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Abstract To extract meaningful and reproducible models of brain function from stroke images, for both clinical and research proposes, is a daunting task severely hindered by the great variability of lesion frequency and patterns. Large datasets are therefore imperative, as well as fully automated image post-processing tools to analyze them. The development of such tools, particularly with artificial intelligence, is highly dependent on the availability of large datasets to model training and testing. We present a public dataset of 2,888 multimodal clinical MRIs of patients with acute and early subacute stroke, with manual lesion segmentation, and metadata. The dataset provides high quality, large scale, human-supervised knowledge to feed artificial intelligence models and enable further development of tools to automate several tasks that currently rely on human labor, such as lesion segmentation, labeling, calculation of disease-relevant scores, and lesion-based studies relating function to frequency lesion maps.

A comparison of neuroanatomical features of the brain between humans and our evolutionary relatives, nonhuman primates, is key to understanding the human brain system and the neural basis of mental and neurological disorders. Although most comparative MRI studies of human and nonhuman primate brains have been based on brains of primates that had been used as subjects in experiments, it is essential to investigate various species of nonhuman primates in order to elucidate and interpret the diversity of neuroanatomy features among humans and nonhuman primates. To develop a research platform for this purpose, it is necessary to harmonize the scientific contributions of studies with the standards of animal ethics, animal welfare, and the conservation of brain information for long-term continuation of the field. In previous research, we first developed a gated data-repository of anatomical images obtained using 9.4-T ex vivo MRI of postmortem brain samples from 12 nonhuman primate species, and which are stored at the Japan Monkey Centre. In the present study, as a second phase, we released a collection of T2-weighted images and diffusion tensor images obtained in nine species: white-throated capuchin, Bolivian squirrel monkey, stump-tailed macaque, Tibet monkey, Sykes’ monkey, Assamese macaque, pig-tailed macaque, crested macaque, and chimpanzee. Our image repository should facilitate scientific discoveries in the field of comparative neuroscience. This repository can also promote animal ethics and animal welfare in experiments with nonhuman primate models by optimizing methods for in vivo and ex vivo MRI scanning of brains and supporting veterinary neuroradiological education. In addition, the repository is expected to contribute to conservation, preserving information about the brains of various primates, including endangered species, in a permanent digital form.

Previous research has emphasized the unique impact of Alzheimer’s Disease (AD) pathology on the medial temporal lobe (MTL), a reflection that tau pathology is particularly striking in the entorhinal and transentorhinal cortex (ERC, TEC) early in the course of disease. However, other brain regions are affected by AD pathology during its early phases. Here, we use longitudinal diffeomorphometry to measure the atrophy rate from MRI of the amygdala compared with that in the ERC and TEC in cognitively unimpaired (CU) controls, CU individuals who progressed to mild cognitive impairment (MCI), and individuals with MCI who progressed to dementia of the AD type (DAT), using a dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Our results show significantly higher atrophy rates of the amygdala in both groups of ‘converters’ (CU→MCI, MCI→DAT) compared to controls, with rates of volume loss comparable to rates of thickness loss in the ERC and TEC. We localize atrophy within the amygdala within each of these groups using fixed effects modeling. Controlling for the familywise error rate highlights the medial regions of the amygdala as those with significantly higher atrophy in both groups of converters than in controls. Using our recently developed method, referred to as Projective LDDMM, we map measures of neurofibrillary tau tangles (NFTs) from digital pathology to MRI atlases and reconstruct dense 3D spatial distributions of NFT density within regions of the MTL. The distribution of NFTs is consistent with the spatial distribution of MR measured atrophy rates, revealing high densities (and atrophy) in the amygdala (particularly medial), ERC, and rostral third of the MTL. The similarity of the location of NFTs in AD and shape changes in a well-defined clinical population suggests that amygdalar atrophy rate, as measured through MRI may be a viable biomarker for AD.

In this study, we examined the independent contributions of structural and functional connectivity markers to individual differences in episodic memory performance in 107 cognitively normal older adults from the BIOCARD study. Structural connectivity, defined by the diffusion tensor imaging (DTI) measure of radial diffusivity (RD), was obtained from two medial temporal lobe white matter tracts: the fornix and hippocampal cingulum, while functional connectivity markers were derived from network-based resting state functional magnetic resonance imaging (rsfMRI) of five large-scale brain networks: the control, default, limbic, dorsal attention, and salience/ventral attention networks. Hierarchical and stepwise linear regression methods were utilized to directly compare the relative contributions of the connectivity modalities to individual variability in a composite delayed episodic memory score, while also accounting for age, sex, cerebrospinal fluid (CSF) biomarkers of amyloid and tau pathology (i.e., Aβ42/Aβ40 and p-tau181), and gray matter volumes of the entorhinal cortex and hippocampus. Results revealed that fornix RD, hippocampal cingulum RD, and salience network functional connectivity were each significant independent predictors of memory performance, while CSF markers and gray matter volumes were not. Moreover, in the stepwise model, the addition of sex, fornix RD, hippocampal cingulum RD, and salience network functional connectivity each significantly improved the overall predictive value of the model. These findings demonstrate that both DTI and rsfMRI connectivity measures uniquely contributed to the model and that the combination of structural and functional connectivity markers best accounted for individual variability in episodic memory function in cognitively normal older adults.

The data show an association between measured and predicted changes in cognitive performance in older adults who are cognitively normal. Changes in cognitive performance over two years were assessed using the Cognitive Composite Score. The prediction of change in cognitive function was based on changes in pairwise functional connectivity between 80 gray matter regions examined by resting-state functional magnetic resonance imaging. A feature extraction process based on the Variable Importance Testing Approach (VITA) identified changes in 11 pairs of functional connections associated with the default mode network as features related to changes in cognitive performance. Linear and elastic net regression models were applied to these 11 features to predict changes in cognitive performance over two years. A relationship between the 11 features and the geriatric depression score was also shown. The dataset supplements the research findings in the ''Changes in pairwise functional connectivity associated with changes in cognitive performance in cognitively normal older individuals: a two-year observational study'' published in Oishi et al. (2022). The raw rs-fMRI correlation matrix and associated clinical data can be accessed upon request from the BIOCARD website (www.biocard-se.org) and can be reused for predictive model building.

BackgroundCompared to unilateral cerebral palsy (CP), less is known about brain reorganization and plasticity in bilateral CP especially in relation or response to motor training. The few trials that reported brain imaging results alongside functional outcomes include a handful of studies in unilateral CP, and one pilot trial of three children with bilateral CP. This study is the first locomotor training randomized controlled trial (RCT) in bilateral CP to our knowledge reporting brain imaging outcomes.MethodsObjective was to compare MRI brain volumes, resting state connectivity and white matter integrity using DTI in children with bilateral CP with PVL and preterm birth history (

Cerebrovascular Reactivity (CVR) provides an assessment of the brain’s vascular reserve and has been postulated to be a sensitive marker in cerebrovascular diseases. MRI-based CVR measurement typically employs alterations in arterial carbon dioxide (CO2) level while continuously acquiring Blood-Oxygenation-Level-Dependent (BOLD) images. CO2-inhalation and resting-state methods are two commonly used approaches for CVR MRI. However, processing of CVR MRI data often requires special expertise and may become an obstacle in broad utilization of this promising technique. The aim of this work was to develop CVR-MRICloud, a cloud-based CVR processing pipeline, to enable automated processing of CVR MRI data. The CVR-MRICloud consists of several major steps including extraction of end-tidal CO2 (EtCO2) curve from raw CO2 recording, alignment of EtCO2 curve with BOLD time course, computation of CVR value on a whole-brain, regional, and voxel-wise basis. The pipeline also includes standard BOLD image processing steps such as motion correction, registration between functional and anatomic images, and transformation of the CVR images to canonical space. This paper describes these algorithms and demonstrates the performance of the CVR-MRICloud in lifespan healthy subjects and patients with clinical conditions such as stroke, brain tumor, and Moyamoya disease. CVR-MRICloud has potential to be used as a data processing tool for a variety of basic science and clinical applications.

