Biology subjects

Culver, J. P.

Publications and source records attributed to Culver, J. P..

At least 19 recordsLinked to original sources

bioRxiv2026

Unconstrained naturalistic human brain imaging and decoding with a fully wearable high-density optical system

Understanding how the brain supports complex cognition in real-world environments requires neuroimaging systems that impose minimal constraints on natural behavior. Existing high-fidelity modalities, such as functional magnetic resonance imaging (fMRI), confine participants to the scanner, while wearable alternatives sacrifice spatial resolution or cortical coverage. Here, we developed a fully untethered whole-head optical neuroimaging system that achieves high-fidelity tomographic reconstruction through dense spatial sampling, configurable source multiplexing, and high dynamic range detection. This wearable high-density diffuse optical tomography (WHD-DOT) system achieves 151 dB effective dynamic range and nearly 3000 source-detector measurements, comparable to the highest-performing fiber-based DOT systems, while maintaining wireless, battery-powered mobility. We validate WHD-DOT across three paradigms of increasing ecological complexity, ranging from standard functional localizers to naturalistic movie viewing and live piano performance. Across all paradigms, WHD-DOT produces robust, well-localized encoding, repeatable single-trial responses, and above-chance decoding of stimulus-specific dynamics. Piano performance, which requires continuous bimanual movement and an unconstrained posture, is a rigorous real-world test for a wearable neuroimaging system. By decoding song-segment identity of free piano performance at 71.1% accuracy (chance 12.5%), WHD-DOT shows that brain activity from unconstrained, real-world behavior, previously beyond reach of high-fidelity imaging, is now both measurable and decodable.

neuroscience↗

bioRxiv2025

Visual Semantic Encoding and Identification of Naturalistic Movies via High-Density Diffuse Optical Tomography

Understanding how the brain represents meaning in real-world contexts is essential for both fundamental neuroscience and clinical applications. Brain encoding and decoding models from naturalistic stimuli provide a powerful window into semantic representations. Yet, existing approaches rely on a constrained scanning environment, or on conventional fNIRS, which has been limited to sparse sampling and/or block-design paradigms. Here, we tested whether high-density diffuse optical tomography (HD-DOT), an advanced high-density tomographic optical imaging method, can support semantic encoding and decoding using naturalistic movies. We collected 3.5 hours of naturalistic movie viewing data from six participants using stimuli labeled with 1,708 categories. Encoding models robustly predicted voxel-level responses, yielding single semantic category maps consistent with prior fMRI studies. In complementary decoding analyses, we showed that DOT responses captured sufficient semantic content to identify which clips participants viewed. To assess organization across individuals, we identified a shared low-dimensional semantic space that captures common semantic dimensions. Finally, clustering analyses revealed interpretable higher-order semantic dimensions like social and animate agents, objects vs natural organisms, and textural scenes, consistently mapped across the cortex. These findings demonstrate that DOT can recover distributed, high-dimensional semantic representations from naturalistic movies, bridging fMRI-level semantic mapping with the accessibility of optical imaging.

neuroscience↗

bioRxiv2024

At the onset of active whisking, the input layer of barrel cortex exhibits a 24 h window of increased excitability that depends on prior experience.

The development of motor control over sensory organs is a critical milestone, enabling active explo-ration and shaping of the sensory environment. Whether the onset of sensory organ motor control directly influences the development of corresponding sensory cortices remains unknown. Here, we confirm and exploit the late onset of whisking behavior in mice to address this question in the somatosensory system. Using ex vivo electrophysiology, we describe a transient increase in the intrinsic excitability of excitatory neurons in layer IV of the barrel cortex, which processes whisker input, immediately following the onset of active whisking around on postnatal days 13 and 14. This increase in neuronal gain is specific to layer IV, independent of changes in synaptic strength, and requires prior sensory experience. Further, these effects are not expressed in inhibitory in-terneurons in barrel cortex. The transient increase in excitability is not evident in layer II/III of barrel cortex or in the visual cortex upon eye opening, suggesting a unique interaction between the development of active sensing and the thalamocortical input layer in the somatosensory iso-cortex. Predictive modeling indicates that, immediately following the onset of active whisking, changes in active membrane conductances alone can reliably distinguish neurons in control but not whisker-deprived hemispheres. Our findings demonstrate an experience-dependent, lamina-specific refinement of neuronal excitability tightly linked to the emergence of active whisking. This tran-sient increase in the gain of the thalamic input layer coincides with a critical period for synaptic plasticity in downstream layers, suggesting a role in cortical maturation and sensory processing.

