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Background: Psychiatric conditions show overlap in their symptoms, genetics, and involvement in brain areas and circuits. Structural alterations in the brain have been found to run in parallel with expression profiles of risk genes at the level of the brain transcriptome, which may point toward a potential transdiagnostic vulnerability of the brain to disease processes., Methods: We characterized the transcriptomic vulnerability of the cortex across 4 major psychiatric disorders based on collated data from patients with psychiatric disorders (n = 390) and matched control participants (n = 293). We compared normative expression profiles of risk genes linked to schizophrenia, bipolar disorder, autism spectrum disorder, and major depressive disorder to examine cross-disorder overlap in spatial expression profiles across the cortex and their concordance with a magnetic resonance imaging-derived cross-disorder profile of structural brain alterations., Results: We showed high expression of psychiatric risk genes converging on multimodal cortical regions of the limbic, ventral attention, and default mode networks versus primary somatosensory networks. Risk genes were found to be enriched among genes associated with the magnetic resonance imaging cross-disorder profile, suggestive of a common link between brain anatomy and the transcriptome in psychiatric conditions. Characterization of this cross-disorder structural alteration map further shows enrichment for gene markers of astrocytes, microglia, and supragranular cortical layers., Conclusions: Our findings suggest that normative expression profiles of disorder risk genes confer a shared and spatially patterned vulnerability of the cortex across multiple psychiatric conditions. Transdiagnostic overlap in transcriptomic risk suggests a common pathway to brain dysfunction across psychiatric disorders., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

A long-standing topic of interest in human neurosciences is the understanding of the neurobiology underlying human cognition. Less commonly considered is to what extent such systems may be shared with other species. We examined individual variation in brain connectivity in the context of cognitive abilities in chimpanzees ( n = 45) and humans in search of a conserved link between cognition and brain connectivity across the two species. Cognitive scores were assessed on a variety of behavioral tasks using chimpanzee- and human-specific cognitive test batteries, measuring aspects of cognition related to relational reasoning, processing speed, and problem solving in both species. We show that chimpanzees scoring higher on such cognitive skills display relatively strong connectivity among brain networks also associated with comparable cognitive abilities in the human group. We also identified divergence in brain networks that serve specialized functions across humans and chimpanzees, such as stronger language connectivity in humans and relatively more prominent connectivity between regions related to spatial working memory in chimpanzees. Our findings suggest that core neural systems of cognition may have evolved before the divergence of chimpanzees and humans, along with potential differential investments in other brain networks relating to specific functional specializations between the two species.

Brains come in many shapes and sizes. Nature has endowed big-brained primate species like humans with a proportionally large cerebral cortex. Comparative studies have suggested, however, that the total volume allocated to white matter connectivity-the brain's infrastructure for long-range interregional communication-does not keep pace with the cortex. We investigated the consequences of this allometric scaling on brain connectivity and network organization. We collated structural and diffusion magnetic resonance imaging data across 14 primate species, describing a comprehensive 350-fold range in brain size across species. We show volumetric scaling relationships that indeed point toward a restriction of macroscale connectivity in bigger brains. We report cortical surface area to outpace white matter volume, with larger brains showing lower levels of overall connectedness particularly through sparser long-range connectivity. We show that these constraints on white matter connectivity are associated with longer communication paths, higher local network clustering, and higher levels of asymmetry in connectivity patterns between homologous areas across the left and right hemispheres. Our findings reveal conserved scaling relationships of major brain components and show consequences for macroscale brain circuitry, providing insights into the connectome architecture that could be expected in larger brains such as the human brain., (© The Author(s) 2021. Published by Oxford University Press.)

In utero brain development underpins brain health across the lifespan but is vulnerable to physiological and pharmacological perturbation. Here, we show that antiepileptic medication during pregnancy impacts on cortical activity during neonatal sleep, a potent indicator of newborn brain health. These effects are evident in frequency-specific functional brain networks and carry prognostic information for later neurodevelopment. Notably, such effects differ between different antiepileptic drugs that suggest neurodevelopmental adversity from exposure to antiepileptic drugs and not maternal epilepsy per se. This work provides translatable bedside metrics of brain health that are sensitive to the effects of antiepileptic drugs on postnatal neurodevelopment and carry direct prognostic value., (© The Author(s) 2021. Published by Oxford University Press.)

