Efficacy of a virtual reality-based cognitive interactive training program for children with traumatic brain injuries: study protocol for a parallel-group randomized controlled trial.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of disability in children. Cognitive rehabilitation for this population is critical for their long-term health outcomes. This trial aims to evaluate the efficacy of a virtual reality-based program (VICT) for training executive functions in children with TBI. METHODS: A parallel group randomized controlled trial will be conducted among up to 32 children with TBI. Children in the intervention group will receive the VICT training while children in the control group will play a comparable VR game without executive function training. Each participant will be assessed at baseline, post-intervention, and 1-month follow-up. Outcomes will include core executive functions, attention, and health-related quality of life measured by computerized tasks or standardized questionnaires. DISCUSSION: Cognitive rehabilitation is among the top healthcare needs for pediatric TBI patients. Virtual reality-based training is promising due to its versatile content, flexibility, and potential cost savings for both patients and providers. Findings of this trial will provide data on the efficacy of the VICT program on core executive functions, attention problems, and health-related quality of life and serve as the empirical foundation for future larger multi-site effectiveness trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04526639 . Registered on August 18, 2020.

Screening for Delirium During Pediatric Brain Injury Rehabilitation.

OBJECTIVE: To assess feasibility of routine delirium screening using the Cornell Assessment of Pediatric Delirium (CAPD) in children admitted for rehabilitation with acquired brain injury (ABI), report on the prevalence of positive delirium screens in this population, and explore longitudinal trends in CAPD scores and their association with rehabilitation outcomes. DESIGN: Retrospective study. SETTING: Pediatric inpatient rehabilitation unit. PARTICIPANTS: 144 children (median 10.8 years) with ABI (N=144). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Percent compliance with twice daily delirium screening; prevalence of positive delirium screens; trajectories in CAPD scores and their relation with FIM for Children (WeeFIM) scores. RESULTS: Screening was feasible (mean 75% compliance for each of 144 children). Of 16,136 delirium screens, 29% were positive. 62% of children had ≥1 positive screen. Four primary patterns of CAPD trajectories were identified: Static Encephalopathy (10%), Episodic Delirium (10%), Improving (32%), and No Delirium (48%). Validity of these trajectories was demonstrated through association with WeeFIM and CALS outcomes. Younger age at admission was associated with positive delirium screens, and rehabilitation length of stay was significantly longer for the Improving group. CONCLUSIONS: Delirium occurs frequently in children with ABI during inpatient rehabilitation. Routine delirium screening provides clinically relevant information including the potential to facilitate early detection and intervention for medical complications. Longitudinal ratings of delirium symptoms may also have a role in developing a standardized definition for Post Traumatic Confusional State (PTCS) stage of recovery in children.

Head Control Contributes to Prediction of Emergence From the Minimally Conscious State in Children Admitted to Inpatient Rehabilitation.

OBJECTIVE: To examine the utility of head and trunk control, assessed using the Physical Abilities and Mobility Scale, for predicting emergence from a minimally conscious state (eMCS) among children with acquired brain injury admitted to inpatient rehabilitation in a disorder of consciousness (DoC). DESIGN: Retrospective study. SETTING: Pediatric inpatient rehabilitation hospital. PARTICIPANTS: Forty patients (2-21 years-old) directly admitted from acute care to pediatric inpatient brain injury rehabilitation in a DoC (average length of stay=85 days; N=40). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: State of consciousness (eMCS vs not) at discharge from inpatient rehabilitation. RESULTS: Forty-five percent of patients emerged from a minimally conscious state during inpatient rehabilitation. Admission state of consciousness and head control (but not trunk control) were significantly associated with eMCS and provided complementary prognostic information. Admission state of consciousness (ie, admitting in a vegetative state/unresponsive wakefulness syndrome) afforded the greatest negative predictive value (93.8%), whereas admission head control ability afforded the greatest positive predictive value (81.8% for any independent head control; 100% for maintaining head-up position for >30 seconds). Fifty percent of patients who emerged during the inpatient stay did not have independent head control at admission, highlighting the importance of exploring head control as a prognostic marker in conjunction with indicators with greater sensitivity (eg, state of consciousness at admission). CONCLUSIONS: A brief measure of head control at admission may contribute to identification of a subgroup of patients who are likely to emerge.

Rethinking recovery in adolescent concussions: Network-level functional connectivity alterations associated with motor deficits.

