Behaviour-correlated profiles of cerebellar-cerebral functional connectivity observed in independent neurodevelopmental disorder cohorts.

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, rPOND-HBN = -0.97; FC feature vectors, rPOND-HBN = -0.68) and social communication deficit contrasted against attention deficit behaviour (behaviour feature vectors, rPOND-HBN = -0.99; FC feature vectors, rPOND-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.

Using optically pumped magnetometers to replicate task-related responses in next generation magnetoencephalography.

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.

Dorsal Striatal Functional Connectivity and Repetitive Behavior Dimensions in Children and Youths With Neurodevelopmental Disorders.

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.

The development of functional connectivity within the dorsal striatum from early childhood to adulthood.

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.

Richer than we thought: neurophysiological methods reveal rich-club network development is frequency- and sex-dependent.

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.

Atypical oscillatory dynamics during emotional face processing in paediatric obsessive-compulsive disorder with MEG.

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.

Identifying Replicable Subgroups in Neurodevelopmental Conditions Using Resting-State Functional Magnetic Resonance Imaging Data.

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.

Characterising the spatial and oscillatory unfolding of Theory of Mind in adults using fMRI and MEG.

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.

Intake of mother's milk by very-low-birth-weight infants and variation in DNA methylation of genes involved in neurodevelopment at 5.5 years of age.

BACKGROUND: Mechanisms responsible for associations between intake of mother's milk in very-low-birth-weight (VLBW, <1500 g) infants and later neurodevelopment are poorly understood. It is proposed that early nutrition may affect neurodevelopmental pathways by altering gene expression through epigenetic modification. Variation in DNA methylation (DNAm) at cytosine-guanine dinucleotides (CpGs) is a commonly studied epigenetic modification. OBJECTIVES: We aimed to assess whether early mother's milk intake by VLBW infants is associated with variations in DNAm at 5.5 y, and whether these variations correlate with neurodevelopmental phenotypes. METHODS: This cohort study was a 5.5-y follow-up (2016-2018) of VLBW infants born in Ontario, Canada who participated in the Donor Milk for Improved Neurodevelopmental Outcomes trial. We performed an epigenome-wide association study (EWAS) to test whether percentage mother's milk (not including supplemental donor milk) during hospitalization was associated with DNAm in buccal cells during early childhood (n = 143; mean ± SD age: 5.7 ± 0.2 y; birth weight: 1008 ± 517 g). DNAm was assessed with the Illumina Infinium MethylationEPIC array at 814,583 CpGs. In secondary analyses, we tested associations between top-ranked CpGs and measures of early childhood neurodevelopment, e.g., total surface area of the cerebral cortex (n = 41, MRI) and Full-Scale IQ (n = 133, Wechsler Preschool and Primary Scale of Intelligence-IV). RESULTS: EWAS analysis demonstrated percentage mother's milk intake by VLBW infants during hospitalization was associated with DNAm at 2 CpGs, cg03744440 [myosin XVB (MYO15B)] and cg00851389 [metallothionein 1A (MT1A)], at 5.5 y (P < 9E-08). Gene set enrichment analysis indicated that top-ranked CpGs (P < 0.001) were annotated to genes enriched in neurodevelopmental biological processes. Corroborating these findings, DNAm at several top identified CpGs from the EWAS was associated with cortical surface area and IQ at 5.5 y (P < 0.05). CONCLUSIONS: In-hospital percentage mother's milk intake by VLBW infants was associated with variations in DNAm of neurodevelopmental genes at 5.5 y; some of these DNAm variations are associated with brain structure and IQ.This trial was registered at isrctn.com as ISRCTN35317141 and at clinicaltrials.gov as NCT02759809.

Memory retrieval brain-behavior disconnection in mild traumatic brain injury: A magnetoencephalography and diffusion tensor imaging study.

Mild traumatic brain (mTBI) injury is often associated with long-term cognitive and behavioral complications, including an increased risk of memory impairment. Current research challenges include a lack of cross-modal convergence regarding the underlying neural-behavioral mechanisms of mTBI, which hinders therapeutics and outcome management for this frequently under-treated and vulnerable population. We used multi-modality imaging methods including magnetoencephalography (MEG) and diffusion tensor imaging (DTI) to investigate brain-behavior impairment in mTBI related to working memory. A total of 41 participants were recruited, including 23 patients with a first-time mTBI imaged within 3 months of injury (all male, age = 29.9, SD = 6.9), and 18 control participants (all male, age = 27.3, SD = 5.3). Whole-brain statistics revealed spatially concomitant functional-structural disruptions in brain-behavior interactions in working memory in the mTBI group compared with the control group. These disruptions are located in the hippocampal-prefrontal region and, additionally, in the amygdala (measured by MEG neural activation and DTI measures of fractional anisotropy in relation to working memory performance; p < .05, two-way ANCOVA, nonparametric permutations, corrected). Impaired brain-behavior connections found in the hippocampal-prefrontal and amygdala circuits indicate brain dysregulation of memory, which may leave mTBI patients vulnerable to increased environmental demands exerting memory resources, leading to related cognitive and emotional psychopathologies. The findings yield clinical implications and highlight a need for early rehabilitation after mTBI, including attention- and sensory-based behavioral exercises.

Social-Cognitive Network Connectivity in Preterm Children and Relations With Early Nutrition and Developmental Outcomes.

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.

Corpus callosum injury after neurosurgical intervention for posthemorrhagic ventricular dilatation and association with neurodevelopmental outcome at 2 years.

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.

Shared and Distinct Patterns of Functional Connectivity to Emotional Faces in Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder Children.

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.

Cortical Gyrification Morphology in ASD and ADHD: Implication for Further Similarities or Disorder-Specific Features?

Shared etiological pathways are suggested in ASD and ADHD given high rates of comorbidity, phenotypic overlap and shared genetic susceptibility. Given the peak of cortical gyrification expansion and emergence of ASD and ADHD symptomology in early development, we investigated gyrification morphology in 539 children and adolescents (6-17 years of age) with ASD (n=197) and ADHD (n=96) compared to typically developing controls (n=246) using the local Gyrification Index (lGI) to provide insight into contributing etiopathological factors in these two disorders. We also examined IQ effects and functional implications of gyrification by exploring the relation between lGI and ASD and ADHD symptomatology beyond diagnosis. General Linear Models yielded no group differences in lGI, and across groups, we identified an age-related decrease of lGI and greater lGI in females compared to males. No diagnosis-by-age interactions were found. Accounting for IQ variability in the model (n=484) yielded similar results. No significant associations were found between lGI and social communication deficits, repetitive and restricted behaviours, inattention or adaptive functioning. By examining both disorders and controls using shared methodology, we found no evidence of atypicality in gyrification as measured by the lGI in these conditions.

White matter alterations and cognitive outcomes in children born very low birth weight.

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.

Do shapes have feelings? Social attribution in children with autism spectrum disorder and attention-deficit/hyperactivity disorder.

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.

Ignore the faces: Neural characterisation of emotional inhibition from childhood to adulthood using MEG.

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.

Atypical development of emotional face processing networks in autism spectrum disorder from childhood through to adulthood.

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.

Altered functional connectivity during face processing in children born with very low birth weight.

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 developing relations between networks of cortical myelin and neurophysiological connectivity.

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.