Biology subjects

Hansen, J. Y.

Publications and source records attributed to Hansen, J. Y..

At least 19 recordsLinked to original sources

bioRxiv2026

EigenBrain maps cortical molecular architecture from functional, geometric, and structural eigenmodes

Neurotransmitter receptor and transporter distributions shape neural communication across the cortex and underpin mechanistic interpretations of brain function. Magnetic resonance imaging (MRI)-derived eigenmodes, low-dimensional spatial patterns that capture the principal axes of cortical organization, are increasingly used to reconstruct brain maps and offer a potential route to approximating molecular topographies in large cohorts where direct measurements are unavailable. Yet whether the type of MRI data used to derive these eigenmodes determines which receptor and transporter distributions can be approximated, and which molecular systems are accessible through this approach at all, remains unknown. Using a spatial reconstruction framework applied to 23 molecular systems spanning neurotransmitter, metabolic, and pathological markers, we show that eight receptor and transporter maps, spanning serotonin, dopamine, histamine, cholinergic, and opioid markers, can be selectively approximated from functional eigenmodes but not structural or geometric ones. This selectivity also reveals that functional brain organization encodes a specific subset of neuromodulatory topographies that structural and geometric organization does not. To illustrate translational potential in clinical cohorts where molecular imaging is unavailable, we applied individual-level eigenmode decompositions of MRI data projected onto the eight validated molecular systems and detected cross-sectional differences in autism and longitudinal changes in schizophrenia. Together, these findings reveal a difference in how geometric, structural, and functional brain organization relate to molecular architecture, offering a method for approximating validated molecular profiles in population neuroimaging cohorts that lack direct molecular imaging.

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bioRxiv2026

The blueprint of human functional architecture shifts from cognition to anatomy during perturbations of consciousness

Consciousness and cognition arise from the ongoing interactions between brain regions. Synchronous fluctuations of fMRI signals may indicate that two brain regions perform similar cognitive functions, but neural interactions are also constrained by anatomical connectivity and regions molecular, cytoarchitectonic, and metabolic profiles. Here we disentangle the respective contributions of ongoing cognition and multimodal neurobiological constraints in shaping functional connectivity. We jointly contextualise haemodynamic FC against eight distinct multimodal representations of the human connectome: (i) structural connectivity from diffusion tractography; (ii) spatial embedding; (iii) similarity of transcriptional profiles from gene expression; (iv) similarity of receptor profiles from Positron Emission Tomography; (v) laminar profile similarity from histology; (vi) correlated electrophysiological activity from magnetoencephalography; (vii) correlated metabolic activity from PET glucose uptake; (viii) coordinated activation across 123 cognitive operations from the NeuroSynth meta-analytic engine. We demonstrate that cognitive co-activation is the dominant predictor of inter-regional fMRI synchrony in the awake human brain, even when quantified using intracranial electrical stimulation. Crucially, this predominance of cognitive co-activation for shaping functional connectivity is systematically obliterated across five datasets of pharmacological and pathological perturbations of consciousness (chronic disorders of consciousness; anaesthesia with sevoflurane, propofol, or ketamine) when cognition is disconnected from the environment or altogether abolished. Altogether, we show that multimodal predictors of functional architecture shift away from cognitive co-activation and toward anatomicalmolecular constraints during pharmacological and pathological perturbations of consciousness.

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bioRxiv2026

Structure-function coupling in the human brainstem

The nuclei of the brainstem fundamentally modulate neuronal activity throughout the central nervous system. Yet connectome reconstructions typically do not include the brainstem because it is notoriously difficult to image. As a result, the influence of the brainstem on structure-function coupling in the brain is unknown. Here we use high-resolution 7 Tesla magnetic resonance imaging (MRI) to reconstruct structural and functional brain connectomes encompassing cortex and 58 brainstem nuclei spanning the midbrain, pons, and medulla. We identify structural connectional profiles of individual brainstem nuclei to the cortex and find that they align with a spectrum of functions, spanning sensory and motor processing to higher-order cognition. Structural and functional connectivity in brainstem-augmented connectomes are positively correlated, and pairs of regions with direct anatomical projections display greater functional connectivity than pairs without. Structure-function coupling is heterogeneous across brainstem nuclei, with greatest coupling in both modulatory and relay nuclei. Collectively, this work presents an initial step towards understanding how the brainstem shapes structure-function relationships in the brain.

