Exploratory assessment of the effect of systemic administration of soluble glycoprotein 130 on cognitive performance and chemokine levels in a mouse model of experimental traumatic brain injury.

Uncontrolled neuroinflammation mediates traumatic brain injury (TBI) pathology and impairs recovery. Interleukin-6 (IL-6), a pleiotropic inflammatory regulator, is associated with poor clinical TBI outcomes. IL-6 operates via classical-signaling through membrane-bound IL-6 receptor (IL-6R) and trans-signaling through soluble IL-6 receptor (s)IL-6R. IL-6 trans-signaling specifically contributes to neuropathology, making it a potential precision therapeutic TBI target. Soluble glycoprotein 130 (sgp130) prevents IL-6 trans-signaling, sparing classical signaling, thus is a possible treatment. Mice received either controlled cortical impact (CCI) (6.0 ± 0.2 m/s; 2 mm; 50-60ms) or sham procedures. Vehicle (VEH) or sgp130-Fc was subcutaneously administered to sham (VEH or 1 µg) and CCI (VEH, 0.25 µg or 1 µg) mice on days 1, 4, 7, 10 and 13 post-surgery to assess effects on cognition [Morris Water Maze (MWM)] and ipsilateral hemisphere IL-6 related biomarkers (day 21 post-surgery). CCI + sgp130-Fc groups (0.25 µg and 1 µg) were combined for analysis given similar behavior/biomarker outcomes. CCI + VEH mice had longer latencies and path lengths to the platform and increased peripheral zone time versus Sham + VEH and Sham + sgp130-Fc mice, suggesting injury-induced impairments in learning and anxiety. CCI + sgp130-Fc mice had shorter platform latencies and path lengths and had decreased peripheral zone time, indicating a therapeutic benefit of sgp130-Fc after injury on learning and anxiety. Interestingly, Sham + sgp130-Fc mice had shorter platform latencies, path lengths and peripheral zone times than Sham + VEH mice, suggesting a beneficial effect of sgp130-Fc, independent of injury. CCI + VEH mice had increased brain IL-6 and decreased sgp130 levels versus Sham + VEH and Sham + sgp130-Fc mice. There was no treatment effect on IL-6, sIL6-R or sgp130 in Sham + VEH versus Sham + sgp130-Fc mice. There was also no treatment effect on IL-6 in CCI + VEH versus CCI + sgp130-Fc mice. However, CCI + sgp130-Fc mice had increased sIL-6R and sgp130 versus CCI + VEH mice, demonstrating sgp130-Fc treatment effects on brain biomarkers. Inflammatory chemokines (MIP-1ß, IP-10, MIG) were increased in CCI + VEH mice versus Sham + VEH and Sham + sgp130-Fc mice. However, CCI + sgp130-Fc mice had decreased chemokine levels versus CCI + VEH mice. IL-6 positively correlated, while sgp130 negatively correlated, with chemokine levels. Overall, we found that systemic sgp130-Fc treatment after CCI improved learning, decreased anxiety and reduced CCI-induced brain chemokines. Future studies will explore sex-specific dosing and treatment mechanisms for sgp130-Fc therapy.

Temporal Profile of Serum Neurofilament Light (NF-L) and Heavy (pNF-H) Level Associations With 6-Month Cognitive Performance in Patients With Moderate-Severe Traumatic Brain Injury.

OBJECTIVE: Identification of biomarkers of cognitive recovery after traumatic brain injury (TBI) will inform care and improve outcomes. This study assessed the utility of neurofilament (NF-L and pNF-H), a marker of neuronal injury, informing cognitive performance following moderate-to-severe TBI (msTBI). SETTING: Level 1 trauma center and outpatient via postdischarge follow-up. PARTICIPANTS: N = 94. Inclusion criteria: Glasgow Coma Scale score less than 13 or 13-15 with clinical evidence of moderate-to-severe injury traumatic brain injury on clinical imaging. Exclusion criteria: neurodegenerative condition, brain death within 3 days after injury. DESIGN: Prospective observational study. Blood samples were collected at several time points post-injury. Cognitive testing was completed at 6 months post-injury. MAIN MEASURES: Serum NF-L (Human Neurology 4-Plex B) pNF-H (SR-X) as measured by SIMOA Quanterix assay. Divided into 3 categorical time points at days post-injury (DPI): 0-15 DPI, 16-90 DPI, and >90 DPI. Cognitive composite comprised executive functioning measures derived from 3 standardized neuropsychological tests (eg, Delis-Kaplan Executive Function System: Verbal Fluency, California Verbal Learning Test, Second Edition, Wechsler Adult Intelligence Scale, Third Edition). RESULTS: pNF-H at 16-90 DPI was associated with cognitive outcomes including a cognitive-executive composite score at 6 months (ß = -.430, t34 = -3.190, P = .003). CONCLUSIONS: Results suggest that "subacute" elevation of serum pNF-H levels may be associated with protracted/poor cognitive recovery from msTBI and may be a target for intervention. Interpretation is limited by small sample size and including only those who were able to complete cognitive testing.

