Cognitive predictors of social adjustment in pediatric brain tumor survivors treated with photon versus proton radiation therapy.

BACKGROUND: Pediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes. PROCEDURE: Survivors who underwent PRT (n = 38) or XRT (n = 20) participated in a neurocognitive evaluation >1 year post radiotherapy. Group differences in cognitive and social functioning were assessed using analysis of covariance (ANCOVA). Regression analyses examined predictors of peer relations and social skills. RESULTS: Age at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p > .05). XRT participants were younger at diagnosis (XRT M = 5.0 years, PRT M = 7.6 years) and further out from radiotherapy (XRT M = 8.7 years, PRT M = 4.6 years). The XRT group performed worse than the PRT group on measures of processing speed (p = .01) and verbal memory (p < .01); however, social outcomes did not differ by radiation type. The proportion of survivors with impairment in peer relations and social skills exceeded expectation; χ2 (1) = 38.67, p < .001; χ2 (1) = 5.63, p < .05. Household poverty predicted peer relation difficulties (t = 2.18, p < .05), and verbal memory approached significance (t = -1.99, p = .05). Tumor diameter predicted social skills (t = -2.07, p < .05). CONCLUSIONS: Regardless of radiation modality, survivors are at risk for social challenges. Deficits in verbal memory may place survivors at particular risk. Results support monitoring of cognitive and social functioning throughout survivorship, as well as consideration of sociodemographic risk factors.

Long-term cognitive and academic outcomes among pediatric brain tumor survivors treated with proton versus photon radiotherapy.

BACKGROUND: Proton radiotherapy (PRT) may be associated with less neurocognitive risk than photon RT (XRT) for pediatric brain tumor survivors. We compared neurocognitive and academic outcomes in long-term survivors treated with XRT versus PRT. METHODS: Survivors underwent neurocognitive evaluation >1 year after craniospinal (CSI) or focal PRT or XRT. Groups were compared using separate one-way analyses of covariance for the CSI and focal groups. RESULTS: PRT (n = 58) and XRT (n = 30) subgroups were similar on gender (66% male), age at RT (median = 6.5 years), age at follow-up (median = 14.6 years), and government assistance status (32%). PRT and XRT focal groups differed on follow-up interval, shunt history, and total RT dose (all p < .05), whereas PRT and XRT CSI groups differed on follow-up interval, baseline neurocognitive performance score, boost volume, and CSI dose (all p < .05). The PRT focal group outperformed the XRT focal group on inhibition/switching (p = .04). The PRT CSI group outperformed the XRT CSI group on inattention/impulsivity (both p < .05). Several clinical variables (i.e., RT dose, boost field, baseline performance) predicted neurocognitive outcomes (all p < .05). The PRT focal group performed comparably to population means on most neurocognitive measures, while both CSI groups performed below expectation on multiple measures. The XRT CSI group was most impaired. All groups fell below expectation on processing speed, fine motor, and academic fluency (most p < .01). CONCLUSIONS: Findings suggest generally favorable neurocognitive and academic long-term outcomes following focal PRT. Impairment was greatest following CSI regardless of modality. Dosimetry and baseline characteristics are important determinants of outcome alone or in combination with modality.

Treatment age and neurocognitive outcomes following proton beam radiotherapy for pediatric low- and intermediate-grade gliomas.

The relationship between age and neurocognitive functioning following proton beam radiotherapy (PRT) in low- and intermediate-grade gliomas (LIGG) has yet to be examined. Eighteen LIGG patients treated with PRT were prospectively enrolled and received annual neurocognitive evaluations of perceptual/verbal reasoning, working memory, and processing speed postradiotherapy. The median age at diagnosis was 8.2 years (range 1.0-14.7) and the median age at PRT was 9.9 years (range 4.2-17.0). Patients' neurocognitive performance did not change on any measure following PRT (p ≥ .142). We did not observe significant changes in cognitive function over time among a small group of LIGG patients treated with PRT.

Premorbid functioning as a predictor of outcome in pediatric brain tumor: An initial examination of the normalcy assumption.

