Publications by authors named "Donald J Mabbott"

60 Publications

Family environment as a predictor and moderator of cognitive and psychosocial outcomes in children treated for posterior fossa tumors.

Child Neuropsychol 2021 Feb 17:1-20. Epub 2021 Feb 17.

Program in Neuroscience and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.

. The current study examined the effects of clinical factors (i.e., treatment type, history of cerebellar mutism) as well as environmental factors (i.e., family environment) as predictors of cognitive and psychosocial outcomes in children treated for posterior fossa tumors.. Twenty-seven children/adolescents treated for posterior fossa tumors (treatment type: radiation [ = 12], surgery [ = 15]; history of mutism: yes [ = 7], no [ = 20]) and = 13 healthy controls, aged 8-17 years, and their caregivers completed measures assessing cognitive and psychosocial functioning, as well as the family environment (i.e., parental education, family functioning, family psychiatric history). Hierarchical linear regression analyses were conducted to examine the role of clinical factors and the family environment as predictors of cognitive and psychosocial outcomes. Family environment was also examined as a moderator of clinical factor group differences in outcomes.. Regression analyses revealed lower intelligence scores among the radiation group compared to the control group, lower verbal memory scores among both treatment groups compared to the control group, and a significant positive effect of parental education on verbal memory scores. Further, history of cerebellar mutism predicted poorer performance on a speeded naming task, and this relationship was moderated by family functioning, with a greater effect of mutism present among those with poorer family functioning.. Interventions aimed at improving the family environment may help to mitigate negative cognitive effects of pediatric brain tumors, particularly among those most at-risk for poor outcomes.
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http://dx.doi.org/10.1080/09297049.2021.1885639DOI Listing
February 2021

Tracking Inhibitory Control in Youth With ADHD: A Multi-Modal Neuroimaging Approach.

Front Psychiatry 2020 19;11:00831. Epub 2020 Nov 19.

Department of Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada.

Background: A decreased ability to inhibit a speeded motor response is a well-studied deficit in Attention Deficit Hyperactivity Disorder (ADHD), and has been proposed as an endophenotype. Inhibitory control has been assessed reliably with the Stop Signal Task (SST) and is associated with prior documented differences in regional brain function using f-MRI. Here, we advance on these findings by examining their structural connectivity and white matter integrity with the goal of identifying a network underlying a core cognitive deficit in ADHD.

Methods: Healthy controls (N=16) and youth diagnosed with ADHD (N=60) were recruited through the Province of Ontario Neurodevelopmental Disorders Network (POND) and the Hospital for Sick Children. An f-MRI activation difference map was co-registered with each participant's white matter imaging data, representing the specific network nodes where ADHD youth diverged significantly from controls while performing the SST. Probabilistic tractography was applied from these nodes, and white matter integrity indices such as fractional anisotropy (FA) within the tracts of interest were contrasted between the groups and correlated with SST output measures, including the measure of inhibitory control, the stop signal reaction time (SSRT).

Results: The tracts that connected the network nodes belonged primarily to the inferior fronto-occipital fasciculus (IFOF) and cingulum. ADHD subjects showed trend differences in FA compared to controls between right inferior frontal gyrus (IFG) and right superior temporal gyrus (P= 0.09), right IFG and right posterior cingulate (P= 0.01), right anterior cingulate to posterior cingulate (p= 0.08), and between left middle temporal gyrus (BA 39) and left posterior cingulate (P=0.02). A trend correlation was found between radial diffusivity within IFG to STG white matter (IFOF) and SSRT.

Conclusions: We identified potential white matter tracts related to deficient inhibitory control, elucidating the brain mechanisms of an important cognitive deficit in ADHD. These findings could be integrated into future endophenotypic biomarker studies, incorporating altogether brain structure, function, and behavior for future studies of ADHD and other psychiatric conditions that exhibit this deficit.
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http://dx.doi.org/10.3389/fpsyt.2020.00831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710692PMC
November 2020

Children's family income is associated with cognitive function and volume of anterior not posterior hippocampus.

Nat Commun 2020 08 12;11(1):4040. Epub 2020 Aug 12.

Department of Psychology, University of Toronto, Toronto, ON, Canada.

Children from lower income backgrounds tend to have poorer memory and language abilities than their wealthier peers. It has been proposed that these cognitive gaps reflect the effects of income-related stress on hippocampal structure, but the empirical evidence for this relationship has not been clear. Here, we examine how family income gaps in cognition relate to the anterior hippocampus, given its high sensitivity to stress, versus the posterior hippocampus. We find that anterior (but not posterior) hippocampal volumes positively correlate with family income up to an annual income of ~$75,000. Income-related differences in the anterior (but not posterior) hippocampus also predicted the strength of the gaps in memory and language. These findings add anatomical specificity to current theories by suggesting a stronger relationship between family income and anterior than posterior hippocampal volumes and offer a potential mechanism through which children from different income homes differ cognitively.
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http://dx.doi.org/10.1038/s41467-020-17854-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423938PMC
August 2020

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

Nat Med 2020 08 27;26(8):1285-1294. Epub 2020 Jul 27.

