Psychiatry - Theses
Now showing items 1-12 of 79
Inflammation in psychosis: Impact on brain structure and symptoms in animal models and humans
Schizophrenia is a severe neuropsychiatric disorder, arising in adolescence and early adulthood and characterised by hallucinations, delusions, blunted affect and disorganised thought patterns. One of the most enduring features of schizophrenia and psychosis are structural brain deficits, whose pathophysiological mechanism is unknown. Accumulating evidence indicates that inflammation both peripherally and centrally in the form of increased activation of the brain’s immune cells, microglia, may be a potential cause of structural deficits in psychosis. The evidence is multi-faceted ranging from mouse models that demonstrate increased numbers of microglia, to clinical studies of patients with schizophrenia showing increased pro- inflammatory molecules within peripheral blood. However, there are still many questions that remain unanswered, including whether inflammation varies across stages of psychosis, whether it is related to structural brain deficits and symptomatology and how inflammation identified in schizophrenia relates to other candidate pathways implicated in psychosis. In this thesis a multi-disciplinary approach was adopted, considered appropriate to tackling the complexity of these questions. Firstly, to determine whether inflammation was associated with other candidate pathways implicated in psychosis, we conducted an animal study, utilising an mGluR5 KO mouse model of psychosis. Glutamate has been shown to influence neuroinflammation, with cellular studies demonstrating that mGluR5 can regulate microglial numbers and activation. At the time of conducting the study, there were no satisfactory mGluR5 PET ligands that enabled in vivo monitoring within the clinical population. The mGluR5 KO mouse had been shown to display neuropsychiatric endophenotypes related to schizophrenia and thereby offered an alternative approach to gaining further insight into the role of mGluR5 in neuroinflammation and how this may impact symptoms associated with psychosis. Our aim was to determine whether neuroinflammation, in the form of increased microglial numbers and activation was present in the mGluR5 KO mouse model thereby giving further insight as to the potential interaction of the glutamatergic system and in particular, mGluR5, with microglial homeostasis. Secondly, we aimed to determine whether peripheral inflammation was related to brain structure and clinical symptomatology. This was executed by conducting two clinical studies, that examined peripheral pro- and anti-inflammatory cytokines and complement proteins in relation to brain regional thickness and volume measurements. We used a multiplex enzyme linked immune-absorbent assays (ELISA) in serum to quantify peripheral cytokines and complement proteins across various stages of psychosis ranging from those at ultra-high risk of psychosis (UHR), to individuals experiencing their first episode (FEP) and subjects with chronic schizophrenia. We sought to determine whether circulating cytokine and complement protein levels were associated with clinical symptomatology and measurements of thickness and brain volume detected using structural magnetic resonance imaging (MRI). This thesis aimed to investigate: 1) whether mGluR5 KO mice, which demonstrate phenotypic features of schizophrenia displayed neuroinflammation in the form of increased microglial numbers when compared to their wildtype littermates 2) whether there was a relationship between cytokine or complement proteins and structural brain measurements across UHR, FEP and chronic schizophrenia 3) whether peripheral inflammatory markers (cytokine or complement proteins) were increased or decreased across stages of psychosis and examine their relationship with clinical symptoms. We found that mGluR5 KO mice have increased microglial numbers compared to WT. This agreed with our hypothesis that animals lacking mGluR5, would show higher rates of inflammation in the brain, in accordance with an anti-inflammatory effect of increased mGluR5 signalling and the psychotic endophenotype of these mice. Our findings indicate that mGluR5 may affect microglial homeostasis in the context of neurodevelopment and may impact on psychosis related behaviours exhibited by mGluR5 KO mice. Secondly, our clinical studies showed that cytokines and complement proteins were related to several brain structures implicated in psychosis, including the frontal cortex and ventricles. We revealed a positive correlation between several anti-inflammatory cytokines such as IL4 and IL13 and increases in frontal cortical thickness, which was absent in patients with psychosis. Conversely, increases in pro-inflammatory cytokine IL5 were associated with decreases in whole brain volume in FEP individuals. Thirdly, we found that while peripheral cytokines did not differ significantly between patients and controls, complement proteins were elevated in UHR and chronic schizophrenia patients. While there were no associations between cytokine proteins and clinical symptoms, we identified a molecular pattern of increased C4 and decreased C3 protein, which was associated with increases in positive and negative symptoms. Taken together, the work of this thesis suggests that inflammation is present in psychosis both in the brain and peripherally but that this depends on the proteins and stage of illness examined. Moreover, we revealed that complement proteins C3 and C4 were associated with alterations in brain structure across the combined cohort; in the case of cytokines however, the positive association between elevated anti-inflammatory cytokines and increased frontal thickness was not preserved or reversed in patient groups, indicating a potential imbalance of pro- and anti- inflammatory cytokines may influence brain structure in psychosis. Finally, we have shown that peripheral inflammation in the form of cytokine and complement proteins, may influence both brain structure and clinical symptomatology, which provides fertile ground for future longitudinal exploration of neuroinflammation in schizophrenia and psychosis.