The brain requires efficient information transfer between neurons and large-scale brain regions. Brain connectivity follows predictable organizational principles. At the cellular level, larger supragranular pyramidal neurons have larger, more branched dendritic trees, more synapses, and perform more complex computations; at the macroscale, region-to-region connections display a diverse architecture with highly connected hub areas facilitating complex information integration and computation. Here, we explore the hypothesis that the branching structure of large-scale region-to-region connectivity follows similar organizational principles as the neuronal scale. We examine microscale connectivity of basal dendritic trees of supragranular pyramidal neurons (300+) across 10 cortical areas in five human donor brains (1 male, 4 female). Dendritic complexity was quantified as the number of branch points, tree length, spine count, spine density, and overall branching complexity. High-resolution diffusion-weighted MRI was used to construct white matter trees of corticocortical wiring. Examining complexity of the resulting white matter trees using the same measures as for dendritic trees shows heteromodal association areas to have larger, more complex white matter trees than primary areas ( p < 0.0001) and macroscale complexity to run in parallel with microscale measures, in terms of number of inputs ( r = 0.677, p = 0.032), branch points ( r = 0.797, p = 0.006), tree length ( r = 0.664, p = 0.036), and branching complexity ( r = 0.724, p = 0.018). Our findings support the integrative theory that brain connectivity follows similar principles of connectivity at neuronal and macroscale levels and provide a framework to study connectivity changes in brain conditions at multiple levels of organization. SIGNIFICANCE STATEMENT Within the human brain, cortical areas are involved in a wide range of processes, requiring different levels of information integration and local computation. At the cellular level, these regional differences reflect a predictable organizational principle with larger, more complexly branched supragranular pyramidal neurons in higher order regions. We hypothesized that the 3D branching structure of macroscale corticocortical connections follows the same organizational principles as the cellular scale. Comparing branching complexity of dendritic trees of supragranular pyramidal neurons and of MRI-based regional white matter trees of macroscale connectivity, we show that macroscale branching complexity is larger in higher order areas and that microscale and macroscale complexity go hand in hand. Our findings contribute to a multiscale integrative theory of brain connectivity., (Copyright © 2022 the authors.)

Post-mortem magnetic resonance imaging (MRI) provides the opportunity to acquire high-resolution datasets to investigate neuroanatomy and validate the origins of image contrast through microscopy comparisons. We introduce the Digital Brain Bank (open.win.ox.ac.uk/DigitalBrainBank), a data release platform providing open access to curated, multimodal post-mortem neuroimaging datasets. Datasets span three themes -Digital Neuroanatomist : datasets for detailed neuroanatomical investigations; Digital Brain Zoo : datasets for comparative neuroanatomy; and Digital Pathologist : datasets for neuropathology investigations. The first Digital Brain Bank data release includes 21 distinctive whole-brain diffusion MRI datasets for structural connectivity investigations, alongside microscopy and complementary MRI modalities. This includes one of the highest-resolution whole-brain human diffusion MRI datasets ever acquired, whole-brain diffusion MRI in fourteen nonhuman primate species, and one of the largest post-mortem whole-brain cohort imaging studies in neurodegeneration. The Digital Brain Bank is the culmination of our lab's investment into post-mortem MRI methodology and MRI-microscopy analysis techniques. This manuscript provides a detailed overview of our work with post-mortem imaging to date, including the development of diffusion MRI methods to image large post-mortem samples, including whole, human brains. Taken together, the Digital Brain Bank provides cross-scale, cross-species datasets facilitating the incorporation of post-mortem data into neuroimaging studies., Competing Interests: BT, TH, OA, SB, GB, MB, KB, SF, Mv, AH, IH, AK, AL, PM, RM, JM, DM, MP, LR, JS, LS, CS, AS, MT, CW, RM No competing interests declared, SJ, KM Reviewing editor, eLife, (© 2022, Tendler et al.)

Multiscale integration of gene transcriptomic and neuroimaging data is becoming a widely used approach for exploring the molecular underpinnings of large-scale brain organization in health and disease. Proper statistical evaluation of determined associations between imaging-based phenotypic and transcriptomic data is key in these explorations, in particular to establish whether observed associations exceed "chance level" of random, nonspecific effects. Recent approaches have shown the importance of statistical models that can correct for spatial autocorrelation effects in the data to avoid inflation of reported statistics. Here, we discuss the need for examination of a second category of statistical models in transcriptomic-neuroimaging analyses, namely those that can provide "gene specificity." By means of a couple of simple examples of commonly performed transcriptomic-neuroimaging analyses, we illustrate some of the potentials and challenges of transcriptomic-imaging analyses, showing that providing gene specificity on observed transcriptomic-neuroimaging effects is of high importance to avoid reports of nonspecific effects. Through means of simulations we show that the rate of reported nonspecific effects (i.e., effects that cannot be specifically linked to a specific gene or gene-set) can run as high as 60%, with only less than 5% of transcriptomic-neuroimaging associations observed through ordinary linear regression analyses showing both spatial and gene specificity. We provide a discussion, a tutorial, and an easy-to-use toolbox for the different options of null models in transcriptomic-neuroimaging analyses., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Large-scale comparative neuroscience requires data from many species and, ideally, at multiple levels of description. Here, we contribute to this endeavor by presenting diffusion and structural MRI data from eight primate species that have not or rarely been described in the literature. The selected samples from the Primate Brain Bank cover a prosimian, New and Old World monkeys, and a great ape. We present preliminary labelling of the cortical sulci and tractography of the optic radiation, dorsal part of the cingulum bundle, and dorsal parietal-frontal and ventral temporal-frontal longitudinal white matter tracts. Both dorsal and ventral association fiber systems could be observed in all samples, with the dorsal tracts occupying much less relative volume in the prosimian than in other species. We discuss the results in the context of known primate specializations and present hypotheses for further research. All data and results presented here are available online as a resource for the scientific community., (© 2021. The Author(s).)

