Biology subjects

Benveniste, H.

Publications and source records attributed to Benveniste, H..

8 recordsLinked to original sources

bioRxiv2026

Greater hypoxic burden predicts weaker gray matter-CSF coordination independent of non-hypoxic arousals: Implications for glymphatic activity

Study ObjectivesObstructive sleep apnea (OSA) is a risk factor for neurodegeneration, and glymphatic impairment may be one mechanistic pathway. Anti-phase coordination between brain pulsations and CSF flow, reflecting compensatory CSF displacement during each vascular pulsation cycle, supports glymphatic activity. This study examined whether hypoxic burden and sleep fragmentation, two distinct OSA pathologies, are differentially associated with brain pulsation-CSF flow dynamics. MethodsThis cross-sectional study included 28 individuals with newly identified OSA and 8 without OSA. Participants completed in-lab polysomnography or WatchPAT testing, providing measures of hypoxic burden, quantified as time below 90% oxygen saturation (T90), and non-hypoxic sleep fragmentation, quantified as respiratory effort-related arousals (RERAs). Participants also completed 7T resting-state functional MRI to estimate global BOLD-CSF, defined as anti-phase cross-correlation between blood-oxygen-level-dependent (BOLD) signal and CSF inflow. Associations were examined using correlation and hierarchical regression. Exploratory analyses examined region-specific BOLD-CSF and brain pulsation strength, quantified as BOLD amplitude. ResultsGreater T90 was associated with weaker global BOLD-CSF, independent of RERAs and covariates ({beta}=0.08,p=0.03). Greater T90 was also associated with higher BOLD amplitude across temporal, frontal, and parietal regions, but this elevation in amplitude was not accompanied by stronger region-specific BOLD-CSF coupling ({beta}=0.001,p>0.05). In contrast, among regions where BOLD amplitude was not associated with T90, greater BOLD amplitude predicted stronger region-specific BOLD-CSF ({beta}=-0.004,p<0.001). RERAs were not associated with global BOLD-CSF or BOLD amplitude. ConclusionsIn OSA, hypoxic burden may be the primary feature associated with impaired brain pulsation and CSF dynamics that support glymphatic activity. These alterations may be pronounced in the temporal lobe, where elevated pulsations were uncoupled from compensatory CSF displacement.

neuroscience↗

bioRxiv2025

CILIATED CELL DOMAINS WITH LOCALLY COORDINATED CILIARY MOTION GENERATE A MOSAIC OF MICROFLOWS IN THE BRAIN'S LATERAL VENTRICLES

Circulation of cerebrospinal fluid (CSF) through the brains ventricles is essential for maintaining brain homeostasis and supporting neurogenesis. CSF flow is supported by the structural polarization of multiciliated cells, which align with the flow direction. However, it remains unclear how the organization of tissue-wide polarity across the ciliary epithelium comprised of thousands of cells, determines the trajectory of the flow and efficient distribution of the CSF. Here, we used new approaches to analyze the organization of translational polarity across extensive areas of the lateral ventricular wall. We also used live imaging to examine cilia motion, flow trajectories, and ciliary beat frequency (CBF) in live preparations of ventricles. In addition to the primary flow running across the ventricular wall from the posterior area to the anterior (P-A), we found multiple local microflows with both direct and curved trajectories that deviate from the mainstream P-A direction. Our results suggest that the ciliated epithelium in the lateral ventricles varies in the alignment of ciliated cell translational polarity: whereas in the narrow dorsal area translational polarity is aligned with the direction of the mainstream flow, in the periphery of the mainstream it is organized into distinct cell clusters with locally aligned polarity vectors. We posit that the cluster organization of the multiciliated ependymal cells underpins the generation of a complex mosaic of flows, with the local microflows facilitating the wide spreading of the CSF across the ependyma. We demonstrate that nNOS is involved in the control of translational polarity, cluster organization, microflows, and CBF in the ependyma. SignificanceThe flow of cerebrospinal fluid (CSF) is crucial for brain homeostasis. This flow is driven by the coordinated beating of cilia on thousands of ciliated cells. Planar polarity vector of the ciliated cells is aligned with the flow direction in the areas of the ependyma underlying the mainstream flow (1). However, the overall alignment of planar cell polarity and flow across the whole tissue is unclear. Here we report a discovery of complex flow patterns over the ependyma, consisting of numerous microflows in the periphery of the mainstream flow. Using new approaches, we found that planar polarity of the ependymal ciliated cells on the periphery of the mainstream flow aligns only locally, indicating a clustered organization of the ependyma that supports various flow directions.