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bioRxiv2026

Multiscale reorganization of brain and behavior under large-scale electrical perturbation

Large-scale electrical perturbation of the human brain provides a unique model for understanding how multiscale biological constraints shape behaviorally relevant reorganization. Here, we integrate longitudinal neuroimaging coordinates from 148 experiments ({approx}2,300 subjects) with normative connectomics, chemoarchitecture, intrinsic electrophysiology, and transcriptomics to identify cross-scale principles governing human brain reconfiguration under strong perturbation. Convergent hubs of structural and functional plasticity embed within default-mode and salience systems and show complementary coupling to visual networks, linking perturbation-induced change to large-scale circuits supporting affective regulation, memory, interoception, and psychosis-relevant processes. These macroscopic patterns align with intrinsic cortical dynamics and chemoarchitectural gradients dominated by 5-HT1A receptors, with additional contributions from D2, -opioid and GABAA systems, and are enriched for astrocytic and microglial gene expression, implicating glial plasticity in systems-level reorganization. Finally, in a separate intervention dataset, regularized statistical-learning models demonstrate that this multiscale signature tracks behaviorally relevant symptom change specifically under strong electrical perturbation. Together, these results outline general organizing principles linking molecular, cellular and network-level constraints to human behavioral adaptation, providing a computational framework for understanding how large-scale perturbations reshape brain systems across levels of biological organization.

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bioRxiv2025

netneurotools: a trainee-oriented approach to network neuroscience

Brain imaging is an increasingly inter-disciplinary field, encompassing multiple data types and multiple analytic traditions. Projects typically involve many moving parts, such as building customized preprocessing pipelines, transforming between data formats, preparing datasets for analysis, and ultimately displaying results. The field is conventionally built on highly specialized software packages that solve these individual challenges well, but are not necessarily designed to be interoperable. Trainees new to the field are therefore often left to come up with isolated heuristics and workarounds to complete a project. Here we present a way to navigate the increasingly complex informatics ecosystem of brain imaging. netneurotools is our labs internal Python toolkit that has been continuously developed and maintained by the labs trainees. The philosophy of the toolkit is that it should be the Swiss army knife of the lab: functions and routines that we often use but that are not part of any established pipeline or package. Since its inception, the toolkit has been open and welcomes contribution from neuroscientists across the globe. netneurotools presents a necessary counterweight to out-of-the-box software packages and highlights the importance of smaller, ad hoc functions for implementing projects. By opening a window into the inner workings of a lab, netneurotools also presents an opportunity to begin a new type of discourse among groups and establish tangible links within the community.

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bioRxiv2025

Inter-individual variability of neurotransmitter receptor and transporter density in the human brain

Neurotransmitter receptors guide the propagation of signals between brain regions. Mapping receptor distributions in the brain is therefore necessary for understanding how neurotransmitter systems mediate the link between brain structure and function. Normative receptor density can be estimated using group averages from Positron Emission Tomography (PET) imaging. However, the generalizability and reliability of group-average receptor maps depends on the inter-individual variability of receptor density, which is currently unknown. Here we collect group standard deviation brain maps of PET-estimated protein abundance for 12 different neurotransmitter receptors and transporters across 7 neurotransmitter systems, including dopamine, serotonin, acetylcholine, glutamate, GABA, cannabinoid, and opioid. We illustrate how cortical and subcortical inter-individual variability of receptor and transporter density varies across brain regions and across neurotransmitter systems. We complement inter-individual variability with inter-regional variability, and show that receptors that vary more across brain regions than across individuals also demonstrate greater out-of-sample spatial consistency. Altogether, this work quantifies how receptor systems vary in healthy individuals, and provides a means of assessing the generalizability of PET-derived receptor density quantification.

