Aberrant White Matter Microstructure in Children with 16p11.2 Deletions

Abstract

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.

16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks

“…Diffusion tension imaging analyses revealed white matter abnormalities in 16p11.2 deletion carriers, especially in the anterior corpus callosum, and bilateral internal and external capsules (Owen et al 2014). More research is needed to delineate the relationship between neuroanatomical changes and intellectual disabilities in people with 16p11.2 deletion syndrome.…”

Can Mouse Imaging Studies Bring Order to Autism Connectivity Chaos?

“…A deeper understanding of the origin and significance of these phenomena is greatly complicated by our very limited understanding of the neurobiological foundations of macro-scale neuroimaging readouts commonly employed in ASD research, such as white matter microstructural parameters (e.g., fractional anisotropy, Owen et al, 2014) or the elusive functional couplings underlying rsfMRI-based functional connectivity. This has left us with a major explanatory gap between mechanistic models of brain function at the cellular and microcircuit level, and the emergence of macroscale functional activity in health and pathological states such as those that are observed in autism.…”

“…Similarly, studies of additional genetic etiologies associated with ASDs, covering heterogeneous pathophysiological pathways, are crucial to achieve a deeper understanding of whether the connectional signatures are mutation specific or can be regarded as a generalizable phenomenon. When coupled to analogous clinical efforts aimed at identification of connectional aberrancies in genetically homogeneous populations [e.g., 16p11.2 deletion (Simons Vip Consortium, 2012; Owen et al, 2014)], the method can also be used to investigate the cellular and physiological basis of clinically relevant neuroimaging readouts and, via a comparison between human and mouse imaging findings, to obtain an assessment of the translational and construct validity of mouse models of ASD. The developmental trajectory of these alterations could in principle also be investigated in mouse models, although critical limitations in the accuracy of physiological control in young mice and pups exist.…”

Brain imaging research in autism spectrum disorders

“…In contrast, ASD, regardless of whether it is idiopathic or associated with TSC, is characterized by decreased long-range connectivity, a proportional increase in short-range connectivity, and evidence of decreased functional specialization and excessive degeneracy within the network [57]. Neuroimaging studies of individuals with different types of 16p11.2 copy number variations with and without autism are underway [60,61]. …”