Publications by authors named "Katrin Amunts"

221 Publications

Generalizing Longitudinal Age Effects on Brain Structure - A Two-Study Comparison Approach.

Front Hum Neurosci 2021 16;15:635687. Epub 2021 Apr 16.

Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany.

Cross-sectional studies indicate that normal aging is accompanied by decreases in brain structure. Longitudinal studies, however, are relatively rare and inconsistent regarding their outcomes. Particularly the heterogeneity of methods, sample characteristics and the high inter-individual variability in older adults prevent the deduction of general trends. Therefore, the current study aimed to compare longitudinal age-related changes in brain structure (measured through cortical thickness) in two large independent samples of healthy older adults ( = 161 each); the Longitudinal Healthy Aging Brain (LHAB) database project at the University of Zurich, Switzerland, and 1000BRAINS at the Research Center Juelich, Germany. Annual percentage changes in the two samples revealed stable to slight decreases in cortical thickness over time. After correction for major covariates, i.e., baseline age, sex, education, and image quality, sample differences were only marginally present. Results suggest that general trends across time might be generalizable over independent samples, assuming the same methodology is used, and similar sample characteristics are present.
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http://dx.doi.org/10.3389/fnhum.2021.635687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085300PMC
April 2021

Autofluorescence enhancement for label-free imaging of myelinated fibers in mammalian brains.

Sci Rep 2021 Apr 13;11(1):8038. Epub 2021 Apr 13.

European Laboratory for Non-Linear Spectroscopy, University of Florence, Florence, Italy.

Analyzing the structure of neuronal fibers with single axon resolution in large volumes is a challenge in connectomics. Different technologies try to address this goal; however, they are limited either by the ineffective labeling of the fibers or in the achievable resolution. The possibility of discriminating between different adjacent myelinated axons gives the opportunity of providing more information about the fiber composition and architecture within a specific area. Here, we propose MAGIC (Myelin Autofluorescence imaging by Glycerol Induced Contrast enhancement), a tissue preparation method to perform label-free fluorescence imaging of myelinated fibers that is user friendly and easy to handle. We exploit the high axial and radial resolution of two-photon fluorescence microscopy (TPFM) optical sectioning to decipher the mixture of various fiber orientations within the sample of interest. We demonstrate its broad applicability by performing mesoscopic reconstruction at a sub-micron resolution of mouse, rat, monkey, and human brain samples and by quantifying the different fiber organization in control and Reeler mouse's hippocampal sections. Our study provides a novel method for 3D label-free imaging of nerve fibers in fixed samples at high resolution, below micrometer level, that overcomes the limitation related to the myelinated axons exogenous labeling, improving the possibility of analyzing brain connectivity.
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http://dx.doi.org/10.1038/s41598-021-86092-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044204PMC
April 2021

Genetic factors influencing a neurobiological substrate for psychiatric disorders.

Transl Psychiatry 2021 Mar 29;11(1):192. Epub 2021 Mar 29.

Institute of Neuroscience and Medicine (INM-1, INM-7), Research Centre Jülich, Jülich, Germany.

A retrospective meta-analysis of magnetic resonance imaging voxel-based morphometry studies proposed that reduced gray matter volumes in the dorsal anterior cingulate and the left and right anterior insular cortex-areas that constitute hub nodes of the salience network-represent a common substrate for major psychiatric disorders. Here, we investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease. To this end, after a data reduction step, we conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts (n = 2271), followed by meta-analysis and replication in a fifth cohort (n = 865). After correction for covariates, the heritability of the common substrate was estimated at 0.50 (standard error 0.18). The top single-nucleotide polymorphism (SNP) rs17076061 was associated with the common substrate at genome-wide significance and replicated, explaining 1.2% of the common substrate variance. This SNP mapped to a locus on chromosome 5q35.2 harboring genes involved in neuronal development and regeneration. In follow-up analyses, rs17076061 was not robustly associated with psychiatric disease, and no overlap was found between the broader genetic architecture of the common substrate and genetic risk for major depressive disorder, bipolar disorder, or schizophrenia. In conclusion, our study identified that common genetic variation indeed influences the common substrate, but that these variants do not directly translate to increased disease risk. Future studies should investigate gene-by-environment interactions and employ functional imaging to understand how salience network structure translates to psychiatric disorder risk.
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http://dx.doi.org/10.1038/s41398-021-01317-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007575PMC
March 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 Mar 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult-onset disorder.

Ann Clin Transl Neurol 2021 04 19;8(4):774-789. Epub 2021 Mar 19.

Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Juelich, Germany.

Objectives: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging.

Methods: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS).

Results: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls.

Interpretation: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG.
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http://dx.doi.org/10.1002/acn3.51315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045942PMC
April 2021

Scattered Light Imaging: Resolving the substructure of nerve fiber crossings in whole brain sections with micrometer resolution.