neuroscience↗

bioRxiv2023

Identifying Naturalistic Movies from Human Brain Activity with High-Density Diffuse Optical Tomography

Modern neuroimaging modalities, particularly functional MRI (fMRI), can decode detailed human experiences. Thousands of viewed images can be identified or classified, and sentences can be reconstructed. Decoding paradigms often leverage encoding models that reduce the stimulus space into a smaller yet generalizable feature set. However, the neuroimaging devices used for detailed decoding are non-portable, like fMRI, or invasive, like electrocorticography, excluding application in naturalistic use. Wearable, non-invasive, but lower-resolution devices such as electroencephalography and functional near-infrared spectroscopy (fNIRS) have been limited to decoding between stimuli used during training. Herein we develop and evaluate model-based decoding with high-density diffuse optical tomography (HD-DOT), a higher-resolution expansion of fNIRS with demonstrated promise as a surrogate for fMRI. Using a motion energy model of visual content, we decoded the identities of novel movie clips outside the training set with accuracy far above chance for single-trial decoding. Decoding was robust to modulations of testing time window, different training and test imaging sessions, hemodynamic contrast, and optode array density. Our results suggest that HD-DOT can translate detailed decoding into naturalistic use.

bioengineering↗

bioRxiv2023

A high-density diffuse optical tomography dataset of naturalistic viewing

Traditional laboratory tasks offer tight experimental control but lack the richness of our everyday human experience. As a result, many cognitive neuroscientists have been motivated to adopt experimental paradigms that are more natural, such as stories and movies. Here we describe data collected from 58 healthy adult participants (aged 18-76 years) who viewed 10 minutes of a movie (The Good, the Bad, and the Ugly, 1966). Most (36) participants viewed the clip more than once, resulting in 106 sessions of data. Cortical responses were mapped using high-density diffuse optical tomography (first-through fourth nearest neighbor separations of 1.3, 3.0, 3.9, and 4.7 cm), covering large portions of superficial occipital, temporal, parietal, and frontal lobes. Consistency of measured activity across subjects was quantified using intersubject correlation analysis. Data are provided in both channel format (SNIRF) and projected to standard space (NIfTI) using an atlas-based light model. These data are suitable for methods exploration as well as investigating a wide variety of cognitive phenomena.

neuroscience↗

bioRxiv2023

Anatomical Modeling and Optimization of Speckle Contrast Optical Tomography

Traditional methods for mapping cerebral blood flow (CBF), such as positron emission tomography and magnetic resonance imaging, offer only isolated snapshots of CBF due to scanner logistics. Speckle contrast optical tomography (SCOT) is a promising optical technique for mapping CBF. However, while SCOT has been established in mice, the method has not yet been demonstrated in humans - partly due to a lack of anatomical reconstruction methods and uncertainty over the optimal design parameters. Herein we develop SCOT reconstruction methods that leverage MRI-based anatomical head models and finite-element modeling of the SCOT forward problem (NIRFASTer). We then simulate SCOT for CBF perturbations to evaluate sensitivity of imaging performance to exposure time and SD-distances. We find image resolution comparable to intensity-based diffuse optical tomography at superficial cortical tissue depth ([~]1.5 cm). Localization errors can be reduced by including longer SD-measurements. With longer exposure times speckle contrast decreases, however, noise decreases faster, resulting in a net increase in SNR. Specifically, extending exposure time from 10s to 10ms increased SCOT SNR by 1000X. Overall, our modeling methods provide anatomically-based image reconstructions that can be used to evaluate a broad range of tissue conditions, measurement parameters, and noise sources and inform SCOT system design.

neuroscience↗

bioRxiv2023

A comprehensive workflow and its validation for simulating diffuse speckle statistics for optical blood flow measurements

