Methods for functional connectivity and morphometry in neonatal neuroimaging to study neurodevelopment.

Preterm birth is a major pediatric health problem that perturbs the genetically determined program of corticogenesis of the developing brain. As a consequence, prematurity has been strongly associated with adverse long-term neurodevelopmental outcome that may persist even into adulthood. Early characterization of the underlying neuronal mechanisms and early identification of infants at risk is of paramount importance since it allows better development of early therapeutic interventions aiming to prevent adverse outcomes through resilience. This dissertation aims to investigate the consequences of preterm birth on brain function and structure and their relation to adverse neurodevelopmental outcome, as well as to unveil the effect of an early music intervention on brain function. Research to date has mainly focused on the effect of early interventions on the long-term outcome but not on the effect of those interventions on brain function in preterm populations. Moreover, a clear consensus about the predictive utility of MRI volumetric data for long-term outcomes is still missing.

This dissertation consists of three main parts. First, we investigate the effects of an early musical intervention in preterm infants using a task-based and resting-state fMRI paradigm. We explore brain effective connectivity changes during task and functional connectivity (FC) modulations at rest. We show that music exposure during hospitalization promotes brain auditory processing maturation. We find increased FC between the auditory cortex and regions involved in familiarity and music processing, such as the thalamus and caudate nucleus. Moreover, we report increased rs-FC in regions involved in associative memory and multisensory processing, such as the calcarine and angular gyrus with a dosage-dependent effect on this modulation. Secondly, we examine brain volumetric development and whether brain volumes are associated with cognitive and behavioural long-term outcomes. We find that perinatal risk factors, such as asphyxia and sepsis have an impact on brain tissue volume. We also find that cognitive and behavioural outcomes are strongly associated with parental SES and that brain tissue volumes at TEA have moderate predictive power. Next, inspired by studies that have characterized the progression of neurodegenerative diseases, we employ an advanced technique to unveil the sequence of biological events along the course of prematurity. Our novel findings might be of clinical use as they allow more targeted early interventions aiming to improve long-term outcomes. Finally, we propose a framework that enables the spectral graph theory analysis of the functional connectome at the voxel level. Our results indicate the presence of both functional gradients and community structure revealing fine-grained connectivity patterns. The proposed framework opens a new avenue for spectral graph theory research at the voxel level.