BACKGROUND: Research on neurodevelopmental outcome in survivors of pediatric brain tumor (BT) is often based on the assumption of normal development up to the onset of overt symptoms. We sought to verify the "normalcy assumption" and to investigate corollary issues including challenges inherent to the measurement of premorbid neurobehavioral functioning. PROCEDURE: The Brain Radiation Investigative Study Consortium (BRISC) is a prospective longitudinal multisite study of 58 children diagnosed with BT. Premorbid functioning was assessed via retrospective parent report on standardized rating scales and detailed questionnaires. Findings were examined for the sample as a whole and in patients grouped by tumor histology (embryonal and non-embryonal). RESULTS: Mean age at diagnosis was 9.84 years (range, 3-16). The overall sample showed low proportions of pre/postnatal risk factors and delays in development. The proportion of children with clinically significant premorbid attention (18%) problems based on the BASC-2 exceeded expectation of that in healthy children (6.68%). Similar findings were obtained for somatization (18%) and anxiety (14%). Delays in talking were significantly more common in children with embryonal than non-embryonal tumors (P = 0.02). The non-embryonal tumor group had significantly higher overall rates of premorbid psychosocial problems than the embryonal tumor group (P < 0.001). CONCLUSIONS: We describe a rigorous approach to estimating premorbid developmental status in pediatric BT. The findings suggest mixed support for the "normalcy assumption" and highlight the complexity of this concept and need for further investigation. Our results also suggest the need for further study of potential premorbid correlates with tumor histology.

[Formula: see text] Reliable change in pediatric brain tumor: A preliminary investigation.

Children treated for brain tumor show evidence of declines in general intellectual abilities (i.e., IQ). Group-level data indicate subtle declines over time on average, but no study has utilized a clinical criterion to identify and describe a reliable change in survivors of pediatric brain tumor (PBT). In this study, we discuss the utility of reliable change index (RCI) methodology to supplement group-level analysis (e.g., repeated measures ANOVA). This pilot sample consisted of 22 children (M age = 10.47 years) treated for PBT who completed initial and follow-up assessments (M interval = 23.58 months). Cognitive data included composite scores from the WISC-IV. An RCI z-score was calculated for each participant on each composite score based on two different test-retest reliability coefficients. As a group, survivors of PBT did not demonstrate a statistically significant change from initial to follow-up on any WISC-IV composite score. When RCI was calculated based on reliability coefficients with shorter test-retest intervals provided by the test publisher, 77% of survivors demonstrated a reliable change in performance on at least one measure. The frequency of RCI decreases in working memory was significantly higher than expected. In contrast, only 32% of survivors showed reliable changes on at least one measure when RCI was based on a reliability coefficient derived from a clinical sample with a longer retest interval. This study demonstrates that highly divergent results may be obtained with RCI and the importance of the source of reliability estimates.

Cognitive mediators of adaptive functioning outcomes in survivors of pediatric brain tumors treated with proton radiotherapy.

BACKGROUND: Cranial radiotherapy (RT) is associated with risk for cognitive and adaptive dysfunction. Proton RT (PRT) is a technique hypothesized to spare cognition by reducing exposure to nontarget brain tissue. However, little is known regarding functional outcomes in survivors of pediatric brain tumor (BT) treated with PRT. The present study examined the relationship between cognitive and adaptive outcomes in pediatric BT survivors post-PRT. METHODS: Survivors treated with either focal (n = 33) or craniospinal irradiation (CSI; n = 37) PRT completed neurocognitive evaluations approximately 5 years post-treatment. Results of intelligence testing and ratings of adaptive functioning are reported. Mediation models examined the relationship among radiation field, cognition, and adaptive functioning. RESULTS: The PRT CSI group demonstrated worse cognitive outcomes than the PRT Focal group across each cognitive index (Cohen's d = 0.56-0.70). Parent ratings of adaptive functioning were also worse in the PRT CSI group than the PRT Focal group (Global Adaptive Composite, d = 0.53; conceptual skills, d = 0.67). Cognitive performance fully mediated the relationship between radiation field and adaptive outcomes, while controlling for group differences in tumor histology and RT dose. CONCLUSIONS: Focal PRT survivors demonstrated generally positive outcomes with weaknesses in processing speed and aspects of adaptive functioning. CSI exposure was associated with more consistently poor cognitive and adaptive outcomes. The increased risk for adaptive dysfunction in the PRT CSI group appeared due to the effects of CSI on cognition. Efforts to reduce the volume of tissue exposure to RT remain important.

