Biology subjects

Urban, A.

Publications and source records attributed to Urban, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Cooperative processing of visual threat across collicular pathways

Rapid defensive actions require the transformation of sensory cues into appropriate motor responses. The superior colliculus is central to this transformation, containing defined cell-types that form parallel output pathways linking visual inputs to distinct behaviors. However, whether these pathways act independently or cooperate remains unclear. Here we combine cell-type-specific inhibition, large-scale electrophysiology, and functional ultrasound imaging to determine how these pathways contribute to visually evoked defensive behaviors. Inhibiting either narrow-field or wide-field neurons impaired escape to overhead visual threats, demonstrating that both pathways contribute to escape. Recordings from downstream targets revealed a compact representation in the deeper layers of the superior colliculus that selectively distinguished visual stimuli associated with escape, whereas the lateral posterior thalamus contained a broader representation of visual stimuli. The representation of visual threat in the deeper layers of the superior colliculus predicted escape initiation and vigor in freely moving animals. Across the brain, functional ultrasound imaging showed that visual stimuli recruited distinct patterns of activity that could not be explained by response magnitude alone or by the contribution of single cell-types. Together, these results reveal a cooperative circuit architecture in which parallel pathways carry distinct but complementary signals that jointly support visually evoked escape.

neuroscience↗

bioRxiv2026

Modular chronic cranial platform for longitudinal functional ultrasound, optical, and ECoG recording in a gyrencephalic model species

Understanding cortical function in large, gyrencephalic brains requires following the same tissue over time and interrogating it through complementary methods - yet in practice each recording modality is run on its own preparation, across separate animals and sessions that cannot be quantitatively related, while the recorded cortex can rarely be revisited. Functional ultrasound (fUS), widefield optical imaging, and electrocorticography (ECoG) are individually mature and strongly complementary, but no single preparation has combined all three within the same chronically accessible tissue in a gyrencephalic brain. Here we present a modular chronic cranial platform, validated in three cats with implants remaining functional for up to 3.3 years that unites these modalities in one customized chamber built around fUS as an anchor modality. The platform also supports fUS imaging in awake, head-unrestrained animals, with activation maps remaining spatially consistent across imaging days. By providing stable, quantitatively reproducible access to the same cortical region over time, this platform enables longitudinal, multimodal characterization of cortical function within individual subjects.

neuroscience↗

bioRxiv2026

Volumetric functional ultrasound imaging in macaques

Linking circuit level activity to large scale functional organization requires imaging methods combining high spatial resolution, broad coverage, and single trial sensitivity. We present volumetric functional ultrasound imaging (3D-fUS) in behaving macaques, enabling imaging of ~1 cm3 cortical volumes at high spatiotemporal resolution (100 x 150 x 150 m3 voxels, 1.67 Hz). Visually evoked responses were reliably detected at the level of single trials and single voxels, substantially reducing experimental time. To enable model-based analyses analogous to functional magnetic resonance imaging (fMRI), we estimated a canonical fUS hemodynamic response function (fUS-HRF) that was consistent across subjects, cortical areas, and visual stimuli and was well approximated by a gamma function. Compared with canonical fMRI HRFs, the fUS-HRF exhibited faster dynamics, enabling shorter and more closely spaced stimulus presentations. Together, these results establish 3D-fUS as a fast, volumetric, and circuit relevant imaging modality for efficient investigation of distributed cortical dynamics in primates.

neuroscience↗

bioRxiv2025

Continuous monitoring of cerebrovascular autoregulation using functional ultrasound imaging in the piglet brain.

