Melbourne School of Psychological Sciences - Theses
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ItemThe role of the serotonin transporter gene, brain structure and family environment in the emergence of depression during adolescence( 2017)Recent findings suggest that complex interrelations between genetics, brain structure and environmental contexts, including stressors and family processes, may have a role in the development of depressive disorders. The role of a functional variant in the 5-HT transporter promoter region polymorphism (5-HTTLPR) and its potential interaction with adverse, stressful life events in predicting depression has been the focus of considerable research attention. The validity of this gene-environment interaction, however, has been queried due to inconsistent findings. The current thesis aims to enhance current understanding of this interaction by considering how two different dimensions of environmental experience (threat versus deprivation) might interact with the serotonin transporter gene during adolescence, while also investigating potential underlying neurobiological mechanisms. Three interconnected studies were conducted that examined the interplay between the serotonin transporter gene, family environment, brain regions of interest and depression. Study 1 examined whether 5-HTTLPR moderated associations between (1) high levels of negative, harsh, critical parenting behaviours (as an index of more threatening environments) and subsequent depression and (2) low levels of positive, supportive parenting behaviours (as an index of more deprived environments) and subsequent depression during adolescence. These GxE interactions were tested in adolescents from two independent longitudinal studies, the Australian Temperament Study (ATP, n=681) a population based sample that relied on questionnaire measures of environment and depression, and the Orygen Adolescent Development Study (ADS, n=174) a sample enhanced for temperamental risk and resilience factors for internalising conditions, that drew on observational measures of the environment and semi-standardised clinical interview measures of depression. In both studies, adolescents carrying at least one copy of the S-allele appeared to be buffered against risk for depression in the context of low positive parenting, whilst adolescents in the L-homozygous group were at greater risk for depression with decreasing levels of positive parenting. Negative parenting did not interact with serotonin transporter genotype in either study. Study 2 was based on the ADS and examined the extent to which variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) volumes in early adolescence mediated a putative association between 5-HTTLPR genotype and first onset of Major Depressive Disorder (MDD) over a six year period. Increasing copies of S-alleles predicted smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes was prospectively associated with a first episode of MDD during adolescence. Study 3 was also based on the ADS and employed an imaging-gene x environment (IGxE) framework to investigate whether the strength of the imaging genetics pathway involving the hippocampus that was identified in Study 2 differed as a function of parenting behaviour. Results were consistent with the presence of an indirect effect of the serotonin transporter S-allele on depression onset via smaller left and right hippocampal volumes that was significant only in family environments involving either higher levels of negative parenting or lower levels of positive parenting. The previously reported finding of S-allele carriers’ increased risk of depression in adverse environments may therefore be partly due to the effects of these environments on a neurobiological pathway from the serotonin transporter gene to depression onset that proceeds through variation in hippocampal volume. It is hoped that approaches that aim to integrate genetic, environmental and neurobiological factors such as those utilised in this thesis will improve the likelihood of developing more targeted prevention and intervention opportunities for individuals at risk of or already experiencing clinical depression.
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ItemWilliams Syndrome: links between brain, cognition, and behaviour( 2005-10)The interrelationships between brain, cognition, and behaviour are complex but can be more clearly characterised by studying disorders with an underlying genetic basis. This thesis examined these interrelationships in the context of Williams syndrome (WS), a neurodevelopmental genetic disorder that affects aspects of cognition, behaviour, and brain structure. The principal aims of this thesis were to evaluate the cognitive, behavioural, and neuroanatomical profile of WS individuals and to explore the relationships between aspects of the cognitive and behavioural profile and the neuroanatomical changes that are evident in WS. Three general hypotheses, and 10 specific hypotheses, were postulated as a means of exploring these aims. The first general hypothesis predicted that WS individuals would demonstrate distinct features within their cognitive and behavioural profile. Specifically, it was predicted that WS individuals would show relative strengths on verbal tasks and significant deficits on visuospatial and mathematical tasks, in contrast to control participants who were predicted to show a more even profile. It was also predicted that WS individuals would show evidence of heightened affect in response to music and demonstrate hypersociability as compared to control participants
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ItemChildhood maltreatment and structural neuroanatomy as risk factors for adolescent onset depression( 2012)This thesis concerns three broad subjects – childhood maltreatment, structural neuroanatomical features in early adolescence, and depressive symptoms in mid-adolescence – with the aim of examining predictive relationships between them. The core focus of the thesis was on investigating relationships between the volumes of key brain structures implicated in emotion regulation, and adolescent onset depression. The measurement of brain structures in a psychiatrically healthy sample of children aged 11-12 years, and the use of these measurements to predict onset of depressive symptoms 2-3 years later, allowed for contribution to theoretical debate about the timing of structural alterations previously associated with depression – specifically, whether observed alterations formed risk factors for depression, or whether they were outcomes of disease-related processes. The evidence of premorbid structural alterations demonstrated by this thesis suggests that there are vulnerability biomarkers for depression, and may assist in better understanding the mechanisms of depressive illness as well as identifying individuals at risk. The secondary focus of the thesis was on retrospectively examining relationships between maltreatment in childhood and structural neuroanatomical features in adolescence, with the aim of identifying effects of childhood adverse experience on brain development. Previous studies have largely utilised adult populations with maltreatment-related psychiatric illness, and therefore have not been able to conclude whether structural alterations following childhood maltreatment only occur in those individuals who later develop psychopathology, or whether these changes occur before the onset of