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To investigate the developmental changes of cerebral blood flow (CBF) and hemodynamic responses to changing neural activity, we used the arterial spin label (ASL) technique to measure resting CBF and simultaneous CBF / blood-oxygen-level dependent (BOLD) signal changes during visual stimulation in 97 typically developing children and young adults (age 13.35 [6.02, 25.25] (median [min, max]) years old at the first time point). The longitudinal study protocol included three MRIs (2.7 ± 0.06 obtained), one year apart, for each participant. Mixed-effect linear and non-linear statistical models were used to analyze age effects on CBF and BOLD signals. Resting CBF decreased exponentially with age ( p = 0.0001) throughout the brain, and developmental trajectories differed across brain lobes. The absolute CBF increase in visual cortex during stimulation was constant over the age range, but the fractional CBF change increased with age ( p = 0.0001) and the fractional BOLD signal increased with age ( p = 0.0001) correspondingly. These findings suggest that the apparent neural hemodynamic coupling in visual cortex does not change after age six years, but age-related BOLD signal changes continue through adolescence primarily due to the changes with age in resting CBF.

BACKGROUND Current R2*-MRI techniques for measuring hepatic iron content (HIC) use various acquisition types and fitting models. PURPOSE To evaluate the accuracy and precision of R2*-HIC acquisition and fitting methods. STUDY TYPE Signal simulations, phantom study, and prospective in vivo cohort. POPULATION In all, 132 patients (58/74 male/female, mean age 17.7 years). FIELD STRENGTH/SEQUENCE 2D-multiecho gradient-echo (GRE) and ultrashort echo time (UTE) acquisitions at 1.5T. ASSESSMENT Synthetic MR signals were created to mimic published GRE and UTE methods, using different R2* values (25-2000 s-1 ) and signal-to-noise ratios (SNR). Phantoms with varying iron concentrations were scanned at 1.5T. In vivo data were analyzed from 132 patients acquired at 1.5T. R2* was estimated by fitting using three signal models. Accuracy and precision of R2* measurements for UTE acquisition parameters (SNR, echo spacing [ΔTE], maximum echo time [TEmax ]) and fitting methods were compared for simulated, phantom, and in vivo datasets. STATISTICAL TESTS R2* accuracy was determined from the relative error and by linear regression analysis. Precision was evaluated using coefficient of variation (CoV) analysis. RESULTS In simulations, all models had high R2* accuracy (error 0.99, P 0.99, P < 0.001) for the noise subtraction model for 25≤R2*≤2000 s-1 . However, both quadratic and constant offset models, using shorter TEmax (≤4.7 msec) overestimated R2* and yielded high CoVs up to ∼170% for low R2* (

Chemotherapeutic agents used to treat acute lymphoblastic leukemia (ALL), the most common cancer affecting young children, have been associated with long-term cognitive impairments that reduce quality of life. Executive dysfunction is one of the most consistently observed deficits and can have substantial and pervasive effects on academic success, occupational achievement, psychosocial function, and psychiatric status. We examined the neural mechanisms of executive dysfunction by measuring structural and functional connectomes in 161 long-term survivors of pediatric ALL, age 8–21 years, who were treated on a single contemporary chemotherapy-only protocol for standard/high- or low-risk disease. Lower global efficiency, a measure of information exchange and network integration, of both structural and functional connectomes was found in survivors with executive dysfunction compared with those without dysfunction (p

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of >90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation / mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.

BACKGROUND: The impact of contemporary chemotherapy treatment for childhood acute lymphoblastic leukemia on central nervous system activity is not fully appreciated. METHODS: Neurocognitive testing and functional magnetic resonance imaging (fMRI) were obtained in 165 survivors five or more years postdiagnosis (average age = 14.4 years, 7.7 years from diagnosis, 51.5% males). Chemotherapy exposure was measured as serum concentration of methotrexate following high-dose intravenous injection. Neurocognitive testing included measures of attention and executive function. fMRI was obtained during completion of two tasks, the continuous performance task (CPT) and the attention network task (ANT). Image analysis was performed using Statistical Parametric Mapping software, with contrasts targeting sustained attention, alerting, orienting, and conflict. All statistical tests were two-sided. RESULTS: Compared with population norms, survivors demonstrated impairment on number-letter switching (P < .001, a measure of cognitive flexibility), which was associated with treatment intensity (P = .048). Task performance during fMRI was associated with neurocognitive dysfunction across multiple tasks. Regional brain activation was lower in survivors diagnosed at younger ages for the CPT (bilateral parietal and temporal lobes) and the ANT (left parietal and right hippocampus). With higher serum methotrexate exposure, CPT activation decreased in the right temporal and bilateral frontal and parietal lobes, but ANT alerting activation increased in the ventral frontal, insula, caudate, and anterior cingulate. CONCLUSIONS: Brain activation during attention and executive function tasks was associated with serum methotrexate exposure and age at diagnosis. These findings provide evidence for compromised and compensatory changes in regional brain function that may help clarify the neural substrates of cognitive deficits in acute lymphoblastic leukemia survivors.

Cogmed is a computerized cognitive intervention utilizing coaches who receive standardized instruction in analyzing training indices and tailoring feedback to remotely monitor participant's performance. The goal of this study was to examine adherence, satisfaction, and efficacy of Cogmed across coaches. Survivors of pediatric brain tumors and acute lymphoblastic leukemia (N = 68) were randomized to intervention (Cogmed) or waitlist control. The intervention group was matched with one of two coaches. Cognitive assessments were completed before and after intervention, and participants and caregivers in the intervention group completed satisfaction surveys. T-tests showed no differences in adherence across coaches (number of sessions completed p = .38; d = .32). Noninferiority statistics were not consistently equivalent for satisfaction, but equivalence was supported for caregiver perceptions of pragmatic utility and participant perceptions of logistical ease of Cogmed. Equivalence was not consistently suggested for cognitive outcomes, but was supported on measures tapping relevant cognitive domains (attention, working memory, processing speed, academic fluency). This study suggests adherence can be maintained across coaches. While aspects of satisfaction and cognitive outcomes were equivalent, the possible influence of coach-based variables cannot be ruled out. Findings highlight challenges in standardizing the coaching component of multicomponent computerized interventions and the need for ongoing research to establish dessiminability.

