Optimizing an exercise training program in pediatric brain tumour survivors: Does timing postradiotherapy matter?

Background: While exercise training (ET) programs show positive outcomes in cognition, motor function, and physical fitness in pediatric brain tumor (PBT) survivors, little is known about the optimal timing of intervention. The aim of this work was to explore the feasibility and benefits of ET based on its timing after radiotherapy. Methods: This retrospective analysis (ClinicalTrials.gov, NCT01944761) analyzed data based on the timing of PBT survivors' participation in an ET program relative to their completion of radiotherapy: <2 years (n = 9), 2-5 years (n = 10), and > 5 years (n = 13). We used repeated measures analysis of variance to compare feasibility and efficacy indicators among groups, as well as correlation analysis between ET program timing postradiotherapy and preliminary treatment effects on cognition, motor function and physical fitness outcomes. Results: Two to five years postradiotherapy was the optimal time period in terms of adherence (88.5%), retention (100%), and satisfaction (more fun, more enjoyable and recommend it more to other children). However, the benefits of ET program on memory recognition (r = -0.379, P = .047) and accuracy (r = -0.430, P = .032) decreased with increased time postradiotherapy. Motor function improved in all groups, with greater improvements in bilateral coordination (P = .043) earlier postradiotherapy, and in running (P = .043) later postradiotherapy. The greatest improvement in pro-rated work rate occurred in the < 2-year group (P = .008). Conclusion: Participation in an ET program should be offered as part of routine postradiotherapy care in the first 1-2 years and strongly encouraged in the first 5 years.

Network connectivity underlying episodic memory in children: Application of a pediatric brain tumor survivor injury model.

Episodic memory involves personal experiences paired with their context. The Medial Temporal, Posterior Medial, Anterior Temporal, and Medial Prefrontal networks have been found to support the hippocampus in episodic memory in adults. However, there lacks a model that captures how the structural and functional connections of these networks interact to support episodic memory processing in children. Using diffusion-weighted imaging, magnetoencephalography, and memory tests, we quantified differences in white matter microstructure, neural communication, and episodic memory performance, respectively, of healthy children (n = 23) and children with reduced memory performance. Pediatric brain tumor survivors (PBTS; n = 24) were used as a model, as they exhibit reduced episodic memory and perturbations in white matter and neural communication. We observed that PBTS, compared to healthy controls, showed significantly (p < 0.05) (1) disrupted white matter microstructure between these episodic memory networks through lower fractional anisotropy and higher mean and axial diffusivity, (2) perturbed theta band (4-7 Hz) oscillatory synchronization in these same networks through higher weighted phase lag indices (wPLI), and (3) lower episodic memory performance in the Transverse Patterning and Children's Memory Scale (CMS) tasks. Using partial-least squares path modeling, we found that brain tumor treatment predicted network white matter damage, which predicted inter-network theta hypersynchrony and lower verbal learning (directly) and lower verbal recall (indirectly via theta hypersynchrony). Novel to the literature, our findings suggest that white matter modulates episodic memory through effect on oscillatory synchronization within relevant brain networks. RESEARCH HIGHLIGHTS: Investigates the relationship between structural and functional connectivity of episodic memory networks in healthy children and pediatric brain tumor survivors Pediatric brain tumor survivors demonstrate disrupted episodic memory, white matter microstructure and theta oscillatory synchronization compared to healthy children Findings suggest white matter microstructure modulates episodic memory through effects on oscillatory synchronization within relevant episodic memory networks.

Polygenic risk for depression and anterior and posterior hippocampal volume in children and adolescents.