Neuroimage 2021 06 11;233:117952. Epub 2021 Mar 11.

Institute of Neuroscience and Medicine (INM-1), Forschungszentrum Jülich, Wilhelm-Johnen-Straße, Jülich 52425, Germany.

For developing a detailed network model of the brain based on image reconstructions, it is necessary to spatially resolve crossing nerve fibers. The accuracy hereby depends on many factors, including the spatial resolution of the imaging technique. 3D Polarized Light Imaging (3D-PLI) allows the three-dimensional reconstruction of nerve fiber tracts in whole brain sections with micrometer in-plane resolution, but leaves uncertainties in pixels containing crossing fibers. Here we introduce Scattered Light Imaging (SLI) to resolve the substructure of nerve fiber crossings. The measurement is performed on the same unstained histological brain sections as in 3D-PLI. By illuminating the brain sections from different angles and measuring the transmitted (scattered) light under normal incidence, light intensity profiles are obtained that are characteristic for the underlying brain tissue structure. We have developed a fully automated evaluation of the intensity profiles, allowing the user to extract various characteristics, like the individual directions of in-plane crossing nerve fibers, for each image pixel at once. We validate the reconstructed nerve fiber directions against results from previous simulation studies, scatterometry measurements, and fiber directions obtained from 3D-PLI. We demonstrate in different brain samples (human optic tracts, vervet monkey brain, rat brain) that the 2D fiber directions can be reliably reconstructed for up to three crossing nerve fiber bundles in each image pixel with an in-plane resolution of up to 6.5 μm. We show that SLI also yields reliable fiber directions in brain regions with low 3D-PLI signals coming from regions with a low density of myelinated nerve fibers or out-of-plane fibers. This makes Scattered Light Imaging a promising new imaging technique, providing crucial information about the organization of crossing nerve fibers in the brain.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117952DOI Listing
June 2021

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs.

Hum Brain Mapp 2021 Feb 21. Epub 2021 Feb 21.

Center for Neuroimaging, Genetics and Genomics, School of Psychology, NUI Galway, Galway, Ireland.

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.
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http://dx.doi.org/10.1002/hbm.25354DOI Listing
February 2021

The natural axis of transmitter receptor distribution in the human cerebral cortex.

Proc Natl Acad Sci U S A 2021 01;118(3)

Institute of Computational Neuroscience, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Transmitter receptors constitute a key component of the molecular machinery for intercellular communication in the brain. Recent efforts have mapped the density of diverse transmitter receptors across the human cerebral cortex with an unprecedented level of detail. Here, we distill these observations into key organizational principles. We demonstrate that receptor densities form a natural axis in the human cerebral cortex, reflecting decreases in differentiation at the level of laminar organization and a sensory-to-association axis at the functional level. Along this natural axis, key organizational principles are discerned: progressive molecular diversity (increase of the diversity of receptor density); excitation/inhibition (increase of the ratio of excitatory-to-inhibitory receptor density); and mirrored, orderly changes of the density of ionotropic and metabotropic receptors. The uncovered natural axis formed by the distribution of receptors aligns with the axis that is formed by other dimensions of cortical organization, such as the myelo- and cytoarchitectonic levels. Therefore, the uncovered natural axis constitutes a unifying organizational feature linking multiple dimensions of the cerebral cortex, thus bringing order to the heterogeneity of cortical organization.
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http://dx.doi.org/10.1073/pnas.2020574118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826352PMC
January 2021

When your brain looks older than expected: combined lifestyle risk and BrainAGE.

Brain Struct Funct 2021 Apr 10;226(3):621-645. Epub 2021 Jan 10.

Institute for Anatomy I, Medical Faculty, Heinrich-Heine University Düsseldorf, Universitätstr. 1, 40225, Düsseldorf, Germany.

Lifestyle may be one source of unexplained variance in the great interindividual variability of the brain in age-related structural differences. While physical and social activity may protect against structural decline, other lifestyle behaviors may be accelerating factors. We examined whether riskier lifestyle correlates with accelerated brain aging using the BrainAGE score in 622 older adults from the 1000BRAINS cohort. Lifestyle was measured using a combined lifestyle risk score, composed of risk (smoking, alcohol intake) and protective variables (social integration and physical activity). We estimated individual BrainAGE from T1-weighted MRI data indicating accelerated brain atrophy by higher values. Then, the effect of combined lifestyle risk and individual lifestyle variables was regressed against BrainAGE. One unit increase in combined lifestyle risk predicted 5.04 months of additional BrainAGE. This prediction was driven by smoking (0.6 additional months of BrainAGE per pack-year) and physical activity (0.55 less months in BrainAGE per metabolic equivalent). Stratification by sex revealed a stronger association between physical activity and BrainAGE in males than females. Overall, our observations may be helpful with regard to lifestyle-related tailored prevention measures that slow changes in brain structure in older adults.
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http://dx.doi.org/10.1007/s00429-020-02184-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981332PMC
April 2021

Deep learning networks reflect cytoarchitectonic features used in brain mapping.