Neurosciences and Mental Health Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1038/s41591-020-0985-2DOI Listing
August 2020

Corrigendum to "A controlled clinical crossover trial of exercise training to improve cognition and neural communication in pediatric brain tumor survivors" [Clin. Neurophysiol. 131 (2020) 1533-1547].

Clin Neurophysiol 2020 Sep 1;131(9):2331-2332. Epub 2020 Jul 1.

Neurosciences & Mental Health, SickKids, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Psychology, University of Toronto, 100 St. George Street, Toronto, ON M5S 3G3, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.clinph.2020.06.002DOI Listing
September 2020

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

J Int Neuropsychol Soc 2020 11 27;26(10):978-992. Epub 2020 May 27.

The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.

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.
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http://dx.doi.org/10.1017/S1355617720000491DOI Listing
November 2020

A controlled clinical crossover trial of exercise training to improve cognition and neural communication in pediatric brain tumor survivors.

Clin Neurophysiol 2020 Jul 13;131(7):1533-1547. Epub 2020 Apr 13.

Neurosciences & Mental Health, SickKids, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Psychology, University of Toronto, 100 St. George Street, Toronto, ON M5S 3G3, Canada. Electronic address:

Objective: To assess the efficacy of aerobic exercise training to improve controlled attention, information processing speed and neural communication during increasing task load and rest in pediatric brain tumor survivors (PBTS) treated with cranial radiation.

Methods: Participants completed visual-motor Go and Go/No-Go tasks during magnetoencephalography recording prior to and following the completion of 12-weeks of exercise training. Exercise-related changes in response accuracy and visual-motor latency were evaluated with Linear Mixed models. The Phase Lag Index (PLI) was used to estimate functional connectivity during task performance and rest. Changes in PLI values after exercise training were assessed using Partial Least Squares analysis.

Results: Exercise training predicted sustained (12-weeks) improvement in response accuracy (p<0.05) during No-Go trials. Altered functional connectivity was detected in theta (4-7Hz) alpha (8-12Hz) and high gamma (60-100Hz) frequency bands (p<0.001) during Go and Go/No-Go trials. Significant changes in response latency and resting state connectivity were not detected.

Conclusion: These findings support the efficacy of aerobic exercise to improve controlled attention and enhance functional mechanisms under increasing task load in participants.

Significance: It may be possible to harness the beneficial effects of exercise as therapy to promote cognitive recovery and enhance brain function in PBTS.
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http://dx.doi.org/10.1016/j.clinph.2020.03.027DOI Listing
July 2020

Treatment of Executive Function Deficits in autism spectrum disorder with repetitive transcranial magnetic stimulation: A double-blind, sham-controlled, pilot trial.

Brain Stimul 2020 May - Jun;13(3):539-547. Epub 2020 Jan 15.

Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Canada; Temerty Centre for Therapeutic Brain Intervention, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Background: In youth and young adults with autism spectrum disorder (ASD), executive function (EF) deficits may be a promising treatment target with potential impact on everyday functioning.

Objective: To conduct a pilot randomized, double-blind, parallel, controlled trial evaluating repetitive transcranial magnetic stimulation (rTMS) for EF deficits in ASD.

Method: In Toronto, Ontario (November 2014 to June 2017), a 20-session, 4-week course of 20 Hz rTMS targeting dorsolateral prefrontal cortex (DLPFC) (90%RMT) was compared to sham stimulation in 16-35 year-olds with ASD (28 male/12 female), without intellectual disability, who had impaired everyday EF performance (n = 20 active/n = 20 sham). Outcome measures evaluated protocol feasibility and clinical effects of active vs. sham rTMS on EF performance. The moderating effect of baseline functioning was explored.

Results: Of eligible participants, 95% were enrolled and 95% of randomized participants completed the protocol. Adverse events across treatment arms were mild-to-moderate. There was no significant difference between active vs. sham rTMS on EF performance. Baseline adaptive functioning moderated the effect of rTMS, such that participants with lower baseline functioning experienced significant EF improvement in the active vs. sham group.

Conclusions: Our pilot RCT demonstrated the feasibility and acceptability of using high frequency rTMS targeting DLPFC in youth and young adults with autism. No evidence for efficacy of active versus sham rTMS on EF performance was found. However, we found promising preliminary evidence of EF performance improvement following active versus sham rTMS in participants with ASD with more severe adaptive functioning deficits. Future work could focus on examining efficacy of rTMS in this higher-need population.

