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

自闭症谱系疾病(ASC)包括一系列神经发育障碍，其特征是社交沟通和互动受损，以及受限的、刻板印象的行为和兴趣。虽然病因尚不清楚，但有一种理论已经获得了相当大的支持，那就是中断的连通性理论。这一理论表明，症状是由于大脑功能活动的非典型同步造成的。患有自闭症的人可能无法像正常发育的人那样有效地参与或脱离大脑网络。静息状态功能磁共振成像(rs-fMRI)研究为ASC的中断连接理论提供了支持[1]。然而，由于ASC是一种神经发育障碍，父母往往早在12-14个月就报告了最初的担忧，目前尚不清楚异常在多大程度上反映了这种疾病的主要病理生理，以及它们在多大程度上是继发性或代偿性影响。这促使人们努力在生命的早期研究大脑，在它被出生后的机制或具有自闭症特征的生活经历塑造之前。由于有ASC家族史(FAM+)的婴儿本身比没有家族史(FAM-)的儿童更容易发生ASC[2]，对这些婴儿的前瞻性研究提供了一种评估与ASC易感性相关的生物学机制的手段。第一项使用功能磁共振成像来表征FAM+婴儿功能连接的研究表明，6个月时功能连接异常可以预测24个月时的诊断结果[3]。随后的研究表明，12个月时枕区和24个月时基底节的过度连接与运动行为的延迟有关[4]，视觉网络与额顶皮质和默认模式网络之间的连接不足与12个月时的仪式性/相同行为有关，背侧注意网络与皮质下区域之间以及默认模式网络与24个月时的刻板行为之间的过度连接与刻板行为有关[5]。最近，我们的研究小组发现，FAM+新生儿在负责处理高阶社会信息的区域也有显著更高的神经活动[6]，然而，迄今为止的研究使用了整个时间序列来得出区域之间的平均连接性。这是在假设大脑的功能结构是静态的基础上进行的。然而，人们越来越认识到，网络之间的神经通信是高度灵活的，因此重要的时间信息可能会在静态功能磁共振分析中丢失[7]。由于发育中大脑的动态功能连接仍未被探索，无论是在典型发育中还是在患有ASC风险增加的婴儿中，拟议的工作旨在探索具有ASC家族史的婴儿的动态功能连接，嵌入到了解典型大脑发育的背景中。这可能为ASC的病因学提供关键的新见解，潜在地导致基于大脑瞬时网络动力学的新生物标记物的开发。这项工作将增加我们团队多年来对异常神经发育的成像生物标记物的研究，这些研究从新生儿成像以及ASC等神经发育障碍的临床方面的专业知识中受益匪浅。1)描述和关联典型发育婴儿的静态和动态功能连通性测量2)为了探索观察到的动态连通性模式如何与睡眠状态的波动相关，候选人然后将通过解决下一组目标来探索与典型连通性模式的差异，即：3)探索典型发育婴儿和有自闭症谱系疾病家族史的婴儿之间瞬时连通性状态的差异

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