Biology subjects

Lehericy, S.

Publications and source records attributed to Lehericy, S..

12 recordsLinked to original sources

bioRxiv2026

Saccadic network dysfunction underlies eye-movement variability in early Parkinson's disease

Parkinsons disease is a neurodegenerative disorder characterized by altered subcortical-cortical connectivity, leading to motor and cognitive deficits. Saccadic eye movement abnormalities are among the earliest and most persistent markers of the disease, serving as sensitive indicators of disrupted oculomotor and cognitive control. While changes in average saccadic behavioral measures are widely reported in Parkinson's disease, intra-individual variability in saccadic performance and the underlying network dysfunction remain poorly understood. Here, we quantified intra-individual saccadic variability in early-stage Parkinsons disease and identified its functional correlates within the resting-state saccadic network. We analyzed data from 91 patients with early-stage Parkinsons disease and 46 healthy controls who underwent oculomotor testing and resting-state functional magnetic resonance imaging. First, at the behavioral level, we assessed intra-individual variability in saccadic performance within each group using the coefficient of variation of reaction time and normalized peak velocity across trials. Second, at the brain level, we assessed group differences in static and dynamic functional connectivity across 39 regions comprising the saccadic network. We examined the relationship between network connectivity and saccadic variability using partial least squares analysis. We also quantified network organization using graph-theory measures of global efficiency and clustering coefficient. Finally, we tested the relevance of intra-individual saccadic variability and network features in distinguishing patients from healthy controls using a multivariate Mahalanobis classifier. Our results showed that, compared to HC, patients had higher intra-individual variability in saccadic behavioral measures of reaction time (pHolm = 0.012) and normalized peak velocity (pHolm = 0.012). Interestingly, patients had (i) reduced static and dynamic connectivity within the saccadic network and (ii) weaker associations between network connectivity and intra-individual saccadic variability of specifically normalized peak velocity. These results were particularly driven by regions within the cognitive saccade network. The classifier that integrated intra-individual saccadic variability and network connectivity achieved 95.62% accuracy in distinguishing patients from healthy controls, with dynamic connectivity contributing more strongly to classification performance than static connectivity. We demonstrate that elevated intra-individual variability of saccades, underpinned by altered functional connectivity within cognitive-oculomotor networks, is a prominent feature of early-stage Parkinsons disease. Emerging as a promising physiological marker of disease pathophysiology, intra-individual variability offers a powerful new framework to refine early diagnosis and improve the tracking of neurodegeneration before severe clinical milestones are reached.

neuroscience↗

bioRxiv2025

Locus coeruleus degeneration is associated with cortical tau deposition and cognitive decline in older adults at familial risk of Alzheimer's disease

INTRODUCTIONThe locus coeruleus (LC) is among the first sites of tau pathology in Alzheimers disease (AD) and may seed neocortical tau. METHODSWe used longitudinal neuromelanin-sensitive MRI to assess LC integrity in vivo in a cohort of cognitively unimpaired older adults with familial risk of AD in relation to tau and amyloid PET and long-term cognitive trajectories. RESULTSWe showed that both LC integrity at baseline and its rate of degeneration over time independently predicted a neocortical pattern of tau deposition. In keeping with the known function of the LC, neuropsychological tests showed that LC integrity at baseline predicted changes in attention. Finally, we found that longitudinal LC degeneration correlated with memory decline in people with elevated neocortical amyloid burden. DISCUSSIONOur findings underscore the importance of LC in AD pathogenesis. Longitudinal measurement of LC degeneration may help distinguish trajectories of age-related cognitive decline and early AD.

neuroscience↗

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↗

bioRxiv2024

The role of dopaminergic, cholinergic and noradrenergic networks in hyposmia in Parkinson's disease