Sci Rep 2020 12 16;10(1):22039. Epub 2020 Dec 16.

Cécile and Oskar Vogt Institute of Brain Research, Univ. Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany.

The distribution of neurons in the cortex (cytoarchitecture) differs between cortical areas and constitutes the basis for structural maps of the human brain. Deep learning approaches provide a promising alternative to overcome throughput limitations of currently used cytoarchitectonic mapping methods, but typically lack insight as to what extent they follow cytoarchitectonic principles. We therefore investigated in how far the internal structure of deep convolutional neural networks trained for cytoarchitectonic brain mapping reflect traditional cytoarchitectonic features, and compared them to features of the current grey level index (GLI) profile approach. The networks consisted of a 10-block deep convolutional architecture trained to segment the primary and secondary visual cortex. Filter activations of the networks served to analyse resemblances to traditional cytoarchitectonic features and comparisons to the GLI profile approach. Our analysis revealed resemblances to cellular, laminar- as well as cortical area related cytoarchitectonic features. The networks learned filter activations that reflect the distinct cytoarchitecture of the segmented cortical areas with special regard to their laminar organization and compared well to statistical criteria of the GLI profile approach. These results confirm an incorporation of relevant cytoarchitectonic features in the deep convolutional neural networks and mark them as a valid support for high-throughput cytoarchitectonic mapping workflows.
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http://dx.doi.org/10.1038/s41598-020-78638-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744572PMC
December 2020

New boundaries and dissociation of the mouse hippocampus along the dorsal-ventral axis based on glutamatergic, GABAergic and catecholaminergic receptor densities.

Hippocampus 2021 Jan 28;31(1):56-78. Epub 2020 Sep 28.

C. & O. Vogt-Institute for Brain Research, Medical Faculty, University Clinic Düsseldof, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.

In rodents, gene-expression, neuronal tuning, connectivity and neurogenesis studies have postulated that the dorsal, the intermediate and the ventral hippocampal formation (HF) are distinct entities. These findings are underpinned by behavioral studies showing a dissociable role of dorsal and ventral HF in learning, memory, stress and emotional processing. However, up to now, the molecular basis of such differences in relation to discrete boundaries is largely unknown. Therefore, we analyzed binding site densities for glutamatergic AMPA, NMDA, kainate and mGluR , GABAergic GABA (including benzodiazepine binding sites), GABA , dopaminergic D and noradrenergic α and α receptors as key modulators for signal transmission in hippocampal functions, using quantitative in vitro receptor autoradiography along the dorsal-ventral axis of the mouse HF. Beside general different receptor profiles of the dentate gyrus (DG) and Cornu Ammonis fields (CA1, CA2, CA3, CA4/hilus), we detected substantial differences between dorsal, intermediate and ventral subdivisions and individual layers for all investigated receptor types, except GABA . For example, striking higher densities of α receptors were detected in the ventral DG, while the dorsal DG possesses higher numbers of kainate, NMDA, GABA and D receptors. CA1 dorsal and intermediate subdivisions showed higher AMPA, NMDA, mGluR , GABA , D receptors, while kainate receptors are higher expressed in ventral CA1, and noradrenergic α and α receptors in the intermediate region of CA1. CA2 dorsal was distinguished by higher kainate, α and α receptors in the intermediate region, while CA3 showed a more complex dissociation. Our findings resulted not only in a clear segmentation of the mouse hippocampus along the dorsal-ventral axis, but also provides insights into the neurochemical basis and likely associated physiological processes in hippocampal functions. Therein, the presented data has a high impact for future studies modeling and investigating dorsal, intermediate and ventral hippocampal dysfunction in relation to neurodegenerative diseases or psychiatric disorders.
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http://dx.doi.org/10.1002/hipo.23262DOI Listing
January 2021

A cortex-like canonical circuit in the avian forebrain.

Science 2020 09;369(6511)

Department of Biopsychology, Institute of Cognitive Neuroscience, Faculty of Psychology, Ruhr-University Bochum, 44801 Bochum, Germany.

Although the avian pallium seems to lack an organization akin to that of the cerebral cortex, birds exhibit extraordinary cognitive skills that are comparable to those of mammals. We analyzed the fiber architecture of the avian pallium with three-dimensional polarized light imaging and subsequently reconstructed local and associative pallial circuits with tracing techniques. We discovered an iteratively repeated, column-like neuronal circuitry across the layer-like nuclear boundaries of the hyperpallium and the sensory dorsal ventricular ridge. These circuits are connected to neighboring columns and, via tangential layer-like connections, to higher associative and motor areas. Our findings indicate that this avian canonical circuitry is similar to its mammalian counterpart and might constitute the structural basis of neuronal computation.
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http://dx.doi.org/10.1126/science.abc5534DOI Listing
September 2020

Hippocampus co-atrophy pattern in dementia deviates from covariance patterns across the lifespan.

