Introduction
Neurodevelopmental disorders (NDD) result from an alteration in brain development and represent a major public health problem, affecting 1 million newborns in Europe each year. Neurodevelopmental disorders are the source of permanent disabilities that manifest as motor, cognitive, learning, or behavioral dysfunction. Prenatal or neonatal factors considered high risk for NDD include: extreme prematurity, newborns with intrauterine growth retardation, brain growth abnormalities, anoxic-ischemic encephalopathy (AIE) with an indication for therapeutic hypothermia, and a family history of severe NDD in the first degree. Establishing a reliable prognosis for neurodevelopmental disorders is extremely difficult because there are currently no early biomarkers to detect and assess potential long-term deficiencies.
The CONEXUS protocol aims to evaluate whether a unique neuroimager, using ultrafast ultrasound imaging, is capable of assessing, at the patient's bedside, the brain's functional connectivity (fC) in newborns at high risk of NDD. This neuroimager uses functional ultrasound imaging (fUS), a technique developed within the Physics for Medicine laboratory (Paris), and thus constitutes the central medical device of this protocol.
Device
The CONEXUS system is composed of several elements necessary for functional brain imaging of newborns: the Conexus station (similar to an ultrasound machine) on which the Conexus software is installed (allowing the acquisition and processing of ultrasound data necessary for imaging), the ultrasound probe (a physical element allowing the emission and reception of ultrasounds, similar to an ultrasound probe), and the headset (a small system adapted to the anatomy of the patient's head and allowing the probe to be held in place over the fontanelle).
This system allows mapping of brain activity via subtle changes in cerebral blood volume. It is quite similar to an ultrasound machine but uses different image reconstruction and signal processing techniques, which give it its properties. Our research hypothesis: the evaluation of fC by fUS imaging (fC-fUS imaging) is feasible in newborns and could eventually reveal early biomarkers of perinatal brain diseases.
This hypothesis is supported by our preliminary work on neonatal fUS imaging: we have shown the possibility of performing fUS imaging in some newborns and thus measuring a change in brain activity during sleep state changes or during epileptic seizures, as well as at different stages of neurodevelopment (premature vs. term). The CONEXUS study aims to go further thanks to improved technical capabilities and ergonomics (notably the ultrasound probe) allowing multiplane imaging approaching 3D imaging and imaging a large clinical cohort including different stages of development and various pathological risks (term newborns, premature newborns, newborns with intrauterine growth retardation (IUGR), AIE newborns placed in therapeutic hypothermia, and newborns at risk of autism spectrum disorder (ASD)).
Study
Conexus is a descriptive research study of neonatal brain connectivity using fUS imaging. It is a national clinical investigation involving the Neonatal Intensive Care and Pediatrics/Maternity and Child Psychiatry Services of the Robert Debré Hospital, and concerning a medical device (MD), classified as IIa non-CE marked, without the objective of establishing CE marking (IC 4.4). It therefore uses a new medical device for research purposes, the "Conexus" system, which is a joint production of the Physics for Medicine Paris laboratory and the Iconeus company carried out under a scientific collaboration contract. It is a prospective feasibility pilot study, multicentric, open, controlled, and non-randomized. The research will last 5 years, including 3 years of inclusion.
The fUS examinations consist of recording brain activity for a few minutes in one of the imaging planes (Posterior Coronal, Median Coronal, Frontal Coronal, Right Para-sagittal, Right/Left Para-sagittal, 3-plane Antero-posterior Coronal) including structures involved in brain functional connectivity networks (somatosensory, auditory, visual, salience). These fUS examinations are conducted to perform longitudinal follow-up of patients in the different groups.
CONEXUS aims to prove the potential of fC-fUS to characterize and monitor brain functions, understand the developing brain, and search for biomarkers of neurological deficiencies. The definition of early biomarkers of neurodevelopmental disorders would allow early management to guide therapeutic decisions and improve treatment effects. fUS imaging and fC-fUS evaluation have the potential to transform the clinical management of newborns and address a pressing clinical need in neonatology.
Objectives
Main objective: To evaluate the feasibility of acquiring data via fUS imaging of brain functional connectivity in 4 groups (G1 to G4) of newborns at high risk of NDD and a control group of term newborns (G5): group G1 of premature newborns born before 32 weeks of amenorrhea (WA) (N = 26), group G2 of newborns with anoxic-ischemic neonatal encephalopathy \>36 WA (AIE) (N = 10), group G3 of newborns with IUGR \<10th percentile (N = 10), group G4 of newborns from siblings with autism spectrum disorder (ASD) (N = 10), compared to a control group (G5) of term newborns without neurological pathology (N = 20).
Secondary objectives:
* To study the evolution of fUS connectivity in premature infants (G1), from birth to corrected term in relation to brain functional connectivity in term newborns (G5), newborns with anoxic-ischemic encephalopathy (AIE) (treated with therapeutic hypothermia) (G2), newborns with IUGR (G3), and newborns from siblings with at least one child with autism spectrum disorder (ASD) (G4).
* To identify a posteriori within the groups of premature infants (group G1), newborns with AIE (group G2), newborns with IUGR (group G3), and newborns from siblings with ASD (group G4), any early markers of an abnormal neurodevelopmental trajectory (identified based on neuropsychological evaluation at 2 years).
* To create 3D vascular atlases specific to fUS imaging to document the evolution of cerebrovascular structures (vessels \>100µm) in premature infants (group G1), newborns with AIE (G2), newborns with IUGR (G3), and term newborns (group G5), as these data are currently non-existent.
* To create for the first time simultaneous clinical fUS-EEG recordings to study their possible correlations for the 5 groups. By studying possible correlations, we mean, for example, the study of the possible difference in the nature of fUS signals during clearly identified EEG activity periods (e.g., sleep phases).
