Functional connectivity based brain signatures of behavioral regulation in children with ADHD, DCD, and ADHD-DCD.

Behavioral regulation problems have been associated with daily-life and mental health challenges in children with neurodevelopmental conditions such as attention-deficit/hyperactivity disorder (ADHD) and developmental coordination disorder (DCD). Here, we investigated transdiagnostic brain signatures associated with behavioral regulation. Resting-state fMRI data were collected from 115 children (31 typically developing (TD), 35 ADHD, 21 DCD, 28 ADHD-DCD) aged 7-17 years. Behavioral regulation was measured using the Behavior Rating Inventory of Executive Function and was found to differ between children with ADHD (i.e., children with ADHD and ADHD-DCD) and without ADHD (i.e., TD children and children with DCD). Functional connectivity (FC) maps were computed for 10 regions of interest and FC maps were tested for correlations with behavioral regulation scores. Across the entire sample, greater behavioral regulation problems were associated with stronger negative FC within prefrontal pathways and visual reward pathways, as well as with weaker positive FC in frontostriatal reward pathways. These findings significantly increase our knowledge on FC in children with and without ADHD and highlight the potential of FC as brain-based signatures of behavioral regulation across children with differing neurodevelopmental conditions.

Pre-reading language abilities and the brain's functional reading network in young children.

Early childhood is an important period for language development that lays the foundation for future reading abilities. However, little research has focused on the functional brain systems supporting pre-reading language abilities in typically developing children. Here, we investigated functional connectivity using passive viewing functional magnetic resonance imaging (fMRI) in 50 healthy children aged 2.85-5.07 years (3.84 â€‹± â€‹0.60 years, 22 female/28 male). Children completed the NEPSY-II Phonological Processing and Speeded Naming subtests and underwent fMRI while watching a movie of their choice. Functional connectivity was measured between key brain reading areas (bilateral angular gyrus, superior temporal gyrus, and inferior frontal gyrus) and the rest of the brain. Age-adjusted pre-reading scores positively correlated with functional connectivity between (1) the right angular gyrus and superior temporal gyrus, (2) the bilateral angular gyri and right pars triangularis and motor areas, (3) the left superior temporal gyrus and bilateral medial frontal gyrus and right cerebellum, (4) the left pars triangularis and middle occipital gyrus and insula, and (5) the right pars triangularis and the bilateral thalamus. Higher pre-reading scores were associated with stronger negative functional connectivity between (1) the left angular gyrus and auditory cortex, (2) the left superior temporal gyrus and occipital vision areas, (3) the right pars triangularis and medial frontal region, and (4) the right superior temporal gyrus and the posterior cingulate/precuneus. These results suggest better integration of the reading network, as well as its connections with other brain areas that support language or reading, and more dissociation between reading areas and the default mode network, in young children with better pre-reading skills. Our findings show that relationships between functional connectivity and pre-reading language skills are evident in young children even before formal reading instruction.

Early childhood development of white matter fiber density and morphology.

Early childhood is an important period for cognitive and brain development, though white matter changes specific to this period remain understudied. Here we utilize a novel analytic approach to quantify and track developmental changes in white matter micro- and macro-structure, calculated from individually oriented fiber-bundle populations, termed "fixels". Fixel-based analysis and mixed-effects models were used to assess tract-wise changes in fiber density and bundle morphology in 73 girls scanned at baseline (ages 4.09-7.02, mean â€‹= â€‹5.47, SD â€‹= â€‹0.81), 6-month (N â€‹= â€‹7), and one-year follow-up (N â€‹= â€‹42). For comparison, we also assessed changes in commonly utilized diffusion tensor metrics: fractional anisotropy (FA), and mean, radial and axial diffusivity (MD, RD, AD). Maturational increases in fixel-metrics were seen in most major white matter tracts, with the most rapid increases in the corticospinal tract and slowest or non-significant increases in the genu of the corpus callosum and uncinate fasciculi. As expected, we observed developmental increases in FA and decreases in MD, RD and AD, though percent changes were smaller relative to fixel-metrics. The majority of tracts showed more substantial morphological than microstructural changes. These findings highlight early childhood as a period of dynamic white matter maturation, characterized by large increases in macroscopic fiber bundle size, mild changes in axonal density, and parallel, albeit less substantial, changes in diffusion tensor metrics.

Maturation and interhemispheric asymmetry in neurite density and orientation dispersion in early childhood.