Here, we report the generation and characterization of a novel Huntington’s disease (HD) mouse model BAC226Q by using a bacterial artificial chromosome (BAC) system, expressing full-length human HTT with ~226 CAG-CAA repeats and containing endogenous human HTT promoter and regulatory elements. BAC226Q recapitulated a full-spectrum of age-dependent and progressive HD-like phenotypes without unwanted and erroneous phenotypes. BAC226Q mice developed normally, and gradually exhibited HD-like psychiatric and cognitive phenotypes at 2 months. From 3 to 4 months, BAC226Q mice showed robust progressive motor deficits. At 11 months, BAC226Q mice showed significant reduced life span, gradual weight loss and exhibited neuropathology including significant brain atrophy specific to striatum and cortex, striatal neuronal death, widespread huntingtin inclusions, and reactive pathology. Therefore, the novel BAC226Q mouse accurately recapitulating robust, age-dependent, progressive HD-like phenotypes will be a valuable tool for studying disease mechanisms, identifying biomarkers, and testing gene-targeting therapeutic approaches for HD.

Cerebrovascular Reactivity (CVR) provides an assessment of the brain's vascular reserve and has been postulated to be a sensitive marker in cerebrovascular diseases. MRI-based CVR measurement typically employs alterations in arterial carbon dioxide (CO2) level while continuously acquiring Blood-Oxygenation-Level-Dependent (BOLD) images. CO2-inhalation and resting-state methods are two commonly used approaches for CVR MRI. However, processing of CVR MRI data often requires special expertise and may become an obstacle in broad utilization of this promising technique. The aim of this work was to develop CVR-MRICloud, a cloud-based CVR processing pipeline, to enable automated processing of CVR MRI data. The CVR-MRICloud consists of several major steps including extraction of end-tidal CO2 (EtCO2) curve from raw CO2 recording, alignment of EtCO2 curve with BOLD time course, computation of CVR value on a whole-brain, regional, and voxel-wise basis. The pipeline also includes standard BOLD image processing steps such as motion correction, registration between functional and anatomic images, and transformation of the CVR images to canonical space. This paper describes these algorithms and demonstrates the performance of the CVR-MRICloud in lifespan healthy subjects and patients with clinical conditions such as stroke, brain tumor, and Moyamoya disease. CVR-MRICloud has potential to be used as a data processing tool for a variety of basic science and clinical applications.

In the hippocampus, a widely accepted model posits that the dentate gyrus improves learning and memory by enhancing discrimination between inputs. To test this model, we studied conditional knockout mice in which the vast majority of dentate granule cells (DGCs) fail to develop – including nearly all DGCs in the dorsal hippocampus – secondary to eliminating Wntless (Wls) in a subset of cortical progenitors with Gfap-Cre. Other cells in the Wlsfl/-;Gfap-Cre hippocampus were minimally affected, as determined by single nucleus RNA sequencing. CA3 pyramidal cells, the targets of DGC-derived mossy fibers, exhibited normal morphologies with a small reduction in the numbers of synaptic spines. Wlsfl/-;Gfap-Cre mice have a modest performance decrement in several complex spatial tasks, including active place avoidance. They were also modestly impaired in one simpler spatial task, finding a visible platform in the Morris water maze. These experiments support a role for DGCs in enhancing spatial learning and memory.

This paper examines the problem of diffeomorphic image registration in the presence of differing image intensity profiles and sparsely sampled, missing, or damaged tissue. Our motivation comes from the problem of aligning 3D brain MRI with 100-micron isotropic resolution to histology sections at 1 × 1 × 1,000-micron resolution with multiple varying stains. We pose registration as a penalized Bayesian estimation, exploiting statistical models of image formation where the target images are modeled as sparse and noisy observations of the atlas. In this injective setting, there is no assumption of symmetry between atlas and target. Cross-modality image matching is achieved by jointly estimating polynomial transformations of the atlas intensity. Missing data is accommodated via a multiple atlas selection procedure where several atlas images may be of homogeneous intensity and correspond to “background” or “artifact.” The two concepts are combined within an Expectation-Maximization algorithm, where atlas selection posteriors and deformation parameters are updated iteratively and polynomial coefficients are computed in closed form. We validate our method with simulated images, examples from neuropathology, and a standard benchmarking dataset. Finally, we apply it to reconstructing digital pathology and MRI in standard atlas coordinates. By using a standard convolutional neural network to detect tau tangles in histology slices, this registration method enabled us to quantify the 3D density distribution of tauopathy throughout the medial temporal lobe of an Alzheimer's disease postmortem specimen.

Abstract Introduction The increasing use of large sample sizes for population and personalized medicine requires high‐throughput tools for imaging processing that can handle large amounts of data with diverse image modalities, perform a biologically meaningful information reduction, and result in comprehensive quantification. Exploring the reproducibility of these tools reveals the specific strengths and weaknesses that heavily influence the interpretation of results, contributing to transparence in science. Methods We tested–retested the reproducibility of MRICloud, a free automated method for whole‐brain, multimodal MRI segmentation and quantification, on two public, independent datasets of healthy adults. Results The reproducibility was extremely high for T1‐volumetric analysis, high for diffusion tensor images (DTI) (however, regionally variable), and low for resting‐state fMRI. Conclusion In general, the reproducibility of the different modalities was slightly superior to that of widely used software. This analysis serves as a normative reference for planning samples and for the interpretation of structure‐based MRI studies.

Linear registration is often the crucial first step for various types of image analysis. Although this is mathematically simple, failure is not uncommon. When investigating the brain by magnetic resonance imaging (MRI), the brain is the target organ for registration but the existence of other tissues, in addition to a variety of fields of view, different brain locations, orientations and anatomical features, poses some serious fundamental challenges. Consequently, a number of different algorithms have been put forward to minimize potential errors. In the present study, we tested a knowledge-based approach that can be combined with any form of registration algorithm. This approach consisted of a library of intermediate images (mediators) with known transformation to the target image. Test images were first registered to all mediators and the best mediator was selected to ensure optimum registration to the target. In order to select the best mediator, we evaluated two similarity criteria: the sum of squared differences and mutual information. This approach was applied to 48 mediators and 96 test images. In order to reduce one of the main drawbacks of the approach, increased computation time, we reduced the size of the library by clustering. Our results indicated clear improvement in registration accuracy.

Background: An anatomical covariance analysis (ACA) enables to elucidate inter-regional connections on a group basis, but little is known about the connections among white matter structures or among gray and white matter structures. Effect of including multiple magnetic resonance imaging (MRI) modalities into ACA framework in detecting white-to-white or gray-to-white connections is yet to be investigated. New method: Proposed extended anatomical covariance analysis (eACA), analyzes correlations among gray and white matter structures (multi-structural) in various types of imaging modalities (T1-weighted images, T2 maps obtained from dual-echo sequences, and diffusion tensor images (DTI)). To demonstrate the capability to detect a disruption of the correlation network affected by pathology, we applied the eACA to two groups of cognitively-normal elderly individuals, one with (PiB+) and one without (PiB-) amyloid deposition in their brains. Results: The volume of each anatomical structure was symmetric and functionally related structures formed a cluster. The pseudo-T2 value was highly homogeneous across the entire cortex in the PiB- group, while a number of physiological correlations were altered in the PiB + group. The DTI demonstrated unique correlation network among structures within the same phylogenetic portions of the brain that were altered in the PiB + group. Comparison with Existing Method: The proposed eACA expands the concept of existing ACA to the connections among the white matter structures. The extension to other image modalities expands the way in which connectivity may be detected. Conclusion: The eACA has potential to evaluate alterations of the anatomical network related to pathological processes.