Continuous real-time assessment of cerebral blood flow (CBF) and cerebrovascular autoregulation (CA) remains a major unmet clinical need in acute brain injury. Methods such as laser Doppler flowmetry (LDF), transcranial Doppler, or indirect indices lack accuracy and robustness. Functional ultrasound (fUS) is an emerging modality combining high spatiotemporal resolution, large field-of-view, and sensitivity to blood velocity and volume, making it a promising neuromonitoring tool. Piglets were equipped with arterial blood pressure (ABP), intracranial pressure (ICP), and LDF probes, plus cranial windows for fUS and red blood cell (RBC) flux imaging. CA was challenged by non-pharmacological ABP manipulation via intraaortic or intracaval balloon inflation. fUS hemodynamic parameters were compared with other modaliters across a CPP range of 10-150 mmHg. fUS provided continuous, stable intensity- and velocity-derived parameters across vessels types. CBF estimates correlated strongly with RBC flux and showed reproducibility comparable to LDF, with lower inter-animal variability. Autoregulation breakpoints were reliably identified by fUS, particularly the lower limit, while the upper limit was more variable. Parcellation confirmed robustness of fUS across brain regions. fUS images CBF and CA with higher stability and reproducibility than standard approaches, supporting its applicability for bedside neuromonitoring and clinical translation.

neuroscience↗

bioRxiv2025

DORA AI Scientist: Multi-agent Virtual Research Team for Scientific Exploration Discovery and Automated Report Generation

Modern goal-oriented scientific research process involves hierarchical teams of researchers of diverse backgrounds performing generalist and domain-specific tasks. Many of these tasks include hypothesis generation, literature review, data collection, cleanup, processing and analysis, experimental design, virtual and physical experiments, research report and academic paper writing, reference management, bibliography and quality control. Most of these tasks can be performed automatically or in a co-pilot mode by the generative reinforcement learning systems. In this paper, we introduce a versatile multi-agent scientific exploration and draft outline research assistant (DORA), which provides multiple templates and workflows for automated or semi-automated research studies and report generation. Under user guidance, it employs hierarchical teams of AI agents based on the plug-and-play generalist and domain-specific large language models (LLMs) exploiting a variety of specialized research tools and open data repositories and generates high-quality research outputs publication drafts with maximally-accurate references. DORA is designed to minimize the time and effort required for manuscript preparation, thereby enabling researchers to devote more attention to high-value discovery tasks. The system is constantly evolving with user feedback with regular feature and resource updates. The platform is available at https://dora.insilico.com.

bioinformatics↗

bioRxiv2024

Precious3GPT: Multimodal Multi-Species Multi-Omics Multi-Tissue Transformer for Aging Research and Drug Discovery

We present a multimodal multi-species multi-omics multi-tissue transformer for aging research and drug discovery capable of performing multiple tasks such as age prediction across species, target discovery, tissue, sex, and disease sample classification, drug sensitivity prediction, replication of omics response and prediction of biological and phenotypic response to compound treatment. This model combines textual, tabular, and knowledge graph-derived representations of biological experiments to provide insights into molecular-level biological processes. We demonstrate that P3GPT has developed an intuition for the interactions between compounds, pathologies, and gene regulation in the context of multiple species and tissues. In these areas, it outperforms existing LLMs and we highlight its utility in diverse case studies. P3GPT is a general model that may be used as a target identification tool, aging clock, digital laboratory, and scientific assistant. The model is intended as a community resource available open source as well as via a Discord server.

bioinformatics↗

bioRxiv2024

Functional ultrasound imaging and neuronal activity: how accurate is the spatiotemporal match?

Over the last decade, functional ultrasound (fUS) has risen as a critical tool in functional neuroimaging, leveraging hemodynamic changes to infer neural activity indirectly. Recent studies have established a strong correlation between neural spike rates (SR) and functional ultrasound signals. However, understanding their spatial distribution and variability across different brain areas is required to thoroughly interpret fUS signals. In this regard, we conducted simultaneous fUS imaging and Neuropixels recordings during stimulus-evoked activity in awake mice within three regions the visual pathway. Our findings indicate that the temporal dynamics of fUS and SR signals are linearly correlated, though the correlation coefficients vary among visual regions. Conversely, the spatial correlation between the two signals remains consistent across all regions with a spread of approximately 300 micrometers. Finally, we introduce a model that integrates the spatial and temporal components of the fUS signal, allowing for a more accurate interpretation of fUS images.

