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Previous studies in psychosis patients have shown hippocampal volume deficits across anterior and posterior regions or across subfields, but subfield specific changes in volume along the hippocampal long axis have not been examined. Here, we tested the hypothesis that volume changes exist across the hippocampus in chronic psychosis but only the anterior CA region is affected in early psychosis patients. We analyzed structural MRI data from 179 patients with a non-affective psychotic disorder (94 chronic psychosis; 85 early psychosis) and 167 heathy individuals demographically matched to the chronic and early psychosis samples respectively (82 matched to chronic patients; 85 matched to early patients). We measured hippocampal volumes using Freesurfer 6-derived automated segmentation of both anterior and posterior regions and the CA, dentate gyrus, and subiculum subfields. We found a hippocampal volume deficit in both anterior and posterior regions in chronic psychosis, but this deficit was limited to the anterior hippocampus in early psychosis patients. This volume change was more pronounced in the anterior CA subfield of early psychosis patients than in the dentate gyrus or subiculum. Our findings support existing models of psychosis implicating initial CA dysfunction with later progression to other hippocampal regions and suggest that the anterior hippocampus may be an important target for early interventions.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Diffusion MRI fiber tractography is widely used to probe the structural connectivity of the brain, with a range of applications in both clinical and basic neuroscience. Despite widespread use, tractography has well-known pitfalls that limits the anatomical accuracy of this technique. Numerous modern methods have been developed to address these shortcomings through advances in acquisition, modeling, and computation. To test whether these advances improve tractography accuracy, we organized the 3-D Validation of Tractography with Experimental MRI (3D-VoTEM) challenge at the ISBI 2018 conference. We made available three unique independent tractography validation datasets - a physical phantom and two ex vivo brain specimens - resulting in 176 distinct submissions from 9 research groups. By comparing results over a wide range of fiber complexities and algorithmic strategies, this challenge provides a more comprehensive assessment of tractography's inherent limitations than has been reported previously. The central results were consistent across all sub-challenges in that, despite advances in tractography methods, the anatomical accuracy of tractography has not dramatically improved in recent years. Taken together, our results independently confirm findings from decades of tractography validation studies, demonstrate inherent limitations in reconstructing white matter pathways using diffusion MRI data alone, and highlight the need for alternative or combinatorial strategies to accurately map the fiber pathways of the brain.
Copyright © 2018 Elsevier Inc. All rights reserved.
For two decades diffusion fiber tractography has been used to probe both the spatial extent of white matter pathways and the region to region connectivity of the brain. In both cases, anatomical accuracy of tractography is critical for sound scientific conclusions. Here we assess and validate the algorithms and tractography implementations that have been most widely used - often because of ease of use, algorithm simplicity, or availability offered in open source software. Comparing forty tractography results to a ground truth defined by histological tracers in the primary motor cortex on the same squirrel monkey brains, we assess tract fidelity on the scale of voxels as well as over larger spatial domains or regional connectivity. No algorithms are successful in all metrics, and, in fact, some implementations fail to reconstruct large portions of pathways or identify major points of connectivity. The accuracy is most dependent on reconstruction method and tracking algorithm, as well as the seed region and how this region is utilized. We also note a tremendous variability in the results, even though the same MR images act as inputs to all algorithms. In addition, anatomical accuracy is significantly decreased at increased distances from the seed. An analysis of the spatial errors in tractography reveals that many techniques have trouble properly leaving the gray matter, and many only reveal connectivity to adjacent regions of interest. These results show that the most commonly implemented algorithms have several shortcomings and limitations, and choices in implementations lead to very different results. This study should provide guidance for algorithm choices based on study requirements for sensitivity, specificity, or the need to identify particular connections, and should serve as a heuristic for future developments in tractography.
Copyright © 2018 Elsevier Inc. All rights reserved.
BACKGROUND - The American Thyroid Association (ATA) recommends fine-needle aspiration (FNA) biopsy of nodules measuring >1.5 cm with low-suspicion sonographic patterns or >1.0 cm with high/intermediate-suspicion features. Routine biopsy of nodules <1 cm is not recommended. However, despite these recommendations, subcentimeter nodules are often referred for FNA biopsy.
METHODS - This was a retrospective chart review of consecutive thyroid FNAs during an 18-month period (1157 patients, 1491 nodules, 2016-2017) to evaluate age, sex, medical history, diagnoses, and follow-up. Radiographic information was used to identify 61 subcentimeter nodules (4%) from 57 patients. Ultrasound studies were re-evaluated using criteria according to the American College of Radiology Thyroid Imaging, Reporting, and Data System (TI-RADS).
