Deciphering the functional specialization of whole-brain spatiomolecular gradients in the adult brain.

Cortical arealization arises during neurodevelopment from the confluence of molecular gradients representing patterned expression of morphogens and transcription factors. However, whether similar gradients are maintained in the adult brain remains unknown. Here, we uncover three axes of topographic variation in gene expression in the adult human brain that specifically capture previously identified rostral-caudal, dorsal-ventral, and medial-lateral axes of early developmental patterning. The interaction of these spatiomolecular gradients i) accurately reconstructs the position of brain tissue samples, ii) delineates known functional territories, and iii) can model the topographical variation of diverse cortical features. The spatiomolecular gradients are distinct from canonical cortical axes differentiating the primary sensory cortex from the association cortex, but radiate in parallel with the axes traversed by local field potentials along the cortex. We replicate all three molecular gradients in three independent human datasets as well as two nonhuman primate datasets and find that each gradient shows a distinct developmental trajectory across the lifespan. The gradients are composed of several well-known transcription factors (e.g., PAX6 and SIX3), and a small set of genes shared across gradients are strongly enriched for multiple diseases. Together, these results provide insight into the developmental sculpting of functionally distinct brain regions, governed by three robust transcriptomic axes embedded within brain parenchyma.

neuromaps: structural and functional interpretation of brain maps.

Imaging technologies are increasingly used to generate high-resolution reference maps of brain structure and function. Comparing experimentally generated maps to these reference maps facilitates cross-disciplinary scientific discovery. Although recent data sharing initiatives increase the accessibility of brain maps, data are often shared in disparate coordinate systems, precluding systematic and accurate comparisons. Here we introduce neuromaps, a toolbox for accessing, transforming and analyzing structural and functional brain annotations. We implement functionalities for generating high-quality transformations between four standard coordinate systems. The toolbox includes curated reference maps and biological ontologies of the human brain, such as molecular, microstructural, electrophysiological, developmental and functional ontologies. Robust quantitative assessment of map-to-map similarity is enabled via a suite of spatial autocorrelation-preserving null models. neuromaps combines open-access data with transparent functionality for standardizing and comparing brain maps, providing a systematic workflow for comprehensive structural and functional annotation enrichment analysis of the human brain.

Distinct patterns of cortical manifold expansion and contraction underlie human sensorimotor adaptation.

Sensorimotor learning is a dynamic, systems-level process that involves the combined action of multiple neural systems distributed across the brain. Although much is known about the specialized cortical systems that support specific components of action (such as reaching), we know less about how cortical systems function in a coordinated manner to facilitate adaptive behavior. To address this gap, our study measured human brain activity using functional MRI (fMRI) while participants performed a classic sensorimotor adaptation task and used a manifold learning approach to describe how behavioral changes during adaptation relate to changes in the landscape of cortical activity. During early adaptation, areas in the parietal and premotor cortices exhibited significant contraction along the cortical manifold, which was associated with their increased covariance with regions in the higher-order association cortex, including both the default mode and fronto-parietal networks. By contrast, during Late adaptation, when visuomotor errors had been largely reduced, a significant expansion of the visual cortex along the cortical manifold was associated with its reduced covariance with the association cortex and its increased intraconnectivity. Lastly, individuals who learned more rapidly exhibited greater covariance between regions in the sensorimotor and association cortices during early adaptation. These findings are consistent with a view that sensorimotor adaptation depends on changes in the integration and segregation of neural activity across more specialized regions of the unimodal cortex with regions in the association cortex implicated in higher-order processes. More generally, they lend support to an emerging line of evidence implicating regions of the default mode network (DMN) in task-based performance.

Correspondence between gene expression and neurotransmitter receptor and transporter density in the human brain.

Neurotransmitter receptors modulate signaling between neurons. Thus, neurotransmitter receptors and transporters play a key role in shaping brain function. Due to the lack of comprehensive neurotransmitter receptor/transporter density datasets, microarray gene expression measuring mRNA transcripts is often used as a proxy for receptor densities. In the present report, we comprehensively test the spatial correlation between gene expression and protein density for a total of 27 neurotransmitter receptors, receptor binding-sites, and transporters across 9 different neurotransmitter systems, using both PET and autoradiography radioligand-based imaging modalities. We find poor spatial correspondences between gene expression and density for all neurotransmitter receptors and transporters except four single-protein metabotropic receptors (5-HT1A, CB1, D2, and MOR). These expression-density associations are related to gene differential stability and can vary between cortical and subcortical structures. Altogether, we recommend using direct measures of receptor and transporter density when relating neurotransmitter systems to brain structure and function.