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bioRxiv2025

Brain network dynamics determine tau presence while regional vulnerability governs tau load in Alzheimer's disease

In Alzheimers disease (AD), tau pathology accumulates gradually throughout the brain, with clinical decline reflecting tau progression. A comprehensive understanding of, first, whether tau propagation is predominantly governed by connectome-based diffusion, regional vulnerability, or an interplay of both, and second, which types of brain connectivity or regional factors best explain tau propagation, remains crucial for advancing our understanding of AD progression. Here, we apply multi-scale, biologically informed disease progression simulations to human data, to disentangle the influence of local mechanisms on global tau progression patterns in AD. We find that whether tau reaches a brain region (presence) and how much tau accumulates there (load) are governed by different mechanisms. Tau presence patterns are highly consistent across the population, and can be largely explained through synaptic spread through white-matter networks and excitatory-inhibitory dynamics. Meanwhile tau load differs across people, and is driven by a combination of synaptic spread and intrinsic or extrinsic regional properties, including regional {beta}-amyloid load, MAPT gene expression and regional blood flow. Finally, while distinct tau patterns in the population could each be explained by established AD mechanisms, our models highlight a role of distinct brain networks (parietal networks in MTL-sparing AD tau subtype) and neurotransmitter systems (cholinergic system in posterior subtype). Together, this work suggests that network dynamics likely determine the sequence of regional tau progression, while individual-specific tissue-vulnerability factors influence regional tau load.

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bioRxiv2025

Mapping energy metabolism systems in the human brain

Energy metabolism involves a network of biochemical reactions that generate ATP, utilizing substrates such as glucose and oxygen supplied via cerebral blood flow. Energy substrates are metabolized in multiple interrelated pathways that are cell- and organelle-specific. These pathways not only generate energy but are also fundamental to the production of essential biomolecules required for neuronal function and survival. How these complex biochemical processes are distributed over the cortex is integral to understanding the structure and function of the brain. Here, using curated gene sets and whole-brain transcriptomics, we generate maps of five fundamental energy metabolic pathways: glycolysis, pentose phosphate pathway, tricarboxylic acid cycle, oxidative phosphorylation and lactate metabolism. We find consistent divergence between primarily energy-producing pathways and anabolic pathways, particularly in unimodal sensory cortices. We then explore the spatial alignment of these maps with multi-scale structural and functional attributes, including metabolic uptake, neurophysiological oscillations, cell type composition, laminar organization and macro-scale connectivity. Finally, we show that metabolic pathways exhibit unique developmental trajectories from the fetal stage to adulthood. The primary energy-producing pathways peak in late childhood, while the anabolic pentose phosphate pathway shows pronounced expression in the fetal stage and declines throughout life. Together, these results highlight the rich biochemical complexity of energy metabolism organization in the brain.

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bioRxiv2025

Cerebral blood perfusion across biological systems and the human lifespan

Blood perfusion delivers oxygen and nutrients to all cells, making it a fundamental feature of brain organization. How cerebral blood perfusion maps onto micro-, meso- and macro-scale brain structure and function is therefore a key question in neuroscience. Here we analyze pseudo-continuous arterial spin labeling (ASL) data from 1 305 healthy individuals in the HCP Lifespan studies (5-100 years) to reconstruct a high-resolution normative cerebral blood perfusion map. At the cellular and molecular level, cerebral blood perfusion co-localizes with granular layer IV, biological pathways for maintenance of cellular relaxation potential and mitochondrial organization, and with neurotransmitter and neuropeptide receptors involved in vasomodulation. At the regional level, blood perfusion aligns with cortical arealization and is greatest in regions with high metabolic demand and resting-state functional hubs. Looking across individuals, blood perfusion is dynamic throughout the lifespan, follows microarchitectural changes in development, and maps onto individual differences in physiological changes in aging. In addition, we find that cortical atrophy in multiple neurodegenerative diseases (late-onset Alzheimers disease, TDP-43C, and dementia with Lewy bodies) is most pronounced in regions with lower perfusion, highlighting the utility of perfusion topography as an indicator of transdiagnostic vulnerability. Finally, we show that ASL-derived perfusion can be used to delineate arterial territories in a data-driven manner, providing insights into how the vascular system is linked to human brain function. Collectively, this work highlights how cerebral blood perfusion is central to, and interlinked with, multiple structural and functional systems in the brain.

