Survivors of childhood brain tumor are historically thought to perform worse on measures of executive functioning, including cognitive flexibility (CF; e.g., set-shifting), when compared to their peers. Commonly utilized measures, such as subtests from the Delis-Kaplan Executive Function System (D-KEFS), have baseline conditions that attempt to measure performances independent of but critical for CF tasks (e.g., motor speed on trail making, letter fluency on verbal fluency). However, in research, conditions measuring CF are often included in analyses without accounting for these important baseline conditions. The aim of the current study is to explore differences in CF performance between survivors and their healthy peers when controlling for baseline conditions. The variance explained by each baseline condition on CF condition performance in survivors is also explored.

A sample of 107 long-term survivors of childhood brain tumor (Mage=21.81, SD=5.99, 50.5% female) and 142 healthy controls (Mage= 23.25, SD=6.61, 61.3% female) were administered the Trail Making Test (TMT), Color-Word Interference (CWI), and Verbal Fluency (VF) subtests from the D-KEFS. For the TMT, baseline conditions include visually scanning for a target, motor speed, and letter and number sequencing. For the CWI subtest, baseline conditions include rapid color naming, word reading, and reading words in a different colored ink. On the VF subtest, baseline conditions include rapidly naming words with a specific letter and from a specific category. An analysis of covariance was conducted for each subtest to determine if groups differed in performance on the CF condition (i.e., Number-Letter Switching, Inhibition/Switching, Category Switching Accuracy) when controlling for baseline conditions. In survivors only, linear regressions investigated the amount of variance explained by each baseline condition on the CF conditions of each subtest.

Groups did not differ in CF performance of each subtest when controlling for baseline conditions (ps>.10). Across subtests, baseline conditions significantly predicted CF performance in survivors. On the TMT, Letter Sequencing (p=.003, unique-R2=.05), but not Visual Scanning, Number Sequencing, or Motor Speed, was a significant predictor of Number-Letter Sequencing performance (p<.001, R2=.50). On the CWI subtest, Word Reading (p<.001, unique-R2=.09) and Inhibition (p<.001, unique-R2=.05), but not Color Naming, were significant predictors of Inhibition/Switching performance (p<.001, R2=.67). On the VF subtest, Letter Fluency (p=.009, unique-R2=.06) and Category Fluency (p<.001, unique-R2=.08) were significant predictors of Category Switching Accuracy performance (p<.001, R2=.37).

Findings suggest that CF may not differ between survivors and their healthy peers, but that other factors of executive functioning, such as processing speed, drive performance differences on measures of CF. As these tasks rely heavily on speed, survivors may be slower than their healthy counterparts, but may not perform worse on set-shifting. In addition, these results highlight the importance of controlling for lower-order processes in analyses to help isolate CF performance and more accurately characterize potential differences between groups. While replication of findings in survivors and other clinical groups (e.g., congenital heart disease, traumatic brain injury) is still needed, this work can help inform which processes are most important to account for, which is not yet established.

Survivors of pediatric brain tumor (BT) experience impaired executive function (EF) and adaptive behavior (i.e. the ability to complete daily living tasks independently). The literature hypothesizes that executive dysfunction contributes to suboptimal adaptive behavior outcomes in BT survivors; however, the aspects of EF that drive this relationship remain unexplored. Task-switching is an EF component that involves switching between concurrently presented tasks. This skill is critical for many day-to-day activities and may therefore contribute to observed adaptive functioning difficulties. This study investigates relationships between performance on two task-switching measures and adaptive behavior outcomes in BT survivors compared to healthy controls.

