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Neurophysiological signals, comprised of both periodic (e.g., oscillatory) and aperiodic (e.g., non-oscillatory) activity, undergo complex developmental changes between childhood and adulthood. With much of the existing literature primarily focused on the periodic features of brain function, our understanding of aperiodic signals is still in its infancy. Here, we are the first to examine age-related changes in periodic (peak frequency and power) and aperiodic (slope and offset) activity using optically pumped magnetometers (OPMs), a new, wearable magnetoencephalography (MEG) technology that is particularly well-suited for studying development. We examined age-related changes in these spectral features in a sample (N=65) of toddlers (1-3 years), children (4-5 years), young adults (20-26 years), and adults (27-38 years). Consistent with the extant literature, we found significant age-related decreases in the aperiodic slope and offset, and changes in peak frequency and power that were frequency-specific; we are the first to show that the effect sizes of these changes also varied across brain regions. This work not only adds to the growing body of work highlighting the advantages of using OPMs, especially for studying development, but also contributes novel information regarding the variation of neurophysiological changes with age across the brain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Processing speed is a foundational skill supporting intelligence and executive function, areas often delayed in preterm-born children. The impact of early-life nutrition on gray matter facilitating processing speed for this vulnerable population is unknown., Methods: Magnetic resonance imaging and the Wechsler Preschool and Primary Scale of Intelligence-IV Processing Speed Index were acquired in forty 5-year-old children born preterm with very low birth weight. Macronutrient (grams per kilogram per day) and mother's milk (percentage of feeds) intakes were prospectively collected in the first postnatal month and associations between early-life nutrition and the primary outcome of brain regions supporting processing speed were investigated., Results: Children had a mean (SD) gestational age of 27.8 (1.8) weeks and 45% were male. Macronutrient intakes were unrelated, but mother's milk was positively related, to greater volumes in brain regions, including total cortical gray matter, cingulate gyri, and occipital gyri., Conclusion: First postnatal month macronutrient intakes showed no association, but mother's milk was positively associated, with volumetric measures of total and regional cortical gray matter related to processing speed in preterm-born children. This exploratory analysis suggests early-life mother's milk supports processing speed by impacting structural underpinnings. Further research is needed on this potential strategy to improve preterm outcomes., (© 2024 The Author(s). Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

With brain structure and function undergoing complex changes throughout childhood and adolescence, age is a critical consideration in neuroimaging studies, particularly for those of individuals with neurodevelopmental conditions. However, despite the increasing use of large, consortium-based datasets to examine brain structure and function in neurotypical and neurodivergent populations, it is unclear whether age-related changes are consistent between datasets and whether inconsistencies related to differences in sample characteristics, such as demographics and phenotypic features, exist. To address this, we built models of age-related changes of brain structure (regional cortical thickness and regional surface area; N = 1218) and function (resting-state functional connectivity strength; N = 1254) in two neurodiverse datasets: the Province of Ontario Neurodevelopmental Network and the Healthy Brain Network. We examined whether deviations from these models differed between the datasets, and explored whether these deviations were associated with demographic and clinical variables. We found significant differences between the two datasets for measures of cortical surface area and functional connectivity strength throughout the brain. For regional measures of cortical surface area, the patterns of differences were associated with race/ethnicity, while for functional connectivity strength, positive associations were observed with head motion. Our findings highlight that patterns of age-related changes in the brain may be influenced by demographic and phenotypic characteristics, and thus future studies should consider these when examining or controlling for age effects in analyses., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes., Competing Interests: Declaration of competing interest A. Kushki received grants from the National Science and Engineering Research Council during the conduct of the study and holds a patent for Anxiety Meter with royalties paid from Awake Labs. E. King reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Goldmuntz reported receiving grants from the NIH during the conduct of the study. T. A. Miller reported receiving grants from the NIH during the conduct of the study. N. H. Thomas reported receiving grants from the NIH, including the Clinical and Translational Science Awards Program, during the conduct of the study. J. F. Cnota reported receiving grants from the NIH during the conduct of the study and from Additional Ventures outside the submitted work. C. S. Goldberg reported receiving grants from the NIH related to work for the Pediatric Heart Network during the conduct of the study. P. McQuillen reported receiving grants from the NIH during the conduct of the study. G. A. Porter reported receiving grants from the University of Rochester Medical Center. A. E. Roberts reported receiving grants from the NIH during the conduct of the study. C. E. Seidman serves as a consultant for Maze Therapeutics and on the board of directors for Merck and the Burroughs Wellcome Fund; these companies had no role in the design, execution, or analyses of this study. J. W. Newburger has served as a consultant to and received grant funds from Pfizer: received honoraria from Daiichi-Sankyo for membership on a trial Steering Committee; and chaired Independent Clinical Events Committees for Bristol Myer Squibb, Pfizer, and Novartis. E. Anagnostou has received grants from Roche and Anavex, served as a consultant to Roche, Quadrant Therapeutics, Ono, and Impel Pharmaceuticals, has received in-kind support from AMO Pharma and CRA-Simons Foundation, holds a patent for the device, “Anxiety Meter”, has received royalties from APPI and Springer, and has received an editorial honorarium from Wiley. The remaining authors have reported no potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The cerebellum, through its connectivity with the cerebral cortex, plays an integral role in regulating cognitive and affective processes, and its dysregulation can result in neurodevelopmental disorder (NDD)-related behavioural deficits. Identifying cerebellar-cerebral functional connectivity (FC) profiles in children with NDDs can provide insight into common connectivity profiles and their correlation to NDD-related behaviours. 479 participants from the Province of Ontario Neurodevelopmental Disorders (POND) network (typically developing = 93, Autism Spectrum Disorder = 172, Attention Deficit/Hyperactivity Disorder = 161, Obsessive-Compulsive Disorder = 53, mean age = 12.2) underwent resting-state functional magnetic resonance imaging and behaviour testing (Social Communication Questionnaire, Toronto Obsessive-Compulsive Scale, and Child Behaviour Checklist - Attentional Problems Subscale). FC components maximally correlated to behaviour were identified using canonical correlation analysis. Results were then validated by repeating the investigation in 556 participants from an independent NDD cohort provided from a separate consortium (Healthy Brain Network (HBN)). Replication of canonical components was quantified by correlating the feature vectors between the two cohorts. The two cerebellar-cerebral FC components that replicated to the greatest extent were correlated to, respectively, obsessive-compulsive behaviour (behaviour feature vectors, r POND-HBN  = -0.97; FC feature vectors, r POND-HBN  = -0.68) and social communication deficit contrasted against attention deficit behaviour (behaviour feature vectors, r POND-HBN  = -0.99; FC feature vectors, r POND-HBN  = -0.78). The statistically stable (|z| > 1.96) features of the FC feature vectors, measured via bootstrap re-sampling, predominantly comprised of correlations between cerebellar attentional and control network regions and cerebral attentional, default mode, and control network regions. In both cohorts, spectral clustering on FC loading values resulted in subject clusters mixed across diagnostic categories, but no cluster was significantly enriched for any given diagnosis as measured via chi-squared test (p > 0.05). Overall, two behaviour-correlated components of cerebellar-cerebral functional connectivity were observed in two independent cohorts. This suggests the existence of generalizable cerebellar network differences that span across NDD diagnostic boundaries., (© 2024. The Author(s).)

