Cancer neuroscience: State of the field, emerging directions.

The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, and promoting plasticity throughout life, the nervous system plays parallel roles in the regulation of cancers. Foundational discoveries have elucidated direct paracrine and electrochemical communication between neurons and cancer cells, as well as indirect interactions through neural effects on the immune system and stromal cells in the tumor microenvironment in a wide range of malignancies. Nervous system-cancer interactions can regulate oncogenesis, growth, invasion and metastatic spread, treatment resistance, stimulation of tumor-promoting inflammation, and impairment of anti-cancer immunity. Progress in cancer neuroscience may create an important new pillar of cancer therapy.

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.

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.

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.

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.

Activity-dependent myelination: A glial mechanism of oscillatory self-organization in large-scale brain networks.

Communication and oscillatory synchrony between distributed neural populations are believed to play a key role in multiple cognitive and neural functions. These interactions are mediated by long-range myelinated axonal fiber bundles, collectively termed as white matter. While traditionally considered to be static after development, white matter properties have been shown to change in an activity-dependent way through learning and behavior-a phenomenon known as white matter plasticity. In the central nervous system, this plasticity stems from oligodendroglia, which form myelin sheaths to regulate the conduction of nerve impulses across the brain, hence critically impacting neural communication. We here shift the focus from neural to glial contribution to brain synchronization and examine the impact of adaptive, activity-dependent changes in conduction velocity on the large-scale phase synchronization of neural oscillators. Using a network model based on primate large-scale white matter neuroanatomy, our computational and mathematical results show that such plasticity endows white matter with self-organizing properties, where conduction delay statistics are autonomously adjusted to ensure efficient neural communication. Our analysis shows that this mechanism stabilizes oscillatory neural activity across a wide range of connectivity gain and frequency bands, making phase-locked states more resilient to damage as reflected by diffuse decreases in connectivity. Critically, our work suggests that adaptive myelination may be a mechanism that enables brain networks with a means of temporal self-organization, resilience, and homeostasis.

Long-term neurocognitive, psychological, and return to work outcomes in meningioma patients.

INTRODUCTION: This study aimed to investigate long-term neurocognitive, psychological, and return to work (RTW) outcomes in meningioma patients, and to explore whether neurocognitive and psychological factors influence RTW outcomes in this population. METHODS: In this retrospective study, 61 meningioma patients completed in-depth clinical neuropsychological assessments. Of these participants, 42 were of working-age and had RTW information available following neuropsychological assessment. Seventy-one percent and 80% of patients received radiation and surgery, respectively, with 49% receiving both radiation and surgery. Associations between demographic, medical, neurocognitive, psychological, and RTW data were analyzed using multivariable logistic regression analyses. RESULTS: In our sample, 68% of patients exhibited global neurocognitive impairment, with the largest effect sizes found on tests of visual memory (d = 0.73), executive function (d = 0.61), and attention (d = 0.54). Twenty-seven percent exhibited moderate to severe levels of depressive symptoms. In addition, 23% and 30% exhibited clinically significant state and trait anxiety, respectively. Forty-eight percent of patients were unable to RTW. Younger age, faster visuomotor processing speed, and, unexpectedly, higher trait anxiety scores were associated with an increased likelihood of returning to work. CONCLUSIONS: Meningioma patients are at risk of experiencing neurocognitive deficits, psychological symptoms, and difficulties returning to work. Our results suggest that neurocognitive and psychological factors contribute to RTW status in meningioma patients. Prospective research studies are necessary to increase our understanding of the complexity of functional disability in this growing population.

Exercise Trials in Pediatric Brain Tumor: A Systematic Review of Randomized Studies.

