Functional connectomes become more longitudinally self-stable, but not more distinct from others, across early childhood.

Functional connectomes, as measured with functional magnetic resonance imaging (fMRI), are highly individualized, and evidence suggests this individualization may increase across childhood. A connectome can become more individualized either by increasing self-stability or decreasing between-subject-similarity. Here we used a longitudinal early childhood dataset to investigate age associations with connectome self-stability, between-subject-similarity, and developmental individualization, defined as an individual's self-stability across a 12-month interval relative to their between-subject-similarity. fMRI data were collected during an 18-minute passive viewing scan from 73 typically developing children aged 4-7 years, at baseline and 12-month follow-up. We found that young children had highly individualized connectomes, with sufficient self-stability across 12-months for 98% identification accuracy. Linear models showed a significant relationship between age and developmental individualization across the whole brain and in most networks. This association appeared to be largely driven by an increase in self-stability with age, with only weak evidence for relationships between age and similarity across participants. Together our findings suggest that children's connectomes become more individualized across early childhood, and that this effect is driven by increasing self-stability rather than decreasing between-subject-similarity.

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.

Reduced White Matter Fiber Density in Autism Spectrum Disorder.

Differences in brain networks and underlying white matter abnormalities have been suggested to underlie symptoms of autism spectrum disorder (ASD). However, robustly characterizing microstructural white matter differences has been challenging. In the present study, we applied an analytic technique that calculates structural metrics specific to differently-oriented fiber bundles within a voxel, termed "fixels". Fixel-based analyses were used to compare diffusion-weighted magnetic resonance imaging data from 25 individuals with ASD (mean age = 16.8 years) and 27 typically developing age-matched controls (mean age = 16.9 years). Group comparisons of fiber density (FD) and bundle morphology were run on a fixel-wise, tract-wise, and global white matter (GWM) basis. We found that individuals with ASD had reduced FD, suggestive of decreased axonal count, in several major white matter tracts, including the corpus callosum (CC), bilateral inferior frontal-occipital fasciculus, right arcuate fasciculus, and right uncinate fasciculus, as well as a GWM reduction. Secondary analyses assessed associations with social impairment in participants with ASD, and showed that lower FD in the splenium of the CC was associated with greater social impairment. Our findings suggest that reduced FD could be the primary microstructural white matter abnormality in ASD.

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.

White matter structural network abnormalities underlie executive dysfunction in amyotrophic lateral sclerosis.

Research in amyotrophic lateral sclerosis (ALS) suggests that executive dysfunction, a prevalent cognitive feature of the disease, is associated with abnormal structural connectivity and white matter integrity. In this exploratory study, we investigated the white matter constructs of executive dysfunction, and attempted to detect structural abnormalities specific to cognitively impaired ALS patients. Eighteen ALS patients and 22 age and education matched healthy controls underwent magnetic resonance imaging on a 4.7 Tesla scanner and completed neuropsychometric testing. ALS patients were categorized into ALS cognitively impaired (ALSci, n = 9) and ALS cognitively competent (ALScc, n = 5) groups. Tract-based spatial statistics and connectomics were used to compare white matter integrity and structural connectivity of ALSci and ALScc patients. Executive function performance was correlated with white matter FA and network metrics within the ALS group. Executive function performance in the ALS group correlated with global and local network properties, as well as FA, in regions throughout the brain, with a high predilection for the frontal lobe. ALSci patients displayed altered local connectivity and structural integrity in these same frontal regions that correlated with executive dysfunction. Our results suggest that executive dysfunction in ALS is related to frontal network disconnectivity, which potentially mediates domain-specific, or generalized cognitive impairment, depending on the degree of global network disruption. Furthermore, reported co-localization of decreased network connectivity and diminished white matter integrity suggests white matter pathology underlies this topological disruption. We conclude that executive dysfunction in ALSci is associated with frontal and global network disconnectivity, underlined by diminished white matter integrity. Hum Brain Mapp 38:1249-1268, 2017. © 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.

Use of cortical volume to predict response to temporary CSF drainage in patients with idiopathic normal pressure hydrocephalus.

