Faculty Bibliography

BACKGROUND AND PURPOSE/OBJECTIVE:Mild traumatic brain injury (MTBI) is a common public health concern with potential long-term consequences, yet its underlying pathophysiology remains poorly understood. Clinical heterogeneity of individuals having diverse extent and array of symptoms has impeded the identification of reliable imaging biomarkers. Traditional group-level analyses may obscure biologically meaningful subtypes. This study uses latent class analysis (LCA) to classify MTBI subjects into symptom-defined subgroups and examines corresponding WM microstructural alterations using advanced diffusion MRI. MATERIALS AND METHODS/METHODS:Sixty-one MTBI patients within one month of injury completed the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). LCA was used to identify symptom-based subgroups. Of these, 54 MTBI patients underwent multi-shell diffusion MRI and were compared with 31 controls. WM changes were assessed across subgroups using ROI-based diffusion analyses. RESULTS:LCA identified three distinct MTBI subgroups: those with minimal to no symptoms (31.5%), the cognitively symptomatic (38.9%), and the more globally symptomatic (29.6%). The three groups were associated with different patterns of diffusion MRI differences compared with controls. The cognitively symptomatic subgroup showed predominantly central WM differences, the globally symptomatic subgroup exhibited more peripheral differences with right-hemisphere predominance and sparing the corpus callosum, marked by reduced fractional anisotropy and kurtosis and elevated diffusivities, the less symptomatic subgroup demonstrated focal differences in the callosal genu, with increased fractional anisotropy and kurtosis and decreased diffusivity measures. CONCLUSIONS:MTBI comprises biologically distinct phenotypes with subgroup-specific WM signatures on diffusion MRI. Even individuals with minimal to no symptoms show WM differences compared with controls, underscoring the limitations of symptom reporting alone. Integrating symptom-based classification with advanced diffusion MRI may improve diagnostic precision to help risk stratification and provide insight into mechanisms of injury. ABBREVIATIONS/BACKGROUND:LCA = latent class analysis; MTBI = mild traumatic brain injury; RPQ = Rivermead post-concussion symptoms questionnaire.

OBJECTIVES/OBJECTIVE:In mild traumatic brain injury, imaging biomarkers are needed to support clinical management. In four antecedent publications, we used two new (sodium and fingerprinting) and two established (spectroscopy and diffusion) MR techniques in a longitudinally followed patient cohort. Here we report final results and combine all data to determine which marker(s) from the four modalities offer the greatest utility for detecting injury and predicting outcomes. We also leverage the independent specificities offered by each modality to explore injury mechanisms. MATERIALS AND METHODS/METHODS:The longitudinal spectroscopy data were analysed to complete a full data set of proton (spectroscopy, fingerprinting, diffusion) and sodium MRI, acquired alongside symptomatic, cognitive, and functional assessments in 27 patients at 1, 3, and 12 months following injury. Twenty-three matched controls were scanned once. Testing for associations between nine MR markers and three outcome measures was standardized across the entire data set, and performed using Spearman correlations and logistic regression. RESULTS:from fingerprinting (marker of the cellular microenvironment). CONCLUSIONS:We identified independent, dynamic, metabolic and ionic changes, with choline and creatine from spectroscopy fulfilling the most criteria for a clinical biomarker.

OBJECTIVES/OBJECTIVE:Alexithymia an emotional processing deficit that interferes with a person's ability to recognize, express, and differentiate emotional states. Study objectives were to (1) determine rates of elevated alexithymia among people with moderate-to-severe traumatic brain injury (TBI) 1-year post-injury, (2) identify demographic and injury-related variables associated with high versus low-average levels of alexithymia, and (3) examine associations among alexithymia with other aspects of emotional functioning and life satisfaction. SETTING/METHODS:Data were collected during follow-up interviews across four TBI Model System (TBIMS) centers. PARTICIPANTS/METHODS:The sample consisted of 196 participants with moderate-to-severe TBI enrolled in the TBIMS. They were predominately male (77%), White (69%), and had no history of pre-injury mental health treatment (66.3%). DESIGN/METHODS:Cross-sectional survey data were obtained at study enrollment and 1-year post-injury. MAIN MEASURES/METHODS:Toronto Alexithymia Scale-20 (TAS-20) as well as measures of anger, aggression, hostility, emotional dysregulation, post-traumatic stress, anxiety, depression, resilience and life satisfaction. Sociodemographic information, behavioral health history and injury-related variables were also included. RESULTS:High levels of alexithymia (TAS-20 score > 1.5 standard deviation above the normative mean) were observed for 14.3%. Compared to individuals with low/average levels of alexithymia, the high alexithymia group tended to have lower levels of education. At 1-year follow-up, high TAS-20 scores were strongly associated with emotional dysregulation and post-traumatic stress; moderately associated with anger, hostility, depression, anxiety, lower resilience and lower satisfaction with life; and weakly associated with aggression. CONCLUSION/CONCLUSIONS:These findings provide further evidence that alexithymia is associated with poor emotional functioning and life satisfaction after TBI. Longitudinal studies are needed to determine if alexithymia is a risk factor that precipitates and predicts worse emotional outcomes in the TBI population. This line of work is important for informing treatment targets that could prevent or reduce of psychological distress after TBI.

