Browsing by Author "Warton, Christopher"

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    Differences in callosal and subcortical volumes and associated neurobehavioural deficits in children with prenatal alcohol exposure
    (2019) Biffen, Stevie Crystal; Meintjes, Ernesta; Warton, Christopher
    Certain high-risk communities in the Western Cape Province of South Africa where heavy maternal prenatal alcohol consumption is perpetuated by historical and societal challenges, have some of the highest prevalence rates of fetal alcohol syndrome (FAS) in the world. FAS has lifelong behavioural and cognitive consequences. Neuroimaging research aims to link deficits in brain structure and function to behavioural outcomes. Manual tracing is considered the gold standard of neuroanatomical volumetric analysis. Combined with neurobehavioural testing it can provide links between structure and function, but is time consuming and labour intensive. Automated segmentation programmes, such as FreeSurfer, are a faster alternative. The challenge is creating automated programmes that can provide results that are comparable to manual tracing, especially in a clinical sample. The aims of this thesis were to investigate (1) the effects of prenatal alcohol exposure (PAE) on the sizes of the caudate nucleus, nucleus accumbens, hippocampus and corpus callosum (CC) and potential relations of regional volumes with IQ and verbal learning, (2) to compare the performance of manual and automated segmentation methods in identifying alcohol-related changes in brain morphometry, and (3) to examine the effects of PAE on inter-hemispheric transfer during adolescence and potential relations of CC size with inter-hemispheric transfer deficits. Participants for this project were recruited from the Cape Town Longitudinal Cohort for whom alcohol exposure data were gathered prospectively from the mothers during pregnancy using the timeline follow-back approach. Participants had been diagnosed previously by two expert dysmorphologists as either control, non-syndromal heavily exposed (HE), partial FAS (PFAS) or FAS. High-resolution T1-weighted images were acquired using a sequence optimized for morphometric neuroanatomical analysis on a Siemens 3T Allegra MRI scanner for 71 right-handed children (9 FAS, 19 PFAS, 24 HE and 19 non-exposed controls) from this cohort at ages 9-11 years. Bilateral caudate nuclei, nucleus accumbens and hippocampi and the CC were manually traced using Multitracer. FreeSurfer was used for automated segmentation. All structures were segmented with both FreeSurfer versions 5.1 and 6.0 to compare progress within development of automated segmentation algorithms. Associations of volumes from manual tracing with IQ and performance on the California Verbal Learning Test-Children’s Version (CVLT-C) were also examined. Inter-hemispheric transfer was assessed using a finger localization task (FLT) administered to 74 participants (12 FAS, 16 PFAS, 14 HE, and 32 controls) from the same cohort at ages 16-17 years. Of these, 34 participants had completed MRI at 9-11 years. Higher levels of PAE were associated with reductions in CC area, as well as bilateral volume reductions in caudate nuclei and hippocampi, effects that remained significant after controlling for alcohol-related reductions in TIV (total intracranial volume). Amongst dysmorphic children (FAS/PFAS), poorer performance on the CVLT-C was related to larger hippocampi and smaller CC. Smaller CC was also associated with lower IQ and partially mediated the effect of PAE on IQ. Manual and automated comparisons showed good agreement in the caudate nuclei, which are simpler to segment, moderate to good agreement in the smaller, more complex nucleus accumbens and hippocampi, and poor agreement in the CC. The latter is not surprising, however, in view of the fact that manual tracing measured the average area of the CC on a mid-sagittal slice, while FreeSurfer measures CC volume over a number of contiguous slices. After controlling for confounders and adjustment for smaller TIV, the latest FreeSurfer version 6.0 provided evidence of alcohol-related volumetric brain reductions comparable to manual segmentation. Only the most severely affected children with FAS demonstrated inter-hemispheric transfer deficits, with the number of transfer-related errors tending to increase with decreasing CC volume among children with PAE. This study confirms and extends evidence of PAE-related decreases in subcortical and CC size and that callosal volume partially mediates alcohol-related impairment in IQ. Although FreeSurfer v 6.0 achieves automated segmentations that are comparable to manual tracing, even in a paediatric clinical sample, performance is more reliable in some structures than others. Improvement and standardization of CC segmentation is especially important given the vulnerability of the CC and its critical role in domains affected by PAE, including verbal learning, IQ and inter-hemispheric transfer of information.
