The importance of combining MRI and large-scale digital histology in neuroimaging studies of brain connectivity and disease

One of the major issues hindering a comprehensive connectivity model for the human brain is the difficulty in linking Magnetic Resonance Imaging (MRI) measurements to anatomical evidence produced by histological methods. In vivo and postmortem neuroimaging methodologies are still largely incompatible in terms of sample size, scale, and resolution. To help bridge the hiatus between different approaches we have established a program that characterizes the brain of individual subjects, combining MRI with postmortem neuroanatomy. The direct correlation of MRI and histological features is possible, because registered images from different modalities represent the same regions in the same brain. Comparisons are also facilitated by large-scale, digital microscopy techniques that afford images of the whole-brain sections at cellular resolution. The goal is to create a neuroimaging catalog representative of discrete age groups and specific neurological conditions. Individually, the datasets allow for investigating the relationship between different modalities; combined, they provide sufficient predictive power to inform analyses and interpretations made in the context of non-invasive studies of brain connectivity and disease

Grey-matter texture abnormalities and reduced hippocampal volume are distinguishing features of schizophrenia

Neurodevelopmental processes are widely believed to underlie schizophrenia. Analysis of brain texture from conventional magnetic resonance imaging (MRI) can detect disturbance in brain cytoarchitecture. We tested the hypothesis that patients with schizophrenia manifest quantitative differences in brain texture that, alongside discrete volumetric changes, may serve as an endophenotypic biomarker. Texture analysis (TA) of grey matter distribution and voxel-based morphometry (VBM) of regional brain volumes were applied to MRI scans of 27 patients with schizophrenia and 24 controls. Texture parameters (uniformity and entropy) were also used as covariates in VBM analyses to test for correspondence with regional brain volume. Linear discriminant analysis tested if texture and volumetric data predicted diagnostic group membership (schizophrenia or control). We found that uniformity and entropy of grey matter differed significantly between individuals with schizophrenia and controls at the fine spatial scale (filter width below 2 mm). Within the schizophrenia group, these texture parameters correlated with volumes of the left hippocampus, right amygdala and cerebellum. The best predictor of diagnostic group membership was the combination of fine texture heterogeneity and left hippocampal size. This study highlights the presence of distributed grey-matter abnormalities in schizophrenia, and their relation to focal structural abnormality of the hippocampus. The conjunction of these features has potential as a neuroimaging endophenotype of schizophrenia

Mapping the Connectome: Multi-Level Analysis of Brain Connectivity

Background and scope The brain contains vast numbers of interconnected neurons that constitute anatomical and functional networks. Structural descriptions of neuronal network elements and connections make up the “connectome ” of the brain (Hagmann, 2005; Sporns et al., 2005; Sporns, 2011), and are important for understanding normal brain function and disease-related dysfunction. A long-standing ambition of the neuroscience community has been to achieve complete connectome maps for the human brain as well as the brains of non-human primates, rodents, and other species (Bohland et al., 2009; Hagmann et al., 2010; Van Essen and Ugurbil, 2012). A wide repertoire of experimental tools is currently available to map neural connectivity at multiple levels, from the tracing of mesoscopic axonal connections and the delineation of white matter tracts (Saleem et al., 2002; Van der Linden et al., 2002; Sporns et al., 2005; Schmahmann et al., 2007; Hagmann et al., 2010), the mappin

Research Scenario of Bio Informatics in Big Data Approach

Big Data can unify all patient related data to get a 360-degree view of the patient to analyze and predict outcomes. This investigation examines the concepts and characteristics of Big Data, concepts about Translational Bio Informatics and some public available big data repositories and major issues of big data. This issue covers the area of medical and healthcare applications and its opportunities.

Abnormalities in fronto-striatal connectivity within language networks relate to differences in grey-matter heterogeneity in Asperger syndrome

Abstract Asperger syndrome (AS) is an Autism Spectrum Disorder (ASD) characterised by qualitative impairment in the development of emotional and social skills with relative preservation of general intellectual abilities, including verbal language. People with AS may nevertheless show atypical language, including rate and frequency of speech production. We previously observed that abnormalities in grey matter homogeneity (measured with texture analysis of structural MR images) in AS individuals when compared with controls are also correlated with the volume of caudate nucleus. Here, we tested a prediction that these distributed abnormalities in grey matter compromise the functional integrity of brain networks supporting verbal communication skills. We therefore measured the functional connectivity between caudate nucleus and cortex during a functional neuroimaging study of language generation (verbal fluency), applying psycho-physiological interaction (PPI) methods to test specifically for differences attributable to grey matter heterogeneity in AS participants. Furthermore, we used dynamic causal modelling (DCM) to characterise the causal directionality of these differences in interregional connectivity during word production. Our results revealed a diagnosis-dependent influence of grey matter heterogeneity on the functional connectivity of the caudate nuclei with right insula/inferior frontal gyrus and anterior cingulate, respectively with the left superior frontal gyrus and right precuneus. Moreover, causal modelling of interactions between inferior frontal gyri, caudate and precuneus, revealed a reliance on bottom-up (stimulus-driven) connections in AS participants that contrasted with a dominance of top-down (cognitive control) connections from prefrontal cortex observed in control participants. These results provide detailed support for previously hypothesised central disconnectivity in ASD and specify discrete brain network targets for diagnosis and therapy in ASD