BACKGROUND: Depression has frequently been associated with smaller hippocampal volume. The hippocampus varies in function along its anterior-posterior axis, with the anterior hippocampus more strongly associated with stress and emotion processing. The goals of this study were to examine the associations among parental history of anxiety/depression, polygenic risk scores for depression (PGS-DEP), and anterior and posterior hippocampal volumes in children and adolescents. To examine specificity to PGS-DEP, we examined associations of educational attainment polygenic scores (PGS-EA) with anterior and posterior hippocampal volume. METHODS: Participants were 350 3- to 21-year-olds (46 % female). PGS-DEP and PGS-EA were computed based on recent, large-scale genome-wide association studies. High-resolution, T1-weighted magnetic resonance imaging (MRI) data were acquired, and a semi-automated approach was used to segment the hippocampus into anterior and posterior subregions. RESULTS: Children and adolescents with higher polygenic risk for depression were more likely to have a parent with a history of anxiety/depression. Higher polygenic risk for depression was significantly associated with smaller anterior but not posterior hippocampal volume. PGS-EA was not associated with anterior or posterior hippocampal volumes. LIMITATIONS: Participants in these analyses were all of European ancestry. CONCLUSIONS: Polygenic risk for depression may lead to smaller anterior but not posterior hippocampal volume in children and adolescents, and there may be specificity of these effects to PGS-DEP rather than PGS-EA. These findings may inform the earlier identification of those in need of support and the design of more effective, personalized treatment strategies. DECLARATIONS OF INTEREST: none. DECLARATIONS OF INTEREST: None.

Delayed oculomotor response associates with optic neuritis in youth with demyelinating disorders.

INTRODUCTION: Impairment in visual and cognitive functions occur in youth with demyelinating disorders such as multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease. Quantitative behavioral assessment using eye-tracking and pupillometry can provide functional metrics for important prognostic and clinically relevant information at the bedside. METHODS: Children and adolescents diagnosed with demyelinating disorders and healthy, age-matched controls completed an interleaved pro- and anti-saccade task using video-based eye-tracking and underwent spectral-domain optical coherence tomography examination for evaluation of retinal nerve fiber layer and ganglion cell inner plexiform layer thickness. Low-contrast visual acuity and Symbol Digit Modalities Test were performed for visual and cognitive functional assessments. We assessed saccade and pupil parameters including saccade reaction time, direction error rate, pupil response latency, peak constriction time, and peak constriction and dilation velocities. Generalized Estimating Equations were used to examine the association of eye-tracking parameters with optic neuritis history, structural metrics, and visual and cognitive scores. RESULTS: The study included 36 demyelinating disorders patients, aged 8-18 yrs. (75% F; median = 15.22 yrs., SD = 2.8) and 34 age-matched controls (65% F; median = 15.26 yrs., SD = 2.3). Surprisingly, pro- and anti-saccade performance was comparable between patients and controls, whereas pupil control was altered in patients. Oculomotor latency measures were strongly associated with the number of optic neuritis episodes, including saccade reaction time, pupil response latency, and peak constriction time. Peak constriction time was associated with both retinal nerve fiber layer and ganglion cell inner plexiform layer thickness. Pupil response latency and peak constriction time were associated with visual acuity. Pupil velocity for both constriction and dilation was associated with Symbol Digit Modalities Test scores. CONCLUSION: The strong associations between oculomotor measures with history of optic neuritis, structural, visual, and cognitive assessments in these cohorts demonstrates that quantitative eye-tracking can be useful for probing demyelinating injury of the brain and optic nerve. Future studies should evaluate their utility in discriminating between demyelinating disorders and tracking disease progression.

Exercise promotes growth and rescues volume deficits in the hippocampus after cranial radiation in young mice.