neuroscience↗

bioRxiv2023

Functional ultrasound imaging of stroke in awake rats

Anesthesia is a major confounding factor in preclinical stroke research as stroke rarely occurs in sedated patients. Moreover, anesthesia affects both brain functions and the stroke outcome acting as neurotoxic or protective agent. So far, no approaches were well suited to induce stroke while imaging hemodynamics along with simultaneous large-scale recording of brain functions in awake animals. For this reason, the first critical hours following the stroke insult and associated functional alteration remain poorly understood. Here, we present a strategy to investigate both stroke hemodynamics and stroke-induced functional alterations without the confounding effect of anesthesia, i.e., under awake condition. Functional ultrasound (fUS) imaging was used to continuously monitor variations in cerebral blood volume (CBV) in +65 brain regions/hemisphere for up to 3hrs after stroke onset. The focal cortical ischemia was induced using a chemo-thrombotic agent suited for permanent middle cerebral artery occlusion in awake rats, and followed by ipsi- and contralesional whiskers stimulation to investigate on the dynamic of the thalamo-cortical functions. Early (0-3hrs) and delayed (day 5) fUS recording enabled to characterize the features of the ischemia (location, CBV loss), spreading depolarizations (occurrence, amplitude) and functional alteration of the somatosensory thalamo-cortical circuits. Post-stroke thalamo-cortical functions were affected not only early after the stroke onset but were also altered secondarly and remotely from the initial insult. Overall, our procedure enables early, continuous, and chronic evaluations of hemodynamics and brain functions which, combined to stroke or other pathologies, aims to better understand physiopathologies toward the development of clinically relevant therapeutic strategies.

neuroscience↗

bioRxiv2022

Functional testing of PI3K inhibitors stratifies responders to idelalisib and identifies treatment vulnerabilities in idelalisib-refractory/intolerant chronic lymphocytic leukemia

PurposePhosphatidylinositol 3-kinase inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). While patients may show an initial response, development of treatment intolerance or resistance remains a clinically challenging. Prediction of individual treatment responses based on clinically actionable biomarkers is needed to overcome these challenges. Here, we investigated whether ex vivo functional responses to targeted therapies can stratify responders to idelalisib and guide precision medicine in CLL. Experimental designCLL cells from treatment naive, idelalisib-responding, and idelalisib-refractory/intolerant patients (n=33 in total) were profiled against ten PI3Ki and the Bcl-2 antagonist venetoclax. Cell signaling and immune phenotypes were analyzed by flow cytometry. Cell viability was monitored by detection of cleaved caspase-3 and the CellTiter-Glo assay. ResultsAmong the ten PI3Ki studied, pan-PI3Ki were most effective at inhibiting PI3K signaling and cell viability, and they showed activity also in CLL cells from idelalisib-refractory/intolerant patients. The pan-PI3Ki copanlisib, but not the p110{delta} inhibitor idelalisib, inhibited PI3K signaling in CD4+ and CD8+ T cells in addition to CD19+ B cells, while it did not significantly affect T cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Based on ex vivo drug sensitivity testing, a relapsed CLL patient was treated with idelalisib plus venetoclax, and the patient achieved a partial response. A more systematic analysis revealed that CLL cells from patients with a long-term response to idelalisib showed significantly higher drug sensitivities to 73 drug combinations at baseline compared to short-term responders. ConclusionsOur findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and demonstrate that ex vivo functional profiling may guide precision medicine and predict treatment responses of individual CLL patients. TRANSLATIONAL RELEVANCEThe phosphatidylinositol 3-kinase inhibitors (PI3Ki) idelalisib and duvelisib are approved for relapsed chronic lymphocytic leukemia (CLL), but their use has been limited by severe toxicity and acquired resistance. Identification of biomarkers that predict individual treatment responses, as well as alternative treatment vulnerabilities in PI3Ki refractory/intolerant patients, is needed to optimally tailor CLL therapy. We performed functional analyses of CLL cells from treatment naive, idelalisib-responding and idelalisib-refractory/intolerant patients to identify clinically actionable biomarkers. We show that CLL cells from idelalisib-refractory/intolerant patients remain sensitive to pan-PI3Ki and PI3Ki plus venetoclax combinations. Ex vivo drug sensitivity testing was used to guide treatment of a relapsed CLL patient who obtained a partial response after idelalisib plus venetoclax therapy. A systematic analysis of drug sensitivities to 73 drug combinations stratified responders to idelalisib using baseline samples from short-term and long-term responders to idelalisib. Our study demonstrates the power of functional precision medicine in relapsed CLL.

