Darren S. Kadis

Understanding how the human brain matures from infancy through adolescence is essential for identifying factors that influence health outcomes. Magnetic resonance imaging (MRI) provides powerful tools for characterizing structural, microstructural, functional, and metabolic aspects of brain development; however, many pediatric imaging studies are constrained by small sample sizes, limited geographic diversity, lack of longitudinal measurement, restricted age ranges, and heterogeneous acquisition protocols. While recent large-scale neuroimaging consortia have begun to address these challenges, such resources remain limited in the Canadian context, creating a critical gap. The Canadian Pediatric Imaging Platform (C-PIP) has developed a multisite neuroimaging framework across three of Canada’s largest pediatric hospitals: Alberta Children’s Hospital (Calgary), Centre Hospitalier Universitaire Sainte-Justine (Montréal), and the Hospital for Sick Children (Toronto). These three sites were united through a national initiative, leveraging high-performance MRI systems to accelerate Canadian neurodevelopmental research. In addition, C-PIP has implemented a centralized data sharing infrastructure to facilitate open science and collaborative research across institutions. Here, we describe the development and implementation of a multimodal MRI acquisition protocol designed to support multimodal longitudinal studies of typical and atypical brain development spanning infancy through adolescence. Within-site stability and cross-site stability of C-PIP core MRI sequences were evaluated using a travelling-participant study. The C-PIP MRI protocol establishes a harmonized, multisite imaging framework that supports large-scale investigations of pediatric brain development and disorders. Highlights: The Canadian Pediatric Imaging Platform (C-PIP) is a national initiative acquiring longitudinal phenotyping and neuroimaging data from 820 children aged 0-18 years across three Canadian provinces (Alberta, Ontario and Québec). C-PIP has developed a harmonized, developmentally sensitive neuroimaging protocol to collect high-quality, comprehensive imaging data across multiple modalities. This paper outlines the development, considerations and implementation of the C-PIP neuroimaging protocol across sites. Preliminary cross-site validation analyses demonstrate good within- and between-site stability in neuroimaging measures. Graphical

Hemispheric specialization is a hallmark of brain organization, yet how functionally specialized circuits develop remains unclear. In humans, the developmental shift toward left-hemisphere dominance for language offers a well-characterized model for investigating this question. Here, we built personalized whole-brain neurophysiological models in children and adolescents to simulate task-evoked dynamics from auditory perception to language production. We demonstrate that expressive language lateralization emerges through distinct inhibitory processes. In early childhood, interhemispheric inhibitory asymmetry is present, characterized by stronger projections from left pyramidal neurons to right interneurons, but is insufficient to drive functional specialization. Using in silico manipulations, we show that developmental reduction in local inhibition is necessary to unmask the functional influence of early structural asymmetries. Our findings provide a mechanistic account in which expressive language specialization emerges from the interaction between early structural asymmetry and developmental disinhibition, and offer a generalizable computational framework for studying circuit specialization across species and cognitive domains.

In childhood, language outcomes following brain injury are inversely related to age. Neuroimaging findings suggest that extensive representation and/or topological redundancy may confer the pediatric advantage. Here, we assess whole brain and language network resilience using in silico attacks, for 85 children participating in a magnetoencephalography (MEG) study. Nodes are targeted based on eigenvector centrality, betweenness centrality, or at random. The size of each connected component is assessed after iterated node removal; the percolation point, or moment of dis-integration, is defined as the first instance where the second largest component peaks in size. To overcome known effects of fixed thresholding on subsequent graph and resilience analyses, we study percolation across all possible network densities, within a Functional Data Analysis (FDA) framework. We observe age-related increases in vulnerability for random and betweenness centrality-based attacks for whole-brain and stories networks (adjusted-p < 0.05). Here we show that changes in topology underlie increasing language network vulnerability in development.

Language comprehension is a complex process involving an extensive brain network. Brain regions responsible for prosodic processing have been studied in adults; however, much less is known about the neural bases of prosodic processing in children. Using magnetoencephalography (MEG), we mapped regions supporting speech envelope tracking (a marker of prosodic processing) in 80 typically developing children, ages 4–18 years, completing a stories listening paradigm. Neuromagnetic signals coherent with the speech envelope were localized using dynamic imaging of coherent sources (DICS). Across the group, we observed coherence in bilateral perisylvian cortex. We observed age-related increases in coherence to the speech envelope in the right superior temporal gyrus (r = 0.31, df = 78, p = 0.0047) and primary auditory cortex (r = 0.27, df = 78, p = 0.016); age-related decreases in coherence to the speech envelope were observed in the left superior temporal gyrus (r = − 0.25, df = 78, p = 0.026). This pattern may indicate a refinement of the networks responsible for prosodic processing during development, where language areas in the right hemisphere become increasingly specialized for prosodic processing. Altogether, these results reveal a distinct neurodevelopmental trajectory for the processing of prosodic cues, highlighting the presence of supportive language functions in the right hemisphere. Findings from this dataset of typically developing children may serve as a potential reference timeline for assessing children with neurodevelopmental hearing and speech disorders.