Kainate receptors are members of the glutamate receptor family that regulate synaptic function in the brain. They modulate synaptic transmission and the excitability of neurons; however, their contributions to neural circuits that underlie behavior are unclear. To understand the net impact of kainate receptor signaling, we generated knockout mice in which all five kainate receptor subunits were ablated (5ko). These mice displayed compulsive and perseverative behaviors, including over-grooming, as well as motor problems, indicative of alterations in striatal circuits. There were deficits in corticostriatal input to spiny projection neurons (SPNs) in the dorsal striatum and correlated reductions in spine density. The behavioral alterations were not present in mice only lacking the primary receptor subunit expressed in adult striatum (GluK2 KO), suggesting that signaling through multiple receptor types is required for proper striatal function. This demonstrates that alterations in striatal function dominate the behavioral phenotype in mice without kainate receptors.

We provide datasets from combined ex vivo diffusion tensor imaging (DTI) and Clear Lipid-exchanged, Anatomically Rigid, Imaging/immunostaining compatible, Tissue hYdrogel (CLARITY) performed on intact mouse brains. DTI-derived measures of fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) were compared to antibody-based labeling of myelin basic protein (MBP), as measured by fluorescence microscopy. We used a customized CLARITY hydrogel solution to facilitate whole brain tissue clearing and subsequent immunolabeling. We describe how CLARITY was made compatible with magnetic resonance imaging with the intention of facilitating future multimodal imaging studies that may combine noninvasive imaging with 3D immunohistochemistry. These data and methods are related to the accompanying research article entitled, ‘The role of myelination in measures of white matter integrity: Combination of diffusion tensor imaging and two-photon microscopy of CLARITY intact brains’ (E.H. Chang, M. Argyelan, M. Aggarwal, T-S. Chandon, K.H. Karlsgodt, S. Mori, A.K. Malhotra, 2016) [1].

A multivariate analytical strategy may pinpoint the structural connectivity patterns associated with Alzheimer's disease (AD) pathology in connectome-wide association studies. Diffusion magnetic resonance imaging data from 161 participants including subjects with healthy controls, AD, stable and converting mild cognitive impairment, were selected for group-wise comparisons. A multivariate distance matrix regression (MDMR) analysis was performed to detect abnormality in brain structural network along with disease progression. Based on the seed regions returned by the MDMR analysis, supervised learning was applied to evaluate the disease predictive performance. Nine brain regions, including the left orbital part of superior and middle frontal gyrus, the bilateral supplementary motor area, the bilateral insula, the left hippocampus, the left putamen, and the left thalamus demonstrated extremely significant structural pattern changes along with the progression of AD. The disease classification was more efficient when based on the key connectivity related to these seed regions than when based on whole-brain structural connectivity. MDMR analysis reveals brain network reorganization caused by AD pathology. The key structural connectivity detected in this study exhibits promising distinguishing capability to predict prodromal AD patients. Keywords: Diffusion tensor imaging, Alzheimer's disease, Mild cognitive impairment, Connectome, Multivariate regression, Tractography

The extent and spatial location of white matter hyperintensities (WMH) on brain MRI may be relevant to the development of cognitive decline in older persons. Here, we introduce a new method, known as the Multi-atlas based Detection and Localization (MADL), to evaluate WMH on fluid-attenuated inversion recovery (FLAIR) data. This method simultaneously parcellates the whole brain into 143 structures and labels hyperintense areas within each WM structure. First, a multi-atlas library was established with FLAIR data of normal elderly brains; and then a multi-atlas fusion algorithm was developed by which voxels with locally abnormal intensities were detected as WMH. At the same time, brain segmentation maps were generated from the multi-atlas fusion process to determine the anatomical location of WMH. Areas identified using the MADL method agreed well with manual delineation, with an interclass correlation of 0.97 and similarity index (SI) between 0.55 and 0.72, depending on the total WMH load. Performance was compared to other state-of-the-art WMH detection methods, such as BIANCA and LST. MADL-based analyses of WMH in an older population revealed a significant association between age and WMH load in deep WM but not subcortical WM. The findings also suggested increased WMH load in selective brain regions in subjects with mild cognitive impairment compared to controls, including the inferior deep WM and occipital subcortical WM. The proposed MADL approach may facilitate location-dependent characterization of WMH in older individuals with memory impairment. Keywords: White matter hyperintensities, FLAIR, Multi-atlas, Segmentation, Mild cognitive disorder

Purpose: To examine the feasibility and potential difficulties of automatically generating radiologic reports (RRs) to articulate the clinically important features of brain magnetic resonance (MR) images.Materials and Methods: We focused on examining brain atrophy by using magnetization-prepared rapid gradient-echo (MPRAGE) images. The technology was based on multi-atlas whole-brain segmentation that identified 283 structures, from which larger superstructures were created to represent the anatomic units most frequently used in RRs. Through two layers of data-reduction filters, based on anatomic and clinical knowledge, raw images (~10 MB) were converted to a few kilobytes of human-readable sentences. The tool was applied to images from 92 patients with memory problems, and the results were compared to RRs independently produced by three experienced radiologists. The mechanisms of disagreement were investigated to understand where machine–human interface succeeded or failed.Results: The automatically generated sentences had low sensitivity (mean: 24.5%) and precision (mean: 24.9%) values; these were significantly lower than the inter-rater sensitivity (mean: 32.7%) and precision (mean: 32.2%) of the radiologists. The causes of disagreement were divided into six error categories: mismatch of anatomic definitions (7.2 ± 9.3%), data-reduction errors (11.4 ± 3.9%), translator errors (3.1 ± 3.1%), difference in the spatial extent of used anatomic terms (8.3 ± 6.7%), segmentation quality (9.8 ± 2.0%), and threshold for sentence-triggering (60.2 ± 16.3%).Conclusion: These error mechanisms raise interesting questions about the potential of automated report generation and the quality of image reading by humans. The most significant discrepancy between the human and automatically generated RRs was caused by the sentence-triggering threshold (the degree of abnormality), which was fixed to z-score >2.0 for the automated generation, while the thresholds by radiologists varied among different anatomical structures.

MRI brain atlases are widely used for automated image segmentation, and in particular, recent developments in multi-atlas techniques have shown highly accurate segmentation results. In this study, we extended the role of the atlas library from mere anatomical reference to a comprehensive knowledge database with various patient attributes, such as demographic, functional, and diagnostic information. In addition to using the selected (heavily-weighted) atlases to achieve high segmentation accuracy, we tested whether the non-anatomical attributes of the selected atlases could be used to estimate patient attributes. This can be considered a context-based image retrieval (CBIR) approach, embedded in the multi-atlas framework. We first developed an image similarity measurement to weigh the atlases on a structure-by-structure basis, and then, the attributes of the multiple atlases were weighted to estimate the patient attributes. We tested this concept first by estimating age in a normal population; we then performed functional and diagnostic estimations in Alzheimer's disease patients. The accuracy of the estimated patient attributes was measured against the actual clinical data, and the performance was compared to conventional volumetric analysis. The proposed CBIR framework by multi-atlas voting would be the first step toward a knowledge-based support system for quantitative radiological image reading and diagnosis.