Group3 medulloblastoma (MBG3) that predominantly occur in young children are usually associated with MYC amplification and/or overexpression, frequent metastasis and a dismal prognosis. Physiologically relevant MBG3 models are currently lacking, making inferences related to their cellular origin thus far limited. Using in utero electroporation, we here report that MBG3 mouse models can be developed in situ from different multipotent embryonic cerebellar progenitor cells via conditional expression of Myc and loss of Trp53 function in several Cre driver mouse lines. The Blbp-Cre driver that targets embryonic neural progenitors induced tumors exhibiting a large-cell/anaplastic histopathology adjacent to the fourth ventricle, recapitulating human MBG3. Enforced co-expression of luciferase together with Myc and a dominant-negative form of Trp53 revealed that GABAergic neuronal progenitors as well as cerebellar granule cells give rise to MBG3 with their distinct growth kinetics. Cross-species gene expression analysis revealed that these novel MBG3 models shared molecular characteristics with human MBG3, irrespective of their cellular origin. We here developed MBG3 mouse models in their physiological environment and we show that oncogenic insults drive this MB subgroup in different cerebellar lineages rather than in a specific cell of origin.

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy only are at risk for neurocognitive impairment. Regions of interest were identified a priori based on glucocorticoid receptor distribution, and sex-stratified multivariable linear regression models were used to test associations between brain MRI morphology and total number of intrathecal injections, and serum concentration of dexamethasone and methotrexate. Compared with controls, ALL survivors have persistently smaller volumes in the bilateral cerebellum (P < 0.005), hippocampal subregions (P < 0.03), temporal lobe regions (P < 0.03), frontal lobe regions (P < 0.04), and parietal lobe regions (precuneus; P < 0.002). Long-term problems with learning may be related to residual posttreatment brain differences.

Objectives: Craniopharyngioma survivors experience cognitive deficits that negatively impact quality of life. Aerobic fitness is associated with cognitive benefits in typically developing children and physical exercise promotes recovery following brain injury. Accordingly, we investigated cognitive and neural correlates of aerobic fitness in a sample of craniopharyngioma patients. Methods: Patients treated for craniopharyngioma [N=104, 10.0±4.6 years, 48% male] participated in fitness, cognitive and fMRI (n=51) assessments following surgery but before proton radiation therapy. Results: Patients demonstrated impaired aerobic fitness [peak oxygen uptake (PKVO2)=23.9±7.1, 41% impaired (i.e., 1.5 SD2 correlated with better executive functions (e.g., WISC-IV WMI r=.27, p=.02) and academic performance (WJ-III Calculation r=.24, p=.04). BOT2 correlated with better attention (e.g., CPT-II omissions r=.26, p=.04) and executive functions (e.g., WISC-IV WMI r=.32, p=.01). Areas of robust neural activation during an n-back task included superior parietal lobule, dorsolateral prefrontal cortex, and middle and superior frontal gyri (ppConclusions: Before adjuvant therapy, children with craniopharyngioma demonstrate significantly reduced aerobic fitness, motor proficiency, and working memory. Better aerobic fitness and motor proficiency are associated with better attention and executive functions, as well as greater activation of a well-established working memory network. These findings may help explain differential risk/resiliency with respect to acute cognitive changes that may portend cognitive late effects. (JINS, 2019, 25, 413–425)

Purpose To examine associations among methotrexate pharmacodynamics, neuroimaging, and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy-only protocol. Patients and Methods This longitudinal study linked pharmacokinetic assays collected during therapy to neurocognitive and brain imaging outcomes during long-term follow-up. A total of 218 (72.2%) of 302 eligible long-term survivors were recruited for outcome studies when they were more than 5 years post-diagnosis and older than 8 years of age. At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis, and 51% were male. Neurocognitive testing, functional magnetic resonance imaging (MRI) during an executive function task, and structural MRI with diffusion tensor imaging were conducted. Generalized linear models were developed to identify predictors, and models were adjusted for age at diagnosis, sex, and parent education. Results Intelligence was within normal limits (mean, 98; standard deviation, 14) compared with population expectations (mean, 100; standard deviation, 15), though measures of executive function, processing speed, and memory were less than population means (all P < .02 after correction for false discovery rates). Higher plasma concentration of methotrexate was associated with a poorer executive function score (P < .02). Higher plasma methotrexate was also associated with higher functional MRI activity, with thicker cortices in dorsolateral prefrontal brain regions, and with white matter microstructure in the frontostriatal tact. Neurocognitive impairment was associated with these imaging findings as well. Associations did not change after adjustment for age or dose of leucovorin rescue. Conclusion Survivors of childhood acute lymphoblastic leukemia treated on contemporary chemotherapy-only protocols demonstrate executive dysfunction. A higher plasma concentration of methotrexate was associated with executive dysfunction as well as with a thicker cortex and higher activity in frontal brain regions, regions often associated with executive function.

Objective Despite excellent survival prognosis, children treated for craniopharyngioma experience significant morbidity. We examined the role of hypothalamic involvement (HI) in excessive daytime sleepiness (EDS) and attention regulation in children enrolled on a Phase II trial of limited surgery and proton therapy. Methods Participants completed a sleep evaluation (N = 62) and a continuous performance test (CPT) during functional magnetic resonance imaging (fMRI; n = 29) prior to proton therapy. Results EDS was identified in 76% of the patients and was significantly related to increased HI extent (p = .04). There was no relationship between CPT performance during fMRI and HI or EDS. Visual examination of group composite fMRI images revealed greater spatial extent of activation in frontal cortical regions in patients with EDS, consistent with a compensatory activation hypothesis. Conclusion Routine screening for sleep problems during therapy is indicated for children with craniopharyngioma, to optimize the timing of interventions and reduce long-term morbidity.

This cross-sectional study examines associations among brain volume, brain network connectivity, and neurocognitive test performance in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only., Key Points Question Are changes in glucocorticoid receptor–rich brain structures of the cerebello-thalamo-cortical network associated with altered network communication and neurocognitive performance in survivors of childhood acute lymphoblastic leukemia (ALL) treated using chemotherapy-only protocols? Findings In this cross-sectional study of 176 survivors of childhood ALL treated with chemotherapy only, a significant interaction association was found among female survivors between glucocorticoid exposure and altered functional and effective connectivity of the cerebellum and dorsolateral frontal cortex. Meaning These findings suggest that female survivors of ALL may be at increased risk of altered connectivity from glucocorticoid exposure during therapy and may benefit from posttreatment strategies that repair altered network communication in the cerebello-thalamo-cortical network., Importance Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL). Objective To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network. Design, Setting, and Participants This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020. Exposure ALL treatment using chemotherapy-only protocols. Main Outcomes and Measures This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. β values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm3/1 SD in z score for cerebellum, mm3/[g×hr/L] for dexamethasone and methotrexate AUC, and mm3/intrathecal count for total intrathecal count). Results Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of both sexes showed decreased mean (SD) cerebellar volumes compared with the control population (female: 70 568 [6465] mm3 vs 75 134 [6780] mm3; P < .001; male: 77 335 [6210] mm3 vs 79 020 [7420] mm3; P