The parcellation of the brain's cortical surface into anatomically and/or functionally distinct areas is a topic of ongoing investigation and interest. We provide digital versions of six classical human brain atlases in common MRI space. The cortical atlases represent a range of modalities, including cyto- and myeloarchitecture (Campbell, Smith, Brodmann and Von Economo), myelogenesis (Flechsig), and mappings of symptomatic information in relation to the spatial location of brain lesions (Kleist). Digital reconstructions of these important cortical atlases widen the range of modalities for which cortex-wide imaging atlases are currently available and offer the opportunity to compare and combine microstructural and lesion-based functional atlases with in-vivo imaging-based atlases., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

In recent years, replicability of neuroscientific findings, specifically those concerning correlates of morphological properties of gray matter (GM), have been subject of major scrutiny. Use of different processing pipelines and differences in their estimates of the macroscale GM may play an important role in this context. To address this issue, here, we investigated the cortical thickness estimates of three widely used pipelines. Based on analyses in two independent large-scale cohorts, we report high levels of within-pipeline reliability of the absolute cortical thickness-estimates and comparable spatial patterns of cortical thickness-estimates across all pipelines. Within each individual, absolute regional thickness differed between pipelines, indicating that in-vivo thickness measurements are only a proxy of actual thickness of the cortex, which shall only be compared within the same software package and thickness estimation technique. However, at group level, cortical thickness-estimates correlated strongly between pipelines, in most brain regions. The smallest between-pipeline correlations were observed in para-limbic areas and insula. These regions also demonstrated the highest interindividual variability and the lowest reliability of cortical thickness-estimates within each pipeline, suggesting that structural variations within these regions should be interpreted with caution., (© The Author(s) 2020. Published by Oxford University Press.)

Degree centrality is a widely used measure in complex networks. Within the brain, degree relates to other topological features, with high-degree nodes (i.e., hubs) exhibiting high betweenness centrality, participation coefficient, and within-module z-score. However, increasing evidence from neuroanatomical and predictive processing literature suggests that topological properties of a brain network may also be impacted by topography, that is, anatomical (spatial) distribution. More specifically, cortical limbic areas (agranular and dysgranular cortices), which occupy an anatomically central position, have been proposed to be topologically central and well suited to initiate predictions in the cerebral cortex. We estimated anatomical centrality and showed that it positively correlated with betweenness centrality, participation coefficient, and communicability, analogously to degree. In contrast to degree, however, anatomical centrality negatively correlated with within-module z-score. Our data suggest that degree centrality and anatomical centrality reflect distinct contributions to cortical organization. Whereas degree would be more related to the amount of information integration performed by an area, anatomical centrality would be more related to an area's position in the predictive hierarchy. Highly anatomically central areas may function as "high-level connectors," integrating already highly integrated information across modules. These results are consistent with a high-level, domain-general limbic workspace, integrated by highly anatomically central cortical areas., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Functional connectivity is defined as the statistical dependency of neurophysiological activity between 2 separate brain areas. To investigate the biological characteristics of resting-state functional connectivity (rsFC)-and in particular the significance of connection-wise variation in time-series correlations-rsFC was compared with strychnine-based connectivity measured in the macaque. Strychnine neuronography is a historical technique that induces activity in cortical areas through means of local administration of the substance strychnine. Strychnine causes local disinhibition through GABA suppression and leads to subsequent activation of functional pathways. Multiple resting-state fMRI recordings were acquired in 4 macaques (examining in total 299 imaging runs) from which a group-averaged rsFC matrix was constructed. rsFC was observed to be higher (P < 0.0001) between region-pairs with a strychnine-based connection as compared with region-pairs with no strychnine-based connection present. In particular, higher resting-state connectivity was observed in connections that were relatively stronger (weak < moderate < strong; P < 0.01) and in connections that were bidirectional (P < 0.0001) instead of unidirectional in strychnine-based connectivity. Our results imply that the level of correlation between brain areas as extracted from resting-state fMRI relates to the strength of underlying interregional functional pathways., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The genetic basis and human-specific character of schizophrenia has led to the hypothesis that human brain evolution may have played a role in the development of the disorder. We examined schizophrenia-related changes in brain connectivity in the context of evolutionary changes in human brain wiring by comparing in vivo neuroimaging data from humans and chimpanzees, one of our closest living evolutionary relatives and a species with which we share a very recent common ancestor. We contrasted the connectome layout between the chimpanzee and human brain and compared differences with the pattern of schizophrenia-related changes in brain connectivity as observed in patients. We show evidence of evolutionary modifications of human brain connectivity to significantly overlap with the cortical pattern of schizophrenia-related dysconnectivity (P < 0.001, permutation testing). We validated these effects in three additional, independent schizophrenia datasets. We further assessed the specificity of effects by examining brain dysconnectivity patterns in seven other psychiatric and neurological brain disorders (including, among others, major depressive disorder and obsessive-compulsive disorder, arguably characterized by behavioural symptoms that are less specific to humans), which showed no such associations with modifications of human brain connectivity. Comparisons of brain connectivity across humans, chimpanzee and macaques further suggest that features of connectivity that evolved in the human lineage showed the strongest association to the disorder, that is, brain circuits potentially related to human evolutionary specializations. Taken together, our findings suggest that human-specific features of connectome organization may be enriched for changes in brain connectivity related to schizophrenia. Modifications in human brain connectivity in service of higher order brain functions may have potentially also rendered the brain vulnerable to brain dysfunction., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Cognitive brain networks such as the default-mode network (DMN), frontoparietal network, and salience network, are key functional networks of the human brain. Here we show that the rapid evolutionary cortical expansion of cognitive networks in the human brain, and most pronounced the DMN, runs parallel with high expression of human-accelerated genes (HAR genes). Using comparative transcriptomics analysis, we present that HAR genes are differentially more expressed in higher-order cognitive networks in humans compared to chimpanzees and macaques and that genes with high expression in the DMN are involved in synapse and dendrite formation. Moreover, HAR and DMN genes show significant associations with individual variations in DMN functional activity, intelligence, sociability, and mental conditions such as schizophrenia and autism. Our results suggest that the expansion of higher-order functional networks subserving increasing cognitive properties has been an important locus of genetic changes in recent human brain evolution.