Human and animal studies suggest that exercise promotes healthy brain development and function, including promoting hippocampal growth. Childhood cancer survivors that have received cranial radiotherapy exhibit hippocampal volume deficits and are at risk of impaired cognitive function, thus they may benefit from regular exercise. While morphological changes induced by exercise have been characterized using magnetic resonance imaging (MRI) in humans and animal models, evaluation of changes across the brain through development and following cranial radiation is lacking. In this study, we used high-resolution longitudinal MRI through development to evaluate the effects of exercise in a pediatric mouse model of cranial radiation. Female mice received whole-brain radiation (7 Gy) or sham radiation (0 Gy) at an infant equivalent age (P16). One week after irradiation, mice were housed in either a regular cage or a cage equipped with a running wheel. In vivo MRI was performed prior to irradiation, and at three subsequent timepoints to evaluate the effects of radiation and exercise. We used a linear mixed-effects model to assess volumetric and cortical thickness changes. Exercise caused substantial increases in the volumes of certain brain regions, notably the hippocampus in both irradiated and nonirradiated mice. Volume increases exceeded the deficits induced by cranial irradiation. The effect of exercise and irradiation on subregional hippocampal volumes was also characterized. In addition, we characterized cortical thickness changes across development and found that it peaked between P23 and P43, depending on the region. Exercise also induced regional alterations in cortical thickness after 3 weeks of voluntary exercise, while irradiation did not substantially alter cortical thickness. Our results show that exercise has the potential to alter neuroanatomical outcomes in both irradiated and nonirradiated mice. This supports ongoing research exploring exercise as a strategy for improving neurocognitive development for children, particularly those treated with cranial radiotherapy.

Sleep Differentially and Profoundly Impairs Recall Memory in a Patient with Fornix Damage.

In March 2020, C.T., a kind, bright, and friendly young woman underwent surgery for a midline tumor involving her septum pellucidum and extending down into her fornices bilaterally. Following tumor diagnosis and surgery, C.T. experienced significant memory deficits: C.T.'s family reported that she could remember things throughout the day, but when she woke up in the morning or following a nap, she would expect to be in the hospital, forgetting all the information that she had learned before sleep. The current study aimed to empirically validate C.T.'s pattern of memory loss and explore its neurological underpinnings. On two successive days, C.T. and age-matched controls watched an episode of a TV show and took a nap or stayed awake before completing a memory test. Although C.T. performed numerically worse than controls in both conditions, sleep profoundly exacerbated her memory impairment, such that she could not recall any details following a nap. This effect was replicated in a second testing session. High-resolution MRI scans showed evidence of the trans-callosal surgical approach's impact on the mid-anterior corpus callosum, indicated that C.T. had perturbed white matter particularly in the right fornix column, and demonstrated that C.T.'s hippocampal volumes did not differ from controls. These findings suggest that the fornix is important for processing episodic memories during sleep. As a key output pathway of the hippocampus, the fornix may ensure that specific memories are replayed during sleep, maintain the balance of sleep stages, or allow for the retrieval of memories following sleep.

Social affective outcomes and brain injury in children and adolescents treated for brain tumours.

In this Review we critically evaluate the empirical literature investigating the effect of paediatric brain tumours and their treatment on social affective function. We focus specifically on relations between social affective function and compromised brain structure and function associated with treatment for a paediatric brain tumour. We concentrate on emotion recognition and regulation, because these are core components of social affective function. First, we provide an overview of the literature in typically developing children and discuss the underlying brain networks thought to subserve emotion (ie, limbic system and supporting white matter microstructure). We then focus on how damage to brain structure and function after treatment for a paediatric brain tumour might be related to compromised emotion recognition and regulation-as well as broader social affective outcomes. On the basis of our review of the literature across typically developing children and those with a paediatric brain tumour, we suggest that structural changes to fronto-limbic tracts might interrupt social network neural communication in children and adolescents treated for brain tumours. A critical analysis of the reviewed literature suggests a relationship between social affective dysfunction and childhood-acquired injury to white matter microstructure. We argue that the knowledge synthesised regarding paediatric brain tumours could extend to other neurological disorders. Finally, we identify considerations for future investigation and recommend research practices to be adopted in forthcoming studies to establish causal links between brain structure and function to social affective processes.

Neurocognitive outcomes in pediatric brain tumors after treatment with proton versus photon radiation: a systematic review and meta-analysis.