Effects of childhood adversity and glutamatergic polygenic risk score on brain structure and cognition in schizophrenia
Schizophrenia is a chronic disabling disorder with complex multifactorial aetiology. It is associated with childhood adversity and glutamatergic genes, both of which contribute to brain development and cognition. However, the relationships between these factors are not fully understood and must still be elucidated. This thesis addresses gaps in understanding of this complex link. These findings will be informative for early identification and treatment of those with schizophrenia. Chapter one provides a conceptual framework for the models used in this thesis. A literature review on schizophrenia, childhood adversity, glutamatergic genes, brain development, and cognition is included. The links between these factors are described and the aims of the thesis are justified. Chapter two aimed to identify the association between metabotropic glutamate receptor 3 genetic variation and schizophrenia and explored potential population stratification. This meta-analysis study consisted of 14 single nucleotide polymorphisms of metabotropic glutamate receptor 3 from a total of 11318 schizophrenia cases, 13820 controls, and 486 parent proband trios. We found significant associations for three single nucleotide polymorphisms. We also found evidence for population stratification in that the risk allele was dependent on the population under study. These findings support the genome wide-implicated link between metabotropic glutamate receptor 3 genetic variation and schizophrenia risk, and further support the notion that alleles conferring this risk may be population specific. Chapter three aimed to examine the extent to which the association between childhood adversity and cognition is mediated by structural brain volumes and moderated by glutamatergic polygenic risk score in the context of brain volumes as a mediator. A total of 176 schizophrenia patients and 118 healthy controls participants were assessed for a history of childhood adversity and underwent cognitive testing and structural neuroimaging. Six glutamatergic genes were genotyped, and a weighted glutamatergic polygenic risk score was calculated. Mediation and moderated-mediation models were tested. We found that that there were significant mediation effects of intracranial and total brain volumes on the association between childhood adversity and delayed memory in the overall sample, as well as in the schizophrenia patients. There was also a significant mediation effect of subcortical volume on the association between childhood adversity and working memory in the schizophrenia patients, but not healthy controls. However, there was no significant moderation effect of glutamatergic polygenic risk score on the association between childhood adversity and cognition in the context of brain volume as a mediator. This study demonstrated that childhood adversity exerts a negative impact on intracranial, total brain, and subcortical volumes in schizophrenia. Adversity encountered during childhood may pre-program the brain for subsequent memory performance in adulthood. The effect of glutamatergic polygenic on the association between childhood adversity, brain volume, and cognition in schizophrenia could be related to illness stage or severity. Chapter four aimed to examine interrelationships between childhood adversity, glutamatergic polygenic risk score, frontal lobe volume, and spatial working memory in 51 treatment-resistant schizophrenia patients and 40 healthy controls from the Cooperative Research Centre for Mental Health psychosis study cohort. We found that treatment-resistant schizophrenia patients displayed impairment in spatial working memory between search errors, spatial working memory strategy, and spatial span relative to healthy controls. A significant moderation effect of glutamatergic polygenic risk score was found on the association between childhood adversity and the spatial working memory factor which comprising spatial working memory between search errors, spatial working memory strategy, and spatial span in the treatment-resistant schizophrenia group, but not in the healthy controls. The conditional effects on the association between childhood adversity and spatial working memory indicated that, in the presence of higher childhood adversity, treatment-resistant schizophrenia patients with higher glutamatergic polygenic risk score demonstrated poorer spatial working memory, while those with lower glutamatergic polygenic risk score showed better spatial working memory. Synergistic effects between childhood adversity and glutamatergic polygenic risk score on spatial working memory performance in treatment-resistant schizophrenia patients suggests that lower glutamatergic polygenic risk score may, in part, protect patients from the detrimental effects of childhood adversity on spatial working memory performance, while higher glutamatergic polygenic risk score increases the risk. Chapter five summarises the main findings of each study and highlights the clinical implications and future directions of this critical research area so as to improve mental health for children subjected to adversity.
Wellbeing of firefighters: the impact of individual factors, potentially traumatic event exposure, and operational and organisational factors on mental health outcomes
Aims: This study aimed to investigate the prevalence of the common mental health disorders associated with increased exposure to potentially traumatic events in career and volunteer firefighters, and to identify which individual, acute stressor, operational and organisational factors predict mental health outcomes. Method: Four Australian services participated in a prospective study, with 335 firefighters completing an online survey twice (12-months apart). The survey comprised demographic and fire service information, self-report measures for PTSD, depression, anxiety, alcohol use, exposure to personal trauma and life stressors, number and types of firefighter-related potentially traumatic events experienced in the previous 12-months, job satisfaction related to operational and organisational characteristics of their role, and a measure of the priority their fire service placed on their psychological wellbeing. Structured clinical interviews were conducted with a sample of survey respondents to assess for PTSD, depression, generalised anxiety disorder and alcohol use disorder. Results: From 297 clinical interviews (91 career firefighters and 206 volunteer firefighters), 24% (n = 22) of the career firefighters met diagnosis for any psychiatric disorder. Of these, 3% met criteria for PTSD, 5% for depression, 4% for generalised anxiety disorder, and almost 12% for alcohol use disorder. The primary regression analyses indicated the following findings for the career firefighters. The main variable associated with each of the four disorders was the respective level of symptoms at baseline. In addition, exposure to more potentially traumatic events in the previous 12 months contributed to, and high job satisfaction associated with the operational aspects of their role protected them against the development of PTSD and depression. Finally, the findings indicated that experiencing more recent life events in the previous 12 months and rank (being a firefighter) contributed to more symptoms of Alcohol Use Disorder. From the interviews 17% (n = 35) of the volunteer firefighters met diagnosis for any psychiatric disorder. Of these, 2% met criteria for PTSD, 4% for depression, 5% for generalised anxiety disorder, and 6% for alcohol use disorder. The primary regression analyses indicated that the only predictor of PTSD, generalised anxiety disorder and alcohol use disorder was the respective baseline level for each disorder. The main predictors of depression were baseline level of symptoms of depression and experiencing more recent life events in the previous 12 months. Conclusions: The relatively low prevalence rates for the career and volunteer firefighters in this study indicate their reasonably good mental health across the four disorders. The rates compare favourably with other firefighter studies and are comparable with the rates in the general population for most disorders. An exception to this was volunteer firefighters’ high rate of alcohol dependence and low rate of PTSD. The findings indicate the importance of fire services developing cultures that support and encourage the early identification and management of symptoms and have systems in place to monitor the types of and frequency of firefighters’ exposure to potentially traumatic events. Finally, particularly for the career firefighters, the findings highlight the protective nature of high job satisfaction associated with operational characteristics of their role and reduced mental health symptoms, and the importance for firefighters and managers to recognise and address reductions in job satisfaction.