Relations Among Suicidal Ideation, Depressive Symptoms, and Functional Independence During the 10 Years After Traumatic Brain Injury: A Model Systems Study.

OBJECTIVE: To investigate relative causality in relations among suicidal ideation (SI), depressive symptoms, and functional independence over the first 10 years after traumatic brain injury (TBI). DESIGN: Prospective longitudinal design with data collected through the Traumatic Brain Injury Model Systems (TBIMS) network at acute rehabilitation hospitalization as well as 1, 2, 5, and 10 years after injury. SETTING: United States Level I/II trauma centers and inpatient rehabilitation centers with telephone follow-up. PARTICIPANTS: Individuals enrolled into the TBIMS National Database (N=9539) with at least 1 SI score at any follow-up data collection (72.1% male; mean age, 39.39y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patient Health Questionnaire-9 and FIM at years 1, 2, 5, and 10 post injury. RESULTS: A cross-lagged panel structural equation model, which is meant to indirectly infer causality through longitudinal correlational data, suggested that SI, depressive symptoms, and functional independence each significantly predicted themselves over time. Within the model, bivariate correlations among variables were all significant within each time point. Between years 1 and 2 and between years 2 and 5, depressive symptoms had a larger effect on SI than SI had on depressive symptoms. Between years 5 and 10, there was reciprocal causality between the 2 variables. Functional independence more strongly predicted depressive symptoms than the reverse between years 1 and 2 as well as years 2 and 5, but its unique effects on SI over time were extremely marginal or absent after controlling for depressive symptoms. CONCLUSIONS: A primary goal for rehabilitation and mental health providers should be to monitor and address elevated symptoms of depression as quickly as possible before they translate into SI, particularly for individuals with TBI who have reduced functional independence. Doing so may be a key to breaking the connection between low functional independence and SI.

Proceedings of the Second Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.

This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six major domains related to disorders of consciousness. The six domains include (1) Biology of Coma, (2) Coma Database, (3) Neuroprognostication, (4) Care of Comatose Patients, (5) Early Clinical Trials, and (6) Long-term Recovery. Following the 1st Curing Coma NIH virtual symposium held on September 9 to September 10, 2020, six workgroups, each consisting of field experts in respective domains, were formed and tasked with identifying gaps and developing key priorities and deliverables to advance the mission of the Curing Coma Campaign. The highly interactive and inspiring presentations and panel discussions during the 3-day virtual NIH symposium identified several action items for the Curing Coma Campaign mission, which we summarize in this article.

Identifying group-based patterns of suicidal ideation over the first 10 years after moderate-to-severe TBI.

OBJECTIVE: To identify group-based patterns in suicidal ideation (SI) over the first 10 years after traumatic brain injury (TBI). METHODS: Participants included 9539 individuals in the TBI Model Systems National Database who responded to Patient Health Questionnaire-9 Item 9 assessing SI at 1, 2, 5, and/or 10 years post-injury. A k-means cluster analysis was conducted to determine group-based patterns of SI, and pre-injury variables were compared with ANOVAs and chi-square tests. RESULTS: SI and attempts decreased over time. Four group-based patterns emerged: Low, increasing, moderate, and decreasing SI. The low SI group comprised 89% of the sample, had the highest pre-injury employment, fewer mental health vulnerabilities, least severe injuries, and were oldest. The increasing SI group had the most severe TBIs, were youngest, and disproportionately Black or Asian/Pacific Islander. CONCLUSION: These findings reinforce the importance of mental health and suicide risk assessment during chronic recovery from TBI.