Superior Intellectual Outcomes After Proton Radiotherapy Compared With Photon Radiotherapy for Pediatric Medulloblastoma.

PURPOSE: Proton radiotherapy (PRT) may lessen the neuropsychological risk traditionally associated with cranial radiotherapy for the treatment of pediatric brain tumors by reducing the dose to normal tissue compared with that of photon radiotherapy (XRT). We examined the change in intellectual scores over time in patients with pediatric medulloblastoma treated with craniospinal PRT versus XRT. METHODS: Intelligence test scores were obtained for a sample of pediatric patients treated between 2007 and 2018 on the same medulloblastoma protocols that differed only in radiotherapy modality (PRT v XRT). Growth curve analyses compared change in scores over time since diagnosis between groups. RESULTS: Longitudinal intelligence data from 79 patients (37 PRT, 42 XRT) were examined. Groups were similar on most demographic/clinical variables, including sex (67.1% male), age at diagnosis (mean, 8.6 years), craniospinal irradiation dose (median, 23.4 Gy), length of follow-up (mean, 4.3 years), and parental education (mean, 14.3 years). Boost dose (P < .001) and boost margin (P = .001) differed between groups. Adjusting for covariates, the PRT group exhibited superior long-term outcomes in global intelligence quotient (IQ), perceptual reasoning, and working memory compared with the XRT group (all P < .05). The XRT group exhibited a significant decline in global IQ, working memory, and processing speed (all P < .05). The PRT group exhibited stable scores over time in all domains with the exception of processing speed (P = .003). CONCLUSION: To our knowledge, this is the first study to compare intellectual trajectories between pediatric patients treated for medulloblastoma with PRT versus those treated with XRT on comparable, contemporary protocols. PRT was associated with more favorable intellectual outcomes in most domains compared with XRT, although processing speed emerged as a vulnerable domain for both groups. This study provides the strongest evidence to date of an intellectual sparing advantage with PRT in the treatment of pediatric medulloblastoma.

Effect of sensorineural hearing loss on neurocognitive and adaptive functioning in survivors of pediatric embryonal brain tumor.

PURPOSE: Survivors of pediatric embryonal brain tumors (BT) are at high risk for sensorineural hearing loss (SNHL) associated with neurocognitive decline. However, previous studies have not assessed the relationship between SNHL and adaptive functioning. We examined neurocognitive and adaptive functioning in patients with and without SNHL. METHODS: Participants included 36 patients treated for an embryonal BT with craniospinal irradiation (CSI) and cisplatin chemotherapy who were assessed 6.7 years post-treatment on average. The impact of SNHL on neurocognitive performance and parent-rated adaptive functioning was assessed in univariate and multivariate analyses. RESULTS: There were 17 cases with SNHL (mean age at evaluation = 14.4) and 19 cases with NH (mean age at evaluation = 13.8). After accounting for age at diagnosis and additional covariates in multivariable analyses, SNHL was associated with worse overall intellectual functioning (p = 0.027) and perceptual reasoning (p = 0.016) performance. There was no effect of SNHL on adaptive functioning in multivariable models. Age at diagnosis and sex were associated with performance on neurocognitive measures. CONCLUSIONS: SNHL in pediatric embryonal BT is associated with increased risk for neurocognitive deficits in conjunction with other demographic and treatment-related factors.

Neuropsychological functioning following surgery for pediatric low-grade glioma: a prospective longitudinal study.

