Altered white matter microstructure is associated with social cognition and psychotic symptoms in 22q11.2 microdeletion syndrome.

22q11.2 Microdeletion Syndrome (22q11DS) is a highly penetrant genetic mutation associated with a significantly increased risk for psychosis. Aberrant neurodevelopment may lead to inappropriate neural circuit formation and cerebral dysconnectivity in 22q11DS, which may contribute to symptom development. Here we examined: (1) differences between 22q11DS participants and typically developing controls in diffusion tensor imaging (DTI) measures within white matter tracts; (2) whether there is an altered age-related trajectory of white matter pathways in 22q11DS; and (3) relationships between DTI measures, social cognition task performance, and positive symptoms of psychosis in 22q11DS and typically developing controls. Sixty-four direction diffusion weighted imaging data were acquired on 65 participants (36 22q11DS, 29 controls). We examined differences between 22q11DS vs. controls in measures of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), using both a voxel-based and region of interest approach. Social cognition domains assessed were: Theory of Mind and emotion recognition. Positive symptoms were assessed using the Structured Interview for Prodromal Syndromes. Compared to typically developing controls, 22q11DS participants showed significantly lower AD and RD in multiple white matter tracts, with effects of greatest magnitude for AD in the superior longitudinal fasciculus. Additionally, 22q11DS participants failed to show typical age-associated changes in FA and RD in the left inferior longitudinal fasciculus. Higher AD in the left inferior fronto-occipital fasciculus (IFO) and left uncinate fasciculus was associated with better social cognition in 22q11DS and controls. In contrast, greater severity of positive symptoms was associated with lower AD in bilateral regions of the IFO in 22q11DS. White matter microstructure in tracts relevant to social cognition is disrupted in 22q11DS, and may contribute to psychosis risk

Individual differences in neonatal white matter are associated with executive function at 3 years of age

The development of executive function (EF) in early childhood contributes to social and academic aspects of school readiness and facilitates emerging self-regulatory competence. Numerous efforts are underway to identify aspects of early brain development that contribute to emerging EF. Existing research supports the importance of multiple white matter tracts for EF in older children and adults. However, this research has not been extended to young children. In this study, we consider neonatal white matter microstructure in relation to children’s performance on a battery of EF tasks three years later. We obtained diffusion tensor imaging data from a sample of neonates (N = 27) shortly after birth. At 3 years of age, children completed a computerized battery of EF tasks. The primary data analyses involved regression models estimated for each white matter tract. Multiple demographic and measure-related covariates were included in each model. A follow-up analysis of tracts determined to be associated with EF examined individual data points along those fibers. Among the white matter tracts analyzed, the cingulum was significantly associated with EF at 3 years of age. Specifically, lower axial diffusivity values along the cingulum were associated with increased performance on the EF battery. Results are discussed as providing initial evidence that individual differences in neonatal brain structure may facilitate the acquisition of EF abilities in early childhood. These findings are consistent with previous research that supports the value of the cingulum for higher-order cognitive abilities. Cautions and implications of these results are considered

Reduced volume of the arcuate fasciculus in adults with high-functioning autism spectrum conditions

Atypical language is a fundamental feature of autism spectrum conditions (ASC), but few studies have examined the structural integrity of the arcuate fasciculus, the major white matter tract connecting frontal and temporal language regions, which is usually implicated as the main transfer route used in processing linguistic information by the brain. Abnormalities in the arcuate have been reported in young children with ASC, mostly in low-functioning or non-verbal individuals, but little is known regarding the structural properties of the arcuate in adults with ASC or, in particular, in individuals with ASC who have intact language, such as those with high-functioning autism or Asperger syndrome. We used probabilistic tractography of diffusion-weighted images (DWI) to isolate and scrutinise the arcuate in a mixed-gender sample of 18 high-functioning adults with ASC (17 Asperger syndrome) and 14 age- and IQ-matched typically-developing controls. Arcuate volume was significantly reduced bilaterally with clearest differences in the right hemisphere. This finding remained significant in an analysis of all male participants alone. Volumetric reduction in the arcuate was significantly correlated with the severity of autistic symptoms as measured by the Autism-Spectrum Quotient. These data reveal that structural differences are present even in high-functioning adults with ASC, who presented with no clinically manifest language deficits and had no reported developmental language delay. Arcuate structural integrity may be useful as an index of ASC severity and thus as a predictor and biomarker for ASC. Implications for future research are discussed

Girls’ Internalizing Symptoms and White Matter Tracts in Cortico-Limbic Circuitry

Dysfunction in cortico-limbic circuitry is implicated in internalizing disorders, but less is known about whether structural abnormalities precede disorder, thus potentially marking risk. I therefore examined associations between white matter tract integrity in cortico-limbic circuitry at age 7, obtained using Diffusion Tensor Imaging, and concurrent and longitudinal patterns of internalizing symptoms, over a 5-year period, in 42 typically developing girls. Using Automated Fiber Quantification, diffusion properties were examined at multiple points along tract length (cf., an average diffusion measure of the entire tract). Concurrent internalizing symptoms were associated with reduced fractional anisotropy in segments of the cingulum bundle and uncinate fasciculus, bilaterally. Moreover, latent profile analysis showed that girls with increasing internalizing symptoms in early and middle childhood had reduced fractional anisotropy in these segments compared to girls with stably low internalizing symptoms. These results point to a putative neural mechanism underlying the course of internalizing symptoms in early childhood

