Insult to Short-Range White Matter Connectivity in Childhood Brain Tumor Survivors.

PURPOSE: Children treated for brain tumors are at an increased risk for cognitive impairments due to the effect of radiation therapy on developing white matter (WM). Although damage to long-range WM is well documented in pediatric brain tumor survivors, the effect of radiation therapy on short-range WM remains unelucidated. We sought to clarify whether radiation treatment affects short-range WM by completing a virtual dissection of these connections and comparing their microstructural properties between brain tumor survivors and typically developing children. METHODS AND MATERIALS: T1-weighted and diffusion-weighted magnetic resonance images were acquired for 26 brain tumor survivors and 26 typically developing children. Short-range WM was delineated using a novel, whole-brain approach. A random forest classifier was used to identify short-range connections with the largest differences in microstructure between patients and typically developing children. RESULTS: The random forest classifier identified differences in short-range WM microstructure across the brain with an accuracy of 87.5%. Nine connections showed the largest differences in short-range WM between patients and typically developing children. For these connections, fractional anisotropy and axial diffusivity were significantly lower in patients. Short-range connections in the posterior fossa were disproportionately affected, suggesting that greater radiation exposure to the posterior fossa was more injurious to short-range WM. Lower craniospinal radiation dose did not predict reduced toxicity to short-range WM. CONCLUSIONS: Our findings indicate that treatment for medulloblastoma resulted in changes in short-range WM in patients. Lower fractional anisotropy and axial diffusivity may reflect altered microstructural organization and coherence of these connections, especially in the posterior fossa. Short-range WM may be especially sensitive to the effect of craniospinal radiation therapy, resulting in compromise to these connections regardless of dose.

Abnormalities of structural brain connectivity in pediatric brain tumor survivors.

Background: Pediatric brain tumor survivors are at an increased risk for white matter (WM) injury. However, damage to whole-brain structural connectivity is unelucidated. The impact of treatment on WM connectivity was investigated. Methods: Whole-brain WM networks were derived from diffusion tensor imaging data acquired for 28 irradiated patients (radiotherapy, RT) (mean age = 13.74 ± 3.32 years), 13 patients not irradiated (No RT) (mean age = 12.57 ± 2.87), and 41 typically developing children (TDC) (mean age = 13.32 ± 2.92 years). Differences in network properties were analyzed using robust regressions. Results: Participation coefficient was lower in both patient groups (RT: adj. P = .015; No RT: adj. P = .042). Compared to TDC, RT had greater clustering (adj. P = .015), local efficiency (adj. P = .003), and modularity (adj. P = .000003). WM traced from hubs was damaged in patients: left hemisphere pericallosal sulcus (FA [F = 4.97; q < 0.01]; MD [F = 11.02; q < 0.0001]; AD [F = 10.00; q < 0.0001]; RD [F = 8.53; q < 0.0001]), right hemisphere pericallosal sulcus (FA [F = 8.87; q < 0.0001]; RD [F = 8.27; q < 0.001]), and right hemisphere parietooccipital sulcus (MD [F = 5.78; q < 0.05]; RD [F = 5.12; q < 0.05]). Conclusions: Findings indicate greater segregation of WM networks after RT. Intermodular connectivity was lower after treatment with and without RT. No significant network differences were observed between patient groups. Our results are discussed in the context of a network approach that emphasizes interactions between brain regions.

Structural connectivity and intelligence in brain-injured children.

In children, higher general intelligence corresponds with better processing speed ability. However, the relationship between structural brain connectivity and processing speed in the context of intelligence is unclear. Furthermore, the impact of brain injury on this relationship is also unknown. Structural networks were constructed for 36 brain tumor patients (mean age: 13.45 ± 2.73, 58% males) and 35 typically developing children (13.30 ± 2.86, 51% males). Processing speed and general intelligence scores were acquired using standard batteries. The relationship between network properties, processing speed, and intelligence was assessed using a partial least squares analysis. Results indicated that structural networks in brain-injured children were less integrated (ß = -.38, p = 0.001) and more segregated (ß = 0.4, p = 0.0005) compared to typically developing children. There was an indirect effect of network segregation on general intelligence via processing speed, where greater network segregation predicted slower processing speed which in turn predicted worse general intelligence (GoF = 0.37). These findings provide the first evidence of relations between structural connectivity, processing speed, and intelligence in children. Injury-related disruption to the structural network may result in worse intelligence through impacts on information processing. Our findings are discussed in the context of a network approach to understanding brain-behavior relationships.

Magnetic Resonance Imaging Findings Are Associated with Long-Term Global Neurological Function or Death after Traumatic Brain Injury in Critically Ill Children.