Treelet transform analysis to identify clusters of systemic inflammatory variance in a population with moderate-to-severe traumatic brain injury.

BACKGROUND: Inflammatory cascades following traumatic brain injury (TBI) can have both beneficial and detrimental effects on recovery. Single biomarker studies do not adequately reflect the major arms of immunity and their relationships to long-term outcomes. Thus, we applied treelet transform (TT) analysis to identify clusters of interrelated inflammatory markers reflecting major components of systemic immune function for which substantial variation exists among individuals with moderate-to-severe TBI. METHODS: Serial blood samples from 221 adults with moderate-to-severe TBI were collected over 1-6 months post-injury (n = 607 samples). Samples were assayed for 33 inflammatory markers using Millipore multiplex technology. TT was applied to standardized mean biomarker values generated to identify latent patterns of correlated markers. Treelet clusters (TC) were characterized by biomarkers related to adaptive immunity (TC1), innate immunity (TC2), soluble molecules (TC3), allergy immunity (TC4), and chemokines (TC5). For each TC, a score was generated as the linear combination of standardized biomarker concentrations and cluster load for each individual in the cohort. Ordinal logistic or linear regression was used to test associations between TC scores and 6- and 12-month Glasgow Outcome Scale (GOS), Disability Rating Scale (DRS), and covariates. RESULTS: When adjusting for clinical covariates, TC5 was significantly associated with 6-month GOS (odds ratio, OR = 1.44; p-value, p = 0.025) and 6-month DRS scores (OR = 1.46; p = 0.013). TC5 relationships were attenuated when including all TC scores in the model (GOS: OR = 1.29, p = 0.163; DRS: OR = 1.33, p = 0.100). When adjusting for all TC scores and covariates, only TC3 was associated with 6- and 12-month GOS (OR = 1.32, p = 0.041; OR = 1.39, p = 0.002) and also 6- and 12-month DRS (OR = 1.38, p = 0.016; OR = 1.58, p = 0.0002). When applying TT to inflammation markers significantly associated with 6-month GOS, multivariate modeling confirmed that TC3 remained significantly associated with GOS. Biomarker cluster membership remained consistent between the GOS-specific dendrogram and overall dendrogram. CONCLUSIONS: TT effectively characterized chronic, systemic immunity among a cohort of individuals with moderate-to-severe TBI. We posit that chronic chemokine levels are effector molecules propagating cellular immune dysfunction, while chronic soluble receptors are inflammatory damage readouts perpetuated, in part, by persistent dysfunctional cellular immunity to impact neuro-recovery.

Determinants of caregiver burden in male patients with epilepsy following penetrating traumatic brain injury.

PURPOSE: We determined burden of caring for patients with post-traumatic epilepsy (PTE) following penetrating traumatic brain injury (TBI) and identified factors predicting higher burden. METHOD: We assessed 331 caregiver-veteran dyads in Phase 2 (136 PTE, 136 non-PTE, and 59 HC dyads), 133 in Phase 4 (47 PTE, 56 non-PTE, and 30 HC dyads) - 30 years later, and 46 dyads in the follow-up study (18 PTE, 19 non-PTE, and 9 HC). Caregiver's burden was measured by Zarit Burden Index and a questionnaire. Veterans completed demographic, mental and physical well-being, quality-of-life, and medical-related information. Caregivers provided information about burden and their assessments of cognitive decline and neuropsychiatric status of the veterans. RESULTS: PTE caregivers perceived significantly more burden than comparison groups at all phases. Bivariate analyses revealed that caregiver distress due to the veteran's neuropsychiatric state including cognitive decline, apathy, and disinhibition and the veteran's characteristics including older age at epilepsy onset and role limitation due to physical problems were associated with higher burden. Finally, we revealed disinhibition distress, and role imitation due to physical problems as the predictors in a model of caregiver burden. CONCLUSION: Elevated PTE caregiver burden is persistent across the life span suggesting that caregivers could benefit from counseling and targeted psychosocial interventions to reduce their burden.

Evaluating the Cross-Sectional and Longitudinal Relationships Predicting Suicidal Ideation Following Traumatic Brain Injury.