The human brain comprises a multiscale network with multiple levels of organization. Neurons with dendritic and axonal connections form the microscale fabric of brain circuitry, and macroscale brain regions and white matter connections form the infrastructure for system-level brain communication and information integration. In this review, we discuss the emerging trend of multiscale neuroscience, the multidisciplinary field that brings together data from these different levels of nervous system organization to form a better understanding of between-scale relationships of brain structure, function, and behavior in health and disease. We provide a broad overview of this developing field and discuss recent findings of exemplary multiscale neuroscience studies that illustrate the importance of studying cross-scale interactions among the genetic, molecular, cellular, and macroscale levels of brain circuitry and connectivity and behavior. We particularly consider a central, overarching goal of these multiscale neuroscience studies of human brain connectivity: to obtain insight into how disease-related alterations at one level of organization may underlie alterations observed at other scales of brain network organization in mental disorders. We conclude by discussing the current limitations, challenges, and future directions of the field., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.

The development of complex cognitive functions during human evolution coincides with pronounced encephalization and expansion of white matter, the brain's infrastructure for region-to-region communication. We investigated adaptations of the human macroscale brain network by comparing human brain wiring with that of the chimpanzee, one of our closest living primate relatives. White matter connectivity networks were reconstructed using diffusion-weighted MRI in humans ( n = 57) and chimpanzees ( n = 20) and then analyzed using network neuroscience tools. We demonstrate higher network centrality of connections linking multimodal association areas in humans compared with chimpanzees, together with a more pronounced modular topology of the human connectome. Furthermore, connections observed in humans but not in chimpanzees particularly link multimodal areas of the temporal, lateral parietal, and inferior frontal cortices, including tracts important for language processing. Network analysis demonstrates a particularly high contribution of these connections to global network integration in the human brain. Taken together, our comparative connectome findings suggest an evolutionary shift in the human brain toward investment of neural resources in multimodal connectivity facilitating neural integration, combined with an increase in language-related connectivity supporting functional specialization., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

The connectome describes the comprehensive set of neuronal connections of a species' central nervous system. Identifying the network characteristics of the human macroscale connectome and comparing these features with connectomes of other species provides insight into the evolution of human brain connectivity and its role in brain function. Several network properties of the human connectome are conserved across species, with emerging evidence also indicating potential human-specific adaptations of connectome topology. This review describes the human macroscale structural and functional connectome, focusing on common themes of brain wiring in the animal kingdom and network adaptations that may underlie human brain function. Evidence is drawn from comparative studies across a wide range of animal species, and from research comparing human brain wiring with that of non-human primates. Approaching the human connectome from a comparative perspective paves the way for network-level insights into the evolution of human brain structure and function., (© 2019 Elsevier B.V. All rights reserved.)

The mammalian brain describes a multiscale system. At the microscale, axonal, dendritic, and synaptic elements ensure neuron-to-neuron communication, and at the macroscale, large-scale projections form the anatomical wiring for communication between cortical areas. Although it is clear that both levels of neural organization play a crucial role in brain functioning, their interaction is not extensively studied. Connectome studies of the mammalian brain in cat, macaque, and human have recently shown that regions with larger and more complex pyramidal cells to have more macroscale corticocortical connections. In this study, we aimed to further validate these cross-scale findings in the human, mouse, and rat brain. We combined neuron reconstructions from the NeuroMorpho.org neuroarchitecture database with macroscale connectivity data derived from connectome mapping by means of tract-tracing (rat, mouse) and in vivo diffusion magnetic resonance imaging (human). Across these three mammalian species, we show cortical variation in neural organization to be associated with features of macroscale connectivity, with cortical variation in neuronal complexity explaining significant proportions of cortical variation in the number of white matter projections of cortical areas. Our findings converge on the notion of a relationship between features of micro- and macroscale neural connectivity to form a central aspect of mammalian neural architecture.