Brain 2020 09;143(9):2788-2802

Institute of Neuroscience and Medicine (INM-1, INM-7), Research Centre Jülich, Jülich, Germany.

The hippocampus is a plastic region and highly susceptible to ageing and dementia. Previous studies explicitly imposed a priori models of hippocampus when investigating ageing and dementia-specific atrophy but led to inconsistent results. Consequently, the basic question of whether macrostructural changes follow a cytoarchitectonic or functional organization across the adult lifespan and in age-related neurodegenerative disease remained open. The aim of this cross-sectional study was to identify the spatial pattern of hippocampus differentiation based on structural covariance with a data-driven approach across structural MRI data of large cohorts (n = 2594). We examined the pattern of structural covariance of hippocampus voxels in young, middle-aged, elderly, mild cognitive impairment and dementia disease samples by applying a clustering algorithm revealing differentiation in structural covariance within the hippocampus. In all the healthy and in the mild cognitive impaired participants, the hippocampus was robustly divided into anterior, lateral and medial subregions reminiscent of cytoarchitectonic division. In contrast, in dementia patients, the pattern of subdivision was closer to known functional differentiation into an anterior, body and tail subregions. These results not only contribute to a better understanding of co-plasticity and co-atrophy in the hippocampus across the lifespan and in dementia, but also provide robust data-driven spatial representations (i.e. maps) for structural studies.
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http://dx.doi.org/10.1093/brain/awaa222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523701PMC
September 2020

Improving a probabilistic cytoarchitectonic atlas of auditory cortex using a novel method for inter-individual alignment.

Elife 2020 08 5;9. Epub 2020 Aug 5.

Department of Cognitive Neuroscience, Maastricht University, Maastricht, Netherlands.

The human superior temporal plane, the site of the auditory cortex, displays high inter-individual macro-anatomical variation. This questions the validity of curvature-based alignment (CBA) methods for in vivo imaging data. Here, we have addressed this issue by developing CBA+, which is a cortical surface registration method that uses prior macro-anatomical knowledge. We validate this method by using cytoarchitectonic areas on 10 individual brains (which we make publicly available). Compared to volumetric and standard surface registration, CBA+ results in a more accurate cytoarchitectonic auditory atlas. The improved correspondence of micro-anatomy following the improved alignment of macro-anatomy validates the superiority of CBA+ compared to CBA. In addition, we use CBA+ to align in vivo and postmortem data. This allows projection of functional and anatomical information collected in vivo onto the cytoarchitectonic areas, which has the potential to contribute to the ongoing debate on the parcellation of the human auditory cortex.
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http://dx.doi.org/10.7554/eLife.56963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406353PMC
August 2020

Julich-Brain: A 3D probabilistic atlas of the human brain's cytoarchitecture.

Science 2020 08 30;369(6506):988-992. Epub 2020 Jul 30.

Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany.

Cytoarchitecture is a basic principle of microstructural brain parcellation. We introduce Julich-Brain, a three-dimensional atlas containing cytoarchitectonic maps of cortical areas and subcortical nuclei. The atlas is probabilistic, which enables it to account for variations between individual brains. Building such an atlas was highly data- and labor-intensive and required the development of nested, interdependent workflows for detecting borders between brain areas, data processing, provenance tracking, and flexible execution of processing chains to handle large amounts of data at different spatial scales. Full cortical coverage was achieved by the inclusion of gap maps to complement cortical maps. The atlas is dynamic and will be adapted as mapping progresses; it is openly available to support neuroimaging studies as well as modeling and simulation; and it is interoperable, enabling connection to other atlases and resources.
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http://dx.doi.org/10.1126/science.abb4588DOI Listing
August 2020

Somatosensory area 3b is selectively unaffected in corticobasal syndrome: combining MRI and histology.

Neurobiol Aging 2020 10 21;94:89-100. Epub 2020 May 21.

Institute for Anatomy I, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany; Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany; JARA-BRAIN, Jülich-Aachen Research Alliance, Research Centre Jülich, Jülich, Germany. Electronic address:

An increasing number of neuroimaging studies addressing patients with corticobasal syndrome use macroscopic definitions of brain regions. As a closer link to functionally relevant units, we aimed at identifying magnetic resonance-based atrophy patterns in regions defined by probability maps of cortical microstructure. For this purpose, three analyses were conducted: (1) Whole-brain cortical thickness was compared between 36 patients with corticobasal syndrome and 24 controls. A pattern of pericentral atrophy was found, covering primary motor area 4, premotor area 6, and primary somatosensory areas 1, 2, and 3a. Within the central region, only area 3b was without atrophy. (2) In 18 patients, longitudinal measures with follow-ups of up to 59 months (mean 21.3 ± 15.4) were analyzed. Areas 1, 2, and 6 showed significantly faster atrophy rates than primary somatosensory area 3b. (3) In an individual autopsy case, longitudinal in vivo morphometry and postmortem pathohistology were conducted. The rate of magnetic resonance-based atrophy was significantly correlated with tufted-astrocyte load in those cytoarchitectonically defined regions also seen in the group study, with area 3b being selectively unaffected.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.05.009DOI Listing
October 2020

Four new cytoarchitectonic areas surrounding the primary and early auditory cortex in human brains.