BackgroundOlfactory impairment is frequently observed in Parkinsons disease (PD) before motor symptom onset. Patients with isolated rapid eye movement sleep behaviour disorder (iRBD) are at risk to develop PD and present olfactory dysfunction. Subcortical neuromodulatory nuclei including the substantia nigra, the nucleus basalis of Meynert, and the locus coeruleus, may all contribute to olfactory dysfunction. ObjectiveThe objective of this study was to understand the network alterations underlying olfactory dysfunction in PD and in the early prodromal iRBD patients using multimodal MRI. MethodsPD (n = 107), iRBD patients (n = 35) and healthy controls (HC, n = 39) were recruited from the ICEBERG cohort for a cross-sectional study. We separated subjects in Healthy Controls, iRBD patients, and PD patients with or without RBD and with or without anosmia. Olfactory, motor, and cognitive scores were assessed and combined with multimodal imaging. ResultsWe found that olfaction positively correlated with (i) striatal DaT signal in PD patients; (ii) neuromelanin contrast in the locus coeruleus and (iii) Nucleus Basalis of Meynert grey matter (GM) volume in all patients. These signals were uncorrelated with motor and cognitive scores. Functional connectivity was reduced in regions of the cholinergic olfactory network in anosmic patients. Functional connectivity was also reduced in the noradrenergic network of patients with RBD. DiscussionOur results indicate the implication of the cholinergic network in PD patients with anosmia and a contribution of the noradrenergic network to olfactory dysfunction, only in patients with RBD.

neuroscience↗

bioRxiv2024

Longitudinal neuromelanin changes in prodromal and early Parkinson's disease in humans and rat model

Studies in animal models of Parkinsons disease (PD) suggested that the accumulation of the neuromelanin (NM), a pigment contained in nigral dopaminergic neurons, could trigger neurodegeneration above a pathogenic threshold. Here we investigated this hypothesis using NM-sensitive MRI in rodents and in patients with isolated rapid eye movement sleep disorders (iRBD) subjects, a prodromal phase of parkinsonism, and early PD. We first combined NM-sensitive MRI and histology to study NM accumulation and neurodegeneration in a humanized rat model of PD. NM-MRI signal changes were biphasic with an initial increase due to the accumulation of NM in dopaminergic neurons, followed signal decrease due to neurodegeneration. In healthy subjects and patients with iRBD, NM-MRI signal increased initially and then decreased similarly as in rodents after reaching a similar maximum signal intensity in both groups. In early PD and converted iRBD patients, NM-MRI signal drop was greater than in healthy individuals. Results in animals and humans show that NM-sensitive MRI is a marker of the intracellular NM accumulation up to a threshold then of neuronal degeneration beyond this threshold and agree with the hypothesis of a pathogenic threshold of NM triggering neurodegeneration.

neuroscience↗

bioRxiv2024

Age-trajectories of higher-order diffusion properties of major brain metabolites in cerebral and cerebellar grey matter using in vivo diffusion-weighted MR spectroscopy at 3T

Healthy brain aging involves changes in both brain structure and function, including alterations in cellular composition and microstructure across brain regions. Unlike diffusion-weighted MRI (dMRI), diffusion-weighted MR spectroscopy (dMRS) can assess cell-type specific microstructural changes, providing indirect information on both cell composition and microstructure through the quantification and interpretation of metabolites diffusion properties. This work investigates age-related changes in the higher-order diffusion properties of three major intracellular metabolites (N-Acetyl-aspartate, Creatine and Choline) beyond the classical apparent diffusion coefficient in cerebral and cerebellar grey matter of healthy human brain. Twenty-five subjects were recruited and scanned using a diffusion-weighted semi-LASER sequence in two brain regions-of-interest (ROI) at 3T: posterior-cingulate (PCC) and cerebellar cortices. Metabolites diffusion was characterized by quantifying metrics from both Gaussian and non-Gaussian signal representations and biophysical models. All studied metabolites exhibited lower apparent diffusivities and higher apparent kurtosis values in the cerebellum compared to the PCC, likely stemming from the higher microstructural complexity of cellular composition in the cerebellum. Multivariate regression analysis (accounting for ROI tissue composition as a covariate) showed slight decrease (or no change) of all metabolites diffusivities and slight increase of all metabolites kurtosis with age, none of which statistically significant (p>0.05). The proposed age-trajectories provide benchmarks for identifying anomalies in the diffusion properties of major brain metabolites which could be related to pathological mechanisms altering both the brain microstructure and cellular composition.

biophysics↗

bioRxiv2023

Non-ablative disease-modifying effects of magnetic resonance-guided focused ultrasound in neuromelanin-producing parkinsonian rodents