In pediatric brain tumor patients, treatment advances have increased survival rates to nearly 70%, while consequently shifting the burden of disease to long-term management. Exercise has demonstrated potential in improving multiple health impairments secondary to brain tumor treatment. However, these effects have not been consolidated through review. Therefore, we performed a systematic review of 6 health sciences databases (Medline, Embase, PsychINFO, CINAHL, SPORTDiscus, and Cochrane Central Database). Two reviewers screened studies against predefined inclusion criteria, namely that the study must: (i) be pediatric-specific; (ii) examine the effects of an exercise intervention; and (iii) employ a randomized or quasi-randomized trial design. The same 2 reviewers performed data extraction and analyses. From a pool of 4442, 5 articles-based on 2 independent trials-were included in our review (N=41). Exercise interventions were primarily aerobic, but included balance or muscle building components. Exercise had a positive effect on volumetric or diffusion-based neuroimaging outcomes, as well as motor performance and cardiorespiratory fitness. The effects of exercise on cognition remains unclear. Exercise did not worsen any of the outcomes studied. This review captures the state of the science, suggesting a potential role for exercise in children treated for brain tumor.

Mapping neural dynamics underlying saccade preparation and execution and their relation to reaction time and direction errors.

Our ability to control and inhibit automatic behaviors is crucial for negotiating complex environments, all of which require rapid communication between sensory, motor, and cognitive networks. Here, we measured neuromagnetic brain activity to investigate the neural timing of cortical areas needed for inhibitory control, while 14 healthy young adults performed an interleaved prosaccade (look at a peripheral visual stimulus) and antisaccade (look away from stimulus) task. Analysis of how neural activity relates to saccade reaction time (SRT) and occurrence of direction errors (look at stimulus on antisaccade trials) provides insight into inhibitory control. Neuromagnetic source activity was used to extract stimulus-aligned and saccade-aligned activity to examine temporal differences between prosaccade and antisaccade trials in brain regions associated with saccade control. For stimulus-aligned antisaccade trials, a longer SRT was associated with delayed onset of neural activity within the ipsilateral parietal eye field (PEF) and bilateral frontal eye field (FEF). Saccade-aligned activity demonstrated peak activation 10ms before saccade-onset within the contralateral PEF for prosaccade trials and within the bilateral FEF for antisaccade trials. In addition, failure to inhibit prosaccades on anti-saccade trials was associated with increased activity prior to saccade onset within the FEF contralateral to the peripheral stimulus. This work on dynamic activity adds to our knowledge that direction errors were due, at least in part, to a failure to inhibit automatic prosaccades. These findings provide novel evidence in humans regarding the temporal dynamics within oculomotor areas needed for saccade programming and the role frontal brain regions have on top-down inhibitory control.

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.

Cognitive and neural effects of exercise following traumatic brain injury: A systematic review of randomized and controlled clinical trials.

Objective: Sub-maximal aerobic exercise can alleviate brain injury-related symptom burden. There is substantial data from animal studies and a growing clinical evidence base to suggest that exercise may also improve cognitive and neural outcomes following brain injury. We performed this systematic review to consolidate evidence from randomized and controlled clinical trials on the effects of exercise on cognitive and neuroimaging outcomes following brain injury in humans.Design: Systematic review.Data sources: MEDLINE, EMBASE, PsychINFO, CINAHL, SPORTDiscus, and Cochrane Central Database.Eligibility criteria for screening studies: Randomized or controlled clinical trials examining the effects of exercise on cognitive and/or neuroimaging outcomes in traumatic brain injury. No restriction was placed on age (or other demographic variables) or severity of injury.Results: Six studies (with an average sample of 42 participants) met eligibility criteria. Three studies used neuroimaging and reported exercise-related improvements as measured by either functional or diffusion-based imaging. The remainder of the trials that employed cognitive outcomes reported largely null findings.Summary/Conclusion: This review demonstrates that exercise shows promise (primarily with respect to neuroimaging outcomes) as a brain injury intervention. While the field is young and heterogeneity between studies precludes meta-analysis, this review raises important questions that need to be addressed by future trials.

Impaired Recent, but Preserved Remote, Autobiographical Memory in Pediatric Brain Tumor Patients.

