Biology subjects

Lake, E. M.

Publications and source records attributed to Lake, E. M..

12 recordsLinked to original sources

bioRxiv2026

Bayesian generative modeling reveals a multi-modal hierarchical architecture in the mouse functional connectome

Understanding the principles governing large-scale functional organization of the brain remains a central challenge in systems neuroscience. Despite convergent findings, substantial variability across analytical approaches suggests that functional networks may not admit a unique partitioning. Here, we propose that this variability reflects an intrinsic property of the connectome itself: its organization may be fundamentally multi-modal rather than singular. To test this hypothesis, we employ a Bayesian generative modeling framework based on stochastic block models, enabling principled comparison of competing organizational principles and characterization of the full posterior distribution over network partitions. Applying this framework to resting-state fMRI data in mice, we find that a non-degree-corrected hierarchical architecture provides the most parsimonious description of the functional connectome. Importantly, the inferred posterior landscape is not dominated by a single configuration, but instead comprises multiple distinct and co-dominant organizational schemes. At the mesoscale, these hierarchical communities are anatomically grounded yet systematically reorganize canonical resting-state networks: primary sensory systems remain cohesive, whereas higher-order association networks are fractionated into multiple interacting sub-circuits. This global structural variation is driven by structured variability at the community level, where integrative systems exhibit variable regional affiliations while sensory systems act as structurally stable anchors. Together, these findings suggest that the resting-state connectome is best described as a distribution over alternative, yet co-dominant, organizational configurations. This perspective reconciles inconsistencies across previous studies and supports a view of brain organization as inherently degenerate, providing a latent repertoire of network configurations that may underlie adaptive information routing and dynamic functional reconfiguration.

neuroscience↗

bioRxiv2026

Channel Capacity for Time-Resolved Effective Connectivity in Functional Neuroimaging

Understanding how brain regions influence one another over time is a central goal of neuroscience. However, existing approaches to effective connectivity often involve tradeoffs among mechanistic interpretability, computational scalability, and time-resolved estimation. Here, we introduce information channel capacity, a model-based measure of directed information transfer between brain regions, and combine it with a sliding-window framework to estimate time-varying directional interactions. We validate channel capacity across multimodal neuroimaging datasets in humans and rodents because this breadth is needed to test three complementary properties that no single dataset can establish alone: sensitivity to evoked information transfer, specificity against false-positive directional effects, and the ability to capture meaningful temporal variability in directed brain-network interactions. Human motor-task fMRI tests sensitivity, showing that channel capacity detects task-related increases in directed interactions and stronger directional effects during task than during rest in motor-related regions. Concurrent rat local field potential (LFP)-fMRI tests specificity, showing minimal spurious directional asymmetry relative to scan-to-scan variability and consistent temporal dynamics across neural and BOLD signals. Mouse Ca2+-fMRI tests temporal variability, showing that channel-capacity patterns identify reproducible connectivity states and transitions over time. Together, these results establish channel capacity as a physiologically grounded framework for measuring dynamic directional interactions across species and neuroimaging modalities.

neuroscience↗

bioRxiv2026

Harmonizing brain rhythms: cortex-wide neuronal dynamics underpin quasi-periodic patterns in resting-state fMRI

Functional magnetic resonance imaging (fMRI) captures whole-brain activity fluctuations non-invasively in humans and animals. Beyond task/stimuli-locked responses, fMRI measures large-scale patterned activity during rest. Among these, quasi-periodic patterns (QPPs) represent recurring waves of activity that unfold over seconds and exhibit consistent spatiotemporal characteristics. Notably, certain fMRI-QPPs are well-preserved across species and altered in various neuropsychiatric and neurodegenerative diseases. Yet, our collective understanding of their neural underpinnings is limited given the indirect nature of blood-oxygen-level dependent (BOLD) fMRI signals. Simultaneous measures of local field potentials have provided some affirmation that fMRI-QPPs have neural origins, but these point-measurements are limited to a handful of sites. Here, we use a unique multimodal implementation of simultaneous wide-field calcium (WF-Ca2+) imaging and fMRI to investigate the neural origins of fMRI-based QPPs. We uncover a robust time-locked correlation between QPPs detected by cortex-wide fluorescent WF-Ca2+ imaging of neural activity and QPPs of BOLD-fMRI. These data validate the hypothesis that BOLD-fMRI QPPs derive from preceding slow waves of neural activity with regional and temporal precision.

