Melbourne School of Psychological Sciences - Theses
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ItemCerebello-cortical and fronto-parietal contributions to working memory function in children born extremely preterm: a diffusion MRI study( 2016)Survivors of extremely preterm birth (<28 weeks’ gestation) and/or extremely low birth weight (<1000 grams) have elevated rates of working memory impairment compared with term-born peers. This impairment may be a core deficit underlying problems experienced by these children in other areas of cognitive, behavioural and academic functioning. Extremely preterm survivors are also at risk of white matter injury and cerebellar injury as a result of neurological disruptions associated with preterm birth. However, it is not yet known whether this injury and developmental disruption to cerebellar white matter connections underlies the working memory deficits seen in this population. It is also unclear whether working memory deficits may be ameliorated through intensive working memory training, and whether white matter microstructural plasticity underlies training gains in working memory capacity. This thesis aimed to examine whether variability in the maturity and microstructural organisation of white matter pathways associated with working memory were related to working memory ability in a group of 7-year-old extremely preterm children. It also aimed to evaluate whether working memory capacity and white matter microstructure were capable of change (functional and neuroplastic change, respectively), in response to the most widely evaluated adaptive working memory training intervention, Cogmed. Sixty participants were recruited from a large cohort of 7-year-old extremely preterm children born in Victoria, Australia. Two white matter pathways in the brain were investigated using probabilistic tractography with diffusion-weighted MRI; the superior longitudinal fasciculus (SLF), a monosynaptic fronto-parietal white matter tract well-recognised for its involvement in working memory function, and the cerebello-thalamo-prefrontal (CTP) pathway, a polysynaptic efferent cerebellar white matter pathway hypothesised to be involved in working memory function. The CTP pathway was further divided into two monosynaptic components; the cerebello-thalamic tract (CT), and the thalamo-prefrontal tract (TP). The diffusion-weighted MRI measures of fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity were used to assess white matter microstructure. The Cogmed working memory training intervention (5-7 weeks) was administered using a double-blinded, placebo-controlled, randomised control trial. In the adaptive Cogmed intervention, activities became more complex with increasing proficiency of the participant, thereby challenging working memory capacity. In the placebo Cogmed intervention, activities remained at a fixed, low level of difficulty. Working memory capacity and white matter microstructure were assessed at baseline and two-weeks post-intervention using gold-standard measures. The study found that, prior to the intervention, immaturity of microstructural connectivity in cerebello-thalamo-prefrontal and fronto-parietal white matter pathways was related to lower working memory performance. Following the intervention, no significant difference in working memory performance or microstructural white matter maturity was noted in children who undertook adaptive versus placebo training. The novel finding of this thesis is that early disruption to the microstructural development of cerebello-cortical white matter pathways (as a result of extremely preterm birth) may represent a potential neurobiological mechanism underlying working memory dysfunction in this population. Evaluation of these tracts in the perinatal period therefore has the potential to identify children at risk of developing working memory deficits later in life, so that close surveillance or early interventions may be applied. However, Cogmed adaptive (versus placebo) working memory training does not appear to be an effective intervention in improving working memory capacity for school-age extremely preterm children.
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ItemThe neuroendocrine system following preterm birth and its effects on cognitive and brain development at age 7( 2012)Preterm birth is associated with a well-defined pattern of neurodevelopmental impairments which include a range of cognitive deficits, as well as structural brain abnormalities. Further, preterm infants are known to have a transiently altered neuroendocrine system during the first weeks of postnatal life. Although recent studies have focused on characterising long-term neurobehavioural deficits, few have examined potential mechanisms that may, at least partly, explain these poorer outcomes. This study aimed to address this shortcoming by focusing on the postnatal neuroendocrine system and its association with neurodevelopmental outcomes at age 7 in a group of children born very preterm. Postnatal concentrations of three hormones, free thyroxine, cortisol, and growth hormone, were examined using both direct hypothesis testing and exploratory hypothesis-generating approaches. Three direct hypotheses were proposed following review of the literature. Firstly, it was hypothesised that lower postnatal free thyroxine concentrations would be associated with poorer performances on measures of intellect, attention, and visuoperceptual abilities, as well as reductions in grey and white matter volumes at age 7 in children born very preterm. Secondly, it was hypothesised that higher postnatal cortisol concentrations would be associated with poorer performances on tasks of new learning and memory and volumetric reductions in the hippocampi at age 7 in children born very preterm. The final hypothesis predicted that elevated postnatal growth hormone concentrations would be related to deficits in attention and executive functioning and reductions in the prefrontal brain volumes at age 7 in children born very preterm. The current study investigated 83 children born very preterm (gestational age <30 weeks and/or birth weight <1250g), born between June 2002 and December 2003 in Melbourne, Victoria. During the neonatal period, hormone analysis was conducted over eight time points during the first 42 days of life (cord, Day 1, Day 4, Day 7, Day 14, Day 21, Day 28, and Day 42) to characterise the hormone profiles associated with preterm birth. At age 7, the children participated in a cognitive assessment and an MRI scan. A broad neuropsychological battery that assessed six domains of cognition, namely intellect, language, visuoperceptual reasoning, memory, attention and executive functioning, and processing speed, was used to characterise the cognitive profiles of this group of children. MRI imaging analysis was conducted using Freesurfer (v 5.1.0) to obtain cortical and subcortical brain volumes. The results did not confirm the direct hypotheses, although some interesting and novel findings arose. Firstly, elevated free thyroxine concentrations were related to poorer processing speed performances. A similar relationship was observed with elevated cortisol concentrations and decrements in processing speed. Lastly, elevated cortisol concentrations were related to volumetric reductions in subcortical regions, particularly the basal ganglia. Possible explanations for these findings were reviewed, though more research is required to confirm these relationships. Using a critical illness theory of endocrinology, it was concluded that the hormone profile exhibited by this cohort of children born very preterm during the early postnatal period, namely low concentrations of free thyroxine, and elevated concentrations of cortisol and growth hormone, reflected a transient reaction to acute critical illness. Moreover, given the adaptive nature of this acute illness phase, it was concluded that this postnatal hormone profile did not explain the diffuse nature of the neurodevelopmental impairments common to the preterm population.