Multi-atlas brain segmentation of human brain MR images allows quantification research in structural neuroimaging. To achieve high accuracy and computational efficiency of segmentation relies on a custom subset of atlases for each target subject. However, the criterion for atlas pre-selection remains an open question. In this study, two atlas pre-selection approaches based on location-based feature matching were proposed and compared to random and mutual information-based methods using a database of 47 atlases. A varying number of atlases ranked top with hierarchical structural granularity were compared using Dice overlap. The results indicated that the proposed 4L approach consistently led to the highest level of accuracy at a given number of employed atlases in both adult and geriatric populations. In addition, the proposed two methods (4L and LV) can reduce 20 times computational time compared with the stereotypical mutual information-based method. Our pre-selection strategy would provide better segmentation performance in terms of both accuracy and efficiency. The proposed atlas pre-selection will be further implemented into our online automatic brain image segmentation system (www.mricloud.org).

Radiological diagnosis is based on subjective judgment by radiologists. The reasoning behind this process is difficult to document and share, which is a major obstacle in adopting evidence-based medicine in radiology. We report our attempt to use a comprehensive brain parcellation tool to systematically capture image features and use them to record, search, and evaluate anatomical phenotypes. Anatomical images (T1-weighted MRI) were converted to a standardized index by using a high-dimensional image transformation method followed by atlas-based parcellation of the entire brain. We investigated how the indexed anatomical data captured the anatomical features of healthy controls and a population with Primary Progressive Aphasia (PPA). PPA was chosen because patients have apparent atrophy at different degrees and locations, thus the automated quantitative results can be compared with trained clinicians' qualitative evaluations. We explored and tested the power of individual classifications and of performing a search for images with similar anatomical features in a database using partial least squares-discriminant analysis (PLS-DA) and principal component analysis (PCA). The agreement between the automated z-score and the averaged visual scores for atrophy (r = 0.8) was virtually the same as the inter-evaluator agreement. The PCA plot distribution correlated with the anatomical phenotypes and the PLS-DA resulted in a model with an accuracy of 88% for distinguishing PPA variants. The quantitative indices captured the main anatomical features. The indexing of image data has a potential to be an effective, comprehensive, and easily translatable tool for clinical practice, providing new opportunities to mine clinical databases for medical decision support.

We explored the performance of structure-based computational analysis in four neurodegenerative conditions [Ataxia (AT, n = 16), Huntington's Disease (HD, n = 52), Alzheimer's Disease (AD, n = 66), and Primary Progressive Aphasia (PPA, n = 50)], all characterized by brain atrophy. The independent variables were the volumes of 283 anatomical areas, derived from automated segmentation of T1-high resolution brain MRIs. The segmentation based volumetric quantification reduces image dimensionality from the voxel level [on the order of O(106)] to anatomical structures [O(102)] for subsequent statistical analysis. We evaluated the effectiveness of this approach on extracting anatomical features, already described by human experience and a priori biological knowledge, in specific scenarios: (1) when pathologies were relatively homogeneous, with evident image alterations (e.g., AT); (2) when the time course was highly correlated with the anatomical changes (e.g., HD), an analogy for prediction; (3) when the pathology embraced heterogeneous phenotypes (e.g., AD) so the classification was less efficient but, in compensation, anatomical and clinical information were less redundant; and (4) when the entity was composed of multiple subgroups that had some degree of anatomical representation (e.g., PPA), showing the potential of this method for the clustering of more homogeneous phenotypes that can be of clinical importance. Using the structure-based quantification and simple linear classifiers (partial least square), we achieve 87.5 and 73% of accuracy on differentiating AT and pre-symptomatic HD patents from controls, respectively. More importantly, the anatomical features automatically revealed by the classifiers agreed with the patterns previously described on these pathologies. The accuracy was lower (68%) on differentiating AD from controls, as AD does not display a clear anatomical phenotype. On the other hand, the method identified PPA clinical phenotypes and their respective anatomical signatures. Although most of the data are presented here as proof of concept in simulated clinical scenarios, structure-based analysis was potentially effective in characterizing phenotypes, retrieving relevant anatomical features, predicting prognosis, and aiding diagnosis, with the advantage of being easily translatable to clinics and understandable biologically.

We report patterns of dysgraphia in participants with primary progressive aphasia that can be explained by assuming disruption of one or more cognitive processes or representations in the complex process of spelling. These patterns are compared to those described in participants with focal lesions (stroke). Using structural imaging techniques, we found that damage to the left extrasylvian regions, including the uncinate, inferior fronto-occipital fasciculus, and sagittal stratum (including geniculostriate pathway and inferior longitudinal fasciculus), as well as other deep white and grey matter structures, was significantly associated with impairments in access to orthographic word forms and semantics (with reliance on phonology-to-orthography to produce a plausible spelling in the spelling to dictation task). These results contribute not only to our understanding of the patterns of dysgraphia following acquired brain damage but also the neural substrates underlying spelling.

OBJECTIVE:Recent epidemiological studies reported an association between maternal intake of acetaminophen (APAP) and attention deficit hyperactivity disorder (ADHD) in their children. However, none of these studies demonstrated causality. Our objective was to determine whether exposure to APAP during pregnancy result in hyperkinetic dysfunctions in offspring, using a murine model. MATERIAL AND METHODS:Pregnant CD1 mice (N = 8/group) were allocated to receive by gavage either APAP (150 mg/kg/day, equivalent to the FDA-approved maximum human clinical dose), or 0.5% carboxymethylcellulose (control group), starting on embryonic day 7 until delivery. Maternal serum APAP and alanine transaminase (ALT) concentrations were determined by ELISA and kinetic colorimetric assays, respectively. Open field locomotor activity (LMA) in the 30-day old mouse offspring was quantified using Photobeam Activity System. Mouse offspring were then sacrificed, whole brains processed for magnetic resonance imaging (MRI; 11.7 Tesla magnet) and for neuronal quantification using Nissl stain. The association between APAP exposure and LMA in mouse offspring was analyzed using a mixed effects Poisson regression model that accounted for mouse offspring weight, gender, random selection, and testing time and day. We corrected for multiple comparisons and considered P

A novel mutation, causing a phenotype we named frogleg because its most obvious characteristic is a severe splaying of the hind limbs, arose spontaneously in a colony of Sprague-Dawley rats. Frogleg is a complex phenotype that includes abnormalities in hind limb function, reduced brain weight with dilated ventricles and infertility. Using micro-satellite markers spanning the entire rat genome, the mutation was mapped to a region of rat chromosome 1 between D1Rat131 and D1Rat287. Analysis of whole genome sequencing data within the linkage interval, identified a missense mutation in the branched-chain alpha-keto dehydrogenase kinase (Bckdk) gene. The protein encoded by Bckdk is an integral part of an enzyme complex located in the mitochondrial matrix of many tissues which regulates the levels of the branched-chain amino acids (BCAAs), leucine, isoleucine and valine. BCAAs are essential amino acids (not synthesized by the body), and circulating levels must be tightly regulated; levels that are too high or too low are both deleterious. BCKDK phosphorylates Ser293 of the E1α subunit of the BCKDH protein, which catalyzes the rate-limiting step in the catabolism of the BCAAs, inhibiting BCKDH and thereby, limiting breakdown of the BCAAs. In contrast, when Ser293 is not phosphorylated, BCKDH activity is unchecked and the levels of the BCAAs will decrease dramatically. The mutation is located within the kinase domain of Bckdk and is predicted to be damaging. Consistent with this, we show that in rats homozygous for the mutation, phosphorylation of BCKDH in the brain is markedly decreased relative to wild type or heterozygous littermates. Further, circulating levels of the BCAAs are reduced by 70-80% in animals homozygous for the mutation. The frogleg phenotype shares important characteristics with a previously described Bckdk knockout mouse and with human subjects with Bckdk mutations. In addition, we report novel data regarding peripheral neuropathy of the hind limbs.

