Characterizing the Effects of Concussion and Head Impact Exposure: Design, Methods, and Participant Traits of the CARE 2.0 Study.

OBJECTIVE: This article describes the design, methods, and participant characteristics of the second phase of the Concussion Assessment, Research, and Education (CARE) Consortium study ("CARE 2.0") of the effects of concussion and repetitive head impact exposure on neuropsychiatric health. METHODS: The authors conducted a prospective multisite observational study of male and female collegiate athletes and military service academy cadets and midshipmen participating in the CARE study. Participants were assessed at three time points: undergraduate baseline (UB), before departure from university or service academy (exit), and up to 6 years following graduation (postgrad) via an online battery of brain health assessments. Participant characteristics were compared across the three time points and four levels of head impact exposure. RESULTS: A total of 4,643 participants completed the exit assessment, and 3,981 completed the postgrad assessment. Relative to the UB assessment cohort, the exit and postgrad assessment cohorts differed with respect to the percentage of women, baseline Wechsler Test of Adult Reading scores, National Collegiate Athletic Association division category, sport contact level, and number of previous concussions. The median standardized difference across balancing variables, assessment time points, and degree of head impact exposure was 0.12 (with 90% of effect sizes ≤0.29). CONCLUSIONS: Although there were some statistically significant differences between participants across assessments, the effect sizes were modest, and overall the data suggest that the exit and postgrad cohorts reflect the characteristics of the baseline cohort. The CARE study design and its large, richly characterized sample provide an opportunity to answer important questions about cumulative and persistent effects of concussion and repetitive head impact exposure on neuropsychiatric health.

Research Letter: Relationship of Blood Biomarkers of Inflammation With Acute Concussion Symptoms and Recovery in the CARE Consortium.

OBJECTIVE: Determine the association of inflammatory biomarkers with clinical measures and recovery in participants with concussion. SETTING: Multicenter study in National Collegiate Athletic Association member institutions including military service academies. PARTICIPANTS: Four hundred twenty-two participants with acute concussion. DESIGN: Clinical visits and blood draws were completed preinjury and at multiple visits postconcussion (0-12 hours, 12-36 hours, and 36-60 hours postinjury). Clinical measures included Sport Concussion Assessment Tool (SCAT) symptom severity, Balance Error Scoring System, Standardized Assessment of Concussion (SAC), Brief Symptom Inventory-18 (BSI-18) scores, time to initiation of graduated return-to-play (RTP) protocol, and time to RTP. Interleukin (IL)-6, IL-10, IL-8, IL-1 receptor antagonist (RA), tumor necrosis factor (TNF), c-reactive protein, and vascular endothelial growth factor (VEGF) were measured in serum. Prespecified analyses focused on IL-6 and IL-1RA at 0 to 12 hours; exploratory analyses were conducted with false discovery rate correction. RESULTS: For prespecified analyses, IL-1RA at 0 to 12 hours in female participants was positively associated with more errors on the SAC (B(standard error, SE) = 0.58(0.27), P < .05) and worse SCAT symptom severity (B(SE) = 0.96(0.44), P < .05). For exploratory analyses, higher levels of IL-1RA at 12 to 36 hours were associated with higher global (B(SE) = 0.55(0.14), q < 0.01), depression (B(SE) = 0.45(0.10), q < 0.005), and somatization scores on the BSI (B(SE) = 0.46(0.12), q < 0.01) in participants with concussion; Higher TNF at 12 to 36 hours was associated with fewer errors on the SAC (B(SE) = - 0.46(0.14), q < 0.05). Subanalyses showed similar results for male participants and participants who were athletes. No associations were discovered in nonathlete cadets. Higher IL-8 at 0 to 12 hours was associated with slower RTP in female participants (OR = 14.47; 95% confidence interval, 2.96-70.66, q < 0.05); no other associations with recovery were observed. CONCLUSIONS: Peripheral inflammatory markers are associated with clinical symptoms following concussion and potentially represent one mechanism for psychological symptoms observed postinjury. Current results do not provide strong support for a potential prognostic role for these markers.