OBJECTIVE: High survival rates have led to an increased emphasis on the functional outcomes of children diagnosed with low-grade glioma. Most outcomes research has focused on risks associated with radiotherapy, but less is known about neuropsychological risks for patients treated with surgery alone. Here, the authors sought to examine the neuropsychological trajectories of children diagnosed with a low-grade glioma and monitored up to 6 years postsurgery. Secondarily, they explored demographic and clinical predictors of neuropsychological performance. METHODS: The neuropsychological functioning of 32 patients (median age at diagnosis 10.0 years) was prospectively assessed annually for up to 6 years after surgery (median days from surgery at baseline = 72). Tumor location was predominately supratentorial (65.6%). A combination of performance-based and parent-reported measures was used to assess intelligence, memory, executive functioning, and fine motor control in all patients. RESULTS: Binomial tests at the postoperative baseline revealed that the proportion of children falling below the average range (< 16th percentile) was significantly higher than the rate expected among healthy peers on measures of verbal memory, processing speed, executive functioning, and fine motor control (p < 0.05). Even so, linear mixed models indicated that neuropsychological functioning at the postoperative baseline did not significantly change over time for up to 6 years after surgery across all domains. A larger tumor size was associated with a slower reaction time (p < 0.01). A supratentorial tumor location and history of seizures were associated with more parent-reported executive difficulties (p < 0.01). CONCLUSIONS: While radiotherapy is a known risk factor for neuropsychological deficits in pediatric brain tumor patients, findings in this study indicate that children treated for low-grade glioma with surgery alone (without radiotherapy or chemotherapy) remain susceptible to difficulties with memory, executive functioning, and motor functioning that persist over time. Over half of the children in the study sample required school support services to address neuropsychological weaknesses. Although low-grade glioma is often conceptualized as a benign tumor, children treated for this lesion require ongoing monitoring and intervention to address neuropsychological weaknesses resulting from the tumor itself as well as the surgery.

Interactions between visual working memory and visual attention among survivors of pediatric acute lymphoblastic leukemia (ALL) and their healthy peers.

Introduction: There is increasing concern for adverse cognitive late effects among survivors of pediatric acute lymphoblastic leukemia (ALL) given the widespread impact they have on academic achievement, particularly working memory and attention. We assessed performance among survivors and their healthy peers on a dual task paradigm measuring visual working memory (VWM) and visual attention independently and the dynamic relationship between the two. Assessing specific subsets within cognitive domains allows for understanding the distinct nature of cognitive impairments. Method: Participants were 34 survivors of ALL who have been off-treatment and disease free for 7.5 years; and 20 healthy controls, all between the ages of 10 and 18 years. We utilized behavioral single- and dual-task paradigms. In the dual tasks, participants maintained several items in VWM while performing a visual attention task (Eriksen Flanker Task) that required processing of a target stimulus while inhibiting the processing of distractor stimuli. The single tasks involved performing only the VWM task or only the visual attention task. Results: Results revealed survivors of ALL performed significantly worse than their healthy peers on the single visual attention task but not the single VWM task. Of particular interest, group differences were obtained on the dual VWM and visual attention tasks, such that the VWM and attention tasks reciprocally interfered with each other only among survivors and not their healthy peers. Conclusions: Our results highlight a core deficit in visual attention that is exacerbated by VWM demands among survivors of ALL. The implementation of tasks from cognitive neuroscience paradigms may be sensitive to cognitive impairments experienced by cancer survivors. Assessment and intervention practices among survivors of pediatric ALL are discussed.

Neuropsychological and socioeconomic outcomes in adult survivors of pediatric low-grade glioma.

