Abstract
There is currently very little known about early brain development; even less about how normal development may be disrupted in individuals genetically predisposed to neurodevelopmental conditions, including autism spectrum disorder (ASD). Hence, by using magnetic resonance imaging (MRI) to examine the structure and chemistry of the fetal, neonatal, and infant human brain, my intention was to provide further insight into early neurodevelopment. The additional focus on individuals with a familial risk of ASD, also aimed to detect any potential deviations from typical brain development that may be associated with an ASD risk status.The first experimental study of this thesis used MRI at 1.5T to reveal that the early environment – specifically, mother-infant interactions – is associated with variations in brain biology, within a sample of assumed-to-be typically developing individuals. Therefore, the next study, which compared brain volume in infants with and without a familial risk of ASD also incorporated measures of mother-infant interactions. In this second study, subcortical and cerebellar enlargements were identified in 4-6 month-old infants at risk of ASD, and larger volumes were associated with more autistic symptoms at 36 months. Within the high-risk group, a higher measure of maternal sensitivity was correlated with lower subcortical brain volumes.
Next, to examine even earlier development and to estimate when differences between risk groups might first appear, fetuses and neonates with and without a familial risk of ASD were scanned using advanced MRI protocols at 3T. At both these timepoints, the cortex and cerebellum were identified as the fastest growing brain regions. In addition, fetuses at risk of ASD had smaller cortical volumes when compared to low-risk controls. Postnatally, within the first month of life, neonates at risk of ASD also had smaller intracranial and total brain volumes, as well as a smaller lentiform nucleus. Placed together with the infant findings, these studies suggest that an ASD genetic risk constrains brain growth in the perinatal period, but is associated with volumetric expansion of both subcortical and cerebellar regions in infancy. The subcortical region also appeared to be particularly affected by the abnormal growth trajectory of high-risk participants, as differences in this region were observed amongst high-risk individuals at both neonatal and infant timepoints.
The subcortex was therefore selected as a region-of-interest in the final study, which mapped metabolic maturation from fetal to early postnatal life using magnetic resonance spectroscopy. In both low and high-risk groups, choline and myo-inositol decreased significantly with age, whilst N-acetylaspartate and creatine increased. In contrast, glutamate (measured as glutamate and glutamine; Glx) decreased from fetal to neonatal life, with a marked ‘dip’ around the time of birth before increasing in early infancy. The sample size at the 4-6 month timepoint also permitted an explicit comparison of low and high-risk infants, and because previous studies of older cohorts have linked glutamate abnormalities to ASD, Glx levels were compared between groups. The results showed, for the first time, that high-risk infants have significantly elevated levels of Glx at 4-6 months of age, when compared to low-risk controls.
In conclusion, both the volume and biochemistry of the human brain undergoes rapid change in the late prenatal and early postnatal periods. Moreover, individuals with a familial risk of ASD already show differences in brain maturation from fetal life, including neurochemical pathways modulating the balance of neuronal excitation and inhibition. This is well before the onset of autistic symptoms, and therefore, has important implications for ASD in terms of risk (and resilience) pathways.
| Date of Award | 2017 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Grainne McAlonan (Supervisor), Declan Murphy (Supervisor) & Mary Rutherford (Supervisor) |