineation of single intracranial vessels., Conclusion:  Perfusion imaging by ASL has shown promise in various diseases of the CNS. Given that ASL does not require intravenous administration of a gadolinium-based contrast agent, it may be of particular interest for investigations in pediatric cohorts, patients with impaired kidney function, patients with relevant allergies, or patients that undergo serial MRI for clinical indications such as disease monitoring., Key Points:   · ASL is an MRI technique that uses labeled blood-water as an endogenous tracer for brain perfusion imaging.. · It allows the assessment of CBF without the need for administration of a gadolinium-based contrast agent.. · CBF quantification by ASL has been used in several pathologies including brain tumors or neurodegenerative diseases.. · Vessel-selective ASL methods can provide brain perfusion territory mapping in cerebrovascular diseases.. · ASL may be of particular interest in patient cohorts with caveats concerning gadolinium administration.., Competing Interests: Stephan Kaczmarz is an employee of Philips GmbH, Hamburg, Germany. All other authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

The gray matter/white matter (GM/WM) boundary of the brain is vulnerable to shear strain associated with mild traumatic brain injury (mTBI). It is, however, unknown whether GM/WM microstructure is associated with long-term outcomes following mTBI. The diffusion and structural MRI data of 278 participants between 18 and 65 years of age with and without military background from the Department of Defense INTRuST study were analyzed. Fractional anisotropy (FA) was extracted at the GM/WM boundary across the brain and for each lobe. Additionally, two conventional analytic approaches were used: whole-brain deep WM FA (TBSS) and whole-brain cortical thickness (FreeSurfer). ANCOVAs were applied to assess differences between the mTBI cohort ( n = 147) and the comparison cohort ( n = 131). Associations between imaging features and post-concussive symptom severity, and functional and cognitive impairment were investigated using partial correlations while controlling for mental health comorbidities that are particularly common among military cohorts and were present in both the mTBI and comparison group. Findings revealed significantly lower whole-brain and lobe-specific GM/WM boundary FA ( p < 0.011), and deep WM FA ( p = 0.001) in the mTBI cohort. Whole-brain and lobe-specific GM/WM boundary FA was significantly negatively correlated with post-concussive symptoms ( p < 0.039), functional ( p < 0.016), and cognitive impairment ( p < 0.049). Deep WM FA was associated with functional impairment ( p = 0.002). Finally, no significant difference was observed in cortical thickness, nor between cortical thickness and outcome ( p > 0.05). Findings from this study suggest that microstructural alterations at the GM/WM boundary may be sensitive markers of adverse long-term outcomes following mTBI.

Neurological soft signs (NSS) are minor deviations in motor performance. During childhood and adolescence, NSS are examined for functional motor phenotyping to describe development, to screen for comorbidities, and to identify developmental vulnerabilities. Here, we investigate underlying brain structure alterations in association with NSS in physically trained adolescents. Male adolescent athletes (n = 136, 13-16 years) underwent a standardized neurological examination including 28 tests grouped into 6 functional clusters. Non-optimal performance in at least 1 cluster was rated as NSS (NSS+ group). Participants underwent T1- and diffusion-weighted magnetic resonance imaging. Cortical volume, thickness, and local gyrification were calculated using Freesurfer. Measures of white matter microstructure (Free-water (FW), FW-corrected fractional anisotropy (FAt), axial and radial diffusivity (ADt, RDt)) were calculated using tract-based spatial statistics. General linear models with age and handedness as covariates were applied to assess differences between NSS+ and NSS- group. We found higher gyrification in a large cluster spanning the left superior frontal and parietal areas, and widespread lower FAt and higher RDt compared with the NSS- group. This study shows that NSS in adolescents are associated with brain structure alterations. Underlying mechanisms may include alterations in synaptic pruning and axon myelination, which are hallmark processes of brain maturation., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players., Methods: A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45-74 years) completed fluid-attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self-report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60., Results: In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log-WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log-WMH was associated with younger age of first exposure to football and worse executive function., Discussion: In older former football players, WMH may have unique presentations, risk factors, and etiologies., Highlights: Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same-age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory., (© 2022 the Alzheimer's Association.)

Military service members are at increased risk for mental health issues, and comorbidity with mild traumatic brain injury (mTBI) is common. Largely overlapping symptoms between conditions suggest a shared pathophysiology. The present work investigates the associations among white matter microstructure, psychological functioning, and serum neuroactive steroids that are part of the stress-response system. Diffusion-weighted brain imaging was acquired from 163 participants (with and without military affiliation) and free-water-corrected fractional anisotropy (FA T ) was extracted. Associations between serum neurosteroid levels of allopregnanolone (ALLO) and pregnenolone (PREGNE), psychological functioning, and whole-brain white matter microstructure were assessed using regression models. Moderation models tested the effect of mTBI and comorbid post-traumatic stress disorder (PTSD) and mTBI on these associations. ALLO is associated with whole-brain white matter FA T ( β  = 0.24, t  = 3.05, p  = 0.006). This association is significantly modulated by PTSD+mTBI comorbidity ( β  = 0.00, t  = 2.50, p  = 0.027), although an mTBI diagnosis alone did not significantly impact this association ( p  = 0.088). There was no significant association between PREGNE and FA T ( p  = 0.380). Importantly, lower FA T is associated with poor psychological functioning ( β  = -0.19, t  = -2.35, p  = 0.020). This study provides novel insight into a potential common pathophysiological mechanism of neurosteroid dysregulation underlying the high risk for mental health issues in military service members. Further, comorbidity of PTSD and mTBI may bring the compensatory effects of the brain's stress response to their limit. Future research is needed to investigate whether neurosteroid regulation may be a promising tool for restoring brain health and improving psychological functioning.