Background: Impairing repetitive behaviors are one of the core diagnostic symptoms in autism spectrum disorder and obsessive-compulsive disorder, but they also manifest in attention-deficit/hyperactivity disorder. Although the dorsal striatal circuit has been implicated in repetitive behaviors, extensive heterogeneity in and cross-diagnostic manifestations of these behaviors have suggested phenotypic and likely neurobiological heterogeneity across neurodevelopmental disorders (NDDs)., Methods: Intrinsic dorsal striatal functional connectivity was examined in 3 NDDs (autism spectrum disorder, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder) and typically developing control participants in a large single-cohort sample (N = 412). To learn how diagnostic labels and overlapping behaviors manifest in dorsal striatal functional connectivity measured with functional magnetic resonance imaging, the main and interaction effects of diagnosis and behavior were examined in 8 models (2 seed functional connectivity [caudate and putamen] × 4 sub-behavioral domains [sameness/ritualistic, self-injury, stereotypy, and compulsions])., Results: The obsessive-compulsive disorder group demonstrated distinctive patterns in visual and visuomotor coordination regions compared with the other diagnostic groups. Lower-order repetitive behaviors (self-injury and stereotypy) manifesting across all participants were implicated in regions involved in motor and cognitive control, although the findings did not survive effects of multiple comparisons, suggesting heterogeneity in these behavioral domains. An interaction between self-injurious behavior and an attention-deficit/hyperactivity disorder diagnosis were observed on caudate-cerebellum functional connectivity., Conclusions: These findings confirmed high heterogeneity and overlapping behavioral manifestations in NDDs and their complex underlying neural mechanisms. A call for diagnosis-free symptom measures that can capture not only observable symptoms and severity across NDDs but also the underlying functions and motivations of such behaviors across diagnoses is needed., (Copyright © 2024. Published by Elsevier Inc.)

Optically pumped magnetometers (OPMs) offer a new wearable means to measure magnetoencephalography (MEG) signals, with many advantages compared to conventional systems. However, OPMs are an emerging technology, thus characterizing and replicating MEG recordings is essential. Using OPM-MEG and SQUID-MEG, this study investigated evoked responses, oscillatory power, and functional connectivity during emotion processing in 20 adults, to establish replicability across the two technologies. Five participants with dental fixtures were included to assess the validity of OPM-MEG recordings in those with irremovable metal. Replicable task-related evoked responses were observed in both modalities. Similar patterns of oscillatory power to faces were observed in both systems. Increased connectivity was found in SQUID-versus OPM-MEG in an occipital and parietal anchored network. Notably, high quality OPM-MEG data were retained in participants with metallic fixtures, from whom no useable data were collected using conventional MEG., (© 2024. The Author(s).)

Dorsal striatum, principally comprising of caudate and putamen, is well-known to support motor function but also various higher-order cognitive functions. This is enabled by developing short- and long-range connections to distributed cortical regions throughout the life span, but few studies have examined developmental changes from young children to adults in the same cohort. Here we investigated the development of dorsal-striatal network in a large (n = 476), single-site sample of healthy subjects 3-42 years of age in three groups (children, adolescence, adults). The results showed that the connectivity within the striatum and to sensorimotor regions was established at an early stage of life and remained strong in adolescence, supporting that sensory-seeking behaviours and habit formation are important learning mechanisms during the developmental periods. This connectivity diminished with age, as many behaviours become more efficient and automated. Adolescence demonstrated a remarkable transition phase where the connectivity to dorsolateral prefrontal cortex emerged but connectivity to the dorsomedial prefrontal and posterior brain, which belong to the ventral attentional and default mode networks, was only seen in adults. This prolonged maturation in between-network integration may explain the behavioural characteristics of adolescents in that they exhibit elaborated cognitive performance but also demonstrate high risk-taking behaviours., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A set of highly connected brain regions called the "rich-club" are vital in integrating information across the functional connectome. Although the literature has identified some changes in rich-club organization with age, little is known about potential sex-specific developmental trajectories, and neurophysiologically relevant frequency-dependent changes have not been established. Here we examine the frequency- and sex-dependent development of rich-club organization using magnetoencephalography in a large normative sample ( N  = 383) over a wide age span (4-39 years). We report strong divergence between males and females across alpha, beta, and gamma frequencies. While males show increased or no change in rich-club organization with age, females show a consistent, non-linear trajectory that increases through childhood, shifting direction in early adolescence. Using neurophysiological modalities for capturing complex inter-relations between oscillatory dynamics, age, and sex, we establish diverging, sex-specific developmental trajectories of the brain's core functional organization, critically important to our understanding of brain health and disease., Competing Interests: E. Anagnostou has served as a consultant to Roche, Quadrant Therapeutics, ONO, and Impel Pharmaceuticals, holds a patent for the device, “Anxiety Meter,” and has received in kind support from AMO pharma and CRA, royalties from APPI and Springer, and editorial honoraria from Wiley. The remaining authors have reported no financial interests or potential conflicts of interest., (© 2023 The Author(s).)

Importance: Neurodevelopmental conditions, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), have highly heterogeneous and overlapping phenotypes and neurobiology. Data-driven approaches are beginning to identify homogeneous transdiagnostic subgroups of children; however, findings have yet to be replicated in independently collected data sets, a necessity for translation into clinical settings., Objective: To identify subgroups of children with and without neurodevelopmental conditions with shared functional brain characteristics using data from 2 large, independent data sets., Design, Setting, and Participants: This case-control study used data from the Province of Ontario Neurodevelopmental (POND) network (study recruitment began June 2012 and is ongoing; data were extracted April 2021) and the Healthy Brain Network (HBN; study recruitment began May 2015 and is ongoing; data were extracted November 2020). POND and HBN data are collected from institutions across Ontario and New York, respectively. Participants who had diagnoses of ASD, ADHD, and OCD or were typically developing (TD); were aged between 5 and 19 years; and successfully completed the resting-state and anatomical neuroimaging protocol were included in the current study., Main Outcomes and Measures: The analyses consisted of a data-driven clustering procedure on measures derived from each participant's resting-state functional connectome, performed independently on each data set. Differences between each pair of leaves in the resulting clustering decision trees in the demographic and clinical characteristics were tested., Results: Overall, 551 children and adolescents were included from each data set. POND included 164 participants with ADHD; 217 with ASD; 60 with OCD; and 110 with TD (median [IQR] age, 11.87 [9.51-14.76] years; 393 [71.2%] male participants; 20 [3.6%] Black, 28 [5.1%] Latino, and 299 [54.2%] White participants) and HBN included 374 participants with ADHD; 66 with ASD; 11 with OCD; and 100 with TD (median [IQR] age, 11.50 [9.22-14.20] years; 390 [70.8%] male participants; 82 [14.9%] Black, 57 [10.3%] Hispanic, and 257 [46.6%] White participants). In both data sets, subgroups with similar biology that differed significantly in intelligence as well as hyperactivity and impulsivity problems were identified, yet these groups showed no consistent alignment with current diagnostic categories. For example, there was a significant difference in Strengths and Weaknesses ADHD Symptoms and Normal Behavior Hyperactivity/Impulsivity subscale (SWAN-HI) between 2 subgroups in the POND data (C and D), with subgroup D having increased hyperactivity and impulsivity traits compared with subgroup C (median [IQR], 2.50 [0.00-7.00] vs 1.00 [0.00-5.00]; U = 1.19 × 104; P = .01; η2 = 0.02). A significant difference in SWAN-HI scores between subgroups g and d in the HBN data was also observed (median [IQR], 1.00 [0.00-4.00] vs 0.00 [0.00-2.00]; corrected P = .02). There were no differences in the proportion of each diagnosis between the subgroups in either data set., Conclusions and Relevance: The findings of this study suggest that homogeneity in the neurobiology of neurodevelopmental conditions transcends diagnostic boundaries and is instead associated with behavioral characteristics. This work takes an important step toward translating neurobiological subgroups into clinical settings by being the first to replicate our findings in independently collected data sets.