Multimodal imaging of the self-regulating developing brain

Self-regulation refers to the ability to control behavior, cognition, and emotions, and self-regulation failure is related to a range of neuropsychiatric problems. It is poorly understood how structural maturation of the brain brings about the gradual improvement in self-regulation during childhood. In a large-scale multicenter effort, 735 children (4-21 y) underwent structural MRI for quantification of cortical thickness and surface area and diffusion tensor imaging for quantification of the quality of major fiber connections. Brain development was related to a standardized measure of cognitive control (the flanker task from the National Institutes of Health Toolbox), a critical component of self-regulation. Ability to inhibit responses and impose cognitive control increased rapidly during preteen years. Surface area of the anterior cingulate cortex accounted for a significant proportion of the variance in cognitive performance. This finding is intriguing, because characteristics of the anterior cingulum are shown to be related to impulse, attention, and executive problems in neurodevelopmental disorders, indicating a neural foundation for self-regulation abilities along a continuum from normality to pathology. The relationship was strongest in the younger children. Properties of large-fiber connections added to the picture by explaining additional variance in cognitive control. Although cognitive control was related to surface area of the anterior cingulate independently of basic processes of mental speed, the relationship between white matter quality and cognitive control could be fully accounted for by speed. The results underscore the need for integration of different aspects of brain maturation to understand the foundations of cognitive development

Identifying brain and behavioral predictors of language and reading development in typically developing and at-risk children

Learning to read is essential, yet many children do not receive a diagnosis of developmental dyslexia (DD) until second or third grade. The aim of this dissertation is to identify brain and behavioral predictors of DD so that diagnosis and intervention can begin sooner. Experiment 1 examines infants with familial risk of DD longitudinally. Infants completed non-sedated diffusion-weighted imaging (DWI) between 4- and 18-months of age and cognitive-linguistic assessment at four years. Infants at- risk of DD displayed reduced fractional anisotropy (FA) and increased radial diffusivity (RD) in the left arcuate fasciculus (AF) and reduced FA and axial diffusivity (AD) of the splenium of the corpus callosum (CC) compared to peers without a familial risk. Both the left AF and CC are implicated in reading and reading-related tasks, and atypicalities have been observed in children and adults with DD. RD may reflect myelination and AD is thought to indicate pathway complexity suggesting infants at-risk of DD exhibit reduced myelination of the left AF and reduced pathway complexity of the CC at or shortly after birth. The left AF assessed in infancy predicted four-year-old vocabulary skills while the CC predicted four-year-old print knowledge. Experiment 2 explores the association between white matter microstructure of the left AF and CC and neural activity during phonological processing assessed via functional magnetic resonance imaging (fMRI). Preschoolers with and without a familial risk of DD completed DWI and an fMRI alliteration task where children indicated via button-press whether two words started with the same initial sound. Positive correlations were observed between FA of the left AF and CC and neural activity in the left medial temporal gyrus and the left lingual gyrus, two regions implicated in phonological processing. Experiment 3 examines whether white matter microstructure of the CC assessed in preschool is associated with school-age reading fluency in children with and without a familial risk of DD. Similar to children and adults with DD, preschoolers with a familial risk of DD displayed greater FA and AD of the CC compared to controls. Furthermore, AD of the CC predicted school-age reading fluency.2018-12-03T00:00:00

Diffusion magnetic resonance imaging assessment of regional white matter maturation in preterm neonates

PURPOSE: Diffusion magnetic resonance imaging (dMRI) studies report altered white matter (WM) development in preterm infants. Neurite orientation dispersion and density imaging (NODDI) metrics provide more realistic estimations of neurite architecture in vivo compared with standard diffusion tensor imaging (DTI) metrics. This study investigated microstructural maturation of WM in preterm neonates scanned between 25 and 45 weeks postmenstrual age (PMA) with normal neurodevelopmental outcomes at 2 years using DTI and NODDI metrics. METHODS: Thirty-one neonates (n = 17 male) with median (range) gestational age (GA) 32+1 weeks (24+2-36+4) underwent 3 T brain MRI at median (range) post menstrual age (PMA) 35+2 weeks (25+3-43+1). WM tracts (cingulum, fornix, corticospinal tract (CST), inferior longitudinal fasciculus (ILF), optic radiations) were delineated using constrained spherical deconvolution and probabilistic tractography in MRtrix3. DTI and NODDI metrics were extracted for the whole tract and cross-sections along each tract to assess regional development. RESULTS: PMA at scan positively correlated with fractional anisotropy (FA) in the CST, fornix and optic radiations and neurite density index (NDI) in the cingulum, CST and fornix and negatively correlated with mean diffusivity (MD) in all tracts. A multilinear regression model demonstrated PMA at scan influenced all diffusion measures, GA and GAxPMA at scan influenced FA, MD and NDI and gender affected NDI. Cross-sectional analyses revealed asynchronous WM maturation within and between WM tracts.). CONCLUSION: We describe normal WM maturation in preterm neonates with normal neurodevelopmental outcomes. NODDI can enhance our understanding of WM maturation compared with standard DTI metrics alone