Cortex 2020 07 14;128:1-21. Epub 2020 Mar 14.

Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany; C. & O. Vogt Institute for Brain Research, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; JARA-BRAIN, Jülich-Aachen Research Alliance, Jülich, Germany.

The architectonical organization of putatively higher auditory areas in the human superior temporal gyrus and sulcus is not yet well understood. To provide a coherent map of this part of the brain, which is involved in language and other functions, we examined the cytoarchitecture and cortical parcellation of this region in histological sections of ten human postmortem brains using an observer-independent mapping approach. Two new areas were identified in the temporo-insular region (areas TeI, TI). TeI is medially adjacent to the primary auditory cortex (area Te1). TI is located between TeI and the insular cortex. Laterally adjacent to previously mapped areas Te2 and Te3, two new areas (STS1, STS2) were identified in the superior temporal sulcus. All four areas were mapped over their whole extent in serial, cell-body stained sections, and their cytoarchitecture was analyzed using quantitative image analysis and multivariate statistics. Interestingly, area TeI, which is located between area Te1 and area TI at the transition to the insula, was more similar in cytoarchitecture to lateral area Te2.1 than to the directly adjacent areas TI and Te1. Such structural similarity of areas medially and laterally to Te1 would be in line with the core-belt-parabelt concept in macaques. The cytoarchitectonic probabilistic maps of all areas show the localization of the areas and their interindividual variability. The new maps are publicly available and provide a basis to further explore structural-functional relationship of the language network in the temporal cortex.
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http://dx.doi.org/10.1016/j.cortex.2020.02.021DOI Listing
July 2020

BigBrain 3D atlas of cortical layers: Cortical and laminar thickness gradients diverge in sensory and motor cortices.

PLoS Biol 2020 04 3;18(4):e3000678. Epub 2020 Apr 3.

McGill Centre for Integrative Neuroscience, Montréal Neurological Institute, Montréal, Canada.

Histological atlases of the cerebral cortex, such as those made famous by Brodmann and von Economo, are invaluable for understanding human brain microstructure and its relationship with functional organization in the brain. However, these existing atlases are limited to small numbers of manually annotated samples from a single cerebral hemisphere, measured from 2D histological sections. We present the first whole-brain quantitative 3D laminar atlas of the human cerebral cortex. It was derived from a 3D histological atlas of the human brain at 20-micrometer isotropic resolution (BigBrain), using a convolutional neural network to segment, automatically, the cortical layers in both hemispheres. Our approach overcomes many of the historical challenges with measurement of histological thickness in 2D, and the resultant laminar atlas provides an unprecedented level of precision and detail. We utilized this BigBrain cortical atlas to test whether previously reported thickness gradients, as measured by MRI in sensory and motor processing cortices, were present in a histological atlas of cortical thickness and which cortical layers were contributing to these gradients. Cortical thickness increased across sensory processing hierarchies, primarily driven by layers III, V, and VI. In contrast, motor-frontal cortices showed the opposite pattern, with decreases in total and pyramidal layer thickness from motor to frontal association cortices. These findings illustrate how this laminar atlas will provide a link between single-neuron morphology, mesoscale cortical layering, macroscopic cortical thickness, and, ultimately, functional neuroanatomy.
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http://dx.doi.org/10.1371/journal.pbio.3000678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159250PMC
April 2020

Functional network reorganization in older adults: Graph-theoretical analyses of age, cognition and sex.

Neuroimage 2020 07 19;214:116756. Epub 2020 Mar 19.

Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany; JARA-BRAIN, Jülich-Aachen Research Alliance, Jülich, Germany; Institute for Anatomy I, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. Electronic address:

Healthy aging has been associated with a decrease in functional network specialization. Importantly, variability of alterations of functional connectivity is especially high across older adults. Whole-brain functional network reorganization, though, and its impact on cognitive performance within particularly the older generation is still a matter of debate. We assessed resting state functional connectivity (RSFC) in 772 older adults (55-85 years, 421 males) using a graph-theoretical approach. Results show overall age-related increases of between- and decreases of within-network RSFC. With similar phenomena observed in young to middle-aged adults, i.e. that RSFC reorganizes towards more pronounced functional network integration, the current results amend such evidence for the old age. The results furthermore indicate that RSFC reorganization in older adults particularly pertain to early sensory networks (e.g. visual and sensorimotor network). Importantly, RSFC differences of these early sensory networks were found to be a relevant mediator in terms of the age-related cognitive performance differences. Further, we found systematic sex-related network differences with females showing patterns of more segregation (i.e. default mode and ventral attention network) and males showing a higher integrated network system (particularly for the sensorimotor network). These findings underpin the notion of sex-related connectivity differences, possibly facilitating sex-related behavioral functioning.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116756DOI Listing
July 2020

Cytoarchitectonic Characterization and Functional Decoding of Four New Areas in the Human Lateral Orbitofrontal Cortex.

Front Neuroanat 2020 5;14. Epub 2020 Feb 5.

Cécile and Oskar Vogt-Institute for Brain Research, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

A comprehensive concept of the biological basis of reward, social and emotional behavior, and language requires a deeper understanding of the microstructure and connectivity of the underlying brain regions. Such understanding could provide deeper insights into their role in functional networks, and form the anatomical basis of the functional segregation of this region as shown in recent imaging studies. Here, we investigated the cytoarchitecture of the lateral orbitofrontal cortex (lateral OFC) in serial histological sections of 10 human postmortem brains by image analysis and a statistically reproducible approach to detect borders between cortical areas. Profiles of the volume fraction of cell bodies were therefore extracted from digitized histological images, describing laminar changes from the layer I/layer II boundary to the white matter. As a result, four new areas, Fo4-7, were identified. Area Fo4 was mainly found in the anterior orbital gyrus (AOG), Fo5 anteriorly in the inferior frontal gyrus (IFG), Fo6 in the lateral orbital gyrus (LOG), and Fo7 in the lateral orbital sulcus. Areas differed in cortical thickness, abundance and size of pyramidal cells in layer III and degree of granularity in layer IV. A hierarchical cluster analysis was used to quantify cytoarchitectonic differences between them. The 3D-reconstructed areas were transformed into the single-subject template of the Montreal Neurological Institute (MNI), where probabilistic maps and a maximum probability map (MPM) were calculated as part of the JuBrain Cytoarchitectonic Atlas. These maps served as reference data to study the functional properties of the areas using the BrainMap database. The type of behavioral tasks that activated them was analyzed to get first insights of co-activation patterns of the lateral OFC and its contribution to cognitive networks. Meta-analytic connectivity modeling (MACM) showed that functional decoding revealed activation in gustatory perception in Fo4; reward and somesthetic perception in Fo5; semantic processing and pain perception in Fo6; and emotional processing and covert reading in Fo7. Together with existing maps of the JuBrain Cytoarchitectonic Atlas, the new maps can now be used as an open-source reference for neuroimaging studies, allowing to further decode brain function.
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http://dx.doi.org/10.3389/fnana.2020.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014920PMC
February 2020

Multimodal mapping and analysis of the cyto- and receptorarchitecture of the human hippocampus.

Brain Struct Funct 2020 Apr 18;225(3):881-907. Epub 2020 Jan 18.

Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, 52425, Jülich, Germany.

The human hippocampal formation is relevant for various aspects of memory and learning, and the different hippocampal regions are differentially affected by neuropsychiatric disorders. Therefore, the hippocampal formation has been subject of numerous cytoarchitectonic and other mapping studies, which resulted in divergent parcellation schemes. To understand the principles of hippocampal architecture, it is necessary to integrate different levels of hippocampal organisation, going beyond one modality. We here applied a multimodal mapping approach combining cyto- and multi-receptorarchitectonic analyses, and generated probabilistic maps in stereotaxic space of the identified regions. Cytoarchitecture in combination with the regional and laminar distribution of 15 neurotransmitter receptors visualized by in vitro receptor autoradiography were analysed in seven hemispheres from 6 unfixed shock frozen and serially sectioned brains. Cytoarchitectonic delineations for generation of probabilistic maps were carried out on histological sections from ten fixed, paraffin embedded and serially sectioned brains. Nine cyto- and receptorarchitectonically distinct regions were identified within the hippocampal formation (i.e., fascia dentata, cornu Ammonis (CA) regions 1-4, prosubiculum, subiculum proper, presubiculum and parasubiculum), as well as the hippocampal-amygdaloid transition area and the periallocortical transsubiculum. Subsequently generated probabilistic maps quantify intersubject variability in the size and extent of these cyto- and receptorarchitectonically distinct regions. The regions did not differ in their volume between the hemispheres and gender. Receptor mapping revealed additional subdivisions which could not be detected by cytoarchitectonic analysis alone. They correspond to parcellations previously found in immunohistochemical and connectivity studies. The multimodal approach enabled the definition of regions not consistently reported, e.g., CA4 region or prosubiculum. The ensuing detailed probabilistic maps of the hippocampal formation constitute the basis for future architectonically informed analyses of in vivo neuroimaging studies.
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http://dx.doi.org/10.1007/s00429-019-02022-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166210PMC
April 2020

Developmental Changes of Glutamate and GABA Receptor Densities in Wistar Rats.

