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ItemExploring the associations of diet quality with mental and gut health in the context of the mediating potential of the gut microbiota in adult women( 2023-03)Background: A rapidly growing evidence base indicates that habitual dietary quality is associated with the common mental disorders. At the same time, the relationships between diet and mental health may be influenced by the co-occurrence of highly prevalent gastrointestinal conditions, such as irritable bowel syndrome (IBS), whose current first-line treatments include dietary alterations which may impact individuals’ dietary habits. It is also increasingly recognised that the gut microbiota (i.e., the community of microorganisms inhabiting the gastrointestinal tract) may be involved in the pathophysiology of internalising disorders and IBS. As the gut microbiota is heavily influenced by habitual diet, a theoretical framework has been proposed whereby the gut microbiota mediates the associations between diet quality and anxiety/depression psychopathology. Accordingly, this thesis conducted a detailed cross-sectional examination of the associations of several diet indices in adult females with clinically diagnosed anxiety and/or depressive disorders (both at the disorder and symptom level) while considering IBS comorbidity (Aim 1). Cross-sectional associations between diet indices and the gut microbiota were also investigated, with consideration of the moderating influence of IBS and internalising disorders (Aim 2). Finally, the proposed theoretical mediation model was examined to assess the relationships between diet indices and anxiety/depression outcomes, and whether this was mediated by the gut microbiota (Aim 3). Methods: This thesis used data from the Bugs and Brains study cohort, a mixed-methods study of 158 adult females with anxiety/depression, IBS, comorbidity, or with no history of any of these conditions. Participants were recruited based on strict inclusion/exclusion criteria related to medical/psychiatric comorbidities, medication use, and lifestyle behaviours (e.g., drinking and/or substance use). Participants attended a semi-structured psychiatric interview, provided a stool sample for 16S rRNA gene sequencing, had their anthropometrics measured, and completed validated questionnaires assessing demographic, lifestyle, diet, psychiatric, and health related factors. Dietary quality was assessed using two measures of whole-of-diet intake (i.e., the ModiMedDiet [MMD] and the Healthy Eating Index for Australian Adults-2013 [HEIFA-2013]) and a measure of the proportion of ultra-processed foods (UPFs) consumed per day. Measures of gut microbiota diversity and community composition (i.e., alpha and beta diversity, respectively) were estimated for all participants. Data analysis was performed using R (v4.2.0), combining a series of multivariate logistic/linear regression analyses and mediation analyses using the PROCESS model. Results: In the first empirical chapter (Aim 1), logistic regressions revealed that all three diet indices predicted odds for an internalising disorder, with the proportion of UPFs most strongly associated with higher odds for internalising disorders. Linear regressions also indicated that the HEIFA-2013 and UPF intake were marginally associated with lower and higher depression symptoms, respectively, while no influence due to IBS comorbidity was evident in any of the analyses. In the second empirical chapter (Aim 2), linear regressions indicated that the HEIFA-2013 was consistently directly associated with higher microbial diversity, and there was evidence for a direct association between the HEIFA-2013 and alpha diversity which was moderated by IBS diagnosis. Meanwhile, the MMD and HEIFA-2013, as well as IBS diagnosis, were directly associated with a gut microbiota composition characterised by more positive loadings of anti-inflammatory bacterial genera (e.g., Ruminococcaceae UCG-002, Christensenellaceae R-7 group, Coprococcus 2), and negative loadings of potentially pathogenic pro-inflammatory genera (e.g., Ruminococcus gnavus group, Flavonifractor, Eggerthella). Finally, in the third empirical chapter (Aim 3), mediation analyses indicated no evidence to suggest that the gut microbiota mediated the associations between diet quality and anxiety/depression outcomes. However, several noteworthy moderation findings were indicated in relation to alpha diversity and depression symptoms. Conclusion: The current thesis adds to the existing literature by revealing clear links between dietary quality and clinical internalising disorders in a rigorous cohort with strict inclusion/exclusion criteria that was independent of key confounding factors, such as age, BMI, and host sex. Findings highlighted that UPFs warrant particular attention in relation to increased odds for anxiety and/or depressive disorders in the present analyses, given the rapid increase and uptake of these foods globally. Furthermore, while the gut microbiota was closely linked with overall dietary quality, no evidence was found to support it as a mediator of the relationships between diet quality and mental health. Several reasons for these unexpected results are discussed, including the complex and multifactorial relationship between habitual diet and anxiety/depression as it relates to underlying biological mechanisms, as well as methodological and conceptual considerations in the trialogue of diet, the gut microbiota, and mental health. Due to the methodological rigour of the Bugs and Brains study, the current thesis was well placed to examine the cross-sectional relationships presented herein. However, further longitudinal research that combines taxonomic and functional outputs is needed to gain mechanistic understanding of the relationships between diet, internalising disorders, and the gut microbiota.