Growth in preterm infants in the neonatal intensive care unit (NICU) is associated with increased global and regional brain volumes at term, and increased postnatal linear growth is associated with higher language scores at age 2. It is unknown whether these relationships persist to school age or if an association between growth and cortical metrics exists. Using regression analyses, we investigated relationships between the growth of 42 children born extremely preterm (< 28 weeks gestation) from their NICU hospitalization, standardized neurodevelopmental/language assessments at 2 and 4–6 years, and multiple neuroimaging biomarkers obtained from T1-weighted images at 4–6 years. We found length at birth and 36 weeks post-menstrual age had positive associations with language scores at 2 years in multivariable linear regression. No growth metric correlated with 4–6 year assessments. Weight and head circumference at 36 weeks post-menstrual age positively correlated with total brain volume and negatively with global cortical thickness at 4–6 years of age. Head circumference relationships remained significant after adjusting for age, sex, and socioeconomic status. Right temporal cortical thickness was related to receptive language at 4–6 years in the multivariable model. Results suggest growth in the NICU may have lasting effects on brain development in extremely preterm children.

Children born with congenital heart disease (CHD) have seen a dramatic decrease in mortality thanks to surgical innovations. However, there are numerous risk factors associated with CHD that can disrupt neurodevelopment. Recent studies have found that psychological deficits and structural brain abnormalities persist into adulthood. The goal of the current study was to investigate white matter connectivity in early school-age children (6–11 years), born with complex cyanotic CHD (single ventricle physiology), who have undergone Fontan palliation, compared to a group of heart-healthy, typically developing controls (TPC). Additionally, we investigated associations between white matter tract connectivity and measures on a comprehensive neuropsychological battery within each group. Our results suggest CHD patients exhibit widespread decreases in white matter connectivity, and the extent of these decreases is related to performance in several cognitive domains. Analysis of network topology showed that hub distribution was more extensive and bilateral in the TPC group. Our results are consistent with previous studies suggesting perinatal ischemia leads to white matter lesions and delayed maturation.

Low-beta (13-23 Hz) event-related desynchrony (ERD), a neural signature of expressive language, lateralizes from bilateral to left hemisphere in development. In contrast, low-beta event-related synchrony (ERS), thought to reflect inhibition, lateralizes from bilateral to the right hemisphere across development. Using whole-brain directed connectivity analyses, we aimed to characterize hemispheric and regional contributions to expressive language, in childhood. We studied 80 children and adolescents, 4 to less than 19 years of age, performing covert auditory verb generation in magnetoencephalography. Outdegree, indegree, and betweenness centrality were used to differentiate regions acting as drivers, receivers, and bridging hubs, respectively. The number of suprathreshold connections significantly increased with age for delta band (p < .01). Delta outflow was mapped to left inferior frontal gyrus (IFG), while regions of right hemisphere, including right IFG, showed significant inflow. The right parietal cortex showed significant ERS, but without corresponding outdegree or indegree. Betweenness mapped to midline cortical and subcortical structures. Results suggest Broca's area develops a driving role in the language network, while Broca's homologue receives information without necessarily propagating it. Subcortical and midline hubs act as intrahemispheric relays. Findings suggest that Broca's homologue is inhibited during expressive language, in development.

Extreme prematurity (EPT, <28 weeks gestation) is associated with language problems. We previously reported hyperconnectivity in EPT children versus term children (TC) using magnetoencephalography (MEG). Here, we aim to ascertain whether functional hyperconnectivity is a marker of language resiliency for EPT children, validating our earlier work with a distinct sample of contemporary well-performing EPT and preterm children with history of language delay (EPT-HLD). A total of 58 children (17 EPT, 9 EPT-HLD, and 32 TC) participated in stories listening during MEG and functional magnetic resonance imaging (fMRI) at 4–6 years. We compared connectivity in EPT and EPT-HLD, investigating relationships with language over time. We measured fMRI activation during stories listening and parcellated the activation map to obtain “nodes” for MEG connectivity analysis. There were no significant group differences in age, sex, race, ethnicity, parental education, income, language scores, or language representation on fMRI. MEG functional connectivity (weighted phase lag index) was significantly different between groups. Preterm children had increased connectivity, replicating our earlier work. EPT and EPT-HLD had hyperconnectivity versus TC at 24–26 Hz, with EPT-HLD exhibiting greatest connectivity. Network strength correlated with change in standardized scores from 2 years to 4–6 years of age, suggesting hyperconnectivity is a marker of advancing language development.

A left perisylvian network is known to support language in healthy adults. Low-beta (13–23 Hz) event-related desynchrony (ERD) has been observed during verb generation, at approximately 700–1200 ms post-stimulus presentation in past studies; the signal is known to reflect increased neuronal firing and metabolic demand during language production. In contrast, concurrent beta event-related synchrony (ERS) is thought to reflect neuronal inhibition but has not been well studied in the context of language. Further, while low-beta ERD for expressive language has been found to gradually shift from bilateral in childhood to left hemispheric by early adulthood, developmental lateralization of ERS has not been established. We used magnetoencephalography to study low beta ERS lateralization in a group of children and adolescents (n = 78), aged 4 to less than 19 years, who performed covert verb generation. We found that the youngest children had bilateral ERD and ERS. By adolescence, low-beta ERD was predominantly left lateralized in perisylvian cortex (i.e., Broca’s and Wernicke’s regions), while beta ERS was predominantly right lateralized. Increasing lateralization was significantly correlated to age for both ERD (Spearman’s r = 0.45, p < 0.01) and ERS (Spearman’s r = − 0.44, p < 0.01). Interestingly, while ERD lateralized in a linear manner, ERS lateralization followed a nonlinear trajectory, suggesting distinct developmental trajectories. Implications to early-age neuroplasticity and neuronal inhibition are discussed.