Reprint of: Minimizing noise in pediatric task-based functional MRI; Adolescents with developmental disabilities and typical development

Functional Magnetic Resonance Imaging (fMRI) represents a powerful tool with which to examine brain functioning and development in typically developing pediatric groups as well as children and adolescents with clinical disorders. However, fMRI data can be highly susceptible to misinterpretation due to the effects of excessive levels of noise, often related to head motion. Imaging children, especially with developmental disorders, requires extra considerations related to hyperactivity, anxiety and the ability to perform and maintain attention to the fMRI paradigm. We discuss a number of methods that can be employed to minimize noise, in particular movement-related noise. To this end we focus on strategies prior to, during and following the data acquisition phase employed primarily within our own laboratory. We discuss the impact of factors such as experimental design, screening of potential participants and pre-scan training on head motion in our adolescents with developmental disorders and typical development. We make some suggestions that may minimize noise during data acquisition itself and finally we briefly discuss some current processing techniques that may help to identify and remove noise in the data. Many advances have been made in the field of pediatric imaging, particularly with regard to research involving children with developmental disorders. Mindfulness of issues such as those discussed here will ensure continued progress and greater consistency across studies

Cerebral language networks and neuropsychological profile in children with frontotemporal lobe epilepsy : a multimodal neuroimaging and neuropsychological approach