Adolescents who are clinically recovered from concussion continue to show subtle motor impairment on neurophysiological and behavioral measures. However, there is limited information on brain-behavior relationships of persistent motor impairment following clinical recovery from concussion. We examined the relationship between subtle motor performance and functional connectivity of the brain in adolescents with a history of concussion, status post-symptom resolution, and subjective return to baseline. Participants included 27 adolescents who were clinically recovered from concussion and 29 never-concussed, typically developing controls (10-17 years); all participants were examined using the Physical and Neurologic Examination of Subtle Signs (PANESS). Functional connectivity between the default mode network (DMN) or dorsal attention network (DAN) and regions of interest within the motor network was assessed using resting-state functional magnetic resonance imaging (rsfMRI). Compared to controls, adolescents clinically recovered from concussion showed greater subtle motor deficits as evaluated by the PANESS and increased connectivity between the DMN and left lateral premotor cortex. DMN to left lateral premotor cortex connectivity was significantly correlated with the total PANESS score, with more atypical connectivity associated with more motor abnormalities. This suggests that altered functional connectivity of the brain may underlie subtle motor deficits in adolescents who have clinically recovered from concussion. More investigation is required to understand the persistence and longer-term clinical relevance of altered functional connectivity and associated subtle motor deficits to inform whether functional connectivity may serve as an important biomarker related to longer-term outcomes after clinical recovery from concussion.

Inter-rater Reliability of the Revised Physical and Neurological Examination of Subtle Signs (PANESS) scored using video review.

The Physical and Neurological Examination of Subtle Signs (PANESS) is a brief neuromotor exam designed for use in children. This study examined the inter-rater reliability of PANESS scoring using video review in 23 typically developing youth, aged 10-18 years, who were either never-concussed or evaluated following clinical recovery from concussion. Moderate to excellent inter-rater reliability was identified across PANESS subscores and total score. The strongest inter-rater reliability was observed for the Timed Motor portion of the PANESS (ICCs >.90) suggesting that this section in particular may be a strong candidate for video-based scoring or telehealth administration.

Randomized controlled trial of cognitive refocusing versus stimulus control treatment for college insomnia: feasibility of a brief, electronic-based, and peer-led approach.

OBJECTIVE: Performance of Cognitive Refocusing Treatment for Insomnia (CRT-I) relative to stimulus control treatment (SCT) remains unknown among college students. This pilot trial compared single-session, electronic-based, peer-led CRT-I to SCT, and as well as awareness-based (AC) and no-treatment (NTC) controls. PARTICIPANTS: College students (N = 82; Mage=18.59 [SD = 0.78]; 58% female; 61% White; 16% Hispanic) with insomnia symptoms were randomly assigned to CRT-I (n = 12), SCT (n = 14), and AC (n = 14) conditions, or non-randomly recruited to NTC (n = 42). METHODS: All participants completed baseline and one-month follow-up surveys, and reported daily task enactment (except NTC). RESULTS: Feasibility ratings were comparable across conditions. Within-group treatment effects revealed greater improvements in (a) insomnia symptom severity among CRT-I (d = 1.13) and SCT (d = 1.66) groups relative to AC (d = 0.90) and (b) pre-sleep cognitive arousal among CRT-I (d = 0.94) and SCT (d = 1.42) groups relative to AC (d = 0.75). CONCLUSIONS: Brief, electronic-based, peer-led CRT-I and SCT interventions appear feasible and potentially efficacious for college insomnia.

Predicting Clinical Outcomes 7-10 Years after Severe Traumatic Brain Injury: Exploring the Prognostic Utility of the IMPACT Lab Model and Cerebrospinal Fluid UCH-L1 and MAP-2.