Gradients of structure-function tethering across neocortex.

The white matter architecture of the brain imparts a distinct signature on neuronal coactivation patterns. Interregional projections promote synchrony among distant neuronal populations, giving rise to richly patterned functional networks. A variety of statistical, communication, and biophysical models have been proposed to study the relationship between brain structure and function, but the link is not yet known. In the present report we seek to relate the structural and functional connection profiles of individual brain areas. We apply a simple multilinear model that incorporates information about spatial proximity, routing, and diffusion between brain regions to predict their functional connectivity. We find that structure-function relationships vary markedly across the neocortex. Structure and function correspond closely in unimodal, primary sensory, and motor regions, but diverge in transmodal cortex, particularly the default mode and salience networks. The divergence between structure and function systematically follows functional and cytoarchitectonic hierarchies. Altogether, the present results demonstrate that structural and functional networks do not align uniformly across the brain, but gradually uncouple in higher-order polysensory areas.

Comparing spatial null models for brain maps.

Technological and data sharing advances have led to a proliferation of high-resolution structural and functional maps of the brain. Modern neuroimaging research increasingly depends on identifying correspondences between the topographies of these maps; however, most standard methods for statistical inference fail to account for their spatial properties. Recently, multiple methods have been developed to generate null distributions that preserve the spatial autocorrelation of brain maps and yield more accurate statistical estimates. Here, we comprehensively assess the performance of ten published null frameworks in statistical analyses of neuroimaging data. To test the efficacy of these frameworks in situations with a known ground truth, we first apply them to a series of controlled simulations and examine the impact of data resolution and spatial autocorrelation on their family-wise error rates. Next, we use each framework with two empirical neuroimaging datasets, investigating their performance when testing (1) the correspondence between brain maps (e.g., correlating two activation maps) and (2) the spatial distribution of a feature within a partition (e.g., quantifying the specificity of an activation map within an intrinsic functional network). Finally, we investigate how differences in the implementation of these null models may impact their performance. In agreement with previous reports, we find that naive null models that do not preserve spatial autocorrelation consistently yield elevated false positive rates and unrealistically liberal statistical estimates. While spatially-constrained null models yielded more realistic, conservative estimates, even these frameworks suffer from inflated false positive rates and variable performance across analyses. Throughout our results, we observe minimal impact of parcellation and resolution on null model performance. Altogether, our findings highlight the need for continued development of statistically-rigorous methods for comparing brain maps. The present report provides a harmonised framework for benchmarking and comparing future advancements.

Segregation of the human basal forebrain using resting state functional MRI.

The basal forebrain (BF) is poised to play an important neuromodulatory role in brain regions important to cognition due to its broad projections and complex neurochemistry. While significant in vivo work has been done to elaborate BF function in nonhuman rodents and primates, comparatively limited work has examined the in vivo function of the human BF. In the current study we used multi-echo resting state functional magnetic resonance imaging (rs-fMRI) from 100 young adults (18-34 years) to assess the potential segregation of human BF nuclei as well as their associated projections. Multi-echo processing provided significant gains in SNR throughout the brain as compared to traditional single-echo processing, with some of the largest increases observed in the BF. Bottom-up clustering of voxel-wise BF functional connectivity maps yielded adjacent functional clusters within the BF that closely aligned with the distinct, hypothesized nuclei important to cognition: the nucleus basalis of Meynert (NBM) and the medial septum/diagonal band of Broca (MS/DB). Examining their separate functional connections, the NBM and MS/DB revealed distinct projection patterns, suggesting a conservation of nuclei-specific functional connectivity with homologous regions known to be anatomically innervated by the BF. Specifically, the NBM demonstrated coupling with a widespread cortical network as well as the amygdala, whereas the MS/DB revealed coupling with a more circumscribed network, including the orbitofrontal cortex and hippocampal complex. Collectively, these in vivo rs-fMRI data demonstrate that the human BF nuclei support distinct aspects of resting-state functional networks, suggesting that the human BF may be a neuromodulatory hub important for orchestrating network dynamics.

Dynamics of Bovine Sperm Interaction with Epithelium Differ Between Oviductal Isthmus and Ampulla.