Thèse de doctorat présentée en vue de l'obtention du doctorat en psychologie (Ph.D).L'enfance et l'adolescence sont des périodes uniques de la vie où les changements neuronaux favorisent l'établissement de réseaux cérébraux matures et le développement des capacités intellectuelles. Le langage est un domaine cognitif qui est, non seulement essentiel pour la communication interhumaine, mais qui contribue également au développement de nombreuse capacités et prédit de manière significative la réussite académique. Les régions cérébrales frontotemporales sont des régions clés du réseau langagier du cerveau. Il a été démontré que les neuropathologies telles que l'épilepsie des lobes frontal et temporal (ELF et ELT) interfèrent avec le développement des réseaux cérébraux du langage et provoquent des circuits cérébraux aberrants. Les patrons exacts de réorganisation des réseaux cérébraux fonctionnels ne sont toutefois, pas entièrement compris et l'association avec le profil neuropsychologique reste spéculative. Par conséquent, l'objectif principal de cette thèse est d'accroître la compréhension des altérations du réseau langagier et d'améliorer les connaissances de l'association de l'architecture du réseau et des capacités cognitives chez les enfants et les adolescents avec ELF ou ELT. La présente thèse est composée de trois articles scientifiques, les deux premiers présentant des travaux méthodologiques qui ont permis d'optimiser les méthodes appliquées dans le troisième article, l'étude empirique principale menée auprès d'enfants avec ELF et ELT. Le premier article présente le bilan neuropsychologique pédiatrique comme un outil important pour estimer les capacités cognitives et dresser un profil cognitif avec ses forces et ses faiblesses. Dans le deuxième article, l'analyse factorielle parallèle (PARAFAC) est présentée et validée comme une nouvelle technique employée pour corriger les artefacts de mouvement qui contaminent le signal hémodynamique évalué par la spectroscopie fonctionnelle proche infrarouge (fNIRS). Une meilleure qualité du signal permet une interprétation fiable de la réponse cérébrale en plis de déduire des métriques d'organisation du réseau cérébral. Le troisième article consiste en une étude empirique, où le traitement cérébral du langage, est comparé entre des enfants avec ELF et ELT, et des pairs neuroptypiques. Les schémas de connectivité fonctionnelle indiquent que le groupe de patients présente moins de connexions intra-hémisphériques dans l'hémisphère gauche et entre les hémisphères, et des connexions accrues dans l'hémisphère droit par rapport au groupe témoin. Les mesures de l'architecture du réseau révèlent en outre une efficacité de traitement local plus élevée dans l'hémisphère droit chez les enfants atteints de ELF et ELT par rapport aux enfants en bonne santé. L'architecture du réseau local de l'hémisphère gauche et la capacité intellectuelle globale dans le groupe de patients sont négativement liées, tandis que dans le groupe contrôle, aucune association de ce type n'est identifiable. Ces résultats suggèrent que la réorganisation du réseau de langage chez les enfants avec ELF ou ELT semble dans certains cas soutenir un meilleur résultat cognitif, soit lorsque l'efficacité du traitement local dans l'hémisphère gauche est diminuée. Au contraire, une plus grande efficacité de traitement local semble être une caractéristique d'un réseau de langage cérébral associé à de moins bonnes capacités cognitives. Les travaux de recherche de cette thèse de doctorat fournissent des lignes directrices pour l'utilisation de l'évaluation neuropsychologique pédiatrique, à la fois dans un contexte clinique et scientifique. L'introduction de PARAFAC pour corriger les artefacts de mouvement dans le signal fNIRS est un ajout important au pipeline de prétraitement qui permet d'augmenter la qualité du signal pour une analyse ultérieure. De futurs projets pourront s'appuyer sur cette validation initiale et étendre l'utilisation de PARAFAC pour les analyses du signal fNIRS. Sur cette base méthodologique solide, le travail empirique confirme l'incidence accrue de circuits cérébraux aberrants liés au traitement du langage chez les enfants atteints de ELF et de ELT, et soutient en outre l'efficacité du réseau local en tant que déterminant clé de l'impact de la plasticité cérébrale précoce sur les capacités cognitives. Afin de mieux comprendre les altérations du réseau en réponse aux neuropathologies et leur impact, des études avec des échantillons plus grands et de différents groupes d'âge, devraient étudier plus spécifiquement le rôle des facteurs cliniques (e.g., le type d'épilepsie, la latéralisation de l'épilepsie, le contrôle des crises, etc.) et aborder leurs influences sur le développement. À long terme, cela augmentera le pronostic des phénotypes cliniques chez les patients pédiatriques atteints de ELF et de ELT, et offrira des opportunités d'interventions précoces pour soutenir un développement typique.Childhood and adolescence are unique periods in life where neuronal changes support the establishment of mature brain networks and the development of intellectual capacities. Language is one cognitive domain that is not only an essential part of inter-human communication but also contributes to the development of other capacities and significantly influences academic achievement. Frontotemporal brain areas are key regions of the brain's language network. Neuropathologies such as frontal and temporal lobe epilepsies (FLE and TLE) have been shown to interfere with developing brain language networks and cause aberrant cerebral circuits. The exact patterns of functional brain network reorganization are not fully understood and the association with the neuropsychological profile remains speculative. Therefore, the main objective of this thesis was to increase comprehension of language network alterations and enhance the knowledge on the association of network topology and cognitive capacities in children and adolescents with FLE or TLE. This thesis consists of three scientific articles, with the first two presenting methodological work that allowed for the optimization of the methods applied in the third article, which is the main empirical study conducted on children with FLE and TLE. The first article presents the pediatric neuropsychological assessment as a valuable tool to estimate cognitive capacities and draw a cognitive profile with strengths and weaknesses. In the second article, parallel factor analysis (PARAFAC) is presented and validated as a novel technique to correct motion artifacts that contaminate the hemodynamic signal assessed with functional near-infrared spectroscopy (fNIRS). A better signal quality is the basis for a reliable interpretation of the cerebral response and derive metrics of brain network organization. The third article consists of an empirical study where cerebral language processing is compared between children with FLE and TLE, and neuroptypical peers. Patterns of functional connectivity indicate that the patient group demonstrates fewer intra-hemispheric connections in the left hemisphere and between hemispheres, and increased connections within the right hemisphere as compared to the control group. Metrics of network architecture further reveal a higher local processing efficiency within the right hemisphere in children with FLE and TLE compared to healthy peers. Local network architecture of the left hemisphere and the overall intellectual capacity in the patient group is negatively related, while in the control group no such association is identifiable. These findings suggest that language network reorganization in children with FLE or TLE in some cases seems to support a better cognitive outcome, namely when local processing efficiency in the left hemisphere is decreased. On the contrary, a higher local processing efficiency seems to be a characteristic of a brain language network that goes along with worse cognitive capacities. The research work of this doctoral thesis provides guidelines for the use of pediatric neuropsychological assessment both in a clinical and scientific context. The introduction of PARAFAC to correct motion artifact in the fNIRS signal is an important add-on to the preprocessing pipeline that allows to increase signal quality for subsequent analysis. Future projects will be able to build on this initial validation and extend PARAFAC's use for fNIRS analysis. On this solid methodological foundation, the empirical work confirms the increased incidence of aberrant brain circuits related to language processing in children with FLE and TLE, and further supports local network efficiency as a key determinant of the impact of early brain plasticity on cognitive capacities. In order to further understand network alterations in response to neuropathologies and their impact, studies with larger samples sizes and different age groups should further investigate the specific role of clinical factors (e.g., epilepsy type, epilepsy lateralization, seizure control, etc.) and address developmental influences. Ultimately, this will increase prognosis of clinical phenotypes in pediatric patients with FLE and TLE, and offer opportunities for early interventions to support a healthy development