BACKGROUND: Advances in cancer treatments, particularly the development of radiation therapy, have led to improvements in survival outcomes in children with brain tumors. However, radiation therapy is associated with significant long-term neurocognitive morbidity. The present systematic review and meta-analysis aimed to compare the neurocognitive outcomes of children and adolescents with brain tumors treated with photon radiation (XRT) or proton therapy (PBRT). METHODS: A systematic search was conducted (PubMed, Embase, Cochrane, and Web of Science from inception until 02/01/2022) for studies comparing the neurocognitive outcomes of children and adolescents with brain tumors treated with XRT vs. PBRT. The pooled mean differences (expressed as Z scores) were calculated using a random effects method for those endpoints analyzed by a minimum of three studies. RESULTS: Totally 10 studies (n = 630 patients, average age range: 1-20 years) met the inclusion criteria. Patients who had received PBRT achieved significantly higher scores (difference in Z scores ranging from 0.29-0.75, all P < 0.05 and significant in sensitivity analyses) after treatment than those who had received XRT for most analyzed neurocognitive outcomes (i.e., intelligence quotient, verbal comprehension and perceptual reasoning indices, visual motor integration, and verbal memory). No robust significant differences (P > 0.05 in main analyses or sensitivity analyses) were found for nonverbal memory, verbal working memory and working memory index, processing speed index, or focused attention. CONCLUSIONS: Pediatric brain tumor patients who receive PBRT achieve significantly higher scores on most neurocognitive outcomes than those who receive XRT. Larger studies with long-term follow-ups are needed to confirm these results.

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.

Magnetization transfer saturation reveals subclinical optic nerve injury in pediatric-onset multiple sclerosis.

BACKGROUND: The presence of subclinical optic nerve (ON) injury in youth living with pediatric-onset MS has not been fully elucidated. Magnetization transfer saturation (MTsat) is an advanced magnetic resonance imaging (MRI) parameter sensitive to myelin density and microstructural integrity, which can be applied to the study of the ON. OBJECTIVE: The objective of this study was to investigate the presence of subclinical ON abnormalities in pediatric-onset MS by means of magnetization transfer saturation and evaluate their association with other structural and functional parameters of visual pathway integrity. METHODS: Eleven youth living with pediatric-onset MS (ylPOMS) and no previous history of optic neuritis and 18 controls underwent standardized brain MRI, optical coherence tomography (OCT), Magnetoencephalography (MEG)-Visual Evoked Potentials (VEPs), and visual battery. Data were analyzed with mixed effect models. RESULTS: While ON volume, OCT parameters, occipital MEG-VEPs outcomes, and visual function did not differ significantly between ylPOMS and controls, ylPOMS had lower MTsat in the supratentorial normal appearing white matter (-0.26 nU, p = 0.0023), and in both in the ON (-0.62 nU, p < 0.001) and in the normal appearing white matter of the optic radiation (-0.56 nU, p = 0.00071), with these being positively correlated (+0.57 nU, p = 0.00037). CONCLUSIONS: Subclinical microstructural injury affects the ON of ylPOMS. This may appear as MTsat changes before being detectable by other currently available testing.

Preliminary Observations of Resting-State Magnetoencephalography in Nonmedicated Children with Obsessive-Compulsive Disorder.

Background: Cortico-striato-thalamo-cortical (CSTC) network alterations are hypothesized to contribute to symptoms of obsessive-compulsive disorder (OCD). To date, very few studies have examined whether CSTC network alterations are present in children with OCD, who are medication naive. Medication-naive pediatric imaging samples may be optimal to study neural correlates of illness and identify brain-based markers, given the proximity to illness onset. Methods: Magnetoencephalography (MEG) data were analyzed at rest, in 18 medication-naive children with OCD (M = 12.1 years ±2.0 standard deviation [SD]; 10 M/8 F) and 13 typically developing children (M = 12.3 years ±2.2 SD; 6 M/7 F). Whole-brain MEG-derived resting-state functional connectivity (rs-fc), for alpha- and gamma-band frequencies were compared between OCD and typically developing (control) groups. Results: Increased MEG-derived rs-fc across alpha- and gamma-band frequencies was found in the OCD group compared to the control group. Increased MEG-derived rs-fc at alpha-band frequencies was evident across a number of regions within the CSTC circuitry and beyond, including the cerebellum and limbic regions. Increased MEG-derived rs-fc at gamma-band frequencies was restricted to the frontal and temporal cortices. Conclusions: This MEG study provides preliminary evidence of altered alpha and gamma networks, at rest, in medication-naive children with OCD. These results support prior findings pointing to the relevance of CSTC circuitry in pediatric OCD and further support accumulating evidence of altered connectivity between regions that extend beyond this network, including the cerebellum and limbic regions. Given the substantial portion of children and youth whose OCD symptoms do not respond to conventional treatments, our findings have implications for future treatment innovation research aiming to target and track whether brain patterns associated with having OCD may change with treatment and/or predict treatment response.