The human brain comprises an efficient communication network, with its macroscale connectome organization argued to be directly associated with the underlying microscale organization of the cortex. Here, we further examine this link in the human brain cortex by using the ultrahigh-resolution BigBrain dataset; 11,660 BigBrain profiles of laminar cell structure were extracted from the BigBrain data and mapped to the MRI based Desikan-Killiany atlas used for macroscale connectome reconstruction. Macroscale brain connectivity was reconstructed based on the diffusion-weighted imaging dataset from the Human Connectome Project and cross-correlated to the similarity of laminar profiles. We showed that the BigBrain profile similarity between interconnected cortical regions was significantly higher than those between nonconnected regions. The pattern of BigBrain profile similarity across the entire cortex was also found to be strongly correlated with the pattern of cortico-cortical connectivity at the macroscale. Our findings suggest that cortical regions with higher similarity in the laminar cytoarchitectonic patterns have a higher chance of being connected, extending the evidence for the linkage between macroscale connectome organization and microscale cytoarchitecture., Competing Interests: Competing Interests: The authors have declared that no competing interests exist.

The human brain is a highly complex system, with a large variety of microscale cellular morphologies and macroscale global properties. Working at multiple scales, it forms an efficient system for processing and integration of multimodal information. Studies have repeatedly demonstrated strong associations between modalities of both microscales and macroscales of brain organization. These consistent observations point toward potential common organization principles where regions with a microscale architecture supportive of a larger computational load have more and stronger connections in the brain network on the macroscale. Conversely, disruptions observed on one organizational scale could modulate the other. First neuropsychiatric micro-macro comparisons in, among other conditions, Alzheimer's disease and schizophrenia, have, for example, shown overlapping alterations across both scales. We give an overview of recent findings on associations between microscale and macroscale organization observed in the healthy brain, followed by a summary of microscale and macroscale findings reported in the context of brain disorders. We conclude with suggestions for future multiscale connectome comparisons linking multiple scales and modalities of organization and suggest how such comparisons could contribute to a more complete fundamental understanding of brain organization and associated disease-related alterations., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The cerebral cortex displays substantial variation in cellular architecture, a regional patterning that has been of great interest to anatomists for centuries. In 1925, Constantin von Economo and George Koskinas published a detailed atlas of the human cerebral cortex, describing a cytoarchitectonic division of the cortical mantle into over 40 distinct areas. Von Economo and Koskinas accompanied their seminal work with large photomicrographic plates of their histological slides, together with tables containing for each described region detailed morphological layer-specific information on neuronal count, neuron size and thickness of the cortical mantle. Here, we aimed to make this legacy data accessible and relatable to in vivo neuroimaging data by constructing a digital Von Economo - Koskinas atlas compatible with the widely used FreeSurfer software suite. In this technical note we describe the procedures used for manual segmentation of the Von Economo - Koskinas atlas onto individual T1 scans and the subsequent construction of the digital atlas. We provide the files needed to run the atlas on new FreeSurfer data, together with some simple code of how to apply the atlas to T1 scans within the FreeSurfer software suite. The digital Von Economo - Koskinas atlas is easily applicable to modern day anatomical MRI data and is made publicly available online., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Emerging evidence suggests disruptions in the wiring organization of the brain's network in schizophrenia (SZ) and bipolar disorder (BD). As the importance of genetic predisposition has been firmly established in these illnesses, children (offspring) of patients constitute an at-risk population. This study examines connectome organization in children at familial high risk for psychosis., Methods: Diffusion-weighted magnetic resonance imaging scans were collected from 127 nonpsychotic offspring 8 to 18 years of age (average age = 13.5 years) of a parent diagnosed with SZ (SZ offspring; n = 28) or BD (BD offspring; N = 60) and community control subjects (n = 39). Resting-state functional magnetic resonance imaging scans were available for 82 subjects. Anatomical and functional brain networks were reconstructed and examined using graph theoretical analysis., Results: SZ offspring were found to show connectivity deficits of the brain's central rich club (RC) system relative to both control subjects and BD offspring. The disruption in anatomical RC connectivity in SZ offspring was associated with increased modularity of the functional connectome. In addition, increased coupling between structural and functional connectivity of long-distance connections was observed in both SZ offspring and BD offspring., Conclusions: This study shows lower levels of anatomical RC connectivity in nonpsychotic young offspring of SZ patients. This finding suggests that the brain's anatomical RC system is affected in at-risk youths, reflecting a connectome signature of familial risk for psychotic illness. Moreover, finding no RC deficits in offspring of BD patients suggest a differential effect of genetic predisposition for SZ versus BD on the developmental formation of the connectome., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Auditory verbal hallucinations (AVH) are a cardinal feature of schizophrenia that has been associated with activation in language processing areas, in concert with higher-order cognitive brain networks. It remains to be determined whether, and if so how, the functional dynamics between these brain regions contributes to the emergence of AVH. The current study recruited 36 first-episode medication-naïve schizophrenia patients, including 18 patients with AVH, 18 patients free of AVH and 18 controls matched on age, gender and level of education. Resting-state functional MRI images were acquired for every subject and used to map functional brain connectivity. We compared functional connectivity in 18 bilateral regions of interest implicated by previous AVH studies among the three subject groups, with the aim of detecting patterns of dysconnectivity unique to or most pronounced in AVH patients. Results showed that AVH patients are characterized by dysconnectivity in neural circuitry involving the anterior cingulate cortex, insular cortex and language-related regions, comparing with both controls and non-AVH patients. Current findings suggest that abnormality in speech-sensitive areas and their functional cooperation with cortical regions involving in source monitoring and salience detection functions may contribute to the occurrence of AVH., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: To investigate the association between white matter organization in the neonatal brain and cognitive capacities at early school age in children born very preterm., Method: Thirty children born very preterm (gestational age median 27.5wks, interquartile range [IQR] 25.5-29.5; 18 males, 12 females) were included in this retrospective observational cohort study. Diffusion-weighted imaging (DWI) had been performed on a 3T system in the neonatal period (median 41.3 [IQR 40.0-42.6]wks) and cognitive functioning was formally assessed at age 5 years and 7 months (IQR 5.4-5.9y) using the Wechsler Preschool and Primary Scale of Intelligence. Structural connectivity maps were reconstructed from the DWI data using deterministic streamline tractography. Network metrics of global and local communication and mean fractional anisotropy of white matter pathways were related to IQ and processing speed at age 5 years using linear regression analyses., Results: Mean fractional anisotropy was significantly related to Performance IQ at age 5 years (F=8.48, p=0.007). Findings persisted after adjustment for maternal education level., Interpretation: Our findings provide evidence that the blueprint of later cognitive achievement is already present at term-equivalent age and suggest that white matter connectivity strength may be a valuable predictor for long-term cognitive functioning., (© 2017 Mac Keith Press.)