OBJECTIVE: Temporary drainage of CSF with lumbar puncture or lumbar drainage has a high predictive value for identifying patients with suspected idiopathic normal pressure hydrocephalus (iNPH) who may benefit from ventriculoperitoneal shunt insertion. However, it is unclear what differentiates responders from nonresponders. The authors hypothesized that nonresponders to temporary CSF drainage would have patterns of reduced regional gray matter volume (GMV) as compared with those of responders. The objective of the current investigation was to compare regional GMV between temporary CSF drainage responders and nonresponders. Machine learning using extracted GMV was then used to predict outcomes. METHODS: This retrospective cohort study included 132 patients with iNPH who underwent temporary CSF drainage and structural MRI. Demographic and clinical variables were examined between groups. Voxel-based morphometry was used to calculate GMV across the brain. Group differences in regional GMV were assessed and correlated with change in results on the Montreal Cognitive Assessment (MoCA) and gait velocity. A support vector machine (SVM) model that used extracted GMV values and was validated with leave-one-out cross-validation was used to predict clinical outcome. RESULTS: There were 87 responders and 45 nonresponders. There were no group differences in terms of age, sex, baseline MoCA score, Evans index, presence of disproportionately enlarged subarachnoid space hydrocephalus, baseline total CSF volume, or baseline white matter T2-weighted hyperintensity volume (p > 0.05). Nonresponders demonstrated decreased GMV in the right supplementary motor area (SMA) and right posterior parietal cortex as compared with responders (p < 0.001, p < 0.05 with false discovery rate cluster correction). GMV in the posterior parietal cortex was associated with change in MoCA (r2 = 0.075, p < 0.05) and gait velocity (r2 = 0.076, p < 0.05). Response status was classified by the SVM with 75.8% accuracy. CONCLUSIONS: Decreased GMV in the SMA and posterior parietal cortex may help identify patients with iNPH who are unlikely to benefit from temporary CSF drainage. These patients may have limited capacity for recovery due to atrophy in these regions that are known to be important for motor and cognitive integration. This study represents an important step toward improving patient selection and predicting clinical outcomes in the treatment of iNPH.

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.

Benchmarking common preprocessing strategies in early childhood functional connectivity and intersubject correlation fMRI.

Preprocessing choices present a particular challenge for researchers working with functional magnetic resonance imaging (fMRI) data from young children. Steps which have been shown to be important for mitigating head motion, such as censoring and global signal regression (GSR), remain controversial, and benchmarking studies comparing preprocessing pipelines have been conducted using resting data from older participants who tend to move less than young children. Here, we conducted benchmarking of fMRI preprocessing steps in a population with high head-motion, children aged 4-8 years, leveraging a unique longitudinal, passive viewing fMRI dataset. We systematically investigated combinations of global signal regression (GSR), volume censoring, and ICA-AROMA. Pipelines were compared using previously established metrics of noise removal as well as metrics sensitive to recovery of individual differences (i.e., connectome fingerprinting), and stimulus-evoked responses (i.e., intersubject correlations; ISC). We found that: 1) the most efficacious pipeline for both noise removal and information recovery included censoring, GSR, bandpass filtering, and head motion parameter (HMP) regression, 2) ICA-AROMA performed similarly to HMP regression and did not obviate the need for censoring, 3) GSR had a minimal impact on connectome fingerprinting but improved ISC, and 4) the strictest censoring approaches reduced motion correlated edges but negatively impacted identifiability.

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.

Visuospatial short-term memory and dorsal visual gray matter volume.

Visual short-term memory (VSTM) is an important cognitive capacity that varies across the healthy adult population and is affected in several neurodevelopmental disorders. It has been suggested that neuroanatomy places limits on this capacity through a map architecture that creates competition for cortical space. This suggestion has been supported by the finding that primary visual (V1) gray matter volume (GMV) is positively associated with VSTM capacity. However, evidence from neurodevelopmental disorders suggests that the dorsal visual stream is more broadly vulnerable and atypical volumes of other map-containing regions may therefore play a role. For example, Turner syndrome is associated with concomitantly reduced volume of the right intraparietal sulcus (IPS) and deficits in VSTM. As posterior IPS regions (IPS0-2) contain topographic maps, together this suggests that posterior IPS volumes may also associate with VSTM. In this study, we assessed VSTM using two tasks, as well as a composite score, and used voxel-based morphometry of T1-weighted magnetic resonance images to assess GMV in V1 and right IPS0-2 in 32 healthy young adults (16 female). For comparison with previous work, we also assessed associations between VSTM and voxel-wise GMV on a whole-brain basis. We found that total brain volume (TBV) significantly correlated with VSTM, and that correlations between VSTM and regional GMV were substantially reduced in strength when controlling for TBV. In our whole-brain analysis, we found that VSTM was associated with GMV of clusters centered around the right putamen and left Rolandic operculum, though only when TBV was not controlled for. Our results suggest that VSTM ability is unlikely to be accounted for by the volume of an individual cortical region, and may instead rely on distributed structural properties.

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.

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.