Neural and cognitive function in a pediatric brain injury model: The impact of task complexity.

Acquired brain injury (ABI) in childhood/adolescence results in dysfunctional neural and attentional resources during minimal and higher task load. Impact of injury on these resources during increasing load, when task design (e.g., stimuli, timing) is held constant, is not yet well understood. We examined neural communication, processing speed and controlled attention in pediatric brain tumor survivors (PBTS; Mtime since treatment = 6.78 years) and typically developing children (TDC; n = 57). Participants performed simple-go and choice reaction time (RxnT) tasks during magnetoencephalography. The weighted phase lag index estimated seed-based and whole-brain functional connectivity. Group differences were assessed using tmax and network based statistics. Mean RxnT and response accuracy measured performance. Linear models assessed group differences. Tasks were analyzed individually to account for a difference in trial numbers. During both tasks, PBTS demonstrated decreased seed-based connectivity in the high gamma frequency (60-100 Hz; p < .01) relative to TDC. During the choice task alone, PBTS also demonstrated decreased theta (4-7 Hz) and alpha (8-12 Hz) seed-based connectivity (p < .01), and increased RxnT in adolescence (p < .05). ABI in childhood/adolescence may predominantly disrupt recruitment of neural and attentional resources necessary for higher load tasks. These findings advance understanding of the impact of task load on brain function and cognition during development, and effects of injury.

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.

Cross-translational models of late-onset cognitive sequelae and their treatment in pediatric brain tumor survivors.

Pediatric brain tumor treatments have a high success rate, but survivors are at risk of cognitive sequelae that impact long-term quality of life. We summarize recent clinical and animal model research addressing pathogenesis or evaluating candidate interventions for treatment-induced cognitive sequelae. Assayed interventions encompass a broad range of approaches, including modifications to radiotherapy, modulation of immune response, prevention of treatment-induced cell loss or promotion of cell renewal, manipulation of neuronal signaling, and lifestyle/environmental adjustments. We further emphasize the potential of neuroimaging as a key component of cross-translation to contextualize laboratory research within broader clinical findings. This cross-translational approach has the potential to accelerate discovery to improve pediatric cancer survivors' long-term quality of life.

Patterns of white and gray structural abnormality associated with paediatric demyelinating disorders.