The influence of parenting and genetic variants on internalising symptoms during late childhood: neural mechanisms and the HPA-axis
Background: Greater levels of internalising symptoms during childhood and adolescence increase the risk of developing depression later in life. As such, investigating risk factors for depression in young people is important for understanding the aetiology of the disorder and for informing prevention strategies. Whilst it is known that extreme forms of childhood adversities, such as childhood trauma and abuse, represent a risk factor for depression, less has been done in investigating the effect of parenting behaviour. Emerging research suggests that negative parenting practices (e.g., parental rejection), as well as the lack of positive parental behaviours, increase the risk of internalising symptoms during childhood and adolescence. One of the proposed mechanisms linking poor parenting practices and depression is the effect of parenting behaviour on brain function and brain structure, particularly in regions involved in processing and regulating responses to emotional stimuli, such as the amygdala, prefrontal cortex and hippocampus. Animal studies suggest that parenting may affect the brain via effects on the hypothalamic-pituitary-adrenal (HPA) axis, which has a central role in the response to stress. Genetic factors are also likely to play a role, whereby genetic variants in HPA axis genes may contribute to the regulation/dysregulation of the system. To date, however, there is a lack of research focusing on genes related to HPA axis function, and their interaction with environmental factors (including parenting) in predicting internalising symptoms. Further, no research has investigated the neural mechanisms by which parenting behaviours, HPA genes, and their interaction, exert their influence on internalising symptoms. The aim of this thesis was to investigate a) whether parenting behaviour interacts with HPA genes to influence internalising symptoms in children/adolescents, and b) whether brain structure/function of regions involved in emotion processing (particularly the amygdala and hippocampus) mediates this link. Method: Data from two longitudinal studies were used in this thesis: the Adolescent Development Study (ADS) and the Families and Childhood Transitions Study (FACTS), to explore aims across three experimental chapters. The first study included 98 adolescents from the ADS, for whom hippocampal structural development was measured from magnetic resonance imaging (MRI) scans performed across three waves (W): W1 (mean age =12.6 years), W2 (mean age=16.5 years), W3 (mean age =18.8 years). Maternal negative behaviour was measured at W1 from an observed interaction task. Adolescents’ depressive symptom severity was measured at W1 and W3 with self-reported questionnaires, and genetic risk was calculated using a composite HPA genetic risk score. The second and third studies included 86 (mean age=10.1 years) and 80 (mean age=10.0 years) children, respectively, from FACTS. Observational measures of maternal parenting behaviour were collected during mother-child interactions. Children underwent functional MRI (fMRI) while performing an implicit emotion-processing task. Self-reported and parent-reported measures of child internalising symptoms were also collected. HPA genetic risk was calculated in a similar fashion to the first study. Results: Across both studies, neither HPA genetic risk score nor the interaction between HPA genetic risk score parenting behaviour predicted internalising symptoms in children/adolescents. For study 1, we did not find support for a mediating role of hippocampal structure in the relationship between parenting behaviour and internalising symptoms. Rather, we found a moderation effect such that negative maternal parenting behaviour predicted depressive symptoms longitudinally in adolescents with flattened hippocampal growth and HPA genetic risk. While maternal behaviour was not associated with hippocampal development, in study 2 it was associated with activity/connectivity in brain regions involved in emotion processing. In particular, maternal negative behaviour during a problem-solving interaction was associated with increased amygdala reactivity and connectivity with parietal cortex in children. Maternal negative behaviour during an event-planning interaction was associated with decreased activity in the lingual gyrus in girls. Maternal communicative behaviour was associated with increased medial orbitofrontal cortex activity. These parenting-related neural findings were not associated with child internalising symptoms. In study 3, HPA genetic risk predicted increased amygdala-precuneus connectivity, which in turn was associated with greater internalising symptoms in children. Moreover, HPA genetic risk interacted with negative maternal parenting behaviour to predict increased connectivity between amygdala and superior frontal gyrus, anterior cingulate cortex and parietal cortex. Conclusion: These results suggest that there is a complex interplay between neurobiological, environmental and genetic factors in predicting internalising symptoms in children and adolescents. Neurobiological factors (e.g., hippocampal development) may act as an independent risk factor for depressive symptom severity, but they may also be influenced by environmental and genetic factors. Parenting behaviour, particularly maternal negative and communicative behaviour, may influence brain activity and connectivity in regions involved in emotion processing. The lack of association with internalising symptoms hampers our ability to draw conclusions on the significance of the parenting-related neural findings for children’s mental health. However, given that depression is characterised by impaired emotion processing, including increased sensitivity towards negative stimuli, we speculate that differences associated with negative parenting behaviour, such as amygdala heightened reactivity to negative stimuli, may represent a risk factor for the disorder. HPA genetic variants may moderate the effect of parenting behaviour on these circuits (particularly the frontoamygdala circuitry), such that not all children are sensitive to parenting effects on neurobiology, and may confer risk for depression via altering corticolimbic connectivity. This study highlights the importance of parenting behaviour for children emotional neurocircuitry development and demonstrates the moderating role of genetic factors.
