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.

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.

The relationship between maintenance and manipulation components of working memory and prefrontal and parietal brain regions in bipolar disorder.

BACKGROUND: A domain of cognition that has been found to be impaired in bipolar disorder across mood states is working memory. Working memory can be separated into two components, maintenance and manipulation. Bipolar patients also demonstrate structural brain abnormalities in prefrontal and parietal regions, which are regions associated with working memory processes. Despite the understanding that working memory consists of multiple separable cognitive processes, no study to date has differentiated maintenance and manipulation, and associated them with underlying structural brain regions in bipolar disorder. METHODS: Twenty-six bipolar patients and 24 controls completed a visuospatial working memory task and structural neuroimaging. Prefrontal and parietal gray matter volume, surface area, and cortical thickness were obtained using FreeSurfer. The relationship between working memory performance, structural integrity, symptoms, and functioning were investigated. RESULTS: Bipolar patients were less accurate on the working memory task compared to controls, without a greater deficit in the manipulation condition. Controls had thicker prefrontal and parietal cortices than bipolar patients. In bipolar patients, thicker prefrontal cortices had a small association with greater accuracy on the maintenance condition, as well as greater depression. LIMITATIONS: This study could have benefitted from a larger sample size. CONCLUSIONS: Bipolar patients demonstrated both poorer accuracy on the visuospatial working memory task compared to controls and thinner cortices in areas associated with working memory, namely the prefrontal and parietal cortices. This demonstrates an underlying relationship between brain and behavior in bipolar disorder.

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.

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.

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.

Largely Typical Electrophysiological Affective Responses to Special Interest Stimuli in Adolescents with Autism Spectrum Disorder.

Circumscribed interests are a symptom of autism spectrum disorder (ASD) that may be related to exaggerated affective neural responses. However, the use of generic ASD-interest image stimuli has left an open question as to whether affective responses towards individual interests are greater in ASD compared to typically developing (TD) controls. We compared amplitudes of the late positive potential (LPP), an affective electroencephalographic response, between adolescents with ASD (N = 19) and TD adolescents (N = 20), using images tailored to individual likes and dislikes. We found an LPP response for liked and disliked images, relative to neutral, with no difference in amplitude between groups. This suggests that the LPP is not atypical in adolescents with ASD towards images of individual interests.

Circumscribed interests in adolescents with Autism Spectrum Disorder: A look beyond trains, planes, and clocks.

Adolescence is a unique developmental period, characterized by physical and emotional growth and significant maturation of cognitive and social skills. For individuals with Autism Spectrum Disorder (ASD), it is also a vulnerable period as cognitive and social skills can deteriorate. Circumscribed interests (CIs), idiosyncratic areas of intense interest and focus, are a core symptom of ASD that may be associated with social development. Yet, relatively little is known about the expression of CIs in adolescents with ASD. Many studies investigating CIs have used images depicting items of special interest; however, it is not clear how images should be customized for adolescent studies. The goal of this study was to gain insight into the types of images that may be appropriate for studies of CIs in adolescents with ASD. To this end, we used a mixed methods design that included, 1) one-on-one interviews with 10 adolescents (4 with ASD and 6 TD), to identify categories of images that were High Autism Interest ('HAI') or High Typically Developing Interest ('HTD'), and 2) an online survey taken by fifty-three adolescents with ASD (42 male) and 135 typically developing (TD) adolescents (55 male) who rated how much they liked 105 'HAI' and 'HTD' images. Although we found a significant interaction between 'HAI' and 'HTD' categories and diagnosis, neither group significantly preferred one category over the other, and only one individual category ('Celebrities') showed a significant group effect, favored by TD adolescents. Males significantly preferred 'HAI' images relative to females, and TD adolescents significantly preferred images with social content relative to adolescents with ASD. Our findings suggest that studies investigating affective or neural responses to CI-related stimuli in adolescents should consider that stereotypical ASD interests (e.g. trains, gadgets) may not accurately represent individual adolescents with ASD, many of whom show interests that overlap with TD adolescents (e.g. video games).

Morphological Alterations in the Thalamus, Striatum, and Pallidum in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with cognitive, motor, and emotional symptoms. The thalamus and basal ganglia form circuits with the cortex supporting all three of these behavioral domains. Abnormalities in the structure of subcortical regions may suggest atypical development of these networks, with implications for understanding the neural basis of ASD symptoms. Findings from previous volumetric studies have been inconsistent. Here, using advanced surface-based methodology, we investigated localized differences in shape and surface area in the basal ganglia and thalamus in ASD, using T1-weighted anatomical images from the Autism Brain Imaging Data Exchange (373 male participants aged 7-35 years with ASD and 384 typically developing). We modeled effects of diagnosis, age, and their interaction on volume, shape, and surface area. In participants with ASD, we found expanded surface area in the right posterior thalamus corresponding to the pulvinar nucleus, and a more concave shape in the left mediodorsal nucleus. The shape of both caudal putamen and pallidum showed a relatively steeper increase in concavity with age in ASD. Within ASD participants, restricted, repetitive behaviors were positively associated with surface area in bilateral globus pallidus. We found no differences in overall volume, suggesting that surface-based approaches have greater sensitivity to detect localized differences in subcortical structure. This work adds to a growing body of literature implicating corticobasal ganglia-thalamic circuits in the pathophysiology of ASD. These circuits subserve a range of cognitive, emotional, and motor functions, and may have a broad role in the complex symptom profile in ASD.