Age-dependent accumulation of the brain pigment neuromelanin has been implicated in the pathogenesis of Parkinsons disease (PD). In humans, intracellular and extracellular neuromelanin levels are increased in PD postmortem brains and boosting neuromelanin production in rodents compromises neuronal function and viability and triggers a PD-like phenotype. Focused ultrasound has been shown to reduce ultraviolet light-induced skin hyperpigmentation in guinea pig and to remove brain extracellular {beta}-amyloid plaques in Alzheimers mouse models. Here we show that repeated application of transcranial focused ultrasound (tFUS) is able to decrease intracellular and extracellular neuromelanin levels in neuromelanin-producing parkinsonian rats, compared to sham-treated animals, without the need for any additional therapeutic agent or intervention. Reduced neuromelanin levels in tFUS-treated animals were associated with decreased Lewy-like pathology, preserved dopaminergic phenotype, attenuated nigrostriatal degeneration, reduced glial activation, and long-term recovery of motor function. Our findings indicate that tFUS treatment applied at prodromal/early disease stages provides by itself extended structural and functional preservation of the nigrostriatal pathway in neuromelanin-producing parkinsonian rats without causing overt neuronal damage. This FDA-approved technology should thus be explored further as a noninvasive method with neuroprotective potential in PD and to maintain neuromelanin to levels below its pathogenic threshold within the aging population. One Sentence SummaryTranscranial focused ultrasound reduces age-dependent neuromelanin accumulation and provides therapeutic benefit in parkinsonian rats

neuroscience↗

bioRxiv2022

3D-imaging reveals conserved cerebrospinal fluid drainage via meningeal lymphatic vasculature in mice and humans

Meningeal lymphatic vessels (MLVs) contribute to waste product elimination and immune surveillance in brain tissues. MLVs were identified in the dorsal and caudo-basal regions of the dura mater, where they ensure the clearance of cerebrospinal fluid (CSF). Whether MLVs exist in the complex anterior part of the murine and human skull, and how they connect with the glymphatic system and extracranial lymphatic vasculature remained unclear. Here, we generated three-dimensional (3D) maps of MLV drainage by light-sheet fluorescence microscopy (LSFM) imaging of mouse whole-head preparations following fluorescent OVA-A555 tracer injections into the CSF. In humans, we performed real-time magnetic resonance vessel wall imaging (MR-VWI) after systemic gadobutrol injections. We observed a conserved 3D-anatomy of MLVs in mice and humans, and we discovered an extended anterior network around the dural cavernous sinus including multiple capillary beds and exit routes through the foramina of emissary veins. MR-VWI may provide a diagnostic tool for patients with CSF drainage defects and neurological diseases. Short abstractWe established the 3D-anatomy of meningeal lymphatic vasculature and associated CSF drainage by postmortem light-sheet imaging in mice and by real-time magnetic resonance imaging in humans, demonstrating conserved lymphatic circuitries in contact with dural venous sinuses.

neuroscience↗

bioRxiv2020

The R1-weighted connectome: complementing brain networks with a myelin-sensitive measure

Myelin plays a crucial role in how well information travels between brain regions. Many neurological diseases affect the myelin in the white matter, making myelin-sensitive metrics derived from quantitative MRI of potential interest for early detection and prognosis of those conditions. Complementing the structural connectome, obtained with diffusion MRI tractography, with a myelin sensitive measure could result in a more complete model of structural brain connectivity and give better insight into how the myeloarchitecture relates to brain function. In this work we weight the connectome by the longitudinal relaxation rate (R1) as a measure sensitive to myelin, and then we assess its added value by comparing it with connectomes weighted by the number of streamlines (NOS). Our analysis reveals differences between the two connectomes both in the distribution of their weights and the modular organization. Additionally, the rank-based analysis shows that R1 is able to separate different classes (unimodal and transmodal), following a functional gradient. Overall, the R1-weighted connectome provides a different perspective on structural connectivity taking into account white matter myeloarchitecture. Author summaryIn the present work, we integrate a myelin sensitive MRI metric into the connectome and compare it with a connectome weighted with a standard diffusion-derived metric, number of streamlines (NOS). Our analysis shows that the R1-weighted connectome complements the NOS-weighted connectome. We show that the R1-weighted average distribution does not follow the same trend as the NOS strength distribution, and the two connectomes exhibit different modular organization. We also show that unimodal cortical regions tend to be connected by more streamlines, but the connections exhibit a lower R1-weighted average, while the transmodal regions tend to have a higher R1-weighted average but fewer streamlines. In terms of network communication, this could imply that the unimodal regions require more connections with lower myelination, whereas the transmodal regions take more myelinated, but fewer, connections for a reliable transfer of information.