Front Neuroanat 2019 20;13:100. Epub 2019 Dec 20.

Institute of Neuroscience and Medicine (INM-1), Jülich Research Centre, Jülich, Germany.

Neurotransmitters and their receptors are key molecules of signal transduction and subject to various changes during pre- and postnatal development. Previous studies addressed ontogeny at the level of neurotransmitters and expression of neurotransmitter receptor subunits. However, developmental changes in receptor densities to this day are not well understood. Here, we analyzed developmental changes in excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) receptors in adjacent sections of the rat brain by means of quantitative receptor autoradiography. Receptor densities of the ionotropic glutamatergic receptors α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) as well as of the ionotropic GABA and metabotropic GABA receptors were investigated using specific high-affinity ligands. For each receptor binding site, significant density differences were demonstrated in the investigated regions of interest [olfactory bulb, striatum, hippocampus, and cerebellum] and developmental stages [postnatal day (P) 0, 10, 20, 30 and 90]. In particular, we showed that the glutamatergic and GABAergic receptor densities were already present between P0 and P10 in all regions of interest, which may indicate the early relevance of these receptors for brain development. A transient increase of glutamatergic receptor densities in the hippocampus was found, indicating their possible involvement in synaptic plasticity. We demonstrated a decline of NMDA receptor densities in the striatum and hippocampus from P30 to P90, which could be due to synapse elimination, a process that redefines neuronal networks in postnatal brains. Furthermore, the highest increase in GABA receptor densities from P10 to P20 coincides with the developmental shift from excitatory to inhibitory GABA transmission. Moreover, the increase from P10 to P20 in GABA receptor densities in the cerebellum corresponds to a point in time when functional GABAergic synapses are formed. Taken together, the present data reveal differential changes in glutamate and GABA receptor densities during postnatal rat brain development, which may contribute to their specific functions during ontogenesis, thus providing a deeper understanding of brain ontogenesis and receptor function.
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http://dx.doi.org/10.3389/fnana.2019.00100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933313PMC
December 2019

Logical negation mapped onto the brain.

Brain Struct Funct 2020 Jan 4;225(1):19-31. Epub 2019 Nov 4.

Institute of Neuroscience and Medicine (INM-1), Forschungszentrum Jülich, Jülich, Germany.

High-level cognitive capacities that serve communication, reasoning, and calculation are essential for finding our way in the world. But whether and to what extent these complex behaviors share the same neuronal substrate are still unresolved questions. The present study separated the aspects of logic from language and numerosity-mental faculties whose distinctness has been debated for centuries-and identified a new cytoarchitectonic area as correlate for an operation involving logical negation. A novel experimental paradigm that was implemented here in an RT/fMRI study showed a single cluster of activity that pertains to logical negation. It was distinct from clusters that were activated by numerical comparison and from the traditional language regions. The localization of this cluster was described by a newly identified cytoarchitectonic area in the left anterior insula, ventro-medial to Broca's region. We provide evidence for the congruence between the histologically and functionally defined regions on multiple measures. Its position in the left anterior insula suggests that it functions as a mediator between language and reasoning areas.
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http://dx.doi.org/10.1007/s00429-019-01975-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957563PMC
January 2020

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.

JAMA Psychiatry 2020 04;77(4):420-430

Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam, Amsterdam, the Netherlands.

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.

Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.

Design, Setting, And Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.

Main Outcomes And Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.

Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.

Conclusions And Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.3779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822096PMC
April 2020

Pathway-Specific Genetic Risk for Alzheimer's Disease Differentiates Regional Patterns of Cortical Atrophy in Older Adults.

Cereb Cortex 2020 03;30(2):801-811

Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, D-52428 Jülich, Germany.

Brain aging is highly variable and represents a challenge to delimit aging from disease processes. Moreover, genetic factors may influence both aging and disease. Here we focused on this issue and investigated effects of multiple genetic loci previously identified to be associated with late-onset Alzheimer's disease (AD) on brain structure of older adults from a population sample. We calculated a genetic risk score (GRS) using genome-wide significant single-nucleotide polymorphisms from genome-wide association studies of AD and tested its effect on cortical thickness (CT). We observed a common pattern of cortical thinning (right inferior frontal, left posterior temporal, medial occipital cortex). To identify CT changes by specific biological processes, we subdivided the GRS effect according to AD-associated pathways and performed follow-up analyses. The common pattern from the main analysis was further differentiated by pathway-specific effects yielding a more bilateral pattern. Further findings were located in the superior parietal and mid/anterior cingulate regions representing 2 unique pathway-specific patterns. All patterns, except the superior parietal pattern, were influenced by apolipoprotein E. Our step-wise approach revealed atrophy patterns that partially resembled imaging findings in early stages of AD. Our study provides evidence that genetic burden for AD contributes to structural brain variability in normal aging.
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http://dx.doi.org/10.1093/cercor/bhz127DOI Listing
March 2020

FAConstructor: an interactive tool for geometric modeling of nerve fiber architectures in the brain.

