Development of an MMPI reference group for outpatients with persisting symptoms following mild TBI.

OBJECTIVE: 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: 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: Compared to established MMPI general population norms, individuals with persisting symptoms demonstrated elevations on several scales, primarily in cognitive and somatic domains. T 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: 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.

King-Devick Test Performance and Cognitive Dysfunction after Concussion: A Pilot Eye Movement Study.

(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.

Genetic Variation in the Vesicular Monoamine Transporter: Preliminary Associations With Cognitive Outcomes After Severe Traumatic Brain Injury.

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.

Duration of Posttraumatic Amnesia Predicts Neuropsychological and Global Outcome in Complicated Mild Traumatic Brain Injury.

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.

A Dopamine Pathway Gene Risk Score for Cognitive Recovery Following Traumatic Brain Injury: Methodological Considerations, Preliminary Findings, and Interactions With Sex.

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 × 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 × 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 × 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.

Posttraumatic Brain Injury Cognitive Performance Is Moderated by Variation Within ANKK1 and DRD2 Genes.

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.

Early trajectory of psychiatric symptoms after traumatic brain injury: relationship to patient and injury characteristics.

Psychiatric disturbance is common and disabling after traumatic brain injury (TBI). Few studies have investigated the trajectory of psychiatric symptoms in the first 6 months postinjury, when monitoring and early treatment might prevent persistent difficulties. The aim of this study was to examine the trajectory of psychiatric symptoms 1-6 months post-TBI, the patient/injury characteristics associated with changes, and characteristics predictive of persisting symptoms. A secondary analysis was performed on data from a clinical trial with three data collection points. Across eight centers, 872 participants with complicated mild to severe TBI were administered the Brief Symptom Inventory (BSI) at 30, 90, and 180 days postinjury. Mixed-effects models were used to assess longitudinal changes in the BSI Global Severity Index (GSI). Multi-variate logistic regression was used to assess predictors of clinically significant GSI elevations persisting to 6 months post-TBI. In general, GSI scores improved over time. Women improved faster than men; race/ethnicity was also significantly associated with rate of change, with Hispanics showing the most and African Americans the least improvement. Clinically significant psychiatric symptoms (caseness) occurred in 42% of the sample at 6 months, and more than one type of symptom was common. Significant predictors of caseness included African American race, age from 30 to 60 years, longer post-traumatic amnesia (PTA) duration, pre-TBI unemployment, and pre-TBI risky alcohol use. Findings indicate that psychiatric symptoms are common in the first 6 months post-TBI and frequently extend beyond the depression and anxiety symptoms that may be most commonly screened. Patients with longer PTA and preinjury alcohol misuse may need more intensive monitoring for symptom persistence.

Corpus callosum integrity and neuropsychological performance after traumatic brain injury: a diffusion tensor imaging study.

OBJECTIVES: (1) Detailed analysis of diffusion tensor imaging (DTI) parameters (fractional anisotropy and radial diffusivity) to evaluate white matter integrity in the corpus callosum (CC), and (2) examine correlations between DTI data and performance on multiple measures of cognitive functioning. PARTICIPANTS: Twelve individuals with a history of complicated mild, moderate, or severe traumatic brain injury (TBI) who were an average of 1.7 years postinjury and 12 control participants. MAIN MEASURES: Standardized and experimental neuropsychological tests; detailed analysis of DTI parameters. RESULTS: The TBI group demonstrated DTI values suggesting decreased white matter integrity and correlations with severity of injury. Both groups showed correlations between DTI parameters and cognitive measures, with more significant correlations observed for the TBI group. White matter changes in the CC were evident chronically and were related to severity of injury. CONCLUSIONS: Diffusion tensor imaging parameters suggesting disruptions in white matter in the CC may be implicated in impaired performance, both in terms of cognitive tasks and reaction time, after TBI.

Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline Brain Injury Treatment Trial (COBRIT).