OBJECTIVE: Characterize relationships among substance misuse, depression, employment, and suicidal ideation (SI) following moderate to severe traumatic brain injury (TBI). DESIGN: Prospective cohort study. SETTING: Inpatient rehabilitation centers with telephone follow-up; level I/II trauma centers in the United States. PARTICIPANTS: Individuals with moderate to severe TBI with data in both the National Trauma Data Bank and the Traumatic Brain Injury Model Systems National Database, aged 18 to 59 years, with SI data at year 1 or year 2 postinjury (N = 1377). MAIN OUTCOME MEASURE: Primary outcome of SI, with secondary employment, substance misuse, and depression outcomes at years 1 and 2 postinjury. RESULTS: Cross-lagged structural equation modeling analysis showed that year 1 unemployment and substance misuse were associated with a higher prevalence of year 1 depression. Depression was associated with concurrent SI at years 1 and 2. Older adults and women had a greater likelihood of year 1 depression. More severe overall injury (injury severity score) was associated with a greater likelihood of year 1 SI, and year 1 SI was associated with a greater likelihood of year 2 SI. CONCLUSIONS: Substance misuse, unemployment, depression, and greater extracranial injury burden independently contributed to year 1 SI; in turn, year 1 SI and year 2 depression contributed to year 2 SI. Older age and female sex were associated with year 1 depression. Understanding and mitigating these risk factors are crucial for effectively managing post-TBI SI to prevent postinjury suicide.

Research Needs for Prognostic Modeling and Trajectory Analysis in Patients with Disorders of Consciousness.

BACKGROUND: The current state of the science regarding the care and prognosis of patients with disorders of consciousness is limited. Scientific advances are needed to improve the accuracy, relevance, and approach to prognostication, thereby providing the foundation to develop meaningful and effective interventions. METHODS: To address this need, an interdisciplinary expert panel was created as part of the Coma Science Working Group of the Neurocritical Care Society Curing Coma Campaign. RESULTS: The panel performed a gap analysis which identified seven research needs for prognostic modeling and trajectory analysis ("recovery science") in patients with disorders of consciousness: (1) to define the variables that predict outcomes; (2) to define meaningful intermediate outcomes at specific time points for different endotypes; (3) to describe recovery trajectories in the absence of limitations to care; (4) to harness big data and develop analytic methods to prognosticate more accurately; (5) to identify key elements and processes for communicating prognostic uncertainty over time; (6) to identify health care delivery models that facilitate recovery and recovery science; and (7) to advocate for changes in the health care delivery system needed to advance recovery science and implement already-known best practices. CONCLUSION: This report summarizes the current research available to inform the proposed research needs, articulates key elements within each area, and discusses the goals and advances in recovery science and care anticipated by successfully addressing these needs.

Serum Biomarkers of Regeneration and Plasticity are Associated with Functional Outcome in Pediatric Neurocritical Illness: An Exploratory Study.

BACKGROUND/OBJECTIVE: Pediatric neurocritical care survivorship is frequently accompanied by functional impairments. Lack of prognostic biomarkers is a barrier to early identification and management of impairment. We explored the association between blood biomarkers and functional impairment in children with acute acquired brain injury. METHODS: This study is a secondary analysis of a randomized control trial evaluating early versus usual care rehabilitation in the pediatric intensive care unit (PICU). Forty-four children (17 [39%] female, median age 11 [interquartile range 6-13] years) with acute acquired brain injury admitted to the PICU were studied. A single center obtained serum samples on admission days 0, 1, 3, 5, and the day closest to hospital discharge. Biomarkers relevant to brain injury (neuron specific enolase [NSE], S100b), inflammation (interleukin [IL-6], C-reactive protein), and regeneration (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor [VEGF]) were collected. Biomarkers were analyzed using a Luminex® bioassay. Functional status scale (FSS) scores were abstracted from the medical record. New functional impairment was defined as a (worse) FSS score at hospital discharge compared to pre-PICU (baseline). Individual biomarker fluorescence index (FI) values for each sample collection day were correlated with new functional impairment using Spearman rank correlation coefficient (ρ). Trends in repeated measures of biomarker FI over time were explored graphically, and the association between repeated measures of biomarker FI and new functional impairment was analyzed using covariate adjusted linear mixed-effect models. RESULTS: Functional impairment was inversely correlated with markers of regeneration and plasticity including BDNF at day 3 (ρ = - 0.404, p = .015), day 5 (ρ = - 0.549, p = 0.005) and hospital discharge (ρ = - 0.420, p = 0.026) and VEGF at day 1 (ρ = - 0.282, p = 0.008) and hospital discharge (ρ = - 0.378, p = 0.047), such that lower levels of both markers at each time point were associated with greater impairment. Similarly, repeated measures of BDNF and VEGF were inversely correlated with new functional impairment (B = - 0.001, p = 0.001 and B = - 0.001, p = 0.003, respectively). NSE, a biomarker of acute brain injury, showed a positive correlation between day 0 levels and new functional impairment (ρ = 0.320, p = 0.044). CONCLUSIONS: Blood-based biomarkers of regeneration and plasticity may hold prognostic utility for functional impairment among pediatric patients with neurocritical illness and warrant further investigation.