Postinjury Alcohol Use Is Associated With Prolonged Recovery After Concussion in NCAA Athletes.

OBJECTIVE: To determine whether alcohol use leads to prolonged clinical recovery or increased severity of concussion symptoms in National Collegiate Athletic Association (NCAA) athletes. DESIGN: Prospective observational study. SETTING: Clinical institutions. PARTICIPANTS: Athletes from the NCAA Concussion Assessment Research and Education consortium who sustained a concussion from 2014 to 2021. INTERVENTIONS: Athletes were divided into 2 groups, those reporting alcohol use postinjury and those reporting no alcohol use postinjury. MAIN OUTCOME MEASURES: Symptom recovery was evaluated as time (in days) from injury to clearance to return to unrestricted play (days until URTP). Severity of concussion symptoms was assessed using the Standardized Sport Concussion Assessment Tool (SCAT3) symptom severity, headache severity, difficulty concentrating, and difficulty remembering scores. These scores were taken a median of 6.6 [interquartile range (IQR) = 4.0-10] and 6 (IQR = 4.0-9.0) days after injury for those who did and did not consume alcohol postinjury respectively and compared with baseline SCAT3 scores. RESULTS: Four hundred eighty four athletes from the data set had complete data for exposure and outcome. The adjusted mean number of days until URTP for athletes reporting alcohol use postinjury [23.3; 95% confidence interval (CI), 20.0-27.2; days] was incidence rate ratio (IRR) 1.32 (95% CI, 1.12-1.55; P < 0.001) times higher than for athletes who reported no alcohol use postinjury [17.7 (95% CI, 16.1-19.3) days]. Postinjury alcohol was not associated with severity of concussion symptoms ( P 's < 0.05). CONCLUSION: Self-reported postinjury alcohol use is associated with prolonged recovery but not severity of concussion symptoms in collegiate athletes. This may inform future clinical recommendations regarding alcohol consumption after concussion.

Test-Retest Reliability and Efficacy of Individual Symptoms in Concussion Management.

OBJECTIVE: (1) To determine test-retest reliability of individual Sport Concussion Assessment Tool-Third Edition (SCAT-3) symptom scores and symptom severity scores, (2) to examine the specificity/sensitivity of individual SCAT-3 symptom severity scores acutely (24-48 hours) postconcussion, and (3) to develop a model of symptoms best able to differentiate concussed from nonconcussed student athletes and cadets. DESIGN: Prospective, longitudinal, and cross-sectional. SETTING: Twenty-six civilian schools and 3 US service academies. PARTICIPANTS: Collegiate student athletes (n = 5519) and cadets (n = 5359) from the National Collegiate Athletic Association-Department of Defense Grand Alliance: Concussion Assessment, Research and Education Consortium, including 290 student athletes and 205 cadets, assessed 24 to 48 hours postconcussion. INDEPENDENT VARIABLES: Concussed and nonconcussed student athlete and cadet groups. MAIN OUTCOME MEASURES: Sport Concussion Assessment Tool-Third Edition individual symptom severity scores, total symptom scores, and symptom severity scores. RESULTS: Results indicated poor test-retest reliability across all symptom scores (intraclass correlation coefficient = 0.029-0.331), but several individual symptoms had excellent predictive capability in discriminating concussed from nonconcussed participants (eg, headache, pressure in the head, and don't feel right had area under the curve >0.8, sensitivity >70%, and specificity >85%) regardless of baseline testing. These symptoms were consistent with Chi-square Automatic Interaction Detector classification trees with the highest mean probability. CONCLUSIONS: Findings support the excellent diagnostic accuracy of honest symptom reporting, notwithstanding the known limitations in symptom underreporting, and suggest that there may be added value in examining individual symptoms rather than total symptom scores and symptom severity scores alone. Finally, findings suggest that baseline testing is not necessary for interpreting postconcussion symptom scores.