The impact of multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) - associated disorders (MOGAD) on brain structure in youth remains poorly understood. Reductions in cortical mantle thickness on structural MRI and abnormal diffusion-based white matter metrics (e.g., diffusion tensor parameters) have been well documented in MS but not in MOGAD. Characterizing structural abnormalities found in children with these disorders can help clarify the differences and similarities in their impact on neuroanatomy. Importantly, while MS and MOGAD affect the entire CNS, the visual pathway is of particular interest in both groups, as most patients have evidence for clinical or subclinical involvement of the anterior visual pathway. Thus, the visual pathway is of key interest in analyses of structural abnormalities in these disorders and may distinguish MOGAD from MS patients. In this study we collected MRI data on 18 MS patients, 14 MOGAD patients and 26 age- and sex-matched typically developing children (TDC). Full-brain group differences in fixel diffusion measures (fibre-bundle populations) and cortical thickness measures were tested using age and sex as covariates. Visual pathway analysis was performed by extracting mean diffusion measures within lesion free optic radiations, cortical thickness within the visual cortex, and retinal nerve fibre layer (RNFL) and ganglion cell layer thickness measures from optical coherence tomography (OCT). Fixel based analysis (FBA) revealed MS patients have widespread abnormal white matter within the corticospinal tract, inferior longitudinal fasciculus, and optic radiations, while within MOGAD patients, non-lesional impact on white matter was found primarily in the right optic radiation. Cortical thickness measures were reduced predominately in the temporal and parietal lobes in MS patients and in frontal, cingulate and visual cortices in MOGAD patients. Additionally, our findings of associations between reduced RNFLT and axonal density in MOGAD and TORT in MS patients in the optic radiations imply widespread axonal and myelin damage in the visual pathway, respectively. Overall, our approach of combining FBA, cortical thickness and OCT measures has helped evaluate similarities and differences in brain structure in MS and MOGAD patients in comparison to TDC.

Impact of home-based cognitive or academic intervention on working memory and mathematics outcomes in pediatric brain tumor survivors: the Keys to Succeed pilot randomized controlled clinical trial.

Pediatric brain tumour survivors experience deficits in mathematics and working memory. An open question is whether it is most optimal to target direct cognitive skills (i.e. working memory) or focus on specific academic outcomes (i.e. mathematics) for in remediation. We conducted a pilot randomized controlled trial to determine the feasibility of comparing a working memory versus mathematics intervention. Pediatric brain tumor survivors (7-17 years) were randomly assigned to Cogmed or JumpMath interventions, or an Active Control/Reading group. All participants received Educational Liaison support and completed ~12-weeks of home-based intervention with weekly, telephone-based consultation in one of the three conditions. Standardized assessments of auditory and visual working memory, mathematics calculation and reasoning were completed pre- and post- intervention. Twenty-nine participants completed the interventions; 94% of parents reported a high degree of satisfaction with the interventions and ease of implementation. Participants in JumpMath demonstrated improved mathematics calculation from pre- to post- intervention (p=0.02). Further, participants in both Cogmed and JumpMath showed evidence of pre- to post- intervention improvements in auditory working memory relative to controls (p=0.01). The Cogmed group also showed improvements in visual working memory (p=0.03). Findings suggest that targeted intervention is feasible in survivors of pediatric brain tumors, though with a relatively low recruitment rate. With preliminary findings of improved calculation and working memory following JumpMath and working memory following Cogmed, this pilot trial lays the groundwork for future programs that investigate different inteCognitiveRehabilitationrventions that may be applied to target the unique needs of each survivor.

Hearing loss and intellectual outcome in children treated for embryonal brain tumors: Implications for young children treated with radiation sparing approaches.

PURPOSE: We investigate the impact of severe sensorineural hearing loss (SNHL) and for the first time evaluate the effect of unilateral versus bilateral SNHL on intellectual outcome in a cohort of children with embryonal brain tumors treated with and without radiation. METHODS: Data were from 94 childhood survivors of posterior fossa (PF) embryonal brain tumors who were treated with either: (1) chemotherapy alone (n = 16, 7.11 [3.41] years, 11M/5F), (2) standard-dose craniospinal irradiation (CSI) and/or large boost volumes (n = 44, 13.05 [3.26] years, 29M/15F), or (3) reduced-dose CSI with a boost restricted to the tumor bed (n = 34, 11.07 [3.80] years, 19M/15F). We compared intellectual outcome between children who: (1) did and did not develop SNHL and (2) developed unilateral versus bilateral SNHL. A Chang grade of ≥2b that required the use of a hearing aid was considered severe SNHL. Comparisons were made overall and within each treatment group separately. RESULTS: Patients who developed SNHL had lower full scale IQ (p = 0.007), verbal comprehension (p = 0.003), and working memory (p = 0.02) than patients without SNHL. No differences were observed between patients who had unilateral versus bilateral SNHL (all p > 0.05). Patients treated with chemotherapy alone who developed SNHL had lower mean working memory (p = 0.03) than patients who did not develop SNHL. Among patients treated with CSI, no IQ indices differed between those with and without SNHL (all p > 0.05). CONCLUSIONS: Children treated for embryonal brain tumors who develop severe SNHL have lower intellectual outcome than patients with preserved hearing: this association is especially profound in young children treated with radiation sparing approaches. We also demonstrate that intellectual outcome is similarly impaired in patients who develop unilateral versus bilateral SNHL. These findings suggest that early intervention to preserve hearing is critical.