Brain parcellation tools based on multiple-atlas algorithms have recently emerged as a promising method with which to accurately define brain structures. When dealing with data from various sources, it is crucial that these tools are robust for many different imaging protocols. In this study, we tested the robustness of a multiple-atlas, likelihood fusion algorithm using Alzheimer's Disease Neuroimaging Initiative (ADNI) data with six different protocols, comprising three manufacturers and two magnetic field strengths. The entire brain was parceled into five different levels of granularity. In each level, which defines a set of brain structures, ranging from eight to 286 regions, we evaluated the variability of brain volumes related to the protocol, age, and diagnosis (healthy or Alzheimer's disease). Our results indicated that, with proper pre-processing steps, the impact of different protocols is minor compared to biological effects, such as age and pathology. A precise knowledge of the sources of data variation enables sufficient statistical power and ensures the reliability of an anatomical analysis when using this automated brain parcellation tool on datasets from various imaging protocols, such as clinical databases.

Using an animal model, we have previously shown that preeclampsia results in long-term adverse neuromotor outcomes in the offspring, and this phenotype was prevented by antenatal treatment with pravastatin. This study aims to localize the altered neuromotor programming in this animal model and to evaluate the role of pravastatin in its prevention.For the preeclampsia model, pregnant CD-1 mice were randomly allocated to injection of adenovirus carrying sFlt-1 or its control virus carrying mFc into the tail vein. Thereafter they received pravastatin (sFlt-1-pra "experimental group") or water (sFlt-1 "positive control") until weaning. The mFc group ("negative control") received water. Offspring at 6 months of age were sacrificed, and whole brains underwent magnetic resonance imaging (MRI). MRIs were performed using an 11.7 Tesla vertical bore MRI scanner. T2 weighted images were acquired to evaluate the volumes of 28 regions of interest, including areas involved in adaptation and motor, spatial and sensory function. Cytochemistry and cell quantification was performed using neuron-specific Nissl stain. One-way ANOVA with multiple comparison testing was used for statistical analysis.Compared with control offspring, male sFlt-1 offspring have decreased volumes in the fimbria, periaquaductal gray, stria medullaris, and ventricles and increased volumes in the lateral globus pallidus and neocortex; however, female sFlt-1 offspring showed increased volumes in the ventricles, stria medullaris, and fasciculus retroflexus and decreased volumes in the inferior colliculus, thalamus, and lateral globus pallidus. Neuronal quantification via Nissl staining exhibited decreased cell counts in sFlt-1 offspring neocortex, more pronounced in males. Prenatal pravastatin treatment prevented these changes.Preeclampsia alters brain development in sex-specific patterns, and prenatal pravastatin therapy prevents altered neuroanatomic programming in this animal model.

To evaluate the accuracy of advanced non-linear registration of serial lung Computed Tomography (CT) images using Large Deformation Diffeomorphic Metric Mapping (LDDMM).FIFTEEN CASES OF LUNG CANCER WITH SERIAL LUNG CT IMAGES (INTERVAL: 62.2±26.9 days) were used. After affine transformation, three dimensional, non-linear volume registration was conducted using LDDMM with or without cascading elasticity control. Registration accuracy was evaluated by measuring the displacement of landmarks placed on vessel bifurcations for each lung segment. Subtraction images and Jacobian color maps, calculated from the transformation matrix derived from image warping, were generated, which were used to evaluate time-course changes of the tumors.The average displacement of landmarks was 0.02±0.16 mm and 0.12±0.60 mm for proximal and distal landmarks after LDDMM transformation with cascading elasticity control, which was significantly smaller than 3.11±2.47 mm and 3.99±3.05 mm, respectively, after affine transformation. Emerged or vanished nodules were visualized on subtraction images, and enlarging or shrinking nodules were displayed on Jacobian maps enabled by highly accurate registration of the nodules using LDDMM. However, some residual misalignments were observed, even with non-linear transformation when substantial changes existed between the image pairs.LDDMM provides accurate registration of serial lung CT images, and temporal subtraction images with Jacobian maps help radiologists to find changes in pulmonary nodules.

In this paper, we propose a novel method for parcellating the human brain into 193 anatomical structures based on diffusion tensor images (DTIs). This was accomplished in the setting of multi-contrast diffeomorphic likelihood fusion using multiple DTI atlases. DTI images are modeled as high dimensional fields, with each voxel exhibiting a vector valued feature comprising of mean diffusivity (MD), fractional anisotropy (FA), and fiber angle. For each structure, the probability distribution of each element in the feature vector is modeled as a mixture of Gaussians, the parameters of which are estimated from the labeled atlases. The structure-specific feature vector is then used to parcellate the test image. For each atlas, a likelihood is iteratively computed based on the structure-specific vector feature. The likelihoods from multiple atlases are then fused. The updating and fusing of the likelihoods is achieved based on the expectation-maximization (EM) algorithm for maximum a posteriori (MAP) estimation problems. We first demonstrate the performance of the algorithm by examining the parcellation accuracy of 18 structures from 25 subjects with a varying degree of structural abnormality. Dice values ranging 0.8-0.9 were obtained. In addition, strong correlation was found between the volume size of the automated and the manual parcellation. Then, we present scan-rescan reproducibility based on another dataset of 16 DTI images - an average of 3.73%, 1.91%, and 1.79% for volume, mean FA, and mean MD respectively. Finally, the range of anatomical variability in the normal population was quantified for each structure.

Machine learning techniques, along with imaging markers extracted from structural magnetic resonance images, have been shown to increase the accuracy to differentiate patients with Alzheimer's disease (AD) from normal elderly controls. Several forms of anatomical features, such as cortical volume, shape, and thickness, have demonstrated discriminative capability. These approaches rely on accurate non-linear image transformation, which could invite several nuisance factors, such as dependency on transformation parameters and the degree of anatomical abnormality, and an unpredictable influence of residual registration errors. In this study, we tested a simple method to extract disease-related anatomical features, which is suitable for initial stratification of the heterogeneous patient populations often encountered in clinical data. The method employed gray-level invariant features, which were extracted from linearly transformed images, to characterize AD-specific anatomical features. The intensity information from a disease-specific spatial masking, which was linearly registered to each patient, was used to capture the anatomical features. We implemented a two-step feature selection for anatomic recognition. First, a statistic-based feature selection was implemented to extract AD-related anatomical features while excluding non-significant features. Then, seven knowledge-based ROIs were used to capture the local discriminative powers of selected voxels within areas that were sensitive to AD or mild cognitive impairment (MCI). The discriminative capability of the proposed feature was measured by its performance in differentiating AD or MCI from normal elderly controls (NC) using a support vector machine. The statistic-based feature selection, together with the knowledge-based masks, provided a promising solution for capturing anatomical features of the brain efficiently. For the analysis of clinical populations, which are inherently heterogeneous, this approach could stratify the large amount of data rapidly and could be combined with more detailed subsequent analyses based on non-linear transformation.