The cerebral cortex is well known to display a large variation in excitatory and inhibitory chemoarchitecture, but the effect of this variation on global scale functional neural communication and synchronization patterns remains less well understood. Here, we provide evidence of the chemoarchitecture of cortical regions to be associated with large-scale region-to-region resting-state functional connectivity. We assessed the excitatory versus inhibitory chemoarchitecture of cortical areas as an ExIn ratio between receptor density mappings of excitatory (AMPA, M1 ) and inhibitory (GABAA , M2 ) receptors, computed on the basis of data collated from pioneering studies of autoradiography mappings as present in literature of the human (2 datasets) and macaque (1 dataset) cortex. Cortical variation in ExIn ratio significantly correlated with total level of functional connectivity as derived from resting-state functional connectivity recordings of cortical areas across all three datasets (human I: P = 0.0004; human II: P = 0.0008; macaque: P = 0.0007), suggesting cortical areas with an overall more excitatory character to show higher levels of intrinsic functional connectivity during resting-state. Our findings are indicative of the microscale chemoarchitecture of cortical regions to be related to resting-state fMRI connectivity patterns at the global system's level of connectome organization. Hum Brain Mapp 37:3103-3113, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.)

Background: Schizophrenia is often described as a disorder of dysconnectivity, with disruptions in neural connectivity reported on the cellular microscale as well as the global macroscale level of brain organization. How these effects on these two scales are related is poorly understood., Methods: First (part I of this study), we collated data on layer 3 pyramidal spine density of the healthy brain from the literature and cross-analyzed these data with new data on macroscale connectivity as derived from diffusion imaging. Second (part II of this study), we examined how alterations in regional spine density in schizophrenia are related to changes in white matter connectivity. Data on group differences in spine density were collated from histology reports in the literature and examined in a meta-regression analysis in context of alterations in macroscale white matter connectivity as derived from diffusion imaging data of a (separately acquired) group of 61 patients and 55 matched control subjects., Results: Densely connected areas of the healthy human cortex were shown to overlap with areas that display high pyramidal complexity, with pyramidal neurons that are more spinous (p = .0027) compared with pyramidal neurons in areas of low macroscale connectivity. Cross-scale meta-regression analysis showed a significant association between regional variation in level of disease-related spine density reduction in schizophrenia and regional level of decrease in macroscale connectivity (two data sets examined, p = .0028 and p = .0011)., Conclusions: Our study presents evidence that regional disruptions in microscale neuronal connectivity in schizophrenia go hand in hand with changes in macroscale brain connectivity., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The mammalian cortex is a complex system of-at the microscale level-interconnected neurons and-at the macroscale level-interconnected areas, forming the infrastructure for local and global neural processing and information integration. While the effects of regional chemoarchitecture on local cortical activity are well known, the effect of local neurotransmitter receptor organization on the emergence of large scale region-to-region functional interactions remains poorly understood. Here, we examined reports of effective functional connectivity-as measured by the action of strychnine administration acting on the chemical balance of cortical areas-in relation to underlying regional variation in microscale neurotransmitter receptor density levels in the macaque cortex. Linking cortical variation in microscale receptor density levels to collated information on macroscale functional connectivity of the macaque cortex, we show macroscale patterns of effective corticocortical functional interactions-and in particular, the strength of connectivity of efferent macroscale pathways-to be related to the ratio of excitatory and inhibitory neurotransmitter receptor densities of cortical areas. Our findings provide evidence for the microscale chemoarchitecture of cortical areas to have a direct stimulating influence on the emergence of macroscale functional connectivity patterns in the mammalian brain. Hum Brain Mapp 37:1856-1865, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The mammalian brain is a complex network of anatomically interconnected regions. Animal studies allow for an invasive measurement of the connections