Purpose Children receiving CNS-directed therapy for cancer are at risk for cognitive problems, with few available empirically supported interventions. Cognitive problems indicate neurodevelopmental disruption that may be modifiable with intervention. This study evaluated short-term efficacy of a computerized cognitive training program and neural correlates of cognitive change. Patient and Methods A total of 68 survivors of childhood acute lymphoblastic leukemia (ALL) or brain tumor (BT) with identified cognitive deficits were randomly assigned to computerized cognitive intervention (male, n = 18; female, n = 16; ALL, n = 23; BT, n = 11; mean age ± standard deviation, 12.21 ± 2.47 years) or waitlist (male, n = 18; female, n = 16; ALL, n = 24; BT, n = 10; median age ± standard deviation, 11.82 ± 2.42 years). Intervention participants were asked to complete 25 training sessions at home with weekly, telephone-based coaching. Cognitive assessments and functional magnetic resonance imaging scans (intervention group) were completed pre- and postintervention, with immediate change in spatial span backward as the primary outcome. Results Survivors completing the intervention (n = 30; 88%) demonstrated greater improvement than controls on measures of working memory (mean ± SEM; eg, Wechsler Intelligence Scale for Children [fourth edition; WISC-IV] spatial span backward, 3.13 ± 0.58 v 0.75 ± 0.43; P = .002; effect size [ES], 0.84), attention (eg, WISC-IV spatial span forward, 3.30 ± 0.71 v 1.25 ± 0.39; P = .01; ES, 0.65), and processing speed (eg, Conners' Continuous Performance Test hit reaction time, −2.10 ± 1.47 v 2.54 ± 1.25; P = .02; ES, .61) and showed greater reductions in reported executive dysfunction (eg, Conners' Parent Rating Scale III, −6.73 ± 1.51 v 0.41 ± 1.53; P = .002; ES, 0.84). Functional magnetic resonance imaging revealed significant pre- to post-training reduction in activation of left lateral prefrontal and bilateral medial frontal areas. Conclusion Study findings show computerized cognitive training is feasible and efficacious for childhood cancer survivors, with evidence for training-related neuroplasticity.

Purpose The purpose of this study was to determine radiation dose effect on the structural integrity of cerebral white matter in craniopharyngioma patients receiving surgery and proton therapy. Methods and Materials Fifty-one patients (2.1-19.3 years of age) with craniopharyngioma underwent surgery and proton therapy in a prospective therapeutic trial. Anatomical magnetic resonance images acquired after surgery but before proton therapy were inspected to identify white matter structures intersected by surgical corridors and catheter tracks. Longitudinal diffusion tensor imaging (DTI) was performed to measure microstructural integrity changes in cerebral white matter. Fractional anisotropy (FA) derived from DTI was statistically analyzed for 51 atlas-based white matter structures of the brain to determine radiation dose effect. FA in surgery-affected regions in the corpus callosum was compared to that in its intact counterpart to determine whether surgical defects affect radiation dose effect. Results Surgical defects were seen most frequently in the corpus callosum because of transcallosal resection of tumors and insertion of ventricular or cyst catheters. Longitudinal DTI data indicated reductions in FA 3 months after therapy, which was followed by a recovery in most white matter structures. A greater FA reduction was correlated with a higher radiation dose in 20 white matter structures, indicating a radiation dose effect. The average FA in the surgery-affected regions before proton therapy was smaller ( P =.0001) than that in their non–surgery-affected counterparts with more intensified subsequent reduction of FA ( P =.0083) after therapy, suggesting that surgery accentuated the radiation dose effect. Conclusions DTI data suggest that mild radiation dose effects occur in patients with craniopharyngioma receiving surgery and proton therapy. Surgical defects present at the time of proton therapy appear to accentuate the radiation dose effect longitudinally. This study supports consideration of pre-existing surgical defects and their locations in proton therapy planning and studies of treatment effect.

Survivors of pediatric brain tumors and acute lymphoblastic leukemia (ALL) are at significant risk for neurocognitive late effects secondary to disease and treatment, with specific risk to attention and working memory (WM).1–3 Attention and WM are thought to be foundational cognitive skills, such that deficits in these domains can have deleterious effects on social, vocational, and academic attainment.4,5 Recent advances in treatment have resulted in improved survival with 5-year event-free survival rates of ∼90% among ALL populations.6 While some pediatric brain tumor diagnoses continue to be associated with poor prognosis, survival is >70% among a number of frequently diagnosed brain tumor populations.7 Improved survival rates1,8 have led to an increased focus on survivorship and quality of life, including investigation of targeted methods for mitigating neurocognitive late effects. Current options for remediating late effects include pharmacological interventions, therapist-delivered cognitive remediation, and computerized interventions. Psychostimulants have been used extensively and successfully to treat attention deficit/hyperactivity disorder (ADHD).9 Due to similarity of cognitive late effects with symptoms of ADHD, clinical trials have investigated the utility of psychostimulant medications for cancer populations.10–12 Methylphenidate (MPH) trials have suggested that MPH is efficacious for improving attention and social skills in childhood cancer survivors with learning impairments, demonstrating both immediate10,11 and long-term benefits.12 While efficacious, drug trials have typically excluded individuals with medical contraindications (eg, history of uncontrolled seizures), rendering these patients inappropriate for pharmacological intervention.11 Side effects in children treated with MPH are generally comparable with those in ADHD patients; however, there appears to be a subset of childhood cancer survivors who experience increased rates of adverse side effects.13 Additionally, childhood cancer survivors respond to MPH at a lower rate than the ADHD population (eg, 45% childhood cancer vs 75% ADHD).13 Finally, many parents are hesitant to put their child on a psychostimulant.11 While pharmacological interventions show promise for many childhood cancer survivors, these findings suggest that nonpharmacological interventions are needed to address cognitive deficits in those who are not viable candidates for medication. Butler and Copeland developed an intensive cognitive remediation program based on techniques from traumatic brain injury rehabilitation, special education, and clinical psychology,14 which involved 20 individual therapy sessions over 4–5 months. Survivors demonstrated improvement in academic and metacognitive skills, as well as parent ratings of attention, but no improvement on attention or memory performance measures.14 Other programs utilize similar strategies and/or focus on particular domains known to be at risk for survivors.15,16 Support for therapist-directed cognitive remediation interventions includes modest academic benefit, involvement of parents and educators who help maintain gains, and lack of medical contraindications. However, these programs require intensive one-on-one intervention with a trained therapist, necessitating close proximity to specialized cancer care centers, while providing only modest training benefit. Ultimately, existing pharmacological and therapist-directed interventions are not tenable for all survivors and thus highlight the need for safe, portable, time-efficient, and efficacious interventions for this population. Computerized interventions are software programs that involve massed practice, graded difficulty, and expert coaching. Home-based computerized training allows immediate feedback, customization for individual client needs/ability levels, ease of data collection for monitoring progress, and an engaging interface.17 Additionally, computerized interventions are not constrained by proximity to a specific facility, which may reduce treatment burden because they can be completed in the home, and have considerably fewer (if any) side effects compared with pharmacological intervention. Computerized training programs have demonstrated efficacy with a wide variety of populations including ADHD18 and traumatic brain injury.19 Currently, there are a few different computerized cognitive training programs on the market that have been tested for use by cancer survivors. Captain's Log, developed by Brain Train (www.braintrain.com), involves computer game-like activities that are designed to strengthen memory, attention, concentration, listening skills, self-control, patience, and processing speed. While initial results indicated efficacy in a small sample,20 several aspects of the program, including an outdated presentation of graphics and lack of ease of administration (eg, dose standardization, progress monitoring), have limited its use. Lumos Laboratories created a Cognitive Rehabilitation Curriculum that specifically targets cognitive flexibility, WM, and attention.21 An initial single-arm trial with cancer survivors demonstrated moderate success with improvements in processing speed, cognitive flexibility, and visual and verbal memory but no improvement in attention or WM.22 Cogmed, a software program created by neuroscientists and game developers at the Karolinska Institute, is designed to exercise different cognitive processes through a series of brain-training sessions. The program has been empirically tested in a wide variety of populations, including children with ADHD,21,22 with notable efficacy. Cogmed specifically targets WM, a domain frequently affected in survivors of pediatric cancer, which makes it particularly well suited for this population.23,24 Hardy et al25 conducted a small pilot study of Cogmed with a sample of 20 childhood cancer survivors who exhibited deficits in attention and WM. Participants were randomized to the adaptive computerized intervention or to a nonadaptive, active control group with brief cognitive assessments completed before and after intervention. Results showed that 85% of participants were compliant with the intervention with no adverse events reported. Preliminary findings suggest postintervention gains in visual WM but call for more rigorous examination in a larger sample.25 In sum, limited research has demonstrated that computerized interventions can reduce treatment burden and the need for proximity to a facility when compared with therapist-delivered cognitive remediation interventions, and result in a much more desirable side-effect profile than pharmacological interventions. Computerized interventions such as Cogmed appear to be particularly well suited for clinical practice. However, past studies were conducted with small sample sizes, using mostly local patient populations with a limited range of socioeconomic statuses, and have not included neuroimaging to investigate early neural correlates of change. With these omissions in mind, the current study aimed to (i) replicate the preliminary feasibility and acceptability demonstrated by Hardy et al25 with a nonlocal sample that was also powered for efficacy and (ii) investigate the feasibility of pre- and postintervention neuroimaging (eg, functional MRI) with a pediatric population. Separate reports with efficacy and neuroimaging findings are forthcoming.