Environment-by-brain development interactions as predictors of adolescent depressive symptoms and psychological well-being: structural brain development as a marker of responsivity to maternal parenting and socioeconomic status
Background Adolescence is widely reported to be a time of increased risk for depression and lower well-being. Importantly, however, outcomes are heterogeneous, and most adolescents do not develop mental health problems. In order to understand how these differences emerge, both environmental and biological factors have been examined in the literature. Evidence indicates that parenting behaviour, socioeconomic status and neurobiology may contribute and, further, that individual differences in brain development may moderate the extent to which contextual factors influence adolescents. That is, individual differences in brain development may confer ‘responsivity’ to context. Several developmental and evolutionary-developmental models provide frameworks with which to interpret such brain-by-environment interactions, and to describe biological responsivity – these are broadly associated with diathesis-stress and differential susceptibility/biological sensitivity frameworks. Broad PhD aim This thesis aims to investigate whether structural brain development moderates adolescent sensitivity to maternal parenting behaviour in the prediction of adolescent depressive symptoms and psychological well-being. Two empirical studies were completed to address this aim. Study 1 examined whether longitudinal change in brain structure modified adolescent vulnerability or susceptibility to aggressive and positive maternal parenting. Effects were assessed to infer evidence in support of either diathesis-stress or differential susceptibility frameworks. Study 2, in light of evidence that positive parenting protects against adversity, considered whether brain development moderated adolescent sensitivity to positive parenting, and whether this association was more pronounced for adolescents with low-socioeconomic status (SES). Methodology During early adolescence (age 13 years), participants completed observed interactions with their mothers, and the frequency of positive maternal behaviour was coded. At three time points (mean ages 13, 17 and 19 years), participants completed structural magnetic resonance imaging (MRI) scans. During late adolescence (age 19 years), participants completed self-report measures of depressive symptoms and psychological well-being. Two separate analyses (studies) were conducted in predicting late adolescent (age 19) outcomes (depressive symptoms and psychological well-being). For both studies, longitudinal brain development was indexed by changes in cortical thickness of structures within the frontal lobe, and volumetric changes of subcortical structures, from early to late adolescence. Study 1: Regression models analysed interactions between maternal behaviour and longitudinal brain development in the prediction of adolescent outcomes. Indices designed to distinguish between diathesis-stress and differential susceptibility effects were employed. Study 2: Regression models were used to investigate interactions between SES (parental occupation), positive maternal behaviour, and longitudinal brain development in the prediction of adolescent outcomes. Results Study 1: Results supported differential susceptibility, whereby less thinning of frontal regions (the left medial orbitofrontal, rostral middle frontal and superior frontal cortices, and the right pars opercularis) was associated with higher well-being in the context of low levels of aggressive maternal behaviour, and lower well-being in the context of high levels of aggressive maternal behaviour. Study 2: Results indicated that individual differences in structural brain development moderated the extent to which positive parenting impacted adolescents dependent on SES. High levels of positive parenting were associated with reduced depressive symptoms for low-SES adolescents with greater volumetric reduction of the right putamen. Further, low positive parenting was associated with reduced psychological well-being for individuals with greater neurobiological sensitivity, however, patterns of brain development that were associated with sensitivity differed by SES. Specifically, low positive parenting was associated with reduced psychological well-being for individuals with more thinning in the context of low-SES, but for individuals with less thinning in the context of high-SES. Significance Results across studies suggested that structural brain development may be associated with individual differences in how sensitive adolescents are to context. Study 1 indicated that reduced frontal cortical thinning during adolescence increased susceptibility to maternal aggressive behaviour in the prediction of well-being, for better and for worse. This finding is significant because it suggests that neither more or less cortical thinning is consistently good or bad for mental health. Results from Study 2 indicated that, although brain change was associated with responsivity to parenting behaviour, patterns of brain development associated with heightened responsivity to parenting were different for high- and low-SES. These results suggested that responsivity functions in a context dependent fashion and highlights the complex interactions that may occur across biological and multilevel environment factors. Results from these studies suggest that structural brain development may be a marker of responsivity to environmental influence. They also emphasise the importance of examining how brain development moderates the impact of multilevel environmental factors on mental health outcomes. Such study designs may better reflect the social settings in which adolescents develop.
