Faculty Bibliography

OBJECTIVE/UNASSIGNED:To develop an MMPI-2-RF reference group for persistently symptomatic patients with mTBI in order to aid interpretation and better evaluate atypical scale elevations. METHOD/UNASSIGNED:Using the Q Local MMPI-2-RF Comparison Group Generator (CGG), 200 valid MMPI-2-RF profiles were aggregated for mTBI outpatients with persisting symptoms 2-24 months post injury. RESULTS/UNASSIGNED:scores > 60 and standard deviations > 10 were observed for the F-r (Infrequent Responses), Fs (Infrequent Somatic Responses), FBS-r (Symptom Validity), RBS (Response Bias Scale), RC1 (Somatic Complaints), MLS (Malaise), HPC (Head Pain Complaints), NUC (Neurological Complaints), and COG (Cognitive Complaints) scales. All other scales were consistent with established norms for the general population. CONCLUSION/UNASSIGNED:This study is the first to establish an empirically derived MMPI reference group for individuals with persisting symptoms following mTBI. By comparing MMPI profiles of patients with mTBI against this reference group, clinicians may be better able to identify abnormal symptomatology. Evaluating profiles within this context may allow for more accurate case conceptualization and targeted treatment recommendations for those patients who demonstrate disproportionate symptomatology outside the range of the mTBI reference group.

(1) Background: The King-Devick (KD) rapid number naming test is sensitive for concussion diagnosis, with increased test time from baseline as the outcome measure. Eye tracking during KD performance in concussed individuals shows an association between inter-saccadic interval (ISI) (the time between saccades) prolongation and prolonged testing time. This pilot study retrospectively assesses the relation between ISI prolongation during KD testing and cognitive performance in persistently-symptomatic individuals post-concussion. (2) Results: Fourteen participants (median age 34 years; 6 women) with prior neuropsychological assessment and KD testing with eye tracking were included. KD test times (72.6 ± 20.7 s) and median ISI (379.1 ± 199.1 msec) were prolonged compared to published normative values. Greater ISI prolongation was associated with lower scores for processing speed (WAIS-IV Coding, r = 0.72, p = 0.0017), attention/working memory (Trails Making A, r = -0.65, p = 0.006) (Digit Span Forward, r = 0.57, p = -0.017) (Digit Span Backward, r= -0.55, p = 0.021) (Digit Span Total, r = -0.74, p = 0.001), and executive function (Stroop Color Word Interference, r = -0.8, p = 0.0003). (3) Conclusions: This pilot study provides preliminary evidence suggesting that cognitive dysfunction may be associated with prolonged ISI and KD test times in concussion.

Cross-sectional approaches to outcome assessment may not adequately capture heterogeneity in recovery after traumatic brain injury (TBI). Using latent class mixed models (LCMM), a data-driven analytic that identifies groups of patients with similar trajectories, we identified distinct 6-month functional recovery trajectories in a large cohort (n=1,046) of adults age 18-70 years with complicated mild to severe TBI who participated in the Citicoline Brain Injury Treatment Trial (COBRIT). We used multinomial logistic fixed effect models and backward elimination, forward selection, and forward stepwise selection with several stopping rules to explore baseline predictors of functional recovery trajectory. Based on statistical and clinical considerations, the 7-class model was deemed superior. Visualization of these 7 functional recovery trajectories revealed that each trajectory class started at one of 3 recovery levels at 1-month, which, for ease of reference we labeled groups A-C: Group A. good recovery (2 classes; A1 and A2), Group B. moderate disability (2 classes; B1 and B2), Group C. severe disability (3 classes; C1, C2, and C3). By 6-months, these 3 groups experienced dramatically divergent trajectories: A experienced stable good recovery (A1, n=115) or dramatic decline (A2, n=4); B, rapid complete recovery (B1, n=71) or gradual recovery (B2, n=742); C, dramatic rapid recovery (C1, n=12), no recovery (C2, n=91), or death (C3, n=11). Trajectory class membership was not predicted by citicoline treatment (p=0.57). The models identified demographic, pre-injury, and injury-related predictors of functional recovery trajectory, including: age, race, education, pre-injury employment, pre-injury diabetes, pre-injury psychiatric disorder, site, Glasgow Coma Scale (GCS), post-traumatic amnesia, TBI mechanism, major extracranial injury, hemoglobin, and acute CT findings. GCS was the most consistently selected predictor across all models. All models also selected at least one demographic or pre-injury medical predictor. LCMM successfully identified dramatically divergent, clinically meaningful 6-month recovery trajectories with utility to inform clinical trial design.