Metformin effects on brain development following cranial irradiation in a mouse model.

BACKGROUND: Cranial radiation therapy (CRT) is a mainstay of treatment for malignant pediatric brain tumors and high-risk leukemia. Although CRT improves survival, it has been shown to disrupt normal brain development and result in cognitive impairments in cancer survivors. Animal studies suggest that there is potential to promote brain recovery after injury using metformin. Our aim was to evaluate whether metformin can restore brain volume outcomes in a mouse model of CRT. METHODS: C57BL/6J mice were irradiated with a whole-brain radiation dose of 7 Gy during infancy. Two weeks of metformin treatment started either on the day of or 3 days after irradiation. In vivo magnetic resonance imaging was performed prior to irradiation and at 3 subsequent time points to evaluate the effects of radiation and metformin on brain development. RESULTS: Widespread volume loss in the irradiated brain appeared within 1 week of irradiation with limited subsequent recovery in volume outcomes. In many structures, metformin administration starting on the day of irradiation exacerbated radiation-induced injury, particularly in male mice. Metformin treatment starting 3 days after irradiation improved brain volume outcomes in subcortical regions, the olfactory bulbs, and structures of the brainstem and cerebellum. CONCLUSIONS: Our results show that metformin treatment has the potential to improve neuroanatomical outcomes after CRT. However, both timing of metformin administration and subject sex affect structure outcomes, and metformin may also be deleterious. Our results highlight important considerations in determining the potential benefits of metformin treatment after CRT and emphasize the need for caution in repurposing metformin in clinical studies.

Visuomotor Activation of Inhibition-Processing in Pediatric Obsessive Compulsive Disorder: A Magnetoencephalography Study.

Background: Response inhibition engages the cortico-striato-thalamo-cortical (CSTC) circuit, which has been implicated in children, and youth with obsessive compulsive disorder (OCD). This study explored whether CSTC engagement during response inhibition, measured using magnetoencephalography (MEG), differed in a sample of medication-naïve youth with OCD, compared to typically developing controls (TDC). Methods: Data was analyzed in 17 medication-naïve children and youth with OCD (11.7 ± 2.2 SD years) and 13 TDC (12.6 ± 2.2 SD years). MEG was used to localize and characterize neural activity during a Go/No-Go task. Task performance on Go/No-Go conditions and regional differences in amplitude of activity during Go and No-Go condition between OCD vs. TDC were examined using two-sample t-tests. Post-hoc analysis with Bayesian t-tests was used to estimate the certainty of outcomes. Results: No differences in Go/No-Go performance were found between OCD and TDC groups. In response to the visual cue presented during the Go condition, participants with OCD showed significantly increased amplitude of activity in the primary motor (MI) cortex compared to TDC. In addition, significantly reduced amplitude of PCu was found following successful stopping to No-Go cues in OCD vs. TDC during No-Go task performance. Bayesian t-tests indicated high probability and large effect sizes for the differences in MI and PCu amplitude found between groups. Conclusion: Our preliminary study in a small medication-naïve sample extends previous work indicating intact response inhibition in pediatric OCD. While altered neural response in the current study was found during response inhibition performance in OCD, differences localized to regions outside of the CSTC. Our findings suggest that additional imaging research in medication-naïve samples is needed to clarify regional differences associated with OCD vs. influenced by medication effects, and suggest that MEG may be sensitive to detecting such differences.