Medulloblastomas, the most common malignant brain tumor in children, are typically treated with radiotherapy. Refinement of this treatment has greatly improved survival rates in this patient population. However, radiotherapy also profoundly affects the developing brain and is associated with reduced hippocampal volume and blunted hippocampal neurogenesis. Such hippocampal (as well as extrahippocampal) abnormalities likely contribute to cognitive impairments in this population. While several aspects of memory have been examined in this population, the impact of radiotherapy on autobiographical memory has not previously been evaluated. Here we evaluated autobiographical memory in male and female patients who received radiotherapy for posterior fossa tumors (PFTs), including medulloblastoma, during childhood. Using the Children's Autobiographical Interview, we retrospectively assessed episodic and nonepisodic details for events that either preceded (i.e., remote) or followed (i.e., recent) treatment. For post-treatment events, PFT patients reported fewer episodic details compared with control subjects. For pretreatment events, PFT patients reported equivalent episodic details compared with control subjects. In a range of conditions associated with reduced hippocampal volume (including medial temporal lobe amnesia, mild cognitive impairment, Alzheimer's disease, temporal lobe epilepsy, transient epileptic amnesia, frontal temporal dementia, traumatic brain injury, encephalitis, and aging), loss of episodic details (even in remote memories) accompanies hippocampal volume loss. It is therefore surprising that pretreatment episodic memories in PFT patients with reduced hippocampal volume are retained. We discuss these findings in light of the anterograde and retrograde impact on memory of experimentally suppressing hippocampal neurogenesis in rodents.SIGNIFICANCE STATEMENT Pediatric medulloblastoma survivors develop cognitive dysfunction following cranial radiotherapy treatment. We report that radiotherapy treatment impairs the ability to form new autobiographical memories, but spares preoperatively acquired autobiographical memories. Reductions in hippocampal volume and cortical volume in regions of the recollection network appear to contribute to this pattern of preserved preoperative, but impaired postoperative, memory. These findings have significant implications for understanding disrupted mnemonic processing in the medial temporal lobe memory system and in the broader recollection network, which are inadvertently affected by standard treatment methods for medulloblastoma tumors in children.

White matter plasticity and maturation in human cognition.

White matter plasticity likely plays a critical role in supporting cognitive development. However, few studies have used the imaging methods specific to white matter tissue structure or experimental designs sensitive to change in white matter necessary to elucidate these relations. Here we briefly review novel imaging approaches that provide more specific information regarding white matter microstructure. Furthermore, we highlight recent studies that provide greater clarity regarding the relations between changes in white matter and cognition maturation in both healthy children and adolescents and those with white matter insult. Finally, we examine the hypothesis that white matter is linked to cognitive function via its impact on neural synchronization. We test this hypothesis in a population of children and adolescents with recurrent demyelinating syndromes. Specifically, we evaluate group differences in white matter microstructure within the optic radiation; and neural phase synchrony in visual cortex during a visual task between 25 patients and 28 typically developing age-matched controls. Children and adolescents with demyelinating syndromes show evidence of myelin and axonal compromise and this compromise predicts reduced phase synchrony during a visual task compared to typically developing controls. We investigate one plausible mechanism at play in this relationship using a computational model of gamma generation in early visual cortical areas. Overall, our findings show a fundamental connection between white matter microstructure and neural synchronization that may be critical for cognitive processing. In the future, longitudinal or interventional studies can build upon our knowledge of these exciting relations between white matter, neural communication, and cognition.

Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: Cure at a cost.