Concussion Risk and Recovery in Athletes With Psychostimulant-Treated Attention-Deficit/Hyperactivity Disorder: Findings From the NCAA-DOD CARE Consortium.

The aim of the present study was to examine the effects of attention-deficit/hyperactivity disorder (ADHD) -related psychostimulant use in the context of concussion risk and symptom recovery. Data were obtained from the National Collegiate Athletic Association Department of Defense Grand Alliance Concussion Assessment, Research, and Education (NCAA-DOD CARE) Consortium from 2014 to 2017. Relative to individuals without diagnosed ADHD (i.e., control), both ADHD diagnosis and the combination of ADHD diagnosis and psychostimulant use were associated with a greater risk of incurring a concussive injury. Following a concussive injury, ADHD diagnosis was associated with longer symptom recovery time relative to the control group. However, individuals with ADHD who use psychostimulants did not take longer to resolve symptoms than controls, suggesting that psychostimulants may have a positive influence on recovery. Regardless of time point, ADHD diagnosis was associated with an elevated number of concussion-related symptoms; however, this effect appears mitigated by having used ADHD-related psychostimulants.

Age-dependent white matter disruptions after military traumatic brain injury: Multivariate analysis results from ENIGMA brain injury.

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.

Test-Retest Reliability of Concussion Baseline Assessments in United States Service Academy Cadets: A Report from the National Collegiate Athletic Association (NCAA)-Department of Defense (DoD) CARE Consortium.

OBJECTIVE: In response to advancing clinical practice guidelines regarding concussion management, service members, like athletes, complete a baseline assessment prior to participating in high-risk activities. While several studies have established test stability in athletes, no investigation to date has examined the stability of baseline assessment scores in military cadets. The objective of this study was to assess the test-retest reliability of a baseline concussion test battery in cadets at U.S. Service Academies. METHODS: All cadets participating in the Concussion Assessment, Research, and Education (CARE) Consortium investigation completed a standard baseline battery that included memory, balance, symptom, and neurocognitive assessments. Annual baseline testing was completed during the first 3 years of the study. A two-way mixed-model analysis of variance (intraclass correlation coefficent (ICC)3,1) and Kappa statistics were used to assess the stability of the metrics at 1-year and 2-year time intervals. RESULTS: ICC values for the 1-year test interval ranged from 0.28 to 0.67 and from 0.15 to 0.57 for the 2-year interval. Kappa values ranged from 0.16 to 0.21 for the 1-year interval and from 0.29 to 0.31 for the 2-year test interval. Across all measures, the observed effects were small, ranging from 0.01 to 0.44. CONCLUSIONS: This investigation noted less than optimal reliability for the most common concussion baseline assessments. While none of the assessments met or exceeded the accepted clinical threshold, the effect sizes were relatively small suggesting an overlap in performance from year-to-year. As such, baseline assessments beyond the initial evaluation in cadets are not essential but could aid concussion diagnosis.

Differences in sport-related concussion for female and male athletes in comparable collegiate sports: a study from the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium.

OBJECTIVES: To examine sex differences in sport-related concussion (SRC) across comparable sports. METHODS: Prospective cohort of collegiate athletes enrolled between 2014 and 2017 in the Concussion Assessment, Research and Education Consortium study. RESULTS: Among 1071 concussions (females=615; 57.4%), there was no difference in recovery (median days to full return to play) (females=13.5 (IQR 9.0, 23.1) vs males=11.8 (IQR 8.1, 19.0), p=0.96). In subgroup analyses, female recovery was longer in contact (females=12.7 days (IQR 8.8, 21.4) vs males=11.0 days (IQR 7.9, 16.2), p=0.0021), while male recovery was longer in limited contact sports (males=16.9 days (IQR 9.7, 101.7) vs females=13.8 days (IQR 9.1, 22.0), p<0.0001). There was no overall difference in recovery among Division I schools (females=13.7 (IQR 9.0, 23.1) vs males=12.2 (IQR 8.2 19.7), p=0.5), but females had longer recovery at the Division II/III levels (females=13.0 (IQR 9.2, 22.7) vs males=10.6 (IQR 8.1, 13.9), p=0.0048). CONCLUSION: Overall, no difference in recovery between sexes across comparable women's and men's sports in this collegiate cohort was found. However, females in contact and males in limited contact sports experienced longer recovery times, while females had longer recovery times at the Division II/III level. These disparate outcomes indicate that, while intrinsic biological sex differences in concussion recovery may exist, important, modifiable extrinsic factors may play a role in concussion outcomes.

