Sick Kids Research Institute

Toronto, Canada

Sick Kids Research Institute

Toronto, Canada
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Theriault B.L.,Campbell Family Cancer Research Institute | Dimaras H.,University of Toronto | Dimaras H.,Western Research Institute | Dimaras H.,Sick Kids Research Institute | And 4 more authors.
Clinical and Experimental Ophthalmology | Year: 2014

Retinoblastoma is a paediatric ocular tumour that continues to reveal much about the genetic basis of cancer development. Study of genomic aberrations in retinoblastoma tumours has exposed important mechanisms of cancer development and identified oncogenes and tumour suppressors that offer potential points of therapeutic intervention. The recent development of next-generation genomic technologies has allowed further refinement of the genomic landscape of retinoblastoma at high resolution. In a relatively short period of time, a wealth of genetic and epigenetic data has emerged on a small number of tumour samples. These data highlight the inherent molecular complexity of this cancer despite the fact that most retinoblastomas are initiated by the inactivation of a single tumour suppressor gene. This review outlines the current understanding of the genomic, genetic and epigenetic changes in retinoblastoma, highlighting recent genome-wide analyses that have identified exciting candidate genes worthy of further validation as potential prognostic and therapeutic targets. copy; 2013 Royal Australian and New Zealand College of Ophthalmologists.


Yu V.Y.,Hospital for Sick Children | Yu V.Y.,Sick Kids Research Institute | De Nil L.F.,University of Toronto | Pang E.W.,Hospital for Sick Children | Pang E.W.,Sick Kids Research Institute
Language and Speech | Year: 2015

Voice onset time (VOT) is a temporal acoustic parameter that reflects motor speech coordination skills. This study investigated the patterns of age and sex differences across development of voice onset time in a group of 70 English-speaking children, ranging in age from 4.1 to 18.4 years, and 12 young adults. The effect of the number of syllables on VOT patterns was also examined. Speech samples were elicited by producing syllables /pa/ and /pataka/. Results supported previous findings showing that younger children produce longer VOT values with higher levels of variability. Markedly higher VOT values and increased variability were found for boys at ages between 8 and 11 years, confirming sex differences in VOT patterns and patterns of variability. In addition, all participants consistently produced shorter VOT with higher variability for multisyllables than monosyllables, indicating an effect of syllable number. Possible explanations for these findings and clinical implications are discussed. © The Author(s) 2014.


Pang E.W.,Hospital for Sick Children | Pang E.W.,Sick Kids Research Institute | Pang E.W.,University of Toronto
Frontiers in Psychiatry | Year: 2015

Mental flexibility is a core executive function that underlies the ability to adapt to changing situations and respond to new information. Individuals with post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) complain of a number of executive function difficulties, one of which is mental inflexibility or an inability to switch between concepts. While the behavioral presentation of mental inflexibility is similar in those with PTSD or mTBI, we hypothesized that the differences in their etiology would manifest as differences in their underlying brain processing. The neural substrates of mental flexibility have been examined with a number of neuroimaging modalities. Functional magnetic resonance imaging has elucidated the brain regions involved, whereas electroencephalography has been applied to understand the timing of the brain activations. Magnetoencephalography, with its high temporal and spatial resolution, has more recently been used to delineate the spatiotemporal progression of brain processes involved in mental flexibility and has been applied to the study of clinical populations. In a number of separate studies, our group has compared the source localization and brain connectivity during a mental flexibility set-shifting task in a group of soldiers with PTSD and civilians with an acute mTBI. In this article, we review the results from these studies and integrate the data between groups to compare and contrast differences in behavioral, neural, and connectivity findings. We show that the different etiologies of PTSD and mTBI are expressed as distinct neural profiles for mental flexibility that differentiate the groups despite their similar clinical presentations. © 2015 Pang.