Repetitive head impacts are associated with structural brain changes and an increased risk for chronic traumatic encephalopathy, a progressive neurodegenerative disease that can only be diagnosed after death. Chronic traumatic encephalopathy is defined by the abnormal accumulation of phosphorylated tau protein, particularly at the depths of the superior frontal sulci, suggesting that sulcal morphology may serve as a relevant structural biomarker. Contact sport athletes, such as former football players, are at elevated risk due to their prolonged exposure to repetitive head impacts. Cortical atrophy linked to underlying tau accumulation may result in shallower and wider sulci, potentially making sulcal morphology an imaging marker for identifying individuals at risk for this disease. This study investigated sulcal morphological differences in former football players and examined associations with age, football-related exposure, clinical diagnosis of traumatic encephalopathy syndrome, levels of certainty for chronic traumatic encephalopathy pathology, neuropsychological performance, and positron emission tomography imaging using flortaucipir. We analysed structural magnetic resonance imaging data from 169 male former football players (mean age 57.2 (8.2) years, range 45-74) and 54 age-matched, unexposed asymptomatic male controls (mean age 59.4 (8.5) years, range 45-74). Sulcal depth and width were quantified using the CalcSulc, focusing on two regions in each hemisphere commonly affected by chronic traumatic encephalopathy pathology: the superior frontal and occipitotemporal sulci. Generalized least squares models were used to assess group differences and interactions with age and football exposure variables, including age of first exposure, total years played, and cumulative head impact exposure. An analysis of covariance evaluated relationships between sulcal morphology, clinical measures, and flortaucipir uptake, adjusting for age, race, body mass index, education, imaging site, apolipoprotein E4 status, and total intracranial volume. Former football players demonstrated significantly shallower sulcal depth in the left superior frontal sulcus compared to unexposed controls. Earlier age of first exposure and longer football careers were associated with greater widening of the left occipitotemporal sulcus. Higher cumulative head impact exposure was linked to reduced sulcal depth in the left superior frontal region. However, sulcal morphology was not associated with clinical diagnosis, levels of certainty, neuropsychological test performance, or flortaucipir imaging. These findings suggest that sulcal morphology may reflect cumulative exposure to repetitive head impacts, particularly in brain regions vulnerable to chronic traumatic encephalopathy pathology. Future ante- and post-mortem validation studies are needed to determine whether sulcal morphology can serve as a reliable in vivo biomarker of risk.

OBJECTIVE:To examine the experience of menopause symptoms in women with traumatic brain injury (TBI). DESIGN/METHODS:Cross-sectional descriptive study. SETTING/METHODS:Five sites of the TBI Model Systems (TBIMS) program. PARTICIPANTS/METHODS:Participants were 210 women, ages 40-60 years, who were not taking systemic hormones and did not have both ovaries removed: Sixty-one participants were enrolled in the TBIMS, who were at least 2 years post TBI and living in the community. One hundred forty-nine participants without TBI were recruited from a research registry and the metropolitan Detroit community. INTERVENTIONS/METHODS:Not applicable. MAIN OUTCOME MEASURES/METHODS:A checklist comprised of 21 menopause symptoms assessing four symptom clusters (vasomotor, somatic, psychological, and cognitive). RESULTS:TBI and non-TBI groups did not significantly differ and showed small effect sizes on vasomotor symptoms. On the remaining symptom clusters, women with TBI showed greater presence and severity of symptoms than women without TBI, as well as fewer differences between premenopausal and postmenopausal women on those symptoms. A profile indicating an additive or potentiating effect of TBI on menopause symptoms was not observed. CONCLUSIONS:Findings support a conceptual model of menopause and TBI indicating that symptoms most closely associated with estrogen decline are similar for women with and without TBI, whereas symptoms that overlap with common TBI sequelae are generally more frequent and severe among these women. Likely due to lower baseline of symptoms premenopause, postmenopausal women without TBI reported more numerous and severe symptoms relative to their premenopausal counterparts without TBI. Overall, it may be that women without TBI experience menopause as more of a "change" of life, whereas women with TBI chronically face significantly more of these symptoms than women without TBI.