BACKGROUND: Severe traumatic brain injury (TBI) is a major contributor to disability and mortality in the industrialized world. Outcomes of severe TBI are profoundly heterogeneous, complicating outcome prognostication. Several prognostic models have been validated for acute prediction of 6-month global outcomes following TBI (e.g., morbidity/mortality). In this preliminary observational prognostic study, we assess the utility of the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) Lab model in predicting longer term global and cognitive outcomes (7-10 years post injury) and the extent to which cerebrospinal fluid (CSF) biomarkers enhance outcome prediction. METHODS: Very long-term global outcome was assessed in a total of 59 participants (41 of whom did not survive their injuries) using the Glasgow Outcome Scale-Extended and Disability Rating Scale. More detailed outcome information regarding cognitive functioning in daily life was collected from 18 participants surviving to 7-10 years post injury using the Cognitive Subscale of the Functional Independence Measure. A subset (n = 10) of these participants also completed performance-based cognitive testing (Digit Span Test) by telephone. The IMPACT lab model was applied to determine its prognostic value in relation to very long-term outcomes as well as the additive effects of acute CSF ubiquitin C-terminal hydrolase-L1 (UCH-L1) and microtubule associated protein 2 (MAP-2) concentrations. RESULTS: The IMPACT lab model discriminated favorable versus unfavorable 7- to 10-year outcome with an area under the receiver operating characteristic curve of 0.80. Higher IMPACT lab model risk scores predicted greater extent of very long-term morbidity (ß = 0.488 p = 0.000) as well as reduced cognitive independence (ß = - 0.515, p = 0.034). Acute elevations in UCH-L1 levels were also predictive of lesser independence in cognitive activities in daily life at very long-term follow-up (ß = 0.286, p = 0.048). Addition of two CSF biomarkers significantly improved prediction of very long-term neuropsychological performance among survivors, with the overall model (including IMPACT lab score, UCH-L1, and MAP-2) explaining 89.6% of variance in cognitive performance 7-10 years post injury (p = 0.008). Higher acute UCH-L1 concentrations were predictive of poorer cognitive performance (ß = - 0.496, p = 0.029), whereas higher acute MAP-2 concentrations demonstrated a strong cognitive protective effect (ß = 0.679, p = 0.010). CONCLUSIONS: Although preliminary, results suggest that existing prognostic models, including models with incorporation of CSF markers, may be applied to predict outcome of severe TBI years after injury. Continued research is needed examining early predictors of longer-term outcomes following TBI to identify potential targets for clinical trials that could impact long-ranging functional and cognitive outcomes.

Rasch Properties of the Cognitive and Linguistic Scale and Optimization for Outcome Trajectory Modeling in Pediatric Acquired Brain Injury.

OBJECTIVES: To (1) determine if items on the Cognitive and Linguistic Scale (CALS) follow a Rasch distribution and (2) explore the relationship between Rasch-derived Cognitive Ability Estimates and outcome trajectory parameters using a nonlinear mixed-effects modeling approach. DESIGN: Retrospective study. SETTING: Pediatric inpatient rehabilitation hospital. PARTICIPANTS: A total of 252 children (N=252) aged of 2-21 years (median, 11.8 [IQR, 6.4-15.9] years) consecutively admitted to an inpatient rehabilitation brain injury unit (2008-2014) for a first inpatient admission after acquired brain injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Rasch-derived Cognitive Ability Estimates from the CALS and associated outcome trajectory parameters. RESULTS: The CALS demonstrates adequate interval-scale properties with removal of scores from the arousal and responsivity items. Rasch-derived Cognitive Ability Estimates were associated with age (ß=0.025, P<.001) such that older age was associated with a faster rate of recovery and more complete ultimate recovery. Slower recovery initiation was associated with a less complete overall cognitive recovery (Spearman ρ=-0.31; P<.001). CONCLUSIONS: The Cognitive Ability Estimates derived from the CALS and associated outcome parameters (eg, rate of recovery) may serve as an ideal outcome measure for clinical trials evaluating interventions for acquired brain injury in a pediatric rehabilitation setting.

New cut-score to improve performance of the Memory Validity Profile (MVP) in heterogenous clinical populations.

The Memory Validity Profile (MVP) is a standalone performance validity test developed specifically for use with children. Prior research has demonstrated the MVP's strength in its ease of administration to children with a wide range of intellectual abilities. However, it has been found to lack sensitivity in detecting noncredible performance in select clinical populations using published cutoffs. The current study examines the MVP's performance in a diagnostically heterogeneous clinical sample and proposes a new cutoff for optimization of sensitivity and specificity. Archival clinical data were examined from 96 participants referred for a comprehensive neuropsychological evaluation (ages 6-18). Receiver operating characteristic analysis was used to assess the discriminative ability of MVP in detecting cases of noncredible performance defined as failures on both the Test of Memory Malingering and Reliable Digit Span. Using published cutoffs, the MVP demonstrated perfect specificity (100%) but suboptimal sensitivity (33.3%). Receiver operating characteristic analysis revealed strong discrimination using MVP Total score (AUC = 0.891 (p < 0.001)) and a MVP Total cut-score of ≤30 resulted in optimal sensitivity (89%) and specificity (63%). Our findings provide additional evidence that published MVP cutoffs may be too lenient to adequately capture instances of noncredible performance and indicate an MVP Total score cutoff of ≤30 may be more appropriate for use with heterogeneous clinical populations.

Making a Difference: Affective Distress Explains Discrepancy Between Objective and Subjective Cognitive Functioning After Mild Traumatic Brain Injury.

