Biology subjects

Sipes, B. S.

Publications and source records attributed to Sipes, B. S..

5 recordsLinked to original sources

bioRxiv2026

Gene Gradients Reveal Directed Structural Connectivity Across Species

Studying the brain's inter-regional structural connectivity (SC) has transformed neuroscience, yet noninvasive neuroimaging remains blind to the directionality of neural wiring. Structural directionality must influence observed brain dynamics, but estimating edge-level directionality from brain function is ill-posed and underdetermined. Here, we show that gene co-expression gradients define a low-dimensional biological manifold that locally biases brain regions to act as network sources or sinks. Embedding gene gradients into a linear, higher-order network diffusion model defines a gene-structure-function relationship that recovers ground-truth directionality in C. elegans (r=0.70), mouse (r=0.57), and macaque (r=0.46). Applying this framework to 770 healthy young adults from the Human Connectome Project yields subject-specific directed connectomes that reproduce established corticothalamic asymmetries and reveal distinct gene ontologies associated with network sources and sinks. Furthermore, integrating directed structure with observed functional covariance enables us to derive a principled measure of directed functional connectivity, termed "angular flow" (AF), related to probability angular momentum in non-equilibrium statistical mechanics. Regional AF recapitulates the principal unimodal--multimodal gradient of functional connectivity, suggesting that this macroscale functional hierarchy emerges from a source--sink organization of signal flow through the brain. This framework resolves a long-standing limitation in connectomics and opens new opportunities to study structural directionality and non-equilibrium brain dynamics in health and disease.

neuroscience↗

bioRxiv2026

Global Signal Removal (GSR) as graph spatial filtering

Global Signal Removal (GSR) is a widely applied step in functional magnetic resonance imaging (fMRI) preprocessing. Although GSR conventionally denotes Global Signal Regression, we use Global Signal Removal to encompass a broader family of spatial filtering operations. GSR in general remains controversial due to concerns about introducing spurious anticorrelations and removing neurally meaningful signals. In this paper, we provide a precise geometric characterization by formalizing GSR as graph spatial filtering. We demonstrate that the most common form of GSR, Regression-GSR, equates to a rank-1 deflation of the covariance matrix (i.e. functional connectivity) by the degree vector. Empirically, the degree vector is dominated by the first principal component of the functional connectivity matrix (correlation = 0.88 {+/-} 0.12 in resting-state HCP data), making Regression-GSR an approximation to first eigenmode removal. This view of GSR as a spatial projection framework allows us to develop a family of GSR variants, each expressible in a unified spatial filter: Naive-GSR removes the uniform vector, PCA-GSR precisely removes the first eigenvector, and SC-GSR, a new variant we introduce that removes the first harmonic of the structural connectivity matrix. A key distinction emerges: while Naive, PCA, and SC-GSR are orthogonal projections, Regression-GSR is an oblique projection that computes regional weights proportional to the degree vector but removes a spatially uniform signal. All GSR variants induce numerical singularity in the covariance matrix, but they differ in their effects on task-state separability, which we examine empirically. In summary, we reframe GSR as a family of graph spatial filters that enable interpretability of its effects, with systematically varying effects on network connectivity across variants.

neuroscience↗

bioRxiv2026

HONeD-in on Brain Activity: Deconvolving Passive Diffusion on the Structural Network from Functional Brain Signals

Brain regions perform distinct computations, and their signals propagate through the whole-brain white matter network. Yet, mathematical models that describe this signal propagation via purely passive diffusion can predict a considerable amount of the observed functional connectivity between regions. This raises a critical question: if so much functional connectivity can be explained by a passive process, how can we isolate the active process? Here, we calculate in closed-form an estimate for such an active signal in functional MRI by spatially deconvolving the effect of passive signal spread over the brains structural connectivity using a higher-order network diffusion (HONeD) model. Across 770 Human Connectome Project subjects, we show that the resulting HONeD-innovation (HONeD-in) signal 1) sparsifies functional connectivity while retaining a well-connected network, 2) remodels resting-state networks (RSNs), 3) mixes the unimodal- multimodal hierarchical organization of RSNs into a circle with no clear hierarchy, and 4) deblurs task-activation maps. Together, our results highlight HONeD deconvolution as a generalizable new way to study resting-state and task fMRI brain signals.

neuroscience↗

bioRxiv2024

Spectral graph model for fMRI: a biophysical, connectivity-based generative model for the analysis of frequency-resolved resting state fMRI

Resting state functional MRI (rs-fMRI) is a popular and widely used technique to explore the brains functional organization and to examine if it is altered in neurological or mental disorders. The most common approach for its analysis targets the measurement of the synchronized fluctuations between brain regions, characterized as functional connectivity (FC), typically relying on pairwise correlations in activity across different brain regions. While hugely successful in exploring state- and disease-dependent network alterations, these statistical graph theory tools suffer from two key limitations. First, they discard useful information about the rich frequency content of the fMRI signal. The rich spectral information now achievable from advances in fast multiband acquisitions is consequently being under-utilized. Second, the analyzed FCs are phenomenological without a direct neurobiological underpinning in the underlying structures and processes in the brain. There does not currently exist a complete generative model framework for whole brain resting fMRI that is informed by its underlying biological basis in the structural connectome. Here we propose that a different approach can solve both challenges at once: the use of an appropriately realistic yet parsimonious biophysical signal generation model followed by graph spectral (i.e. eigen) decomposition. We call this model a Spectral Graph Model (SGM) for fMRI, using which we can not only quantify the structure-function relationship in individual subjects, but also condense the variable and individual-specific repertoire of fMRI signals spectral and spatial features into a small number of biophysically-interpretable parameters. We expect this model-based inference of rs-fMRI that seamlessly integrates with structure can be used to examine state and trait characteristics of structure-function relations in a variety of brain disorders.

neuroscience↗

bioRxiv2024

Integrative, Segregative, and Degenerate Harmonics of the Structural Connectome

Unifying integration and segregation in the brain has been a fundamental puzzle in neuroscience ever since the conception of the "binding problem." Here, we introduce a framework that places integration and segregation within a continuum based on a fundamental property of the brain-its structural connectivity graph Laplacian harmonics and a new feature we term the gap-spectrum. This framework organizes harmonics into three regimes-integrative, segregative, and degenerate- that together account for various group-level properties. Integrative and segregative harmonics occupy the ends of the continuum, and they share properties such as reproducibility across individuals, stability to perturbation, and involve "bottom-up" sensory networks. Degenerate harmonics are in the middle of the continuum, and they are subject-specific, flexible, and involve "top-down" networks. The proposed framework accommodates inter-subject variation, sensitivity to changes, and structure-function coupling in ways that offer promising avenues for studying cognition and consciousness in the brain.

neuroscience↗