BACKGROUND: The brain's white matter undergoes profound changes during early childhood, which are believed to underlie the rapid development of cognitive and behavioral skills during this period. Neurite density, and complexity of axonal projections, have been shown to change across the life span, though changes during early childhood are poorly characterized. Here, we utilize neurite orientation dispersion and density imaging (NODDI) to investigate maturational changes in tract-wise neurite density index (NDI) and orientation dispersion index (ODI) during early childhood. Additionally, we assess hemispheric asymmetry of tract-wise NDI and ODI values, and longitudinal changes. METHODS: Two sets of diffusion weighted images with different diffusion-weighting were collected from 125 typically developing children scanned at baseline (N = 125; age range = 4.14-7.29; F/M = 73/52), 6-month (N = 8; F/M = 8/0), and 12-month (N = 52; F/M = 39/13) timepoints. NODDI and template-based tractography using constrained spherical deconvolution were utilized to calculate NDI and ODI values for major white matter tracts. Mixed-effects models controlling for sex, handedness, and in-scanner head motion were utilized to assess developmental changes in tract-wise NDI and ODI. Additional mixed-effects models were used to assess interhemispheric differences in tract-wise NDI and ODI values and hemispheric asymmetries in tract-wise development. RESULTS: Maturational increases in NDI were seen in all major white matter tracts, though we did not observe the expected tract-wise pattern of maturational rates (e.g. fast commissural/projection and slow frontal/temporal tract change). ODI did not change significantly with age in any tract. We observed greater NDI and ODI values in the right as compared to the left hemisphere for most tracts, but no hemispheric asymmetry for rate of change with age. CONCLUSIONS: These findings suggest that neurite density, but not orientation dispersion, increases with age during early childhood. In relation to NDI growth trends reported in infancy and late-childhood, our results suggest that early childhood may be a transitional period for neurite density maturation wherein commissural/projection fibers are approaching maturity, maturation in long range association fibers is increasing, and changes in limbic/frontal fibers remain modest. Rightward asymmetry in NDI and ODI values, but no asymmetry in developmental changes, suggests that rightward asymmetry of neurite density and orientation dispersion is established prior to age 4.

Functional Connectivity of the Dorsal Attention Network Predicts Selective Attention in 4-7 year-old Girls.

Early childhood is a period of profound neural development and remodeling during which attention skills undergo rapid maturation. Attention networks have been extensively studied in the adult brain, yet relatively little is known about changes in early childhood, and their relation to cognitive development. We investigated the association between age and functional connectivity (FC) within the dorsal attention network (DAN) and the association between FC and attention skills in early childhood. Functional magnetic resonance imaging data was collected during passive viewing in 44 typically developing female children between 4 and 7 years whose sustained, selective, and executive attention skills were assessed. FC of the intraparietal sulcus (IPS) and the frontal eye fields (FEF) was computed across the entire brain and regressed against age. Age was positively associated with FC between core nodes of the DAN, the IPS and the FEF, and negatively associated with FC between the DAN and regions of the default-mode network. Further, controlling for age, FC between the IPS and FEF was significantly associated with selective attention. These findings add to our understanding of early childhood development of attention networks and suggest that greater FC within the DAN is associated with better selective attention skills.

The neural networks of subjectively evaluated emotional conflicts.

Previous work on the neural underpinnings of emotional conflict processing has largely focused on designs that instruct participants to ignore a distracter which conflicts with a target. In contrast, this study investigated the noninstructed experience and evaluation of an emotional conflict, where positive or negative cues can be subjectively prioritized. To this end, healthy participants freely watched short film scenes that evoked emotional conflicts while their BOLD responses were measured. Participants' individual ratings of conflict and valence perception during the film scenes were collected immediately afterwards, and the individual ratings were regressed against the BOLD data. Our analyses revealed that (a) amygdala and medial prefrontal cortex were significantly involved in prioritizing positive or negative cues, but not in subjective evaluations of conflict per se, and (b) superior temporal sulcus (STS) and inferior parietal lobule (IPL), which have been implicated in social cognition and emotion control, were involved in both prioritizing positive or negative cues and subjectively evaluating conflict, and may thus constitute "hubs" or "switches" in emotional conflict processing. Psychophysiological interaction (PPI) analyses further revealed stronger functional connectivity between IPL and ventral prefrontal-medial parietal areas in prioritizing negative cues, and stronger connectivity between STS and dorsal-rostral prefrontal-medial parietal areas in prioritizing positive cues. In sum, our results suggest that IPL and STS are important in the subjective evaluation of complex conflicts and influence valence prioritization via prefrontal and parietal control centers. Hum Brain Mapp 37:2234-2246, 2016. © 2016 Wiley Periodicals, Inc.