cancer biology↗

bioRxiv2022

Large scale in vivo acquisition, segmentation and 3D reconstruction of cortical vasculature using functional ultrasound imaging.

The brain is composed of a dense and ramified vascular network comprising various sizes of arteries, veins, and capillaries. One way to assess the risk of cerebrovascular pathologies is to use computational models to predict the physiological effects of a reduction of blood supply and correlate these responses with observations of brain damage. Therefore, it is crucial to establish a detailed 3D organization of the brain vasculature, which could be used to develop more accurate in silico models. For this purpose, we have adapted our open-access functional ultrasound imaging platform previously designed for recording brain-wide activity that is now capable of fast and reproducible acquisition, segmentation, and reconstruction of the cortical vasculature. For the first time, it allows us to digitize the cortical vasculature in awake rodents with a [~]100 {micro}m3 spatial resolution. Contrary to most available strategies, our approach can be performed in vivo within minutes. Moreover, it is easy to implement since it neither requires exogenous contrast agents nor long post-processing time. Hence, we performed a cortex-wide reconstruction of the vasculature and its quantitative analysis, including i) classification of descending arteries versus ascending veins in more than 1500 vessels/animal, ii) quick estimation of their length. Importantly, we confirmed the relevance of our approach in a model of cortical stroke, which enables quick visualization of the ischemic lesion. This development contributes to extending the capabilities of ultrasound neuroimaging to understand better cerebrovascular pathologies such as stroke, vascular cognitive impairment, and brain tumors and is highly scalable for the clinic.

neuroscience↗

bioRxiv2022

A deep learning classification task for accurate brain navigation during functional ultrasound imaging

Positioning and navigation are essential components of neuroimaging as they improve the quality and reliability of data acquisition, leading to advances in diagnosis, treatment outcomes, and fundamental understanding of the brain. Functional ultrasound (fUS) imaging is an emerging technology providing high-resolution images of the brain vasculature, allowing for the monitoring of brain activity. However, as the technology is relatively new, there is no standardized tool for inferring the position in the brain from the vascular images. This study presents a deep learning-based framework designed to address this challenge. Our approach uses an image classification task coupled with a regression on the resulting probabilities to determine the position of a single image. We conducted experiments using a dataset of 51 rat brain scans to evaluate its performance. The training positions were extracted at intervals of 375 {micro}m, resulting in a positioning error of 176 {micro}m. Further GradCAM analysis revealed that the predictions were primarily driven by subcortical vascular structures. Finally, we assessed the robustness of our method in a cortical stroke where the brain vasculature is severely impaired. Remarkably, no specific increase in the number of misclassifications was observed, confirming the methods reliability in challenging conditions. Overall, our framework provides accurate and flexible positioning, not relying on a pre-registered reference but on conserved vascular patterns.

neuroscience↗

bioRxiv2022

Brain-wide continuous functional ultrasound imaging for real-time monitoring of hemodynamics during ischemic stroke