BACKGROUND: Current estimates suggest that 75% of children diagnosed with a central nervous system (CNS) tumor will become 5-year survivors. However, survivors of childhood CNS tumors are at increased risk for long-term morbidity. METHODS: To determine long-term neuropsychological and socioeconomic status (SES) outcomes, adult survivors of pediatric low-grade gliomas (n = 181) in the Childhood Cancer Survivor Study and a sibling comparison group that was frequency-matched by age and sex (n = 105) completed a comprehensive battery of standardized neuropsychological tests and an SES assessment. Multivariable regression models compared treatment-specific groups for neuropsychological and SES outcomes and evaluated associations with tumor location, age at diagnosis, sex, and age at evaluation. RESULTS: In adjusted models, survivors treated with surgery and radiotherapy (surgery+RT; median age at diagnosis, 7 years; median age at assessment, 41 years) scored lower on estimated IQ than survivors treated with surgery only, who scored lower than siblings (surgery+RT, 93.9; surgery only, 101.2; siblings, 108.5; all P values <.0001). Survivors diagnosed at younger ages had low scores for all outcomes (P < .05) except for attention/processing speed. For SES outcomes, survivors treated with surgery+RT had lower occupation scores (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.1-5.9), lower income (OR, 2.6; 95% CI, 1.3-5.0), and less education (OR, 2.1; 95% CI, 1.1-4.0) than those treated with surgery only. CONCLUSIONS: Decades after treatment, survivors treated with radiotherapy and at younger ages had poorer neuropsychological and SES outcomes. Lifelong surveillance of survivors of pediatric low-grade gliomas may be warranted as life events, stages, and transitions (employment, family, and aging) present new challenges and risks.

Adaptive functioning in pediatric brain tumor survivors: An examination of ethnicity and socioeconomic status.

BACKGROUND: Survivors of pediatric brain tumor are at risk for adaptive difficulties. The present study examined adaptive functioning in a multiethnic sample of survivors accounting for socioeconomic status, and whether demographic, diagnostic, and/or treatment-related variables predict adaptive outcomes. METHOD: Participants included a multiethnic sample of survivors (58 Caucasian, 34 Hispanic, and 22 other non-Caucasian; M age = 14.05 years, SD = 4.33) who were approximately seven years post-treatment. Parents rated adaptive functioning and provided demographic information. Diagnostic and treatment-related information was abstracted from the electronic medical record. RESULTS: Parent ratings of adaptive functioning were similar across Caucasian, Hispanic, and other non-Caucasian survivors covarying for family income and primary caregiver education, both of which served as proxies for socioeconomic status. All ethnic groups were rated lower than the normative mean in overall adaptive functioning as well as the specific domains of conceptual, social, and practical skills. Demographic, diagnostic, and treatment-related variables were differentially associated with adaptive functioning in survivors of pediatric brain tumor, though socioeconomic status emerged as a strong significant predictor of adaptive functioning domains. CONCLUSIONS: Adaptive outcomes do not differ as a function of ethnicity after accounting for primary caregiver education and family income. Racial and ethnic minorities may be at increased risk for poorer outcomes given their overrepresentation at lower income levels. Assessing demographic and treatment-related variables early on may be helpful in identifying children likely to develop adaptive difficulties.

Processing speed in children treated for brain tumors: effects of radiation therapy and age.

The current study examined processing speed in children two years post-treatment for brain tumors (BT) with radiation therapy (RT) compared to those treated with without RT. Participants included 59 children (4-17 years) with BT assessed as part of the Brain Radiation Investigative Study Consortium (BRISC). Processing speed was assessed at two time points: Time1 (3-9 months post-surgery) for 26 children who received whole brain or focal RT (RT group) and 33 treated without RT (no-RT group), and again two years later (Time2) for 42 participants (17 RT, 25 no-RT). Linear mixed effects (LME) regression analyses examined differences in cognitive and motor speed between groups and across visits, with age at Time1 (age1) treated as a moderating variable, and sex and primary tumor size as covariates. No effects for treatment group or visit were found for motor speed (Pegboard) or mean reaction time (Attention Network Task). On the Wechsler Processing Speed Index (PSI), the no-RT group performed better than the RT group, with a group-by-age interaction such that across visits, the difference between the no-RT and RT groups was larger among children who were older at initial treatment (≥10 years) than among those who were younger (<10 years). Cumulative brain injury earlier in life (tumor, surgery, plus RT) may result in greater impact on more complex tasks of cognitive efficiency. Children receiving RT showed reduced processing speed over time, with a larger group difference among those who were over 10 years at treatment.

Dose-volume metrics and their relation to memory performance in pediatric brain tumor patients: A preliminary study.