OBJECTIVE: To assess the relationship between subjective cognitive symptoms and objective cognitive test scores in patients after concussion. We additionally examined factors associated with subjective and objective cognitive dysfunction, as well as their discrepancy. PARTICIPANTS: Eighty-six individuals (65.1% female; 74.4% adult) from an interdisciplinary concussion clinic. METHODS: Subjective and objective cognitive functioning was measured via the SCAT-Symptom Evaluation and the CNS Vital Signs Neurocognition Index (NCI), respectively. Cognitive discrepancy scores were derived by calculating standardized residuals (via linear regression) using subjective symptoms as the outcome and NCI score as the predictor. Hierarchical regression assessed predictors (age, education, time postinjury, attention-deficit/hyperactivity disorder, affective distress, and sleep disturbance) of cognitive discrepancy scores. Nonparametric analyses evaluated relationships between predictor variables, subjective symptoms, and NCI. RESULTS: More severe affective and sleep symptoms (large and medium effects), less time postinjury (small effect), and older age (small effect) were associated with higher subjective cognitive symptoms. Higher levels of affective distress and less time since injury were associated with higher cognitive discrepancy scores (ß = .723, P < .001; ß = -.204, P < .05, respectively). CONCLUSION: Clinical interpretation of subjective cognitive dysfunction should consider these additional variables. Evaluation of affective distress is warranted in the context of higher subjective cognitive complaints than objective test performance.

Predicting long-term cognitive and neuropathological consequences of moderate to severe traumatic brain injury: Review and theoretical framework.

Prognostic modeling in moderate to severe traumatic brain injury (TBI) has historically focused primarily on the projection of crude outcomes such as the risk of mortality and disability. Initial work in this area has perpetuated the notion that prognosis after moderate to severe TBI can be measured as a single, static, and dichotomous outcome. However, more recent conceptualizations describe moderate to severe TBI as the initiation of a chronic disease state with high levels of inter-individual variability in terms of symptom manifestation and disease progression. Unfortunately, existing prognostic models provide limited insight into the extent of chronic cognitive and neurodegenerative changes experienced by moderate to severe TBI survivors. Though prior research has identified a variety of acute factors that appear to influence post-injury cognitive and neuropathological outcomes, an empirically supported framework for prognostic modeling of these injury-distal outcomes does not exist. The current review considers the literature on an expanded array of empirically supported predictors (both premorbid and injury-related) in association with long-term sequelae of moderate to severe TBI. We also provide a theoretical framework and statistical approach for prognostic modeling in moderate to severe TBI in order to unify efforts across research groups and facilitate important progress in this research area.

Exploratory study of sport-related concussion effects on peripheral micro-RNA expression.

OBJECTIVE: Explore changes in micro-RNA (miRNA) expression in blood after sport-related concussion (SRC) in collegiate athletes. METHODS: Twenty-seven collegiate athletes (~41% male, ~75% white, age 18.8 ± 0.8 years) provided both baseline and post-SRC blood samples. Serum was analyzed for expression of miR-153-3p (n = 27), miR-223-3p (n = 23), miR-26a-5p (n = 26), miR-423-3p (n = 23), and miR-let-7a-5p (n = 23) at both time points via quantitative polymerase chain reaction (qPCR). Nonparametric analyses were used to compare miRNA expression changes between baseline and SRC and to evaluate associations with clinical outcomes (symptom severity, cognition, balance, and oculomotor function, and clinical recovery time). RESULTS: Participants manifested a significant increase in miRNA expression following SRC for miR153-3p (Z = -2.180, p = .029, 59% of the participants increased post-SRC), miR223-3p (Z = -1.998, p = .046, 70% increased), and miR-let-7a-5p (Z = -2.190, p = .029, 65% increased). There were no statistically significant associations between changes in miRNA expression and clinical test scores, acute symptom severity, or clinical recovery time. CONCLUSION: MiR-153-3p, miR-223-3p, and miR-let-7a-5p were significantly upregulated acutely following SRC in male and female collegiate athletes compared to baseline levels, though several athletes demonstrated no change or a decrease in expression. The biological mechanisms and functional implications of the increased expression of these circulating miRNA are unclear and require more research, as does their relevance to clinical outcomes.

Concussion BASICS III: Serum biomarker changes following sport-related concussion.

