The variegation of human brain vulnerability to rare genetic disorders and convergence with behaviorally defined disorders

BACKGROUND: Diverse gene dosage disorders (GDDs) increase risk for psychiatric impairment, but characterization of GDD effects on the human brain has so far been piecemeal with few simultaneous analyses of multiple brain features across different GDDs. METHODS: Here, through multimodal neuroimaging of 3 aneuploidy syndromes [XXY (total n = 191, 92 controls), XYY (total n=81, 47 controls) , trisomy 21 (total n=69, 41 controls)], we systematically map the effects of supernumerary X, Y and chromosome 21 dosage across a breadth of 15 different macrostructural, microstructural, and functional imaging derived phenotypes (IDPs). RESULTS: We reveal considerable diversity in cortical changes across GDDs and IDPs. This variegation of IDP change underlines the limitations of studying GDD effects unimodally. Integration across all IDP change maps reveals highly distinct architectures of cortical change in each GDD along with partial coalescence onto a common spatial axis of cortical vulnerability that is evident in all three GDDs. This common axis shows strong alignment with shared cortical changes in behaviorally defined psychiatric disorders and is enriched for specific molecular and cellular signatures. CONCLUSION: Use of multimodal neuroimaging data in three aneuploidies indicates that different GDDs impose unique fingerprints of change in the human brain that differ widely depending on the imaging modality being considered. Embedded in this variegation is a spatial axis of shared multimodal change that aligns with shared brain changes across psychiatric disorders and therefore represents a major high-priority target for future translational research in neuroscience

High-resolution Diffusion-weighted Magnetic Resonance Imaging: Development and Application of Novel Radial Fast Spin-echo Acquisitions

Diffusion-weighted Magnetic Resonance Imaging (DWI) has become a useful tool in medicine for the purpose of diagnosis, tracking disease progression, and monitoring response to therapy. The current techniques used for DWI suffer from artifacts due to magnetic field inhomogeneities, image distortion, and low spatial resolution. The aim of the presented work is to advance DWI by improving upon and developing novel high-resolution acquisition techniques. The approach taken for this purpose was to utilize radial fast spin-echo data acquisitions, which have been shown to produce high-resolution DWI without artifacts due to magnetic field inhomogeneities. In addition, there is little image distortion in radial fast spin-echo DWI, which allows for direct overlay onto anatomical MRI. However, a draw back is that radial methods require longer scan times. By increasing the imaging speed of existing radial fast spin-echo acquisitions, it may become a more practical clinical tool. In addition, novel acquisition techniques are developed that push high-resolution to all three dimensions. By employing a three-dimensional radial fast spin-echo acquisition, voxels in an image have equal size in each dimension and can be on the order of 1mm3. By decreasing the voxel size, the tissue contained within a voxel is more homogeneous. This is important for DWI applications that aim to measure the microscopic integrity of the tissue. The development and analysis of the novel radial fast spin-echo techniques are presented in this work along with several clinical applications. The remaining issues to be addressed for application to quantitative DWI measures are also presented, along with possible solutions

Effectiveness of navigator-based prospective motion correction in MPRAGE data acquired at 3T.

In MRI, subject motion results in image artifacts. High-resolution 3D scans, like MPRAGE, are particularly susceptible to motion because of long scan times and acquisition of data over multiple-shots. Such motion related artifacts have been shown to cause a bias in cortical measures extracted from segmentation of high-resolution MPRAGE images. Prospective motion correction (PMC) techniques have been developed to help mitigate artifacts due to subject motion. In this work, high-resolution MPRAGE images are acquired during intentional head motion to evaluate the effectiveness of navigator-based PMC techniques to improve both the accuracy and reproducibility of cortical morphometry measures obtained from image segmentation. The contribution of reacquiring segments of k-space affected by motion to the overall performance of PMC is assessed. Additionally, the effect of subject motion on subcortical structure volumes is investigated. In the presence of head motion, navigator-based PMC is shown to improve both the accuracy and reproducibility of cortical and subcortical measures. It is shown that reacquiring segments of k-space data that are corrupted by motion is an essential part of navigator-based PMC performance. Subcortical structure volumes are not affected by motion in the same way as cortical measures; there is not a consistent underestimation

White Matter Microstructure Alterations: A Study of Alcoholics with and without Post-Traumatic Stress Disorder