neuroscience↗

bioRxiv2019

Rere-dependent Retinoic Acid signaling controls brain asymmetry and handedness

While the vertebrate brain appears largely bilaterally symmetrical in humans, it presents local morphological Left-Right (LR) asymmetries as, for instance, in the petalia. Moreover, higher functions such as speech or handedness are asymmetrically localized in the cortex. How these brain asymmetries are generated remains unknown. Here, we reveal a striking parallel between the control of bilateral symmetry in the brain and in the precursors of vertebrae called somites, where a \"default\" asymmetry is buffered by Retinoic Acid (RA) signaling. This mechanism is evident in zebrafish and mouse and, when perturbed in both species, it translates in the brain into lateralized alterations of patterning, neuronal differentiation and behavior. We demonstrate that altering levels of the mouse RA coactivator Rere results in subtle cortex asymmetry and profoundly altered handedness, linking patterning and function in the motor cortex. Together our data uncover a novel mechanism that could underlie the establishment of brain asymmetries and handedness in vertebrates.

neuroscience↗

bioRxiv2018

Non-invasive ultrasonic modulation of visual evoked response by GABA delivery through the blood brain barrier

We demonstrate the feasibility of non-invasively modulating the visual cortex activity of non-human primates by local ultrasound-induced delivery of an inhibitory neurotransmitter (GABA). GABA was injected intravenously after the blood brain barrier (BBB) was transiently disrupted with focused ultrasound (FUS) coupled with ultrasound contrast agents (UCA). Visual evoked potentials exhibited a significant and progressive decrease of the activity. Combined effects of neuromodulation and BBB opening were shown to be 8.7 times less important than GABA-induced inhibition. During the sonication, the UCA harmonic response was monitored to estimate the level of stable cavitation (signature of BBB opening efficiency) and to avoid damages due to inertial cavitation (automatic shutdown of the sonication when detected). As recent developments in beam forming have shown that ultrasound beams can be focused non-invasively in deep-seated human brain locations, our results hold promise to explore and treat the brain with a non-invasive, controllable, repeatable and reversible method.

neuroscience↗

bioRxiv2018

Offline impact of transcranial focused ultrasound on cortical activation in primates

To understand brain circuits it is necessary both to record and manipulate their activity. Despite increased availability of techniques for manipulating neural activity in rodents, manipulating neural activity in primates remains difficult. Here we show that a minimally invasive technique, transcranial focused ultrasound stimulation (TUS), induced offline changes to activity of circumscribed brain regions in the macaque. Applying TUS to the supplementary motor area or frontal polar cortex resulted in spatially specific patterns of activity change measurable with functional magnetic resonance imaging. In each case changes reflected each areas known network of interactions with the rest of the brain. Independent of these specific neural effects, TUS over these regions also induced widespread signal changes that might have a non-neuronal origin possibly mediated by the cerebral spinal fluid compartment. Although sustained for more than one hour beyond the 40s stimulation period, TUS effects were reversible and not associated with histological changes.\n\nHighlights O_LIMany studies of ultrasound neuromodulation focus on online effects in rodents.\nC_LIO_LIWe use fMRI connectivity to investigate its offline impact in the primate brain.\nC_LIO_LI40 s of ultrasound leads to a sustained, specific, reversible neural modulation.\nC_LIO_LIUltrasound caused a sharpening of the stimulated regions connectivity profile.\nC_LI\n\nIn BriefA new application of focused ultrasound safely modulates brain activation in primates for up to 2 hours after 40 seconds of stimulation. Ultrasound caused the stimulated area to interact more selectively with the rest of the brain.

neuroscience↗