This paper examines the multiple atlas random diffeomorphic orbit model in Computational Anatomy (CA) for parameter estimation and segmentation of subcortical and ventricular neuroanatomy in magnetic resonance imagery. We assume that there exist multiple magnetic resonance image (MRI) atlases, each atlas containing a collection of locally-defined charts in the brain generated via manual delineation of the structures of interest. We focus on maximum a posteriori estimation of high dimensional segmentations of MR within the class of generative models representing the observed MRI as a conditionally Gaussian random field, conditioned on the atlas charts and the diffeomorphic change of coordinates of each chart that generates it. The charts and their diffeomorphic correspondences are unknown and viewed as latent or hidden variables. We demonstrate that the expectation-maximization (EM) algorithm arises naturally, yielding the likelihood-fusion equation which the a posteriori estimator of the segmentation labels maximizes. The likelihoods being fused are modeled as conditionally Gaussian random fields with mean fields a function of each atlas chart under its diffeomorphic change of coordinates onto the target. The conditional-mean in the EM algorithm specifies the convex weights with which the chart-specific likelihoods are fused. The multiple atlases with the associated convex weights imply that the posterior distribution is a multi-modal representation of the measured MRI. Segmentation results for subcortical and ventricular structures of subjects, within populations of demented subjects, are demonstrated, including the use of multiple atlases across multiple diseased groups.

Due to the high sensitivity of diffusion tensor imaging (DTI) to physiological motion, clinical DTI scans often suffer a significant amount of artifacts. Tensor-fitting-based, post-processing outlier rejection is often used to reduce the influence of motion artifacts. Although it is an effective approach, when there are multiple corrupted data, this method may no longer correctly identify and reject the corrupted data. In this paper, we introduce a new criterion called "corrected Inter-Slice Intensity Discontinuity" (cISID) to detect motion-induced artifacts. We compared the performance of algorithms using cISID and other existing methods with regard to artifact detection. The experimental results show that the integration of cISID into fitting-based methods significantly improves the retrospective detection performance at post-processing analysis. The performance of the cISID criterion, if used alone, was inferior to the fitting-based methods, but cISID could effectively identify severely corrupted images with a rapid calculation time. In the second part of this paper, an outlier rejection scheme was implemented on a scanner for real-time monitoring of image quality and reacquisition of the corrupted data. The real-time monitoring, based on cISID and followed by post-processing, fitting-based outlier rejection, could provide a robust environment for routine DTI studies.

Niemann-Pick Disease, type C1 (NPC1) is a rapidly progressive neurodegenerative disorder characterized by cholesterol sequestration within late endosomes and lysosomes, for which no reliable imaging marker exists for prognostication and management. Cerebellar volume deficits are found to correlate with disease severity and diffusion tensor imaging (DTI) of the corpus callosum and brainstem, which has shown that microstructural disorganization is associated with NPC1 severity. This study investigates the utility of cerebellar DTI in clinical severity assessment. We hypothesize that cerebellar volume, fractional anisotropy (FA) and mean diffusivity (MD) negatively correlate with NIH NPC neurological severity score (NNSS) and motor severity subscores. Magnetic resonance imaging (MRI) was obtained for thirty-nine NPC1 subjects, ages 1–21.9 years (mean = 11.1, SD = 6.1). Using an atlas-based automated approach, the cerebellum of each patient was measured for FA, MD and volume. Additionally, each patient was given an NNSS. Decreased cerebellar FA and volume, and elevated MD correlate with higher NNSS. The cognition subscore and motor subscores for eye movement, ambulation, speech, swallowing, and fine motor skills were also statistically significant. Microstructural disorganization negatively correlated with motor severity in subjects. Additionally, Miglustat therapy correlated with lower severity scores across ranges of FA, MD and volume in all regions except the inferior peduncle, where a paradoxical effect was observed at high FA values. These findings suggest that DTI is a promising prognostication tool.

White matter disruption has been suggested as one of anatomical features associated with Alzheimer's disease (AD). Diffusion tensor imaging (DTI), which has been widely used in AD studies, obtains new insights into the white matter structure.We introduced surface-based geometric models of the deep white matter tracts extracted from DTI, allowing the characterization of their shape variations relative to an atlas as well as fractional anisotropy (FA) variations on the atlas surface through large deformation diffeomorphic metric mapping (LDDMM). We applied it to assess local shapes and FA variations of twenty-three deep white matter tracts in 13 patients with AD and 19 healthy control subjects.Our results showed regionally-specific shape abnormalities and FA reduction in the cingulum tract and the sagittal stratum tract in AD, suggesting that disruption in the white matter tracts near the temporal lobe may represent the secondary consequence of the medial temporal lobe pathology in AD. Moreover, the regionally-specific patterns of FA and shape of the white matter tracts were shown to be of sufficient sensitivity to robustly differentiate patients with AD from healthy comparison controls when compared with the mean FA and volumes within the regions of the white matter tracts. Finally, greater FA or deformation abnormalities of the white matter tracts were associated with lower MMSE scores.The regionally-specific shape and FA patterns could be potential imaging markers for differentiating AD from normal aging.

Duplication of chromosome 15q11–13 has been reported to be one of the most frequent cytogenetic copy number variations in autism spectrum disorder (ASD), and a mouse model of paternal 15q11–13 duplication was generated, termed 15q dup mice. While previous studies have replicated some of the behavioral and brain structural phenotypes of ASD separately, the relationship between brain structure and behavior has rarely been examined. In this study, we performed behavioral experiments related to anxiety and social behaviors and magnetic resonance imaging (MRI) using the same set of 15q dup and wild-type mice. 15q dup mice showed increased anxiety and a tendency toward alterations in social behaviors, as reported previously, as well as variability in terms of sociability. MRI analysis revealed that a lower sociability index was correlated with a smaller gray matter volume in the right medial entorhinal cortex. These results may help to understand how variability in behavioral phenotypes of ASD arises even in individuals with the same genetic background and to determine the individual differences in neurodevelopmental trajectory correlated with specific brain structures that underlie these phenotypes.

Abstract This study integrated bacterial community and soil chemicals to characterize the soil ecosystem in an open upland field managed by six controlled fertilizer programs using the minimum amount of pesticides. Amplicon sequencing the 16S rRNA gene revealed that inorganic nitrogen fertilizer and compost altered the diversity and structure of the soil bacterial community throughout buckwheat (Fagopyrum esculentum Moench ‘Hitachiakisoba’) cultivation. The bacterial community comprised three clusters that contained bacteria that are prevalent in soils fertilized with nitrogen (cluster 1, 340 taxa), without nitrogen and compost (cluster 2, 234 taxa), and with compost-fertilized (cluster 3, 296 taxa). Cluster 2 contained more taxa in Actinobacteriota and less in Acidobacteriota, and cluster 3 contained more taxa in Gemmatimonadota compared with the other clusters. The most frequent taxa in cluster 1 were within the Chloroflexi phylum. The bacterial community structure correlated with soil chemical properties including pH, total organic carbon, SO4 2−, soluble Ca2+. A co-occurrence network of bacterial taxa and chemicals identified key bacterial groups comprising the center of a community network that determined topology and dynamics of the network. Temporal dynamics of the bacterial community structure indicated that Burkholderiales were associated with buckwheat ripening, indicating plant-bacteria interaction in the ecosystem.