CONTEXT: Traumatic brain injury (TBI) is a serious public health problem in the United States, yet no treatment is currently available to improve outcome after TBI. Approved for use in TBI in 59 countries, citicoline is an endogenous substance offering potential neuroprotective properties as well as facilitated neurorepair post injury. OBJECTIVE: To determine the ability of citicoline to positively affect functional and cognitive status in persons with complicated mild, moderate, and severe TBI. DESIGN, SETTING, AND PATIENTS: The Citicoline Brain Injury Treatment Trial (COBRIT), a phase 3, double-blind randomized clinical trial conducted between July 20, 2007, and February 4, 2011, among 1213 patients at 8 US level 1 trauma centers to investigate effects of citicoline vs placebo in patients with TBI classified as complicated mild, moderate, or severe. INTERVENTION: Ninety-day regimen of daily enteral or oral citicoline (2000 mg) or placebo. MAIN OUTCOME MEASURES: Functional and cognitive status, assessed at 90 days using the TBI-Clinical Trials Network Core Battery. A global statistical test was used to analyze the 9 scales of the core battery. Secondary outcomes were functional and cognitive improvement, assessed at 30, 90, and 180 days, and examination of the long-term maintenance of treatment effects. RESULTS: Rates of favorable improvement for the Glasgow Outcome Scale-Extended were 35.4% in the citicoline group and 35.6% in the placebo group. For all other scales the rate of improvement ranged from 37.3% to 86.5% in the citicoline group and from 42.7% to 84.0% in the placebo group. The citicoline and placebo groups did not differ significantly at the 90-day evaluation (global odds ratio [OR], 0.98 [95% CI, 0.83-1.15]); in addition, there was no significant treatment effect in the 2 severity subgroups (global OR, 1.14 [95% CI, 0.88-1.49] and 0.89 [95% CI, 0.72-1.49] for moderate/severe and complicated mild TBI, respectively). At the 180-day evaluation, the citicoline and placebo groups did not differ significantly with respect to the primary outcome (global OR, 0.87 [95% CI, 0.72-1.04]). CONCLUSION: Among patients with traumatic brain injury, the use of citicoline compared with placebo for 90 days did not result in improvement in functional and cognitive status. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00545662.

Association of KIBRA rs17070145 polymorphism and episodic memory in individuals with severe TBI.

BACKGROUND: Studies implicate single nucleotide polymorphism (SNP) rs17070145, a common T → C polymorphism on the KIBRA gene, in mediating differences in episodic memory. In healthy adults, T-allele carriers perform better than non-carriers on episodic memory measures. However, this association is reversed in adults with subjective memory complaints and populations vulnerable to memory deficits, a problem common in traumatic brain injury (TBI). METHODS: This study assessed associations between variation in the KIBRA gene and cognitive function in 129 adults with severe TBI. In addition to other executive functioning and functional/global outcomes, the Buschke Selective Reminding Test (SRT), Rey-Osterrieth Complex Figure Test and California Verbal Learning Test-II (CVLT-II) were administered 6 and 12 months post-injury. RESULTS: T-allele non-carriers performed better than carriers on multiple episodic memory measures. At 6 months, T-allele non-carriers performed better for delayed recall measures on the SRT. At 12 months, T-allele non-carriers performed better on multiple SRT measures and on List-B learning with CVLT-II. No associations occurred with executive function or global outcome measures. CONCLUSION: These results suggest that rs17070145 T-allele effects are specific to episodic memory and support the hypothesis that associations between rs17070145 variation and memory are disparate between healthy and impaired populations.

Persistent hypogonadism influences estradiol synthesis, cognition and outcome in males after severe TBI.