cell biology↗

bioRxiv2024

Cerebral Venous Blood Flow Regulates Brain Fluid Clearance via Dural Lymphatics

The vascular system regulates brain clearance through arterial blood flow and lymphatic drainage of cerebrospinal fluid (CSF). Idiopathic intracranial hypertension (IIH), characterized by elevated intracranial pressure and dural venous sinus stenoses, can be treated by restoring venous blood flow via venous stenting, suggesting a role for venous blood flow in brain fluid clearance. Using magnetic resonance imaging (MRI) in IIH patients and healthy controls, we identified that dural venous stenoses in IIH were associated with impaired lymphatic drainage, perivenous fluid retention, and brain fluid accumulation. To investigate this further, we developed a mouse model with bilateral jugular vein ligation (JVL), which recapitulated key human findings, including intracranial hypertension, calvarial lymphatic regression, and brain swelling due to impaired clearance. To further dissect the respective roles of dural lymphatics and venous blood flow in brain clearance, we performed JVL in mice with dural lymphatic depletion. These mice exhibited spontaneous elevated intracranial pressure, but JVL did not further exacerbate this effect. Moreover, the synchronous restoration of brain clearance and dural lymphatics observed in mice after JVL was absent in lymphatic-deficient mice.Transcriptomic analyses revealed that lymphatic remodeling induced by JVL was driven by VEGF-C signaling between dural mesenchymal and lymphatic endothelial cells. These findings establish the dural venous sinuses as a critical platform where venous blood flow interacts with mesenchymal cells to preserve dural lymphatic integrity and function, essential for brain fluid clearance.

neuroscience↗

bioRxiv2023

VEGF-C promotes brain-derived fluid drainage, confers neuroprotection, and improves stroke outcomes

Meningeal lymphatic vessels promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelium growth factor-C (VEGF-C) is essential for meningeal lymphatic development and maintenance and has therapeutic potential for treating neurological disorders, including ischemic stroke. We have investigated the effects of VEGF-C overexpression on brain fluid drainage, single cell transcriptome in the brain, and stroke outcomes in adult mice. Intra-cerebrospinal fluid administration of an adeno-associated virus expressing VEGF-C (AAV-VEGF-C) increases the CNS lymphatic network. Post-contrast T1 mapping of the head and neck showed that deep cervical lymph node size and drainage of CNS-derived fluids were increased. Single nuclei RNA sequencing revealed a neuro-supportive role of VEGF-C via upregulation of calcium and brain-derived neurotrophic factor (BDNF) signaling pathways in brain cells. In a mouse model of ischemic stroke, AAV-VEGF-C pretreatment reduced stroke injury and ameliorated motor performances in the subacute stage. AAV-VEGF-C thus promotes CNS-derived fluid and solute drainage, confers neuroprotection, and reduces ischemic stroke damage. Short abstractIntrathecal delivery of VEGF-C increases the lymphatic drainage of brain-derived fluids confers neuroprotection, and improves neurological outcomes after ischemic stroke.

neuroscience↗

bioRxiv2022

Choroid plexus tissue perfusion and secretory function in rats measured by non-invasive MRI reveal significant effects of anesthesia

The choroid plexus (ChP) of the cerebral ventricles is a source of cerebrospinal fluid (CSF) production and also plays a key role in immune surveillance at the level of blood-to-CSF-barrier (BCSFB). In this study, we quantify ChP blood perfusion and BCSFB mediated water exchange from arterial blood into ventricular CSF using non-invasive continuous arterial spin labelling magnetic resonance imaging (CASL-MRI). Systemic administration of anti-diuretic hormone (vasopressin) was used to validate BCSFB mediated water exchange as a metric of choroidal CSF secretory function. To further investigate the coupling between ChP perfusion and CSF secretory function, we characterized the effects of two anesthetic regimens known to have large-scale differential effects on cerebral blood flow. For quantification of ChP blood perfusion a multi-compartment perfusion model was employed, and we discovered that partial volume correction improved measurement accuracy. Vasopressin significantly reduced both ChP blood perfusion and CSF secretory function. ChP perfusion was significantly higher with pure isoflurane anesthesia (2-2.5%) when compared to a balanced anesthesia with dexmedetomidine and low-dose isoflurane (1.0 %), however there was no significant difference in BCSFB water secretory function. In summary, here we introduce a non-invasive, robust, and spatially resolved in vivo imaging platform to quantify ChP perfusion as well as BCSFB water secretory function which can be applied to study coupling of these two key parameters in future clinical translational studies.