Ischemic stroke occurs with no warning, and therefore, very little is known about hemodynamic perturbations in the brain immediately after stroke onset. Here, functional ultrasound imaging was used to monitor variations in relative cerebral blood volume (rCBV) compared to baseline. rCBV levels were analyzed brain-wide and continuously at high spatiotemporal resolution (100m, 2Hz) until 70mins after stroke onset in rats. We compared two stroke models, with either a permanent occlusion of the middle cerebral artery (MCAo) or a tandem occlusion of both the common carotid and middle cerebral arteries (CCAo+MCAo). We observed a typical hemodynamic pattern, including a quick drop of the rCBV after MCAo, followed by spontaneous reperfusion of several brain regions located in the vicinity of the ischemic core. The severity and location of the ischemia were highly variable between animals. Still, both parameters were, on average, in good agreement with the final ischemic lesion volume measured 24hrs after stroke onset for the MCAo but not the CCAo+MCAo model. For the latter, we observed that the infarct was extended to regions that were initially not ischemic and located rostrally of the ischemic core. These regions strongly colocalize with the origin of transient hemodynamic events associated with spreading depolarizations.

neuroscience↗

bioRxiv2021

Social-vocal brain networks in a non-human primate

During social interactions, individuals influence each other to coordinate their actions. Vocal communication is an exceptionally efficient way to exert such influence. Where and how social interactions are dynamically modulated in the brain is unknown. We used functional ultrasound imaging in marmoset monkeys - a highly vocal species - to investigate the dynamics of medial social brain areas in vocal perception, production, and audio-vocal interaction. We found that the activity of a distributed network of subcortical and cortical regions distinguishes calls associated with different social contexts. This same brain network showed different dynamics during externally and internally driven vocalizations. These findings suggest the existence of a social-vocal brain network in medial cortical and subcortical areas that is fundamental in social communication. One Sentence SummaryA network of medial subcortical and cortical brain areas gate social communication in primates.

neuroscience↗

bioRxiv2021

Brain networks in human conscious visual perception

Consciousness is not explained by a single mechanism, rather it involves multiple specialized neural systems overlapping in space and time. We hypothesize that synergistic, large-scale subcortical and cortical attention and signal processing networks encode conscious experiences. To identify brain activity in conscious perception without overt report, we classified visual stimuli as perceived or not using eye measurements. Report-independent event-related potentials and functional magnetic resonance imaging (fMRI) signals both occurred at early times after stimuli. Direct recordings revealed a novel thalamic awareness potential linked to conscious visual perception based on report. fMRI showed thalamic and cortical detection, arousal, attentional salience, task-positive, and default mode networks were involved independent of overt report. These findings identify a specific sequence of neural mechanisms in human conscious visual perception. One-Sentence SummaryHuman conscious visual perception engages large-scale subcortical and cortical networks even without overt report.

neuroscience↗

bioRxiv2021

Neural basis of functional ultrasound signals

Functional ultrasound imaging (fUSI) is a popular method for measuring blood flow and thus infer brain activity, but it relies on the physiology of neurovascular coupling and requires extensive signal processing. To establish to what degree its trial-by-trial signals reflect neural activity, we performed simultaneous fUSI and neural recordings with Neuropixels probes in awake mice. fUSI signals strongly correlated with the slow (<0.3 Hz) fluctuations in local firing rate, and were closely predicted by the smoothed firing rate of local neurons, particularly putative inhibitory neurons. The optimal smoothing filter had width ~3 s, matched the hemodynamic response function of awake mouse, was invariant across mice and stimulus conditions, and similar in cortex and hippocampus. fUSI signals also matched neural firing spatially: firing rates were as highly correlated across hemispheres as fUSI signals. Thus, hemodynamic signals measured by ultrasound bear a simple and accurate relationship to neuronal firing.

neuroscience↗

bioRxiv2020

Quantifying a Frequency Modulation Response Biomarker in Responsive Neurostimulation