Contributions of posttraumatic stress disorder (PTSD) and mild TBI (mTBI) history to suicidality in the INTRuST consortium.

OBJECTIVE: Mild TBI (mTBI) and posttraumatic stress disorder (PTSD) are independent risk factors for suicidal behaviour (SB). Further, co-occurring mTBI and PTSD increase one's risk for negative health and psychiatric outcomes. However, little research has examined the role of comorbid mTBI and PTSD on suicide risk. METHODS: The present study utilized data from the Injury and TRaUmatic STress (INTRuST) Consortium to examine the prevalence of suicidal ideation (SI) and behaviours among four groups: 1) comorbid mTBI+PTSD, 2) PTSD only, 3) mTBI only, and 4) healthy controls. RESULTS: Prevalence of lifetime SI, current SI, and lifetime SB for individuals with mTBI+PTSD was 40%, 25%, and 19%, respectively. Prevalence of lifetime SI, current SI, and lifetime SB for individuals with PTSD only was 29%, 11%, and 11%, respectively. Prevalence of lifetime SI, current SI, and lifetime SB for individuals with mTBI only was 14%, 1%, and 2%, respectively. Group comparisons showed that individuals with mTBI alone experienced elevated rates of lifetime SI compared to healthy controls. History of mTBI did not add significantly to risk for suicidal ideation and behaviour beyond what is accounted for by PTSD. CONCLUSION: Findings suggest that PTSD seems to be driving risk for suicidal behaviour.

Influence of Postconcussion Sleep Duration on Concussion Recovery in Collegiate Athletes.

OBJECTIVE: To determine whether decreased sleep duration postconcussion influences days to asymptomatic and assessment of performance throughout recovery. DESIGN: Prospective. SETTING: Institutional Clinical Research Laboratory. PATIENTS: Four hundred twenty-three collegiate athletes were diagnosed with concussion. INTERVENTIONS: Multidimensional concussion assessment battery was conducted at baseline, within 24 to 48 hours, daily [2-4 days postinjury (PI); symptoms only], once asymptomatic, and after return-to-play. The battery included the following: 22-item symptom checklist, Standardized Assessment of Concussion (SAC), Balance Error Scoring System (BESS), and computerized neurocognitive test [Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT)]. MAIN OUTCOME MEASURES: We subtracted baseline sleep duration from 24 to 48 hours postconcussion sleep duration and categorized athletes into the following groups: shorter sleep (≤-1 hour), no change (>-1 hour, <+1 hour), and longer sleep (≥+1 hour). A 1-way analysis of variance (ANOVA) was conducted to compare days to asymptomatic and separate mixed-model ANOVAs to compare total symptom scores, SAC total scores, BESS total error scores, and ImPACT composite scores between sleep categories across time points (α = 0.05). RESULTS: Sleep groups did not differ in days to asymptomatic. The shorter sleep group had greater symptom severity than no sleep change and longer sleep groups at 24 to 48 hours (shorter: 39.1 ± 20.7; no change: 25.1 ± 18.4, P = 0.007; longer: 25.7 ± 21.8, P = 0.004), and at 2 to 4 days PI (shorter: 21.8 ± 21.8; no change: 10.5 ± 10.8, P = 0.013; longer: 11.9 ± 14.2, P = 0.007), but did not differ at other time points (ie, asymptomatic and return-to-play). Participants with shorter sleep exhibited slower ImPACT reaction times at 24 to 48 hours (shorter: 0.68 ± 0.14; no change: 0.61 ± 0.09, P = 0.016; and longer: 0.62 ± 0.12, P = 0.028) and asymptomatic time points (shorter: 0.62 ± 0.11; no change: 0.56 ± 0.05; P = 0.015). CONCLUSION: Postinjury sleep declines may be associated with symptom severity and worsened reaction time during initial stages of recovery or may be the result of the concussion itself. Clinicians should be aware of alterations in sleep duration and manage appropriately to mitigate initial symptom burden postconcussion.