PubMed | University of Toronto, Holland Bloorview Kids Rehabilitation Hospital, Hospital for Sick Children and Sick Kids Research Institute
Type: Journal Article | Journal: Autism research : official journal of the International Society for Autism Research | Year: 2016

A large proportion of children with autism spectrum disorder (ASD) have speech and/or language difficulties. While a number of structural and functional neuroimaging methods have been used to explore the brain differences in ASD with regards to speech and language comprehension and production, the neurobiology of basic speech function in ASD has not been examined. Magnetoencephalography (MEG) is a neuroimaging modality with high spatial and temporal resolution that can be applied to the examination of brain dynamics underlying speech as it can capture the fast responses fundamental to this function. We acquired MEG from 21 children with high-functioning autism (mean age: 11.43 years) and 21 age- and sex-matched controls as they performed a simple oromotor task, a phoneme production task and a phonemic sequencing task. Results showed significant differences in activation magnitude and peak latencies in primary motor cortex (Brodmann Area 4), motor planning areas (BA 6), temporal sequencing and sensorimotor integration areas (BA 22/13) and executive control areas (BA 9). Our findings of significant functional brain differences between these two groups on these simple oromotor and phonemic tasks suggest that these deficits may be foundational and could underlie the language deficits seen in ASD.


Wasserman J.D.,University of Toronto | Wasserman J.D.,Sick Kids Research Institute | Novokmet A.,University of Toronto | Eichler-Jonsson C.,University of Toronto | And 5 more authors.
Journal of Clinical Oncology | Year: 2015

Purpose: Adrenocortical carcinoma (ACC) is a rare pediatric malignancy. It occurs in excess among individuals with the Li-Fraumeni syndrome, which results primarily from germline mutations in the TP53 gene. Prior series exploring frequencies of germline TP53 mutation among children with ACC have been small, geographically limited, or subject to referral bias. The functional consequence of mutations has not been related to phenotype. We provide a genotype-phenotype analysis of TP53 mutations in pediatric ACC and propose a model for tissue-specific effects based on adrenocortical ontogeny. Patients and Methods: Eighty-eight consecutive, unrelated children with ACC, unselected for family history, underwent germline TP53 sequencing. Rate and distribution of mutations were identified. Functional analysis was performed for novel TP53 variants. Correlation with the International Agency for Research on Cancer p53 database further delineated mutational distribution, association with family history, and risk for multiple primary malignancies (MPMs). Results: Germline mutations were present in 50% of children. These mutations did not correspond to the conventional hotspot mutations. There was a wide range of mutant protein function. Patients bearing alleles encoding protein with higher functionality were less likely to have a strong family cancer history, whereas those with greater loss of function had MPMs and/or positive family history. In patients with MPMs, ACC was the most frequent initial malignancy. Finally, we demonstrated age-dependent rates of TP53 mutation positivity. Conclusion: TP53 mutations are prevalent in children with ACC but decline with age. Mutations result in a broad spectrum of functional loss. Effect of individual mutations may predict carrier and familial disease penetrance with potentially broad implications for clinical surveillance and counseling. © 2015 by American Society of Clinical Oncology.


Yu V.Y.,Sick Kids Research Institute | MacDonald M.J.,Sick Kids Research Institute | Oh A.,Sick Kids Research Institute | Hua G.N.,Sick Kids Research Institute | And 2 more authors.
Developmental psychology | Year: 2014

It is well supported by behavioral and neuroimaging studies that typical language function is lateralized to the left hemisphere in the adult brain and this laterality is less well defined in children. The behavioral literature suggests there maybe be sex differences in language development, but this has not been examined systematically with neuroimaging. In this study, magnetoencephalography was used to investigate the spatiotemporal patterns of language lateralization as a function of age and sex. Eighty typically developing children (46 female, 34 male; 4-18 years) participated in an overt visual verb generation task. An analysis method called differential beamforming was used to analyze language-related changes in oscillatory activity referred to as low-gamma event-related desynchrony (ERD). The proportion of ERD over language areas relative to total ERD was calculated. We found different patterns of laterality between boys and girls. Boys showed left-hemisphere lateralization in the frontal and temporal language-related areas across age groups, whereas girls showed a more bilateral pattern, particularly in frontal language-related areas. Differences in patterns of ERD were most striking between boys and girls in the younger age groups, and these patterns became more similar with increasing age, specifically in the preteen years. Our findings show sex differences in language lateralization during childhood; however, these differences do not seem to persist into adulthood. We present possible explanations for these differences. We also discuss the implications of these findings for presurgical language mapping in children and highlight the importance of examining the question of sex-related language differences across development.