Children and youth with obsessive-compulsive disorder (OCD) demonstrate difficulties with social, emotional and cognitive functions in addition to the core diagnosis of obsessions and compulsions. This is the first magnetoencephalography (MEG) study to examine whole-brain neurophysiological functional connectivity of emotional face processing networks in paediatric OCD. Seventy-two participants (OCD: n = 36; age 8-17 yrs; typically developing controls: n = 36, age 8-17 yrs) completed an implicit emotional face processing task in the MEG. Functional connectivity networks in canonical frequency bands were compared between groups, and within OCD and control groups between emotions (angry vs. happy). Between groups, participants with OCD showed increased functional connectivity in the gamma band to angry faces, suggesting atypical perception of angry faces in OCD. Within groups, the OCD group showed greater engagement of the beta band, suggesting the over-use of top-down processing when perceiving happy versus angry emotions, while controls engaged in bottom-up gamma processing, also greater to happy faces. Over-activation of top-down processing has been linked to difficulties modifying one's cognitive set. Findings establish altered patterns of neurophysiological connectivity in children with OCD, and are striking in their oscillatory specificity. Our results contribute to a greater understanding of the neurobiology of the disorder, and are foundational for the possibility of alternative targets for intervention., Competing Interests: Declaration of Competing Interest EA has consulted for and received personal fees from Roche, Quadrant Therapeutics, ONO and Impel Pharmaceuticals. EA has also received grants from Roche and Anavex. In addition, EA holds a patent for the device, “Anxiety Meter”, and has received nonfinancial support from AMO Pharma and CRA-Simons Foundation, royalties from APPI and Springer, and editorial honoraria from Wiley. The remaining authors (KS, EWP, MMV, KD, PDA, AI, MA, EK, JPL, and MJT) declare no commercial or financial interests or potential conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Theory of Mind (ToM) is a core social cognitive skill that refers to the ability to attribute mental states to others. ToM involves understanding that others have beliefs, thoughts and desires that may be different from one's own and from reality. ToM is crucial to predict behaviour and navigate social interactions. This study employed the complementary methodological advantages of both functional MRI (fMRI) and magnetoencephalography (MEG) to examine the neural underpinnings of ToM in adults. Twenty healthy adults were first recruited to rate and describe 28 videos (15s long), each containing three moving shapes designed to depict either social interactions or random motion (control condition). The first sample of adults produced consistent narratives for 6 of those social videos and of those, 4 social videos and 4 control videos were chosen to include in the neuroimaging study. Another sample of twenty-five adults were then recruited to complete the neuroimaging in MEG and fMRI. In fMRI, we found increased activation in frontal-parietal regions in the social compared to the control condition corroborating previous fMRI findings. In MEG, we found recruitment of ToM networks in the social condition in theta, beta and gamma bands. The right supramarginal and angular gyri (right temporal parietal junction), right inferior parietal lobe and right temporal pole were recruited in the first 5s of the videos. Frontal regions such as the superior frontal gyrus were recruited in the second time window (5-10s). Brain regions such as the bilateral amygdalae were also recruited (5-10s), indicating that various social processes were integrated in understanding the social videos. Our study is one of the first to combine multi-modal neuroimaging to examine the neural networks underlying social cognitive processes, combining the strengths of the spatial resolution of fMRI and temporal resolution of MEG. Understanding this information from both modalities helped delineate the mechanism by which ToM processing unfolds over time in healthy adults. This allows us to determine a benchmark against which clinical populations can be compared., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mossad, Vandewouw, Villa, Pang and Taylor.)

Objective: Direct injury to the corpus callosum (CC) due to neurosurgical interventions in infants with posthemorrhagic ventricular dilatation (PHVD) has not been reported in the literature. The authors observed a subset of infants who had suffered penetrating CC injury after neurosurgical interventions for PHVD and hypothesized that this pattern of injury may result in suboptimal CC maturation and neurodevelopmental impairment., Methods: In this multicenter, retrospective, observational study, 100 preterm and 17 full-term infants with PHVD were included and compared with 23 preterm controls. Both neonatal and postneonatal brain MRI scans were assessed for injury, and measurements were performed on postneonatal MRI scans at 2 years' corrected age. Neurodevelopmental outcome was assessed at 2 years' corrected age., Results: A total of 269 brain MRI scans of 140 infants were included. Of infants with PHVD, 48 (41%) had penetrating CC injury following neurosurgical interventions. The median (IQR) CC midsagittal surface area was smaller in infants with CC injury when compared with infants with PHVD who had intact CC and controls (190 mm2 [149-262 mm2] vs 268 mm2 [206-318 mm2] vs 289 mm2 [246-320 mm2], respectively; p < 0.001). In the univariate analysis, the area of the CC was associated with cognitive Z score (coefficient 0.009 [95% CI 0.005-0.012], p < 0.001) and motor Z score (coefficient 0.009 [95% CI 0.006-0.012], p < 0.001). In the multivariable model, CC injury was not independently associated with cognitive and motor Z score after adjusting for gestational age and presence of periventricular hemorrhagic infarction (coefficient 0.04 [95% CI -0.36 to 0.46] and -0.37 [95% CI -0.83 to 0.09], p = 0.7 and 0.1, respectively)., Conclusions: CC injury was not uncommon following neurosurgical interventions for PHVD in both preterm and full-term infants. At the age of 2 years, the CC midsagittal surface area was smaller in infants with injury, but CC injury was not independently associated with cognitive and motor outcomes at 2 years' corrected age.

