Biology subjects

Perot, J.-B.

Publications and source records attributed to Perot, J.-B..

10 recordsLinked to original sources

bioRxiv2026

A Comprehensive Analysis Comparing Isotropic ADC to BOLD-fMRI: Sensitivity to Resting State Networks and Grey to White Matter Functional Connectivity

While Blood Oxygenation Level-Dependent (BOLD) fMRI remains the gold standard for mapping functional brain networks with MRI, its vascular origins inherently conflate haemodynamic effects with neural activity, limiting its sensitivity in white matter (WM) or its interpretation in neurovascular diseases. Apparent Diffusion Coefficient (ADC) fMRI offers an alternative, diffusion-based contrast that is theoretically more sensitive to neuromorphological coupling and therefore more specific to neuronal activation, though investigated primarily during task-based conditions. This study aimed to comprehensively evaluate the efficacy of isotropic ADC-fMRI in detecting established resting-state networks (RSNs) and to extend this methodology to the investigation of grey-to-white matter (GM-WM) functional connectivity. Our analyses revealed a gradient of ADC detectability shaped by the degree of static functional cohesion and structural tethering of each network. The visual and somatomotor networks, being both highly segregated and strongly anchored to underlying structural pathways, yielded the most robust detection. The default mode network (DMN) and dorsal attention network (DAN) reached group-level significance but with lower effect sizes, and their detection proved fragile across analytical approaches. The frontoparietal network (FPN) and salience network (SAN), whose functional identity is defined by dynamic cross-network reconfiguration, did not reach significance. This gradient partially mirrors the established hierarchy of network segregation observed in BOLD, while further suggesting that ADC sensitivity depends on the structural grounding of each network. Furthermore, ADC demonstrated superior sensitivity to GM-WM functional coupling compared to BOLD. GM-WM functional connectivity profiles derived from ADC were significantly more aligned with underlying structural WM architecture across subjects. Taken together, these findings position isotropic ADC-fMRI as a viable complementary modality to BOLD, offering a more direct window into the neural and structural foundations of brain connectivity.

neuroscience↗

bioRxiv2026

Characterising the diffusion functional signature of negative BOLD with interleaved TMS-fMRI in the human brain

The coupling between brain excitatory activity and positive blood oxygen level-dependent (BOLD) responses is well-established. Although often associated with inhibition, negative BOLD remains partially understood. Moving away from neurovascular coupling, apparent diffusion coefficient (ADC)-fMRI provides a more direct measure of excitatory activity, possibly mediated by transient cellular deformations. While decreases in ADC align with positive BOLD, the possible translation of negative BOLD into positive ADC has not been investigated in humans. Diffusion-weighted fMRI (dfMRI) combines vascular and microstructural contributions. Using interleaved subthreshold transcranial magnetic stimulation (TMS)-fMRI on the primary motor cortex (M1), we induced negative BOLD responses in contralateral M1 and primary somatosensory cortex (S1). This was accompanied by a negative dfMRI response, but no ADC-fMRI response, indicating minimal microstructural fluctuations. In ipsilateral M1/S1, no BOLD response was detected while dfMRI revealed a positive cluster, suggesting sensitivity to subtle neural activity. These findings provide new insights into vascular and neuronal responses underlying subthreshold TMS and negative BOLD.

neuroscience↗

bioRxiv2025

Complementary BOLD- and ADC-fMRI explore the role of lateral superior colliculus in flicker fusion frequency

The transition from static to dynamic vision is encoded in the superior colliculus, as recently shown using blood-oxygen-level-dependent functional MRI (BOLD-fMRI) of the rat brain. Visual stimulation at higher frequency than the flicker fusion frequency threshold leads to continuity illusion and is associated with negative BOLD response in the visual cortex, triggered by the superior colliculus. In this paper, we explored this mechanism using fMRI of the rat brain with visual stimulation at low (1Hz) and high (25Hz) frequency. We compared responses between different brain regions (the dorsolateral geniculate nucleus of the thalamus, the medial and lateral parts of the superior colliculus, and the visual cortex), sexes, and field strengths (9.4T and 14T, with varying contributions from large vessels). Results confirmed distinct neural responses to low and high frequency stimulation and highlighted the role of the lateral part of the superior colliculus in the transition from static to dynamic vision. Finally, we evaluated the ability of apparent diffusion coefficient (ADC)-fMRI to detect response to visual stimulation without vascular contribution. We found significant ADC-fMRI response in the medial and lateral parts of the superior colliculus but also in the corpus callosum. Our results highlight the ADC-fMRI high spatial specificity and high sensitivity to white matter.

neuroscience↗

bioRxiv2025

CATERPillar: A Flexible Framework for Generating White Matter Numerical Substrates with incorporated Glial Cells