A Systematic Approach to Dissection of the Equine Brain–Evaluation of a Species-Adapted Protocol for Beginners and Experts

Introduction of new imaging modalities for the equine brain have refocused attention on the horse as a natural model for ethological, neuroanatomical, and neuroscientific investigations. As opposed to imaging studies, strategies for equine neurodissection still lack a structured approach, standardization and reproducibility. In contrast to other species, where adapted protocols for sampling have been published, no comparable guideline is currently available for equids. Hence, we developed a species-specific slice protocol for whole brain vs. hemispheric dissection and tested its applicability and practicability in the field, as well as its neuroanatomical accuracy and reproducibility. Dissection steps are concisely described and depicted by schematic illustrations, photographs and instructional videos. Care was taken to show the brain in relation to the raters' hands, cutting devices and bench surface. Guidance is based on a minimum of external anatomical landmarks followed by geometric instructions that led to procurement of 14 targeted slabs. The protocol was performed on 55 formalin-fixed brains by three groups of investigators with different neuroanatomical skills. Validation of brain dissection outcomes addressed the aptitude of slabs for neuroanatomical studies as opposed to simplified routine diagnostic purposes. Across all raters, as much as 95.2% of slabs were appropriate for neuroanatomical studies, and 100% of slabs qualified for a routine diagnostic setting. Neither autolysis nor subfixation significantly affected neuroanatomical accuracy score, while a significant negative effect was observed with brain extraction artifacts. Procedure times ranged from 14 to 66 min and reached a mean duration of 23.25 ± 7.93 min in the last of five trials in inexperienced raters vs. 16 ± 2.83 min in experts, while acceleration of the dissection did not negatively impact neuroanatomical accuracy. This protocol, derived analogously to the consensus report of the International Veterinary Epilepsy Task Force in dogs and cats, allows for systematic, quick and easy dissection of the equine brain, even for inexperienced investigators. Obtained slabs feature virtually all functional subcompartments at suitable planes for both diagnostic and neuroscientific investigations and complement the data obtained from imaging studies. The instructive protocol and brain dissection videos are available in Supplementary Material

Robust joint registration of multiple stains and MRI for multimodal 3D histology reconstruction: Application to the Allen human brain atlas

Joint registration of a stack of 2D histological sections to recover 3D structure ("3D histology reconstruction") finds application in areas such as atlas building and validation of in vivo imaging. Straightforward pairwise registration of neighbouring sections yields smooth reconstructions but has well-known problems such as "banana effect" (straightening of curved structures) and "z-shift" (drift). While these problems can be alleviated with an external, linearly aligned reference (e.g., Magnetic Resonance (MR) images), registration is often inaccurate due to contrast differences and the strong nonlinear distortion of the tissue, including artefacts such as folds and tears. In this paper, we present a probabilistic model of spatial deformation that yields reconstructions for multiple histological stains that that are jointly smooth, robust to outliers, and follow the reference shape. The model relies on a spanning tree of latent transforms connecting all the sections and slices of the reference volume, and assumes that the registration between any pair of images can be see as a noisy version of the composition of (possibly inverted) latent transforms connecting the two images. Bayesian inference is used to compute the most likely latent transforms given a set of pairwise registrations between image pairs within and across modalities. We consider two likelihood models: Gaussian (ℓ2 norm, which can be minimised in closed form) and Laplacian (ℓ1 norm, minimised with linear programming). Results on synthetic deformations on multiple MR modalities, show that our method can accurately and robustly register multiple contrasts even in the presence of outliers. The framework is used for accurate 3D reconstruction of two stains (Nissl and parvalbumin) from the Allen human brain atlas, showing its benefits on real data with severe distortions. Moreover, we also provide the registration of the reconstructed volume to MNI space, bridging the gaps between two of the most widely used atlases in histology and MRI. The 3D reconstructed volumes and atlas registration can be downloaded from https://openneuro.org/datasets/ds003590. The code is freely available at https://github.com/acasamitjana/3dhirest

Erstellung und Neuroanatomische Validierung eines IVETF-angelehnten Protokolls zur Systematischen Sektion von Equidenhirnen zu neurowissenschaftlichen und diagnostischen Zwecken