Infants born very low birth weight (VLBW, < 1,500 g) are at a heightened risk for structural brain abnormalities and social-cognitive deficits, which can impair behavioural functioning. Resting-state fMRI, reflecting a baseline level of brain activity and underlying social-cognitive processes, has also been reported to be altered in children born VLBW. Yet very little is known about the functional networks underlying social cognition using magnetoencephalography (MEG) and how it relates to neonatal factors and developmental outcomes. Thus, we investigated functional connectivity at rest in VLBW children and the associations with early nutrition and IQ and behavioural problems. We collected resting-state MEG recordings and measures of IQ and social-cognitive behaviour, as well as macronutrient/energy intakes during initial hospitalisation in 5-year-old children born VLBW ( n = 37) compared to full-term (FT; n = 27) controls. We examined resting-state network differences controlling for sex and age at scan. Functional connectivity was estimated using the weighted phase lag index. Associations between functional connectivity with outcome measures and postnatal nutrition were also assessed using regression analyses. We found increased resting-state functional connectivity in VLBW compared to FT children in the gamma frequency band (65-80 Hz). This hyper-connected network was primarily anchored in frontal regions known to underlie social-cognitive functions such as emotional processing. In VLBW children, increased functional connectivity was related to higher IQ scores, while reduced connectivity was related to increased behavioural problems at 5 years of age. These within-group associations were found in the slower frequency bands of theta (4-7 Hz) and alpha (8-12 Hz), frequently linked to higher-order cognitive functions. We also found significant associations between macronutrient (protein and lipid) and energy intakes during the first postnatal month with functional connectivity at preschool-age, highlighting the long-term impacts of postnatal nutrition on preterm brain development. Our findings demonstrate that at preschool-age, VLBW children show altered resting-state connectivity despite IQ and behaviour being in the average range, possibly reflecting functional reorganisation of networks to support social-cognitive and behavioural functioning. Further, our results highlight an important role of early postnatal nutrition in the development of resting-state networks, which in turn may improve neurodevelopmental outcomes in this vulnerable population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sato, Vandewouw, Safar, Ng, Bando, O’Connor, Unger, Pang and Taylor.)

Impairments in emotional face processing are demonstrated by individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), which is associated with altered emotion processing networks. Despite accumulating evidence of high rates of diagnostic overlap and shared symptoms between ASD and ADHD, functional connectivity underpinning emotion processing across these two neurodevelopmental disorders, compared to typical developing peers, has rarely been examined. The current study used magnetoencephalography to investigate whole-brain functional connectivity during the presentation of happy and angry faces in 258 children (5-19 years), including ASD, ADHD and typically developing (TD) groups to determine possible differences in emotion processing. Data-driven clustering was also applied to determine whether the patterns of connectivity differed among diagnostic groups. We found reduced functional connectivity in the beta band in ASD compared to TD, and a further reduction in the ADHD group compared to the ASD and the TD groups, across emotions. A group-by-emotion interaction in the gamma frequency band was also observed. Greater connectivity to happy compared to angry faces was found in the ADHD and TD groups, while the opposite pattern was seen in ASD. Data-driven subgrouping identified two distinct subgroups: NDD-dominant and TD-dominant; these subgroups demonstrated emotion- and frequency-specific differences in connectivity. Atypicalities in specific brain networks were strongly correlated with the severity of diagnosis-specific symptoms. Functional connectivity strength in the beta network was negatively correlated with difficulties in attention; in the gamma network, functional connectivity strength to happy faces was positively correlated with adaptive behavioural functioning, but in contrast, negatively correlated to angry faces. Our findings establish atypical frequency- and emotion-specific patterns of functional connectivity between NDD and TD children. Data-driven clustering further highlights a high degree of comorbidity and symptom overlap between the ASD and ADHD children., Competing Interests: EA has served as a consultant to Roche and Quadrant Therapeutics, has received consultation fees from Roche, holds a patent for the device, ‘Anxiety Meter’, and has received in kind support from AMO pharma, royalties from APPI and Springer, and editorial honoraria from Wiley. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Safar, Vandewouw, Pang, de Villa, Crosbie, Schachar, Iaboni, Georgiades, Nicolson, Kelley, Ayub, Lerch, Anagnostou and Taylor.)

The ability to effectively and automatically regulate one's response to emotional information is a basic, fundamental skill for social functioning. The neural mechanisms underlying emotion regulation processing have been assessed, however few investigations have leveraged neurophysiological techniques, particularly magnetoencephalography (MEG) to determine the development of this critical ability. The current MEG study is the first to examine developmental changes in the neural mechanisms supporting automatic emotion regulation. We used an emotional go/no-go task with happy and angry faces in a single-site cohort of 97 healthy participants, 4-40 years of age. We found age-related changes as a function of emotion and condition in brain regions key to emotion regulation, including the right inferior frontal gyrus, orbitofrontal cortices and primarily right-lateralized temporal areas. Interaction effects, including an age by emotion and condition, were also found in the left angular gyrus, an area critical in emotion regulation and attention. Findings demonstrate protracted and nonlinear development, due to the adolescent group, of emotion regulation processing from child to adulthood, and highlight that age-related differences in emotion regulation are modulated by emotional face type., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Structural brain alterations have been reported in key emotional face processing regions following preterm birth; however, few studies have investigated the functional networks underlying these processes in children born with very low birth weight (VLBW). Using magnetoencephalography (MEG), we examined the functional networks related to the implicit processing of happy and angry faces in 5-year-old VLBW (n = 28) and full-term (FT; n = 24) children. We found that VLBW children showed atypical recruitment of emotional face processing networks in theta (4-7 Hz) compared to FT children. VLBW children showed reduced theta connectivity during processing of angry faces only. This hypo-connected theta-band network was anchored in the left orbitofrontal and parietal regions, involved in the higher level processing of faces and emotion regulation. At the behavioural level, despite VLBW children performing within the normal range, FT children had significantly higher affect recognition scores. Our MEG results suggest a selective impairment in processing angry faces, which would negatively impact social functioning in VLBW children. In FT children, greater recruitment of this theta-band network was positively associated with improved affect recognition scores. Thus, our findings suggest an important role of theta oscillations in early face processing, deficits which may contribute to broader socio-emotional impairments in VLBW children., (© The Author(s) 2021. Published by Oxford University Press.)

Impairments in social functioning are hallmarks of autism spectrum disorder (ASD) and atypical functional connectivity may underlie these difficulties. Emotion processing networks typically undergo protracted maturational changes, however, those with ASD show either hyper- or hypo-connectivity with little consensus on the functional connectivity underpinning emotion processing. Magnetoencephalography was used to investigate age-related changes in whole-brain functional connectivity of eight regions of interest during happy and angry face processing in 190 children, adolescents and adults (6-39 years) with and without ASD. Findings revealed age-related changes from child- through to mid-adulthood in functional connectivity in controls and in ASD in theta, as well as age-related between-group differences across emotions, with connectivity decreasing in ASD, but increasing for controls, in gamma. Greater connectivity to angry faces was observed across groups in gamma. Emotion-specific age-related between-group differences in beta were also found, that showed opposite trends with age for happy and angry in ASD. Our results establish altered, frequency-specific developmental trajectories of functional connectivity in ASD, across distributed networks and a broad age range, which may finally help explain the heterogeneity in the literature., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Theory of mind (ToM) deficits are common in children with neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), which contribute to their social and cognitive difficulties. The social attribution task (SAT) involves geometrical shapes moving in patterns that depict social interactions and is known to recruit brain regions from the classic ToM network. To better understand ToM in ASD and ADHD children, we examined the neural correlates using the SAT and functional magnetic resonance imaging (fMRI) in a cohort of 200 children: ASD (N = 76), ADHD (N = 74) and typically developing (TD; N = 50) (4-19 years). In the scanner, participants were presented with SAT videos corresponding to social help, social threat, and random conditions. Contrasting social vs. random, the ASD compared with TD children showed atypical activation in ToM brain areas-the middle temporal and anterior cingulate gyri. In the social help vs. social threat condition, atypical activation of the bilateral middle cingulate and right supramarginal and superior temporal gyri was shared across the NDD children, with between-diagnosis differences only being observed in the right fusiform. Data-driven subgrouping identified two distinct subgroups spanning all groups that differed in both their clinical characteristics and brain-behaviour relations with ToM ability., (© 2021. The Author(s).)