neuroscience↗

bioRxiv2025

Longitudinal, simultaneous wide-field fluorescent Ca2+ imaging and fMRI in awake mice

Functional magnetic resonance imaging (fMRI) can be applied in mice and humans making it a key technology in translational neuroimaging research. Yet, most fMRI studies in rodents use anesthesia to limit subject motion and stress. This puts a hard boundary on the range of brain and behavioral states that can be studied in animals, and deviates from the near-universal practice of imaging people whilst awake. Recent years have seen a push towards the development of acclimation protocols for performing fMRI in mice without anesthesia, but the results have been mixed. In parallel, imaging mice without anesthesia has become routine for complementary neuroimaging methods including wide-field fluorescence calcium (WF-Ca2+) imaging. Our group works with a unique co-implementation of WF-Ca2+ and fMRI which enables the collection of complementary measures of brain function, but, until now, has necessitated the use of anesthesia. We present the first longitudinal protocol for simultaneous WF-Ca2+ and fMRI in awake mice. Our approach is comprised of a two-phase (biphasic) acclimation protocol that results in high-quality multimodal data. Comparisons of cortex-wide neuronal activity (WF-Ca2+ imaging) and blood-oxygen-level dependent fMRI signals between isoflurane-anesthetized and awake mice reveal both convergent and divergent patterns in brain function between modalities, and across time.

neuroscience↗

bioRxiv2025

Geometric influences on the regional organization of the mammalian brain

The mammalian brain comprises anatomically and functionally distinct regions, yet the principles governing their organization across scales remain unclear. Efforts to map regional boundaries use expert judgement or data-driven clustering of functional, connectional, and/or architectonic properties, but these approaches are often descriptive, have limited generalizability, and do not elucidate generative mechanisms. Here, we develop a geometrically constrained framework for the hierarchical, multiscale regional organization of neocortical and non-neocortical structures. The framework yields parcels at any resolution with high internal homogeneity across hundreds of anatomical, functional, cellular, and molecular properties in humans, macaques, marmosets, and mice, and it generalizes to understudied mammalian species. Finally, we demonstrate that the framework captures the essence of a reaction-diffusion mechanism in which brain geometry shapes the spatial expression of putative patterning molecules that establish a blueprint of regional identity during development. Our findings point to a conserved, universal influence of geometry on mammalian brain organization.

neuroscience↗

bioRxiv2024

Repetitive mild closed-head injury induced synapse loss and increased local BOLD-fMRI signal homogeneity

Repeated mild head injuries due to sports, or domestic violence and military service are increasingly linked to debilitating symptoms in the long term. Although symptoms may take decades to manifest, potentially treatable neurobiological alterations must begin shortly after injury. Better means to diagnose and treat traumatic brain injuries, requires an improved understanding of the mechanisms underlying progression and means through which they can be measured. Here, we employ a repetitive mild closed-head injury (rmTBI) and chronic variable stress (CVS) mouse model to investigate emergent structural and functional brain abnormalities. Brain imaging is achieved with [18F]SynVesT-1 positron emission tomography, with the synaptic vesicle glycoprotein 2A ligand marking synapse density and BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI). Animals were scanned six weeks after concluding rmTBI/Stress procedures. Injured mice showed widespread decreases in synaptic density coupled with an increase in local BOLD-fMRI synchrony detected as regional homogeneity. Injury-affected regions with higher synapse density showed a greater increase in fMRI regional homogeneity. Taken together, these observations may reflect compensatory mechanisms following injury. Multimodal studies are needed to provide deeper insights into these observations.

