PROFouNd

Many neurodevelopmental disorders (NDDs) are associated with perturbations of functional interactions between cerebral areas. This makes the quantitative and non-invasive assessment of those interactions a potential efficient biomarker to ensure early detection and better prognosis of these pathologies. However, limitations in the currently available neuroimaging techniques in terms of spatiotemporal resolutions and clinical applicability has hindered the wide clinical deployement of such functional connectivity-based diagnosis. Our project tackles this challenge by developing spatiotemporal functional connectivity (STFC), an innovative characterisation of multiscale (mesoscopic to large scale) brain activity expected to offer unprecedented sensitivity and specificity. It leverages functional UltraSound (fUS) neuroimaging, a cutting-edge brain imaging modality with high translational potential, and innovative post-processing techniques focusing on propagative brain activity. The ultimate goal is to identify potential fUS-based STFC biomarkers of NDDs suitable both for preclinical and clinical neonatal imaging. First, we will develop a set of descriptor tools tailored to specifically capture propagative activity in neural (Optical and fUS) data and further derive a STFC processing technique, relying on these descriptors, to estimate repetitive propagative spatiotemporal patterns. Secondly, we will benchmark the performance of these methods in scoring spontaneous cortical dynamics associated with distinct animal states (e.g., active, quiet, sleep phases, sedation), using calcium and intrinsic optical imaging data recorded synchronously in GCaMP6 mice. This will be a crucial step to retain the most pertinent (robustness, reproducibility) spatiotemporal descriptor of cortical propagative activity extracted from both neuronal and hemodynamic-related signals. It will also enable to better characterize how hemodynamics, which can be non-invasively observed through functional ultrasound (fUS) are tied to underlying neuronal activity (calcium imaging). Furthermore the technique will also be used to score animal states in ferrets using fUS as ferrets have a mid-sized brain and folded cortex with closer homology with humans for frontal and sensory regions. Our final aim is to validate that fUS-based STFC can efficiently score pathological brain states. We will assess the potential of STFC applied on fUS data as an early biomarker for NDDs in a relevant cross-species (mice and ferrets) preclinical model of NDDs. We will implement the maternal immune activation (MIA) model in those two species and then track specific STFC signatures evidencing alterations in spontaneous cerebral dynamics in the young adult (mice and ferrets) and at perinatal stages (ferret pups at P5-P12). Building from the biomarkers defined in ferrets, we will then search for comparable STFC signatures in fUS data acquired in human neonates (via a clinical trial external to this ANR proposal). This project will bridge the gap between animal models and human neonates to reveal early indicators of NDDs with a new type of analytical biomarkers, offering the potential for timely intervention and improved long-term outcomes for affected individuals.