Perinatal brain maturation in children at risk of developing Autism Spectrum Conditions

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Autism spectrum conditions (ASC) comprise a range of neurodevelopmental disorders, characterized by impaired social communication and interaction and restricted, stereotyped behaviours and interests. Although the aetiology remains unclear, one theory that has gained considerable traction is the disrupted connectivity theory. This theory suggests that symptoms are due to atypical synchronization of brain functional activity. Individuals with ASD may be unable to engage or disengage brain networks as effectively as typically developing individuals. Resting-state functional magnetic resonance imaging (rs-fMRI) studies offer support to the disrupted connectivity theory of ASC [1]. However, with ASC being a neurodevelopmental disorder, and parents often reporting initial concerns as early as 12-14 months, it is unclear to what extent abnormalities reflect a primary pathophysiology of the condition, and to what extent they are secondary or compensatory effects. This has motivated efforts to study the brain as early in life as possible, before it is shaped by postnatal mechanisms or the experiences of living with autistic traits. As infants with a family history of ASC (FAM+) are more vulnerable to developing ASC themselves than children without a family history (FAM-)[2], prospective study of these infants provides a mean of assessing biological mechanisms associated with vulnerability to ASC. The first study using fMRI to characterize functional connectivity in FAM+ infants demonstrated that abnormalities in functional connectivity at 6 months can predict diagnostic outcome at 24 months [3]. Subsequent studies showed that over-connectivity in occipital regions at 12 months and basal ganglia at 24 months is linked to delays in motor behaviour [4], that underconnectivity between the visual network and frontoparietal cortex and the default mode network is associated with ritualistic/sameness behaviour at 12 months, and that overconnectivity between dorsal attention network and subcortical regions, and between default mode network and the frontoparietal network is associated with stereotyped behaviours at 24 months [5]. Most recently, our group showed that FAM+ neonates also have significantly higher neural activity in regions responsible for processing higher-order social information [6]However, studies to date have used the entire time series to derive the average connectivity between regions. This operates under the assumption that the brain's functional architecture is static. There is however growing appreciation that neural communication between networks is highly flexible, and important temporal information may therefore be lost in static fMRI analysis [7]. As dynamic functional connectivity in the developing brain remains unexplored, both in typical development and in infants with an increased risk of ASC, the proposed work aims to explore dynamic functional connectivity in infants with a family history of ASC, embedded within the context of understanding typical brain development. This may provide critical new insights into the aetiology of ASC, potentially leading to the development of new biomarkers based on the brains transient network dynamics. This work will add to years of research in imaging biomarkers for abnormal neurodevelopment performed by our group, which benefits strongly from expertise in neonatal imaging, as well as the clinical aspects of neurodevelopmental disorders such as ASC. 1)To describe and relate static and dynamic functional connectivity measures in typically developing infants 2)To explore how the observed dynamic connectivity patterns relate to fluctuations in sleep state The candidate will then explore divergence from typical connectivity patterns by addressing the next set of aims, namely: 3)To explore differences in transient connectivity states between typically developing infants and infants with a family history of autism spectrum conditions