Objective: To examine, among persons discharged from inpatient rehabilitation for traumatic brain injury (TBI), the degree to which pre-TBI factors were associated with post-TBI hospitalization for psychiatric reasons. The authors hypothesized that pre-TBI psychiatric hospitalization and other pre-TBI mental health treatment would predict post-TBI psychiatric hospitalization following rehabilitation discharge, up to 5 years post-TBI. Setting: Five Veterans Affairs Polytrauma Rehabilitation Centers. Participants: Participants with nonmissing rehospitalization status and reason, who were followed at 1 year (N = 1006), 2 years (N = 985), and 5 years (N = 772) post-TBI. Design: A secondary analysis of the Veterans Affairs TBI Model Systems, a multicenter, longitudinal study of veterans and active-duty service members with a history of mild, moderate, or severe TBI previously admitted to comprehensive inpatient medical rehabilitation. This study examined participants cross-sectionally at 3 follow-up timepoints. Main Measures: Psychiatric Rehospitalization was classified according to Healthcare Cost and Utilization Project multilevel Clinical Classifications diagnosis terminology (Category 5). Results: Rates of post-TBI psychiatric hospitalization at years 1, 2, and 5 were 4.3%, 4.7%, and 4.1%, respectively. While bivariate comparisons identified pre-TBI psychiatric hospitalization and pre-TBI mental health treatment as factors associated with psychiatric rehospitalization after TBI across all postinjury timepoints, these factors were statistically nonsignificant when examined in a multivariate model across all timepoints. In the multivariable analysis, pre-TBI psychiatric hospitalization was significantly associated with increased odds of post-TBI psychiatric hospitalization only at 1-year post-TBI (adjusted odds ratio = 2.65; 95% confidence interval, 1.07-6.55, P = .04). Posttraumatic amnesia duration was unrelated to psychiatric rehospitalization. Conclusions: Study findings suggest the limited utility of age, education, and pre-TBI substance use and mental health utilization in predicting post-TBI psychiatric hospitalization. Temporally closer social and behavior factors, particularly those that are potentially modifiable, should be considered in future research.

Research ObjectivesMost studies of rehospitalization following traumatic brain injury (TBI) examine all-cause, with scant research on hospitalization for psychiatric reasons. This is despite research showing that psychiatric disorders are common following TBI, with rates of psychiatric hospitalization ranging from 5-10% during the chronic recovery phase. In this study, persons with and without psychiatric hospitalization within the first 5 years of TBI were compared on demographic and injury-related characteristics.DesignSecondary analysis of the TBI Model Systems longitudinal multicenter study. Follow up interviews occurred at 1-, 2-, and/or 5-years post-TBI.SettingFive Veterans Affairs Polytrauma Rehabilitation Centers.ParticipantsIn this observational study, Veterans who completed a 1 year (N=1006), 2-year (N=985), or 5-year (N=772) post-TBI follow up. Lost to follow up rate was 7.8-14.5% depending on follow up year. Retention rate at each year was 79%, 77%, and 72%, respectively.InterventionsN/A.Main Outcome MeasuresPsychiatric rehospitalization.ResultsPer univariable analyses, predictors of psychiatric rehospitalization at 1-, 2-, and 5-year follow-up were pre-TBI psychiatric hospitalization (OR=4.48, p<.01; OR=4.49, p<.01; OR=3.74, p<.01) and pre-TBI mental health treatment (OR=2.20, p=.01;OR=2.46, p<.01; OR=2.97, p<.01). At years 1 and 2 follow up only, pre-TBI suicide attempts predicted psychiatric rehospitalization (OR=3.68, p<.01; OR=2.61, p=.01), while active duty status (versus veteran) at time of TBI were less likely to be psychiatrically rehospitalized. Duration of posttraumatic amnesia did not predict psychiatric rehospitalization at 1, 2, or 5-years post-TBI.ConclusionsAnalysis revealed that pre-TBI psychiatric hospitalization and mental health treatment predicted post-TBI psychiatric rehospitalization consistently during the first 5 years post-TBI. Follow up multivariable analysis is needed to better account for shared variance and shed light on unique predictors.Author(s) DisclosuresThe authors declare no conflicts of interest. The views expressed are those of the authors and do not necessarily represent the official policy or position of the Defense Health Agency, Department of Defense, or any other U.S. government agency. This work was prepared under Contract HT0014-22-C-0016 with DHA Contracting Office (CO-NCR) HT0014 and, therefore, is defined as U.S. Government work under Title 17 U.S.C.§101.