In mammals, many sperm that reach the oviduct are held in a reservoir by binding to epithelium. To leave the reservoir, sperm detach from the epithelium; however, they may bind and detach again as they ascend into the ampulla toward oocytes. In order to elucidate the nature of binding interactions along the oviduct, we compared the effects of bursts of strong fluid flow (as would be caused by oviductal contractions), heparin, and hyperactivation on detachment of bovine sperm bound in vitro to epithelium on intact folds of isthmic and ampullar mucosa. Intact folds of oviductal mucosa were used to represent the strong attachments of epithelial cells to each other and to underlying connective tissue that exist in vivo. Effects of heparin on binding were tested because heparin binds to the Binder of SPerm (BSP) proteins that attach sperm to oviductal epithelium. Sperm bound by their heads to beating cilia on both isthmic and ampullar epithelia and could not be detached by strong bursts of fluid flow. Addition of heparin immediately detached sperm from isthmic epithelium but not ampullar epithelium. Addition of 4-aminopyridine immediately stimulated hyperactivation of sperm but did not detach them from isthmic or ampullar epithelium unless added with heparin. These observations indicate that the nature of binding of sperm to ampullar epithelium differs from that of binding to isthmic epithelium; specifically, sperm bound to isthmic epithelium can be detached by heparin alone, while sperm bound to ampullar epithelium requires both heparin and hyperactivation to detach from the epithelium.

Cortical gene expression architecture links healthy neurodevelopment to the imaging, transcriptomics and genetics of autism and schizophrenia.

Human brain organization involves the coordinated expression of thousands of genes. For example, the first principal component (C1) of cortical transcription identifies a hierarchy from sensorimotor to association regions. In this study, optimized processing of the Allen Human Brain Atlas revealed two new components of cortical gene expression architecture, C2 and C3, which are distinctively enriched for neuronal, metabolic and immune processes, specific cell types and cytoarchitectonics, and genetic variants associated with intelligence. Using additional datasets (PsychENCODE, Allen Cell Atlas and BrainSpan), we found that C1-C3 represent generalizable transcriptional programs that are coordinated within cells and differentially phased during fetal and postnatal development. Autism spectrum disorder and schizophrenia were specifically associated with C1/C2 and C3, respectively, across neuroimaging, differential expression and genome-wide association studies. Evidence converged especially in support of C3 as a normative transcriptional program for adolescent brain development, which can lead to atypical supragranular cortical connectivity in people at high genetic risk for schizophrenia.

Toward Best Practices for Imaging Transcriptomics of the Human Brain.

Modern brainwide transcriptional atlases provide unprecedented opportunities for investigating the molecular correlates of brain organization, as quantified using noninvasive neuroimaging. However, integrating neuroimaging data with transcriptomic measures is not straightforward, and careful consideration is required to make valid inferences. In this article, we review recent work exploring how various methodological choices affect 3 main phases of imaging transcriptomic analyses, including 1) processing of transcriptional atlas data; 2) relating transcriptional measures to independently derived neuroimaging phenotypes; and 3) evaluating the functional implications of identified associations through gene enrichment analyses. Our aim is to facilitate the development of standardized and reproducible approaches for this rapidly growing field. We identify sources of methodological variability, key choices that can affect findings, and considerations for mitigating false positive and/or spurious results. Finally, we provide an overview of freely available open-source toolboxes implementing current best-practice procedures across all 3 analysis phases.

Pattern learning reveals brain asymmetry to be linked to socioeconomic status.

Socioeconomic status (SES) anchors individuals in their social network layers. Our embedding in the societal fabric resonates with habitus, world view, opportunity, and health disparity. It remains obscure how distinct facets of SES are reflected in the architecture of the central nervous system. Here, we capitalized on multivariate multi-output learning algorithms to explore possible imprints of SES in gray and white matter structure in the wider population (n ≈ 10,000 UK Biobank participants). Individuals with higher SES, compared with those with lower SES, showed a pattern of increased region volumes in the left brain and decreased region volumes in the right brain. The analogous lateralization pattern emerged for the fiber structure of anatomical white matter tracts. Our multimodal findings suggest hemispheric asymmetry as an SES-related brain signature, which was consistent across six different indicators of SES: degree, education, income, job, neighborhood and vehicle count. Hence, hemispheric specialization may have evolved in human primates in a way that reveals crucial links to SES.

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex.

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

Standardizing workflows in imaging transcriptomics with the abagen toolbox.