neuroscience↗

bioRxiv2020

Development of an MRI Compatible Nasal Drug Delivery Method: Probing Nicotine Addiction Dynamics

BackgroundSubstance abuse is a fundamentally dynamic disease, characterized by repeated oscillation between craving, drug self-administration, reward, and satiety. To model nicotine addiction as a control system, an MR-compatible nicotine delivery system is needed to elicit cyclical cravings. MethodUsing a concentric nebulizer, inserted into one nostril, we delivered each dose--each equivalent to a single cigarette puff--using a syringe pump by nebulizing the nicotine solution using pressurized medical air. A control mechanism permits dual modes: one delivers puffs on a fixed interval programmed by researchers; with the other, subjects press a button to self-administer each nicotine dose. Subjects were therefore able to intuitively "smoke" the equivalent of a cigarette, one "puff" at a time. We dosed each "puff" such that one cigarette would be equal, in nicotine content, to 10 puffs. ResultsWe tested the viability of this delivery method for studying the brains response to nicotine addiction in three steps. First, we established the pharmacokinetics of nicotine delivery, using a dosing scheme designed to gradually achieve saturation, as with a cigarette. Second, we lengthened the time between micro-doses to elicit craving cycles, using both fixed-interval and subject-driven behavior. Finally, we confirmed that the fixed-interval protocol reliably activates brain circuits linked to addiction. ConclusionOur MR-compatible nasal delivery method enables the measurement of neural circuit responses to drug doses on a single-subject level, allowing the development of data-driven predictive models to quantify individual dysregulations of the reward control circuit causing addiction.

neuroscience↗

bioRxiv2019

Glymphatic Optimal Mass Transport with Lagrangian Workflow Reveals Advective and Diffusion Driven Solute Transport

The presence of advection in neuropil is contested and solute transport is claimed to occur by diffusion only. To address this controversy, we implemented a regularized version of the optimal mass transport (rOMT) problem, wherein the advection/diffusion equation is the only a priori assumption required. rOMT analysis with a Lagrangian perspective of glymphatic system (GS) transport revealed that solute speed was faster in cerebrospinal fluid (CSF) compared to grey and white matter. rOMT analysis also demonstrated 2-fold differences in regional particle speed within the brain parenchyma. Collectively, these results imply that advective transport dominates in CSF while diffusion and advection both contribute to transport in parenchyma. In rats with chronic hypertension, solute transport in perivascular spaces (PVS) and PVS-to-tissue transfer was slower compared to normotension. Thus, the analytical framework of rOMT provides novel insights in local variation and dynamics of GS transport that may have implications for neurodegenerative diseases.

physiology↗

bioRxiv2019

Peculiar cases of a \"sleeping\" brain in alert cancer patients

Cognitive and constitutional symptomatology is common in cancer patients but the causes are not well understood. To investigate whether cancers cause these symptoms by changing cerebral metabolism, we measured the cerebral rate of glucose consumption (CMRglc) in patients diagnosed with a lung lesion.\n\nMethodsThe CMRglc was quantified in 20 patients undergoing 18F-FDG PET for lesion staging. The cognitive status was assessed by neuropsychological testing.\n\nResultsParadoxically, despite being alert three of the patients had CMRglc typical of people who are in deep sleep or anesthetized. All three had cancers, two died within 2 months of scanning. Remaining patients including four with early stage cancer had CMRglc within normal range.\n\nConclusionsWe speculate that the low CMRglc reflects a switch to an alternative energy source that is mediated by cancers remotely. Identifying the underlying mechanism and the alternative energy sources may help to understand how cancers can change body metabolism.

cancer biology↗