Abstract Birth order is a crucial environmental factor for child development. For example, later-born children are relatively unlikely to feel secure due to sibling competition or diluted parental resources. The positive effect of being earlier-born on cognitive intelligence is well-established. However, whether birth order is linked to social behavior remains controversial, and the neural correlates of birth order effects in adolescence when social cognition develops remain unknown. Here, we explored the birth order effect on prosociality using a large-scale population-based adolescent cohort. Next, since the amygdala is a key region for sociality and environmental stress, we examined amygdala substrates of the association between birth order and prosociality using a subset neuroimaging cohort. We found enhanced prosociality in later-born adolescents (N = 3160), and observed the mediating role of larger amygdala volume (N = 208) and amygdala-prefrontal functional connectivity with sex-selective effects (N = 183). We found that birth order, a non-genetic environmental factor, affects adolescent social development via different neural substrates. Our findings may indicate the later-born people’s adaptive survival strategy in stressful environments.

Maternal breastfeeding has an impact on motor and emotional development in children of the next generation. Elucidating how breastfeeding during infancy affects brain regional structural development in early adolescence will be helpful for promoting healthy development. However, previous studies that have shown relationships between breastfeeding during infancy and cortical brain regions in adolescence are usually based on maternal retrospective recall of breastfeeding, and the accuracy of the data is unclear. In this study, we investigated the association between breastfeeding duration and brain regional volume in a population-neuroimaging study of early adolescents in Japan (N ​= ​207; 10.5–13.4 years) using voxel-based morphometry, which enabled us to analyze the whole brain. We evaluated breastfeeding duration as indexed by maternal and child health handbook records during infancy. The results showed a significant positive correlation between the duration of breastfeeding and gray matter volume in the dorsal and ventral striatum and the medial orbital gyrus. Post hoc exploratory analyses revealed that the duration of breastfeeding was significantly correlated with emotional behavior. Additionally, the volume in the medial orbital gyrus mediated an association between breastfeeding duration and emotional behavior. This is the first study to evaluate the effect of breastfeeding during infancy on regional brain volumes in early adolescence based on maternal and child health handbook records. Our findings shed light upon the importance of maternal breastfeeding for brain development related to emotional and motivational processing in early adolescence.

BackgroundIn the early intervention in psychosis, ultra-high risk (UHR) criteria have been used to identify individuals who are prone to develop psychosis. Although the transition rate to psychosis in individuals at UHR is 10% to 30% within several years, some individuals at UHR present with poor prognoses even without transition occurring. Therefore, it is important to identify biomarkers for predicting the prognosis of individuals at UHR, regardless of transition. We investigated whether mismatch negativity (MMN) in response to both duration deviant stimuli (dMMN) and frequency deviant stimuli (fMMN) could predict prognosis, including remission and neurocognitive function in individuals at UHR.Materials and MethodsIndividuals at UHR (n = 24) and healthy controls (HC; n = 18) participated in this study. In an auditory oddball paradigm, both dMMN and fMMN were measured at baseline. Remission and neurocognitive function after > 180 days were examined in the UHR group. Remission from UHR was defined as functional and symptomatic improvement using the Global Assessment of Functioning (GAF) score and Scale of Prodromal Symptoms (SOPS) positive subscales. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia (BACS). We examined differences in MMN amplitude at baseline between those who achieved remission (remitters) and those who did not (non-remitters). Multiple regression analyses were performed to identify predictors for functioning, positive symptoms, and neurocognitive function.ResultsCompared with the HC group, the UHR group had a significantly attenuated dMMN amplitude (p = 0.003). In the UHR group, GAF scores significantly improved during the follow-up period (mean value 47.1 to 55.5, p = 0.004). The dMMN amplitude at baseline was significantly larger in the remitter (n = 6) than in the non-remitter group (n = 18) (p = 0.039). The total SOPS positive subscale scores and fMMN amplitude at baseline could predict BACS attention subscore at the follow-up point (SOPS positive subscales, p = 0.030; fMMN, p = 0.041).ConclusionOur findings indicate that dMMN and fMMN predicted remission and neurocognitive function, respectively, in individuals at UHR, which suggests that there are both promising biomarker candidates for predicting prognosis in individuals at UHR.

Summary: S-adenosylmethionine is an important compound, because it serves as the methyl donor in most methyl transfer reactions, including methylation of proteins, nucleic acids, and lipids. However, cellular defects in the genetic disruption of S-adenosylmethionine synthesis are not well understood. Here, we report the isolation and characterization of temperature-sensitive mutants of fission yeast S-adenosylmethionine synthetase (Sam1). Levels of S-adenosylmethionine and methylated histone H3 were greatly diminished in sam1 mutants. sam1 mutants stopped proliferating in vegetative culture and arrested specifically in G2 phase without cell elongation. Furthermore, sam1 mutants lost viability during nitrogen starvation-induced G0 phase quiescence. After release from the G0 state, sam1 mutants could neither increase in cell size nor re-initiate DNA replication in the rich medium. Sam1 is thus required for cell growth and proliferation, and maintenance of and exit from quiescence. sam1 mutants lead to broad cellular and drug response defects, as expected, since S. pombe contains more than 90 S-adenosylmethionine-dependent methyltransferases. : Molecular Mechanism of Behavior; Cell Biology; Functional Aspects of Cell Biology; Model Organism Subject Areas: Molecular Mechanism of Behavior, Cell Biology, Functional Aspects of Cell Biology, Model Organism

Depressive disorders in epilepsy often present characteristic clinical manifestations atypical in primary, endogenous depression. Here, we report a case of a 64-year-old woman with right mesial temporal lobe epilepsy, who complained of bizarre, antipsychotic-refractory cenesthetic hallucinations in her interictal phase, and was hospitalized after a suicide attempt. Detailed clinical observations revealed mood symptoms, which led to the diagnosis of interictal dysphoric disorder comorbid with interictal psychosis. Sertraline with low-dose aripiprazole markedly alleviated both depressive and psychotic symptoms. This case suggested that the two diagnostic entities may overlap and that depressive symptoms tend to be concurrent when concurring with psychosis, which hampers the appropriate choice of a treatment option. Keywords: Temporal lobe epilepsy, Interictal depression, Interictal dysphoric disorder, Interictal psychosis, Sertraline, Aripiprazole

The association between emotional stimuli and temporal lobe epilepsy (TLE) is largely unknown. Here, we report the case of a depressed, 50-year-old female complaining of episodes of a “spaced out” experience precipitated by emotional stimuli. Psychogenic non-epileptic attacks were suspected. However, video-EEG coupled with emotional stimuli-provoked procedures and MRI findings of amygdala enlargement, led to the diagnosis of left TLE. Accurate diagnosis and explanation improved her subjective depression and seizure frequency. This case demonstrated that emotional stimuli can provoke seizures in TLE and suggested the involvement of the enlarged amygdala and the modulation of emotion-related neural circuits. Keywords: Video-EEG, Psychogenic non-epileptic attacks, Temporal lobe epilepsy, Amygdala enlargement, Reflex seizure, Provoked seizure

Glecaprevir/pibrentasvir (G/P) are direct-acting antivirals (DAAs) that achieve a high sustained virological response (SVR) rate for hepatitis C virus (HCV) infection. We investigated G/P effectiveness for HCV patients based on real-world experience and the clinical features of retreatment cases. HCV patients (n = 182) were compared for clinical features and outcomes between first treatment (n = 159) and retreatment (n = 23) G/P groups. Overall, 77 patients (42.3%) were male, the median age was 68 years, and 86/66/1/4 cases had genotype 1/2/1 + 2/3, respectively. An SVR was achieved in 97.8% (178/182) of cases by intention-to-treat analysis and 99.4% (178/179) of cases by per-protocol analysis. There were no remarkable differences between the first treatment and retreatment groups for male (42.8% vs. 39.1%, p = 0.70), median age (68 vs. 68 years, p = 0.36), prior hepatocellular carcinoma (5.8% vs. 8.7%, p = 0.59), or the fibrosis markers AST-to-platelet ratio index (APRI) (0.5 vs. 0.5, p = 0.80) and fibrosis-4 (FIB-4) index (2.2 vs. 2.6, p = 0.59). The retreatment group had a significantly more frequent history of interferon treatment (12.3% vs. 52.2%, p < 0.01) and the Y93H mutation (25.0% vs. 64.7%, p = 0.02). The number of retreatment patients who had experienced 3, 2, and 1 DAA treatment failures was 1, 3, and 19, respectively, all of whom ultimately achieved an SVR by G/P treatment. In conclusion, G/P was effective and safe for both HCV first treatment and retreatment cases despite the retreatment group having specific resistance mutations for other prior DAAs. As G/P treatment failure has been reported for P32 deletions, clinicians should consider resistance mutations during DAA selection.