PURPOSE: Children with cancer frequently require MRI scans for clinical purposes. Sedation with general anesthesia (GA) is often used to promote compliance, reduce motion, and alleviate anxiety. The use of GA for MRI scans is costly in terms of time, personnel, and medications. In addition, prominent risks are associated with anesthesia exposure in patients with complex medical conditions. Successful behavioral interventions have been implemented in clinical research settings to promote scan success and compliance. To our knowledge, parent/caregiver acceptability of behavioral interventions to promote nonsedated MRI has not been systematically investigated in a medically complex population. As a first step toward developing a protocol-based intervention to promote nonsedated scanning, we conducted a survey to explore parental perspectives regarding acceptability of nonsedated scanning and to gain information regarding preference for specific behavioral interventions to facilitate nonsedated MRI exams. METHODS: Parents or guardians of 101 patients diagnosed with childhood cancer participated in a semi-structured survey via telephone. The sample was stratified by age group (8–12 years; 13–18 years), gender, and diagnosis (solid tumor (ST), brain tumor (BT), and acute lymphoblastic leukemia (ALL)). RESULTS: The majority of parents indicated that nonsedated MRI scans would be acceptable. Reduced anesthesia exposure was the most frequently identified benefit, followed by decreased irritability post-MRI scan, and shorter appointment time. Challenges included fear of movement and noise during scans and change in routine, with parents of younger children and those with a history of sedated exams identifying more challenges. Behavioral intervention preference differed by patient age and gender; however, education was ranked as most preferred overall. CONCLUSION: Parents of children treated for cancer consider behavior interventions to promote nonsedated scanning as acceptable. Patient characteristics should be considered when tailoring behavioral interventions. Results can inform future studies of behavioral interventions to promote nonsedated MRI scans. Future research should also investigate the risks associated with failed exams, both in terms of patient medical care and cost effectiveness.

Background Treatment of pediatric medulloblastoma is associated with known neurocognitive deficits that we hypothesize are caused by microstructural damage to frontal white matter (WM). Methods Longitudinal MRI examinations were collected from baseline (after surgery but before therapy) to 36 months in 146 patients and at 3 time points in 72 controls. Regional analyses of frontal WM volume and diffusion tensor imaging metrics were performed and verified with tract-based spatial statistics. Age-adjusted, linear mixed-effects models were used to compare patient and control images and to associate imaging changes with Woodcock-Johnson Tests of Cognitive Abilities. Results At baseline, WM volumes in patients were similar to those in controls; fractional anisotropy (FA) was lower bilaterally (P < 0.001) and was associated with decreased Processing Speed (P = 0.014) and Broad Attention (P = 0.025) performance at 36 months. During follow-up, WM volumes increased in controls but decreased in patients (P < 0.001) bilaterally. Smaller WM volumes in patients at 36 months were associated with concurrent decreased Working Memory (P = 0.026) performance. Conclusions Lower FA in patients with pediatric medulloblastoma compared with age-similar controls indicated that patients suffer substantial acute microstructural damage to supratentorial frontal WM following surgery but before radiation therapy or chemotherapy. Additionally, this damage to the frontal WM was associated with decreased cognitive performance in executive function 36 months later. This early damage also likely contributed to posttherapeutic failure of age-appropriate WM development and to the known association between decreased WM volumes and decreased cognitive performance.