RESULTS - Reported reasons for biopsy included a larger companion nodule (44%), a personal or family history of cancer (26%), or a suspicious sonogram, including calcification and/or irregular contours (16%). FNA diagnoses included: 69% benign (42 of 61 nodules), 10% papillary thyroid carcinoma (PTC) (6 of 61 nodules), and 15% atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) (9 of 61 nodules). Seven percent of nodules were unsatisfactory/nondiagnostic (4 of 61 nodules) compared with a 3% nondiagnostic rate for all sized nodules. Fifty-one nodules had an ultrasound available for re-review using the TI-RADS scoring system. A high TI-RADS score (4-5) was indicative of PTC in 29.4% of nodules. A low TI-RADS score (1-2) was indicative of PTC in 0% of nodules (P < .01). High and intermediate TI-RADS scores (3 and 4-5, respectively) were indicative of PTC/AUS/FLUS in 32% of nodules compared with 0% in those with low TI-RADS scores (P < .01).
CONCLUSIONS - The current results demonstrate successful use of the TI-RADS scoring system in evaluation of the risk of malignancy in subcentimeter nodules. Larger studies will be necessary to determine whether biopsy is warranted for TI-RADS high-subcentimeter nodules. Cancer Cytopathol 2018. © 2018 American Cancer Society.
© 2018 American Cancer Society.
Ultrasound imaging for kidney stones suffers from poorer sensitivity, diminished specificity, and overestimation of stone size compared to computed tomography (CT). The purpose of this study was to demonstrate in vitro feasibility of novel ultrasound imaging methods comparing traditional B-mode to advanced beamforming techniques including plane wave synthetic focusing (PWSF), short-lag spatial coherence (SLSC) imaging, mid-lag spatial coherence (MLSC) imaging with incoherent compounding, and aperture domain model image reconstruction (ADMIRE). The ultrasound techniques were evaluated using a research-based ultrasound system applied to an in vitro kidney stone model at 4 and 8 cm depths. Stone diameter sizing and stone contrast were compared among the different techniques. Analysis of variance was used to analyze the differences among group means, with p < 0.05 considered significant, and a Student's t test was used to compare each method with B-mode, with p < 0.0025 considered significant. All stones were detectable with each method. MLSC performed best with stone sizing and stone contrast compared to B-mode. On average, B-mode sizing error ± SD was > 1 mm (1.2 ± 1.1 mm), while those for PWSF, ADMIRE, and MLSC were < 1 mm (- 0.3 ± 2.9 mm, 0.6 ± 0.8, 0.8 ± 0.8, respectively). Subjectively, MLSC appeared to suppress the entire background thus highlighting only the stone. The ADMIRE and SLSC techniques appeared to highlight the stone shadow relative to the background. The detection and sizing of stones in vitro are feasible with advanced beamforming methods with ultrasound. Future work will include imaging stones at greater depths and evaluating the performance of these methods in human stone formers.
Direct reprogramming of fibroblasts into cardiomyocytes is a promising approach for cardiac regeneration but still faces challenges in efficiently generating mature cardiomyocytes. Systematic optimization of reprogramming protocols requires scalable, objective methods to assess cellular phenotype beyond what is captured by transcriptional signatures alone. To address this question, we automatically segmented reprogrammed cardiomyocytes from immunofluorescence images and analyzed cell morphology. We also introduce a method to quantify sarcomere structure using Haralick texture features, called SarcOmere Texture Analysis (SOTA). We show that induced cardiac-like myocytes (iCLMs) are highly variable in expression of cardiomyocyte markers, producing subtypes that are not typically seen in vivo. Compared to neonatal mouse cardiomyocytes, iCLMs have more variable cell size and shape, have less organized sarcomere structure, and demonstrate reduced sarcomere length. Taken together, these results indicate that traditional methods of assessing cardiomyocyte reprogramming by quantifying induction of cardiomyocyte marker proteins may not be sufficient to predict functionality. The automated image analysis methods described in this study may enable more systematic approaches for improving reprogramming techniques above and beyond existing algorithms that rely heavily on transcriptome profiling.
Genetic mutations in the human small heat shock protein αB-crystallin have been implicated in autosomal cataracts and skeletal myopathies, including heart muscle diseases (cardiomyopathy). Although these mutations lead to modulation of their chaperone activity , the functions of αB-crystallin in the maintenance of both lens transparency and muscle integrity remain unclear. This lack of information has hindered a mechanistic understanding of these diseases. To better define the functional roles of αB-crystallin, we generated loss-of-function zebrafish mutant lines by utilizing the CRISPR/Cas9 system to specifically disrupt the two αB-crystallin genes, α and α We observed lens abnormalities in the mutant lines of both genes, and the penetrance of the lens phenotype was higher in α than α mutants. This finding is in contrast with the lack of a phenotype previously reported in αB-crystallin knock-out mice and suggests that the elevated chaperone activity of the two zebrafish orthologs is critical for lens development. Besides its key role in the lens, we uncovered another critical role for αB-crystallin in providing stress tolerance to the heart. The αB-crystallin mutants exhibited hypersusceptibility to develop pericardial edema when challenged by crowding stress or exposed to elevated cortisol stress, both of which activate glucocorticoid receptor signaling. Our work illuminates the involvement of αB-crystallin in stress tolerance of the heart presumably through the proteostasis network and reinforces the critical role of the chaperone activity of αB-crystallin in the maintenance of lens transparency.