Clinical Trial Registration: Repetitive Transcranial Magnetic Stimulation (rTMS) for Executive Function Deficits in Autism Spectrum Disorder and Effects on Brain Structure: A Pilot Study; https://clinicaltrials.gov/ct2/show/NCT02311751?term = ameis&rank = 1; NCT02311751. The trial was funded by: an American Academy of Child and Adolescent Psychiatry (AACAP) Pilot Research Award, the Innovation Fund from the Alternate Funding Plan of the Academic Health Sciences Centres of Ontario, and an Ontario Mental Health Foundation (OMHF) Project A Grant and New Investigator Fellowship.
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http://dx.doi.org/10.1016/j.brs.2020.01.007DOI Listing
November 2020

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

Hum Brain Mapp 2020 05 9;41(7):1934-1949. Epub 2020 Jan 9.

Program in Neurosciences and Mental Health, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1002/hbm.24922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268073PMC
May 2020

Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort.

Cancer Med 2020 01 21;9(2):447-459. Epub 2019 Nov 21.

Department of Psychology, The Hospital for Sick Children, Toronto, ON, Canada.

Background: Understanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients.

Methods: Seventy-six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered-including molecular subgroup.

Results: The majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy-assessed. Self-care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P = .02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P < .05. Patients treated with a gross total resection also had better outcomes for the HUI3 hearing (P = .04). However, those who underwent a gross total resection reported having worse outcomes on the HUI3 vision (P = .02). No differences in HRQL were evident as a function of subgroup.

Conclusions: By examining an international sample of survivors, we characterized the worldwide impact of medulloblastoma. This is a critical first step in developing global standards for evaluating long-term outcomes.
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http://dx.doi.org/10.1002/cam4.2701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970040PMC
January 2020

Early neuroaxonal injury is seen in the acute phase of pediatric optic neuritis.

Mult Scler Relat Disord 2019 Nov 7;36:101387. Epub 2019 Sep 7.

Division of Neurosciences and Mental Health, SickKids Research Institute, Toronto, Ontario, Canada; Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics (Neurology), University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Thinning of the retinal nerve fiber layer (RNFL) and ganglion cell/inner plexiform layer (GCIPL) occur in the chronic phase after optic neuritis (ON) in children and reflect neuroaxonal injury. The objective of this study was to describe changes in RNFL and GCIPL thickness in the acute phase following pediatric ON.

Methods: Data were collected prospectively from consecutive children presenting with ON as part of an incident acquired demyelinating event. Children with a final diagnosis of multiple sclerosis (n = 9, 10 ON-affected eyes) or monophasic demyelination (n = 16, 25 ON-affected eyes) who underwent spectral-domain optical coherence tomography (OCT) testing within 30 days of symptom onset were included. Standardized visual assessment was performed at presentation and 6-18 months follow-up. OCT measures were compared to those of healthy controls (n = 25, 50 eyes).

Results: Median (interquartile range [IQR]) global RNFL thickness was increased in ON-affected eyes (155 μm [114-199 μm]) compared to control eyes (104 μm [98.5-107.5 μm]; p < 0.0001). Compared to controls, fellow eyes demonstrated a reduced temporal quadrant RNFL thickness (59 μm [53-72 μm] versus 71.5 μm [65-81 μm]; p = 0.013) and lower GCIPL thickness (80.5 μm [74-88 μm] versus 87 μm [85-89 μm]; p = 0.003). The ON-affected eyes of children with monophasic demyelination demonstrated a greater global RNFL thickness (183.5 μm [146.5-206 μm]) compared to the ON-affected eyes of children with multiple sclerosis (108.5 μm [95-124 μm]; p = 0.01). OCT measures at presentation did not predict low-contrast visual acuity nor color vision at 6-18 months follow-up.

Conclusion: Children with multiple sclerosis show less RNFL swelling in their ON-affected eyes at onset compared to children with monophasic demyelination. Lower GCIPL and temporal RNFL thickness in the clinically unaffected eyes of those children with unilateral ON suggests the presence of pre-existing neuroaxonal injury in children presenting with a first episode of ON. This finding may be driven by the subset of children with multiple sclerosis.
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http://dx.doi.org/10.1016/j.msard.2019.101387DOI Listing
November 2019

Molecular correlates of cerebellar mutism syndrome in medulloblastoma.

Neuro Oncol 2020 02;22(2):290-297

Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Cerebellar mutism syndrome (CMS) is a common complication following resection of posterior fossa tumors, most commonly after surgery for medulloblastoma. Medulloblastoma subgroups have historically been treated as a single entity when assessing CMS risk; however, recent studies highlighting their clinical heterogeneity suggest the need for subgroup-specific analysis. Here, we examine a large international multicenter cohort of molecularly characterized medulloblastoma patients to assess predictors of CMS.