The role of adrenarche in shaping the mind: how adrenarcheal hormones contribute to the development of brain connectivity and internalising symptoms
The transition from childhood to adolescence is a particularly vulnerable period for the development of internalising symptoms and disorders. Hormonal changes as well as changes in brain structure and function may play a role in this increased vulnerability. Most of the research to date has focused on the hormonal and brain changes during gonadarche, whereas the literature is much more limited for adrenarche, an earlier pubertal phase that takes place prior to gonadarche. Therefore, this thesis aimed to examine how (changes in) adrenarcheal hormones relate to the development of brain structural and functional connectivity, and how that in turn affects internalising symptoms in late childhood to early adolescence. Data were used from two longitudinal community-based samples with two time points each (sample 1 M ages 9.5 and 12.2 years; sample 2 M ages 8.5 and 10 years). At each time point in each study, levels of dehydroepiandrosterone (DHEA), its sulfate (DHEAS) and testosterone were measured and averaged from morning saliva samples collected across several days. Participants also underwent Magnetic Resonance Imaging (MRI) scans, and completed self-report questionnaires, at both time points. Diffusion-weighted imaging scans were analysed to examine white matter structural connectivity. Functional Magnetic Resonance Imaging (fMRI) scans during an affective face processing paradigm were analysed to examine functional connectivity. Levels of internalising symptoms were based on self-report questionnaires: the Spence Children’s Anxiety Scale, the Children’s Depression Inventory, and the Positive And Negative Affect scale. Analyses were conducted to investigate associations between hormone levels (initial levels and changes in levels over time) and brain structural and functional connectivity (baseline and change over time). Analyses were also conducted to investigate whether hormone-related changes in structural/functional connectivity were associated with symptoms. The results showed that children with high DHEA levels at age 9 had higher mean diffusivity (cross-sectionally) in a wide range of white matter tracts, suggesting that relatively early exposure to DHEA might be negatively associated with white matter microstructure. Changes in testosterone from age 8.5 to 10 years were negatively associated with the development of white matter structure as quantified by fibre cross-section in posterior white matter tracts. Higher levels of testosterone at age 8.5 years, however, were related to stronger development of fibre cross-section from age 8.5 to age 10 years. These hormone-related changes in white matter structure were not significantly associated with levels of internalising symptoms. Analyses of functional connectivity during affective face processing focused on connectivity of the amygdala to the rest of the brain, because of the crucial role of the amygdala in emotion processing and consistent findings of its involvement in internalising disorders. Indirect effects were found of adrenarcheal hormone levels (controlled for age, potentially indicating a timing effect, i.e. maturation relative to same-age peers) on anxiety symptoms at age 9 years, mediated by amygdala connectivity to visual and limbic areas. Timing of adrenarcheal hormone exposure was also found to have indirect effects on anxiety symptoms longitudinally. Specifically, higher DHEA at age 9 years was indirectly related to more anxiety symptoms at age 12 years, controlling for symptoms at age 9 years, via more positive amygdala to inferior frontal gyrus connectivity. Thus, the findings in this thesis have demonstrated that elevated adrenarceal hormone levels (potentially reflecting early timing of adrenarche) are both cross-sectionally and longitudinally associated with anxiety symptoms through an effect on amygdala functional connectivity. We also showed that the hormonal processes of adrenarche have an impact on white matter microstructure development. These findings have implications for the understanding of how individual variation in adrenarcheal processes can impact children’s brain development and mental health. Future studies should examine whether effects of variation in adrenarcheal processes on brain development and mental health are persistent, as well as establish whether predictors found in the current thesis are also relevant in clinical samples.
Tau and beta-amyloid deposition, structural integrity, and cognitive function following traumatic brain injury in Australian war veterans
Background: Traumatic brain injury (TBI), has been diagnosed in over 355,000 US military service personnel since 2000. Epidemiological research indicates that veterans with TBI are two-to-four times more likely to develop dementia than controls; however, mechanisms contributing to this relationship are poorly understood. The aim of this study was to investigate if Vietnam war veterans with a TBI show evidence of Alzheimer’s disease (AD) pathological markers, as assessed by A-amyloid, tau and glucose metabolism using PET, as well as structural MRI, including diffusion tensor imaging, and neuropsychological testing. Methods: Sixty-nine male veterans - 40 with TBI (aged 68.0±2.5 years) and 29 controls (aged 70.1±5.3 years) - underwent A-amyloid (18F-Florbetaben), tau (18F-AV1451) and 18F-FDG PET, MRI, psychiatric and neuropsychological assessment. The TBI cohort included 15 participants with mild, 16 with moderate, and 9 with severe injury. Fractional Anisotropy (FA) was employed as a measure of white matter tissue integrity. PET Standardized Uptake Value Ratios (SUVR) were calculated using the cerebellar cortex as reference region. Analyses were adjusted for IQ, age, ApoE status and psychiatric comorbidities. Results: Veterans with moderate-to-severe TBI performed significantly worse than controls on composite measures of memory and learning (M = -0.55 0.69, t(67) = 2.86, p=0.006, d=0.70) and attention and processing speed (M = -0.71 1.08, t(52) = 2.53, p=0.014, d=0.69). The moderate-to-severe TBI group had significantly lower FA than controls in the genu (F(3,36)=8.81, p<0.05, partial 2 = 0.17), and body (F(3,36)=4.39, p <0.05, partial 2=0.14) of the corpus callosum, as well as in global white matter (F(3,36)=5.35, p <0.05, partial 2=0.13). There were no significant differences in 18F-Florbetaben or 18F-AV1451 uptake amongst the groups, however the moderate-to-severe TBI group had significantly lower 18F-FDG retention than controls in the mesial temporal region (F(8,44) = 2.21, p <0.05, partial 2 = 0.13). No differences were found between the mTBI group and controls on any of the outcome measures. Conclusions: These findings indicate that moderate-to-severe TBI, but not mTBI, is associated with later-life cognitive deficits, and diminished global white matter integrity, specifically in the corpus callosum. However, these deficits are not associated with AD pathology. These results are consistent with current evidence of white matter axonal damage as the primary source of cognitive impairment in TBI, and are not reflective of a neurodegenerative process.