neuroscience↗

bioRxiv2024

Multimodal identification of the mouse brain using simultaneous Ca2+ imaging and fMRI

Individual differences in neuroimaging are of interest to clinical and cognitive neuroscientists based on their potential for guiding the personalized treatment of various heterogeneous neurological conditions and diseases. Despite many advantages, the workhorse in this arena, BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI) suffers from low spatiotemporal resolution and specificity as well as a propensity for noise and spurious signal corruption. To better understand individual differences in BOLD-fMRI data, we can use animal models where fMRI, alongside complementary but more invasive contrasts, can be accessed. Here, we apply simultaneous wide-field fluorescence calcium imaging and BOLD-fMRI in mice to interrogate individual differences using a connectome-based identification framework adopted from the human fMRI literature. This approach yields high spatiotemporal resolution cell-type specific signals (here, from glia, excitatory, as well as inhibitory interneurons) from the whole cortex. We found mouse multimodal connectome-based identification to be successful and explored various features of these data.

neuroscience↗

bioRxiv2023

Aberrant Connectivity Across the Lifespan in a Mouse Model of Alzheimer's disease and Rescue by mGlur5 Modulator Treatment

Amyloid accumulation in Alzheimers disease (AD) is associated with synaptic damage and altered connectivity in brain networks. While measures of amyloid accumulation and biochemical changes in mouse models have utility for translational studies of certain therapeutics, preclinical analysis of altered brain connectivity using clinically relevant fMRI measures has not been well developed for agents intended to improve neural networks. Here, we conduct a longitudinal study in a double knock-in mouse model for AD (AppNL-G-F/hMapt), monitoring brain connectivity by means of resting-state fMRI. While the 4-month-old AD mice are indistinguishable from wild-type controls (WT), decreased connectivity in the default-mode network is significant for the AD mice relative to WT mice by 6 months of age and is pronounced by 9 months of age. In a second cohort of 20-month-old mice with persistent functional connectivity deficits for AD relative to WT, we assess the impact of two-months of oral treatment with a silent allosteric modulator of mGluR5 (BMS-984923) known to rescue synaptic density. Functional connectivity deficits in the aged AD mice are reversed by the mGluR5-directed treatment. The longitudinal application of fMRI has enabled us to define the preclinical time trajectory of AD-related changes in functional connectivity, and to demonstrate a translatable metric for monitoring disease emergence, progression, and response to synapse-rescuing treatment.

neuroscience↗

bioRxiv2022

Functional network organization of the mouse cortex determined by wide-field fluorescence imaging shares some --but not all-- properties revealed with simultaneous fMRI-BOLD

Work in humans and animals shows that the brain can be decomposed into large-scale functional networks. Whereas most studies, especially in humans, use the blood-oxygenation-level-dependent (BOLD) signal, the relationship between BOLD and neuronal activity is complex and incompletely understood. This limits our ability to interpret and apply measures derived from fMRI-BOLD. Here, we employ wide-field Ca2+ imaging simultaneously recorded with fMRI-BOLD in highly-sampled mice expressing GCaMP6f in excitatory neurons. These unique data enabled us to characterize the similarities and differences between networks discoverable by each modality. Importantly, we applied a network partitioning approach that uses a mixed-membership algorithm, which allows brain regions to participate in multiple networks with varying strengths. This contrasts with assuming regions belong to only one network. Our findings demonstrate that (1) most BOLD networks are detected via Ca2+ signals. (2) There is considerable overlapping--as opposed to disjoint--network organization that is evident from both modalities. (3) Large-scale networks determined by Ca2+ signals at low temporal frequencies (0.01 - 0.5 Hz)--as opposed to higher frequencies (0.5 - 5 Hz)--are more similar to those determined by BOLD. (4) Despite many similarities, differences emerge across modes including the spatial distribution of membership diversity (the extent to which regions affiliate with multiple networks). In sum, Ca2+ imaging of excitatory neurons confirms that the mouse cortex is functionally organized into overlapping large-scale networks in a manner that reflects many, but not all, properties observable with simultaneous fMRI-BOLD; affirming the neural origins of patterns of brain organization that are evident in a clinically accessible neuroimaging modality.