Methods: We assembled a cohort of 370 molecularly characterized medulloblastoma subjects with available neuroimaging from 5 sites globally, including Great Ormond Street Hospital, Christian Medical College and Hospital, the Hospital for Sick Children, King Hussein Cancer Center, and Lucile Packard Children's Hospital. Age at diagnosis, sex, tumor volume, and CMS development were assessed in addition to molecular subgroup.

Results: Overall, 23.8% of patients developed CMS. CMS patients were younger (mean difference -2.05 years ± 0.50, P = 0.0218) and had larger tumors (mean difference 10.25 cm3 ± 4.60, P = 0.0010) that were more often midline (odds ratio [OR] = 5.72, P < 0.0001). In a multivariable analysis adjusting for age, sex, midline location, and tumor volume, Wingless (adjusted OR = 4.91, P = 0.0063), Group 3 (adjusted OR = 5.56, P = 0.0022), and Group 4 (adjusted OR = 8.57 P = 9.1 × 10-5) tumors were found to be independently associated with higher risk of CMS compared with sonic hedgehog tumors.

Conclusions: Medulloblastoma subgroup is a very strong predictor of CMS development, independent of tumor volume and midline location. These findings have significant implications for management of both the tumor and CMS.
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http://dx.doi.org/10.1093/neuonc/noz158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442348PMC
February 2020

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

Neuroimage Clin 2019 12;23:101886. Epub 2019 Jun 12.

The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; University of Toronto, Toronto, ON M5S 3G3, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.nicl.2019.101886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603305PMC
June 2020

White matter plasticity and maturation in human cognition.

Glia 2019 11 24;67(11):2020-2037. Epub 2019 Jun 24.

Neurosciences and Mental Health Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1002/glia.23661DOI Listing
November 2019

Disrupted network connectivity in pediatric brain tumor survivors is a signature of injury.

J Comp Neurol 2019 12 7;527(17):2896-2909. Epub 2019 Jun 7.

Neurosciences and Mental Health Program, Research Institute, Hospital for Sick Children, Toronto, Canada.

Cognition is compromised in pediatric brain tumor survivors but the neurophysiological basis of this compromise remains unclear. We hypothesized that reduced neural synchronization across brain networks is involved. To test this, we evaluated group differences using a retrospective cohort comparison design between 24 pediatric brain tumor survivors [11.81 ± 3.27)] and 24 age matched healthy children [12.04 ± 3.28)] in functional connectivity within a cerebellar network to examine local effects of the tumor, a whole brain network to examine diffuse effects of treatment (i.e., chemotherapy and radiation), and across multiple intrinsic connectivity networks. Neural activity was recorded during magnetoencephalography scanning while participants were at rest and functional connectivity within networks was measured using the phase lag index. We corroborated our findings using a computational model representing the local tumor effects on neural synchrony. Compared to healthy children, pediatric brain tumor survivors show increased functional connectivity for theta and beta frequency bands within the cerebellar network and increased functional connectivity for the theta band within the whole brain network that again localized to the cerebellum. Computational modeling showed that increased synchrony in the theta bad is observed following local clustering as well as sparse interarea brain connectivity. We also observed increased functional connectivity for the alpha frequency band in the ventral attention network and decreased functional connectivity within the gamma frequency band in the motor network within paedatric brain tumor survivors versus healthy children. Notably, increased gamma functional connectivity within the motor network predicted decreased reaction time on behavioral tasks in pediatric brain tumor survivors. Disrupted network synchrony may be a signature of neurological injury and disease.
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http://dx.doi.org/10.1002/cne.24717DOI Listing
December 2019

Cognitive Implications of Ototoxicity in Pediatric Patients With Embryonal Brain Tumors.

J Clin Oncol 2019 06 2;37(18):1566-1575. Epub 2019 May 2.

1 St Jude Children's Research Hospital, Memphis, TN.

Purpose: Sensorineural hearing loss (SNHL) is associated with intellectual and academic declines in children treated for embryonal brain tumors. This study expands upon existing research by examining core neurocognitive processes that may result in reading difficulties in children with treatment-related ototoxicity.

Patients And Methods: Prospectively gathered, serial, neuropsychological and audiology data for 260 children and young adults age 3 to 21 years (mean, 9.15 years) enrolled in a multisite research and treatment protocol, which included surgery, risk-adapted craniospinal irradiation (average risk, n = 186; high risk, n = 74), and chemotherapy, were analyzed using linear mixed models. Participants were assessed at baseline and up to 5 years after diagnosis and grouped according to degree of SNHL. Included were 196 children with intact hearing or mild to moderate SNHL (Chang grade 0, 1a, 1b, or 2a) and 64 children with severe SNHL (Chang grade 2b or greater). Performance on eight neurocognitive variables targeting reading outcomes (eg, phonemics, fluency, comprehension) and contributory cognitive processes (eg, working memory, processing speed) was analyzed.