Both physiological and imaging approaches have led to often-disparate conclusions about the organization of taste information in gustatory cortex (GC). In this study, we used neuroanatomical and imaging approaches to delineate the likely area of insular cortex given to gustatory function and to characterize taste responses within this delineated area in female and male C57BL/6J mice. Anterograde tracers were injected into the taste thalamus (the medial parvicellular portion of the ventral posterior medial division, VPMpc) of mice and the thalamic terminal field was investigated across the cortex. Working within the delineated area, we used two-photon imaging to measure basic taste responses in >780 neurons in layer 2/3 located just posterior to the middle cerebral artery. A nonbiased, hierarchical cluster analysis revealed multiple clusters of cells responding best to either individual or combinations of taste stimuli. Taste quality was represented in the activity of taste-responsive cells; however, there was no apparent spatial organization of primary taste qualities in this region.SIGNIFICANCE STATEMENT Recent studies investigating taste coding within the gustatory cortex have reported highly segregated, taste-specific regions containing only narrowly tuned cells responding to a single taste separated by large non-taste-coding areas. However, focusing on the center of this area, we found a large number of taste responsive cells ranging from narrowly to broadly responsive with no apparent local spatial organization. Further, population analysis reveals that activity in the neuronal population in this area appears to be related to measures of taste quality or hedonics.

Development of reading skills is vulnerable to disruption in children treated for brain tumors. Interventions, remedial and prophylactic, are needed to mitigate reading and other learning difficulties faced by survivors. A functional magnetic resonance imaging (fMRI) study was conducted to investigate long-term effects of a prophylactic reading intervention administered during radiation therapy in children treated for medulloblastoma. The fMRI study included 19 reading-intervention (age 11.7 ± 0.6 years) and 21 standard-of-care (age 12.1 ± 0.6 years) medulloblastoma survivors, and 21 typically developing children (age 12.3 ± 0.6 years). The survivors were 2.5 [1.2, 5.4] years after completion of tumor therapies and reading-intervention survivors were 2.9 [1.6, 5.9] years after intervention. Five fMRI tasks (Rapid Automatized Naming, Continuous Performance Test using faces and letters, orthographic and phonological processing of letter pairs, implicit word reading, and story reading) were used to probe reading-related neural activation. Woodcock-Johnson Reading Fluency, Word Attack, and Sound Awareness subtests were used to evaluate reading abilities. At the time of fMRI, Sound Awareness scores were significantly higher in the reading-intervention group than in the standard-of-care group (p = 0.046). Brain activation during the fMRI tasks was detected in left inferior frontal, temporal, ventral occipitotemporal, and subcortical regions, and differed among the groups (p < 0.05, FWE). The pattern of group activation differences, across brain areas and tasks, was a normative trend in the reading-intervention group. Standardized reading scores and patterns of brain activation provide evidence of long-term effects of prophylactic reading intervention in children treated for medulloblastoma.

Survivors of childhood cancer are at an increased risk of developing subsequent neoplasms. In long-term survivors of childhood malignancies treated with and without cranial radiation therapy (CRT), undergoing unenhanced magnetic resonance imaging (MRI) of the brain, we estimated detection of intracranial neoplasms.To investigate neurocognitive outcomes, 219 survivors of childhood cancer underwent unenhanced screening MRI of the brain. Of the survivors, 164 had been treated for acute lymphoblastic leukemia (ALL) (125 received CRT) and 55 for Hodgkin lymphoma (HL) (none received CRT). MRI examinations were reviewed and systematically coded by a single neuroradiologist. Demographic and treatment characteristics were compared for survivors with and without subsequent neoplasms.Nineteen of the 219 survivors (8.7 %) had a total of 31 subsequent intracranial neoplasms identified by neuroimaging at a median time of 25 years (range 12-46 years) from diagnosis. All neoplasms occurred after CRT, except for a single vestibular schwannoma within the cervical radiation field in a HL survivor. The prevalence of subsequent neoplasms after CRT exposure was 14.4 % (18 of 125). By noncontrast MRI, intracranial neoplasms were most suggestive of meningiomas. Most patients presented with no specific, localizing neurological complaints. In addition to the schwannoma, six tumors were resected based on results of MRI screening, all of which were meningiomas on histologic review.Unenhanced brain MRI of long-term survivors of childhood cancer detected a substantial number of intracranial neoplasms. Screening for early detection of intracranial neoplasms among aging survivors of childhood cancer who received CRT should be evaluated.The high prevalence of incidentally detected subsequent intracranial neoplasms after CRT in long-term survivors of childhood cancer and the minimal symptoms reported by those with intracranial tumors in our study indicate that brain MRI screening of long-term survivors who received CRT may be warranted. Prospective studies of such screening are needed.

SWI is a powerful tool for imaging of the cerebral venous system. The SWI venous contrast is affected by blood flow, which may be altered in sickle cell disease. In this study, we characterized SWI venous contrast in patients with sickle cell disease and healthy control participants and examined the relationships among SWI venous contrast, and hematologic variables in the group with sickle cell disease.A retrospective review of MR imaging and hematologic variables from 21 patients with sickle cell disease and age- and sex-matched healthy control participants was performed. A Frangi vesselness filter was used to quantify the attenuation of visible veins from the SWI. The normalized visible venous volume was calculated for quantitative analysis of venous vessel conspicuity.The normalized visible venous volume was significantly lower in the group with sickle cell disease vs the control group (P.001). Normalized visible venous volume was not associated with hemoglobin, percent hemoglobin F, percent hemoglobin S, absolute reticulocyte count, or white blood cell count. A hypointense arterial signal on SWI was observed in 18 of the 21 patients with sickle cell disease and none of the 21 healthy control participants.This study demonstrates the variable and significantly lower normalized visible venous volume in patients with sickle cell disease compared with healthy control participants. Decreased venous contrast in sickle cell disease may reflect abnormal cerebral blood flow, volume, velocity, or oxygenation. Quantitative analysis of SWI contrast may be useful for investigation of cerebrovascular pathology in patients with sickle cell disease, and as a tool to monitor therapies. However, future studies are needed to elucidate physiologic mechanisms of decreased venous conspicuity in sickle cell disease.

Background Survivors of childhood brain tumors are at increased risk for neurocognitive impairments, including deficits in abilities supported by frontal brain regions. Catechol-O-methyltransferase (COMT) metabolizes dopamine in the prefrontal cortex, with the Met allele resulting in greater dopamine availability and better performance on frontally mediated tasks compared to the Val allele. Given the importance of identifying resiliency factors against the emergence of cognitive late effects, the current study examined the relationship between COMT genotype and working memory performance among childhood brain tumor survivors. Procedure Children treated for a brain tumor with conformal radiation therapy (N = 50; mean age at irradiation = 7.41 ± 3.41; mean age at assessment = 13.18 ± 2.88) were administered two computerized measures of working memory (self-ordered search verbal and object tasks). Buccal (cheek) swabs were used to provide tissue from which DNA was extracted. Results Findings revealed an association between COMT genotype and performance on the self-ordered verbal (P = 0.03) but not object task (P = 0.33). Better performance was found for the Met/Val group compared to either Met/Met or Val/Val. Conclusions COMT may indicate a potential resiliency factor against neurocognitive effects of cancer and its treatment; however, there is a need for replication with larger samples of childhood brain tumor survivors. Pediatr Blood Cancer 2014;61:40–45. © 2013 Wiley Periodicals, Inc.