neuroscience↗

bioRxiv2022

A preprocessing and functional connectivity analysis pipeline for mesoscale calcium imaging

To improve bench-to-bedside translation, it is integral that knowledge flow bidirectionally--from animal models to humans, and vice versa. This requires common analytical frameworks, as well as open software and data sharing practices. We share a new pipeline (and test dataset) for the preprocessing of wide-field optical fluorescence imaging data--an emerging mode applicable in animal models--as well as results from a functional connectivity and graph theory analysis inspired by recent work in the human neuroimaging field. The approach is demonstrated using a dataset comprised of two test-cases: (1) data from animals imaged during awake and anesthetized conditions with excitatory neurons labeled, and (2) data from awake animals with different genetically encoded fluorescent labels that target either excitatory neurons or inhibitory interneuron subtypes. Both seed-based connectivity and graph theory measures (global efficiency, transitivity, modularity, and characteristic path-length) are shown to be useful in quantifying differences between wakefulness states and cell populations. Wakefulness state and cell type show widespread effects on canonical network connectivity with variable frequency band dependence. Differences between excitatory neurons and inhibitory interneurons are observed, with somatostatin expressing inhibitory interneurons emerging as notably dissimilar from parvalbumin and vasoactive polypeptide expressing cells. In sum, we demonstrate that our pipeline can be used to examine brain state and cell-type differences in mesoscale imaging data, aiding translational neuroscience efforts. In line with open science practices, we freely release the pipeline and data to encourage other efforts in the community.

neuroscience↗

bioRxiv2021

Arousal impacts distributed hubs modulating the integration of brain functional connectivity

Even when subjects are at rest, it is thought that brain activity is organized into distinct brain states during which reproducible patterns are observable. Yet, it is unclear how to define or distinguish different brain states. A potential source of brain state variation is arousal, which may play a role in modulating functional interactions between brain regions. Here, we use simultaneous resting state functional magnetic resonance imaging and pupillometry to study the impact of arousal levels indexed by pupil area on the integration of large-scale brain networks. We employ a novel sparse dictionary learning-based method to identify hub regions participating in between-network integration stratified by arousal, by measuring k-hubness, the number (k) of functionally overlapping networks in each brain region. We show evidence of a brain-wide decrease in between-network integration and inter-subject variability at low relative to high arousal, with differences emerging across regions of the frontoparietal, default mode, motor, limbic, and cerebellum networks. State-dependent changes in k-hubness relate to the actual patterns of network integration within these hubs, suggesting a brain state transition from high to low arousal characterized by global synchronization and reduced network overlaps. We demonstrate that arousal is not limited to specific brain areas known to be directly associated with arousal regulation, but instead has a brain-wide impact that involves high-level between-network communications.

neuroscience↗

bioRxiv2018

Spanning spatiotemporal scales with simultaneous mesoscopic Ca2+ imaging and functional MRI

Neuroscience encompasses the investigation of brain function across multiple spatiotemporal scales. Yet, most research is confined to Ca2+ one spatiotemporal milieu limiting the integration of knowledge across scales. Here we describe an imaging and analytic approach that spans spatiotemporal scales by combining simultaneous wide field mesoscopic 1-photon Ca2+ imaging and functional magnetic resonance imaging (fMRI) at 11.7T. Given the confined space within the magnet, that metal is prohibited, and the unique/conflicting needs of each methodology, these techniques have never before been combined. In addition to describing the new hardware and software, we present evoked and spontaneous activity measurements made in lightly anesthetized animals. We have three findings: (1) for both evoked and spontaneous activity the magnitude of the Ca2+ and fMRI signals show correspondence, (2) connectivity matrices derived from Ca2+ and fMRI measurements are stable throughout an imaging session, and (3) there is correspondence between Ca2+ and fMRI spontaneous activity patterns.

neuroscience↗