of these networks at the macroscale level by means of neuronal tracing of axonal projections, providing a unique opportunity for the formation of detailed 'connectome maps'. Here we analyzed the macroscale connectome of the rat brain, including detailed information on the macroscale interregional pathways between 67 cortical and subcortical regions as provided by the high-quality, open-access BAMS-II database on rat brain anatomical projections, focusing in particular on the non-uniform distribution of projection strength across pathways. First, network analysis confirmed a small-world, modular and rich club organization of the rat connectome; findings in clear support of previous studies on connectome organization in other mammalian species. More importantly, analyzing network properties of different connection weight classes, we extend previous observations by showing that pathways with different topological roles have significantly different levels of connectivity strength. Among other findings, intramodular connections are shown to display a higher connectivity strength than intermodular connections and hub-to-hub rich club connections are shown to include significantly stronger pathways than connections spanning between peripheral nodes. Furthermore, we show evidence indicating that edges of different weight classes display different topological structures, potentially suggesting varying roles and origins of pathways in the mammalian brain network.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor function. While the pathogenesis of ALS remains largely unknown, recent histological examinations of Brettschneider and colleagues have proposed four time-sequential stages of neuropathology in ALS based on levels of phosphorylated 43kDa TAR DNA-binding protein (pTDP-43) aggregation. What governs dissemination of these aggregates between segregated regions of the brain is unknown. Here, we cross-reference stages of pTDP-43 pathology with in vivo diffusion weighted imaging data of 215 adult healthy control subjects, and reveal that regions involved in pTDP-43 pathology form a strongly interconnected component of the brain network (p=0.04) likely serving as an anatomical infrastructure facilitating pTDP-43 spread. Furthermore, brain regions of subsequent stages of neuropathology are shown to be more closely interconnected than regions of more distant stages (p=0.002). Computational simulation of disease spread from first-stage motor regions across the connections of the brain network reveals a pattern of pTDP-43 aggregation that reflects the stages of sequential involvement in neuropathology (p=0.02), a pattern in favor of the hypothesis of pTDP-43 pathology to spread across the brain along axonal pathways. Our findings thus provide computational evidence of disease spread in ALS to be directed and constrained by the topology of the anatomical brain network., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The rich variation in cytoarchitectonics of the human cortex is well known to play an important role in the differentiation of cortical information processing, with functional multimodal areas noted to display more branched, more spinous, and an overall more complex cytoarchitecture. In parallel, connectome studies have suggested that also the macroscale wiring profile of brain areas may have an important contribution in shaping neural processes; for example, multimodal areas have been noted to display an elaborate macroscale connectivity profile. However, how these two scales of brain connectivity are related-and perhaps interact-remains poorly understood. In this communication, we combined data from the detailed mappings of early twentieth century cytoarchitectonic pioneers Von Economo and Koskinas (1925) on the microscale cellular structure of the human cortex with data on macroscale connectome wiring as derived from high-resolution diffusion imaging data from the Human Connectome Project. In a cross-scale examination, we show evidence of a significant association between cytoarchitectonic features of human cortical organization-in particular the size of layer 3 neurons-and whole-brain corticocortical connectivity. Our findings suggest that aspects of microscale cytoarchitectonics and macroscale connectomics are related., Significance Statement: One of the most widely known and perhaps most fundamental properties of the human cortex is its rich variation in cytoarchitectonics. At the same time, neuroimaging studies have also revealed cortical areas to vary in their level of macroscale connectivity. Here, we provide evidence that aspects of local cytoarchitecture are associated with aspects of global macroscale connectivity, providing insight into the question of how the scales of micro-organization and macro-organization of the human cortex are related., (Copyright © 2015 the authors 0270-6474/15/3513943-06$15.00/0.)