Functional MRI responses to naturalistic stimuli are increasingly typical across early childhood.

While findings show that throughout development, there are child- and age-specific patterns of brain functioning, there is also evidence for significantly greater inter-individual response variability in young children relative to adults. It is currently unclear whether this increase in functional "typicality" (i.e., inter-individual similarity) is a developmental process that occurs across early childhood, and what changes in BOLD response may be driving changes in typicality. We collected fMRI data from 81 typically developing 4-8-year-old children during passive viewing of age-appropriate television clips and asked whether there is increasing typicality of brain response across this age range. We found that the "increasing typicality" hypothesis was supported across many regions engaged by passive viewing. Post hoc analyses showed that in a priori ROIs related to language and face processing, the strength of the group-average shared component of activity increased with age, with no concomitant decline in residual signal or change in spatial extent or variability. Together, this suggests that increasing inter-individual similarity of functional responses to audiovisual stimuli is an important feature of early childhood functional brain development.

Inattentive and hyperactive traits differentially associate with interindividual functional synchrony during video viewing in young children without ADHD.

Inattention and hyperactivity present on a spectrum and may influence the way children perceive and interact with the world. We investigated whether normative variation in inattentive and hyperactive traits was associated with differences in brain function, while children watched clips from an age-appropriate television program. Functional magnetic resonance imaging (fMRI) data and parent reports of inattention and hyperactivity traits were collected from 81 children 4-7 years of age with no parent-reported diagnoses. Data were analyzed using intersubject correlations (ISCs) in mixed effects models to determine if inattentive and hyperactive traits were associated with idiosyncrasy of fMRI response to the video. We hypothesized that pairs of children with higher average inattention and hyperactivity scores would show less interindividual brain synchrony to one another than pairs with lower average scores on these traits. Video watching engaged widespread visual, auditory, default mode and dorsal prefrontal regions. Inattention and hyperactivity were separably associated with ISC in many of these regions. Our findings suggest that the spectrum of inattention and hyperactivity traits in children without ADHD are differentially associated with neural processing of naturalistic video stimuli, which may have implications for understanding how children with different levels of these traits process audiovisual information in unconstrained conditions.

Videogame exposure positively associates with selective attention in a cross-sectional sample of young children.

There is growing interest in how exposure to videogames is associated with young children's development. While videogames may displace time from developmentally important activities and have been related to lower reading skills, work in older children and adolescents has suggested that experience with attention-demanding/fast-reaction games positively associates with attention and visuomotor skills. In the current study, we assessed 154 children aged 4-7 years (77 male; mean age 5.38) whose parents reported average daily weekday recreational videogame time, including information about which videogames were played. We investigated associations between videogame exposure and children's sustained, selective, and executive attention skills. We found that videogame time was significantly positively associated only with selective attention. Longitudinal studies are needed to elucidate the directional association between time spent playing recreational videogames and attention skills.

Building functional connectivity neuromarkers of behavioral self-regulation across children with and without Autism Spectrum Disorder.

Behavioral self-regulation develops rapidly during childhood and struggles in this area can have lifelong negative outcomes. Challenges with self-regulation are common to several neurodevelopmental conditions, including Autism Spectrum Disorder (ASD). Little is known about the neural expression of behavioral regulation in children with and without neurodevelopmental conditions. We examined whole-brain brain functional correlations (FC) and behavioral regulation through connectome predictive modelling (CPM). CPM is a data-driven protocol for developing predictive models of brain-behavior relationships and assessing their potential as 'neuromarkers' using cross-validation. The data stems from the ABIDE II and comprises 276 children with and without ASD (8-13 years). We identified networks whose FC predicted individual differences in behavioral regulation. These network models predicted novel individuals' inhibition and shifting from FC data in both a leave-one-out, and split halves, cross-validation. We observed commonalities and differences, with inhibition relying on more posterior networks, shifting relying on more anterior networks, and both involving regions of the DMN. Our findings substantially add to our knowledge on the neural expressions of inhibition and shifting across children with and without a neurodevelopmental condition. Given the numerous behavioral issues that can be quantified dimensionally, refinement of whole-brain neuromarker techniques may prove useful in the future.

Grey and white matter volumes in early childhood: A comparison of voxel-based morphometry pipelines.