Interrelationships Between Post-TBI Employment and Substance Abuse: A Cross-lagged Structural Equation Modeling Analysis.

OBJECTIVE: To describe the interrelationship of postinjury employment and substance abuse (SA) among individuals with traumatic brain injury. DESIGN: Structural equation model (SEM) and logistic regression analytic approach using a merged database of the National Trauma Data Bank (NTDB) and Traumatic Brain Injury Model Systems (TBIMS) National Database, with acute care and rehabilitation hospitalization data and 1, 2, and 5 year follow-up data. SETTING: United States Level I/II trauma centers and inpatient rehabilitation centers with telephone follow-up. PARTICIPANTS: Individuals in the TBIMS National Database successfully matched to their NTDB data, aged 18-59 years, with trauma severity, age, sex, employment, and SA data at 1, 2, and/or 5 years postinjury (N=2890). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Employment status (employed/unemployed) and SA (present/absent) at year 1, year 2, and year 5 postinjury. RESULTS: SEM analysis showed older age at injury predicted lower likelihood of employment at all time points postinjury (ßYR1=-0.016; ßYR2=-0.006; ßYR5=-0.016; all P<.001), while higher injury severity score (ISS) predicted lower likelihood of employment (ß=-0.008; P=.027) and SA (ß=-0.007; P=.050) at year 1. Male sex predicted higher likelihood of SA at each follow-up (ßYR1=0.227; ßYR2=0.184; ßYR5=0.161; all P<.100). Despite associations of preinjury unemployment with higher preinjury SA, postinjury employment at year 1 predicted SA at year 2 (ß=0.118; P=.028). Employment and SA during the previous follow-up period predicted subsequent employment and SA, respectively. CONCLUSIONS: Employment and SA have unique longitudinal interrelationships and are additionally influenced by age, sex, and ISS. The present work suggests the need for more research on causal, confounding, and mediating factors and appropriate screening and intervention tools that minimize SA and facilitate successful employment-related outcomes.

Employment Stability in the First 5 Years After Moderate-to-Severe Traumatic Brain Injury.

OBJECTIVE: To characterize employment stability and identify predictive factors of employment stability in working-age individuals after moderate-to-severe traumatic brain injury (TBI) that may be clinically addressed. DESIGN: Longitudinal observational study of an inception cohort from the Traumatic Brain Injury Model Systems National Database (TBIMS-NDB) using data at years 1, 2, and 5 post-TBI. SETTING: Inpatient rehabilitation centers with telephone follow-up. PARTICIPANTS: Individuals enrolled in the TBIMS-NDB since 2001, aged 18-59, with employment data at 2 or more follow-up interviews at years 1, 2, and 5 (N=5683). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Employment stability, categorized using post-TBI employment data as no paid employment (53.25%), stably (27.20%), delayed (10.24%), or unstably (9.31%) employed. RESULTS: Multinomial regression analyses identified predictive factors of employment stability, including younger age, white race, less severe injuries, preinjury employment, higher annual earnings, male sex, higher education, transportation independence postinjury, and no anxiety or depression at 1 year post-TBI. CONCLUSIONS: Employment stability serves as an important measure of productivity post-TBI. Psychosocial, clinical, environmental, and demographic factors predict employment stability post-TBI. Notable predictors include transportation independence as well as the presence of anxiety and depression at year 1 post-TBI as potentially modifiable intervention targets.