BACKGROUND: Advances in radiation treatment (RT), specifically volumetric planning with detailed dose and volumetric data for specific brain structures, have provided new opportunities to study neurobehavioral outcomes of RT in children treated for brain tumor. The present study examined the relationship between biophysical and physical dose metrics and neurocognitive ability, namely learning and memory, 2 years post-RT in pediatric brain tumor patients. PROCEDURE: The sample consisted of 26 pediatric patients with brain tumor, 14 of whom completed neuropsychological evaluations on average 24 months post-RT. Prescribed dose and dose-volume metrics for specific brain regions were calculated including physical metrics (i.e., mean dose and maximum dose) and biophysical metrics (i.e., integral biological effective dose and generalized equivalent uniform dose). We examined the associations between dose-volume metrics (whole brain, right and left hippocampus), and performance on measures of learning and memory (Children's Memory Scale). RESULTS: Biophysical dose metrics were highly correlated with the physical metric of mean dose but not with prescribed dose. Biophysical metrics and mean dose, but not prescribed dose, correlated with measures of learning and memory. CONCLUSIONS: These preliminary findings call into question the value of prescribed dose for characterizing treatment intensity; they also suggest that biophysical dose has only a limited advantage compared to physical dose when calculated for specific regions of the brain. We discuss the implications of the findings for evaluating and understanding the relation between RT and neurocognitive functioning.

Performance-based and parent ratings of attention in children treated for a brain tumor: The significance of radiation therapy and tumor location on outcome.

Children are at increased risk for cognitive difficulties following the diagnosis and treatment of a brain tumor. Radiation therapy (RT) and tumor location are commonly-cited predictors of neurocognitive functioning. Disruptions to foundational neurocognitive processes such as attention, working memory, and processing speed underlie declines on measures of general intellectual functioning. While several studies have examined visual sustained attention in pediatric brain tumor patients, auditory sustained attention has yet to be examined. This study employs a longitudinal design to examine performance-based and parent ratings of attention in children undergoing surgical resection of a brain tumor (n = 29) and treated with (n = 11) or without (n = 18) RT at 6.79 months post-surgery (baseline) and then again at 30.56 months post-surgery (follow-up). The measures include an auditory continuous performance test (CPT) and parent ratings of attention and hyperactivity on a behavior rating scale. Ultimately, children treated with and without RT performed similarly on performance-based and parent ratings of attention. However, the performance on the auditory CPT differed according to tumor location, with children with infratentorial tumors committing more inattention and inhibitory control errors compared to children with supratentorial tumors. Parent ratings did not differ according to tumor location, and parent ratings and auditory sustained attention performance are not significantly correlated. The findings are interpreted in the context of neurocognitive and brain development.

Predicting changes in adaptive functioning and behavioral adjustment following treatment for a pediatric brain tumor: A report from the Brain Radiation Investigative Study Consortium.

BACKGROUND: Children are at risk for behavioral and adaptive difficulties following pediatric brain tumor. This study explored whether familial/demographic, developmental, diagnostic, or treatment-related variables best predict posttreatment behavioral and adaptive functioning. METHODS: Participants included 40 children (mean age = 12.76 years, SD = 4.01) posttreatment (mean time since diagnosis = 1.99 years, SD = 0.21) for pediatric brain tumor. Parents rated children's behavioral adjustment and adaptive functioning and provided demographic and developmental histories. Diagnostic and treatment-related information was abstracted from medical records. RESULTS: Ratings of adaptive and behavioral functioning approximately 2 years postdiagnosis were within the average range, although the percentage of children exceeding clinical cutoffs for impairment in adaptive skills exceeded expectation, particularly practical skills. Premorbid behavior problems and tumor size predicted posttreatment adaptive functioning. After accounting for adaptive functioning near diagnosis, premorbid behavior problems predicted declines in adaptive functioning 2 years postdiagnosis. After accounting for adjustment near diagnosis, no variables predicted declines in behavioral adjustment. CONCLUSIONS: Children may be vulnerable to reduced adaptive functioning following pediatric brain tumor treatment, especially in practical skills. Assessing prediagnosis functioning and diagnostic and treatment-related variables may improve our ability to predict those at greatest risk, although those factors may be less helpful in identifying children likely to develop behavioral difficulties. Screening of these factors in tertiary care and long-term follow-up settings may improve identification of those at greatest need for support services.