86 survivors of pediatric BT (Mage(SD)= 23.42(4.24), 44 females) and 86 age- and sex-matched controls (Mage(SD) = 23.09(4.40), 44 females) from the Atlanta area completed the Delis-Kaplan Executive Function System Trail Making Test (TMT) and Verbal Fluency Test (VFT). Respectively, the Letter-Number Sequencing (LNS) and Category Switching (CS) conditions were isolated as measures of task-switching. Baseline conditions, representing the foundational skills needed to perform these timed task-switching measures rapidly (TMT: Letter Sequencing, Number Sequencing; VFT: Category Fluency), were included as covariates in all regressions. Informants familiar with the participants’ daily living were interviewed with the Scales of Independent Behavior-Revised (SIB-R) to measure adaptive behavior in four domains (Motor Skills, Social Communication, Personal Living, Community Living). Linear regressions and t-tests confirmed group differences on task-switching performance and on adaptive functioning outcomes, respectively. Then, linear regressions investigated relationships between performance on each task-switching measure (LNS, CS) and SIB-R scores for survivors. A group by task-switching interaction was added to directly explore group differences in these relationships. α=.0125 was used due to Bonferroni correction for the four SIB-R comparisons within each task-switching measure.

BT survivors were more impaired than controls on LNS, CS, and SIB-R scores (p<.05, except Personal Living p=.058). For TMT, decreased performance on LNS predicted lower SIB-R scores in Social Communication (p=.001, r2semipartial=.14), Personal Living (p=.002, r2semipartial=.13), and Community Living (p=.003, r2semipartial =.11), but not Motor Skills (p=.184) in BT survivors. Strength of significant relationships was greater for survivors than controls (all p<.002). For VFT, decreased performance on CS predicted lower SIB-R scores in Personal Living (p=.036, r2semipartial =.06) and Community Living (p=.04, r2semipartial =.05), but not in Motor Skills (p=.716) or Social Communication (p=.14) in BT survivors. Positive relationships between CS and SIB-R scores for all 4 domains were greater in survivors than controls (p<.0125).

These findings reveal a robust, positive relationship between task-switching performance and independent, daily behaviors that is specific to BT survivors. The relationship between LNS and Motor Skills may have been weakened by covariates involving baseline motor abilities; however, CS results suggest that task-switching is important for motor skills in survivors relative to controls. Community living skills were impaired in survivors and consistently related to task-switching performance. This work may inform interventions to target task-switching abilities and consequently, promote everyday living skills. Interventions aimed at vulnerabilities in adaptive behavior may help increase independence and quality-of-life as survivors transition to adulthood.

Machine learning studies of PTSD show promise for identifying neurobiological signatures of this disorder, but studies to date have largely excluded Black American women, who experience disproportionately greater trauma and have relatively higher rates of PTSD. PTSD is characterized by four symptom clusters: trauma reexperiencing, trauma avoidance, hyperarousal, and anhedonia. A prior machine learning study reported successful PTSD symptom cluster severity prediction using functional MRI data but did not examine white matter predictors. White matter microstructural integrity has been related to PTSD presence and symptoms, and unexplored metrics such as estimates of tract shape may provide unique predictive utility. Therefore, this study examines the relationship between white matter tract shape and PTSD symptom cluster severity amongst trauma-exposed Black American women using multiple machine learning models.

Participants included 45 Black American women with PTSD (Mage=40.4(12.9)) and 89 trauma-exposed controls (Mage=39.8(11.6)). Shape and diffusion metrics for the cingulum, corpus callosum, fornix, inferior longitudinal fasciculus, superior longitudinal fasciculus, and uncinate fasciculus were calculated using deterministic tractography. Current symptom severity was calculated using the PTSD Symptom Scales. Input features included tract metrics, questionnaire responses, and age. The following regression models were generated: least absolute shrinkage and selection operator (LASSO), ridge, elastic net, and gaussian process (GPR). Additionally, two forms of latent-scale GPR, one without (lsGPR) and with (sp-lsGPR) node selection via spike and slab priors, were calculated. The performance of regression models was estimated using mean square error (MSE) and R2.

sp-lsGPR performed at or above other models across all symptom clusters. LASSO models were comparable to sp-lsGPR for avoidance and hyperarousal clusters. Ridge regression and GPR had the weakest performance across clusters. Scores for sp-lsGPR by cluster are as follows: reexperiencing Mmse =0.70(0.17), Mr2=0.56(0.13); avoidance Mmse =0.75(0.17), Mr2= 0.51(0.13); hyperarousal Mmse =0.57(0.18), Mr2=0.66(0.12); anhedonia Mmse =0.74(0.27), Mr2=0.57(0.13). The top three ranked posterior inclusion probabilities for white matter tracts across sp-lsGPR models include four sections of the cingulum, three sections of the corpus callosum, the right fornix, the left inferior longitudinal fasciculus, the first segment of the right superior longitudinal fasciculus, and the right uncincate fasciculus. The greatest posterior inclusion probability value for the sp-lsGPR models was the left frontal parahippocampal cingulum for the hyperarousal cluster.