Diffuse optical methods including speckle contrast optical spectroscopy and tomography (SCOS and SCOT), use speckle contrast (k) to measure deep blood flow. In order to design practical systems, parameters such as signal-to-noise ratio (SNR) and the effects of limited sampling of statistical quantities, should be considered. To that end, we have developed a method for simulating speckle contrast signals including effects of detector noise. The method was validated experimentally, and the simulations were used to study the effects of physical and experimental parameters on the accuracy and precision of k. These results revealed that systematic detector effects resulted in decreased accuracy and precision of k in the regime of low detected signals. The method can provide guidelines for the design and usage of SCOS and/or SCOT instruments.

bioengineering↗

bioRxiv2023

Evaluation of gliovascular functions of Aqp4 readthrough isoforms

Aquaporin-4 (AQP4) is a water channel protein that links astrocytic endfeet to the blood-brain barrier (BBB) and regulates water and potassium homeostasis in the brain, as well as the glymphatic clearance of waste products that would otherwise potentiate neurological diseases. Recently, translational readthrough was shown to generate a C-terminally extended variant of AQP4, known as AQP4x, that preferentially localizes around the BBB through interaction with the scaffolding protein -syntrophin, and loss of AQP4x disrupts waste clearance from the brain. To investigate the function of AQP4x, we generated a novel mouse AQP4 line (AllX) to increase relative levels of the readthrough variant above the [~]15% of AQP4 in the brain of wildtype (WT) mice. We validated the line and assessed characteristics that are affected by the presence of AQP4x, including AQP4 and -syntrophin localization, integrity of the BBB, and neurovascular coupling. We compared AllXHom and AllXHet mice to wildtype, and to previously characterized AQP4 NoXHet and NoXHom mice, which cannot produce AQP4x. Increased dose of AQP4x enhanced perivascular localization of - syntrophin and AQP4, while total protein expression of the two were unchanged. However, at 100% readthrough, AQP4x localization and formation of higher-order complexes was disrupted. Electron microscopy showed that overall blood vessel morphology was unchanged except for increased endothelial cell vesicles in NoXHom mice, which may correspond to a leakier BBB or altered efflux that was identified in NoX mice using MRI. These data demonstrate that AQP4x plays a small but measurable role in maintaining BBB integrity as well as recruiting structural and functional support proteins to the blood vessel. This also establishes a new set of genetic tools for quantitatively modulating AQP4x levels. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/549379v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@18f8f32org.highwire.dtl.DTLVardef@25afeorg.highwire.dtl.DTLVardef@a3e0e1org.highwire.dtl.DTLVardef@100f2e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Ultra-high density imaging arrays for diffuse optical tomography of human brain improve resolution, signal-to-noise, and information decoding

Functional magnetic resonance imaging (fMRI) has dramatically advanced non-invasive human brain mapping and decoding. Functional near-infrared spectroscopy (fNIRS) and high-density diffuse optical tomography (HD-DOT) non-invasively measure blood oxygen fluctuations related to brain activity, like fMRI, at the brain surface, using more-lightweight equipment that circumvents ergonomic and logistical limitations of fMRI. HD-DOT grids have smaller inter-optode spacing ([~]13 mm) than sparse fNIRS ([~]30 mm) and therefore provide higher image quality, with spatial resolution [~]1/2 that of fMRI. Herein, simulations indicated reducing inter-optode spacing to 6.5 mm would further improve image quality and noise-resolution tradeoff, with diminishing returns below 6.5 mm. We then constructed an ultra-high-density DOT system (6.5-mm spacing) with 140 dB dynamic range that imaged stimulus-evoked activations with 30-50% higher spatial resolution and repeatable multi-focal activity with excellent agreement with participant-matched fMRI. Further, this system decoded visual stimulus position with 19-35% lower error than previous HD-DOT, throughout occipital cortex.

bioengineering↗

bioRxiv2023

Myeloid cell activation during Zika virus encephalitis predicts recovery of functional cortical connectivity