Examining the efficacy of Tuning Relationships with Music™ in helping parents with a history of interpersonal trauma reduce conflict and improve emotional responsiveness with their adolescent
Parents who have experienced interpersonal trauma in childhood often struggle with relational functioning including difficulties with nonverbal communication (NVC), which may influence their ability to remain regulated during parent-child interaction. The challenges of parenting an adolescent may trigger memories of maltreatment, intensifying conflict, resulting in negative cycles of relating and poorer responsiveness to emotions when parenting. The thesis first explored existing knowledge about NVC in parent-child relationships. Then, the efficacy of Tuning Relationships with Music™ (TRM), an intervention developed by the author for parent- adolescent dyads experiencing heightened conflict where the parent has an interpersonal trauma history, was examined. TRM was expected to reduce conflict and adolescent mental health difficulties and improve parent responsiveness and emotion coaching. A randomised control (RCT) design was used where 26 parent-adolescent dyads were recruited from community services. Dyads were randomly allocated into intervention or wait-list control, completing self-report and observational measures at baseline, and again four months later. The thesis includes three studies. Study 1 reviews the literature about how nonverbal communication (NVC) is assessed and intervened with in parent-child relationships, in order to inform TRM development. Results showed that reliable and validated NVC assessment tools are not routinely used to inform intervention development or measure effectiveness, and that very few interventions directly target parent-child NVC. Study 2 reports on outcomes from the RCT of TRM, which found dyads that participated in TRM reported significantly reduced conflict, and parents were clinically observed to be less reactive and more responsive compared with dyads in the control condition. Although parents reported they were less dismissive and punitive, and more encouraging of their adolescent’s emotions, and both parents and adolescents reported improvements in the young person’s mental health, these were not statistically significant. Study 3 examined dyads as a single dynamic system during nonverbal conflict interaction, and aimed to examine relationships between parents’ trauma history, parent-adolescent conflict, parents’ reactivity and non-responsiveness, and dyads’ emotion regulation, consistency and predictability. A second aim was to discover whether TRM’s focus on NVC and emotion regulation would have an impact on post-intervention dyads’ nonverbal conflict interaction compared with controls. State space grid analyses showed that where parents reported higher levels of parent conflict this was correlated with predictable NVC sequences while dyads were emotionally dysregulated, and parents’ reactivity was correlated with dyads’ inconsistent NVC. Post-intervention dyads were more emotionally regulated, consistent and predictable during their nonverbal conflict interaction. Findings have important implications for intervention with parent-adolescent dyads where a parent has a childhood interpersonal trauma history, suggesting that a systemic focus on NVC and emotion regulation may assist dyads to reduce conflict and increase responsive interaction. This thesis makes a contribution to existing understandings of the systemic dynamics of parent-adolescent conflict where a parent has experienced interpersonal trauma, suggesting that using music to improve emotion regulation and NVC may reduce conflict and improve parents’ responsiveness in parent-adolescent relationships. Further research of TRM with a larger sample will be useful, to determine whether a focus on nonverbal processes may improve relational functioning.
