BACKGROUND & PURPOSE Precision Medicine is an approach to disease diagnosis, treatment and prevention which relies on quantitative biomarkers that minimize the variability of individual patient measurements. The aim of this study is to assess the inter-site variability after harmonization of a high angular resolution 3T diffusion tensor imaging protocol across 13 scanners at the 11 academic medical centers participating in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) multisite study. MATERIALS AND METHODS Diffusion MRI was acquired from a novel isotropic diffusion phantom developed at the National Institute of Standards and Technology (NIST) and from the brain of a traveling volunteer on thirteen 3T MR scanners representing three major vendors (General Electric, Philips and Siemens). Means of the DTI parameters and their coefficients of variation (CoVs) across scanners were calculated for each DTI metric and white matter tract. RESULTS For the NIST diffusion phantom, the CoV of apparent diffusion coefficient (ADC) across the 13 scanners was < 3.8% for a range of diffusivities from 0.4 to1.1×10−6 mm2/s. For the volunteer, the CoVs across scanners of the 4 primary DTI metrics, each averaged over the entire white matter skeleton, were all < 5%. In individual white matter tracts, large central pathways showed good reproducibility with the CoV consistently below 5%. However, smaller tracts showed more variability with the CoV of some DTI metrics reaching 10%. CONCLUSION The results suggest the feasibility of standardizing DTI across 3T scanners from different MR vendors in a large-scale neuroimaging research study.

Over 90% of children with Autism Spectrum Disorders (ASD) demonstrate atypical sensory behaviors. In fact, hyper- or hyporeactivity to sensory input or unusual interest in sensory aspects of the environment is now included in the DSM-5 diagnostic criteria. However, there are children with sensory processing differences who do not meet an ASD diagnosis but do show atypical sensory behaviors to the same or greater degree as ASD children. We previously demonstrated that children with Sensory Processing Disorders (SPD) have impaired white matter microstructure, and that this white matter microstructural pathology correlates with atypical sensory behavior. In this study, we use diffusion tensor imaging (DTI) fiber tractography to evaluate the structural connectivity of specific white matter tracts in boys with ASD (n = 15) and boys with SPD (n = 16), relative to typically developing children (n = 23). We define white matter tracts using probabilistic streamline tractography and assess the strength of tract connectivity using mean fractional anisotropy. Both the SPD and ASD cohorts demonstrate decreased connectivity relative to controls in parieto-occipital tracts involved in sensory perception and multisensory integration. However, the ASD group alone shows impaired connectivity, relative to controls, in temporal tracts thought to subserve social-emotional processing. In addition to these group difference analyses, we take a dimensional approach to assessing the relationship between white matter connectivity and participant function. These correlational analyses reveal significant associations of white matter connectivity with auditory processing, working memory, social skills, and inattention across our three study groups. These findings help elucidate the roles of specific neural circuits in neurodevelopmental disorders, and begin to explore the dimensional relationship between critical cognitive functions and structural connectivity across affected and unaffected children.

Sensory processing disorders (SPDs) affect up to 16% of school-aged children, and contribute to cognitive and behavioral deficits impacting affected individuals and their families. While sensory processing differences are now widely recognized in children with autism, children with sensory-based dysfunction who do not meet autism criteria based on social communication deficits remain virtually unstudied. In a previous pilot diffusion tensor imaging (DTI) study, we demonstrated that boys with SPD have altered white matter microstructure primarily affecting the posterior cerebral tracts, which subserve sensory processing and integration. This disrupted microstructural integrity, measured as reduced white matter fractional anisotropy (FA), correlated with parent report measures of atypical sensory behavior. In this present study, we investigate white matter microstructure as it relates to tactile and auditory function in depth with a larger, mixed-gender cohort of children 8–12 years of age. We continue to find robust alterations of posterior white matter microstructure in children with SPD relative to typically developing children (TDC), along with more spatially distributed alterations. We find strong correlations of FA with both parent report and direct measures of tactile and auditory processing across children, with the direct assessment measures of tactile and auditory processing showing a stronger and more continuous mapping to the underlying white matter integrity than the corresponding parent report measures. Based on these findings of microstructure as a neural correlate of sensory processing ability, diffusion MRI merits further investigation as a tool to find biomarkers for diagnosis, prognosis and treatment response in children with SPD. To our knowledge, this work is the first to demonstrate associations of directly measured tactile and non-linguistic auditory function with white matter microstructural integrity – not just in children with SPD, but also in TDC.

BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure. METHODS: Using voxel-and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV. RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion . control . duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion . control; Cohen's d . 1), the superior and middle temporal gyri (deletion , control; Cohen's d , 21), and the caudate and hippocampus (control . duplication; 20.5 . Cohen's d . 21). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results. CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria. Autism spectrum disorder (ASD) and related neurodevelopmental disorders are defined behaviorally and characterized by a significant clinical and etiologic heterogeneity. As a consequence, investigating ASD under the assumption of an underlying homogeneous condition has resulted in controversial findings in the field of neuroimaging (1). Increased brain growth early in development (2-4) and alterations of many regional brain volumes (5) have been implicated in ASD, but results have proven difficult to replicate (1,(6)(7)(8).To mitigate some of these issues, cohorts of individuals with shared genetic risk factors have been assembled to minimize the noise introduced by etiologic and biological heterogeneity (9). Such a "genetic-first" study design provides the opportunity to investigate a given neurodevelopmental risk (and associated mechanism) shared by individuals who carry the same genetic etiology irrespective of the psychiatric diagnosis.Copy number variants (CNVs) at the 16p11.2 (breakpoints 4-5, 29.6-30.2 Mb-hg19) (10) are among the most frequent risk factors for neurodevelopmental and psychiatric conditions.