Neurologic complications of Zika virus (ZIKV) infection across the lifespan have been described during outbreaks in Southeast Asia, South America, and Central America since 2016. In the adult CNS ZIKV tropism for neurons is tightly linked to its effects, with neuronal loss within the hippocampus during acute infection and protracted synapse loss during recovery, which is associated with cognitive deficits. The effects of ZIKV on cortical networks have not been evaluated. Although animal behavior assays have been used previously to model cognitive impairment, in vivo brain imaging can provide orthogonal information regarding the health of brain networks in real time, providing a tool to translate findings in animal models to humans. In this study, we use widefield optical imaging to measure cortical functional connectivity (FC) in mice during acute infection with, and recovery from, intracranial infection with a mouse-adapted strain of ZIKV. Acute ZIKV infection leads to high levels of myeloid cell activation, with loss of neurons and presynaptic termini in the cerebral cortex and associated loss of FC primarily within the somatosensory cortex. During recovery, neuron numbers, synapses and FC recover to levels near those of healthy mice. However, hippocampal injury and impaired spatial cognition persist. The magnitude of activated myeloid cells during acute infection predicted both recovery of synapses and the degree of FC recovery after recovery from ZIKV infection. These findings suggest that a robust inflammatory response may contribute to the health of functional brain networks after recovery from infection. Significance StatementDetermining the long-term cognitive impact of infections is clinically challenging. We found that the degree of myeloid cell activation correlated with the degree of recovery of functional connectivity after recovery from ZIKV encephalitis. Using functional cortical connectivity, we demonstrate that interhemispheric cortical connectivity is decreased in individuals with acute ZIKV encephalitis. This correlates with decreased presynaptic terminals in the somatosensory cortex. During recovery from ZIKV infection, presynaptic terminals recover, which is associated with recovered interhemispheric connectivity. This suggests a role for activated myeloid cells in maintenance of cognition and further supports the contribution of synapses in the cortex to functional networks in the brain, which can be detected by widefield optical imaging. These findings also suggest neuroinflammation may play a neuroprotective role in addition to aiding in local virologic control.

biophysics↗

bioRxiv2023

Visual deprivation during mouse critical period reorganizes network-level functional connectivity

A classic example of experience-dependent plasticity is ocular dominance (OD) shift, in which the responsiveness of neurons in the visual cortex is profoundly altered following monocular deprivation (MD). It has been postulated that OD shifts also modify global neural networks, but such effects have never been demonstrated. Here, we used longitudinal wide-field optical calcium imaging to measure resting-state functional connectivity during acute (3-day) MD in mice. First, delta GCaMP6 power in the deprived visual cortex decreased, suggesting that excitatory activity was reduced in the region. In parallel, interhemispheric visual homotopic functional connectivity was rapidly reduced by the disruption of visual drive through MD and was sustained significantly below baseline state. This reduction of visual homotopic connectivity was accompanied by a reduction in parietal and motor homotopic connectivity. Finally, we observed enhanced internetwork connectivity between visual and parietal cortex that peaked at MD2. Together, these findings support the hypothesis that early MD induces dynamic reorganization of disparate functional networks including association cortices. Significance StatementMonocular deprivation during the visual critical period triggers several plasticity mechanisms that collaborate to shift the excitability of neurons in the visual cortex. However, little is known about the impacts of MD on cortex-wide functional networks. Here, we measured cortical functional connectivity during short-term critical period MD. We demonstrate that critical period MD has immediate effects on functional networks beyond the visual cortex, and identify regions of substantial functional connectivity reorganization in response to MD.