We consider a capacity expansion problem for a railway network under uncertainty. In our approach, integer and stochastic programming provide a basic framework. We develop a multistage stochastic programming model in which some of the variables are restricted to integer values. Given the distribution of the number of customers in a scenario, the problem of minimizing the expected value of the total investment cost is considered. The problem is reformulated as a problem with first stage integer variables and continuous second stage variables. An L-shaped algorithm is proposed to solve this problem.

We consider the allocation of a running time supplement to a railway timetable. Previously, Vekas et al. examined the optimal way to allocate the running time supplement. The uncertain disturbances in a railway were modeled using random variables. In their model, it was assumed that there was an upper limit to the total supplement, but its allocation was not restricted. In this paper, we suggest an improvement to the previous model and present a new stochastic programming model in which there is a constraint on the running time supplement allocated to each trip to minimize the expected delay. Then a solution algorithm to solve the problem is developed. In the previous model, allocation of the running time supplement was biased because it was not allocated to all trips. We balance the amounts of supplements for trips by adding upper and lower bounds. The uctuations of the supplements for trips become small, and the probability of a delay decreases using our new model. Then the calculation times using the L-shaped algorithm and the former method solving a deterministic equivalent of large-scale problems are compared. It is shown that the large-scale problems can be solved effectively by using the L-shaped method.

Optimization of daily vehicle routes with deliveries and pickups as well as multiple use of vehicles for a rental business is considered. The problem is formulated as a variant of generalized set covering problems in which variables correspond to workdays of vehicles. Two variants of column generation heuristic algorithms are developed: one to obtain near-optimal solutions with moderate amount of CPU time together with the associated lower bound, and the other to get solutions with maximum of 8% GAP within 30 CPU seconds. The speed-up of the algorithm is achieved by approximately solving subproblems which exploits information of optimal dual prices associated with the restricted LP master problem. The column generation heuristic algorithms are applied successfully not only to single-depot problems but also to multi-depot problems.

Intracellular thiols like L-cystine and L-cystine play a critical role in the regulation of cellular processes. Here we show that Escherichia coli has two L-cystine transporters, the symporter YdjN and the ATP-binding cassette importer FliY-YecSC. These proteins import L-cystine, an oxidized product of L-cystine from the periplasm to the cytoplasm. The symporter YdjN, which is expected to be a new member of the L-cystine regulon, is a low affinity L-cystine transporter (Km = 1.1 μM) that is mainly involved in L-cystine uptake from outside as a nutrient. E. coli has only two L-cystine importers because ΔydjNΔyecS mutant cells are not capable of growing in the minimal medium containing L-cystine as a sole sulfur source. Another protein YecSC is the FliY-dependent L-cystine transporter that functions cooperatively with the L-cystine transporter YdeD, which exports L-cystine as reducing equivalents from the cytoplasm to the periplasm, to prevent E. coli cells from oxidative stress. The exported L-cystine can reduce the periplasmic hydrogen peroxide to water, and then generated L-cystine is imported back into the cytoplasm via the ATP-binding cassette transporter YecSC with a high affinity to L-cystine (Km = 110 nM) in a manner dependent on FliY, the periplasmic L-cystine-binding protein. The double disruption of ydeD and fliY increased cellular levels of lipid peroxides. From these findings, we propose that the hydrogen peroxide-inducible L-cystine/L-cystine shuttle system plays a role of detoxification of hydrogen peroxide before lipid peroxidation occurs, and then might specific prevent damage to membrane lipids.

Natural killer cell responses play a crucial role in virus clearance by the innate immune system. Although the killer immunoglobulin-like receptor (KIR) in combination with its cognate human leukocyte antigen (HLA) ligand, especially KIR2DL3-HLA-C1, is associated with both treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection in Caucasians, these innate immunity genes have not been fully clarified in Japanese patients. We therefore investigated 16 KIR genotypes along with HLA-B and -C ligands and a genetic variant of interleukin (IL) 28B (rs8099917) in 115 chronic hepatitis C genotype 1 patients who underwent pegylated-interferon-α2b (PEG-IFN) and ribavirin therapy. HLA-Bw4 was significantly associated with a sustained virological response (SVR) to treatment (P = 0.017; odds ratio [OR] = 2.50, ), as was the centromeric A/A haplotype of KIR (P = 0.015; OR 3.37). In contrast, SVR rates were significantly decreased in patients with KIR2DL2 or KIR2DS2 (P = 0.015; OR = 0.30, and P = 0.025; OR = 0.32, respectively). Multivariate logistic regression analysis subsequently identified the IL28B TT genotype (P = 0.00009; OR = 6.87, 95% confidence interval [CI] = 2.62 - 18.01), KIR2DL2/HLA-C1 (P = 0.014; OR = 0.24, 95% CI = 0.08 - 0.75), KIR3DL1/HLA-Bw4 (P = 0.008, OR = 3.32, 95% CI = 1.37 - 8.05), and white blood cell count at baseline (P = 0.009; OR = 3.32, 95% CI = 1.35 - 8.16) as independent predictive factors of an SVR. We observed a significant association between the combination of IL28B TT genotype and KIR3DL1-HLA-Bw4 in responders (P = 0.0019), whereas IL28B TT along with KIR2DL2-HLA-C1 was related to a non-response (P = 0.0067). In conclusion, combinations of KIR3DL1/HLA-Bw4, KIR2DL2/HLA-C1, and a genetic variant of the IL28B gene are predictive of the response to PEG-IFN and ribavirin therapy in Japanese patients infected with genotype 1b HCV.

GABA (γ-amino-butylic acid)-mediated inhibition in the dendrites of CA1 pyramidal neurons was characterized by two-photon uncaging of a caged-GABA compound, BCMACM-GABA, and one-photon uncaging of RuBi-GABA in rat hippocampal slice preparations. Although we found that GABA(A)-mediated currents were diffusely distributed along the dendrites, currents elicited at the branch points of the apical dendritic trunk were approximately two times larger than those elsewhere in the dendrite. We examined the inhibitory action of the GABA-induced currents on Ca(2+) transients evoked with a single back-propagating action potential (bAP) in oblique dendrites. We found that GABA uncaging selectively inhibited the Ca(2+) transients in the region adjacent (20 µm). Our data indicate that GABA inhibition results in spatially confined inhibition of Ca(2+) transients shortly after bAP, and suggest that this effect is particularly potent at the dendritic branch points where GABA receptors cluster.