Recent work identified that patterns of distributed brain regions sharing similar myeloarchitecture are related to underlying functional connectivity, demonstrating cortical myelin's plasticity to changes in functional demand. However, the changing relations between functional and structural architecture throughout child and adulthood are poorly understood. We show that structural covariance connectivity (T1-weighted/T2-weighted ratio) and functional connectivity (magnetoencephalography) exhibit nonlinear developmental changes. We then show significant relations between structural and functional connectivity, which have shared and distinct characteristics dependent on the neural oscillatory frequency. Increases in structure-function coupling are visible during the protracted myelination observed throughout childhood and adolescence and are followed by decreases near the onset of adulthood. Our work lays the foundation for understanding the mechanisms by which myeloarchitecture supports brain function, enabling future investigations into how clinical populations may deviate from normative patterns., (Copyright © 2021. Published by Elsevier Inc.)

Background: Autism spectrum disorder (ASD) is classically associated with poor emotional face processing. Few studies, however, have used more ecological dynamic stimuli. We contrasted functional magnetic resonance imaging measures of dynamic emotional face processing in ASD and typically developing (TD) cohorts across a wide age range to determine if the processing and age-related trajectories differed between participants with and without ASD., Methods: Functional magnetic resonance imaging data collected from 200 participants (5-42 years old; 107 in ASD cohort, 93 in TD cohort) during the presentation of dynamic emotional faces (neutral-to-happy, neutral-to-angry) and dynamic flowers (closed-to-open) were analyzed. Group differences and group-by-age interactions in the faces versus flowers and between emotion contrasts were investigated., Results: Differences in activation between dynamic faces and flowers in occipital regions, including the fusiform gyri, were reduced in the ASD group. Contrasting the two emotions, ASD compared with TD participants showed increased engagement of the precentral, postcentral, and superior temporal gyri to happy faces and increased activation to angry faces occipitally. Emotion processing regions, such as insula, temporal pole, and frontal regions, showed increased recruitment with age to happy faces compared with both angry faces and flowers in the TD group, but decreased recruitment with age in the ASD group., Conclusions: Using dynamic stimuli, we demonstrated that participants with ASD processed faces similarly to nonface stimuli, and age-related atypicalities were more pronounced to happy faces in participants with ASD. We demonstrated emotion-specific atypicalities in a large group of participants with ASD that underscore persistent difficulties from childhood into mid-adulthood., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Infants born at very low birth weight (<1500 g) are vulnerable to nutritional deficits during their first postnatal month, which are associated with poor neurodevelopmental outcomes. Despite this knowledge, the impact of early postnatal nutrition on white matter microstructure in children born with very low birth weight has not been investigated. In this prospective cohort study, we employed a whole-brain approach to investigate associations between precise estimates of nutrient intake within the first postnatal month with white matter microstructure at 5 years of age. Detailed information about breastmilk, macronutrient and energy intakes during this period were prospectively recorded for all participants. Multi-shell diffusion and T 1 -weighted MRIs were acquired in 41 children (21 males; mean scan age: 5.75 ± 0.22 years; mean birth weight: 1028.6 ± 256.8 g). The diffusion tensor imaging and neurite orientation dispersion and density imaging models were used to obtain maps of fractional anisotropy, radial diffusivity, orientation dispersion and neurite density indices. Tract-based spatial statistics was used to test associations between metrics of white matter microstructure with breastmilk, macronutrient (protein, lipids and carbohydrate) and energy intake. Associations between white matter microstructure and cognitive outcomes were also examined. Compared to children who did not meet enteral feeding recommendations, those who achieved enteral protein, lipid and energy recommendations during the first postnatal month showed improved white matter maturation at 5 years. Among the macronutrients, greater protein intake contributed most to the beneficial effect of nutrition, showing widespread increases in fractional anisotropy and reductions in radial diffusivity. No significant associations were found between white matter metrics with breastmilk or carbohydrate intake. Voxel-wise analyses with cognitive outcomes revealed significant associations between higher fractional anisotropy and neurite density index with higher processing speed scores. Lower radial diffusivity and orientation dispersion index were also associated with improved processing speed. Our findings support the long-term impacts of early nutrition on white matter microstructure, which in turn is related to cognitive outcomes. These results provide strong support for early postnatal nutritional intervention as a promising strategy to improve long-term cognitive outcomes of infants born at very low birth weight., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Attachment security is formed through interactions with a main caregiver during the first three years of life and reflects inter-individual differences in mental representations for the relationship. The striatum is known to be a key structure to initiate attachment behaviours and maintain attachment relationships as well as to modulate reward-related processing as part of the approach module in current neurobiological models of human attachment. Although findings have suggested critical roles of the striatum in inter-individual differences in attachment, most studies were based on a wide variety of tasks and very few have investigated these associations in intrinsic brain connectivity in typically developing children. In the present study, using resting-state functional magnetic resonance imaging, we examined the striatal functional connectivity according to children's attachment security in 68 nine-year-olds (Secure attachment = 39, Insecure attachment = 29, mean age/SD = 9.62/0.69). Children with secure attachment demonstrated increased functional connectivity in the tempro-limbic region, compared to children with insecure attachment. In addition, the child-reported attachment security scores were negatively associated with the caudate-prefrontal connectivity, but positively with the putamen-visual area connectivity. These data demonstrate that inter-individual differences in attachment can be captured in striatal functional connectivity organization in the typical brain., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neurodevelopmental difficulties emerge in very preterm born children (<32-week gestation) in infancy and continue to early adulthood but little is known about their social-cognitive development. This study utilized the complementary methodological advantages of both functional MRI and magnetoencephalography to examine the neural underpinnings of Theory of Mind in very preterm birth. Theory of Mind, one of the core social-cognitive skills, is the ability to attribute mental states to others, and is crucial for predicting others' behaviours in social interactions. Eighty-three children (40 very preterm born, 24 boys, age = 8.7 ± 0.5 years, and 43 full-term born, 22 boys, age = 8.6 ± 0.5 years) completed the study. In functional MRI, both groups recruited classic Theory of Mind areas, without significant group differences. However, reduced Theory of Mind connectivity in the very preterm born group was found in magnetoencephalography in distinct theta, alpha and beta-band networks anchored in a set of brain regions that comprise the social brain. These networks included regions such as the angular gyrus, the medial pre-frontal cortex, the superior temporal gyrus and the temporal poles. Very preterm born children showed increased connectivity compared to controls in a network anchored in the occipital gyri rather than classical social-processing regions. Very preterm born children made significantly more attribution errors and mis-construed the social scenarios. Findings offer novel insight into the neural networks, supporting social cognition in very preterm born children and highlight the importance of multimodal neuroimaging to interrogate the social brain in clinical populations., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Examining the brain at rest is a powerful approach used to understand the intrinsic properties of typical and disordered human brain function, yet task-free paradigms are associated with greater head motion, particularly in young and/or clinical populations such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Inscapes, a non-social and non-verbal movie paradigm, has been introduced to increase attention, thus mitigating head motion, while reducing the task-induced activations found during typical movie watching. Inscapes has not yet been validated for use in magnetoencephalography (MEG), and it has yet to be shown whether its effects are stable in clinical populations. Across typically developing (N = 32) children and adolescents and those with ASD (N = 46) and ADHD (N = 42), we demonstrate that head motion is reduced during Inscapes. Due to the task state evoked by movie paradigms, we also expectedly observed concomitant modulations in local neural activity (oscillatory power) and functional connectivity (phase and envelope coupling) in intrinsic resting-state networks and across the frequency spectra compared to a fixation cross resting-state. Increases in local activity were accompanied by decreases in low-frequency connectivity within and between resting-state networks, primarily the visual network, suggesting that task-state evoked by Inscapes moderates ongoing and spontaneous cortical inhibition that forms the idling intrinsic networks found during a fixation cross resting-state. Importantly, these effects were similar in ASD and ADHD, making Inscapes a well-suited advancement for investigations of resting brain function in young and clinical populations., Competing Interests: Declaration of Competing Interest E. Anagnostou has served as a consultant to Roche and Quadrant Therapeutics, holds a patent for the device, “Anxiety meter”, and has received in kind support from AMO pharma, royalties from APPI and Springer, and editorial honoraria from Wiley. The remaining authors (M. M. Vandewouw, B. T. Dunkley, J. P. Lerch, and M. J. Taylor) have reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2020. Published by Elsevier Inc.)