<div><p>Many brain imaging studies have demonstrated reductions in gray and white matter volumes in alcoholism, with fewer investigators using diffusion tensor imaging (DTI) to examine the integrity of white matter pathways. Among various medical conditions, alcoholism and post-traumatic stress disorder (PTSD) are two comorbid diseases that have similar degenerative effects on the white matter integrity. Therefore, understanding and differentiating these effects would be very important in characterizing alcoholism and PTSD. Alcoholics are known to have neurocognitive deficits in decision-making, particularly in decisions related to emotionally-motivated behavior, while individuals with PTSD have deficits in emotional regulation and enhanced fear response. It is widely believed that these types of abnormalities in both alcoholism and PTSD are related to fronto-limbic dysfunction. In addition, previous studies have shown cortico-limbic fiber degradation through fiber tracking in alcoholism. DTI was used to measure white matter fractional anisotropy (FA), which provides information about tissue microstructure, possibly indicating white matter integrity. We quantitatively investigated the microstructure of white matter through whole brain DTI analysis in healthy volunteers (HV) and alcohol dependent subjects without PTSD (ALC) and with PTSD (ALC+PTSD). These data show significant differences in FA between alcoholics and non-alcoholic HVs, with no significant differences in FA between ALC and ALC+PTSD in any white matter structure. We performed a post-hoc region of interest analysis that allowed us to incorporate multiple covariates into the analysis and found similar results. HV had higher FA in several areas implicated in the reward circuit, emotion, and executive functioning, suggesting that there may be microstructural abnormalities in white matter pathways that contribute to neurocognitive and executive functioning deficits observed in alcoholics. Furthermore, our data do not reveal any differences between ALC and ALC+PTSD, suggesting that the effect of alcohol on white matter microstructure may be more significant than any effect caused by PTSD.</p> </div

TBSS results from A) HV>All_ALC B) HV>ALC, and C) HV>ALC+PTSD comparisons.

<p>Blue and light blue indicate significant differences (threshholding at p < 0.05) superimposed on a green FA skeleton and overlaid on an MNI template.</p

Investigation of vibration-induced artifact in clinical diffusion-weighted imaging of pediatric subjects.

It has been reported that mechanical vibrations of the MRI scanner could produce spurious signal dropouts in diffusion-weighted images resulting in artifactual anisotropy in certain regions of the brain with red appearance in the Directionally Encoded Color maps. We performed a review of the frequency of this artifact across pediatric studies, noting differences by scanner manufacturer, acquisition protocol, as well as weight and position of the subject. We also evaluated the ability of automated and quantitative methods to detect this artifact. We found that the artifact may be present in over 50% of data in certain protocols and is not limited to one scanner manufacturer. While a specific scanner had the highest incidence, low body weight and positioning were also associated with appearance of the artifact for both scanner types evaluated, making children potentially more susceptible than adults. Visual inspection remains the best method for artifact identification. Software for automated detection showed very low sensitivity (10%). The artifact may present inconsistently in longitudinal studies. We discuss a published case report that has been widely cited and used as evidence to set policy about diagnostic criteria for determining vegetative state. That report attributed longitudinal changes in anisotropy to white matter plasticity without considering the possibility that the changes were caused by this artifact. Our study underscores the need to check for the presence of this artifact in clinical studies, analyzes circumstances for when it may be more likely to occur, and suggests simple strategies to identify and potentially avoid its effects

Evaluating effects of sex and age on white matter microstructural alterations in alcohol use disorder: A diffusion tensor imaging study.

BackgroundAlterations in white matter microstructure associated with chronic alcohol use have been demonstrated in previous diffusion tensor imaging (DTI) research. However, there is conflicting evidence as to whether such differences are influenced by an individual's biological sex. The purpose of the present study was to investigate the prevalence of sex differences in the white matter microstructure of the brains of individuals with alcohol use disorder (AUD) and healthy controls.MethodsOne hundred participants with AUD (38 female, aged 21 to 68) participating in the National Institute on Alcohol Abuse and Alcoholism's inpatient treatment program and 98 healthy control participants (52 female) underwent a diffusion-weighted scan. Images collected were processed for each subject individually, and voxelwise, tract-based spatial statistics analysis was conducted to test for differences in the DTI measures of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD).ResultsA 2-way, between-subjects ANCOVA that tested for differences by group and sex revealed widespread differences between AUD and control subjects, but no interaction between group and sex. Additional analyses exploring demographic and alcohol use variables showed significant impacts of age on white matter microstructure that were more pronounced in individuals with AUD. Plots of FA by age, sex, and group in major white matter tracts suggest a need to explore higher order interactions in larger samples.ConclusionsThese results bolster recent findings of similar microstructural properties in men and women with AUD but provide a rationale for the consideration of age when investigating the impacts of chronic alcohol use on the brain's white matter

Graph of the norm. ws-stdev. of whole cortex and sub-cortical structure volumes.

<p>Graph of the norm. ws-stdev. of whole cortex and sub-cortical structure volumes.</p