Monte Carlo diffusion simulations in numerical substrates are valuable for exploring the sensitivity and specificity of the diffusion MRI (dMRI) signal to realistic cell microstructure features. A crucial component of such simulations is the use of numerical phantoms that accurately represent the target tissue, which is in this case, cerebral white matter (WM). This study introduces CATERPillar (Computational Axonal Threading Engine for Realistic Proliferation), a novel method that simulates the mechanic of axonal growth using overlapping spheres as elementary units. CATERPillar facilitates parallel axon development while preventing collisions, offering user control over key structural parameters such as cellular density, undulation, beading and myelination. Its uniqueness lies in its ability to generate not only realistic axonal structures but also realistic glial cells, enhancing the biological fidelity of simulations. We showed that our grown substrates feature distributions of key morphological parameters that agree with those from histological studies. The structural realism of the astrocytic components was quantitatively validated using Sholl analysis. Furthermore, the time-dependent diffusion in the extra- and intra-axonal compartments accurately reflected expected characteristics of short-range disorder, as predicted by theoretical models. CATERPillar is open source and can be used to (a) develop new acquisition schemes that sensitise the MRI signal to unique tissue microstructure features, (b) test the accuracy of a broad range of analytical models, and (c) build a set of substrates to train machine learning models on. HighlightsO_LICATERPillar generates realistic synthetic voxels of white matter containing packed axons and glial cells. C_LIO_LISynthetic axons had similar morphologies to those segmented from human electron microscopy in previous works. C_LIO_LIThe morphological features of synthetic astrocytes closely matched those observed in histology. C_LIO_LIThe functional form of diffusion and kurtosis time-dependence in the intraand extra-axonal spaces agreed with experimentally observed disorder power laws in voxels composed of synthetic axons. C_LI

neuroscience↗

bioRxiv2025

Evaluating the dependence of ADC-fMRI on haemodynamics inbreath-hold and resting-state conditions

Apparent diffusion coefficient (ADC)-fMRI offers a promising functional contrast, capable of mapping neuronal activity directly in both grey and white matter. However, previous studies have shown that diffusion-weighted fMRI (dfMRI), from which ADC-fMRI derives, is influenced by BOLD effects, leading to a concern that the dfMRI contrast is still rooted in neurovascular rather than neuromorphological coupling. Mitigation strategies have been proposed to remove vascular contributions while retaining neuromorphological coupling, by: i) analysing ADC timecourses calculated from two interleaved diffusion-weightings, known as ADC-fMRI; ii) using b-values of at least 200 s mm-2; and iii) using a sequence compensated for cross-terms with fluctuating background field gradients associated with blood oxygenation. Respiration-induced haemodynamic fluctuations, which are dissociated from neural activity, are an excellent test-bed for the robustness of ADC-fMRI to vascular contributions. In this study, we investigate the association between end-tidal CO2 and ADC-fMRI, in comparison with dfMRI and BOLD, in both breath-hold and resting-state paradigms in the human brain. We confirm a strong dependence of the BOLD signal on respiration, and a pattern of delayed haemodynamic response in white matter. While dfMRI mitigates much of the vascular contribution, it retains some association with respiration, as expected. Conversely, ADC-fMRI is mostly unaffected by vascular contribution, exhibiting minimal correlation between expired CO2 and ADC timeseries, as well as low interand intra-subject reproducibility in correlation maps. These findings validate ADC-fMRI as a predominantly non-vascular contrast sensitive to microstructural dynamics, enabling whole-brain functional imaging unconstrained by vascular confounds.

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

Mapping activity and functional organisation of the motor and visual pathways using ADC-fMRI in the human brain

In contrast to blood-oxygenation-level-dependent (BOLD) functional MRI (fMRI), which relies on changes in blood flow and oxygenation levels to infer brain activity, diffusion fMRI (DfMRI) investigates brain dynamics by monitoring alterations in the Apparent Diffusion Coefficient (ADC) of water. These ADC changes may arise from fluctuations in neuronal morphology, providing a distinctive perspective on neural activity. The potential of ADC as an fMRI contrast (ADC-fMRI) lies in its capacity to reveal neural activity independently of neurovascular coupling, thus yielding complementary insights into brain function. To demonstrate the specificity and value of ADC-fMRI, both ADC-and BOLD-fMRI data were collected at 3T in human subjects during visual stimulation and motor tasks. The first aim of this study was to identify an acquisition design for ADC that minimises BOLD contributions. By examining the timings in responses, we report that ADC 0/1 timeseries (acquired with b-values of 0 and 1 ms/{micro}m2) exhibit residual vascular contamination while ADC 0.2/1 timeseries (with b-values of 0.2 and 1 ms/{micro}m2) show minimal BOLD influence and higher sensitivity to neuromorphological coupling. Second, a General Linear Model was employed to identify activation clusters for ADC 0.2/1 and BOLD, from which average ADC and BOLD responses were calculated. The negative ADC response exhibited a significantly reduced delay relative to the task onset and offset as compared to BOLD. This early onset further supports the notion that ADC is sensitive to neuromorphological rather than neurovascular coupling. Remarkably, in the group-level analysis, positive BOLD activation clusters were detected in the visual and motor cortices, while the negative ADC clusters mainly highlighted pathways in white matter connected to the motor cortex. In the averaged individual level analysis, negative ADC activation clusters were also present in the visual cortex. This finding confirmed the reliability of negative ADC as an indicator of brain function, even in regions with lower vascularisation such as white matter. Finally, we established that ADC-fMRI timecourses yield the expected functional organisation of the visual system, including both gray and white matter regions of interest. Functional connectivity matrices were used to perform hierarchical clustering of brain regions, where ADC-fMRI successfully reproduced the expected structure of the dorsal and ventral visual pathways. This organisation was not replicated with the b=0.2 ms/{micro}m2 diffusion-weighted time courses, which can be seen as a proxy for BOLD (via T2-weighting). These findings underscore the robustness of ADC time courses in functional MRI studies, offering complementary insights to BOLD-fMRI regarding brain function and connectivity patterns. KeypointsO_LIThe functional time course of the Apparent Diffusion Coefficient (ADC), specifically measured with alternating b-values of 0.2 and 1 ms/{micro}m2 at 3T, appears to be minimally affected by BOLD contamination. C_LIO_LIIn the activity maps, the location of negative ADC clusters suggests neural activity in WM tracts that are connected to the motor cortex, which is not detected with positive BOLD. C_LIO_LIFunctional Connectivity analysis utilising ADC is better able to detect the organisation of the dorsal and ventral visual streams than diffusion- and T2-weighted time courses. C_LI