Gene expression fundamentally shapes the structural and functional architecture of the human brain. Open-access transcriptomic datasets like the Allen Human Brain Atlas provide an unprecedented ability to examine these mechanisms in vivo; however, a lack of standardization across research groups has given rise to myriad processing pipelines for using these data. Here, we develop the abagen toolbox, an open-access software package for working with transcriptomic data, and use it to examine how methodological variability influences the outcomes of research using the Allen Human Brain Atlas. Applying three prototypical analyses to the outputs of 750,000 unique processing pipelines, we find that choice of pipeline has a large impact on research findings, with parameters commonly varied in the literature influencing correlations between derived gene expression and other imaging phenotypes by as much as ρ ≥ 1.0. Our results further reveal an ordering of parameter importance, with processing steps that influence gene normalization yielding the greatest impact on downstream statistical inferences and conclusions. The presented work and the development of the abagen toolbox lay the foundation for more standardized and systematic research in imaging transcriptomics, and will help to advance future understanding of the influence of gene expression in the human brain.

Mapping gene transcription and neurocognition across human neocortex.

Regulation of gene expression drives protein interactions that govern synaptic wiring and neuronal activity. The resulting coordinated activity among neuronal populations supports complex psychological processes, yet how gene expression shapes cognition and emotion remains unknown. Here, we directly bridge the microscale and macroscale by mapping gene expression patterns to functional activation patterns across the cortical sheet. Applying unsupervised learning to the Allen Human Brain Atlas and Neurosynth databases, we identify a ventromedial-dorsolateral gradient of gene assemblies that separate affective and perceptual domains. This topographic molecular-psychological signature reflects the hierarchical organization of the neocortex, including systematic variations in cell type, myeloarchitecture, laminar differentiation and intrinsic network affiliation. In addition, this molecular-psychological signature strengthens over neurodevelopment and can be replicated in two independent repositories. Collectively, our results reveal spatially covarying transcriptomic and cognitive architectures, highlighting the influence that molecular mechanisms exert on psychological processes.

Multimodal phenotypic axes of Parkinson's disease.

Individuals with Parkinson's disease present with a complex clinical phenotype, encompassing sleep, motor, cognitive, and affective disturbances. However, characterizations of PD are typically made for the "average" patient, ignoring patient heterogeneity and obscuring important individual differences. Modern large-scale data sharing efforts provide a unique opportunity to precisely investigate individual patient characteristics, but there exists no analytic framework for comprehensively integrating data modalities. Here we apply an unsupervised learning method-similarity network fusion-to objectively integrate MRI morphometry, dopamine active transporter binding, protein assays, and clinical measurements from n = 186 individuals with de novo Parkinson's disease from the Parkinson's Progression Markers Initiative. We show that multimodal fusion captures inter-dependencies among data modalities that would otherwise be overlooked by field standard techniques like data concatenation. We then examine how patient subgroups derived from the fused data map onto clinical phenotypes, and how neuroimaging data is critical to this delineation. Finally, we identify a compact set of phenotypic axes that span the patient population, demonstrating that this continuous, low-dimensional projection of individual patients presents a more parsimonious representation of heterogeneity in the sample compared to discrete biotypes. Altogether, these findings showcase the potential of similarity network fusion for combining multimodal data in heterogeneous patient populations.

Brain atrophy progression in Parkinson's disease is shaped by connectivity and local vulnerability.

Brain atrophy has been reported in the early stages of Parkinson's disease, but there have been few longitudinal studies. How intrinsic properties of the brain, such as anatomical connectivity, local cell-type distribution and gene expression combine to determine the pattern of disease progression also remains unknown. One hypothesis proposes that the disease stems from prion-like propagation of misfolded alpha-synuclein via the connectome that might cause varying degrees of tissue damage based on local properties. Here, we used MRI data from the Parkinson Progression Markers Initiative to map the progression of brain atrophy over 1, 2 and 4 years compared with baseline. We derived atrophy maps for four time points using deformation-based morphometry applied to T1-weighted MRI from 120 de novo Parkinson's disease patients, 74 of whom had imaging at all four time points (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). In order to determine factors that may influence neurodegeneration, we related atrophy progression to brain structural and functional connectivity, cell-type expression and gene ontology enrichment analyses. After regressing out the expected age and sex effects associated with normal ageing, we found that atrophy significantly progressed over 2 and 4 years in the caudate, nucleus accumbens, hippocampus and posterior cortical regions. This progression was shaped by both structural and functional brain connectivity. Also, the progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses and was inversely related to the prevalence of oligodendrocytes and endothelial cells. In sum, we demonstrate that the progression of atrophy in Parkinson's disease is in line with the prion-like propagation hypothesis of alpha-synuclein and provide evidence that synapses may be especially vulnerable to synucleinopathy. In addition to identifying vulnerable brain regions, this study reveals different factors that may be implicated in the neurotoxic mechanisms leading to progression in Parkinson's disease. All brain maps generated here are available on request.