King-Devick Test Time Varies by Testing Modality.

OBJECTIVE: To explore differences in baseline King-Devick Test (KD) completion time between 2 testing modalities: (1) spiral-bound paper cards (cards) and (2) iPad application (iPad). DESIGN: Cross-sectional cohort analysis. SETTING: National Collegiate Athlete Association (NCAA) institutions. PARTICIPANTS: Student athletes from 13 women's and 11 men's collegiate sports who completed KD baseline testing as part of their first year in the Concussion Assessment, Research and Education (CARE) Consortium from 2014 to 2016 (n = 2003, 52.2% male). INDEPENDENT VARIABLES: King-Devick Test modalities; cards or iPad. MAIN OUTCOME MEASURE: Baseline KD completion time (seconds). RESULTS: Mean baseline KD completion time of the iPad modality group [42.8 seconds, 95% confidence interval (CI), 42.1-43.3] was 2.8 seconds (95% CI, 2.1-3.4) greater than the cards group (40.0 seconds, 95% CI, 39.7-40.3) (t(1, 1010.7) = -8.0, P < 0.001, Cohen's d = 0.41). CONCLUSIONS: Baseline KD performance is slower when tested on an iPad than when tested on spiral-bound paper cards. The 2 KD modalities should not be used interchangeably in concussion assessments because differences in the modalities can lead to time differences similar in magnitude to those used to indicate concussion. From a research perspective, modality may influence interpretation and/or synthesis of findings across studies.

The Relationship between Sport-Related Concussion and Sensation-Seeking.

Sensation-seeking, or the need for novel and exciting experiences, is thought to play a role in sport-related concussion (SRC), yet much remains unknown regarding these relationships and, more importantly, how sensation-seeking influences SRC risk. The current study assessed sensation-seeking, sport contact level, and SRC history and incidence in a large sample of NCAA collegiate athletes. Data included a full study sample of 22,374 baseline evaluations and a sub-sample of 2037 incident SRC. Independent samples t-test, analysis of covariance, and hierarchical logistic regression were constructed to address study hypotheses. Results showed that (1) among participants without SRC, sensation-seeking scores were higher in athletes playing contact sports compared to those playing limited- or non-contact sports (p < 0.001, R2 = 0.007, η2p = 0.003); (2) in the full study sample, a one-point increase in sensation-seeking scores resulted in a 21% greater risk of prior SRC (OR = 1.212; 95% CI: 1.154-1.272), and in the incident SRC sub-sample, a 28% greater risk of prior SRC (OR = 1.278; 95% CI: 1.104-1.480); (3) a one-point increase in sensation-seeking scores resulted in a 12% greater risk of incident SRC among the full study sample; and (4) sensation-seeking did not vary as a function of incident SRC (p = 0.281, η2p = 0.000). Our findings demonstrate the potential usefulness of considering sensation-seeking in SRC management.

Multivariate Base Rates of Low Scores and Reliable Decline on ImPACT in Healthy Collegiate Athletes Using CARE Consortium Norms.