Objective:To characterize reasons for rehospitalization of Veterans and Service Members with mild, moderate, and severe traumatic brain injury (TBI) who received inpatient rehabilitation at a Veterans Affairs (VA) Polytrauma Rehabilitation Center (PRC) up to 10 years postinjury. TBI is a chronic condition, and a subset of TBI survivors experience rehospitalization after discharge from inpatient rehabilitation. Extant literature focuses primarily on persons with moderate-to-severe TBI and utilizes broad categories when determining readmission reasons. The present study aimed to delineate with greater specificity the reasons for rehospitalization up to 10 years postinjury across the TBI severity spectrum.Participants and Methods:Participants were drawn from the VA TBI Model Systems multicenter longitudinal study for a cross-sectional analysis. Eligibility criteria included TBI diagnosis per case definition; age > 16 years at TBI; admitted for inpatient rehabilitation at one of the five VA PRCs; and informed consent by the participant or legally authorized representative. At follow up interviews 1, 2, 5, and 10 years post-TBI, participants were asked whether they were rehospitalized within the past year (up to five admissions). Rehospitalizations were classified according to the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project classification (18 categories). In the present analyses, TBI severity was classified by duration of posttraumatic amnesia (PTA; 0-1 days=mild, 2+ days=moderate-severe). Statistical analyses were conducted in SPSS.Results:Participants (N=1101; n=338 0-1 days PTA, n=513 2+ days PTA, n=250 no PTA data) ranged in age from 17 years to 91 years at the time of interview. Participants across all follow up timepoints reported 317 rehospitalizations in the past year. 19.45% of Year 1 participants, 24.37% of Year 2 participants, 16.19% of Year 5 participants, and 16.25% of Year 10 participants reported 1+ rehospitalizations in the past year. When controlling for age, participants with at least 2 days of PTA were more likely to be rehospitalized at least once compared to those with 0-1 days of PTA at Year 2 (OR=4.05, p<0.001) and Year 5 (OR=2.39, p=0.03) post-TBI. The three most common reasons for rehospitalization across all timepoints were injury and poisoning (17.3%), mental illness (16.7%), and diseases of the nervous system and sense organs (9.1%). Mental illness was the modal reason for rehospitalization at Years 2, 5, and 10, frequently due to substance- or alcohol-related disorders and suicide/intentional self-inflicted injury.Conclusions:Compared to prior research, rates of rehospitalization were lower in this sample across follow-up time points. The inclusion of mild TBI in this analysis may partially explain the discrepancy. Importantly, two of the top three rehospitalization reasons are potentially preventable, and strategies to reduce risk of re-injury and minimize escalation of psychiatric distress should therefore be explored. Psychoeducation, supervision, and mental health support during the transition from hospital to community should be considered in order mitigate preventable causes of rehospitalization among long-term TBI survivors.

Background: Assessments of functional connectivity of default mode network (DMN) and positive task-related networks (TRNs) using independent component analysis (ICA) may help describe long-term effects of childhood brain tumors and adjuvant treatments. Methods: Aiming to identify potential neuronal markers that may aid in prognosis and inform interventions to optimize outcomes, this study used ICA to evaluate the presence of functional connectivity networks and their recruitment during a letter n-back task in 23 adult survivors of childhood posterior fossa tumors (9 low grade, 14 high grade) at least 5 years past diagnosis compared with 40 age- and sex-matched healthy peers. Results: DMN components generally demonstrated increasing disengagement as task difficulty increased, and relationships between effective DMN disengagement and improved performance were observed in healthy controls (HCs). Low-grade brain tumor survivors (LGS) demonstrated unique patterns in DMN recruitment that suggested increased involvement of the medial prefrontal cortex in LGS during tasks. TRN components generally demonstrated increasing engagement, which was related to improved task performance in HCs for one executive control network (ECN) component. High-grade brain tumor survivors (HGS) demonstrated distinct challenges recruiting an ECN component at more difficult task levels and showed a relationship between recruitment of another ECN component and task performance, indicating a potential compensatory mechanism for some HGS. Conclusions: Findings suggest the importance of cognitive intervention in both survivor groups and the necessity to track LGS despite their cognitive abilities often resembling those of their healthy peers.