OBJECTIVE: Acute hypogonadotropic hypogonadism (AHH) occurs frequently after TBI, as does chronic hypogonadotropic hypogonadism. However, AHH and persistent hypogonadotropic hypogonadism (PHH) after TBI are not well studied. The objective of this study was to characterize longitudinal hormone profiles and the impact of AHH and PHH on outcome. METHODS: In this prospective cohort study, men with severe TBI (n = 38) had serum gonadal and gonadotropic hormones measured during weeks 1-52 post-injury. AHH, PHH and/or early resolving hypogonadotropic hypogonadism (ERHH) were based on temporal hormone assessments. PHH and hormone profiles were then compared to multiple outcome measures 6-12 months post-TBI. RESULTS: AHH affected 100% of the population, while 37% subsequently developed PHH. Acute testosterone (TEST) and estradiol/testosterone (E2/TEST) ratios were associated with PHH and outcome. Over time, post-acute TEST and E2 levels for the ERHH group approached normal range, while levels for the PHH group remained low. Post-acute gonadotrophin levels were within the normal range for both groups. PHH, along with lower post-acute TEST and E2 profiles, was associated with worse functional and cognitive outcomes at 6 and 12 months post-injury. CONCLUSIONS: These results support screening for post-acute secondary hypogonadism and further research to assess the mechanisms underlying PHH and associated functional and cognitive deficits.

Hemispheric and executive influences on low-level language processing after traumatic brain injury.

OBJECTIVE: The purpose of this study was to examine whether minor high-level language deficits found after traumatic brain injury (TBI) might be due to low-level language processing issues or executive control influences. A possible mechanism was also investigated. METHOD: Nineteen age- and education-matched healthy controls (16 M, 3 F) and 19 persons who had experienced a complicated mild, moderate or severe TBI between 1-3 years prior (16 M, 3 F; mean GCS = 9.44) participated in two computerized behavioural experiments utilizing two paradigms standard in the psycholinguistic literature (priming with lexical decision and verb generation), which included trials of greater and lesser executive demand. RESULTS: Response time and accuracy differences were found in both experiments, indicating deficits in single-word processing for the patient group. Disproportionate difficulty was found for trials which included an executive component. Right visual field (left hemisphere) preferences were found to be stronger in the TBI group than in controls. CONCLUSIONS: Results suggest that persons with TBI may have difficulties in processing single words alone, especially under conditions of increased executive demand, and that atypical patterns of hemispheric recruitment may be associated with these difficulties.

Encoding and recognition after traumatic brain injury: neuropsychological and functional magnetic resonance imaging findings.

Although impairment of episodic memory is common after traumatic brain injury (TBI), the complex nature of human memory suggests the need to study more than recall alone. For this reason, we are presenting an extension with additional analyses of persons reported in a previous publication ( Russell, Arenth, Scanlon, Kessler, & Ricker, 2011 ). We examined both the encoding and recognition components of an episodic memory paradigm containing both word and letter string blocks using functional magnetic resonance imaging (fMRI) and neuropsychological testing. This paradigm was completed by 12 persons with complicated mild, moderate, or severe TBI and 12 matched uninjured controls. Comparisons were made between groups and stimulus types. While task behavioral performance was not significantly different between groups, imaging results showed greater activation for the TBI group during the encoding portion of the task, while the control group exhibited more activation on the recognition portion. Observed areas of activation suggest that the TBI group may have used a less effective, but more automatic verbal strategy for encoding the nonpronounceable letter strings, while controls may have opted for more of a recognition-focused strategy. Group differences in California Verbal Learning Test-Second Edition (CVLT-II) performance supported these ideas, and further neuropsychological testing also suggested limitations in executive functioning in the TBI group that may have influenced performance. Implications for intervention are discussed.

CDP-choline as a biological supplement during neurorecovery: a focused review.