Results: Participants with severe SNHL performed significantly worse on all variables compared with children with normal or mild to moderate SNHL ( ≤ .05), except for tasks assessing awareness of sounds and working memory. Controlling for age at diagnosis and risk-adapted craniospinal irradiation dose, performance on the following four variables remained significantly lower for children with severe SNHL: phonemic skills, phonetic decoding, reading comprehension, and speed of information processing ( ≤ .05).

Conclusion: Children with severe SNHL exhibit greater reading difficulties over time. Specifically, they seem to struggle most with phonological skills and processing speed, which affect higher level skills such as reading comprehension.
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http://dx.doi.org/10.1200/JCO.18.01358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599406PMC
June 2019

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

Cancer 2019 06 15;125(11):1867-1876. Epub 2019 Feb 15.

Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1002/cncr.31995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508980PMC
June 2019

Medulloblastoma.

Nat Rev Dis Primers 2019 02 14;5(1):11. Epub 2019 Feb 14.

Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.

Medulloblastoma (MB) comprises a biologically heterogeneous group of embryonal tumours of the cerebellum. Four subgroups of MB have been described (WNT, sonic hedgehog (SHH), Group 3 and Group 4), each of which is associated with different genetic alterations, age at onset and prognosis. These subgroups have broadly been incorporated into the WHO classification of central nervous system tumours but still need to be accounted for to appropriately tailor disease risk to therapy intensity and to target therapy to disease biology. In this Primer, the epidemiology (including MB predisposition), molecular pathogenesis and integrative diagnosis taking histomorphology, molecular genetics and imaging into account are reviewed. In addition, management strategies, which encompass surgical resection of the tumour, cranio-spinal irradiation and chemotherapy, are discussed, together with the possibility of focusing more on disease biology and robust molecularly driven patient stratification in future clinical trials.
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http://dx.doi.org/10.1038/s41572-019-0063-6DOI Listing
February 2019

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

J Neurooncol 2019 Mar 3;142(1):39-48. Epub 2019 Jan 3.

Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.

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, mean = 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.
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http://dx.doi.org/10.1007/s11060-018-03083-xDOI Listing
March 2019

Early changes in white matter predict intellectual outcome in children treated for posterior fossa tumors.

Neuroimage Clin 2018 6;20:697-704. Epub 2018 Sep 6.

The Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address:

Purpose: Prospective and longitudinal neuroimaging studies of posterior fossa tumors are scarce. Here we evaluate the early changes in white matter and intellectual outcome up to 3 years after diagnosis.

Patients And Methods: Twenty-two children with posterior fossa tumors and 24 similarly-aged healthy children participated. Patients included: (a) 12 individuals who received surgery, cranial-spinal radiation (CSR), and focal radiation to the tumor bed (CSR group) and (b) 10 individuals who received local therapy, either surgery only or surgery and focal radiation to the tumor bed (Local group). Diffusion tensor imaging (DTI) and intelligence measures were obtained an average of 3 months after diagnosis and then at 12, 24, and 36 months later. DTI tractography and voxel-wise approaches were employed. The Neurological Predictor Scale was used to summarize the type and amount of treatment for PF tumor patients. Linear mixed modelling was used to evaluate group differences at baseline and changes over time in DTI metrics for both the specific white matter tracts and voxel-wise, as well as for intelligence measures.

Results: Based on tractography, patients treated with CSR had significantly higher Axial and Mean diffusivity in the cortical-spinal tracts (CST) 3 month after diagnosis - particularly on the right side, p < .003, compared to healthy children. Mean diffusivity in right CST decreased over time in this group of patients, p = .001. No differences compared to controls were evident in specific tracts for the Local group, p > .10. Voxel-wise analyses revealed multiple areas of white matter compromise in both patients groups. Notably, both patient groups had lower scores on intelligence measures compared to the Control group: The CSR group displayed lower performance 3 months following diagnosis, ps < 0.001, and their performance remained stable over time ps > 0.10, whereas the Local group displayed no differences at 3 months, ps> 0.10, but their performance declined over time, ps < 0.01. At baseline, higher MD in right CST predicted lower Perceptual Reasoning scores across all participants, p = .001. Furthermore, lower FA in left IFOF at baseline predicted decline in Processing Speed over time, p = .001. In patients, more aggressive treatment protocols and presence of mutism were related to lower performance on intelligence measures at baseline, ps < 0.04.

Conclusions: Children treated with CSR displayed diffuse white matter compromise and poor intellectual outcome shortly after radiation treatment. There was evidence of subsequent growth of white matter structure, but stable intellectual insult. Conversely, in children treated with either surgery only or surgery and focal radiation to the tumor bed we observed less compromise of white matter early following treatment and no intellectual insult compared to healthy children. However, declines in intellectual function were evident for these children, though their performance remained within the average normative range. Overall, results suggest that early intervention is necessary to circumvent these deficits.
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http://dx.doi.org/10.1016/j.nicl.2018.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139996PMC
January 2019

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

J Neurosci 2018 09 20;38(38):8251-8261. Epub 2018 Aug 20.

Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada,

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. 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.
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http://dx.doi.org/10.1523/JNEUROSCI.1056-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596162PMC
September 2018

Repairing the brain with physical exercise: Cortical thickness and brain volume increases in long-term pediatric brain tumor survivors in response to a structured exercise intervention.

Neuroimage Clin 2018 5;18:972-985. Epub 2018 Mar 5.

Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Psychology, University of Toronto, Toronto, Ontario, Canada. Electronic address:

There is growing evidence that exercise induced experience dependent plasticity may foster structural and functional recovery following brain injury. We examined the efficacy of exercise training for neural and cognitive recovery in long-term pediatric brain tumor survivors treated with radiation. We conducted a controlled clinical trial with crossover of exercise training (vs. no training) in a volunteer sample of 28 children treated with cranial radiation for brain tumors (mean age = 11.5 yrs.; mean time since diagnosis = 5.7 yrs). The endpoints were anatomical T1 MRI data and multiple behavioral outcomes presenting a broader analysis of structural MRI data across the entire brain. This included an analysis of changes in cortical thickness and brain volume using automated, user unbiased approaches. A series of general linear mixed effects models evaluating the effects of exercise training on cortical thickness were performed in a voxel and vertex-wise manner, as well as for specific regions of interest. In exploratory analyses, we evaluated the relationship between changes in cortical thickness after exercise with multiple behavioral outcomes, as well as the relation of these measures at baseline. Exercise was associated with increases in cortical thickness within the right pre and postcentral gyri. Other notable areas of increased thickness related to training were present in the left pre and postcentral gyri, left temporal pole, left superior temporal gyrus, and left parahippocampal gyrus. Further, we observed that compared to a separate cohort of healthy children, participants displayed multiple areas with a significantly thinner cortex prior to training and fewer differences following training, indicating amelioration of anatomical deficits. Partial least squares analysis (PLS) revealed specific patterns of relations between cortical thickness and various behavioral outcomes both after training and at baseline. Overall, our results indicate that exercise training in pediatric brain tumor patients treated with radiation has a beneficial impact on brain structure. We argue that exercise training should be incorporated into the development of neuro-rehabilitative treatments for long-term pediatric brain tumor survivors and other populations with acquired brain injury. (ClinicalTrials.gov, NCT01944761).
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http://dx.doi.org/10.1016/j.nicl.2018.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987848PMC
January 2019

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

Hum Brain Mapp 2018 01 14;39(1):204-217. Epub 2017 Oct 14.

Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario.

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.
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http://dx.doi.org/10.1002/hbm.23836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866408PMC
January 2018

Posterior fossa syndrome and long-term neuropsychological outcomes among children treated for medulloblastoma on a multi-institutional, prospective study.

Neuro Oncol 2017 Nov;19(12):1673-1682

Department of Psychology, Department of Biostatistics, and Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA; Department of Psychology, The Hospital for Sick Children, Toronto, Ontario, Canada; Lady Cilento Children's Hospital, South Brisbane, Queensland, Australia; Department of Psychiatry, Duke University Medical Center, Durham, North Carolina, USA; Department of Pediatric Medicine, Texas Children's Hospital, Houston, Texas, USA.

Background: Patients treated for medulloblastoma who experience posterior fossa syndrome (PFS) demonstrate increased risk for neurocognitive impairment at one year post diagnosis. The aim of the study was to examine longitudinal trajectories of neuropsychological outcomes in patients who experienced PFS compared with patients who did not.

Methods: Participants were 36 patients (22 males) who experienced PFS and 36 comparison patients (21 males) who were matched on age at diagnosis and treatment exposure but did not experience PFS. All patients underwent serial evaluation of neurocognitive functioning spanning 1 to 5 years post diagnosis.

Results: The PFS group demonstrated lower estimated mean scores at 1, 3, and 5 years post diagnosis on measures of general intellectual ability, processing speed, broad attention, working memory, and spatial relations compared with the non-PFS group. The PFS group exhibited estimated mean scores that were at least one standard deviation below the mean for intellectual ability, processing speed, and broad attention across all time points and for working memory by 5 years post diagnosis. Processing speed was stable over time. Attention and working memory declined over time. Despite some change over time, caregiver ratings of executive function and behavior problem symptoms remained within the average range.