The identification of children with traumatic brain injury (TBI) who are at risk of death or poor global neurological functional outcome remains a challenge. Magnetic resonance imaging (MRI) can detect several brain pathologies that are a result of TBI; however, the types and locations of pathology that are the most predictive remain to be determined. Forty-two critically ill children with TBI were recruited prospectively from pediatric intensive care units at five Canadian children's hospitals. Pathologies detected on subacute phase MRIs included cerebral hematoma, herniation, cerebral laceration, cerebral edema, midline shift, and the presence and location of cerebral contusion or diffuse axonal injury (DAI) in 28 regions of interest were assessed. Global functional outcome or death more than 12 months post-injury was assessed using the Pediatric Cerebral Performance Category score. Linear modeling was employed to evaluate the utility of an MRI composite score for predicting long-term global neurological function or death after injury, and nonlinear Random Forest modeling was used to identify which MRI features have the most predictive utility. A linear predictive model of favorable versus unfavorable long-term outcomes was significantly improved when an MRI composite score was added to clinical variables. Nonlinear Random Forest modeling identified five MRI variables as stable predictors of poor outcomes: presence of herniation, DAI in the parietal lobe, DAI in the subcortical white matter, DAI in the posterior corpus callosum, and cerebral contusion in the anterior temporal lobe. Clinical MRI has prognostic value to identify children with TBI at risk of long-term unfavorable outcomes.

Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin.

We asked whether pharmacological stimulation of endogenous neural precursor cells (NPCs) may promote cognitive recovery and brain repair, focusing on the drug metformin, in parallel rodent and human studies of radiation injury. In the rodent cranial radiation model, we found that metformin enhanced the recovery of NPCs in the dentate gyrus, with sex-dependent effects on neurogenesis and cognition. A pilot double-blind, placebo-controlled crossover trial was conducted (ClinicalTrials.gov, NCT02040376) in survivors of pediatric brain tumors who had been treated with cranial radiation. Safety, feasibility, cognitive tests and MRI measures of white matter and the hippocampus were evaluated as endpoints. Twenty-four participants consented and were randomly assigned to complete 12-week cycles of metformin (A) and placebo (B) in either an AB or BA sequence with a 10-week washout period at crossover. Blood draws were conducted to monitor safety. Feasibility was assessed as recruitment rate, medication adherence and procedural adherence. Linear mixed modeling was used to examine cognitive and MRI outcomes as a function of cycle, sequence and treatment. We found no clinically relevant safety concerns and no serious adverse events associated with metformin. Sequence effects were observed for all cognitive outcomes in our linear mixed models. For the subset of participants with complete data in cycle 1, metformin was associated with better performance than placebo on tests of declarative and working memory. We present evidence that a clinical trial examining the effects of metformin on cognition and brain structure is feasible in long-term survivors of pediatric brain tumors and that metformin is safe to use and tolerable in this population. This pilot trial was not intended to test the efficacy of metformin for cognitive recovery and brain growth, but the preliminary results are encouraging and warrant further investigation in a large multicenter phase 3 trial.

Eye Movements and White Matter are Associated with Emotional Control in Children Treated for Brain Tumors.

OBJECTIVE: Children treated for brain tumors often experience social and emotional difficulties, including challenges with emotion regulation; our goal was to investigate the attention-related component processes of emotion regulation, using a novel eye-tracking measure, and to evaluate its relations with emotional functioning and white matter (WM) organization. METHOD: Fifty-four children participated in this study; 36 children treated for posterior fossa tumors, and 18 typically developing children. Participants completed two versions of an emotion regulation eye-tracking task, designed to differentiate between implicit (i.e., automatic) and explicit (i.e., voluntary) subprocesses. The Emotional Control scale from the Behavior Rating Inventory of Executive Function was used to evaluate emotional control in daily life, and WM organization was assessed with diffusion tensor imaging. RESULTS: We found that emotional faces captured attention across all groups (F(1,51) = 32.18, p < .001, η2p = .39). However, unlike typically developing children, patients were unable to override the attentional capture of emotional faces when instructed to (emotional face-by-group interaction: F(2,51) = 5.58, p = .006, η2p = .18). Across all children, our eye-tracking measure of emotion regulation was modestly associated with the parent-report emotional control score (r = .29, p = .045), and in patients it was associated with WM microstructure in the body and splenium of the corpus callosum (all t > 3.03, all p < .05). CONCLUSIONS: Our findings suggest that an attention-related component process of emotion regulation is disrupted in children treated for brain tumors, and that it may relate to their emotional difficulties and WM organization. This work provides a foundation for future theoretical and mechanistic investigations of emotional difficulties in brain tumor survivors.