Exploring candidate loci, genes, pathways, and evolutionary markers in schizophrenia by re-analyzing candidate gene and genome-wide association studies
In the last decade, consistent efforts have been made by psychiatric geneticists to elucidate the genetic mechanisms of schizophrenia, especially after the rise of genome-wide association studies (GWAS). However, the genetic etiology of schizophrenia has not been fully discovered, and enormous genetic datasets have been produced, allowing for additional investigation. In my PhD study, I have systematically identified candidate gene and GWAS in schizophrenia. Furthermore, I have re-analyzed these genetic datasets using meta-analyses, pathway analyses and evolutionary-based analyses. The results of these studies revealed new and supported current candidate loci, genes and pathways associated with increased risk of schizophrenia. I also provided evidence supporting a novel evolutionary mechanism for schizophrenia that extended the current conceptualizations of how schizophrenia emerged. In Chapter 1, I introduced the progress of genetic studies already achieved in schizophrenia, including family and twin studies, linkage studies, candidate gene association studies, genome-wide association studies, copy number variation studies and wholeexome/genome sequencing studies. A literature review of GWAS in schizophrenia and the aims of the thesis are included in this Chapter. Chapter 2 of this thesis provides a systematic review of genetic association studies in schizophrenia. In this study, I have reviewed more than 3000 association studies and merged them with the data from the existing schizophrenia knowledgebase (SzGene). Two rounds of meta-analyses, i.e. candidate-gene-only meta-analyses and expanded meta-analyses combined with samples from GWAS, have been conducted. In total, I have identified 21 Bonferroni significant single nucleotide polymorphisms (SNPs) in 14 Linkage disequilibrium (LD)-independent loci associated with schizophrenia susceptibility. Three of these loci, including methylenetetrahydrofolate reductase (MTHFR), D-amino acid oxidase activator (DAOA) and ARVCF, delta catenin family member (ARVCF), had never been implicated by a schizophrenia GWAS. Chapter 3 aimed to test the notion that schizophrenia is a pathway disorder. In this study, I conducted a pathway-wide association study, testing the association between schizophrenia and 255 biological pathways. Five independent GWAS datasets across three distinct ethnic populations were collected for pathway analyses. Almost half of biological pathways were associated with schizophrenia in each of three populations, and five of them (serotonergic synapse, ubiquitin mediated proteolysis, hedgehog signaling, adipocytokine signaling and renin secretion) were shared across three populations. These findings suggest schizophrenia is a poly-pathway disorder, and provide empirical support for that notion. In Chapter 4, I attempted to address the evolutionary paradox of schizophrenia: why negative genetic selection has not eliminated the deleterious alleles associated to schizophrenia susceptibility from the modern human genome? Using evolutionary markers in the genome, I showed that modern humans carried more protective SNPs for schizophrenia compared with our collateral ancestors: Neanderthals and Denisovans. Based on these findings, I proposed a novel framework to explain the evolutionary paradox and genetic origin of schizophrenia. In Chapter 5, the main findings and conclusion of my thesis are summarized. In addition, an expanded discussion of the meta-analyses of genetic association studies, the pathway-wide association study, and the evolutionary analysis are provided along with limitations and future directions.
The neuropsychiatric disorders of focal epilepsy
Neuropsychiatric disorders commonly co-exist with focal epilepsy. Despite intense investigation there remains significant limitations to our current understanding of the aetiological relationship between these conditions, as well as the clinical and radiological factors that are associated with the development of mental illness in epileptic patients. To address these questions I assembled a large cohort of consecutive focal epilepsy patients reviewed at a large tertiary referral centre over an 11-year period, and analysed relevant clinical, radiological and demographic findings using both cross-sectional (baseline evaluation) and longitudinal (serial assessments) study designs. For cross-sectional analyses, psychiatric and epilepsy comorbidity were comprehensively identified and compared to baseline MRI-determined Deep Brain Structure (DSB) volumes. In the prospective study, standardised psychiatric and quality of life assessments were obtained in a subset of patients and the development of mental illness compared to interval changes in DSB volumes. I focus on depression and psychosis, as they represent the two most prevalent psychiatric disorders identified, and classify focal epilepsy patients according to the site of seizure origin and presence of a lesion. Contrary to the common medical belief, I found that the rates of neuropsychiatric disorders in temporal lobe epilepsy were equivalent to those in extratemporal lobe epilepsy. There were no differences between those with and without psychiatric disorder by age, gender, and laterality of seizure, epilepsy severity or duration. Patients with non-lesional epilepsy, both temporal and extratemporal, have double the rate of depression compared to those with lesional focal epilepsy. There were high rates of quality of life difficulties in people with epilepsy and comorbid psychiatric disorders but the pattern of subjective concerns does not match objective clinician ratings. The hippocampal and amygdalae volumes of epilepsy patients were reduced compared to normal controls. People with co-existing epilepsy and depression had a trend towards smaller reductions in temporal lobe structures, which may represent differential expressions of progression through inflammation, trauma or emotional processing needs with either relative sparing or volumetric increases. People with psychosis and epilepsy have bilaterally reduced hippocampi compared to those with epilepsy, where reductions are predominantly ipsilateral to seizure focus. There is less evidence for amygdala change in psychosis, but a small relative increased volume was observed compared to those with epilepsy alone. There was no evidence of progression over time at a population level over 3.9 years, although there was greater variability in size in all epilepsy subjects compared to normal controls. These results convincingly argue against assumptions about the primary role of temporal lobe foci in the pathogenesis of psychiatric comorbidities in patients with epilepsy, whilst allowing for the possibility that disruption to frontotemporal networks may be a component in the development of psychiatric disorders. Progression is not an inevitable part of the natural history, at least over a 4 year period but it is possible that individuals may exhibit marked changes. They highlight the as yet unexplored possibility that the absence of a lesion as an epileptic site may be associated with greater risks of neuropsychiatric illness and allow for speculation that this may be related to inhibitory surround impacts, more extensive underlying diffuse abnormalities and disruption to frontotemporal connectivity.
Is the epidermal growth factor system a biomarker for clozapine response in schizophrenia?