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    The effects of HIV-1 infection on subcortical brain structures in children receiving ART : a structural MRI study
    (2015) Randall, Steven Ronald; Meintjes, Ernesta M; Warton, Christopher
    INTRODUCTION This project investigated volumetric differences in certain subcortical structures as measured on high-resolution structural Magnetic Resonance Imaging (MRI) scans traced manually. The sample comprised 79 5-year old children, 52 with HIV and 27 uninfected controls. Infected children were all stable on antiretroviral therapy (ART) and were from the Children with HIV early antiretroviral (CHER) cohort who have been followed since birth. The study aimed to investigate the long-term effects of HIV and ART on the developing brain. While high-resolution structural data has been analysed using automated FreeSurfer to determine volume and cortical thickness, manual tracing remains the gold standard. Thus, manual tracing was used to validate automated measures and investigate subtle group differences in selected regions of interest. METHODS Extensive clinical data were available for all participants in the study. MR images were AC-PC transformed and converted to analyse format. Structures were traced using MultiTracer software. Structures selected included the caudate, nucleus accumbens (NA), putamen (Pu), globus pallidus (GP) and corpus callosum (CC). Four of these structures occur bilaterally. Tracing was performed in 79 subjects. Three subjects were excluded due to poor quality images or pathology; 5 HIV-1 infected children were excluded as they were not randomized between treatment groups. Certain subjects were retraced for inter and intrarater reliabilities. The effect and association of ethnicity, age, birthweight and sex as possible confounders were investigated. As the groups were not well matched for ethnicity, all Cape Coloured children were excluded from further analyses. Analysis of variance was used to test the effect on structure size between HIV-1 infected children and controls, as well as between 3 treatment arms (ART deferred until clinical criteria were met, early ART for 40 weeks, early ART for 96 weeks) and uninfected controls. Analysis of covariance was used to control for the possible confounding effects of sex and age. Each structure was tested for possible association with clinical variables (CD4, CD8, CD4/CD8 ratio and CD4%) both at enrolment and time of scanning. Linear regressions were modelled using clinical variables that showed significant correlation with structure size whilst controlling for covariates. Congruence between automated FreeSurfer and manual segmentation were evaluated via Bland-Altman, Pearson r and Cronbach's alpha.
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    Effects of prenatal alcohol exposure on cerebellar volume in children an MRI study
    (2012) Boonzaier, Natalie Rosella; Meintjes, Ernesta; Warton, Christopher
    Years of research have demonstrated that prenatal exposure to alcohol contributes to a range of effects in exposed children. These include problems in attention and hyperactivity, deficits in memory and learning, and problems with social, as well as emotional development. Past research has demonstrated that the cerebellum is a significant target of the teratogenic effects of alcohol. The aim of this study was to determine whether prenatal exposure to alcohol has specific effects on the volumes of specific lobules of the cerebellum. Lobule tracing was performed manually, with Multitracer, using a refined methodology. Lobule volumes (normalized for total cerebellar cortical volume) were analysed as functions of diagnosis as well as alcohol exposure. Lobules IX and X were affected when analysing normalized volumes as a function of diagnosis, with the fetal alcohol syndrome diagnostic group being most specifically affected. Significant differences between sex groups were found only for right lobules I-V and left lobule VIII, and hemisphere differences were found in lobule X. When analysing normalized lobule volume as a function of alcohol exposure, in the left hemisphere, lobules I-V showed positive correlations with alcohol exposure, suggesting that this region is relatively spared. Lobule IX and the vermis of the right hemisphere showed negative correlations with alcohol exposure. The strongest negative correlations were found for measures of absolute alcohol per day averaged across the period of pregnancy as opposed to at time of conception. Overall findings suggest that prenatal alcohol exposure causes disproportionate reductions in volume in specific lobules of the cerebellums of children with fetal alcohol spectrum disorders.