ObjectiveResponsive Neurostimulation (RNS) is an effective treatment for controlling seizures in patients with drug-resistant focal epilepsy who are not suitable candidates for resection surgery. A lack of tools for detecting and characterizing potential response biomarkers, however, contributes to a limited understanding of mechanisms by which RNS improves seizure control. We developed a method to quantify ictal frequency modulation, previously identified as a biomarker of clinical responsiveness to RNS. ApproachFrequency modulation is characterized by shifts in power across spectral bands during ictal events, over several months of neurostimulation. This effect was quantified by partitioning each seizure pattern into segments with distinct spectral content and measuring the extent change from the baseline distribution of spectral content using the squared Earthmovers distance. Main resultsWe analyzed intracranial electroencephalography data from 13 patients who received RNS therapy, six of whom exhibited frequency modulation on expert evaluation. Subjects in the frequency modulation group had, on average, significantly larger and more sustained changes in their Earthmovers distances (mean = 13.97x10-3 {+/-} 1.197x10-3). In contrast, those subjects without expert-identified frequency modulation exhibited statistically insignificant or negligible distances (mean = 4.994x10-3 {+/-} 0.732x10-3). SignificanceThis method is the first step towards a quantitative, feedback-driven system for systematically optimizing RNS stimulation parameters, with an ultimate goal of truly personalized closed-loop therapy for epilepsy.

neuroscience↗

bioRxiv2020

Brain-wide mapping of neural activity mediating collicular-dependent behaviors

Neuronal cell-types are arranged in brain-wide circuits to guide behavior. In mice, the superior colliculus is comprised of a set of cell-types that each innervate distinct downstream targets. Here we reveal the brain-wide networks downstream of four collicular cell-types by combining functional ultrasound imaging (fUSi) with optogenetics to monitor neural activity at a resolution of ~100 m. Each neuronal group triggered different behaviors, and activated distinct, partially overlapping sets of brain nuclei. This included regions not previously thought to mediate defensive behaviors, e.g. the posterior paralaminar nuclei of the thalamus (PPnT), that we show to play a role in suppressing habituation. Electrophysiological recordings support the fUSi findings and show that neurons in the downstream nuclei preferentially respond to innately threatening visual stimuli. This work provides insight into the functional organization of the networks governing defensive behaviors and demonstrates an experimental approach to explore the whole-brain neuronal activity downstream of targeted cell-types.

neuroscience↗

bioRxiv2018

IgA-deficient humans exhibit gut microbiota dysbiosis despite production of compensatory IgM

Immunoglobulin A is the dominant antibody isotype found in mucosal secretions and enforces host-microbiota symbiosis in mice, yet selective IgA-deficiency (sIgAd) is the most common primary immunodeficiency in humans and is often described as asymptomatic. Here, we determined the effects of IgA deficiency on human gut microbiota composition and evaluated the possibility that secretion of IgM can compensate for a lack of secretory IgA. We used 16S rRNA gene sequencing and bacterial cell sorting to evaluate gut microbiota composition and IgA or IgM coating of the gut microbiota in 15 sIgAd subjects and 15 matched controls. Although sIgAd subjects secreted a significant amount of IgM into the intestinal lumen, this was insufficient to fully compensate for the lack of secretory IgA. Indeed, sIgAd subjects displayed an altered gut microbiota composition as compared to healthy controls, which was characterized by a trend towards decreased overall microbial diversity and significant shifts in the relative abundances of specific microbial taxa. While IgA targets a defined subset of the microbiota via high-level coating, compensatory IgM binds a broader subset of the microbiota in a less targeted manner. We conclude that IgA plays a critical and non-redundant role in controlling gut microbiota composition in humans and that secretory IgA has evolved to maintain a diverse and stable gut microbial community that promotes human health, enhances resistance to infection, and is resilient to perturbation.

immunology↗