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bioRxiv2025

Synaptome architecture shapes regional dynamics in the mouse brain

Synapses are the connections that transform neurons from simple electrically charged cells into complex circuits that support perception, cognition and action. Recent advances in single-punctum synapse mapping in mice have made it possible to study the diversity of synapses and how these synapse types are differentially expressed across the brain. A salient question is how synapse diversity shapes the spatial patterning of whole-brain dynamics. Here we derive > 6 000 time-series features from fMRI recordings in awake mice to construct a comprehensive macroscale dynamical phenotype of each synapse type. We find that spatial variation in synapse types colocalizes with spatial variation in regional dynamics. Time-series in regions enriched for SAP102-expressing synapses display high-amplitude events while time-series in regions enriched for PSD95-expressing synapses display low stationarity. These regional variations in synapse types and dynamics are associated with patterns of structural and functional connectivity and the placement of hubs. Finally, using two additional fMRI datasets in anaesthetized mice, we show that synapses expressing short- and long-lifetime proteins are differentially engaged across behavioural states. Collectively, this work demonstrates that the spatial organization of microscale synapse types fundamentally shapes whole-brain dynamics.

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bioRxiv2024

Mapping neuropeptide sigaling in the human brain

Neuropeptides are functionally diverse signaling molecules in the brain, regulating a wide range of basal bodily and cognitive processes. Despite their importance, the distribution and function of neu-ropeptides in the human brain remains underexplored. Here we comprehensively map the organization of human whole-brain neuropeptide receptors across multiple levels of description; from molecular and cellular embedding to mesoscale connectivity and macroscale cognitive specialization. Using gene transcription as a proxy, we reconstruct a topographic cortical and subcortical atlas of neuropeptide receptors for 38 neuropeptide receptors, across 14 different neuropeptide families. We find that most neuropeptide receptors are highly expressed either in cortex or subcortex, delineating an anatomical cortical-subcortical gradient. Neuropeptides preferentially co-localize with metabotropic neurotrans-mitters, suggesting a system-wide correspondence between slow-acting molecular signaling mechanisms. Mapping neuropeptide receptors and their cognate ligands onto white-matter connectomes, we demonstrate that specific neuropeptides families shape electrophysiological and haemodynamic interregional connectivity. To investigate the behavioural consequences of distributed neuropeptide systems, we apply meta-analytic decoding to neuropeptide maps and show a gradient of functions, from sensory-cognitive to reward and bodily functions. Finally, evolutionary analysis indicates extended positive selection for neuropeptides in early mammals, suggesting that refinement of neuropeptides coincides with the emergence of neocortex and higher cognitive function. Collectively, these results show that the neuropeptide receptors are highly organized across the human brain and closely intertwined with multiple features of brain structure and function.