Background: Very low birth weight (VLBW) infants are at risk for disrupted white matter maturation, yet little is known about the contributing factors, particularly at preschool-age when cognitive difficulties begin to emerge. We examined white matter microstructure in five-year-old VLBW and full-term (FT) children, and its association with cognitive outcomes and birth weight., Methods: Multi-shell diffusion and MR images were obtained for 41 VLBW (mean birth weight: 1028.6 ± 256.8 g) and 26 FT (3295.4 ± 493.9 g) children. Fractional anisotropy (FA), radial diffusivity (RD), neurite orientation dispersion index (ODI) and density index (NDI) were estimated using diffusion tensor and neurite orientation dispersion and density imaging models. Between-group analyses used a general linear model with group and sex as explanatory variables. Within-group associations between white matter microstructure, cognitive outcomes and birth weight were also investigated., Results: VLBW compared to FT children showed lower FA and NDI across widespread white matter regions. Smaller clusters of atypical ODI were also found in VLBW children. Within-group analyses in FT children revealed that lower RD and higher NDI were associated with vocabulary acquisition and working memory. In VLBW children, higher FA and NDI, and lower RD and ODI, were associated with improved processing speed. In both groups, FA was positively associated with birth weight., Conclusions: Our findings demonstrate white matter alterations in young VLBW children, including widespread reductions in axon density that may reflect sustained myelination disruptions. The associations with cognitive outcomes may also highlight which of the VLBW children are at higher risk for later cognitive difficulties., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Autism spectrum disorder (ASD) is classically associated with poor face processing skills, yet evidence suggests that those with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) also have difficulties understanding emotions. We determined the neural underpinnings of dynamic emotional face processing across these three clinical paediatric groups, including developmental trajectories, compared with typically developing (TD) controls. We studied 279 children, 5-19 years of age but 57 were excluded due to excessive motion in fMRI, leaving 222: 87 ASD, 44 ADHD, 42 OCD and 49 TD. Groups were sex- and age-matched. Dynamic faces (happy, angry) and dynamic flowers were presented in 18 pseudo-randomized blocks while fMRI data were collected with a 3T MRI. Group-by-age interactions and group difference contrasts were analysed for the faces vs. flowers and between happy and angry faces. TD children demonstrated different activity patterns across the four contrasts; these patterns were more limited and distinct for the NDDs. Processing happy and angry faces compared to flowers yielded similar activation in occipital regions in the NDDs compared to TDs. Processing happy compared to angry faces showed an age by group interaction in the superior frontal gyrus, increasing with age for ASD and OCD, decreasing for TDs. Children with ASD, ADHD and OCD differentiated less between dynamic faces and dynamic flowers, with most of the effects seen in the occipital and temporal regions, suggesting that emotional difficulties shared in NDDs may be partly attributed to shared atypical visual information processing.

Children born very preterm (VPT) are at high-risk for altered brain development and impaired neurodevelopmental outcomes but are not well-studied before school-age. We investigated 64 four-year-olds: 37 VPT children [<32 weeks gestational age [GA]; 22 males; mean GA: 28.8 weeks ± 1.6], 25 full-term (FT) children (12 males), plus two VPT cases with ventriculomegaly and exceptionally resilient outcomes. All children underwent high-resolution structural magnetic resonance imaging and developmental assessments. Measures of brain volume, cortical thickness, and surface area were obtained. Children born VPT demonstrated reduced cerebral and cerebellar white matter volumes yet increased cerebral gray matter, temporal lobe, occipital lobe and ventricle volumes after adjusting for total brain volume. Cortical thickness was greater in the VPT children compared to FT children across all lobes. On developmental assessments, the VPT children scored lower on average than FT children while the two cases had intact cognitive abilities. In addition to larger ventricle volumes, the two cases had white matter and gray matter volumes within the ranges of the FT children. The VPT children displayed distinct differences in structural brain volumes at 4 years of age, consistent with delayed maturation. The cases with persistent ventriculomegaly and good cognitive outcomes displayed typical gray matter and increased white matter volumes, indicating a potential protective developmental phenomenon contributing to their intact cognitive abilities., (Copyright © 2020 Young, Vandewouw, Whyte, Leijser and Taylor.)