Functional Magnetic Resonance Imaging in Pediatrics

Functional magnetic resonance imaging (fMRI) allows non-invasive assessment of human brain function in vivo by detecting blood flow differences. In this review, we want to illustrate the background and different aspects of performing functional magnetic resonance imaging (fMRI) in the pediatric age group. An overview over current and future applications of fMRI will be given, and typical problems, pitfalls, and benefits of doing fMRI in the pediatric age group are discussed. We conclude that fMRI can successfully be applied in children and holds great promise for both research and clinical purposes

Multivariate pattern classification of pediatric Tourette syndrome using functional connectivity MRI

Tourette syndrome (TS) is a developmental neuropsychiatric disorder characterized by motor and vocal tics. Individuals with TS would benefit greatly from advances in prediction of symptom timecourse and treatment effectiveness. As a first step, we applied a multivariate method - support vector machine (SVM) classification - to test whether patterns in brain network activity, measured with resting state functional connectivity (RSFC) MRI, could predict diagnostic group membership for individuals. RSFC data from 42 children with TS (8-15 yrs) and 42 unaffected controls (age, IQ, in-scanner movement matched) were included. While univariate tests identified no significant group differences, SVM classified group membership with ~70% accuracy (p < .001). We also report a novel adaptation of SVM binary classification that, in addition to an overall accuracy rate for the SVM, provides a confidence measure for the accurate classification of each individual. Our results support the contention that multivariate methods can better capture the complexity of some brain disorders, and hold promise for predicting prognosis and treatment outcome for individuals with TS

Genetic and environmental influences on MRI scan quantity and quality.

The current study provides an overview of quantity and quality of MRI data in a large developmental twin sample (N = 512, aged 7–9), and investigated to what extent scan quantity and quality were influenced by genetic and environmental factors. This was examined in a fixed scan protocol consisting of two functional MRI tasks, high resolution structural anatomy (3DT1) and connectivity (DTI) scans, and a resting state scan. Overall, scan quantity was high (88% of participants completed all runs), while scan quality decreased with increasing session length. Scanner related distress was negatively associated with scan quantity (i.e., completed runs), but not with scan quality (i.e., included runs). In line with previous studies, behavioral genetic analyses showed that genetics explained part of the variation in head motion, with heritability estimates of 29% for framewise displacement and 65% for absolute displacement. Additionally, our results revealed that subtle head motion (after exclusion of excessive head motion) showed lower heritability estimates (0–14%), indicating that findings of motion-corrected and quality-controlled MRI data may be less confounded by genetic factors. These findings provide insights in factors contributing to scan quality in children, an issue that is highly relevant for the field of developmental neuroscience

An Investigation into the Neurodevelopmental Profile of Infants and Children with chronic liver disease