Research Objectives: To investigate the associations between the SCAT3 Cognitive factor with neuropsychological performance measures. Design: Retrospective study of adult patients diagnosed with concussions. Setting: Outpatient concussion center in a major urban medical center. Participants: Participants were 89 patients diagnosed with uncomplicated mild traumatic brain injuries/concussions ages 18 years or older referred for neuropsychological evaluation. Interventions: Neuropsychological assessment. Main Outcome Measures: Sport Concussion Assessment Tool (SCAT3), Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) Digit Span Backward Subscale, WAIS-IV Coding, Delis-Kaplan Executive Function System Verbal Fluency, California Verbal Learning Test II (CVLT-II) Long Delayed Free Recall, Stroop Color and Word Interference score, Trails Making Test B (TMTB). Results: Separated hierarchical multiple regression analyses were computed. Results indicated that a higher SCAT3 cognitive measure was predictive of lower performance on Digit Span Backward Scaled Score (T= -.32, R2 =.23, p=.005), Coding (T= -.31, R2 =.37, p=.004), CVLT-II Long Delayed Recall (T= -.22, R2 =.36, p=.030), and TMTB (T= -.41, R2 =.27, p < .001) after controlling for years of education, gender, age, numbers of prior concussions, and loss of consciousness. Conclusions: Neuropsychological measures examining concentration, visuomotor processing speed, memory, and set shifting are associated with the SCAT3 Cognitive Factor score. The SCAT3 may be a useful tool to identify individuals who may benefit from follow-up and management of cognitive symptoms. While the SCAT3 was designed for athletes, it may be helpful in the general population

INTRODUCTION: Traumatic brain injury (TBI) frequently results in impaired cognition, a function that can be modulated by monoaminergic signaling. Genetic variation among monoaminergic genes may affect post-TBI cognitive performance. The vesicular monoamine transporter-2 (VMAT2) gene may be a novel source of genetic variation important for cognitive outcomes post-TBI given VMAT2's role in monoaminergic neurotransmission. OBJECTIVE: To evaluate associations between VMAT2 variability and cognitive outcomes post-TBI. METHODS: We evaluated 136 white adults with severe TBI for variation in VMAT2 using a tagging single nucleotide polymorphism (tSNP) approach (rs363223, rs363226, rs363251, and rs363341). We show genetic variation interacts with assessed cognitive impairment (cognitive composite [Comp-Cog] T-scores) to influence functional cognition (functional independence measure cognitive [FIM-Cog] subscale] 6 and 12 months postinjury. RESULTS: Multivariate analyses at 6 months postinjury showed rs363226 genotype was associated with Comp-Cog (P = .040) and interacted with Comp-Cog to influence functional cognition (P < .001). G-homozygotes had the largest cognitive impairment, and their cognitive impairment had the greatest adverse effect on functional cognition. DISCUSSION: We provide the first evidence that genetic variation within VMAT2 is associated with cognitive outcomes after TBI. Further work is needed to validate this finding and elucidate mechanisms by which genetic variation affects monoaminergic signaling, mediating differences in cognitive outcomes.

Research Objectives: Examine gender differences in self-reported postconcussion symptoms among individuals referred for neuropsychological services. Research has shown female gender is associated with increased susceptibility to emotional, physiological, sensory, and cognitive symptom clusters (King, 2014). Few studies have demonstrated which symptom cluster females are more likely to endorse. This study evaluates gender differences in symptomatology subsequent to various causes of concussion as research has shown this has implications for outcomes. Design: Retrospective study of adult concussion patients. Setting: Outpatient concussion center in an urban medical center. Participants: 100 patients (female = 59; mean age = 40.69 years) diagnosed with concussion or Post-Concussion Syndrome (PCS). Falls (33%), motor vehicle injuries (24%), and struck by an object (21%) were the top causes of injury. Interventions: Neuropsychological or psychological assessment. Main Outcome Measure(s): Sport Concussion Assessment Tool (SCAT 3). Results: Results indicated female concussion patients endorsed more physiological and sensory symptoms including nausea/vomiting (t(85.83)=-2.02, p <.05), dizziness (t(91) = -2.17, p <.05), balance problems (t(85.94) = -2.33, p <.05), sensitivity to light (t(91) = -3.18, p <.01 ), and sensitivity to noise (t(91) = -2.30, p <.05) than males. Additionally, females reported experiencing higher total numbers of symptoms (t(54.45)=-2.03, p <.05) and symptom severity (t(91) = -2.29, p <.05 ) than males. No gender differences were found with regard to cognitive, emotional, and sleep symptoms. Conclusions: A gender effect was demonstrated on several physiological and sensory concussion symptoms suggesting females to be more symptomatic than males. Results are consistent with previous findings indicating female athletes reported increased somatic symptoms postconcussion than male athletes. These findings can provide insight for rehabilitation specialists to develop more gender-specific approaches for treating female non-sport concussion patients

