Reciprocal white matter alterations due to 16p11.2 chromosomal deletions versus duplications.

Copy number variants at the 16p11.2 chromosomal locus are associated with several neuropsychiatric disorders, including autism, schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, and speech and language disorders. A gene dosage dependence has been suggested, with 16p11.2 deletion carriers demonstrating higher body mass index and head circumference, and 16p11.2 duplication carriers demonstrating lower body mass index and head circumference. Here, we use diffusion tensor imaging to elucidate this reciprocal relationship in white matter organization, showing widespread increases of fractional anisotropy throughout the supratentorial white matter in pediatric deletion carriers and, in contrast, extensive decreases of white matter fractional anisotropy in pediatric and adult duplication carriers. We find associations of these white matter alterations with cognitive and behavioral impairments. We further demonstrate the value of imaging metrics for characterizing the copy number variant phenotype by employing linear discriminant analysis to predict the gene dosage status of the study subjects. These results show an effect of 16p11.2 gene dosage on white matter microstructure, and further suggest that opposite changes in diffusion tensor imaging metrics can lead to similar cognitive and behavioral deficits. Given the large effect sizes found in this study, our results support the view that specific genetic variations are more strongly associated with specific brain alterations than are shared neuropsychiatric diagnoses. Hum Brain Mapp 37:2833-2848, 2016. © 2016 Wiley Periodicals, Inc.

Aberrant white matter microstructure in children with 16p11.2 deletions.

Copy number variants (CNVs) of the chromosomal locus 16p11.2, consisting of either deletions or duplications, have been implicated in autism, schizophrenia, epilepsy, and other neuropsychiatric disorders. Since abnormal white matter microstructure can be seen in these more broadly defined clinical disorders, we used diffusion magnetic resonance imaging and tract-based spatial statistics to investigate white matter microstructural integrity in human children with 16p11.2 deletions. We show that deletion carriers, compared with typically developing matched controls, have increased axial diffusivity (AD) in many major central white matter tracts, including the anterior corpus callosum as well as bilateral internal and external capsules. Higher AD correlated with lower nonverbal IQ in the deletion carriers, but not controls. Increases in fractional anisotropy and mean diffusivity were also found in some of the same tracts with elevated AD. Closer examination with neurite orientation dispersion and density imaging revealed that fiber orientation dispersion was decreased in some central white matter tracts. Notably, these alterations of white matter are unlike microstructural differences reported for any other neurodevelopmental disorders, including autism spectrum disorders that have phenotypic overlap with the deletion carriers. These findings suggest that deletion of the 16p11.2 locus is associated with a unique widespread pattern of aberrant white matter microstructure that may underlie the impaired cognition characteristic of this CNV.

White Matter Changes of Neurite Density and Fiber Orientation Dispersion during Human Brain Maturation.

Diffusion tensor imaging (DTI) studies of human brain development have consistently shown widespread, but nonlinear increases in white matter anisotropy through childhood, adolescence, and into adulthood. However, despite its sensitivity to changes in tissue microstructure, DTI lacks the specificity to disentangle distinct microstructural features of white and gray matter. Neurite orientation dispersion and density imaging (NODDI) is a recently proposed multi-compartment biophysical model of brain microstructure that can estimate non-collinear properties of white matter, such as neurite orientation dispersion index (ODI) and neurite density index (NDI). In this study, we apply NODDI to 66 healthy controls aged 7-63 years to investigate changes of ODI and NDI with brain maturation, with comparison to standard DTI metrics. Using both region-of-interest and voxel-wise analyses, we find that NDI exhibits striking increases over the studied age range following a logarithmic growth pattern, while ODI rises following an exponential growth pattern. This novel finding is consistent with well-established age-related changes of FA over the lifespan that show growth during childhood and adolescence, plateau during early adulthood, and accelerating decay after the fourth decade of life. Our results suggest that the rise of FA during the first two decades of life is dominated by increasing NDI, while the fall in FA after the fourth decade is driven by the exponential rise of ODI that overcomes the slower increases of NDI. Using partial least squares regression, we further demonstrate that NODDI better predicts chronological age than DTI. Finally, we show excellent test-retest reliability of NODDI metrics, with coefficients of variation below 5% in all measured regions of interest. Our results support the conclusion that NODDI reveals biologically specific characteristics of brain development that are more closely linked to the microstructural features of white matter than are the empirical metrics provided by DTI.