neuroscience↗

bioRxiv2021

Identification of the key role of white matter alteration in the pathogenesis of Huntington's Disease

Pathogenesis of the inherited neurodegenerative disorder Huntingtons Disease (HD) is complex and progressive, with a long presymptomatic phase in which subtle changes occur in the brain of gene carriers up to 15 years before the onset of symptoms. Thus, there is a need of early, functional biomarker to better understand disease progression and to evaluate treatment efficacy far from onset. In particular, recent studies have shown that white matter may be affected early in HD. In this study, we scanned longitudinally Ki140CAG mice with structural MRI, Diffusion Tensor Imaging (DTI), Chemical Exchange Saturation Transfer of glutamate (gluCEST) and Magnetization Transfer (MT) imaging, in order to assess white matter integrity over the life of this very progressive mouse model. Our results show early defects of diffusion properties in the anterior part of the corpus callosum, preceding gluCEST defects in the same region (-10.8% at 8 months, -19% at 12 months) that spread to adjacent regions. At 12 months, frontal (-7.3%) and piriform (-16.7%) cortices showed reduced gluCEST, as well as the pallidum (-21.0%). MT imaging showed reduced signal in the septum (-21.7%) at 12 months. Cortical and striatal atrophy then appear at 18 months. Vulnerability of the striatum and motor cortex, combined with alterations of anterior corpus callosum, seems to point out the pivotal role of white matter, in the pathogenesis of HD and the pertinence of gluCEST and DTI as biomarkers in HD. Highlights- A knock-in mouse model of Huntingtons disease is longitudinally characterized - A multimodal MRI protocol is performed to identify biomarkers of the disease - The white matter plays a pivotal role in the pathogenesis of the disease - The cortico-striatal pathway seems particularly vulnerable in Huntingtons disease

neuroscience↗

bioRxiv2021

Broad influence of mutant ataxin-3 on the proteome of the adult brain, young neurons, and axons reveals central molecular processes and biomarkers in SCA3/MJD using knock-in mouse model

Spinocerebellar ataxia type 3 (SCA3/MJD) has a polyQ etiology but, the current knowledge on molecular processes and proteins involved in pathogenesis is not sufficient to fully determine the disease mechanism and find drug targets. Proteases and deubiquitinases, such as Ataxin-3, often have a profound impact on other proteins, yet the global model picture of SCA3 disease progression on the protein level, showing the most crucial proteins and pathways in the brain, and neurons, was not investigated previously. Here, we investigated molecular SCA3 mechanism using interdisciplinary research paradigm combining SCA3 knock-in model, behavior, MRI, brain proteomics, precise axonal proteomics, neuronal energy recordings, labeling of vesicles, and inclusions and focusing in axonal compartment. We have demonstrated that altered metabolic and mitochondrial proteins in the brain and the lack of weight gain in Ki91 SCA3/MJD mice is reflected by the failure of energy metabolism recorded in neonatal SCA3 cerebellar neurons. We have determined that further, during disease progression, proteins responsible for metabolism, cytoskeletal architecture, vesicular and axonal transport proteins are disturbed, revealing axons as one of the essential cell compartments in SCA3 pathogenesis. Therefore we focus on SCA3 pathogenesis in axonal and somatodendritic compartments revealing highly increased axonal localization of protein synthesis machinery, including ribosomes, translation factors, and RNA binding proteins, while the level of proteins responsible for cellular transport, and mitochondria was decreased. We demonstrate the accumulation of axonal vesicles in neonatal SCA3 cerebellar neurons and increased phosphorylation of SMI-312 positive adult cerebellar axons, which indicate axonal dysfunction in SCA3. In summary, the SCA3 disease mechanism is based on the broad influence of mutant ataxin-3 on the neuronal proteome. Processes central in our SCA3 model include disturbed localization of proteins between axonal and somatodendritic compartment, early neuronal energy deficit, altered neuronal cytoskeletal structure, an overabundance of protein synthetic machinery in axons.

neuroscience↗