Background Dexamethasone is used in acute lymphoblastic leukemia (ALL) treatment, though long-term impact on central nervous system (CNS) function is unclear. As glucocorticoids influence hippocampal function, we investigated memory networks in survivors of childhood ALL treated with dexamethasone or prednisone. Procedure Neurocognitive assessment and functional magnetic resonance imaging (fMRI) were conducted in 38 adult survivors randomly recruited from cohorts treated on one of two standard treatment protocols, which differed primarily in the glucocorticoid administered during continuation therapy (dexamethasone [n = 18] vs. prednisone [n = 20]). Groups did not differ in age at diagnosis, age at evaluation, or cumulative intravenous or intrathecal methotrexate exposure. Results Survivors treated with dexamethasone demonstrated lower performance on multiple memory-dependent measures, including story memory (P = 0.01) and word recognition (P = 0.04), compared to survivors treated with only prednisone. Dexamethasone treatment was associated with decreased fMRI activity in the left retrosplenial brain region (effect size = 1.3), though the small sample size limited statistical significance (P = 0.08). Story memory was associated with altered activation in left inferior frontal–temporal brain regions (P = 0.007). Conclusions Results from this pilot study suggest that adult survivors of ALL treated with dexamethasone are at increased risk for memory deficits and altered neural activity in specific brain regions and networks associated with memory function. Pediatr Blood Cancer 2013;60:1778–1784. © 2013 Wiley Periodicals, Inc.

Object Advances in brain imaging have allowed for more sophisticated mapping of crucial neural structures. Functional MRI (fMRI) measures local changes in blood oxygenation associated with changes in neural activity and is useful in mapping cortical activation. Applications of this imaging modality have generally been restricted to cooperative patients; however, fMRI has proven successful in localizing the motor cortex for neurosurgical planning in uncooperative children under sedation. The authors demonstrate that the use of fMRI to localize the visual cortex in sedated children can be safely and effectively performed, allowing for more accurate presurgical planning to spare visual structures. Methods Between 2007 and 2009, 11 children (age range 1–11 years) underwent fMRI for neurosurgical planning while under sedation. Blood oxygen level–dependent fMRI was performed to detect visual cortex activation during stimulation through closed eyelids. Visual stimulation was presented in block design with periods of flashing light alternated with darkness. Results Functional MRI was successful in identifying visual cortex in each of the 11 children tested. There were no complications with propofol sedation or the fMRI. All children suffered from epilepsy, 5 had brain tumors, and 1 had tuberous sclerosis. After fMRI was performed, 6 patients underwent surgery. Frameless stereotactic guidance was synchronized with fMRI data to design an approach to spare visual structures during resection. There were no cases where a false negative led to unexpected visual field deficits or other side effects of surgery. In 2 cases, the fMRI results demonstrated that the tracts were already disrupted: in one case from a prior tumor operation and in another from dysplasia. Conclusions Functional MRI for evaluation of visual pathways can be safely and reproducibly performed in young or uncooperative children under light sedation. Identification of primary visual cortex aids in presurgical planning to avoid vision loss in appropriately selected patients.

Cranial radiotherapy (CRT) is a known risk factor for neurocognitive impairment in survivors of childhood cancer and may increase risk for mild cognitive impairment and dementia in adulthood.We performed a cross-sectional evaluation of survivors of childhood acute lymphoblastic leukemia (ALL) treated with 18 Gy (n = 127) or 24 Gy (n = 138) CRT. Impairment (age-adjusted score1 standard deviation below expected mean, two-sided exact binomial test) on the Wechsler Memory Scale IV (WMS-IV) was measured. A subset of survivors (n = 85) completed structural and functional neuroimaging.Survivors who received 24 Gy, but not 18 Gy, CRT had impairment in immediate (impairment rate = 33.8%, 95% confidence interval [CI] = 25.9% to 42.4%; P.001) and delayed memory (impairment rate = 30.2%, 95% CI = 22.6% to 38.6%; P.001). The mean score for long-term narrative memory among survivors who received 24 Gy CRT was equivalent to that for individuals older than 69 years. Impaired immediate memory was associated with smaller right (P = .02) and left (P = .008) temporal lobe volumes, and impaired delayed memory was associated with thinner parietal and frontal cortices. Lower hippocampal volumes and increased functional magnetic resonance imaging activation were observed with memory impairment. Reduced cognitive status (Brief Cognitive Status Exam from the WMS-IV) was identified after 24 Gy (18.5%, 95% CI = 12.4% to 26.1%; P.001), but not 18 Gy (8.7%, 95% CI = 4.4% to 15.0%; P = .11), CRT, suggesting a dose-response effect. Employment rates were equivalent (63.8% for 24 Gy CRT and 63.0% for 18 Gy CRT).Adult survivors who received 24 Gy CRT had reduced cognitive status and memory, with reduced integrity in neuroanatomical regions essential in memory formation, consistent with early onset mild cognitive impairment.

Advantages of computerized assessment of neuropsychological functions include improved standardization and increased reliability of response time variables. Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) is a computerized battery developed for monitoring recovery following mild brain injuries that assesses attention, memory and processing speed. Despite evidence that core areas of deficit among cancer survivors are those assessed by ImPACT, it has not previously been used with this population. Twenty four childhood brain tumor (BT) survivors treated with conformal radiation therapy (mean age = 15.7 ± 1.6; mean age at irradiation = 9.8 ± 2.5), twenty solid tumor (ST) survivors treated without CNS-directed therapy (mean age = 16.2 ± 1.8) and twenty healthy siblings (mean age = 15.1 ± 1.6 years) were administered an age modified version of ImPACT. Additional computerized measures of working memory and recognition memory were administered. Univariate ANOVAs revealed group differences (p