Conclusion: Compared with patients who do not experience PFS, patients who experience PFS exhibit greater neurocognitive impairment, show little recovery over time, and decline further in some domains. Findings highlight the particularly high risk for long-term neurocognitive problems in patients who experience PFS and the need for close follow-up and intervention.
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http://dx.doi.org/10.1093/neuonc/nox135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716082PMC
November 2017

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

J Neurosci 2017 08 25;37(34):8227-8238. Epub 2017 Jul 25.

Neurosciences and Mental Health,

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. 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.
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http://dx.doi.org/10.1523/JNEUROSCI.0560-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596784PMC
August 2017

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

Hippocampus 2017 11 20;27(11):1140-1154. Epub 2017 Jul 20.

Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Canada.

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.
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http://dx.doi.org/10.1002/hipo.22758DOI Listing
November 2017

Repetitive Transcranial Magnetic Stimulation for the Treatment of Executive Function Deficits in Autism Spectrum Disorder: Clinical Trial Approach.

J Child Adolesc Psychopharmacol 2017 Jun 27;27(5):413-421. Epub 2017 Mar 27.

1 Centre for Brain and Mental Health, The Hospital for Sick Children , Toronto, Canada .

Objective: Executive function (EF) deficits in patients with autism spectrum disorder (ASD) are ubiquitous and understudied. Further, there are no effective, neuroscience-based treatments to address this impairing feature of ASD. Repetitive transcranial magnetic stimulation (rTMS) has demonstrated promise in addressing EF deficits in adult neuropsychiatric disorders. This article will outline the design of a novel randomized-controlled trial of bilateral, 20 Hz, rTMS applied to the dorsolateral prefrontal cortex (DLPFC) for treatment of EF deficits in ASD that is currently ongoing. We describe prior therapeutic rTMS research for ASD and prior rTMS trials targeting EFs in adult neuropsychiatric disorders. A neurophysiological rationale for rTMS treatment of EF deficits in ASD is presented.

Methods: An ongoing protocol will enroll participants aged 16-35 with ASD and no intellectual disability. Psychotropic medications will be continued during the 4-week trial of active 20 Hz versus sham rTMS applied to the DLPFC. Twenty, active treatment sessions consisting of 25 stimulation trains at a 90% motor threshold will be administered. The primary outcome measure is the Cambridge Neuropsychological Test Automated Battery (CANTAB) spatial working memory task. At present, recruitment, enrollment, and treatment within the described clinical trial are ongoing.

Conclusions: EF deficits are common and impairing symptoms of ASD. There are no evidence-based treatments for EF deficits in ASD. The protocol described here will provide important preliminary data on the feasibility and efficacy of 20 Hz rTMS to DLPFC for EF deficits in ASD.
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http://dx.doi.org/10.1089/cap.2016.0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510034PMC
June 2017

Exercise training for neural recovery in a restricted sample of pediatric brain tumor survivors: a controlled clinical trial with crossover of training versus no training.

Neuro Oncol 2017 03;19(3):440-450

Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Exercise promotes repair processes in the mouse brain and improves cognition in both mice and humans. It is not known whether these benefits translate to human brain injury, particularly the significant injury observed in children treated for brain tumors.

Methods: We conducted a clinical trial with crossover of exercise training versus no training in a restricted sample of children treated with radiation for brain tumors. The primary outcome was change in brain structure using MRI measures of white matter (ie, fractional anisotropy [FA]) and hippocampal volume [mm3]). The secondary outcome was change in reaction time (RT)/accuracy across tests of attention, processing speed, and short-term memory. Linear mixed modeling was used to test the effects of time, training, training setting, and carryover.

Results: Twenty-eight participants completed training in either a group (n=16) or a combined group/home (n=12) setting. Training resulted in increased white matter FA (Δ=0.05, P<.001). A carryover effect was observed for participants ~12 weeks after training (Δ=0.05, P<.001). Training effects were observed for hippocampal volume (Δ=130.98mm3; P=.001) and mean RT (Δ=-457.04ms, P=0.36) but only in the group setting. Related carryover effects for hippocampal volume (Δ=222.81mm3, P=.001), and RT (Δ=-814.90ms, P=.005) were also observed. Decreased RT was predicted by increased FA (R=-0.62, P=.01). There were no changes in accuracy.

Conclusions: Exercise training is an effective means for promoting white matter and hippocampal recovery and improving reaction time in children treated with cranial radiation for brain tumors.
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http://dx.doi.org/10.1093/neuonc/now177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464296PMC
March 2017

Intellectual Outcome in Molecular Subgroups of Medulloblastoma.

J Clin Oncol 2016 12 31;34(34):4161-4170. Epub 2016 Oct 31.