Schizophrenia is a severe neuropsychiatric disorder associated with significant disability. The antipsychotic drugs, the mainstay of treatment, are only effective in a proportion of patients. For those who do not respond, so-called treatment refractory schizophrenia (TRS) patients, the only available treatment is the atypical antipsychotic drug, clozapine. Although it has singular efficacy in treating TRS patients its use is restricted and delayed due to rare and potentially fatal side effects. Ability to predict response can help identify potential responders and introduce treatment early, but studies have so far not been able to identify any clinically useful biomarkers of response. A system that has been implicated in both schizophrenia and mechanism of action of clozapine is the epidermal growth factor (EGF) system. This study sought to examine the EGF system for potential predictors of response and did so by measuring peripheral EGF and betacellulin (BTC) levels in a prospective cohort of TRS patients commencing clozapine treatment. It also examined a larger cross-sectional sample of long-term clozapine treated patients for potential associations with EGF system single nucleotide polymorphisms (SNPs). The prospective sample of TRS patients were followed up over twenty-six weeks and clinical data and blood samples were collected at set time points. Symptom severity was measured using the Positive and Negative Syndrome Scale (PANSS). Additional clinical information was gathered using the Clinical Global Impression – Severity (CGI-S) scale, Global Assessment of Functioning (GAF) scale, Simpson Angus Scale (SAS) and the Calgary Depression Scale (CDS). Both EGF and BTC levels were determined using commercially available enzyme linked immuno-sorbent assay (ELISA) kits. Of the sixty-four patients who consented for the prospective study sixty entered the study and forty-nine completed the twenty-six weeks of clozapine treatment. Socio-demography of the patients revealed the significant disadvantages suffered by TRS patients. While 78.3% of the patients had completed more than ten years of education and 93.3% had been previously employed, at the time of the study 83.3% were dependent on the disability support pension. The average duration of illness of 11.2 years reflected the general reluctance and delay in introducing clozapine treatment. Although the response rate of 51.9% reiterated the unique efficacy of clozapine in treating TRS, the absence of any effect on negative symptoms highlighted this major gap in the treatment of schizophrenia. Significant improvement in both CGI-S and GAF scales in both responders and non-responders, while justifying continuation of treatment in the non-responders, also questions the current definition of response that is based solely on symptom improvement. Trends in smoking and psycho-active substance use, even though statistically not significant suggested possible additional advantages of clozapine. The low peripheral EGF and BTC levels in this study provide further support for an EGF system dysfunction in schizophrenia. Although clozapine treatment increased the EGF levels they still remained significantly lower than the healthy controls, implying that regardless of the duration of treatment, clozapine does not normalize EGF levels. Peripheral BTC levels were not affected by clozapine, but the correlation with positive symptoms suggest they could be a state marker. Neither EGF nor BTC levels predicted response to clozapine. The genetic analyses did not show any significant associations. Being an observational study, there was no provision to control for possible confounding factors, and having exclusively TRS patients limits its generalizability. Nevertheless, the findings of this study further implicate the EGF system both in schizophrenia and the mechanism of action of clozapine. Further exploration of this system would help better understand the pathogenesis of schizophrenia at the same time inform future development of antipsychotic medications.
An FMRI investigation of emotion regulation in youth depression
The ability to regulate emotions plays an important role in social development during adolescence and young adulthood. Further, impaired ability to regulate emotions using cognitive strategies is a hallmark feature of major depressive disorder. Currently, there is a limited understanding of the neural underpinnings of emotion regulation in young people and how cognitive forms of emotion regulation (like cognitive reappraisal) develop. This issue is particularly pertinent to improving our understanding of depression in young people, given that the period from adolescence to young adulthood is associated with substantial brain maturational changes in regions associated with emotion–regulation and it is a time when most first episodes of depression occur. In the present study, a cognitive reappraisal paradigm containing social–stimuli was designed to probe the neural correlates of emotion regulation in depressed youth: in particular, to determine whether there were differences in the way that depressed and control participants regulated social–affective material, as well as developmental effects observed within the two groups. tudy participants—a large group of 15– to 25–year–old depressed participants and a matched control group—underwent fMRI where they used cognitive strategies to reinterpret negative social imagery. As expected, this cognitive reappraisal paradigm robustly activated regions involved in cognitive control and social–affective processing in both groups. Among healthy 15– to 25–year–olds (Study One), younger participants exhibited greater activation of temporal and occipital brain regions during reappraisal—implicated in processing social material—in combination with weaker suppression of amygdala reactivity. Further analyses demonstrated that these age–related influences on amygdala reactivity were specifically mediated by activation of the fusiform face area. Study Two revealed that depressed youth were significantly less able to reduce negative affect during reappraisal (compared to healthy individuals), which corresponded to blunted modulation of amygdala activity. Depressed youth also showed heightened activation of the ventromedial prefrontal cortex (vmPFC) and reduced activation of the dorsal midline cortex. Further, as distinct from the healthy youth, there was no relationship between development and modulation of amygdala activation in the depressed group. As the largest study of reappraisal in a young sample to date, our results in healthy controls highlight the importance of activation changes in social–processing and emotion processing networks, as being crucial to potential differences in the ability for adolescents to regulate their emotions. Enhanced neural sensitivity to social stimuli (e.g., facial stimuli) in younger individuals suggests a sensitivity to emotions of others during reappraisal that may be both adaptive in facilitating learning, but might also suggest difficulty disengaging from aversive social–cues. Findings in depressed youth are consistent with those in adults which suggest depression–related disturbances in both extended medial prefrontal (‘generative’) as well as dorsal (‘regulatory’) systems that contribute to adaptive emotional processing. Excessive engagement of the vmPFC—a region emphasised in contemporary neural systems models of MDD— may, in particular, be central to understanding how the process of assigning a new meaning to negative emotional material may be altered in depressed youth, with implications for treatment.