OBJECTIVES: To describe multivariate base rates (MBRs) of low scores and reliable change (decline) scores on Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) in college athletes at baseline, as well as to assess MBR differences among demographic and medical history subpopulations. METHODS: Data were reported on 15,909 participants (46.5% female) from the NCAA/DoD CARE Consortium. MBRs of ImPACT composite scores were derived using published CARE normative data and reliability metrics. MBRs of sex-corrected low scores were reported at <25th percentile (Low Average), <10th percentile (Borderline), and ≤2nd percentile (Impaired). MBRs of reliable decline scores were reported at the 75%, 90%, 95%, and 99% confidence intervals. We analyzed subgroups by sex, race, attention-deficit/hyperactivity disorder and/or learning disability (ADHD/LD), anxiety/depression, and concussion history using chi-square analyses. RESULTS: Base rates of low scores and reliable decline scores on individual composites approximated the normative distribution. Athletes obtained ≥1 low score with frequencies of 63.4% (Low Average), 32.0% (Borderline), and 9.1% (Impaired). Athletes obtained ≥1 reliable decline score with frequencies of 66.8%, 32.2%, 18%, and 3.8%, respectively. Comparatively few athletes had low scores or reliable decline on ≥2 composite scores. Black/African American athletes and athletes with ADHD/LD had higher rates of low scores, while greater concussion history was associated with lower MBRs (p < .01). MBRs of reliable decline were not associated with demographic or medical factors. CONCLUSIONS: Clinical interpretation of low scores and reliable decline on ImPACT depends on the strictness of the low score cutoff, the reliable change criterion, and the number of scores exceeding these cutoffs. Race and ADHD influence the frequency of low scores at all cutoffs cross-sectionally.

Optimizing Outcome Assessment in Multicenter TBI Trials: Perspectives From TRACK-TBI and the TBI Endpoints Development Initiative.

Traumatic brain injury (TBI) is a global public health problem that affects the long-term cognitive, physical, and psychological health of patients, while also having a major impact on family and caregivers. In stark contrast to the effective trials that have been conducted in other neurological diseases, nearly 30 studies of interventions employed during acute hospital care for TBI have failed to identify treatments that improve outcome. Many factors may confound the ability to detect true and meaningful treatment effects. One promising area for improving the precision of intervention studies is to optimize the validity of the outcome assessment battery by using well-designed tools and data collection strategies to reduce variability in the outcome data. The Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, conducted at 18 sites across the United States, implemented a multidimensional outcome assessment battery with 22 measures aimed at characterizing TBI outcome up to 1 year postinjury. In parallel, through the TBI Endpoints Development (TED) Initiative, federal agencies and investigators have partnered to identify the most valid, reliable, and sensitive outcome assessments for TBI. Here, we present lessons learned from the TRACK-TBI and TED initiatives aimed at optimizing the validity of outcome assessment in TBI.

DRD2 C957T polymorphism is associated with improved 6-month verbal learning following traumatic brain injury.

Traumatic brain injury (TBI) often leads to heterogeneous clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism (SNP) in the dopamine D2 receptor (DRD2) may influence cognitive deficits following TBI. However, part of the association with DRD2 has been attributed to genetic variability within the adjacent ankyrin repeat and kinase domain containing 1 protein (ANKK1). Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether a novel DRD2 C957T polymorphism (rs6277) influences outcome on a cognitive battery at 6 months following TBI-California Verbal Learning Test (CVLT-II), Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), and Trail Making Test (TMT). Results in 128 Caucasian subjects show that the rs6277 T-allele associates with better verbal learning and recall on CVLT-II Trials 1-5 (T-allele carrier 52.8 ± 1.3 points, C/C 47.9 ± 1.7 points; mean increase 4.9 points, 95% confidence interval [0.9 to 8.8]; p = 0.018), Short-Delay Free Recall (T-carrier 10.9 ± 0.4 points, C/C 9.7 ± 0.5 points; mean increase 1.2 points [0.1 to 2.5]; p = 0.046), and Long-Delay Free Recall (T-carrier 11.5 ± 0.4 points, C/C 10.2 ± 0.5 points; mean increase 1.3 points [0.1 to 2.5]; p = 0.041) after adjusting for age, education years, Glasgow Coma Scale, presence of acute intracranial pathology on head computed tomography scan, and genotype of the ANKK1 SNP rs1800497 using multivariable regression. No association was found between DRD2 C947T and non-verbal processing speed (WAIS-PSI) or mental flexibility (TMT) at 6 months. Hence, DRD2 C947T (rs6277) may be associated with better performance on select cognitive domains independent of ANKK1 following TBI.