BACKGROUND: Posterior fossa ependymoma (PFE) comprises 2 groups, PF group A (PFA) and PF group B (PFB), with stark differences in outcome. However, to the authors' knowledge, the long-term outcomes of PFA ependymoma have not been described fully. The objective of the current study was to identify predictors of survival and neurocognitive outcome in a large consecutive cohort of subgrouped patients with PFE over 30 years. METHODS: Demographic, survival, and neurocognitive data were collected from consecutive patients diagnosed with PFE from 1985 through 2014 at the Hospital for Sick Children in Toronto, Ontario, Canada. Subgroup was assigned using genome-wide methylation array and/or immunoreactivity to histone H3 K27 trimethylation (H3K27me3). RESULTS: A total of 72 PFE cases were identified, 89% of which were PFA. There were no disease recurrences noted among patients with PFB. The 10-year progression-free survival rate for all patients with PFA was poor at 37.1% (95% confidence interval, 25.9%-53.1%). Analysis of consecutive 10-year epochs revealed significant improvements in progression-free survival and/or overall survival over time. This pertains to the increase in the rate of gross (macroscopic) total resection from 35% to 77% and the use of upfront radiotherapy increasing from 65% to 96% over the observed period and confirmed in a multivariable model. Using a mixed linear model, analysis of longitudinal neuropsychological outcomes restricted to patients with PFA who were treated with focal irradiation demonstrated significant continuous declines in the full-scale intelligence quotient over time with upfront conformal radiotherapy, even when correcting for hydrocephalus, number of surgeries, and age at diagnosis (-1.33 ± 0.42 points/year; P = .0042). CONCLUSIONS: Data from a molecularly informed large cohort of patients with PFE clearly indicate improved survival over time, related to more aggressive surgery and upfront radiotherapy. However, to the best of the authors' knowledge, the current study is the first, in a subgrouped cohort, to demonstrate that this approach results in reduced neurocognitive outcomes over time.

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.

Predictors of neuropsychological late effects and white matter correlates in children treated for a brain tumor without radiation therapy.

BACKGROUND: Little is known about cognition and predictors of neuropsychological outcomes in pediatric low-grade glioma (PLGG) survivors treated without radiation therapy. This research expands upon our previous work by further identifying the cognitive profile of PLGG patients treated without radiation therapy, investigating the specific medical and demographic variables that predict functioning, and examining white matter structure and its relationship to neuropsychological performance. PROCEDURE: Nineteen PLGG patients (11-19 years) were administered the Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale, and subtests from the Woodcock-Johnson Tests of Cognition (visual matching, rapid picture naming, and pair cancellation) and Cambridge Neuropsychological Test Automated Battery (pattern recognition memory, delayed matching to sample, intra-extra dimensional set shift, motor screening task, rapid visual information processing, and spatial span). RESULTS: The sample had normative weaknesses in verbal working memory, brief attention/vigilance, psychomotor speeded output, visual perception and matching, overall cognition, working memory, and processing speed. Increased surgeries or subtotal resections, hydrocephalus, shunting procedures, chemotherapy, NF1, and supratentorial location were predictive of cognitive deficits. Broad white matter involvement of the frontal, temporal, parietal, and occipital lobes as well as the cerebellum, as inferred from diffusion tensor imaging indices of decreased fiber orientation and increased water diffusion, was related to many cognitive difficulties. CONCLUSIONS: This study comprehensively examines cognitive functioning in PLGG patients treated without radiation therapy, predictors of cognition, and its relation to white matter structure. Our findings indicate that medical and demographic variables other than radiation therapy can lead to cognitive late effects with diffuse white matter involvement.

Changes in White Matter Microstructure Impact Cognition by Disrupting the Ability of Neural Assemblies to Synchronize.