Cytidine 5'-diphosphocholine (CDP-choline or citicoline) is a highly bioavailable compound with potential benefits for aiding neural repair and increasing acetylcholine levels in the central and peripheral nervous system. As a result, many researchers have investigated the use of CDP-choline for various types of neurological insult or conditions, including stroke, traumatic brain injury, and Alzheimer disease. Despite the fact that the safety of the compound has been verified across multiple international studies, evidence for efficacy remains less clear. This may be attributable, at least in part, to several issues, including a lack of randomized clinical trials, a lack of availability of the compound in the United States, and statistical power issues in reported trials. In addition, the fact that CDP-choline has multiple potential points of therapeutic impact makes it an exciting treatment option in theory but also complicates the analysis of efficacy in the sense that multiple mechanisms and time points must be evaluated. Although some clinical conditions do not appear to benefit from CDP-choline treatment, the majority of findings to date have suggested at least minor benefits of treatment. In this review we will examine the evidence in the published literature pertaining to use of CDP-choline in rehabilitation populations and briefly consider the work yet to be done.

Cognitive impairment in acquired brain injury: a predictor of rehabilitation outcomes and an opportunity for novel interventions.

Cognitive impairment is a common sequela in acquired brain injury and one that predicts rehabilitation outcomes. There is emerging evidence that impairments in cognitive functions can be manipulated by both pharmacologic and nonpharmacologic interventions to improve rehabilitation outcomes. By using stroke as a model for acquired brain injury, we review the evidence that links cognitive impairment to poor rehabilitation outcomes and discuss possible mechanisms to explain this association. Furthermore, we examine nascent promising research that suggests that interventions that target cognitive impairments can lead to better rehabilitation outcomes.

A functional magnetic resonance imaging investigation of episodic memory after traumatic brain injury.

Traumatic brain injury often negatively impacts episodic memory; however, studies of the neural substrates of this impairment have been limited. In this study, both encoding and recognition of visually presented stimuli were examined with functional magnetic resonance imaging. Twelve adults with chronic complicated mild, moderate, and severe injuries were compared with a matched group of 12 controls. Behavioral task performance did not differentiate the groups. During neuroimaging, however, the group of individuals with traumatic brain injury exhibited increased activation, as well as increased bilaterality and dispersion as compared to controls. Findings are discussed in terms of increased resource recruitment.

The citicoline brain injury treatment (COBRIT) trial: design and methods.

Traumatic brain injury (TBI) is a major cause of death and disability. In the United States alone approximately 1.4 million sustain a TBI each year, of which 50,000 people die, and over 200,000 are hospitalized. Despite numerous prior clinical trials no standard pharmacotherapy for the treatment of TBI has been established. Citicoline, a naturally occurring endogenous compound, offers the potential of neuroprotection, neurorecovery, and neurofacilitation to enhance recovery after TBI. Citicoline has a favorable side-effect profile in humans and several meta-analyses suggest a benefit of citicoline treatment in stroke and dementia. COBRIT is a randomized, double-blind, placebo-controlled, multi-center trial of the effects of 90 days of citicoline on functional outcome in patients with complicated mild, moderate, and severe TBI. In all, 1292 patients will be recruited over an estimated 32 months from eight clinical sites with random assignment to citicoline (1000 mg twice a day) or placebo (twice a day), administered enterally or orally. Functional outcomes are assessed at 30, 90, and 180 days after the day of randomization. The primary outcome consists of a set of measures that will be analyzed as a composite measure using a global test procedure at 90 days. The measures comprise the following core battery: the California Verbal Learning Test II; the Controlled Oral Word Association Test; Digit Span; Extended Glasgow Outcome Scale; the Processing Speed Index; Stroop Test part 1 and Stroop Test part 2; and Trail Making Test parts A and B. Secondary outcomes include survival, toxicity, and rate of recovery.

Building a research program in rehabilitation sciences, Part II: case studies: University of Texas Medical Branch, Boston University, University of Pittsburgh, and University of Washington.

This article presents four case studies of rehabilitation science programs that have created enduring research efforts: one in physical therapy, one in interdisciplinary rehabilitation sciences, and two in physical medicine and rehabilitation. Several themes emerge from these case studies. First, building an enduring research program takes time and significant foundational work. Most importantly, it is crucial to have the support of the dean, academic institution, and medical center. This seems to be a prerequisite for success in this area.