The Reliable Digit Span (RDS) is a performance validity test (PVT) used widely within non-clinical samples, but its utility is in question in clinical groups with cognitive impairment. To investigate, RDS scores were calculated and correlated with the Neurological Predictor Scale, an informant-reported Activities of Daily Living score, and a proxy measure of intelligence (Vocabulary) for 83 adult survivors of childhood brain tumors and 105 healthy controls. Analyses were covaried for age at examination. Participants were divided into passing and failing groups at each RDS cutoff, and ANCOVAs for each of the three variables of interest covaried for age at the examination were run. RDS was correlated with all three variables of interest in survivors but only Vocabulary in controls. At the ≤7 cutoff, passing and failing survivors demonstrated significant differences across all variables of interest, while passing and failing controls differed only on Vocabulary. Differences were also found between passing and failing survivors at lower cutoffs. RDS is related to and likely impacted by various neurological and cognitive challenges faced by brain tumor survivors. Using the standard RDS cutoff of ≤7 may result in inaccurate interpretation of valid performance in this population; therefore, the use of other PVTs is recommended.

Abstract Objectives: Survivors of childhood brain tumors experience neurological sequelae that disrupt everyday adaptive functioning (AF) skills. The Neurological Predictor Scale (NPS), a cumulative measure of tumor treatments and sequelae, predicts cognitive outcomes, but findings on its relation to informant-reported executive dysfunction (ED) and AF are mixed. Given known effects of frontal-subcortical system disruptions on AF, this study assessed the NPS’ relationship with AF as mediated by frontal systems dysfunction, measured by the Frontal Systems Behavior Scale (FrSBe). Methods: 75 participants (Mage = 23.5, SDage = 4.5) were young adult survivors of childhood brain tumors at least 5 years past diagnosis. FrSBe and Scales of Independent Behavior-Revised (SIB-R), a measure of AF, were administered to informants. Parallel multiple mediator models included Apathy and ED as mediators, and age at diagnosis and time between diagnosis and assessment as covariates. Results: More complex treatment and sequelae were correlated with poorer functioning. Mediation models were significant for all subscales: Motor Skills (MS), p = .0001; Social Communication (SC), p = .002; Personal Living (PL), p = .004; Community Living (CL), p = .007. The indirect effect of ED on SC and CL was significant; the indirect effect of Apathy was not significant for any subscales. Conclusions: More complex tumor treatment and sequelae were associated with poorer long-term AF via increased ED. Cognitive rehabilitation programs may focus on the role of executive function and initiation that contribute to AF, particularly SC and CL skills, to help survivors achieve comparable levels of independence in everyday function as their peers.

Objective: Radiation therapy (RT) improves rates of survival of patients with childhood brain tumors but increases deficits in cognition and independent living skills. Previous literature has studied difficulties in basic cognitive processes, but few explore impairment in higher-order skills such as adaptive functioning. Some studies identify females as at risk for cognitive deficits due to RT, but few investigate sex differences in adaptive functioning. It was hypothesized that females would exhibit poorer long-term independent living skills and core cognitive skills relative to males following RT. Methods: Forty-five adult survivors of posterior fossa childhood brain tumors (24 females) completed the Wechsler Abbreviated Scale of Intelligence (WASI-II), Wechsler Memory Scale, Third Edition (WMS-III) Digit Span Forward (DSF) and Backward (DSB), and Oral Symbol Digit Modalities Test (OSDMT). Informants completed the Scales of Independent Behavior-Revised (SIB-R). Results: DSF and OSDMT were positively correlated with all five SIB-R domains, full-scale IQ (FSIQ) was positively correlated with four SIB-R domains, and DSB was positively correlated with three SIB-R domains. There was an interaction between sex and RT for OSDMT and community living skills with trend level interactions for personal living skills and broad independent living skills, where females without RT had higher scores than females with RT. Conclusions: Female survivors were more affected by RT than males across the community living skills domain of adaptive functioning as well as processing speed. Processing speed deficits may have a cascading impact on daily living skills. Future studies should investigate how clinical and biological factors may contribute to personalized treatment plans between sexes. (JINS, 2019, 25, 729-739)