Facial emotion recognition in children treated for posterior fossa tumours and typically developing children: A divergence of predictors.

Facial emotion recognition (FER) deficits are evident and pervasive across neurodevelopmental, psychiatric, and acquired brain disorders in children, including children treated for brain tumours. Such deficits are thought to perpetuate challenges with social relationships and decrease quality of life. The present study combined eye-tracking, neuroimaging and cognitive assessments to evaluate if visual attention, brain structure, and general cognitive function contribute to FER in children treated for posterior fossa (PF) tumours (patients: n = 36) and typically developing children (controls: n = 18). To assess FER, all participants completed the Diagnostic Analysis of Nonverbal Accuracy (DANVA2), a computerized task that measures FER using photographs, while their eye-movements were recorded. Patients made more FER errors than controls (p < .01). Although we detected subtle deficits in visual attention and general cognitive function in patients, we found no associations with FER. Compared to controls, patients had evidence of white matter (WM) damage, (i.e., lower fractional anisotropy [FA] and higher radial diffusivity [RD]), in multiple regions throughout the brain (all p < .05), but not in specific WM tracts associated with FER. Despite the distributed WM differences between groups, WM predicted FER in controls only. In patients, factors associated with their disease and treatment predicted FER. Our study provides insight into predictors of FER that may be unique to children treated for PF tumours, and highlights a divergence in associations between brain structure and behavioural outcomes in clinical and typically developing populations; a concept that may be broadly applicable to other neurodevelopmental and clinical populations that experience FER deficits.

PPAR and GST polymorphisms may predict changes in intellectual functioning in medulloblastoma survivors.

PURPOSE: Advances in the treatment of pediatric medulloblastoma have led to improved survival rates, though treatment-related toxicity leaves children with significant long-term deficits. There is significant variability in the cognitive outcome of medulloblastoma survivors, and it has been suggested that this variability may be attributable to genetic factors. The aim of this study was to explore the contributions of single nucleotide polymorphisms (SNPs) in two genes, peroxisome proliferator activated receptor (PPAR) and glutathione-S-transferase (GST), to changes in general intellectual functioning in medulloblastoma survivors. METHODS: Patients (n = 44, meanage = 6.71 years, 61.3% males) were selected on the basis of available tissue samples and neurocognitive measures. Patients received surgical tumor resection, craniospinal radiation, radiation boost to the tumor site, and multiagent chemotherapy. Genotyping analyses were completed using the Illumina Human Omni2.5 BeadChip, and 41 single nucleotide polymorphisms (SNPs) were assessed across both genes. We used a machine learning algorithm to identify polymorphisms that were significantly associated with declines in general intellectual functioning following treatment for medulloblastoma. RESULTS: We identified age at diagnosis, radiation therapy, chemotherapy, and eight SNPs associated with PPARs as predictors of general intellectual functioning. Of the eight SNPs identified, PPARα (rs6008197), PPARγ (rs13306747), and PPARδ (rs3734254) were most significantly associated with long-term changes in general intellectual functioning in medulloblastoma survivors. CONCLUSIONS: PPAR polymorphisms may predict intellectual outcome changes in children treated for medulloblastoma. Importantly, emerging evidence suggests that PPAR agonists may provide an opportunity to minimize the effects of treatment-related cognitive sequelae in these children.

Development of short-range white matter in healthy children and adolescents.

Neural communication is facilitated by intricate networks of white matter (WM) comprised of both long and short range connections. The maturation of long range WM connections has been extensively characterized, with projection, commissural, and association tracts showing unique trajectories with age. There, however, remains a limited understanding of age-related changes occurring within short range WM connections, or U-fibers. These connections are important for local connectivity within lobes and facilitate regional cortical function and greater network economy. Recent studies have explored the maturation of U-fibers primarily using cross-sectional study designs. Here, we analyzed diffusion tensor imaging (DTI) data for healthy children and adolescents in both a cross-sectional (n = 78; mean age = 13.04 ± 3.27 years) and a primarily longitudinal (n = 26; mean age = 10.78 ± 2.69 years) cohort. We found significant age-related differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) across the frontal, parietal, and temporal lobes of participants within the cross-sectional cohort. By contrast, we report significant age-related differences in only FA for participants within the longitudinal cohort. Specifically, larger FA values were observed with age in frontal, parietal, and temporal lobes of the left hemisphere. Our results extend previous findings restricted to long range WM to demonstrate regional changes in the microstructure of short range WM during childhood and adolescence. These changes possibly reflect continued myelination and axonal organization of short range WM with increasing age in more anterior regions of the left hemisphere. Hum Brain Mapp 39:204-217, 2018. © 2017 Wiley Periodicals, Inc.