Temporal profile of care following mild traumatic brain injury: predictors of hospital admission, follow-up referral and six-month outcome.

OBJECTIVE: To investigate the clinical management and medical follow-up of patients with mild traumatic brain injury (mTBI) presenting to emergency departments (EDs). METHODS: Overall, 168 adult patients with mTBI from the prospective, multicentre Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot study with Glasgow Coma Scale (GCS) 13-15, no polytrauma and alive at six months were included. Predictors for hospital admission, three-month follow-up referral and six-month functional disability (Glasgow Outcome Scale-Extended (GOSE) ≤ 6) were analysed using multivariable regression. RESULTS: Overall, 48% were admitted to hospital, 22% received three-month referral and 27% reported six-month functional disability. Intracranial pathology on ED head computed tomography (multivariable odds ratio (OR) = 81.08, 95% confidence interval (CI) [10.28-639.36]) and amnesia (>30-minutes: OR = 5.27 [1.75-15.87]; unknown duration: OR = 4.43 [1.26-15.62]) predicted hospital admission. Older age (per-year OR = 1.03 [1.01-1.05]) predicted three-month referral, while part-time/unemployment predicted lack of referral (OR = 0.17 [0.06-0.50]). GCS < 15 (OR = 2.46 [1.05-5.78]) and prior history of seizures (OR = 3.62 [1.21-10.89]) predicted six-month functional disability, while increased education (per-year OR = 0.86 [0.76-0.97]) was protective. CONCLUSIONS: Clinical factors modulate triage to admission, while demographic/socioeconomic elements modulate follow-up care acquisition; six-month functional disability associates with both clinical and demographic/socioeconomic variables. Improving triage to acute and outpatient care requires further investigation to optimize resource allocation and outcome after mTBI. ClinicalTrials.gov registration: NCT01565551.

Age effects and sex differences in human brain white matter of young to middle-aged adults: A DTI, NODDI, and q-space study.

Microstructural changes in human brain white matter of young to middle-aged adults were studied using advanced diffusion Magnetic Resonance Imaging (dMRI). Multiple shell diffusion-weighted data were acquired using the Hybrid Diffusion Imaging (HYDI). The HYDI method is extremely versatile and data were analyzed using Diffusion Tensor Imaging (DTI), Neurite Orientation Dispersion and Density Imaging (NODDI), and q-space imaging approaches. Twenty-four females and 23 males between 18 and 55years of age were included in this study. The impact of age and sex on diffusion metrics were tested using least squares linear regressions in 48 white matter regions of interest (ROIs) across the whole brain and adjusted for multiple comparisons across ROIs. In this study, white matter projections to either the hippocampus or the cerebral cortices were the brain regions most sensitive to aging. Specifically, in this young to middle-aged cohort, aging effects were associated with more dispersion of white matter fibers while the tissue restriction and intra-axonal volume fraction remained relatively stable. The fiber dispersion index of NODDI exhibited the most pronounced sensitivity to aging. In addition, changes of the DTI indices in this aging cohort were correlated mostly with the fiber dispersion index rather than the intracellular volume fraction of NODDI or the q-space measurements. While men and women did not differ in the aging rate, men tend to have higher intra-axonal volume fraction than women. This study demonstrates that advanced dMRI using a HYDI acquisition and compartmental modeling of NODDI can elucidate microstructural alterations that are sensitive to age and sex. Finally, this study provides insight into the relationships between DTI diffusion metrics and advanced diffusion metrics of NODDI model and q-space imaging.