Exercise ameliorates neurocognitive impairments in a translational model of pediatric radiotherapy.

Background: While cranial radiation therapy (CRT) is an effective treatment, healthy areas surrounding irradiation sites are negatively affected. Frontal lobe functions involving attention, processing speed, and inhibition control are impaired. These deficits appear months to years after CRT and impair quality of life. Exercise has been shown to rejuvenate the brain and aid in recovery post-injury through its effects on neurogenesis and cognition. Methods: We developed a juvenile rodent CRT model that reproduces neurocognitive deficits. Next, we utilized the model to test whether exercise ameliorates these deficits. Fischer rats (31 days old) were irradiated with a fractionated dose of 4 Gy × 5 days, trained and tested at 6, 9, and 12 months post-CRT using 5-choice serial reaction time task. After testing, fixed rat brains were imaged using diffusion tensor imaging and immunohistochemistry. Results: CRT caused early and lasting impairments in task acquisition, accuracy, and latency to correct response, as well as causing stunting of growth and changes in brain volume and diffusion. Exercising after irradiation improved acquisition, behavioral control, and processing speed, mitigated the stunting of brain size, and increased brain fiber numbers compared with sedentary CRT values. Further, exercise partially restored global connectome organization, including assortativity and characteristic path length, and while it did not improve the specific regional connections that were lowered by CRT, it appeared to remodel these connections by increasing connectivity between alternate regional pairs. Conclusions: Our data strongly suggest that exercise may be useful in combination with interventions aimed at improving cognitive outcome following pediatric CRT.

Attention, processing speed, and executive functioning in pediatric brain tumor survivors treated with proton beam radiation therapy.

BACKGROUND AND PURPOSE: This study examines attention, processing speed, and executive functioning in pediatric brain tumor survivors treated with proton beam radiation therapy (PBRT). MATERIAL AND METHODS: We examined 39 survivors (age 6-19years) who were 3.61years post-PBRT on average. Craniospinal (CSI; n=21) and focal (n=18) subgroups were analyzed. Attention, processing speed, and executive functioning scores were compared to population norms, and clinical/demographic risk factors were examined. RESULTS: As a group, survivors treated with focal PBRT exhibited attention, processing speed, and executive functioning that did not differ from population norms (all p>0.05). Performance in the CSI group across attention scales was normative (all p>0.05), but areas of relative weakness were identified on one executive functioning subtest and several processing speed subtests (all p<0.01). CONCLUSIONS: Survivors treated with PBRT may exhibit relative resilience in cognitive domains traditionally associated with radiation late effects. Attention, processing speed, and executive functioning remained intact and within normal limits for survivors treated with focal PBRT. Among survivors treated with CSI, a score pattern emerged that was suggestive of difficulties in underlying component skills (i.e., processing speed) rather than true executive dysfunction. No evidence of profound cognitive impairment was found in either group.

Measurement of neurodevelopmental changes in children treated with radiation for brain tumors: what is a true 'baseline?'

OBJECTIVE: To review the various ways in which baseline neuropsychological functioning is measured in the extant literature on pediatric brain tumors, describe the pros and cons of each approach, and increase the awareness of researchers as to the implications of each. METHOD: We reviewed the literature from 1993 to 2013, and classified studies by baseline approach and explicitness of selection of approach. RESULTS: There are multiple approaches to operationalizing baseline levels of ability and to assess change from baseline. Each approach has strengths and weaknesses, and selection may depend on the question under investigation. Approaches to baseline estimation varied widely with a trend over time toward reliance on statistical modeling. Researchers were often insufficiently explicit about the reasons for adopting a particular approach. The common use of standardized scores requires caution as they obscure critical inferential limitations about change and magnitude of change. Some viable approaches were infrequently used, such as actuarial prediction formulas. Multiple simultaneous methods akin to theory testing and formal methods of construct validation could enhance scientific yield since all approaches are fallible. CONCLUSIONS: Estimating baseline neuropsychological functioning is very challenging, particularly when it concerns children in the preschool years. Nevertheless, it is a crucial methodological decision with important implications for the interpretation of research findings that needs to be dealt with explicitly.