Mit der zunehmenden Implementierung bildgebender Verfahren in der Pferdeneurologie und der damit verbundenen Notwendigkeit zur neuroanatomischen Ko-Registrierung von Ergebnissen aus Bildgebung und Histologie, ist eine systematische Herangehensweise zur überschneidenden Darstellung neurophysiologischer und -pathologischer Zustände im Pferdehirn erforderlich geworden. Während in der bildgebenden Diagnostik erste Vorlagen zur Standardisierung wesentlicher Schnittebenen für das Pferdehirn publiziert wurden, sind ebensolche Hilfestellung für die strukturierte und reproduzierbare postmortale Aufarbeitung des equinen Hirns nicht existent. Insbesondere weniger erfahrene Wissenschaftler/-innen und Diagnostiker/-innen werden somit vor die Herausforderung gestellt, symptomatogene Zonen und Regionen mit definierter oder unklarer Vulnerabilität im voluminösen Pferdehirn zu untersuchen oder zumindest sachgemäß zu beproben. Diese Doktorarbeit hat sich deshalb zum Ziel gesetzt, ein Spezies-spezifisches Zuschnittprotokoll, analog zum Konsensus Statement der International Veterinary Epilepsy Task Force (IVETF) für Hunde und Katzen, für die sequenzielle hemisphärische und bihemisphärische Sektion des Pferdegehirns auszuarbeiten, das 1. an Hirnen unterschiedlicher Volumina anhand simpler externer anatomischer Orientierungspunkte anwendbar ist, 2. von Personen mit heterogenen neuroanatomischen Kenntnissen eingesetzt werden kann und 3. die 3-dimensionale Anordnung von Hirnstrukturen berücksichtigt und somit in repräsentativen und reproduzierbaren Zuschnitten unter Erhalt der Histomorphologie und -architektur resultiert. Hierfür wurde eine bebilderte Zuschnittserie, begleitet von schematischen Illustrationen und instruktiven Videos, zusammengestellt und zur Überprüfung an 55 Formalin-fixierten Gehirnen, zugeschnitten von Personen mit unterschiedlichen neuroanatomischen Vorkenntnissen, getestet. Die hieraus resultierenden 14 Hirnschnitte pro Gehirn wurden anhand 36 makro- und mikroskopischer Kriterien auf Eignung für neuroanatomische Studien und die neuropathologische Routinediagnostik beurteilt. Über alle Untersuchergruppen hinweg stellten sich dabei 95,2% der Hirnschnitte als geeignet für neuroanatomische Studien bei gleichzeitiger 100%-iger Eignung für die Routinediagnostik heraus. Obwohl die Untersucher/-innen mit heterogenem Material in Bezug auf Volumen, Fixierung und Autolyse konfrontiert waren, konnte ein signifikant negativer Effekt auf die neuroanatomische Akkuranz, beurteilt anhand erwähnter Kriterien, nur bei durch die Entnahme beschädigten Gehirnen nachgewiesen werden. Die notwendige Zeit für die Durchführung der Sektion erstreckte sich über einen Zeitraum von 14 bis 66 Minuten und konnte ohne negative Auswirkungen auf die neuroanatomische Akkuranz mit zunehmender Erfahrung auf ~20 Minuten reduziert werden. Das erarbeitete Protokoll bewies sich somit als praktikabel, aussagekräftig und personenungebunden reproduzierbar und kann generell für Forschungen am Pferdehirn im Praxisalltag empfohlen werden.The implementation of advanced imaging modalities in equine neurology entails the need for accurate co-registration of imaging findings, neuroanatomical data and histological changes. Whilst imaging templates for standardization of scanning planes and the algorithms for 3D reconstruction of the horse brain are readily available, there are no such aids for a structured and reproducible post-mortem processing. In the broad field, trimming in transverse sections is most common. This approach however provides unsatisfactory results for those structures with complex spatial organization. Moreover, section levels were chosen empirically without mentioning clear landmarks and therefore sections and data cannot be easily reproduced by other raters. In addition, it cannot be expected from routine pathologists to have sufficient knowledge of neuroanatomy to address symptomatogenic zones nor of neuropathology to address and sample explicitly vulnerable zones. This doctoral thesis has therefore set itself the goal of developing a species-specific dissection protocol for sequential hemispheric and bihemispheric dissection of the horse brain, that 1. refers to simple and unequivocal external anatomical landmarks, 2. can be used by people with heterogenous neuroanatomical knowledge and 3. respects the 3-dimensional arrangement of complex areas and therefore results in representative and reproducible samples while preserving histomorphology and -architecture. For this purpose, a systematic dissection protocol was created analogously to the consensus guidelines of the International Veterinary Epilepsy Task Force (IVETF) for dogs and cats (MATIASEK et al., 2015). After sequences went smoothly, the protocol was introduced to and tested in a group of volunteers with variable neuroanatomical skills using text instructions, a series of figures of landmarks and dissection planes, schematic illustrations and instructive videos for both hemispheric and bihemispheric dissection. Altogether 55 dissections were monitored concerning time, performance and neuroanatomical accuracy. All raters felt confident to apply the protocol from the scratch. Across investigators, 95.2% of brain slabs were suitable for neuroanatomical studies while at the same 100% of reference structures considered appropriate for routine diagnostics were appropriately presented. Although the investigators were confronted to the field situation of heterogenous volumes, structural preservation, fixation and autolysis, a significantly negative effect on neuroanatomical accuracy could only be ascertained in brains damaged during extraction. Time required for performing the dissection ranged over a period of 14 to 66 minutes and could be reduced to ~20 minutes with repetition. Acceleration of performance did not negatively impact on the neuroanatomical accuracy. The developed protocol therefore proved to be practicable, representative, and reproducible for young and experienced investigators and therefore can generally be recommended for application in equine brain research and diagnostics