Children born with serious early-onset organ disease are now surviving into adulthood, but the impact of a lifelong physical condition is rarely restricted to one organ. For example, Biliary Atresia (BA) is a progressive life-threatening liver disease that requires surgical intervention in infants to clear jaundice and support survival past the second year of life. It is the most common cause of end-stage liver failure in children and the most frequent indication for paediatric liver transplantation worldwide. Its associated educational difficulties, under-or unemployment, and adverse mental health outcomes suggests that BA has a considerable impact on brain maturation. However, previous studies have examined cohorts over a wide age range and with multiple disease etiologies, making it impossible to determine when difficulties start, and which problems are secondary to the effects of living with a chronic condition. Disease onset occurs during the highly sensitive perinatal period of brain development, making an influence on foundational steps of neurodevelopment likely. It also involves an inflammatory process, and early exposure to immune activation is linked to neurodevelopmental conditions such as autism spectrum disorder (ASD). However, no one has comprehensively examined early neurodevelopmental outcomes in young children with BA, nor their pathophysiological correlates. This is critical to do because disrupting early childhood brain development can have a lifelong impact; whereas identifying intervention targets may be a much-needed step to improve outcomes. The overall goal of this thesis was to assess the impact of BA on neurodevelopment. My first task was to gain a descriptive overview of neurodevelopment in BA children obtained through a parental survey. Once I gained an initial understanding of the typical problems faced by these children, I recruited a homogeneous BA infant group to take part in standardized developmental assessments. Using the Mullens Scale of Early Learning and the Vineland Adaptive Behaviour Interview, I assessed the language, motor, and cognitive abilities of BA infants and compared the assessment results to a matched cohort of typically developing infants. I then carried out an exploratory analysis to determine whether the extent of any neurodevelopmental difficulties in infants with BA was related to key disease-related variables, namely transplant status, prolonged jaundice, and nutritional status. I also administered a standard observational assessment, the Autism Diagnostic Observation Schedule, to a sub-sample of the older BA infants to capture early emerging autistic behaviours. Finally, to explore the brain mechanisms behind any neurodevelopmental outcomes observed, I developed a protocol to acquire Magnetic Resonance Imaging (MRI) scans in unsedated 6-month-old infants to give participants a choice of scanning under sedation or scanning under natural sleep. I compared the metabolite profile obtained under sedation with the unsedated data from typical infants to determine if any metabolites were especially sensitive to sedation. I then carried out a pilot Magnetic Resonance Spectroscopy (MRS) study of key brain metabolites in a small subgroup of 6-month-old infants with BA – the first study at this early age. In line with my hypothesis, the parental survey highlighted neurodevelopmental concerns, with over half of the BA paediatric population utilizing one or more additional developmental service, and a higher rate of ASD diagnoses than would be expected in the population. Subsequently, deeper phenotyping of an early childhood sample revealed significantly lower composite and sub-domain scores across the Mullens and the Vineland. Further analysis revealed that early disease-related factors such as earlier surgical intervention and subsequent faster clearance of jaundice after surgical intervention predicted better neurodevelopmental outcomes. In the sample where ADOS was possible, 40% scored above the diagnostic threshold for ASD. The unsedated MRI protocol I designed delivered an 80% scanning success rate. This allowed for a comparison of metabolite values across cohorts which showed significant changes in metabolite concentrations across sedation conditions. Finally, the pilot study highlighted a significantly different metabolite profile in the BA 6-month cohort compared to a reference sample, coupled with global developmental delay as measured by the Mullens at the time of scanning. Overall, this thesis demonstrates significant and wide-ranging neurodevelopmental difficulties in the BA cohort compared to their age-matched peers. Thus, early exposure to this serious systemic insult caused by liver disease has a contemporaneous influence on the developing brain. This influence has a dramatic effect on general neurodevelopment, but results from our autism instrument also indicates an impact on the development of the social brain. Findings suggest that earlier Kasai and earlier clearance of jaundice may be useful intervention targets, and an MRI protocol has been devised to allow for the mechanisms of neurodevelopmental growth to be investigated further.This work highlights the importance of integrating physical and neurodevelopmental healthcare protocols, not only to improve prognostication, but to begin to develop intervention protocols which may well limit adverse outcomes in childhood (and beyond). I advocate for the implementation of simple, reliable neurodevelopmental assessments into the patient’s regular care to allow for early identification of difficulties and earlier intervention programmes. This will allow children with BA to grow up to experience the least possible interferences of their disease on brain health

The Human Auditory System

This book presents the latest findings in clinical audiology with a strong emphasis on new emerging technologies that facilitate and optimize a better assessment of the patient. The book has been edited with a strong educational perspective (all chapters include an introduction to their corresponding topic and a glossary of terms). The book contains material suitable for graduate students in audiology, ENT, hearing science and neuroscience

Structural gray matter features and behavioral preliterate skills predict future literacy – A machine learning approach

When children learn to read, their neural system undergoes major changes to become responsive to print. There seem to be nuanced interindividual differences in the neurostructural anatomy of regions that later become integral parts of the reading network. These differences might affect literacy acquisition and, in some cases, might result in developmental disorders like dyslexia. Consequently, the main objective of this longitudinal study was to investigate those interindividual differences in gray matter morphology that might facilitate or hamper future reading acquisition. We used a machine learning approach to examine to what extent gray matter macrostructural features and cognitive-linguistic skills measured before formal literacy teaching could predict literacy 2 years later. Forty-two native German-speaking children underwent T1-weighted magnetic resonance imaging and psychometric testing at the end of kindergarten. They were tested again 2 years later to assess their literacy skills. A leave-one-out cross-validated machine-learning regression approach was applied to identify the best predictors of future literacy based on cognitive-linguistic preliterate behavioral skills and cortical measures in a priori selected areas of the future reading network. With surprisingly high accuracy, future literacy was predicted, predominantly based on gray matter volume in the left occipito-temporal cortex and local gyrification in the left insular, inferior frontal, and supramarginal gyri. Furthermore, phonological awareness significantly predicted future literacy. In sum, the results indicate that the brain morphology of the large-scale reading network at a preliterate age can predict how well children learn to read

Contemporary Trends in ADHD Research

With many children and adults affected by Attention Deficit Hyperactivity Disorder, researchers strive to understand the underpinnings of ADHD and associated factors on both a basic and applied level. The goal of this volume is to explore some of the broad array of research in the field of ADHD. The 12 chapters cover a variety of topics as varied as postural control, endocrine dysfunction, juvenile justice, and academic outcomes. These chapters will provide valuable insights for students reading about ADHD for the first time, researchers wishing to learn about the latest advances, and practitioners seeking new insight in the field