Those born very preterm (VPT; <32 weeks gestational age) have an increased risk in developing a wide range of cognitive deficits. In early-to-late childhood, brain structure has been shown to be altered in VPT compared to full-term (FT) children; however, the results are inconsistent. The current study examined subcortical volumes, cortical thickness, and surface area in a large cohort of VPT and FT children aged 4-12 years. Structural magnetic resonance imaging (MRI) was obtained on 120 VPT and 146 FT children who returned up to three times, resulting in 176 VPT and 173 FT unique data points. For each participant, Corticometric Iterative Vertex-based Estimation of Thickness was used to obtain global measurements of total brain, cortical grey and cortical white matter volumes, along with surface-based measurements of cortical thickness and surface area, and Multiple Automatically Generated Templates (MAGeT) brain segmentation tool was used to segment the subcortical structures. To examine group differences and group-age interactions, mixed-effects models were used (controlling for whole-brain volume). We found few differences between the two groups in subcortical volumes. The VPT children showed increased cortical thickness in frontal, occipital and fusiform gyri and inferior pre-post-central areas, while thinning occurred in the midcingulate. Cortical thickness in occipital regions showed more rapid decreases with age in the VPT compared to the FT children. VPT children also showed both regional increases, particularly in the temporal lobe, and decreases in surface area. Our results indicate a delayed maturational trajectory in those born VPT., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Anophthalmia, characterized by the absence of an eye(s), is a rare major birth defect with a relatively unexplored neuroanatomy. Longitudinal comparison of white matter development in an anophthalmic (AC) very preterm (VPT) child with both binocular VPT and full-term (FT) children provides unique insights into early neurodevelopment of the visual system. VPT-born neonates (<32wks gestational age), including the infant with unilateral anophthalmia, underwent neuroimaging every two years from birth until 8 years. DTI images (N = 168) of the optic radiation (OR) and a control track, the posterior limb of the internal capsule (PLIC), were analysed. The diameter of the optic nerves (ON) were analysed using T1-weighted images. Significant group differences in FA and AD were found bilaterally in the OR and PLIC. This extends the literature on altered white matter development in VPT children, being the first longitudinal study showing stable group differences across the 4, 6 and 8 year timepoints. AC showed greater deficits in FA and AD bilaterally, but recovered towards VPT group means from 4 to 8 years-of-age. Complete lack of binocular input would be responsible for these early deficits; compensatory mechanisms may facilitate structural improvement over time. AC's ON exhibited significant atrophy ipsilateral to the anophthalmic eye. Functionally, AC displayed normal visual acuity and form perception, but naso-temporal bias in motion perception. Following these groups and AC longitudinally enabled novel understanding of the joint influence of monocular vision and VPT birth on neurodevelopment., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Children with neurodevelopmental disorders (NDDs) share common behavioural manifestations despite distinct categorical diagnostic criteria. Here, we examined canonical resting-state network connectivity in three diagnostic groups (autism spectrum disorder, attention-deficit/hyperactivity disorder and paediatric obsessive-compulsive disorder) and typically developing controls (TD) in a large single-site sample (N = 407), applying diagnosis-based and dimensional approaches to understand underlying neurobiology across NDDs. Each participant's functional network graphs were computed using five graph metrics. In diagnosis-based comparisons, an analysis of covariance was performed to compare all NDDs to TD, followed by pairwise comparisons between NDDs. In the dimensional approach, participants' functional network graphs were correlated with continuous behavioural measures, and a data-driven k-means clustering analysis was applied to determine if subgroups of participants were seen, without diagnostic information having been included. In the diagnosis-based comparisons, children with NDDs did not differ significantly from the TD group and the NDD categorical groups also did not differ significantly from each other, across all graph metrics. In the dimensional, diagnostic-independent approach, however, subcortical functional connectivity was significantly correlated with participants' general adaptive functioning across all participants. The clustering analysis identified an optimal solution of two clusters, and participants assigned in the same data-driven cluster were highly heterogeneous in diagnosis. Neither cluster exclusively contained a specific diagnostic group, nor did NDDs separate cleanly from TDs. Each participant's distance ratio between the two clusters was significantly correlated with general adaptive functioning, social deficits and attentional problems. Our results suggest the neurobiological similarity and dissimilarity between NDDs need to be investigated beyond DSM/ICD-based, behaviourally-defined diagnostic categories., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Detailed characterization of typical human neurodevelopment is key if we are to understand the nature of mental and neurological pathology. While research on the cellular processes of neurodevelopment has made great advances, in vivo human imaging is crucial to understand our uniquely human capabilities, as well as the pathologies that affect them. Using magnetoencephalography data in the largest normative sample currently available (324 participants aged 6-45 years), we assess the developmental trajectory of resting-state oscillatory power and functional connectivity from childhood to middle age. The maturational course of power, indicative of local processing, was found to both increase and decrease in a spectrally dependent fashion. Using the strength of phase-synchrony between parcellated regions, we found significant linear and nonlinear (quadratic and logarithmic) trajectories to be characterized in a spatially heterogeneous frequency-specific manner, such as a superior frontal region with linear and nonlinear trajectories in theta and gamma band respectively. Assessment of global efficiency revealed similar significant nonlinear trajectories across all frequency bands. Our results link with the development of human cognitive abilities; they also highlight the complexity of neurodevelopment and provide quantitative parameters for replication and a robust footing from which clinical research may map pathological deviations from these typical trajectories., Competing Interests: Competing Interests: The authors have declared that no competing interests exist.