Object Whereas diffuse intrinsic pontine gliomas generally have a short symptom duration and more cranial nerve involvement, focal brainstem gliomas are commonly low grade, with fewer cranial neuropathies. Although these phenotypic distinctions are not absolute predictors of outcome, they do demonstrate correlation in most cases. Because there is a limited literature on focal brainstem gliomas in pediatric patients, the objective of this paper was to report the management and outcome of these tumors. Methods The authors reviewed the records of all children diagnosed with radiographically confirmed low-grade focal brainstem gliomas from 1986 to 2010. Each patient underwent biopsy or resection for tissue diagnosis. Event-free survival (EFS) and overall survival were evaluated. Univariate analysis was conducted to identify demographic and treatment variables that may affect EFS. Results Fifty-two patients (20 girls, 32 boys) with follow-up data were identified. Median follow-up was 10.0 years, and the median age at diagnosis was 6.5 years (range 1–17 years). The tumor locations were midbrain (n = 22, 42%), pons (n = 15, 29%), and medulla (n = 15, 29%). Surgical extirpation was the primary treatment in 25 patients (48%). The 5- and 10-year EFS and overall survival were 59%/98% and 52%/90%, respectively. An event or treatment failure occurred in 24 patients (46%), including 5 deaths. Median time to treatment failure was 3.4 years. Disease progression in the other 19 patients transpired within 25.1 months of diagnosis. Thirteen of these patients received radiation, including 11 within 2 months of primary treatment failure. Although children with intrinsic tumors had slightly better EFS at 5 years compared with those with exophytic tumors (p = 0.054), this difference was not significant at 10 years (p = 0.147). No other variables were predictive of EFS. Conclusions Surgery suffices in many children with low-grade focal brainstem gliomas. Radiation treatment is often reserved for disease progression but offers comparable disease control following biopsy. In the authors' experience, combining an assessment of clinical course, imaging, and tumor biopsy yields a reasonable model for managing children with focal brainstem tumors.

Childhood brain tumor survivors are at increased risk for neurocognitive impairments, including working memory (WM) problems. WM is typically assessed using performance measures. Little is known about the value of parent ratings for identifying WM difficulties, the relationship between rater and performance measures, or predictors of parent-reported WM problems in this population. Accordingly, the current study examined the utility of parent report in detecting WM difficulties among childhood brain tumor survivors treated with conformal radiation therapy (n= 50) relative to siblings (n= 40) and solid tumor survivors not receiving central nervous system-directed therapy (n= 40). Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). Participants were administered WM measures (digit span, self-ordered search tasks). Findings revealed parents rated brain tumor survivors as having significantly more WM problems (p< .01) compared to controls. However, the BRIEF-WM scale demonstrated poor sensitivity and specificity for detecting performance-based problems. Significant, albeit modest, correlations were found between the BRIEF-WM scale and performance measures (r= −.24–.22;p< .05) for the combined group. Age at testing, socioeconomic status, and IQ were significant predictors of parent reported WM problems. Rater and performance measures offer complimentary yet different information in assessing WM, which reiterates the importance of using both within the context of clinical assessment. (JINS, 2013,19, 1–10)

Imaging descriptions of posterior fossa ependymoma in children have focused on magnetic resonance imaging (MRI) signal and local anatomic relationships with imaging location only recently used to classify these neoplasms. We developed a quantitative method for analyzing the location of ependymoma in the posterior fossa, tested its effectiveness in distinguishing groups of tumors, and examined potential associations of distinct tumor groups with treatment and prognostic factors. Pre-operative MRI examinations of the brain for 38 children with histopathologically proven posterior fossa ependymoma were analyzed. Tumor margin contours and anatomic landmarks were manually marked and used to calculate the centroid of each tumor. Landmarks were used to calculate a transformation to align, scale, and rotate each patient’s image coordinates to a common coordinate space. Hierarchical cluster analysis of the location and morphological variables was performed to detect multivariate patterns in tumor characteristics. The ependymomas were also characterized as “central” or “lateral” based on published radiological criteria. Therapeutic details and demographic, recurrence, and survival information were obtained from medical records and analyzed with the tumor location and morphology to identify prognostic tumor characteristics. Cluster analysis yielded two distinct tumor groups based on centroid location The cluster groups were associated with differences in PFS (p = .044), “central” vs. “lateral” radiological designation (p = .035), and marginally associated with multiple operative interventions (p = .064). Posterior fossa ependymoma can be objectively classified based on quantitative analysis of tumor location, and these classifications are associated with prognostic and treatment factors.

Increased understanding of the underlying mechanisms of cognitive remediation is needed to facilitate development of intervention strategies for childhood cancer survivors experiencing cognitive late effects. Accordingly, a pilot functional magnetic resonance imaging (fMRI) study was conducted with 14 cancer survivors (12.02 ± 0.09 years old), who participated in a cognitive remediation clinical trial, and 28 healthy children (12.7 ± 0.6 years old). The ventral visual areas, cerebellum, supplementary motor area, and left inferior frontal cortex were significantly activated in the healthy participants during a continuous performance task. In survivors, brain activation in these regions was diminished at baseline, and increased upon completion of remediation and at a 6-month follow-up. The fMRI activation index for each region of interest was inversely associated with the Conners' Clinical Competence Index (p

Children treated for posterior fossa tumors experience reduced cognitive processing speed and, after imaging, show damage to white matter (WM) tracts in the brain. This study explores relationships between white matter microstructure, assessed by fractional anisotropy (FA), and speed of cognitive processing using tract-based spatial statistics (TBSS). At 36 months after treatment with radiotherapy and chemotherapy, 40 patients completed an MRI examination and neuropsychological evaluation. Patients were matched with healthy control subjects based on age, sex, and race. Individual FA values were extracted from examinations for all voxels identified as having significant association between processing speed and FA using TBSS. The regions were labeled anatomically, and fiber tracts were grouped into larger fiber bundle categories based on their anatomical and functional associations. Analyses were performed between mean skeletal FA values in each of the fiber bundles and each of the cognitive processing scores controlling for age. Children 3 years after treatment for posterior fossa brain tumors demonstrate significantly lower processing speed associated with decreased FA, compared with their healthy peers. Commissural fibers in the corpus callosum were negatively affected by disease and therapy with detrimental consequence on patients' cognitive processing. Diffusion tensor imaging of the white matter tracts in the brain is relevant to determining potential mechanisms underlying clinically meaningful change in cognitive performance. Neuroprotective strategies are needed to preserve critical functions.

Purpose To characterize therapy-induced changes in normal-appearing brainstems of childhood brain tumor patients by serial diffusion tensor imaging (DTI). Methods and Materials We analyzed 109 DTI studies from 20 brain tumor patients, aged 4 to 23 years, with normal-appearing brainstems included in the treatment fields. Those with medulloblastomas, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors ( n = 10) received postoperative craniospinal irradiation (23.4–39.6 Gy) and a cumulative dose of 55.8 Gy to the primary site, followed by four cycles of high-dose chemotherapy. Patients with high-grade gliomas ( n = 10) received erlotinib during and after irradiation (54–59.4 Gy). Parametric maps of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were computed and spatially registered to three-dimensional radiation dose data. Volumes of interest included corticospinal tracts, medial lemnisci, and the pons. Serving as an age-related benchmark for comparison, 37 DTI studies from 20 healthy volunteers, aged 6 to 25 years, were included in the analysis. Results The median DTI follow-up time was 3.5 years (range, 1.6–5.0 years). The median mean dose to the pons was 56 Gy (range, 7–59 Gy). Three patterns were seen in longitudinal FA and apparent diffusion coefficient changes: ( 1 ) a stable or normal developing time trend, ( 2 ) initial deviation from normal with subsequent recovery, and ( 3 ) progressive deviation without evidence of complete recovery. The maximal decline in FA often occurred 1.5 to 3.5 years after the start of radiation therapy. A full recovery time trend could be observed within 4 years. Patients with incomplete recovery often had a larger decline in FA within the first year. Radiation dose alone did not predict long-term recovery patterns. Conclusions Variations existed among individual patients after therapy in longitudinal evolution of brainstem white matter injury and recovery. Early response in brainstem anisotropy may serve as an indicator of the recovery time trend over 5 years after radiation therapy.