Linking Structure and Function in Macroscale Brain Networks.

Structure-function relationships are a fundamental principle of many naturally occurring systems. However, network neuroscience research suggests that there is an imperfect link between structural connectivity and functional connectivity in the brain. Here, we synthesize the current state of knowledge linking structure and function in macroscale brain networks and discuss the different types of models used to assess this relationship. We argue that current models do not include the requisite biological detail to completely predict function. Structural network reconstructions enriched with local molecular and cellular metadata, in concert with more nuanced representations of functions and properties, hold great potential for a truly multiscale understanding of the structure-function relationship.

Topographic gradients of intrinsic dynamics across neocortex.

The intrinsic dynamics of neuronal populations are shaped by both microscale attributes and macroscale connectome architecture. Here we comprehensively characterize the rich temporal patterns of neural activity throughout the human brain. Applying massive temporal feature extraction to regional haemodynamic activity, we systematically estimate over 6000 statistical properties of individual brain regions' time-series across the neocortex. We identify two robust spatial gradients of intrinsic dynamics, one spanning a ventromedial-dorsolateral axis and dominated by measures of signal autocorrelation, and the other spanning a unimodal-transmodal axis and dominated by measures of dynamic range. These gradients reflect spatial patterns of gene expression, intracortical myelin and cortical thickness, as well as structural and functional network embedding. Importantly, these gradients are correlated with patterns of meta-analytic functional activation, differentiating cognitive versus affective processing and sensory versus higher-order cognitive processing. Altogether, these findings demonstrate a link between microscale and macroscale architecture, intrinsic dynamics, and cognition.

Spatial Patterning of Tissue Volume Loss in Schizophrenia Reflects Brain Network Architecture.

BACKGROUND: There is growing recognition that connectome architecture shapes cortical and subcortical gray matter atrophy across a spectrum of neurological and psychiatric diseases. Whether connectivity contributes to tissue volume loss in schizophrenia in the same manner remains unknown. METHODS: Here, we relate tissue volume loss in patients with schizophrenia to patterns of structural and functional connectivity. Gray matter deformation was estimated in a sample of 133 individuals with chronic schizophrenia (48 women, mean age 34.7 ± 12.9 years) and 113 control subjects (64 women, mean age 23.5 ± 8.4 years). Deformation-based morphometry was used to estimate cortical and subcortical gray matter deformation from T1-weighted magnetic resonance images. Structural and functional connectivity patterns were derived from an independent sample of 70 healthy participants using diffusion spectrum imaging and resting-state functional magnetic resonance imaging. RESULTS: We found that regional deformation is correlated with the deformation of structurally and functionally connected neighbors. Distributed deformation patterns are circumscribed by specific functional systems (the ventral attention network) and cytoarchitectonic classes (limbic class), with an epicenter in the anterior cingulate cortex. CONCLUSIONS: Altogether, the present study demonstrates that brain tissue volume loss in schizophrenia is conditioned by structural and functional connectivity, accounting for 25% to 35% of regional variance in deformation.

Latent Clinical-Anatomical Dimensions of Schizophrenia.

Widespread structural brain abnormalities have been consistently reported in schizophrenia, but their relation to the heterogeneous clinical manifestations remains unknown. In particular, it is unclear whether anatomical abnormalities in discrete regions give rise to discrete symptoms or whether distributed abnormalities give rise to the broad clinical profile associated with schizophrenia. Here, we apply a multivariate data-driven approach to investigate covariance patterns between multiple-symptom domains and distributed brain abnormalities in schizophrenia. Structural magnetic resonance imaging and clinical data were derived from one discovery sample (133 patients and 113 controls) and one independent validation sample (108 patients and 69 controls). Disease-related voxel-wise brain abnormalities were estimated using deformation-based morphometry. Partial least-squares analysis was used to comprehensively map clinical, neuropsychological, and demographic data onto distributed deformation in a single multivariate model. The analysis identified 3 latent clinical-anatomical dimensions that collectively accounted for 55% of the covariance between clinical data and brain deformation. The first latent clinical-anatomical dimension was replicated in an independent sample, encompassing cognitive impairments, negative symptom severity, and brain abnormalities within the default mode and visual networks. This cognitive-negative dimension was associated with low socioeconomic status and was represented across multiple races. Altogether, we identified a continuous cognitive-negative dimension of schizophrenia, centered on 2 intrinsic networks. By simultaneously taking into account both clinical manifestations and neuroanatomical abnormalities, the present results open new avenues for multi-omic stratification and biotyping of individuals with schizophrenia.