Pang E.W.,University of Toronto | Pang E.W.,Sick Kids Research Institute | MacDonald M.J.,Sick Kids Research Institute
Brain Research | Year: 2012

Studies of first (L1) and second (L2) language representation in the brain have not identified the timing and locations of neural regions involved in L1 and L2 processing. Magnetoencephalography offers high spatial and temporal resolution and can be employed to disentangle subtle timing and neural control differences between L1 and L2 use. We tested bilingual adults in the MEG as they completed a picture verb generation task in L1 and L2. We found the expected progression of activation from occipital to temporal to inferior frontal areas. We also observed the following differences. A sustained insula and early cingulate event-related desynchrony was observed only with L2; the fMRI literature suggests that the former reflects an activation, and the latter an inhibition, sub-process for language selection. L2 processes exhibited a lag and were bilateral compared to L1 processes. Finally, L1 and L2 activated adjacent language control in dorsolateral pre-frontal cortex. © 2012 Elsevier B.V.


PubMed | Sick Kids Research Institute
Type: Journal Article | Journal: Clinical linguistics & phonetics | Year: 2014

This study evaluated changes in motor speech control and inter-gestural coordination for children with speech sound disorders (SSD) subsequent to Prompts for Restructuring Oral and Muscular Phonetic Targets (PROMPT) intervention. We measured the distribution patterns of voice onset time (VOT) for a voiceless stop (/p/) to examine the changes in inter-gestural coordination. Two standardized tests were used (Verbal Motor Production Assessment for Children (VMPAC), GFTA-2) to assess the changes in motor speech skills and articulation. Data showed positive changes in patterns of VOT with a lower pattern of variability. All children showed significantly higher scores for VMPAC, but only some children showed higher scores for GFTA-2. Results suggest that the proprioceptive feedback provided through PROMPT had a positive influence on speech motor control and inter-gestural coordination in voicing behavior. This set of VOT data for children with SSD adds to our understanding of the speech characteristics underlying speech motor control. Directions for future studies are discussed.


PubMed | Sick Kids Research Institute and University of Toronto
Type: Journal Article | Journal: Developmental psychology | Year: 2014

It is well supported by behavioral and neuroimaging studies that typical language function is lateralized to the left hemisphere in the adult brain and this laterality is less well defined in children. The behavioral literature suggests there maybe be sex differences in language development, but this has not been examined systematically with neuroimaging. In this study, magnetoencephalography was used to investigate the spatiotemporal patterns of language lateralization as a function of age and sex. Eighty typically developing children (46 female, 34 male; 4-18 years) participated in an overt visual verb generation task. An analysis method called differential beamforming was used to analyze language-related changes in oscillatory activity referred to as low-gamma event-related desynchrony (ERD). The proportion of ERD over language areas relative to total ERD was calculated. We found different patterns of laterality between boys and girls. Boys showed left-hemisphere lateralization in the frontal and temporal language-related areas across age groups, whereas girls showed a more bilateral pattern, particularly in frontal language-related areas. Differences in patterns of ERD were most striking between boys and girls in the younger age groups, and these patterns became more similar with increasing age, specifically in the preteen years. Our findings show sex differences in language lateralization during childhood; however, these differences do not seem to persist into adulthood. We present possible explanations for these differences. We also discuss the implications of these findings for presurgical language mapping in children and highlight the importance of examining the question of sex-related language differences across development.


PubMed | Sick Kids Research Institute
Type: Journal Article | Journal: Neuroscience letters | Year: 2012

We used whole-head magnetoencephalography to investigate cortical activity during two oromotor activities foundational to speech production. 13 adults performed mouth opening and phoneme (/pa/) production tasks to a visual cue. Jaw movements were tracked with an ultrasound-emitting device. Trials were time-locked to both stimulus onset and peak of jaw displacement. An event-related beamformer source reconstruction algorithm was used to detect areas of cortical activity for each condition. Beamformer output was submitted to iterative K-means clustering analyses. The time course of neural activity at each cluster centroid was computed for each individual and condition. Peaks were identified and latencies submitted for statistical analysis to reveal the relative timing of activity in each brain region. Stimulus locked activations for the mouth open task included a progression from left cuneus to left frontal and then right pre-central gyrus. Phoneme generation revealed the same sequence but with bilateral frontal activation. When time locked to jaw displacement, the mouth open condition showed left frontal followed by right frontal-temporal areas. Phoneme generation showed a complicated sequence of bilateral temporal and frontal areas. This study used three unique approaches (beamforming, clustering and jaw tracking) to demonstrate the temporal progression of neural activations that underlie the motor control of two simple oromotor tasks. These findings have implications for understanding clinical conditions with deficits in articulatory control or motor speech planning.

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