neuroscience↗

bioRxiv2022

TRPV1-mediated sonogenetic neuromodulation of motor cortex in freely moving mice

BackgroundNoninvasive and cell-type-specific neuromodulation tools are critically needed for probing intact brain function. Sonogenetics for noninvasive activation of neurons engineered to express thermosensitive transient receptor potential vanilloid 1 (TRPV1) by transcranial focused ultrasound (FUS) was recently developed to address this need. However, using TRPV1-mediated sonogenetics to evoke behavior by targeting the cortex is challenged by its proximity to the skull due to high skull absorption of ultrasound and increased risks of thermal-induced tissue damage. ObjectiveThis study evaluated the feasibility and safety of TRPV1-mediated sonogenetics in targeting the motor cortex to modulate the locomotor behavior of freely moving mice. MethodsAdeno-associated virus was delivered to the mouse motor cortex via intracranial injection to express TRPV1 in excitatory neurons. A wearable FUS device was installed on the mouse head after a month to control neuronal activity by activating virally expressed TRPV1 through FUS sonication at different acoustic pressures. Immunohistochemistry staining of ex vivo brain slices was performed to verify neuron activation and evaluate safety. ResultsTRPV1-mediated sonogenetic stimulation at 0.7 MPa successfully evoked rotational behavior in the direction contralateral to the stimulation site, activated cortical neurons as indicated by the upregulation of c-Fos, and did not induce significant changes in inflammatory or apoptotic markers (GFAP, lba1, and Caspase-3). Sonogenetic stimulation of TRPV1 mice at a higher acoustic pressure, 1.1 MPa, induced significant changes in motor behavior and upregulation of c-Fos compared with FUS sonication of naive mice at 1.1 MPa. However, signs of damage at the meninges were observed at 1.1 MPa. ConclusionsTRPV1-mediated sonogenetics can achieve effective and safe neuromodulation at the cortex with carefully selected FUS parameters. These findings expand the application of this technique to include superficial brain targets.

bioengineering↗

bioRxiv2022

Multi-Mode Fiber-Based Speckle Contrast Optical Spectroscopy: Analysis of Speckle Statistics

Speckle contrast optical spectroscopy/tomography (SCOS/T) provides a real-time, non-invasive, and cost-efficient optical imaging approach to mapping of cerebral blood flow. By measuring many speckles (n>>10), SCOS/T has increased signal-to-noise ratio relative to diffuse correlation spectroscopy, which measures one or a few speckles. However, the current free-space SCOS/T designs are not ideal for large field-of-view imaging in humans because the curved head contour cannot be readily imaged with a single flat sensor and hair obstructs optical access. Herein we evaluate the feasibility of using cost-efficient multi-mode fiber (MMF) bundles for use in SCOS/T systems. One challenge with speckle contrast measurements is the potential for confounding noise sources (e.g., shot noise, readout noise) to contribute to the standard deviation measure and corrupt the speckle contrast measure that is central to the SCOS/T systems. However, for true speckle measurements, the histogram of pixel intensities from light interference follows a non-Gaussian distribution, specifically a gamma distribution with non-zero skew, whereas most noise sources have pixel intensity distributions that are Gaussian. By evaluating speckle data from static and dynamic targets imaged through MMF, we use histograms and statistical analysis of pixel histograms to evaluate whether the statistical properties of the speckles are retained. We show that flow-based speckle can be distinguished from static speckle and from sources of system noise through measures of skew in the pixel intensity histograms. Finally, we illustrate in humans that MMF bundles relay blood flow information. (C) 2022 Optica Publishing Group

bioengineering↗

bioRxiv2021

Mecp2 deletion results in profound alterations of developmental and adult functional connectivity

As a regressive neurodevelopmental disorder with a well-established genetic cause, Rett Syndrome and its Mecp2 loss-of-function mouse model provide an excellent opportunity to define potentially translatable functional signatures of disease progression, as well as offer insight into Mecp2s role in functional circuit development. Thus, we applied optical fluorescence imaging to assess mesoscale calcium functional connectivity (FC) in the Mecp2 cortex prior to symptom onset as well as during decline. We found that FC was profoundly disrupted in Mecp2 males both in juvenile development and early adulthood. Female Mecp2 mice displayed a subtle homotopic contralateral increase in motor cortex as juveniles but not in adulthood, where instead parietal regions were implicated. Additionally, conditional rescue studies indicated FC phenotypes are driven by excitatory neurons. Altogether, the female results identify subtle candidate translatable biomarkers of disease progression, while the male results indicate MeCP2 protein is needed in a circuit-specific manner for FC.

neuroscience↗

bioRxiv2021

Dorsolateral prefrontal cortex supports speech perception in listeners with cochlear implants