Int J Comput Assist Radiol Surg 2019 Nov 11;14(11):1881-1889. Epub 2019 Aug 11.

Institute of Neuroscience and Medicine (INM-1), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany.

Purpose: The technique 3D polarized light imaging (3D-PLI) allows to reconstruct nerve fiber orientations of postmortem brains with ultra-high resolution. To better understand the physical principles behind 3D-PLI and improve the accuracy and reliability of the reconstructed fiber orientations, numerical simulations are employed which use synthetic nerve fiber models as input. As the generation of fiber models can be challenging and very time-consuming, we have developed the open source FAConstructor tool which enables a fast and efficient generation of synthetic fiber models for 3D-PLI simulations.

Methods: The program was developed as an interactive tool, allowing the user to define fiber pathways with interpolation methods or parametric functions and providing visual feedback.

Results: Performance tests showed that most processes scale almost linearly with the amount of fiber points in FAConstructor. Fiber models consisting of < 1.6 million data points retain a frame rate of more than 30 frames per second, which guarantees a stable and fluent workflow. The applicability of FAConstructor was demonstrated on a well-defined fiber model (Fiber Cup phantom) for two different simulation approaches, reproducing effects known from 3D-PLI measurements.

Conclusion: We have implemented a user-friendly and efficient tool that enables an interactive and fast generation of synthetic nerve fiber configurations for 3D-PLI simulations. Already existing fiber models can easily be modified, allowing to simulate many different fiber models in a reasonable amount of time.
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http://dx.doi.org/10.1007/s11548-019-02053-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851223PMC
November 2019

Bilingualism and "brain reserve": a matter of age.

Neurobiol Aging 2019 09 5;81:157-165. Epub 2019 Jun 5.

Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany; C. & O. Vogt Institute for Brain Research, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany; JARA-BRAIN, Jülich-Aachen Research Alliance, Jülich, Germany.

There is a lively debate whether bilingualism as a state of permanent cognitive control contributes to so-called brain reserve, thus delaying the onset of symptoms associated with neurodegeneration by up to 5 years. Here, we address this question in a large-scale (n = 399) population-based study. We compared the gray matter volume of monolinguals versus bilinguals in the left inferior frontal gyrus and inferior parietal lobule cortex and its modulation by biological age. Three core findings emerged: (1) Brain volume was systematically higher in bilinguals than monolinguals. (2) This difference disappeared at higher ages, and the slope of decline was steeper for bilinguals than monolinguals. (3) The volume difference between age groups disappeared in the inferior frontal gyrus at earlier ages than in the inferior parietal lobule. Thus, bilingualism might indeed contribute to brain reserve in older age, with posterior regions showing a particular resilience to atrophy and thus less necessity for functions to shift to anterior control regions.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.05.021DOI Listing
September 2019

The Human Brain Project-Synergy between neuroscience, computing, informatics, and brain-inspired technologies.

PLoS Biol 2019 07 1;17(7):e3000344. Epub 2019 Jul 1.

Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.

The Human Brain Project (HBP) is a European flagship project with a 10-year horizon aiming to understand the human brain and to translate neuroscience knowledge into medicine and technology. To achieve such aims, the HBP explores the multilevel complexity of the brain in space and time; transfers the acquired knowledge to brain-derived applications in health, computing, and technology; and provides shared and open computing tools and data through the HBP European brain research infrastructure. We discuss how the HBP creates a transdisciplinary community of researchers united by the quest to understand the brain, with fascinating perspectives on societal benefits.
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http://dx.doi.org/10.1371/journal.pbio.3000344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625714PMC
July 2019

Progress update from the hippocampal subfields group.

Alzheimers Dement (Amst) 2019 Dec 13;11:439-449. Epub 2019 Jun 13.

Department of Psychology, Florida State University, Tallahassee, FL, USA.

Introduction: Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence.

Methods: Our international working group, funded by the EU Joint Programme-Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel data set and online consensus procedures to ensure validity and facilitate adoption.

Results: This progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures.

Discussion: A harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide.
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http://dx.doi.org/10.1016/j.dadm.2019.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581847PMC
December 2019

Publisher Correction: Diattenuation Imaging reveals different brain tissue properties.

Sci Rep 2019 Apr 19;9(1):6521. Epub 2019 Apr 19.

Department of Physics, RWTH Aachen University, 52056, Aachen, Germany.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-019-42189-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473000PMC
April 2019