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
Diffusion magnetic resonance imaging (dMRI) is widely used to probe tissue microstructure, and is currently the only non-invasive way to measure the brain's fiber architecture. While a large number of approaches to recover the intra-voxel fiber structure have been utilized in the scientific community, a direct, 3D, quantitative validation of these methods against relevant histological fiber geometries is lacking. In this study, we investigate how well different high angular resolution diffusion imaging (HARDI) models and reconstruction methods predict the ground-truth histologically defined fiber orientation distribution (FOD), as well as investigate their behavior over a range of physical and experimental conditions. The dMRI methods tested include constrained spherical deconvolution (CSD), Q-ball imaging (QBI), diffusion orientation transform (DOT), persistent angular structure (PAS), and neurite orientation dispersion and density imaging (NODDI) methods. Evaluation criteria focus on overall agreement in FOD shape, correct assessment of the number of fiber populations, and angular accuracy in orientation. In addition, we make comparisons of the histological orientation dispersion with the fiber spread determined from the dMRI methods. As a general result, no HARDI method outperformed others in all quality criteria, with many showing tradeoffs in reconstruction accuracy. All reconstruction techniques describe the overall continuous angular structure of the histological FOD quite well, with good to moderate correlation (median angular correlation coefficient > 0.70) in both single- and multiple-fiber voxels. However, no method is consistently successful at extracting discrete measures of the number and orientations of FOD peaks. The major inaccuracies of all techniques tend to be in extracting local maxima of the FOD, resulting in either false positive or false negative peaks. Median angular errors are ∼10° for the primary fiber direction and ∼20° for the secondary fiber, if present. For most methods, these results did not vary strongly over a wide range of acquisition parameters (number of diffusion weighting directions and b value). Regardless of acquisition parameters, all methods show improved successes at resolving multiple fiber compartments in a voxel when fiber populations cross at near-orthogonal angles, with no method adequately capturing low to moderate angle (<60°) crossing fibers. Finally, most methods are limited in their ability to capture orientation dispersion, resulting in low to moderate, yet statistically significant, correlation with histologically-derived dispersion with both HARDI and NODDI methodologies. Together, these results provide quantitative measures of the reliability and limitations of dMRI reconstruction methods and can be used to identify relative advantages of competing approaches as well as potential strategies for improving accuracy.
Copyright © 2017 Elsevier Inc. All rights reserved.
PURPOSE - Numerous studies have adopted resting-state functional MRI methods to infer functional connectivity between cortical regions, but very few have translated them to the spinal cord, despite its critical role in the central nervous system. Resting-state functional connectivity between gray matter horns of the spinal cord has previously been shown to be detectable in humans and nonhuman primates, but it has not been reported previously in rodents.
METHODS - Resting-state functional MRI of the cervical spinal cord of live anesthetized rats was performed at 9.4 T. The quality of the functional images acquired was assessed, and quantitative analyses of functional connectivity in C4-C7 of the spinal cord were derived.
RESULTS - Robust gray matter horn-to-horn connectivity patterns were found that were statistically significant when compared with adjacent control regions. Specifically, dorsal-dorsal and ventral-ventral connectivity measurements were most prominent, while ipsilateral dorsal-ventral connectivity was also observed but to a lesser extent. Quantitative evaluation of reproducibility also revealed moderate robustness in the bilateral sensory and motor networks that was weaker in the dorsal-ventral connections.
CONCLUSIONS - This study reports the first evidence of resting-state functional circuits within gray matter in the rat spinal cord, and verifies their detectability using resting-state functional MRI at 9.4 T. Magn Reson Med 79:2773-2783, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
© 2017 International Society for Magnetic Resonance in Medicine.
Purpose - The eye and its accessory structures, the optic nerve and the extraocular muscles, form a complex dynamic system. In vivo magnetic resonance imaging (MRI) of this system in motion can have substantial benefits in understanding oculomotor functioning in health and disease, but has been restricted to date to imaging of static gazes only. The purpose of this work was to develop a technique to image the eye and its accessory visual structures in motion.
Methods - Dynamic imaging of the eye was developed on a 3-Tesla MRI scanner, based on a golden angle radial sequence that allows freely selectable frame-rate and temporal-span image reconstructions from the same acquired data set. Retrospective image reconstructions at a chosen frame rate of 57 ms per image yielded high-quality in vivo movies of various eye motion tasks performed in the scanner. Motion analysis was performed for a left-right version task where motion paths, lengths, and strains/globe angle of the medial and lateral extraocular muscles and the optic nerves were estimated.
Results - Offline image reconstructions resulted in dynamic images of bilateral visual structures of healthy adults in only ∼15-s imaging time. Qualitative and quantitative analyses of the motion enabled estimation of trajectories, lengths, and strains on the optic nerves and extraocular muscles at very high frame rates of ∼18 frames/s.
Conclusions - This work presents an MRI technique that enables high-frame-rate dynamic imaging of the eyes and orbital structures. The presented sequence has the potential to be used in furthering the understanding of oculomotor mechanics in vivo, both in health and disease.