COMT Val 158 Met polymorphism is associated with nonverbal cognition following mild traumatic brain injury.

Mild traumatic brain injury (mTBI) results in variable clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism in catechol-o-methyltransferase (COMT), an enzyme which degrades catecholamine neurotransmitters, may influence cognitive deficits following moderate and/or severe head trauma. However, this has been disputed, and its role in mTBI has not been studied. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val (158) Met polymorphism influences outcome on a cognitive battery 6 months following mTBI--Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), Trail Making Test (TMT) Trail B minus Trail A time, and California Verbal Learning Test, Second Edition Trial 1-5 Standard Score (CVLT-II). All patients had an emergency department Glasgow Coma Scale (GCS) of 13-15, no acute intracranial pathology on head CT, and no polytrauma as defined by an Abbreviated Injury Scale (AIS) score of ≥3 in any extracranial region. Results in 100 subjects aged 40.9 (SD 15.2) years (COMT Met (158) /Met (158) 29 %, Met (158) /Val (158) 47 %, Val (158) /Val (158) 24 %) show that the COMT Met (158) allele (mean 101.6 ± SE 2.1) associates with higher nonverbal processing speed on the WAIS-PSI when compared to Val (158) /Val (158) homozygotes (93.8 ± SE 3.0) after controlling for demographics and injury severity (mean increase 7.9 points, 95 % CI [1.4 to 14.3], p = 0.017). The COMT Val (158) Met polymorphism did not associate with mental flexibility on the TMT or with verbal learning on the CVLT-II. Hence, COMT Val (158) Met may preferentially modulate nonverbal cognition following uncomplicated mTBI.Registry: ClinicalTrials.gov Identifier NCT01565551.

Apathy Is Associated With Ventral Striatum Volume in Schizophrenia Spectrum Disorder.

Apathy is prevalent in schizophrenia, but its etiology has received little investigation. The ventral striatum (VS), a key brain region involved in motivated behavior, has been implicated in studies of apathy. We therefore evaluated whether apathy is associated with volume of the VS on MRI in 23 patients with schizophrenia using voxel-based morphometry. Results indicated that greater self-reported apathy severity was associated with smaller volume of the right VS even when controlling for age, gender, depression, and total gray matter volume. The finding suggests that apathy is related to abnormality of brain circuitry subserving motivated behavior in patients with schizophrenia.

Association of a common genetic variant within ANKK1 with six-month cognitive performance after traumatic brain injury.

Genetic association analyses suggest that certain common single nucleotide polymorphisms (SNPs) may adversely impact recovery from traumatic brain injury (TBI). Delineating their causal relationship may aid in development of novel interventions and in identifying patients likely to respond to targeted therapies. We examined the influence of the (C/T) SNP rs1800497 of ANKK1 on post-TBI outcome using data from two prospective multicenter studies: the Citicoline Brain Injury Treatment (COBRIT) trial and Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot). We included patients with ANKK1 genotyping results and cognitive outcomes at six months post-TBI (n = 492: COBRIT n = 272, TRACK-TBI Pilot n = 220). Using the California Verbal Learning Test Second Edition (CVLT-II) Trial 1-5 Standard Score, we found a dose-dependent effect for the T allele, with T/T homozygotes scoring lowest on the CVLT-II Trial 1-5 Standard Score (T/T 45.1, C/T 51.1, C/C 52.1, ANOVA, p = 0.008). Post hoc testing with multiple comparison-correction indicated that T/T patients performed significantly worse than C/T and C/C patients. Similar effects were observed in a test of non-verbal processing (Wechsler Adult Intelligence Scale, Processing Speed Index). Our findings extend those of previous studies reporting a negative relationship of the ANKK1 T allele with cognitive performance after TBI. In this study, we demonstrate the value of pooling shared clinical, biomarker, and outcome variables from two large datasets applying the NIH TBI Common Data Elements. The results have implications for future multicenter investigations to further elucidate the role of ANKK1 in post-TBI outcome.