Cognition is compromised by white matter (WM) injury but the neurophysiological alterations linking them remain unclear. We hypothesized that reduced neural synchronization caused by disruption of neural signal propagation is involved. To test this, we evaluated group differences in: diffusion tensor WM microstructure measures within the optic radiations, primary visual area (V1), and cuneus; neural phase synchrony to a visual attention cue during visual-motor task; and reaction time to a response cue during the same task between 26 pediatric patients (17/9: male/female) treated with cranial radiation treatment for a brain tumor (12.67 ± 2.76 years), and 26 healthy children (16/10: male/female; 12.01 ± 3.9 years). We corroborated our findings using a corticocortical computational model representing perturbed signal conduction from myelin. Patients show delayed reaction time, WM compromise, and reduced phase synchrony during visual attention compared with healthy children. Notably, using partial least-squares-path modeling we found that WM insult within the optic radiations, V1, and cuneus is a strong predictor of the slower reaction times via disruption of neural synchrony in visual cortex. Observed changes in synchronization were reproduced in a computational model of WM injury. These findings provide new evidence linking cognition with WM via the reliance of neural synchronization on propagation of neural signals.SIGNIFICANCE STATEMENT By comparing brain tumor patients to healthy children, we establish that changes in the microstructure of the optic radiations and neural synchrony during visual attention predict reaction time. Furthermore, by testing the directionality of these links through statistical modeling and verifying our findings with computational modeling, we infer a causal relationship, namely that changes in white matter microstructure impact cognition in part by disturbing the ability of neural assemblies to synchronize. Together, our human imaging data and computer simulations show a fundamental connection between WM microstructure and neural synchronization that is critical for cognitive processing.

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.

Smaller hippocampal subfield volumes predict verbal associative memory in pediatric brain tumor survivors.

The developing hippocampus is highly sensitive to chemotherapy and cranial radiation treatments for pediatric cancers, yet little is known about the effects that cancer treatents have on specific hippocampal subfields. Here, we examined hippocampal subfield volumes in 29 pediatric brain tumor survivors treated with cranial radiation and chemotherapy, and 30 healthy developing children and adolescents. We also examined associations between hippocampal subfield volumes and short-term verbal memory. Hippocampal subfields (Cornus Ammonis (CA) 1, CA2-3, dentate gyrus (DG)-CA4, stratum radiatum-lacunosum-moleculare, and subiculum) were segmented using the Multiple Automatically Generated Templates for Different Brains automated segmentation algorithm. Neuropsychological assessment of short-term verbal associative memory was performed in a subset of brain tumor survivors (N = 11) and typically developing children (N = 16), using the Children's Memory Scale or Wechsler's Memory Scale-third edition. Repeated measures analysis of variance showed that pediatric brain tumor survivors had significantly smaller DG-CA4, CA1, CA2-3, and stratum radiatum-lacunosum-moleculare volumes compared with typically developing children. Verbal memory performance was positively related to DG-CA4, CA1, and stratum radiatum-lacunosum-moleculare volumes in pediatric brain tumor survivors. Unlike the brain tumor survivors, there were no associations between subfield volumes and memory in typically developing children and adolescents. These data suggest that specific subfields of the hippocampus may be vulnerable to brain cancer treatments, and may contribute to impaired episodic memory following brain cancer treatment in childhood.

Gamma deficits as a neural signature of cognitive impairment in children treated for brain tumors.

Cognitive impairment is consistently reported in children treated for brain tumors, particularly in the categories of processing speed, memory, and attention. Although tumor site, hydrocephalus, chemotherapy, and cranial radiation therapy (CRT) are all associated with poorer function, CRT predicts the greatest deficits. There is a particularly high correlation between CRT and slowed information-processing speed. Cortical gamma-band oscillations have been associated with processing behaviorally relevant information; however, their role in the maintenance of cognition in individuals with processing deficits is unclear. We examined gamma oscillations using magnetoencephalography (MEG) in children undergoing CRT to test whether gamma characteristics can be a signature of cognitive impairment in this population. We collected resting-state data as well as data from baseline and active periods during two visual-motor reaction time tasks of varying cognitive loads from 18 healthy children and 20 patients. We found that only high-gamma oscillations (60-100 Hz), and not low-gamma oscillations (30-59 Hz), showed significant group differences in absolute power levels. Overall, compared with healthy children, patients showed the following: (1) lower total high-gamma (60-100 Hz) power during the resting state, as well as during task-related baseline and performance measures; (2) no change in gamma reactivity to increases in cognitive load; and (3) slower processing speeds both inside and outside MEG. Our findings show that high-gamma oscillations are disrupted in children after treatment for a brain tumor. The temporal dynamic of the high-gamma response during information processing may index cognitive impairment in humans with neurological injury.