Comorbid Conditions Among Adults 50 Years and Older With Traumatic Brain Injury: Examining Associations With Demographics, Healthcare Utilization, Institutionalization, and 1-Year Outcomes.

OBJECTIVES: To assess the relationship of acute complications, preexisting chronic diseases, and substance abuse with clinical and functional outcomes among adults 50 years and older with moderate-to-severe traumatic brain injury (TBI). DESIGN: Prospective cohort study. PARTICIPANTS: Adults 50 years and older with moderate-to-severe TBI (n = 2134). MEASURES: Clusters of comorbid health conditions empirically derived from non-injury International Classification of Diseases, Ninth Revision codes, demographic/injury variables, and outcome (acute and rehabilitation length of stay [LOS], Functional Independence Measure efficiency, posttraumatic amnesia [PTA] duration, institutionalization, rehospitalization, and Glasgow Outcome Scale-Extended (GOS-E) at 1 year). RESULTS: Individuals with greater acute hospital complication burden were more often middle-aged men, injured in motor vehicle accidents, and had longer LOS and PTA. These same individuals experienced higher rates of 1-year rehospitalization and greater odds of unfavorable GOS-E scores at 1 year. Those with greater chronic disease burden were more likely to be rehospitalized at 1 year. Individuals with more substance abuse burden were most often younger (eg, middle adulthood), black race, less educated, injured via motor vehicle accidents, and had an increased risk for institutionalization. CONCLUSION: Preexisting health conditions and acute complications contribute to TBI outcomes. This work provides a foundation to explore effects of comorbidity prevention and management on TBI recovery in older adults.

Variability in daily self-reported emotional symptoms and fatigue measured over eight weeks in community dwelling individuals with traumatic brain injury.

OBJECTIVE: To investigate within-person variability in daily self-reported emotional and fatigue symptoms and factors associated with high within-person variability among individuals with chronic traumatic brain injury (TBI). DESIGN: This was a prospective descriptive pilot study of n = 18 adults with chronic TBI (2-27 years post-injury) who owned and could independently use an Apple or Android device. METHODS: Participants completed daily assessments for 8 weeks via smartphone. Outcome measures included the Positive and Negative Affect Schedule, Patient Health Questionnaire-2, Generalized Anxiety Disorder-2, and a 7-point fatigue rating. We examined within-person variability over time using individual Multilevel Linear Models. We categorized within-person variability as High or Low based on individual standard deviations in relationship to sample standard deviation. RESULTS: Significant temporal within-person variability occurred for all measures. High variability was associated with more symptom reporting versus Low variability, and variability was associated with sex (High variability: 88% women; Low variability 90% men). CONCLUSIONS: Symptom measurement at a single time point among adults with chronic TBI may not capture day-to-day symptom fluctuation and may misidentify individuals in need of intervention. Assessing symptom profiles over time to capture temporal and individual variability may provide a more ecologically valid measure for managing long-term symptoms after TBI.

A mathematical model of neuroinflammation in severe clinical traumatic brain injury.

BACKGROUND: Understanding the interdependencies among inflammatory mediators of tissue damage following traumatic brain injury (TBI) is essential in providing effective, patient-specific care. Activated microglia and elevated concentrations of inflammatory signaling molecules reflect the complex cascades associated with acute neuroinflammation and are predictive of recovery after TBI. However, clinical TBI studies to date have not focused on modeling the dynamic temporal patterns of simultaneously evolving inflammatory mediators, which has potential in guiding the design of future immunomodulation intervention studies. METHODS: We derived a mathematical model consisting of ordinary differential equations (ODE) to represent interactions between pro- and anti-inflammatory cytokines, M1- and M2-like microglia, and central nervous system (CNS) tissue damage. We incorporated variables for several cytokines, interleukin (IL)-1ß, IL-4, IL-10, and IL-12, known to have roles in microglial activation and phenotype differentiation. The model was fit to cerebrospinal fluid (CSF) cytokine data, collected during the first 5 days post-injury in n = 89 adults with severe TBI. Ensembles of model fits were produced for three patient subgroups: (1) a favorable outcome group (GOS = 4,5) and (2) an unfavorable outcome group (GOS = 1,2,3) both with lower pro-inflammatory load, and (3) an unfavorable outcome group (GOS = 1,2,3) with higher pro-inflammatory load. Differences in parameter distributions between subgroups were ranked using Bhattacharyya metrics to identify mechanistic differences underlying the neuroinflammatory patterns of patient groups with different TBI outcomes. RESULTS: Optimal model fits to data showed different microglial and damage responses by patient subgroup. Upon comparison of model parameter distributions, unfavorable outcome groups were characterized by either a prolonged, pathophysiological or a transient, sub-physiological course of neuroinflammation. CONCLUSION: By developing a mathematical characterization of inflammatory processes informed by clinical data, we have created a system for exploring links between acute neuroinflammatory components and patient outcome in severe TBI.