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bioRxiv2024

Benchmarking macaque gene expression for horizontal and vertical translation

The spatial patterning of gene expression shapes cortical organization and emergent function. Advances in spatial transcriptomics make it possible to comprehensively map cortical gene expression in both humans and model organisms. The macaque is a particularly valuable model organism, due to its evolutionary similarity with the human. The translational potential of macaque gene expression rests on the assumption that it is a good proxy for spatial patterns of corresponding proteins (vertical translation) and for spatial patterns of ortholog human genes (horizontal translation). Here we systematically benchmark the spatial distribution of gene expression in the macaque cortex against (a) cortical receptor density in the macaque and (b) cortical gene expression in the human. We find that there is moderate cortex-wide correspondence between gene expression and protein density in the macaque, which is improved by considering layer-specific gene expression. We find greater correspondence between orthologous gene expression in the macaque and human. Inter-species correspondence of gene expression exhibits systematic regional heterogeneity, with greater correspondence in unimodal than transmodal cortex, mapping onto patterns of evolutionary cortical expansion. We extend these results to additional micro-architectural features using macaque immunohistochemistry and T1w:T2w ratio, and replicate them using macaque RNA-seq and human RNA-seq gene expression. Collectively, the present results showcase both the potential and limitations of macaque spatial transcriptomics as an engine of translational discovery within and across species.

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bioRxiv2024

Genetic Foundations of Neurophysiological and Behavioural Variability Across the Lifespan

Neurophysiological brain activity shapes cognitive functions and individual traits. Here, we investigated the extent to which individual neurophysiological properties are genetically determined and how these adult traits align with cortical gene expression patterns across development. Using task-free magnetoencephalography in monozygotic and dizygotic twins, as well as unrelated individuals, we found that neurophysiological traits were significantly more similar between monozygotic twins, indicating a genetic influence, although individual-specific variability remained predominant. These heritable brain dynamics were predominantly associated with genes involved in neurotransmission, expressed along a topographical gradient that mirrors psychological functions, including attention, planning, and emotional processes. Furthermore, the cortical expression patterns of genes associated with individual differentiation aligned most strongly with gene expression profiles observed during adulthood in previously published longitudinal datasets. These findings underscore a persistent genetic influence on neurophysiological activity, supporting individual cognitive and behavioral variability.

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bioRxiv2024

Benchmarking methods for mapping functional connectivity in the brain

The networked architecture of the brain promotes synchrony among neuronal populations and the emergence of coherent dynamics. These communication patterns can be comprehensively mapped using noninvasive functional imaging, resulting in functional connectivity (FC) networks. Despite its popularity, FC is a statistical construct and its operational definition is arbitrary. While most studies use zero-lag Pearsons correlations by default, there exist hundreds of pairwise interaction statistics in the broader scientific literature that can be used to estimate FC. How the organization of the FC matrix varies with the choice of pairwise statistic is a fundamental methodological question that affects all studies in this rapidly growing field. Here we comprehensively benchmark the topological and geometric organization, neurobiological associations, and cognitive-behavioral relevance of FC matrices computed using a large library of 239 pairwise interaction statistics. We comprehensively investigate how canonical features of FC networks vary with the choice of pairwise statistic, including (1) hub mapping, (2) weight-distance trade-offs, (3) structure-function coupling, (4) correspondence with other neurophysiological networks, (5) individual fingerprinting, and (6) brain-behavior prediction. We find substantial quantitative and qualitative variation across FC methods. Throughout, we observe that measures such as covariance (full correlation), precision (partial correlation) and distance display multiple desirable properties, including close correspondence with structural connectivity, the capacity to differentiate individuals and to predict individual differences in behavior. Using information flow decomposition, we find that differences among FC methods may arise from differential sensitivity to the underlying mechanisms of inter-regional communication, with some more sensitive to redundant and some to synergistic information flow. In summary, our report highlights the importance of tailoring a pairwise statistic to a specific neurophysiological mechanism and research question, providing a blueprint for future studies to optimize their choice of FC method.