OBJECTIVE: To evaluate changes in serum biomarker concentrations (ß-amyloid peptide 42 [Aß42], total tau, ubiquitin carboxy-terminal hydrolyzing enzyme L1, S100 calcium binding protein B [S100B], glial fibrillary acidic protein [GFAP], microtubule associated protein 2 [MAP2], and 2',3'-cyclic-nucleotide 3'-phosphodiesterase [CNPase]) after sport-related concussion (SRC) in a sample of collegiate athletes. Associations with clinical outcomes were also investigated. METHODS: Participants in this case-control study included 36 athletes (50% male, 61% white, aged 19.7 ± 1.0 years) with SRC. Twenty-nine also had baseline blood drawn, allowing for within-patient analyses of concentration changes. Between-group analyses incorporated 86 demographically matched controls (51% male, 63% white, aged 19.6 ± 1.1 years). Biomarker sensitivity/specificity for SRC vs controls and relative to standardized normative cutoffs was evaluated (receiver operating characteristics). We also analyzed associations between post-SRC clinical outcomes and both biomarker change from baseline and post-SRC concentrations. RESULTS: The majority of blood samples had concentrations of GFAP, MAP2, and CNPase below limits of quantification. Within-patient analyses indicated elevated S100B after SRC (p = 0.003, 67% of patients elevated), especially for blood samples collected <4 hours post-SRC (88% of patients). Significant between-group differences were limited to blood draws <4 hours post-SRC: Aß42 (81% of SRC > control median, area under the curve [AUC] = 0.75 [95% confidence interval 0.59-0.91]), total tau (75% SRC > control, AUC = 0.74 [0.56-0.79]), and S100B (88% SRC > control; AUC [specific to white race] = 0.82 [0.72-0.93]). Using standardized normative cutoffs (z > 1.0), specificity ranged from 79.1% to 89.3% while sensitivity was <70%. Biomarkers were not associated with clinical outcomes. CONCLUSION: For SRC, diagnostic accuracy of serum biomarkers appears best if blood is collected within a few hours. Accurate blood marker identification of SRC appears somewhat dependent on the "healthy" comparison. Additional research must evaluate whether physiologic changes in the absence of clinical changes, or vice versa, are relevant for concurrent or future neurologic health. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that certain serum biomarkers are elevated from baseline and higher than demographically matched controls after sport-related concussion.

The Role of Executive Functioning and Academic Achievement in the Academic Self-Concept of Children and Adolescents Referred for Neuropsychological Assessment.

The current study evaluated a model of youth academic self-concept which incorporates practical executive functioning behaviors and academic achievement. Though greater academic achievement has been linked to both positive self-concept and better executive functioning, these constructs have not been examined simultaneously. It was hypothesized that academic achievement would mediate the association between problems with executive functioning and academic self-concept such that youth with more problems with executive functioning would have lower academic achievement and, in turn, lower academic self-concept. Clinical data was analyzed from a diagnostically heterogeneous sample of youth (n = 122) who underwent neuropsychological evaluation. Problems with executive functioning were assessed using the Behavior Rating Inventory of Executive Function. Academic achievement was assessed using the Woodcock⁻Johnson Tests of Achievement or Wechsler Individual Achievement Test. Academic self-concept was assessed using the youth-report version of the Behavioral Assessment System for Children. Surprisingly, findings indicate that academic achievement is not significantly associated with problems with executive functioning or academic self-concept. However, greater problems with executive functioning are associated with decreased academic self-concept. The overall model included several covariates and accounted for 10% of the variance in academic self-concept. Findings suggest that executive skills may be essential for aligning academic achievement with classroom performance. Though various child characteristic covariates were included, the model accounted for a small amount of variance suggesting that future studies should examine contributing contextual factors.

The Relationship Between Sleep and Cognition in Children Referred for Neuropsychological Evaluation: A Latent Modeling Approach.

Children with conditions affecting cognitive processes experience high levels of sleep disturbance, which may further compound the cognitive ramifications of their disorders. Despite this, existing studies in this area have been primarily confined to only particular diagnostic groups and/or a limited scope of sleep and cognitive parameters. The current study characterized the nature of sleep problems and examined the relationship between a wide range of sleep-related problems and cognitive functioning in a large (N = 103) diagnostically heterogeneous sample of youth (aged 6-16) referred for neuropsychological assessment. Structural equation modeling was used to examine the relationship between sleep-related problems (i.e., daytime sleepiness, sleep onset latency, sleep fragmentation, sleep time variability, sleep debt) and cognitive performance (i.e., executive functioning, sustained attention, memory, processing speed). Sleep fragmentation emerged as the most prominent sleep-related problem in the present sample. Structural equation modeling demonstrated a negative association between sleep-related problems and cognition that did not reach statistical significance (ß = -0.084, p = 0.629). The current statistical approach may be used as a conceptual framework for future work examining these multi-dimensional constructs in a parsimonious fashion.