any psychopathology. This thesis investigated whether structural changes were associated with childhood maltreatment in a healthy sample of young adolescents, allowing the separation of early experiential effects from later psychopathological processes. This research also explored whether the volumes of selected brain structures mediated relationships between childhood maltreatment and adolescent onset depression, however no such relationships were detected. As this was an exploratory measure secondary to the key themes of the thesis, and interpretations were constrained by issues of sample size, it is not dealt with in detail. The most robust aspect of this research design was the examination of neurostructural risk factors for depression, and this formed the central content of the thesis. There is also a large extant body of research and literature on depression and brain development, from which to gain a strong theoretical grounding on the role of each brain structure examined in terms of the cognitive and affective processes it is thought to subserve. For this reason, material on the epidemiology and neurobiological models of depression form the first three chapters. An exploration of the emerging body of literature on the relationships between childhood maltreatment and brain development is contained subsequently. Chapter 1 provides an introduction to the epidemiology and selected etiological influences on adolescent depression. Chapter 2 gives an overview of the current understanding of brain development in adolescence, and describes some of the key theoretical models linking brain development to adolescent onset depression. Key structures highlighted in these models were selected for investigation within this thesis, and detailed examination of the evidence and resultant hypotheses for each of five selected structures’ relationships with depression is contained in Chapter 3. The focus then turns to childhood maltreatment as a second major contributor to adolescent onset depression; Chapter 4 summarises research on the prevalence and types of childhood maltreatment and the relationships between childhood maltreatment and adverse outcomes including the development of depression. Chapter 5 reviews literature from the emerging field of developmental traumatology, drawing inferences from the body of work examining neuroendocrinological sequelae of childhood maltreatment and bringing together preliminary findings from a range of sources to form hypotheses regarding potential relationships between childhood maltreatment and the brain structures discussed in previous chapters. Chapter 6 gives detail on the design and methodology of the thesis, and Chapter 7 explains the data analysis used and reports on the results. Interpretation of findings, discussion of strengths and limitations of the research, and implications for future work are contained in Chapter 8.
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ItemAffective responsivity in Williams Syndrome: behaviour, psychophysiology, and brain( 2013)The primary goal of this thesis was to evaluate the behavioural and psychophysiological affective response profiles of Williams syndrome (WS) individuals, and to examine the links between these affective responses and amygdala structure and function. It is proposed that abnormalities in the structure and function of the amygdala would be associated with atypical affective responsivity in WS individuals. To achieve these goals, three studies were conducted. Study 1 compared affective behavioural responsivity of WS and control groups across domains of music, anxiety, fear, and sociability. This study also evaluated the relationships between these affective behaviour domains to compare inter-domain relationships between WS and controls. A secondary goal of this study was to evaluate the stability in sociability scores in WS individuals over a five year period. Study 2 compared affective psychophysiological responsivity of WS and control groups in terms of several psychophysiological measures, namely, startle eyeblink, (SEB), zygomatic activity (ZY), corrugator activity (CO), skin conductance (SC), and heart rate (HR). Psychophysiological responsivity, especially affective SEB modulation, was considered an indirect means of evaluating amygdala functioning. Study 3 evaluated relationships between behavioural and psychophysiological affective responsivity and amygdala volume in WS individuals. Data for Study 1 and Study 2 were collected concurrently. In brief, 25 genetically confirmed WS individuals and 25 normal control participants, matched on chronological age, sex, and handedness, ranging in age from 10 to 37 years, were evaluated. Participants were administered measures that assessed handedness, intelligence, affective behavioural responsivity in domains of music and sociability, and psychophysiological responsivity. Parents/guardians completed questionnaires detailing participants’ fears, anxieties, and musical interests. In Study 1, for a subset of 19 of the 25 WS participants, sociability scores were collected at two time points, at Time 1, five years prior by Martens (2005) and Time 2, during the current study, to examine stability of scores over time. In Study 3, for 17 of the 25 WS participants, amygdala volumes, measured via MRI scans at Time 1 were used to predict affective behavioural and psychophysiological responsivity at Time 2. The findings in Study 1 showed higher affective responsivity to music, elevated fear and anxiety, and hyper-sociability in WS participants, compared to controls. The associations between affective responsivity in these behaviour domains differed across the WS and control groups. The findings in Study 1 also showed stability in sociability scores over a five year period between Time 1 and Time 2. The findings in Study 2 demonstrated exaggerated psychophysiological responsivity in the WS group, compared to the control group, in terms of SEB, ZY activity, CO activity and HR, but not SC. The findings of Study 3 indicated that disproportionately large right amygdala structure and atypical right function in particular are markers of abnormality, which appear to underpin an affective response profile characterised by reduced defensiveness and increased heightened attentional processing of affective stimuli. The observed patterns of affective behavioural responsivity provided some preliminary support that the left and right amygdalae modulate affective behavioural responses in a different manner. Taken together, the findings in Study 1 and Study 2 suggest heightened affective responsivity in WS individuals, compared to controls. The findings in Study 3 suggest that disproportionately large right amygdala volume and atypical right amygdala function in particular are associated with some aspects of the affective response profile of WS individuals, although not always in a manner consistent with between group differences. Overall, the findings provide some limited support for the argument made in this thesis that abnormalities in the amygdala would be associated with atypical affective responsivity in WS individuals, but the need for further research on the role of other structures is clear. The findings across the three studies are discussed in relation to an integrated and overarching model, the Hyper-responsive Amygdala Model, which links affective behavioural responsivity, psychophysiological responsivity, amygdala structure, and amygdala function in WS individuals.