Results support the combined predictive utility of white matter metrics for brain imaging regression models of PTSD. Results also support the use of sp-lsGPR models, which are designed to balance interpretable linear models and highly-flexible non-linear models. The sp-lsGPR model performance was similar across clusters but was relatively better for the hyperarousal cluster. This finding contrasts with prior machine learning work using functional data which was unable to predict hyperarousal scores above chance (MR2=0.06). These diverging findings highlight the importance of examining both functional and structural data in PTSD populations. Differing findings may also be related to sample characteristics as the prior study was conducted in China. Black American women and Chinese individuals have unique lived experiences that may differentially impact brain structure and function. Future work should continue to include diverse research samples to account for such experiences.

Functional magnetic resonance imaging (fMRI) research has generally focused on drawing conclusions from average brain activation patterns. Importantly, the brain is inherently variable; growing literature has found that within-individual blood oxygen level-dependent (BOLD) signal variability may be meaningful, and not just “noise.” For example, recent research has identified increased BOLD signal variability in healthy younger and older adults during more effortful/complex task loads of n-back paradigms, commonly used tasks that involve important elements of executive function (e.g., attention, working memory, planning, inhibition, etc.). Verbal fluency is a complex cognitive domain that also involves similar processes to generate words given certain rules. As a result, the current study builds on existing literature to investigate within-individual BOLD signal variability patterns in peak coordinates of a verbal fluency network during different loads of a letter n-back task. Due to greater executive demands, greater variability was expected during more effortful/complex n-back task loads in regions of a verbal fluency network.

Forty-eight healthy young adults (Mage(SD) = 22.41(4.47), 25 females) from the Atlanta area completed a letter n-back task in an MRI scanner. After standard processing in AFNI, images were corrected for motion and physiological artifacts, which may be confounding sources of variability. Volumes associated with each load of the letter n-back task (0-back, 1-back, 2-back, 3-back, crosshair) were identified. Task runs were normalized and respective run means were subtracted prior to concatenating all runs for each load type. Standard deviations were calculated across this mean-run corrected time series. Ten peak regions of interest (ROIs) were identified from a verbal fluency network generated from 84 peer-reviewed publications for this domain gathered on NeuroSynth. Paired samples t-tests with Benjamini-Hochberg correction for multiple comparisons were conducted to explore differences in variability during n-back task loads.

In several of the verbal fluency network ROIs, within-individual BOLD signal variability was significantly greater for 2-back versus 0-back loads with medium to large effect sizes (p’s < .001 - < .01, Cohen’s d range: .53-.93). Variability was also significantly greater for 3-back versus 0-back loads with small to medium effect sizes (p’s < .001 - < .01, Cohen’s d range: .48-.74). Specific regions that evidenced this pattern included ROIs in the left inferior frontal gyrus, left cingulate, right inferior frontal gyrus, left middle frontal gyrus, and left superior parietal lobule. Only two regions demonstrated increased variability in the 1-back load versus crosshair (left middle frontal gyrus, p < .001, d = .63; left lentiform nucleus, p < .05, d = .42). No regions demonstrated a significant difference in variability in the 0-back load versus crosshair.

This study contributes to growing literature examining within-individual BOLD signal variability in healthy individuals by exploring variability patterns in a verbal fluency network. The observed pattern of results supports the hypothesis and is in line with previous research, demonstrating that greater variability occurs with greater executive task demands. Future research can use an inscanner task of verbal fluency and can extend variability findings during this in-scanner task to out-of-scanner measures of verbal fluency.

