Convergence of Brain Transcriptomic and Neuroimaging Patterns in Schizophrenia, Bipolar Disorder, Autism Spectrum Disorder, and Major Depressive Disorder.

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.

Human and chimpanzee shared and divergent neurobiological systems for general and specific cognitive brain functions.

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.

Scaling Principles of White Matter Connectivity in the Human and Nonhuman Primate Brain.

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.

Statistical testing in transcriptomic-neuroimaging studies: A how-to and evaluation of methods assessing spatial and gene specificity.

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.

Diffusion MRI data, sulcal anatomy, and tractography for eight species from the Primate Brain Bank.

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.

Myelo- and cytoarchitectonic microstructural and functional human cortical atlases reconstructed in common MRI space.

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.

Activation response and functional connectivity change in rat cortex after bilateral transcranial direct current stimulation-An exploratory study.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique implicated as a promising adjunct therapy to improve motor function through the neuromodulation of brain networks. Particularly bilateral tDCS, which affects both hemispheres, may yield stronger effects on motor learning than unilateral stimulation. Therefore, the aim of this exploratory study was to develop an experimental model for simultaneous magnetic resonance imaging (MRI) and bilateral tDCS in rats, to measure instant and resultant effects of tDCS on network activity and connectivity. Naïve, male Sprague-Dawley rats were divided into a tDCS (n = 7) and sham stimulation group (n = 6). Functional MRI data were collected during concurrent bilateral tDCS over the sensorimotor cortex, while resting-state functional MRI and perfusion MRI were acquired directly before and after stimulation. Bilateral tDCS induced a hemodynamic activation response, reflected by a bilateral increase in blood oxygenation level-dependent signal in different cortical areas, including the sensorimotor regions. Resting-state functional connectivity within the cortical sensorimotor network decreased after a first stimulation session but increased after a second session, suggesting an interaction between multiple tDCS sessions. Perfusion MRI revealed no significant changes in cerebral blood flow after tDCS. Our exploratory study demonstrates successful application of an MRI-compatible bilateral tDCS setup in an animal model. Our results indicate that bilateral tDCS can locally modulate neuronal activity and connectivity, which may underlie its therapeutic potential.

The human connectome from an evolutionary perspective.

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.

Connection strength of the macaque connectome augments topological and functional network attributes.

Mammalian brains constitute complex organized networks of neural projections. On top of their binary topological organization, the strength (or weight) of these neural projections can be highly variable across connections and is thus likely of additional importance to the overall topological and functional organization of the network. Here we investigated the specific distribution pattern of connection strength in the macaque connectome. We performed weighted and binary network analysis on the cortico-cortical connectivity of the macaque provided by the unique tract-tracing dataset of Markov and colleagues (2014) and observed in both analyses a small-world, modular and rich club organization. Moreover, connectivity strength showed a distribution augmenting the architecture identified in the binary network version by enhancing both local network clustering and the central infrastructure for global topological communication and integration. Functional consequences of this topological distribution were further examined using the Kuramoto model for simulating interactions between brain regions and showed that the connectivity strength distribution across connections enhances synchronization within modules and between rich club hubs. Together, our results suggest that neural pathway strength promotes topological properties in the macaque connectome for local processing and global network integration.

Genetic mapping and evolutionary analysis of human-expanded cognitive networks.

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.

Evolutionary expansion of connectivity between multimodal association areas in the human brain compared with chimpanzees.

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.

Automated touch sensing in the mouse tapered beam test using Raspberry Pi.

BACKGROUND: Rodent models of neurological disease such as stroke are often characterized by motor deficits. One of the tests that are used to assess these motor deficits is the tapered beam test, which provides a sensitive measure of bilateral motor function based on foot faults (slips) made by a rodent traversing a gradually narrowing beam. However, manual frame-by-frame scoring of video recordings is necessary to obtain test results, which is time-consuming and prone to human rater bias. NEW METHOD: We present a cost-effective method for automated touch sensing in the tapered beam test. Capacitive touch sensors detect foot faults onto the beam through a layer of conductive paint, and results are processed and stored on a Raspberry Pi computer. RESULTS: Automated touch sensing using this method achieved high sensitivity (96.2%) as compared to 'gold standard' manual video scoring. Furthermore, it provided a reliable measure of lateralized motor deficits in mice with unilateral photothrombotic stroke: results indicated an increased number of contralesional foot faults for up to 6days after ischemia. COMPARISON WITH EXISTING METHOD: The automated adaptation of the tapered beam test produces results immediately after each trial, without the need for labor-intensive post-hoc video scoring. It also increases objectivity of the data as it requires less experimenter involvement during analysis. CONCLUSIONS: Automated touch sensing may provide a useful adaptation to the existing tapered beam test in mice, while the simplicity of the hardware lends itself to potential further adaptations to related behavioral tests.