Rett syndrome is the second most common cause of intellectual disability in females worldwide. The severity of many individuals’ impairment limits the effectiveness of traditional assessment. However, clinician and parent reports of adaptive functioning may provide insight into these patients’ abilities. This review aims to synthesize the current literature assessing adaptive functioning in Rett syndrome and evaluate existing measurement tools in this population. A search was conducted on PubMed using the search term “Rett syndrome.” Studies that quantitatively assessed adaptive functioning outcomes in Rett syndrome with published and normed questionnaire measures were included. Twenty-three studies met inclusion criteria. Overall results indicate that the population of people with Rett syndrome is highly impaired, both in overall adaptive functioning as well as in specific subdomains (e.g., mobility, activities of daily living). Atypical Rett syndrome groups performed better on measures of adaptive functioning relative to patients with classic Rett syndrome. Our findings identified measurement weaknesses, as many of the studies found floor effects and therefore were unable to capture meaningful variability in outcomes. Individuals with Rett syndrome are highly reliant on caregivers due to disrupted adaptive functioning abilities. Optimizing measurement of adaptive skills in Rett syndrome will facilitate the quantification of meaningful change in skills and the identification of efficacious interventions aimed at improving outcomes and quality of life.

OBJECTIVE:Organizational strategies have been shown to improve one's ability to recall items from a list. Specifically, use of semantic clustering, the tendency to group items by category when recalling them, predicts better free recall of word lists after short and long delays. The present study utilized a healthy adult sample to examine use of efficient memory strategies as a predictor of differences in neurocognitive findings between African American and white participants.METHOD:Participants provided demographic information and completed the California Verbal Learning Test-Second Edition (CVLT-II) and Wechsler Abbreviated Scale of Intelligence-Second Edition (WASI-2).RESULTS:Groups were matched across socioeconomic status and years of education. White participants used more semantic clustering and performed better on recall measures after short and long delays than their African American peers, and semantic clustering predicted recall in both groups. Regression analyses suggested that use of semantic clustering is a significant partial mediator of the relationship between race and free recall abilities. Intelligence scores from the WASI-2 were correlated with CVLT-II measures in white participants but not African American participants.CONCLUSIONS:Despite quantitatively similar backgrounds, white and African American participants differed in recall performance. However, this study showed that African American participants' poorer recall may be partially attributed to less frequent use of semantic clustering as a strategy. These discrepancies may be rooted in inequalities in educational experiences and suggest that providing organizational strategies during early learning may be an area of intervention to mitigate racial differences seen in neuropsychological testing.

Brain tumor (BT) patients often experience reduced cognitive abilities and disrupted adaptive functioning before and after treatment. An innovative approach to understanding the underlying brain networks associated with these outcomes has been to study the brain's functional connectivity (FC), the spatially distributed and temporally correlated activity throughout the brain, and how it can be affected by a tumor. The present review synthesized the extant BT FC literature that utilizes functional magnetic resonance imaging to study FC strength of commonly observed networks during rest and task. A systematic review of English articles using PubMed was conducted. Search terms included brain tumor OR glioma AND functional connectivity, independent component analysis, ICA, psychophysiological interaction, OR PPI. Studies in which participants were diagnosed with BTs as adults that evaluated specific networks of interest using independent component analysis or seed-based component analysis were included. Twenty-five studies met inclusion criteria. BT patients often presented with decreases in FC strength within well-established networks and increases in atypical FC patterns. Network differences were tumor adjacent and distal, and left hemisphere tumors generally had a greater impact on FC. FC alterations often correlated with behavioral or cognitive outcomes when assessed. Overall, BTs appear to lead to various alterations in FC across different functional networks, and the most common change is a decrease in expected FC strength. More longitudinal studies are needed to determine the time course of network alterations across treatment and recovery, the role of medical treatments in BT survivors' FC, and the potential of FC patterns as biomarkers of cognitive outcomes.