Cochlear implants are neuroprosthetic devices that can restore hearing in people with severe to profound hearing loss by electrically stimulating the auditory nerve. Because of physical limitations on the precision of this stimulation, the acoustic information delivered by a cochlear implant does not convey the same level of acoustic detail as that conveyed by normal hearing. As a result, speech understanding in listeners with cochlear implants is typically poorer and more effortful than in listeners with normal hearing. The brain networks supporting speech understanding in listeners with cochlear implants are not well understood, partly due to difficulties obtaining functional neuroimaging data in this population. In the current study, we assessed the brain regions supporting spoken word understanding in adult listeners with right unilateral cochlear implants (n=20) and matched controls (n=18) using high-density diffuse optical tomography (HD-DOT), a quiet and non-invasive imaging modality with spatial resolution comparable to that of functional MRI. We found that while listening to spoken words in quiet, listeners with cochlear implants showed greater activity in left prefrontal cortex than listeners with normal hearing, specifically in a region engaged in a separate spatial working memory task. These results suggest that listeners with cochlear implants require greater cognitive processing during speech understanding than listeners with normal hearing, supported by compensatory recruitment of left prefrontal cortex.

neuroscience↗

bioRxiv2021

An open source statistical and data processing toolbox for wide-field optical imaging in mice

Wide-field optical imaging (WOI) produces concurrent hemodynamic and cell-specific calcium recordings across the entire cerebral cortex. There have been multiple studies using WOI to image mouse models with various environmental or genetic manipulations to understand various diseases. Despite the obvious utility of pursuing mouse WOI alongside human functional magnetic resonance imaging (fMRI), and the multitude of analysis toolboxes in the fMRI literature, there is not an available open-source, user-friendly data processing and statistical analysis toolbox for WOI data. Here, we present our MATLAB toolbox for pre-processing WOI data, as described and adapted to combine processing techniques from multiple WOI groups. Additionally, we provide multiple data analysis packages and translate two commonly used statistical approaches from the fMRI literature to the WOI data. To illustrate the utility, we demonstrate the ability of the processing and analysis framework to detect a well-established deficit in a mouse model of stroke. Additionally, we evaluate resting state data in healthy mice.

neuroscience↗

bioRxiv2021

Functional connectivity of the developing mouse cortex

Cross-sectional studies have established a variety of structural, synaptic and cell physiological changes corresponding to key critical periods in cortical development. However, the emergence of functional connectivity (FC) in development has not been fully characterized, and hemodynamic-based measures are vulnerable to any neurovascular coupling changes occurring in parallel. We therefore used optical fluorescence imaging to trace longitudinal calcium FC in the awake, resting-state mouse cortex in the same mice at 5 developmental time points beginning at postnatal day 15 (P15) and ending in early adulthood (P60), resulting in over 500 imaging epochs with both calcium and hemodynamics available as a resource for the field. Proof-of-principle analyses revealed that calcium FC displayed coherent functional maps as early as P15, and FC significantly varied in connections between many regions across development, with the developmental trajectorys shape specific to the functional region. This longitudinal developmental calcium FC dataset provides an essential resource for further algorithm development and studies of healthy development and neurodevelopmental disorders.

neuroscience↗

bioRxiv2020

Global Motion Detection and Censoring in High-Density Diffuse Optical Tomography

Motion-induced artifacts can significantly corrupt optical neuroimaging, as in most neuroimaging modalities. For high-density diffuse optical tomography (HD-DOT) with hundreds to thousands of source-detector pair measurements, motion detection methods are underdeveloped relative to both functional magnetic resonance imaging (fMRI) and standard functional near-infrared spectroscopy (fNIRS). This limitation restricts the application of HD-DOT in many challenging situations and subject populations (e.g., bedside monitoring and children). Here, we evaluate a new motion detection method for multichannel optical imaging systems that leverages spatial patterns across channels. Specifically, we introduce a global variance of temporal derivatives (GVTD) metric as a motion detection index. We show that GVTD strongly correlates with external measures of motion and has high sensitivity and specificity to instructed motion - with area under the receiver operator characteristic curve of 0.88, calculated based on five different types of instructed motion. Additionally, we show that applying GVTD-based motion censoring on both task and resting state HD-DOT data with natural head motion results in an improved spatial similarity to fMRI mapping for the same respective protocols (task or rest). We then compare the GVTD similarity scores with several commonly used motion correction methods described in the fNIRS literature, including correlation-based signal improvement (CBSI), temporal derivative distribution repair (TDDR), wavelet filtering, and targeted principal component analysis (tPCA). We find that GVTD motion censoring outperforms other methods and results in spatial maps more similar to matched fMRI data.

neuroscience↗