OBJECTIVES: Examine the effects of posttraumatic amnesia (PTA) duration on neuropsychological and global recovery from 1 to 6 months after complicated mild traumatic brain injury (cmTBI). PARTICIPANTS: A total of 330 persons with cmTBI defined as Glasgow Coma Scale score of 13 to 15 in emergency department, with well-defined abnormalities on neuroimaging. METHODS: Enrollment within 24 hours of injury with follow-up at 1, 3, and 6 months. MEASURES: Glasgow Outcome Scale-Extended, California Verbal Learning Test II, and Controlled Oral Word Association Test. Duration of PTA was retrospectively measured with structured interview at 30 days postinjury. RESULTS: Despite all having a Glasgow Coma Scale Score of 13 to 15, a quarter of the sample had a PTA duration of greater than 7 days; half had PTA duration of 1 of 7 days. Both cognitive performance and Extended Glasgow Outcome Scale outcomes were strongly associated with time since injury and PTA duration, with those with PTA duration of greater than 1 week showing residual moderate disability at 6-month assessment. CONCLUSIONS: Findings reinforce importance of careful measurement of duration of PTA to refine outcome prediction and allocation of resources to those with cmTBI. Future research would benefit from standardization in computed tomographic criteria and use of severity indices beyond Glasgow Coma Scale to characterize cmTBI.

OBJECTIVES: With evidence of sexual dimorphism involving the dopamine (DA)-pathway, and the importance of DA pathways in traumatic brain injury (TBI) recovery, we hypothesized that sex x DA-gene interactions may influence cognition post-TBI. PARTICIPANTS: Adult survivors of severe TBI (n = 193) consecutively recruited from a level 1 trauma center. DESIGN: Risk allele assignments were made for multiple DA pathway genes using a sex-specific stratified approach. Genetic risk alleles, and their impacts on cognition, were assessed at 6 and 12 months postinjury using unweighted, semiweighted, and weighted gene risk score (GRS) approaches. MAIN MEASURES: A cognitive composite score generated from 8 standardized neuropsychological tests targeting multiple cognitive domains. RESULTS: A significant sex x gene interaction was observed at 6 and 12 months for ANKK1 rs1800497 (6M: P = .002, 12M: P = .001) and COMT rs4680 (6M: P = .048; 12M: P = .004); DRD2 rs6279 (P = .001) and VMAT rs363226 (P = .043) genotypes were independently associated with cognition at 6 months, with trends for a sex x gene interaction at 12 months. All GRS methods were significant predictors of cognitive performance in multivariable models. Weighted GRS multivariate models captured the greatest variance in cognition: R = 0.344 (6 months); R = 0.441 (12 months), significantly increasing the variance captured from the base prediction models. CONCLUSIONS: A sex-specific DA-pathway GRS may be a valuable tool when predicting cognitive recovery post-TBI. Future work should validate these findings and explore how DA-pathway genetics may guide therapeutic intervention.

OBJECTIVE: As dopamine neurotransmission impacts cognition, we hypothesized that variants in the linked dopamine D2 receptor (DRD2) and ankyrin repeat and kinase domain (ANKK1) genes might account for some individual variability in cognitive recovery following traumatic brain injury (TBI). PARTICIPANTS: Prospective cohort of 108 survivors of severe TBI, recruited consecutively from a level 1 trauma center. DESIGN: We examined relationships between DRD2 genetic variation and functional recovery at 6 and 12 months post-TBI. MAIN MEASURES: Cognitive performance was evaluated using 8 neuropsychological tests targeting different cognitive domains. An overall cognitive composite was developed using normative data. We also assessed functional cognition, depression status, and global outcome. Subjects were genotyped for 6 DRD2 tagging single-nucleotide polymorphisms and Taq1A within ANKK1. RESULTS: ANKK1 Taq1A heterozygotes performed better than homozygotes across several cognitive domains at both time points postinjury. When adjusting for age, Glasgow Coma Scale score, and education, the Taq1A (ANKK1) and rs6279 (DRD2) variants were associated with overall composite scores at 6 months post-TBI (P = .0453 and P = .0452, respectively). At 12 months, only Taq1A remained a significant genetic predictor of cognition (P = .0128). Following multiple-comparisons correction, there were no significant associations between examined genetic variants and functional cognition, depression status, and global outcome. CONCLUSION: These data suggest that genetic variation within DRD2 influences cognitive recovery post-TBI. Understanding genetic influences on dopaminergic systems post-TBI may impact current treatment paradigms.