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bioRxiv2024

Transcriptional and neurochemical signatures of cerebral blood flow alterations in schizophrenia and the clinical high-risk state for psychosis

The brain integrates multiple scales of description, from the level of cells and molecules to large-scale networks and behaviour, and understanding the relationships between these layers may be fundamental to advancing our understanding of how the brain works in health and disease. Recent neuroimaging research has shown that alterations in brain function that are associated with schizophrenia spectrum disorders (SSD) are already present in young adults at clinical high-risk for psychosis (CHR-P), yet the cellular and molecular determinants of these alterations are not well understood. Here, combining regional cerebral blood flow (rCBF) data with existing transcriptomic and neurotransmitter data, we show that cell-types involved in stress response and inflammation, as well as the dopamine, acetylcholine, GABAA and NMDA receptor systems, align as shared and distinct cellular and neurochemical signatures of rCBF phenotypes in people with SSD and those at CHR-P. Decoding the biological pathways involved in neuroimaging-based psychosis phenotypes may provide a basis for the development of novel interventions.

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bioRxiv2024

HippoMaps: Multiscale cartography of the human hippocampal formation

The hippocampus has a unique microarchitecture, is situated at the nexus of multiple macroscale functional networks, contributes to numerous cognitive as well as affective processes, and is highly susceptible to brain pathology across common disorders. These features make the hippocampus a model to understand how brain structure covaries with function, in both health and disease. Here, we introduce HippoMaps, an open access toolbox and online data warehouse for the mapping and contextualization of subregional hippocampal data in the human brain (http://hippomaps.readthedocs.io). HippoMaps capitalizes on a unified hippocampal unfolding approach as well as shape intrinsic registration capabilities to allow for cross-subject and cross-modal data aggregation. We initialize this repository with an unprecedented combination of hippocampal data spanning 3D ex-vivo histology, ex-vivo 9.4 Tesla MRI, as well as in-vivo structural MRI and resting-state functional MRI (rsfMRI) obtained at 3 and 7 Tesla, together with intracranial encephalography (iEEG) recordings in epilepsy patients. HippoMaps also contains validated tools for spatial map association analysis in the hippocampus that correct for autocorrelation. All code and data are compliant with community standards, and comprehensive online tutorials facilitate broad adoption. Applications of this work span methodologies and modalities, spatial scales, as well as clinical and basic research contexts, and we encourage community feedback and contributions in the spirit of open and iterative scientific resource development.

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bioRxiv2024

Molecular, physiological and functional features underlying cortical thinning related to antipsychotic medication use

Use of antipsychotic medication is related to thinning of the cerebral cortex, but the underlying mechanisms of this effect remain largely unknown. Here, we investigated potential mechanisms across multiple levels of description, from molecular and physiological factors to whole-brain functional patterns. We first analyzed a single site discovery sample of patients (N=131) with early psychosis for whom antipsychotic related cortical thinning was estimated based on lifetime exposure to antipsychotics. Findings were replicated using data from a large (N[≥]2168) ENIGMA meta-analysis. We discovered that antipsychotic related cortical thinning is associated with a number of neurotransmitter systems, most notably the serotonin system, physiological measures, and functional networks and neural oscillatory power distributions typical for regions subserving higher cognition. At the functional level, antipsychotic related cortical thinning affects regions involved in executive function and motivation, but not perception. These results show how molecular, physiological, and large-scale functional patterns underlie antipsychotic related cortical thinning.

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bioRxiv2023

Integrating brainstem and cortical functional architectures

The brainstem is a fundamental component of the central nervous system yet it is typically excluded from in vivo human brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function. Here we use high-resolution 7 Tesla fMRI to derive a functional connectome encompassing cortex as well as 58 brainstem nuclei spanning the midbrain, pons and medulla. We identify a compact set of integrative hubs in the brainstem with widespread connectivity with cerebral cortex. Patterns of connectivity between brainstem and cerebral cortex manifest as multiple emergent phenomena including neurophysiological oscillatory rhythms, patterns of cognitive functional specialization, and the unimodal-transmodal functional hierarchy. This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters. We replicate all findings using 3 Tesla data from the same participants. Collectively, we find that multiple organizational features of cortical activity can be traced back to the brainstem.

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