Sleep disturbances are strongly associated with mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). PTSD and mTBI have been linked to alterations in white matter (WM) microstructure, but whether poor sleep quality has a compounding effect on WM remains largely unknown. We evaluated sleep and diffusion magnetic resonance imaging (dMRI) data from 180 male post-9/11 veterans diagnosed with (1) PTSD ( n = 38), (2) mTBI ( n = 25), (3) comorbid PTSD+mTBI ( n = 94), and (4) a control group with neither PTSD nor mTBI ( n = 23). We compared sleep quality (Pittsburgh Sleep Quality Index, PSQI) between groups using ANCOVAs and calculated regression and mediation models to assess associations between PTSD, mTBI, sleep quality, and WM. Veterans with PTSD and comorbid PTSD+mTBI reported poorer sleep quality than those with mTBI or no history of PTSD or mTBI ( p = 0.012 to <0.001). Poor sleep quality was associated with abnormal WM microstructure in veterans with comorbid PTSD+mTBI ( p < 0.001). Most importantly, poor sleep quality fully mediated the association between greater PTSD symptom severity and impaired WM microstructure ( p < 0.001). Our findings highlight the significant impact of sleep disturbances on brain health in veterans with PTSD+mTBI, calling for sleep-targeted interventions.

The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) assesses post-concussion symptoms (PCS) after traumatic brain injury (TBI). The current study examines the applicability of self-report and proxy versions of the German RPQ in adolescents (13-17 years) after TBI. We investigated reliability and validity on the total and scale score level. Construct validity was investigated by correlations with the Post-Concussion Symptoms Inventory (PCSI-SR13), Generalized Anxiety Disorder Scale 7 (GAD-7), and Patient Health Questionnaire 9 (PHQ-9) and by hypothesis testing regarding individuals' characteristics. Intraclass correlation coefficients (ICC) assessed adolescent-proxy agreement. In total, 148 adolescents after TBI and 147 proxies completed the RPQ. Cronbach's α (0.81-0.91) and McDonald's ω (0.84-0.95) indicated good internal consistency. The three-factor structure outperformed the unidimensional model. The RPQ was strongly correlated with the PCSI-SR13 (self-report: r = 0.80; proxy: r = 0.75) and moderately-strongly with GAD-7 and PHQ-9 (self-report: r = 0.36, r = 0.35; proxy: r = 0.53, r = 0.62). Adolescent-proxy agreement was fair (ICC [2,1] = 0.44, CI 95% [0.41, 0.47]). Overall, both self-report and proxy assessment forms of the German RPQ are suitable for application in adolescents after TBI. As proxy ratings tend to underestimate PCS, self-reports are preferable for evaluations. Only if a patient is unable to answer, a proxy should be used as a surrogate.

Background: Exposure to repetitive head impacts (RHI) is associated with an increased risk of later-life neurobehavioral dysregulation and neurodegenerative disease. The underlying pathomechanisms are largely unknown., Purpose: To investigate whether RHI exposure is associated with later-life corpus callosum (CC) microstructure and whether CC microstructure is associated with plasma total tau and neuropsychological/neuropsychiatric functioning., Study Type: Retrospective cohort study., Population: Seventy-five former professional American football players (age 55.2 ± 8.0 years) with cognitive, behavioral, and mood symptoms., Field Strength/sequence: Diffusion-weighted echo-planar MRI at 3 T., Assessment: Subjects underwent diffusion MRI, venous puncture, neuropsychological testing, and completed self-report measures of neurobehavioral dysregulation. RHI exposure was assessed using the Cumulative Head Impact Index (CHII). Diffusion MRI measures of CC microstructure (i.e., free-water corrected fractional anisotropy (FA), trace, radial diffusivity (RD), and axial diffusivity (AD)) were extracted from seven segments of the CC (CC1-7), using a tractography clustering algorithm. Neuropsychological tests were selected: Trail Making Test Part A (TMT-A) and Part B (TMT-B), Controlled Oral Word Association Test (COWAT), Stroop Interference Test, and the Behavioral Regulation Index (BRI) from the Behavior Rating Inventory of Executive Function, Adult version (BRIEF-A)., Statistical Tests: Diffusion MRI metrics were tested for associations with RHI exposure, plasma total tau, neuropsychological performance, and neurobehavioral dysregulation using generalized linear models for repeated measures., Results: RHI exposure was associated with increased AD of CC1 (correlation coefficient (r) = 0.32, P < 0.05) and with increased plasma total tau (r = 0.34, P < 0.05). AD of the anterior CC1 was associated with increased plasma total tau (CC1: r = 0.30, P < 0.05; CC2: r = 0.29, P < 0.05). Higher trace, AD, and RD of CC1 were associated with better performance (P < 0.05) in TMT-A (trace, r = 0.33; AD, r = 0.31; and RD, r = 0.28) and TMT-B (trace, r = 0.31; RD, r = 0.34). Higher FA and AD of CC2 were associated with better performance (P < 0.05) in TMT-A (FA, r = 0.36; AD, r = 0.28), TMT-B (FA, r = 0.36; AD, r = 0.27), COWAT (FA, r = 0.36; AD, r = 0.32), and BRI (AD, r = 0.29)., Data Conclusion: These results suggest an association among RHI exposure, CC microstructure, plasma total tau, and clinical functioning in former professional American football players., Level of Evidence: 3 Technical Efficacy Stage: 1., (© 2021 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC. on behalf of International Society for Magnetic Resonance in Medicine.)