Epidemiology of Comorbid Conditions Among Adults 50 Years and Older With Traumatic Brain Injury.

OBJECTIVES: Aging individuals with traumatic brain injury (TBI) experience multiple comorbidities that can affect recovery from injury. The objective of this study was to describe the most commonly co-occurring comorbid conditions among adults 50 years and older with TBI. SETTING: Level I Trauma centers. PARTICIPANTS: Adults 50 years and older with moderate/severe TBI enrolled in the TBI-Model Systems (TBI-MS) from 2007 to 2014 (n = 2134). DESIGN: A TBI-MS prospective cohort study. MAIN MEASURES: International Classification of Disease-9th Revision codes collapsed into 45 comorbidity categories. Comorbidity prevalence estimates and trend analyses were conducted by age strata (50-54, 55-64, 65-74, 75-84, ≥85 years). A dimension reduction method, Treelet Transform, classified clusters of comorbidities that tended to co-occur. RESULTS: The 3 most commonly occurring comorbid categories were hypertensive disease (52.6/100 persons), other diseases of the respiratory system (51.8/100 persons), and fluid component imbalances (43.7/100 persons). Treelet Transform classified 3 clusters of comorbid codes, broadly classified as (1) acute medical diseases/infections, (2) chronic conditions, and (3) substance abuse disorders. CONCLUSION: This study provides valuable insight into comorbid conditions that co-occur among adults 50 years and older with TBI and provides a foundation for future studies to explore how specific comorbidities affect TBI recovery.

Ventricular fibrillation cardiac arrest produces a chronic striatal hyperdopaminergic state that is worsened by methylphenidate treatment.

Cardiac arrest survival rates have improved with modern resuscitation techniques, but many survivors experience impairments associated with hypoxic-ischemic brain injury (HIBI). Currently, little is understood about chronic changes in striatal dopamine (DA) systems after HIBI. Given the common empiric clinical use of DA enhancing agents in neurorehabilitation, investigation evaluating dopaminergic alterations after cardiac arrest (CA) is necessary to optimize rehabilitation approaches. We hypothesized that striatal DA neurotransmission would be altered chronically after ventricular fibrillation cardiac arrest (VF-CA). Fast-scan cyclic voltammetry was used with median forebrain bundle (MFB) maximal electrical stimulations (60Hz, 10s) in rats to characterize presynaptic components of DA neurotransmission in the dorsal striatum (D-Str) and nucleus accumbens 14 days after a 5-min VF-CA when compared to Sham or Naïve. VF-CA increased D-Str-evoked overflow [DA], total [DA] released, and initial DA release rate versus controls, despite also increasing maximal velocity of DA reuptake (Vmax ). Methylphenidate (10 mg/kg), a DA transporter inhibitor, was administered to VF-CA and Shams after establishing a baseline, pre-drug 60 Hz, 5 s stimulation response. Methylphenidate increased initial evoked overflow [DA] more-so in VF-CA versus Sham and reduced D-Str Vmax in VF-CA but not Shams; these findings are consistent with upregulated striatal DA transporter in VF-CA versus Sham. Our work demonstrates that 5-min VF-CA increases electrically stimulated DA release with concomitant upregulation of DA reuptake 2 weeks after brief VF-CA insult. Future work should elucidate how CA insult duration, time after insult, and insult type influence striatal DA neurotransmission and related cognitive and motor functions.