Childhood brain tumors and related treatments disrupt the developing brain and have a cascading impact on core cognitive skills and intellectual (intelligence quotient [IQ]) and academic achievement outcomes. Theoretical models for this cascade have been developed based on the literature, but no studies thus far have empirically evaluated the models. The current study aimed to empirically test the two extant models and generate a new data-driven model of the relationships among neurodevelopmental risk factors, core cognitive skills (i.e., processing speed, attention span, working memory), and IQ and achievement outcomes. Fifty-seven adult survivors of childhood brain tumors and fifty-seven demographically matched neurotypical individuals were included in the current study. The average age at brain tumor diagnosis was 8 years, and the average time since diagnosis was 17 years. Three a priori path models tested the hypothesized relationships among variables. Results of the path analyses revealed that the hybrid model best fit the data for both survivors and controls based on all statistical criteria. For survivors, processing speed was the core cognitive skill most widely associated with neurodevelopmental risk factors and outcomes. However, working memory and attention span also had unique contributions to IQ and academic achievement. Processing speed appears to be the central cognitive skill that disrupts the other core cognitive skills of attention span and working memory, and all three make a unique contribution to IQ and academic achievement. This is best demonstrated by a novel neurodevelopmental model that combines components of two earlier untested theoretical models.

Stress and emotion involve diverse developmental and individual differences. Partially attributed to the development of the prefrontal cortex (PFC), the amygdala, and hypothalamic-pituitary-adrenal axis, the precise genetic and experiential contributions remain unknown. In previous work, childhood basal cortisol function predicted adolescent resting-state functional connectivity (rs-FC) and psychopathology. To parse experience-driven (non-genetic) contributions, we investigated these relations with a monozygotic (MZ) twin design. Specifically, we examined whether intrapair differences in childhood afternoon cortisol levels predicted cotwin differences in adolescent brain function and coping. As expected, intrapair differences in childhood cortisol forecast amygdala-perigenual PFC rs-FC (R2 = 0.84, FWE-corrected p = 0.01), and amygdala recovery following unpleasant images (R2 = 0.40, FWE-corrected p < 0.05), such that the cotwin with higher childhood cortisol evinced relatively lower rs-FC and poorer amygdala recovery in adolescence. Cotwin differences in amygdala recovery also predicted coping styles. These data highlight experience-dependent change in childhood and adolescence.

Objectives: The cerebellum (CB) is known for its role in supporting processing speed (PS) and cognitive efficiencies. The CB often sustains damage from treatment and resection in pediatric patients with posterior fossa tumors. Limited research suggests that CB atrophy may be associated with the radiation treatment experienced during childhood. The purpose of the study was to measure cerebellar atrophy to determine its neurobehavioral correlates. Methods: Brain magnetic resonance images were collected from 25 adult survivors of CB tumors and age- and gender-matched controls (M-age = 24 years (SD = 5), 52% female). Average age at diagnosis was 9 years (SD = 5) and average time since diagnosis was 15 years (SD = 5). PS was measured by the Symbol Digit Modality Test. To quantify atrophy, an objective formula was developed based on prior literature, in which Atrophy = [(CB White + CB Gray Volume)/Intracranial Vault (ICV)](controls) - [(CB White + CB Gray + Lesion Size Volume)/ICV](survivors). Results: Regression analyses found that the interaction term (age at diagnosis*radiation) predicts CB atrophy; regression equations included the Neurological Predictor Scale, lesion size, atrophy, and the interaction term and accounted for 33% of the variance in oral PS and 48% of the variance in written PS. Both interactions suggest that individuals with smaller CB lesion size but a greater degree of CB atrophy had slower PS, whereas individuals with a larger CB lesion size and less CB atrophy were less affected. Conclusion: The results of the current study suggest that young age at diagnosis and radiation is associated with CB atrophy, which interacts with lesion size to impact both written and oral PS.