Early childhood is an important period of sensory, motor, cognitive and socio-emotional maturation, yet relatively little is known about the brain changes specific to this period. Voxel-based morphometry (VBM) is a technique to estimate regional brain volumes from magnetic resonance (MR) images. The default VBM processing pipeline can be customized to increase accuracy of segmentation and normalization, yet the impact of customizations on analyses in young children are not clear. Here, we assessed the impact of different preprocessing steps on T1-weighted MR images from typically developing children in two separate cohorts. Data were processed with the Computational Anatomy Toolbox (CAT12), using seven different VBM pipelines with distinct combinations of tissue probability maps (TPMs) and DARTEL templates created using the Template-O-Matic, and CerebroMatic. The first cohort comprised female children aged 3.9-7.9 years (N = 62) and the second included boys and girls aged 2.7-8 years (N = 74). We found that pipelines differed significantly in their tendency to classify voxels as grey or white matter and the conclusions about some age effects were pipeline-dependent. Our study helps to both understand age-associations in grey and white matter volume across early childhood and elucidate the impact of VBM customization on brain volumes in this age range.

Alteration in Cerebral Activation during a Working Memory Task after Pediatric Mild Traumatic Brain Injury: A Prospective Controlled Cohort Study.

Mild traumatic brain injuries (mTBIs) commonly occur in children and adolescents and can result in persistent cognitive symptoms. The neurophysiological changes that underlie persistent post-concussive symptoms (PPCS) have not been characterized. Our objective was to compare working-memory related functional magnetic resonance imaging (fMRI) response in children with persistent symptoms after mTBI at one month post-injury to children with typical recovery and healthy controls. This was a prospective, controlled cohort study of children with mTBI at one month post-injury. PPCS was defined as children with a 10-point increase in their post-concussion symptom inventory score (compared with pre-injury score) at one month post-injury and a two-point increase in at least two symptom categories compared with pre-injury. One hundred and seven participants (60 PPCS, 30 recovered mTBI, and 17 controls) with a mean age of 14.2 years (standard deviation [SD] 2.5) (44% male) were assessed 38 (SD 5.9) days after mTBI. The primary outcome measures were visuospatial n-back working memory task performance and fMRI blood oxygen level dependent (BOLD) signal change. Children with PPCS had decreased activation relative to children with typical recovery in the posterior cingulate and precuneus during the one-back working memory condition, despite similar task performance. Differences in cortical activation in children with PPCS at one month highlight the persistent neurobiological consequences of pediatric mTBI on working memory cortical activation. These findings encourage recommendations to avoid contact sports and provide continued care at school for children with persistent symptoms at one month post-injury.

Girls' attentive traits associate with cerebellar to dorsal attention and default mode network connectivity.

Attention traits are a cornerstone to the healthy development of children's performance in the classroom, their interactions with peers, and in predicting future success and problems. The cerebellum is increasingly appreciated as a region involved in complex cognition and behavior, and moreover makes important connections to key brain networks known to support attention: the dorsal attention and default mode networks (DAN; DMN). The cerebellum has also been implicated in childhood disorders affecting attention, namely autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), suggesting that attention networks extending to the cerebellum may be important to consider in relation to attentive traits. Yet, direct investigations into the association between cerebellar FC and attentive traits are lacking. Therefore, in this study we examined attentive traits, assessed using parent reports of ADHD and ASD symptoms, in a community sample of 52 girls aged 4-7 years, i.e. around the time of school entry, and their association with cerebellar connections with the DAN and DMN. We found that cortico-cerebellar functional connectivity (FC) jointly and differentially correlated with attentive traits, through a combination of weaker and stronger FC across anterior and posterior DAN and DMN nodes. These findings suggest that cortico-cerebellar integration may play an important role in the manifestation of attentive traits.

Learning with individual-interest outcomes in Autism Spectrum Disorder.

Recent work has suggested atypical neural reward responses in individuals with Autism Spectrum Disorder (ASD), particularly for social reinforcers. Less is known about neural responses to restricted interests and few studies have investigated response to rewards in a learning context. We investigated neurophysiological differences in reinforcement learning between adolescents with ASD and typically developing (TD) adolescents (27 ASD, 31 TD). FMRI was acquired during a learning task in which participants chose one of two doors to reveal an image outcome. Doors differed in their probability of showing liked and not-liked images, which were individualized for each participant. Participants chose the door paired with liked images, but not the door paired with not-liked images, significantly above chance and choice allocation did not differ between groups. Interestingly, participants with ASD made choices less consistent with their initial door preferences. We found a neural prediction-error response at the time of outcome in the ventromedial prefrontal and posterior cingulate cortices that did not differ between groups. Together, behavioural and neural findings suggest that learning with individual interest outcomes is not different between individuals with and without ASD, adding to our understanding of motivational aspects of ASD.