The cerebral cortex is a distinctive part of the mammalian nervous system, displaying a spatial variety in cyto-, chemico-, and myelinoarchitecture. As part of a rich history of histological findings, pioneering anatomists von Economo and Koskinas provided detailed mappings on the cellular structure of the human cortex, reporting on quantitative aspects of cytoarchitecture of cortical areas. Current day investigations into the structure of human cortex have embraced technological advances in Magnetic Resonance Imaging (MRI) to assess macroscale thickness and organization of the cortical mantle in vivo. However, direct comparisons between current day MRI estimates and the quantitative measurements of early anatomists have been limited. Here, we report on a simple, but nevertheless important cross-analysis between the histological reports of von Economo and Koskinas on variation in thickness of the cortical mantle and MRI derived measurements of cortical thickness. We translated the von Economo cortical atlas to a subdivision of the commonly used Desikan-Killiany atlas (as part of the FreeSurfer Software package and a commonly used parcellation atlas in studies examining MRI cortical thickness). Next, values of "width of the cortical mantle" as provided by the measurements of von Economo and Koskinas were correlated to cortical thickness measurements derived from high-resolution anatomical MRI T1 data of 200+ subjects of the Human Connectome Project (HCP). Cross-correlation revealed a significant association between group-averaged MRI measurements of cortical thickness and histological recordings (r = 0.54, P < 0.001). Further validating such a correlation, we manually segmented the von Economo parcellation atlas on the standardized Colin27 brain dataset and applied the obtained three-dimensional von Economo segmentation atlas to the T1 data of each of the HCP subjects. Highly consistent with our findings for the mapping to the Desikan-Killiany regions, cross-correlation between in vivo MRI cortical thickness and von Economo histology-derived values of cortical mantle width revealed a strong positive association (r = 0.62, P < 0.001). Linking today's state-of-the-art T1-weighted imaging to early histological examinations our findings indicate that MRI technology is a valid method for in vivo assessment of thickness of human cortex., (© 2015 Wiley Periodicals, Inc.)

With the mapping of macroscale connectomes by means of in vivo diffusion-weighted MR Imaging (DWI) rapidly gaining in popularity, one of the necessary steps is the examination of metrics of connectivity strength derived from these reconstructions. In the field of human macroconnectomics the number of reconstructed fiber streamlines (NOS) is more and more used as a metric of cortico-cortical interareal connectivity strength, but the link between DWI NOS and in vivo animal tract-tracing measurements of anatomical connectivity strength remains poorly understood. In this technical report, we communicate on a comparison between DWI derived metrics and tract-tracing metrics of projection strength. Tract-tracing information on projection strength of interareal pathways was extracted from two commonly used macaque connectome datasets, including (1) the CoCoMac database of collated tract-tracing experiments of the macaque brain and (2) the high-resolution tract-tracing dataset of Markov and Kennedy and coworkers. NOS and density of reconstructed fiber pathways derived from DWI data acquired across 10 rhesus macaques was found to positively correlate to tract-tracing based measurements of connectivity strength across both the CoCoMac and Markov dataset (both P < 0.001), suggesting DWI NOS to form a valid method of assessment of the projection strength of white matter pathways. Our findings provide confidence of in vivo DWI connectome reconstructions to represent fairly realistic estimates of the wiring strength of white matter projections. Our cross-modal comparison supports the notion of in vivo DWI to be a valid methodology for robust description and interpretation of brain wiring., (© 2015 Wiley Periodicals, Inc.)

With the prevalence of obesity rapidly increasing worldwide, understanding the processes leading to excessive eating behavior becomes increasingly important. Considering the widely recognized crucial role of reward processes in food intake, we examined the white matter wiring and integrity of the anatomical reward network in obesity. Anatomical wiring of the reward network was reconstructed derived from diffusion weighted imaging in 31 obese participants and 32 normal-weight participants. Network wiring was compared in terms of the white matter volume as well as in terms of white matter microstructure, revealing lower number of streamlines and lower fiber integrity within the reward network in obese subjects. Specifically, the orbitofrontal cortex and striatum nuclei including accumbens, caudate and putamen showed lower strength and network clustering in the obesity group as compared to healthy controls. Our results provide evidence for obesity-related disruptions of global and local anatomical connectivity of the reward circuitry in regions that are key in the reinforcing mechanisms of eating-behavior processes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Macroscale connectivity of the mammalian brain has been shown to display several characteristics of an efficient communication network architecture. In parallel, at the microscopic scale, histological studies have extensively revealed large interregional variation in cortical neural architectonics. However, how these two "scales" of cerebrum organization are linked remains an open question. Collating and combining data across multiple studies on the cortical cytoarchitecture of the macaque cortex with information on macroscale anatomical wiring derived from tract tracing studies, this study focuses on examining the interplay between macroscale organization of the macaque connectome and microscale cortical neuronal architecture. Our findings show that both macroscale degree as well as the topological role in the overall network are related to the level of neuronal complexity of cortical regions at the microscale, showing (among several effects) a positive overall association between macroscale degree and metrics of microscale pyramidal complexity. Macroscale hub regions, together forming a densely interconnected "rich club," are noted to display a high level of neuronal complexity, findings supportive of a high level of integrative neuronal processes to occur in these regions. Together, we report on cross-scale observations that jointly suggest that a region's microscale neuronal architecture is tuned to its role in the global brain network., (Copyright © 2014 the authors 0270-6474/14/3412192-14$15.00/0.)