BACKGROUND:Much research has focused on the deleterious neurobiological effects of childhood adversity that may underlie internalizing disorders. While most youth show emotional adaptation following adversity, the corresponding neural mechanisms remain poorly understood.METHODS:In this longitudinal community study, we examined the associations among childhood family adversity, adolescent internalizing symptoms, and their interaction on regional brain activation and amygdala/hippocampus functional connectivity during emotion processing in 132 adolescents.RESULTS:Consistent with prior work, childhood adversity predicted heightened amygdala reactivity to negative, but not positive, images in adolescence. However, amygdala reactivity was not related to internalizing symptoms. Furthermore, childhood adversity predicted increased fronto-amygdala connectivity to negative, but not positive, images, yet only in lower internalizing adolescents. Childhood adversity also predicted increased fronto-hippocampal connectivity to negative images, but was not moderated by internalizing. These findings were unrelated to adolescence adversity or externalizing symptoms, suggesting specificity to childhood adversity and adolescent internalizing.CONCLUSIONS:Together, these findings suggest that adaptation to childhood adversity is associated with augmentation of fronto-subcortical circuits specifically for negative emotional stimuli. Conversely, insufficient enhancement of fronto-amygdala connectivity, with increasing amygdala reactivity, may represent a neural signature of vulnerability for internalizing by late adolescence. These findings implicate early childhood as a critical period in determining the brain's adaptation to adversity, and suggest that even normative adverse experiences can have significant impact on neurodevelopment and functioning. These results offer potential neural mechanisms of adaptation and vulnerability which could be used in the prediction of risk for psychopathology following childhood adversity.

Background: The relationship between apathy and endocrine dysfunction, both frequent outcomes of neurological insult, has not yet been investigated in brain tumor survivors. The present study aimed to assess the relationship between pituitary disorders and apathy and other facets of executive function in long-term adult survivors of childhood brain tumors and to differentiate between apathy and depression in this population.Procedure: Seventy-six adult survivors of childhood brain tumors at least 5 years past diagnosis participated. An informant completed the Frontal Systems Behavior Scale (FrSBe), and 75 of the 76 participants completed a Structured Clinical Interview for the DSM-IV-TR (SCID). Information on neuroendocrine dysfunction was obtained through medical chart review.Results: Clinically significant levels of apathy on the FrSBe were identified in 41% of survivors. Pituitary dysfunction significantly explained 9% of the variance in apathy scores and affected whether an individual presented with clinical levels of apathy. Pituitary dysfunction predicted higher levels of executive dysfunction but did not impact whether a participant reached clinical levels of executive dysfunction. A past major depressive episode (MDE) significantly predicted current apathy but showed no relationship with pituitary disorders. Radiation treatment predicted pituitary dysfunction but not the differences in apathy or executive functions.Conclusions: Apathy and executive dysfunction in survivors of childhood brain tumors are strongly predicted by pituitary dysfunction, and individuals with pituitary dysfunction are more likely to present with clinical levels of apathy as adults. Clinical levels of apathy may present absent of current depression, and pituitary dysfunction impacts apathy uniquely.

Early life stress (ELS) and function of the hypothalamic-pituitary-adrenal axis predict later psychopathology. Animal studies and cross-sectional human studies suggest that this process might operate through amygdala-ventromedial prefrontal cortex (vmPFC) circuitry implicated in the regulation of emotion. Here we prospectively investigated the roles of ELS and childhood basal cortisol amounts in the development of adolescent resting-state functional connectivity (rs-FC), assessed by functional connectivity magnetic resonance imaging (fcMRI), in the amygdala-PFC circuit. In females only, greater ELS predicted increased childhood cortisol levels, which predicted decreased amygdala-vmPFC rs-FC 14 years later. For females, adolescent amygdala-vmPFC functional connectivity was inversely correlated with concurrent anxiety symptoms but positively associated with depressive symptoms, suggesting differing pathways from childhood cortisol levels function through adolescent amygdala-vmPFC functional connectivity to anxiety and depression. These data highlight that, for females, the effects of ELS and early HPA-axis function may be detected much later in the intrinsic processing of emotion-related brain circuits.