A mind-brain-body dataset of MRI, EEG, cognition, emotion, and peripheral physiology in young and old adults.

We present a publicly available dataset of 227 healthy participants comprising a young (N=153, 25.1±3.1 years, range 20-35 years, 45 female) and an elderly group (N=74, 67.6±4.7 years, range 59-77 years, 37 female) acquired cross-sectionally in Leipzig, Germany, between 2013 and 2015 to study mind-body-emotion interactions. During a two-day assessment, participants completed MRI at 3 Tesla (resting-state fMRI, quantitative T1 (MP2RAGE), T2-weighted, FLAIR, SWI/QSM, DWI) and a 62-channel EEG experiment at rest. During task-free resting-state fMRI, cardiovascular measures (blood pressure, heart rate, pulse, respiration) were continuously acquired. Anthropometrics, blood samples, and urine drug tests were obtained. Psychiatric symptoms were identified with Standardized Clinical Interview for DSM IV (SCID-I), Hamilton Depression Scale, and Borderline Symptoms List. Psychological assessment comprised 6 cognitive tests as well as 21 questionnaires related to emotional behavior, personality traits and tendencies, eating behavior, and addictive behavior. We provide information on study design, methods, and details of the data. This dataset is part of the larger MPI Leipzig Mind-Brain-Body database.

Functional network integration and attention skills in young children.

Children acquire attention skills rapidly during early childhood as their brains undergo vast neural development. Attention is well studied in the adult brain, yet due to the challenges associated with scanning young children, investigations in early childhood are sparse. Here, we examined the relationship between age, attention and functional connectivity (FC) during passive viewing in multiple intrinsic connectivity networks (ICNs) in 60 typically developing girls between 4 and 7 years whose sustained, selective and executive attention skills were assessed. Visual, auditory, sensorimotor, default mode (DMN), dorsal attention (DAN), ventral attention (VAN), salience, and frontoparietal ICNs were identified via Independent Component Analysis and subjected to a dual regression. Individual spatial maps were regressed against age and attention skills, controlling for age. All ICNs except the VAN showed regions of increasing FC with age. Attention skills were associated with FC in distinct networks after controlling for age: selective attention positively related to FC in the DAN; sustained attention positively related to FC in visual and auditory ICNs; and executive attention positively related to FC in the DMN and visual ICN. These findings suggest distributed network integration across this age range and highlight how multiple ICNs contribute to attention skills in early childhood.

Reinforcement Learning in Autism Spectrum Disorder.

Early behavioral interventions are recognized as integral to standard care in autism spectrum disorder (ASD), and often focus on reinforcing desired behaviors (e.g., eye contact) and reducing the presence of atypical behaviors (e.g., echoing others' phrases). However, efficacy of these programs is mixed. Reinforcement learning relies on neurocircuitry that has been reported to be atypical in ASD: prefrontal-sub-cortical circuits, amygdala, brainstem, and cerebellum. Thus, early behavioral interventions rely on neurocircuitry that may function atypically in at least a subset of individuals with ASD. Recent work has investigated physiological, behavioral, and neural responses to reinforcers to uncover differences in motivation and learning in ASD. We will synthesize this work to identify promising avenues for future research that ultimately can be used to enhance the efficacy of early intervention.

Affect and the brain's functional organization: a resting-state connectivity approach.

The question of how affective processing is organized in the brain is still a matter of controversial discussions. Based on previous initial evidence, several suggestions have been put forward regarding the involved brain areas: (a) right-lateralized dominance in emotional processing, (b) hemispheric dominance according to positive or negative valence, (c) one network for all emotional processing and (d) region-specific discrete emotion matching. We examined these hypotheses by investigating intrinsic functional connectivity patterns that covary with results of the Positive and Negative Affective Schedule (PANAS) from 65 participants. This approach has the advantage of being able to test connectivity rather than activation, and not requiring a potentially confounding task. Voxelwise functional connectivity from 200 regions-of-interest covering the whole brain was assessed. Positive and negative affect covaried with functional connectivity involving a shared set of regions, including the medial prefrontal cortex, the anterior cingulate, the visual cortex and the cerebellum. In addition, each affective domain had unique connectivity patterns, and the lateralization index showed a right hemispheric dominance for negative affect. Therefore, our results suggest a predominantly right-hemispheric network with affect-specific elements as the underlying organization of emotional processes.