Introduction: The underlying microstructural properties of white matter differences in children born very preterm (<32 weeks gestational age) can be investigated in depth using multi-shell diffusion imaging. The present study compared white matter across the whole brain using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) metrics in children born very preterm and full-term children at six years of age. We also investigated associations between white matter microstructure with early brain injury and developmental outcomes., Method: Multi-shell diffusion imaging, T1-weighted anatomical MR images and developmental assessments were acquired in 23 children born very preterm (16 males; mean scan age: 6.57 ± 0.34 years) and 24 full-term controls (10 males, mean scan age: 6.62 ± 0.37 years). DTI metrics were obtained and neurite orientation dispersion index (ODI) and density index (NDI) were estimated using the NODDI diffusion model. FSL's tract-based spatial statistics were performed on traditional DTI metrics and NODDI metrics. Voxel-wise comparisons were performed to test between-group differences and within-group associations with developmental outcomes (intelligence and visual motor abilities) as well as early white matter injury and germinal matrix/intraventricular haemorrhage (GMH/IVH)., Results: In comparison to term-born children, the children born very preterm exhibited lower fractional anisotropy (FA) across many white matter regions as well as higher mean diffusivity (MD), radial diffusivity (RD), and ODI. Within-group analyses of the children born very preterm revealed associations between higher FA and NDI with higher IQ and VMI. Lower ODI was found within the corona radiata in those with a history of white matter injury. Within the full-term group, associations were found between higher NDI and ODI with lower IQ., Conclusion: Children born very preterm exhibit lower FA and higher ODI than full-term children. NODDI metrics provide more biologically specific information beyond DTI metrics as well as additional information of the impact of prematurity and white matter microstructure on cognitive outcomes at six years of age., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Children born very preterm (VPT; <32 weeks gestational age [GA]) are at greater risk for a range of cognitive deficits that typically manifest at school age. Here we examine the hypothesis that these children have altered myelin maturational that can be detected by myelin sensitive MRI measures prior to school age. We included 33 four-year old children born VPT (mean GA; 28.7 weeks) and 23 four-year old full term (FT) children and completed magnetization transfer (MT), T1-weighted (T1-w) and T2-weighted (T1-w) magnetic resonance imaging as well as developmental assessments. Both MT ratio (MTR) and T1-w/T2-w ratio images were calculated, and group differences were probed using tract-based spatial statistics (TBSS) in white matter, and region of interest (ROI) analysis in white, subcortical gray and cortical gray matter. The relations between MTR and T1-w/T2-w ratio, as well as with developmental assessments, were investigated in all three brain divisions. In children born VPT, TBSS and ROI analysis revealed that both MTR and T1-w/T2-w ratio were significantly reduced in white matter compared to children born FT. ROI analysis showed reductions in T1-w/T2-w ratio in VPT children compared to FT children in the thalamus, putamen and amygdala, as well as in the occipital and temporal lobes. Across the VPT and FT children, T1-w/T2-w ratio and MTR were highly correlated across white, subcortical gray and cortical gray matter. Both measures correlated positively with developmental assessments in individual white matter tracts and cortical and subcortical ROIs, suggesting that higher MTR and T1-w/T2-w ratio is related to better cognitive performance. Together these findings are consistent with delayed myelination in VPT born children., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Language deficits are reported in preterm born children across development. Recent neuroimaging studies have found functional alterations in large-scale brain networks underlying these language deficits, but the early childhood development of the language network has not been investigated. Here, we compared intrinsic language network connectivity in 4-year-old children born VPT and term-born controls, using defined language regions (Broca's area, Wernicke's areas, and their homologues in the right hemisphere). Resting-state functional magnetic resonance imaging (fMRI) was obtained, and the group differences in whole-brain connectivity were examined from each seed as well as correlations with language outcomes. We found significantly decreased functional connectivity in almost all language regions in children born VPT compared to their term controls. Notably, Broca's area homologue in the right hemisphere emerged as a functional hub of decreased connectivity in VPT group, specifically to bilateral inferior frontal and supramarginal gyri; connectivity strength between Broca's area homologue with the right supramarginal and the left inferior frontal gyri was associated with better language outcomes at 4 years of age. Wernicke's area and its homologue also showed decreased inter-hemispheric connections to bilateral supramarginal gyri in the VPT group. Decreased intra- and inter-hemispheric connectivity among primary language regions suggests immature and altered function in the language network in children born VPT.

Purpose: Brain metabolites show very rapid maturation over infancy, particularly following very preterm (VPT) birth, and can provide an index of brain injury. The utility of magnetic resonance imaging (MRS, magnetic resonance spectroscopy) in predicting outcome in VPT-born infants is largely limited to 2-year outcomes. We examined the value of MRS in VPT followed longitudinally to 4 years., Methods: MRS datasets were acquired in 45 VPT infants (< 32 weeks gestational age) longitudinally: at birth, at term-equivalent and at 4 years of age. Using LCModel analyses in a basal ganglia voxel, we investigated metabolite ratios as a function of age, brain injury and outcome. We also studied a full-term (FT) cohort at 4 years and compared group differences with outcome., Results: We found significant age-related changes in many brain metabolites in infancy, including phosphocreatine (CR)/phosphocholine (CHO), N-acetylaspartylglutamate (NAA)/CHO, myoinositol (INS)/CHO and INS/CR; there were no significant MRS differences between VPT and FT groups at 4 years of age, or differences at 4 years as a function of early brain injury or outcome. The rate of change in metabolite ratios from VPT birth to term-equivalent age did not predict outcome in the VPT children at 4 years., Conclusion: Brain metabolite ratios measured in VPT-born infants have shown associations with short-term outcomes, but these correlations did not extend to early childhood nor predict cognitive sequelae. The most frequently reported poor outcome in VPT-born children is cognitive difficulties starting at early school age. MRS metrics early in the infant's life do not appear to predict these longer-term outcomes.

Children born very preterm (VPT) at less than 32 weeks' gestational age (GA) are prone to disrupted white matter maturation and impaired cognitive development. The aims of the present study were to identify differences in white matter microstructure and connectivity of children born VPT compared to term-born children, as well as relations between white matter measures with cognitive outcomes and early brain injury. Diffusion images and T1-weighted anatomical MR images were acquired along with developmental assessments in 31 VPT children (mean GA: 28.76 weeks) and 28 term-born children at 4 years of age. FSL's tract-based spatial statistics was used to create a cohort-specific template and mean fractional anisotropy (FA) skeleton that was applied to each child's DTI data. Whole brain deterministic tractography was performed and graph theoretical measures of connectivity were calculated based on the number of streamlines between cortical and subcortical nodes derived from the Desikan-Killiany atlas. Between-group analyses included FSL Randomise for voxel-wise statistics and permutation testing for connectivity analyses. Within-group analyses between FA values and graph measures with IQ, language and visual-motor scores as well as history of white matter injury (WMI) and germinal matrix/intraventricular haemorrhage (GMH/IVH) were performed. In the children born VPT, FA values within major white matter tracts were reduced compared to term-born children. Reduced measures of local strength, clustering coefficient, local and global efficiency were present in the children born VPT within nodes in the lateral frontal, middle and superior temporal, cingulate, precuneus and lateral occipital regions. Within-group analyses revealed associations in term-born children between FA, Verbal IQ, Performance IQ and Full scale IQ within regions of the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, forceps minor and forceps major. No associations with outcome were found in the VPT group. Global efficiency was reduced in the children born VPT with a history of WMI and GMH/IVH. These findings are evidence for under-developed and less connected white matter in children born VPT, contributing to our understanding of white matter development within this population.

Purpose: Continuous dose delivery in radiation therapy treatments has been shown to decrease total treatment time while improving the dose conformity and distribution homogeneity over the conventional step-and-shoot approach. The authors develop an inverse treatment planning method for Gamma Knife® Perfexion™ that continuously delivers dose along a path in the target., Methods: The authors' method is comprised of two steps: find a path within the target, then solve a mixed integer optimization model to find the optimal collimator configurations and durations along the selected path. Robotic path-finding techniques, specifically, simultaneous localization and mapping (SLAM) using an extended Kalman filter, are used to obtain a path that travels sufficiently close to selected isocentre locations. SLAM is novelly extended to explore a 3D, discrete environment, which is the target discretized into voxels. Further novel extensions are incorporated into the steering mechanism to account for target geometry., Results: The SLAM method was tested on seven clinical cases and compared to clinical, Hamiltonian path continuous delivery, and inverse step-and-shoot treatment plans. The SLAM approach improved dose metrics compared to the clinical plans and Hamiltonian path continuous delivery plans. Beam-on times improved over clinical plans, and had mixed performance compared to Hamiltonian path continuous plans. The SLAM method is also shown to be robust to path selection inaccuracies, isocentre selection, and dose distribution., Conclusions: The SLAM method for continuous delivery provides decreased total treatment time and increased treatment quality compared to both clinical and inverse step-and-shoot plans, and outperforms existing path methods in treatment quality. It also accounts for uncertainty in treatment planning by accommodating inaccuracies.