OBJECTIVES/OBJECTIVE:To identify personal, clinical, and environmental factors associated with 4 previously identified distinct multidimensional participation profiles of individuals following traumatic brain injury (TBI). SETTING/METHODS:Community. PARTICIPANTS/METHODS:Participants (n = 408) enrolled in the TBI Model Systems (TBIMS) Participation Module, all 1 year or more postinjury. DESIGN/METHODS:Secondary data analysis of cross-sectional data from participants in a multicenter TBIMS module study on participation conducted between May 2006 and September 2007. Participants provided responses to questionnaires via a telephone interview at their study follow-up (1, 2, 5, 10, or 15 years postinjury). MAIN MEASURES/METHODS:Participants provided responses to personal (eg, demographic), clinical (eg, function), environmental (eg, neighborhood type), and participation measures to create multidimensional participation profiles. Data from measures collected at the time of injury (preinjury questionnaire, injury characteristics) were also included. The primary outcome was assignment to one of 4 multidimensional participation profile groups based on participation frequency, importance, satisfaction, and enfranchisement. The measures used to develop the profiles were: Participation Assessment with Recombined Tools-Objective, Importance, and Satisfaction scores, each across 3 domains (Productivity, Social Relationships, Out and About in the Community) and the Enfranchisement Scale (contributing to one's community, feeling valued by the community, choice and control). RESULTS:Results of the multinomial regression analysis, with 4 distinct participation profile groups as the outcome, indicated that education, current employment, current illicit drug use, current driving status, community type, and Functional Independence Measure Cognitive at follow-up significantly distinguished participation profile groups. Findings suggest a trend toward differences in participation profile groups by race/Hispanic ethnicity. CONCLUSIONS:Understanding personal, clinical, and environmental factors associated with distinct participation outcome profiles following TBI may provide more personalized and nuanced guidance to inform rehabilitation intervention planning and/or ongoing clinical monitoring.

OBJECTIVE:To examine the unique contribution of alexithymia at 1 year after traumatic brain injury (TBI) to the prospective prediction of emotional and social health outcomes at 2 years after injury. DESIGN/METHODS:Multicenter, longitudinal cohort study. SETTING/METHODS:Data were collected during year 1 and year 2 postinjury follow-up interviews across 4 TBI Model System centers. PARTICIPANTS/METHODS:Persons with TBI (N=175; 134 men and 41 women) who had English fluency and were capable of providing self-reported data. INTERVENTIONS/METHODS:Not applicable. MAIN OUTCOME MEASURES/METHODS:Primary independent variable was the Toronto Alexithymia Scale-20. Outcome measures included the Interpersonal Reactivity Index, National Institute of Health Toolbox Emotion Battery Anger, Difficulty with Emotion Regulation Scale, Connor-Davidson Resilience Scale, Posttraumatic Stress Disorder Checklist - Civilian, Satisfaction with Life Scale, General Anxiety Disorder-7, Patient Health Questionnaire 9, suicidal ideation, and problematic substance use. RESULTS:Simple adjusted models demonstrated that after controlling for the specific outcome at year 1, Toronto Alexithymia Scale-20 scores significantly predicted year 2 scores for perspective-taking, physical aggression, emotional dysregulation, resilience, anxiety, depression, and suicidal ideation. All of these predictive findings except for physical aggression were maintained in the fully adjusted models that also controlled for age, sex, education level, number of prior TBIs, and motor and cognitive functioning. CONCLUSIONS:Compared with those with lower alexithymia scores, persons with TBI who had higher alexithymia scores at 1 year after injury reported poorer emotional health at 2 years after TBI, even after controlling for year 1 outcome scores, sociodemographic characteristics, and injury-related factors. These results support the need to assess for elevated alexithymia and to provide interventions targeting alexithymia early in the TBI recovery process.

BACKGROUND AND PURPOSE/OBJECTIVE:Because the corpus callosum connects the left and right hemispheres and a variety of WM bundles across the brain in complex ways, damage to the neighboring WM microstructure may specifically disrupt interhemispheric communication through the corpus callosum following mild traumatic brain injury. Here we use a mediation framework to investigate how callosal interhemispheric communication is affected by WM microstructure in mild traumatic brain injury. MATERIALS AND METHODS/METHODS:Multishell diffusion MR imaging was performed on 23 patients with mild traumatic brain injury within 1 month of injury and 17 healthy controls, deriving 11 diffusion metrics, including DTI, diffusional kurtosis imaging, and compartment-specific standard model parameters. Interhemispheric processing speed was assessed using the interhemispheric speed of processing task (IHSPT) by measuring the latency between word presentation to the 2 hemivisual fields and oral word articulation. Mediation analysis was performed to assess the indirect effect of neighboring WM microstructures on the relationship between the corpus callosum and IHSPT performance. In addition, we conducted a univariate correlation analysis to investigate the direct association between callosal microstructures and IHSPT performance as well as a multivariate regression analysis to jointly evaluate both callosal and neighboring WM microstructures in association with IHSPT scores for each group. RESULTS:Several significant mediators in the relationships between callosal microstructure and IHSPT performance were found in healthy controls. However, patients with mild traumatic brain injury appeared to lose such normal associations when microstructural changes occurred compared with healthy controls. CONCLUSIONS:This study investigates the effects of neighboring WM microstructure on callosal interhemispheric communication in healthy controls and patients with mild traumatic brain injury, highlighting that neighboring noncallosal WM microstructures are involved in callosal interhemispheric communication and information transfer. Further longitudinal studies may provide insight into the temporal dynamics of interhemispheric recovery following mild traumatic brain injury.

BACKGROUND AND PURPOSE/OBJECTIVE: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/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.