Iska Moxon-Emre, Michael D. Taylor, Eric Bouffet, David Malkin, Cynthia Hawkins, Normand Laperriere, Vijay Ramaswamy, Ute Bartels, Nadia Scantlebury, Laura Janzen, Nicole Law, and Donald J. Mabbott, Hospital for Sick Children; Iska Moxon-Emre, Michael D. Taylor, David Malkin, Cynthia Hawkins, Normand Laperriere, Laura Janzen, Nicole Law, and Donald J. Mabbott, University of Toronto; Iska Moxon-Emre and David Malkin, Pediatric Oncology Group of Ontario; Normand Laperriere, Princess Margaret Hospital, Toronto, ON, Canada; Kristina Hardy and Karin S. Walsh, Children's National Health System, Washington, DC; and Cynthia J. Campen, Lucile Packard Children's Hospital, Palo Alto, CA.

Purpose To evaluate intellectual functioning and the implications of limiting radiation exposure in the four biologically distinct subgroups of medulloblastoma: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Patients and Methods A total of 121 patients with medulloblastoma (n = 51, Group 4; n = 25, Group 3; n = 28, SHH; and n = 17, WNT), who were treated between 1991 and 2013 at the Hospital for Sick Children (Toronto, Ontario, Canada), Children's National Health System (Washington, DC), or the Lucile Packard Children's Hospital (Palo Alto, CA), had intellectual assessments. First, we compared intellectual trajectories between subgroups. Next, we evaluated the effect of treatment with reduced-dose craniospinal irradiation (CSI) plus a tumor bed boost versus treatments that deliver higher CSI doses and/or larger boost volumes to the brain (all other treatments) within subgroups. Linear mixed modeling was used to determine the stability or change in intelligence scores over time. Results Intellectual outcomes declined comparably in each subgroup except for processing speed; SHH declined less than Group 3 ( P = .04). SHH had the lowest incidence of cerebellar mutism and motor deficits. Treatment with reduced-dose CSI plus a tumor bed boost was associated with preserved intellectual functioning in WNT and Group 4 patients considered together (ie, subgroups containing patients who are candidates for therapy de-escalation), and not in Group 3 or SHH. Across all subgroups, patients in the all other treatments group declined over time (all P < .05). Conclusion SHH patients appear to have the most distinct functional (ie, motor deficits and mutism) outcomes and a unique processing speed trajectory. Only WNT and Group 4 patients seem to benefit from limiting radiation exposure. Our findings highlight the value of conducting subgroup-specific analyses, and can be used to inform novel biologically based treatment protocols for patients with medulloblastoma.
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http://dx.doi.org/10.1200/JCO.2016.66.9077DOI Listing
December 2016

Vulnerability of white matter to insult during childhood: evidence from patients treated for medulloblastoma.

J Neurosurg Pediatr 2016 Jul 25;18(1):29-40. Epub 2016 Mar 25.

Program in Neuroscience and Mental Health and 

OBJECTIVE Craniospinal irradiation damages the white matter in children treated for medulloblastoma, but the treatment-intensity effects are unclear. In a cross-sectional retrospective study, the effects of treatment with the least intensive radiation protocol versus protocols that delivered more radiation to the brain, in addition to the effects of continuous radiation dose, on white matter architecture were evaluated. METHODS Diffusion tensor imaging was used to assess fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity. First, regional white matter analyses and tract-based spatial statistics were conducted in 34 medulloblastoma patients and 38 healthy controls. Patients were stratified according to those treated with 1) the least intensive radiation protocol, specifically reduced-dose craniospinal irradiation plus a boost to the tumor bed only (n = 17), or 2) any other dose and boost combination that delivered more radiation to the brain, which was also termed the "all-other-treatments" group (n = 17), and comprised patients treated with standard-dose craniospinal irradiation plus a posterior fossa boost, standard-dose craniospinal irradiation plus a tumor bed boost, or reduced-dose craniospinal irradiation plus a posterior fossa boost. Second, voxel-wise dose-distribution analyses were conducted on a separate cohort of medulloblastoma patients (n = 15). RESULTS The all-other-treatments group, but not the reduced-dose craniospinal irradiation plus tumor bed group, had lower fractional anisotropy and higher radial diffusivity than controls in all brain regions (all p < 0.05). The reduced-dose craniospinal irradiation plus tumor bed boost group had higher fractional anisotropy (p = 0.05) and lower radial diffusivity (p = 0.04) in the temporal region, and higher fractional anisotropy in the frontal region (p = 0.04), than the all-other-treatments group. Linear mixed-effects modeling revealed that the dose and age at diagnosis together 1) better predicted fractional anisotropy in the temporal region than models with either alone (p < 0.005), but 2) did not better predict fractional anisotropy in comparison with dose alone in the occipital region (p > 0.05). CONCLUSIONS Together, the results show that white matter damage has a clear association with increasing radiation dose, and that treatment with reduced-dose craniospinal irradiation plus tumor bed boost appears to preserve white matter in some brain regions.
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http://dx.doi.org/10.3171/2016.1.PEDS15580DOI Listing
July 2016