There is increasing interest in the utilization of proton beam radiation therapy (PRT) to treat pediatric brain tumors based upon presumed advantages over traditional photon radiation therapy (XRT). PRT provides more conformal radiation to the tumor with reduced dose to healthy brain parenchyma. Less radiation exposure to brain tissue beyond the tumor is thought to reduce neuropsychological sequelae. This systematic review aimed to provide an overview of published studies comparing neuropsychological outcomes between PRT and XRT.

PubMed, PsychINFO, Embase, Web of Science, Scopus, and Cochrane were systematically searched for peer-reviewed published studies that compared neuropsychological outcomes between PRT and XRT in pediatric brain tumor patients.

Eight studies were included. Six of the studies utilized retrospective neuropsychological data; the majority were longitudinal studies (n = 5). XRT was found to result in lower neuropsychological functioning across time. PRT was associated with generally stable neuropsychological functioning across time, with the exception of working memory and processing speed, which showed variable outcomes across studies. However, studies inconsistently included or considered medical and sociodemographic differences between treatment groups, which may have impacted neuropsychological outcomes.

Despite methodological limitations, including limited baseline neuropsychological evaluations, temporal variability between radiation treatment and first evaluation or initial and follow-up evaluations, and heterogenous samples, there is emerging evidence of sociodemographic inequities in access to PRT. With more institutions dedicating funding towards PRT, there may be the opportunity to objectively evaluate the neuropsychological benefits of patients matched on medical and sociodemographic variables.

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).

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.

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.

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.

Right cerebellar-left frontal (RC-LF) white matter integrity (WMI) has been associated with working memory. However, prior studies have employed measures of working memory that include processing speed and attention. We examined the relationships between the RC-LF WMI and processing speed, attention, and working memory to clarify the relationship of RC-LF WMI with a specific cognitive function. Right superior longitudinal fasciculus II (SLF II) WMI and visual attention were included as a negative control tract and task to demonstrate a double dissociation.

Adult survivors of childhood brain tumors [n = 29, age: M = 22 years (SD = 5), 45% female] and demographically matched controls were recruited (n = 29). Tests of auditory attention span, working memory, and visual attention served as cognitive measures. Participants completed a 3-T MRI diffusion-weighted imaging scan. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. Partial correlations between WMI and cognitive scores included controlling for type of treatment.

A correlational double dissociation was found. RC-LF WMI was associated with auditory attention (FA: r = .42, p = .03; RD: r = −.50, p = .01) and was not associated with visual attention (FA: r = −.11, p = .59; RD: r = −.11, p = .57). SLF II FA WMI was associated with visual attention (FA: r = .44, p = .02; RD: r = −.17, p = .40) and was not associated with auditory attention (FA: r = .24, p = .22; RD: r = −.10, p = .62).

The results show that RC-LF WMI is associated with auditory attention span rather than working memory per se and provides evidence for a specificity based on the correlational double dissociation.

Traumatic brain injuries (TBIs) often adversely affect adaptive functioning (AF). However, the cognitive mechanisms by which AF is disrupted are not well understood in young children who sustain TBI. This study examined pragmatic language (PL) and executive functioning (EF) as potential mechanisms for AF disruption in children with early, predominantly mild-complicated, TBI.

The sample consisted of 76 children between the ages of 6 and 10 years old who sustained a TBI (n = 36) or orthopedic injury (OI; n = 40) before 6 years of age and at least 1 year prior to testing (M = 4.86 years, SD = 1.59). Children’s performance on a PL and an expressive vocabulary task (which served as a control task), and parent report of child’s EF and AF were examined at two time points 1 year apart (i.e., at age 8 and at age 9 years).

Injury type (TBI vs. OI) significantly predicted child’s social and conceptual, but not practical, AF. Results indicated that PL, and not expressive vocabulary or EF at time 1, mediated the relationship between injury type and both social and conceptual AF at time 2.

A TBI during early childhood appears to subtly, but uniquely, disrupt complex language skills (i.e., PL), which in turn may disrupt subsequent social and conceptual AF in middle childhood. Additional longitudinal research that examines different aspects of PL and adaptive outcomes into adolescence is warranted.