TBI Rehabilomics Research: an Exemplar of a Biomarker-Based Approach to Precision Care for Populations with Disability.

PURPOSE OF REVIEW: The purpose of this review is to summarize how "-omics" technologies can inform rehabilitation-relevant outcomes for a range of populations with neurologically related disability by including outcome metrics linked to the World Health Organization's International Classification of Functioning, Disability, and Health (WHO-ICF) domains of impairments in body function, activity limitations, and participation restrictions. RECENT FINDINGS: To date, nearly every area of medicine uses biomarkers in some capacity to aid in understanding how personal biology informs clinical care. "-Omics"-based approaches use high throughput genomics, proteomics, and transcriptomics assay platforms to tailor and personalize treatments for subgroups of similar individuals based on these results. The recent Precision Medicine Initiative (PMI), sponsored by the National Institutes of Health (NIH), has propelled biomarker-based and genomics research to the forefront of many translational research and care programs addressing a variety of medical populations. Yet, the literature is sparse on precision medicine approaches for those with neurologically related and other disability. We demonstrate how the Rehabilomics Research model represents a translational framework for programs of precision rehabilitation research and care focused on linking personal biology to the biopsychosocial constructs that represent the WHO-ICF model and multidimensional outcome. We provide multiple exemplars from our own research program involving individuals with moderate-to-severe traumatic brain injury (TBI) to demonstrate how genomics and other biomarkers can be identified and assessed for their capacity to assist with personalized (precision) neurorehabilitation care and management.

Cross-Lagged Panel Analysis of Depression and Behavioral Dysfunction in the First Year After Moderate-to-Severe Traumatic Brain Injury.

Timely treatment of depression and behavioral dysfunction after moderate-to-severe traumatic brain injury (TBI) could improve health, function, and quality of life. The authors hypothesized that 6-month depression would be the stronger contributor to later depression and behavioral dysfunction in a sample of 88 adults with moderate-to-severe TBI. A structural equation modeling cross-lagged panel analysis, adjusting for all 6-month predictors, revealed that 6-month depression had a stronger relationship to 12-month depression (ßstand=0.55, p=0.002) and behavioral dysfunction (ßstand=0.41, p=0.004) than did 6-month behavioral dysfunction (ßstand=0.17, p=0.270, ßstand=0.30, p=0.035). Depression may be in the developmental pathway to behavioral dysfunction, triggering a cycle of reciprocal causality.

Post-traumatic epilepsy associations with mental health outcomes in the first two years after moderate to severe TBI: A TBI Model Systems analysis.

PURPOSE: Research suggests that there are reciprocal relationships between mental health (MH) disorders and epilepsy risk. However, MH relationships to post-traumatic epilepsy (PTE) have not been explored. Thus, the objective of this study was to assess associations between PTE and frequency of depression and/or anxiety in a cohort of individuals with moderate-to-severe TBI who received acute inpatient rehabilitation. METHODS: Multivariate regression models were developed using a recent (2010-2012) cohort (n=867 unique participants) from the TBI Model Systems (TBIMS) National Database, a time frame during which self-reported seizures, depression [Patient Health Questionnaire (PHQ)-9], and anxiety [Generalized Anxiety Disorder (GAD-7)] follow-up measures were concurrently collected at year-1 and year-2 after injury. RESULTS: PTE did not significantly contribute to depression status in either the year-1 or year-2 cohort, nor did it contribute significantly to anxiety status in the year-1 cohort, after controlling for other known depression and anxiety predictors. However, those with PTE in year-2 had 3.34 times the odds (p=.002) of having clinically significant anxiety, even after accounting for other relevant predictors. In this model, participants who self-identified as Black were also more likely to report clinical symptoms of anxiety than those who identified as White. PTE was the only significant predictor of comorbid depression and anxiety at year-2 (Odds Ratio 2.71; p=0.049). CONCLUSIONS: Our data suggest that PTE is associated with MH outcomes 2years after TBI, findings whose significance may reflect reciprocal, biological, psychological, and/or experiential factors contributing to and resulting from both PTE and MH status post-TBI. Future work should consider temporal and reciprocal relationships between PTE and MH as well as if/how treatment of each condition influences biosusceptibility to the other condition.