Object Thalamopeduncular tumors arise at the junction of the inferior thalamus and cerebral peduncle and present with a common clinical syndrome of progressive spastic hemiparesis. Pathologically, these lesions are usually juvenile pilocytic astrocytomas and are best treated with resection with the intent to cure. The goals of this study are to define a common clinical syndrome produced by thalamopeduncular tumors and to discuss imaging characteristics as well as surgical adjuncts, intraoperative nuances, and postoperative complications relating to the resection of these neoplasms. Methods The authors present a retrospective review of their experience with 10 children presenting between 3 and 15 years of age with a thalamopeduncular syndrome. Formal preoperative MR imaging was obtained in all patients, and diffusion tensor (DT) imaging was performed in 9 patients. Postoperative MR imaging was obtained to evaluate the extent of tumor resection. A prospective analysis of clinical outcomes was then conducted by the senior author. Results Pilocytic astrocytoma was the pathological diagnosis in 9 cases, and the other was fibrillary astrocytoma. Seven of 9 pilocytic astrocytomas were completely resected. Radical surgery was avoided in 1 child after DT imaging revealed that the corticospinal tract (CST) coursed through the center of the tumor, consistent with the infiltrative nature of fibrillary astrocytoma as identified by stereotactic biopsy. In 8 patients, tractography served as an important adjunct for designing a surgical approach that spared the CST. In 6 cases the CSTs were pushed anterolaterally, making a transsylvian approach a poor choice, as was evidenced by the first patient in the series, who underwent operation prior to the advent of tractography, and who awoke with a dense contralateral hemiparesis. Thus, subsequent patients with this deviation pattern underwent a transcortical approach via the middle temporal gyrus. One patient exhibited medial deviation of the tracts and another had lateral deviation, facilitating a transtemporal and a transfrontal approach, respectively. Conclusions The thalamopeduncular syndrome of progressive spastic hemiparesis presenting in children with or without symptoms of headache should alert the examiner to the possibility of a tumoral involvement of CSTs. Preoperative tractography is a useful adjunct to surgical planning in tumors that displace motor pathways. Gross-total resection of pilocytic astrocytomas usually results in cure, and therefore should be entertained when developing a treatment strategy for thalamopeduncular tumors of childhood.

Object In this study, the authors examined whether passive range of motion (ROM) under conscious sedation could be used to localize sensorimotor cortex using functional MR (fMR) imaging in children as part of their presurgical evaluation. Methods After obtaining institutional review board approval (for retrospective analysis of imaging data acquired for clinical purposes) and informed consent, 16 children underwent fMR imaging. All 16 had lesions; masses were found in 9 patients and cortical dysplasia was found in 4; the lesions in 3 patients were not diagnosed. Passive ROM was performed during blood oxygen level–dependent MR imaging sequences. Three of the patients also performed active motor tasks during the fMR imaging study. All patients were evaluated using passive ROM of the hand and/or foot; 3 patients were evaluated for passive touch of the face. In 9 cases, intraoperative electrocorticography (ECoG) was used. Five of the patients underwent intraoperative ECoG to evaluate for seizure activity. Four patients had intraoperative ECoG for motor mapping. Five of the patients had subdural grids placed for extraoperative monitoring. Results In 3 cases, the active and passive ROMs colocalized. In 4 patients ECoG was used to identify motor cortex, and in all 4 motor ECoG yielded results consistent with the passive ROM localization. Thirteen of 16 children have undergone resection based on passive ROM fMR imaging findings with no unanticipated deficits. Conclusions These preliminary data suggest that passive ROM fMR imaging can accurately detect functional hand, leg, and face regions of the sensorimotor cortex in the sedated child. This extends current extraoperative mapping capabilities to patients unable or unwilling to cooperate for active motor tasks.

In this work, we investigate the effectiveness of fusing two novel texture features along with intensity in multimodal magnetic resonance (MR) images for pediatric brain tumor segmentation and classification. One of the two texture features involves our Piecewise-Triangular-Prism-Surface-Area (PTPSA) algorithm for fractal feature extraction. The other texture feature exploits our novel fractional Brownian motion (fBm) framework that combines both fractal and wavelet analyses for fractalwavelet feature extraction. We exploit three MR image modalities such as T1 (gadolinium-enhanced), T2 and FLuid-Attenuated Inversion-Recovery (FLAIR), respectively. The extracted features from these multimodality MR images are fused using Self-Organizing Map (SOM). For a total of 204 T1 contrast-enhanced, T2 and FLAIR MR images obtained from nine different pediatric patients, our successful tumor segmentation is 100%. Our experimental results suggest that the fusion of fractal, fractalwavelet and intensity features in multimodality MR images offers better tumor segmentation results when compared to that of just fractal and intensity features in single modality MR images. Next, we exploit a multi-layer feedforward neural network with automated Bayesian regularization to classify the tumor regions from non-tumor regions. The Receiver Operating Characteristic (ROC) curves are obtained to evaluate tumor classification performance. The ROC suggests that at a threshold value of 0.7, the True Positive Fraction (TPF) values range from 75% to 100% for different patients, with the average value of 90%.

Background Changes in cerebral perfusion are an important feature of the pathophysiology of sickle cell anemia (SCA); cerebrovascular ischemia occurs frequently and leads to neurocognitive deficits, silent infarcts, and overt stroke. Non-invasive MRI methods to measure cerebral blood flow (CBF) by arterial spin labeling (ASL) afford new opportunities to characterize disease- and therapy-induced changes in cerebral hemodynamics in patients with SCA. Recent studies have documented elevated gray matter (GM) CBF in untreated children with SCA, but no measurements of white matter (WM) CBF have been reported. Procedures Pulsed ASL with automated brain image segmentation-classification techniques were used to determine the CBF in GM, WM, and abnormal white matter (ABWM) of 21 children with SCA, 18 of whom were receiving hydroxyurea therapy. Results GM and WM CBF were highly associated (R2 = 0.76, P