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ItemThe Brain-Behavioural Basis of Human Safety Learning: An investigation of Pavlovian conditioned inhibition( 2022)Safety learning allows individuals to associate stimuli with the absence of threat, thus conferring the ability to suppress fear and anxiety in safe situations, and by consequence, maintain psychological and physiological well-being. Disrupted safety learning is thought to be a key component of anxiety-related disorders, but as yet, the basic mechanisms of safety learning remain incompletely understood and lack a formal theoretical definition. Across two studies of healthy adults, this thesis sought to examine the behavioural (Study 1) and neural (Study 2) basis of safety learning in humans. Based on long-standing principles of associative learning theory, a novel iteration of the Pavlovian conditioned inhibition paradigm was developed and implemented in lab-based and 7-Tesla functional magnetic resonance imaging (fMRI) settings. Study 1 (N = 73) was an investigation of the behavioural aspects of safety learning, and moreover, sought to validate the utility of the Pavlovian conditioned inhibition paradigm as an experimental model for safety learning, as well as examining individual differences in trait measures of anxiety. This paradigm trained a robust safety signal (the conditioned inhibitor, X) which was conditioned by delivering threat (loud noise) to a conditioned stimulus on its own (A+), but omitting threat when that stimulus was presented in conjunction with the inhibitor (AX-). As a control cue, two stimuli were similarly unreinforced in compound, but neither was presented alone on other trials (BC-). The paradigm also controlled for several possible confounds, including the use of a safety signal as a control cue, rather than using a novel or neutral cue, among other factors. Both the control safety signal and the conditioned inhibitor were shown to inhibit physiological and cognitive threat responses at test, when paired with aversive conditioned stimuli. However, the inhibitor conferred a significantly greater degree of inhibition for cognitive threat responses, as measured by threat-expectancy ratings during a summation test. Further, trait anxiety was positively correlated with threat expectancy towards the inhibitor during learning, indicative of threat responses to safety signals, which are thought be a feature of maladaptive anxiety. Study 2 (N = 49) investigated the functional neural correlates of safety learning via conditioned inhibition. The same paradigm from Study 1 was adapted for use in neuroimaging, using ultra-high field fMRI. Activations were compared between the safety signals directly (AX vs BC), and learning-specific activation was assessed via contrasts between early and late conditioning trials, and conditioning phase activity versus test phase, under the hypothesis that this should identify regions recruited to form stimulus-safety associations when these contingencies are new and unfamiliar. It was found that conditioned inhibition involved activity across a distinct set of cortico-striatal regions, which aligned with known subcortical circuits of the basal ganglia. Further, though showing similar behavioural responses to the inhibitor, the standard safety signal evoked no subcortical engagement, and instead was associated with an expanse of cortical activity, consistent with regions observed in differential fear-safety processing. In total, these studies indicate that the framework of Pavlovian conditioned inhibition can serve as an experimental model for characterising safety learning in humans, with implications for clinical translational work. It suggests that robust safety learning occurs by way of expectancy violation, or in other words, that a stimulus acquires safety value by predicting the unexpected omission of threat, in line with the principles of formal learning theory. Further, though current human studies often emphasise the safety-learning roles of various higher prefrontal regions, Study 2 demonstrates that safety learn- ing engages several subcortical brain regions that are well-known for their involvement in other domains of reinforcement learning. I discuss the theoretical implications that this research has for defining safety through the lens of associative learning, the neurobiology of safety acquisition, and a basis for separating processes of safety acquisition and safety expression between associative subcortical systems and higher cortical brain regions respectively. Several future directions are proposed for the ongoing study of safety learning, including characterisation of safety prediction errors and testing hypotheses of deficient safety learning in psychiatric disorders.
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ItemNeuroimaging Biomarkers in Generalised Anxiety Disorder, and Associated Modulations Following an Anxiolytic Intervention( 2020)Introduction and Aims Generalised anxiety disorder (GAD) comprises a debilitating cluster of psychological and physiological symptoms that markedly impairs quality of life. GAD is characterised by hallmark cognitions of persistent worry and anticipatory anxiety. Evidence exists for dysregulation in excitatory/inhibitory neurobiological pathways in prefrontal and limbic brain regions, with the dorsal anterior cingulate cortex an area of particular interest. However, limited research exists assessing regional activations and the role of metabolites such as gamma-aminobutyric acid in these regions, nor modulations as a function of treatment. The aim of the thesis was to investigate the functional and metabolic features of this region, and to assess the role of neuroimaging biomarkers of anxiolytic treatment response. Methods Two investigations were conducted utilising structural features of the region of interest: task-based functional magnetic resonance blood oxygen level-dependant signal activation and GABA levels via magnetic resonance spectroscopy together with relevant psychometric and psychiatric measures. The first study was a cross-sectional investigation undertaken to compare neuroimaging biomarkers in 41 participants with GAD with 35 healthy control participants. The second study was an 8-week RCT sub-study involving 41 participants randomised to either daily 240mg of kavalactones Piper methysticum (Kava) extract or a matching placebo. This proof-of-concept study assessed the aforementioned outcomes and whether these markers signal the plant’s anxiolytic activity. Results The results of the first investigation did not reveal group differences in GABA level (p = .302). The relationship between GABA and anxiety severity was different for each group; a significant positive correlation in GAD (e.g., HAM-A, p = .018) and a negative correlation in healthy controls (e.g., trait anxiety, p = .019). The functional task was successful in eliciting regional BOLD signal differences between valent congruency conditions. Two regions exhibited significant group differences (at p < .05), showing hyperactivation in GAD and reduced activation in healthy controls. In both groups BOLD signal significantly predicted severity of state anxiety (GAD p = .027; HC p = .041). Gender, age, and comorbidity in the GAD group also influenced the biomarker-anxiety relationships. The results of the second study showed that Kava treatment was associated with a reduction to GABA levels at eight weeks (p = .049). The treatment was not associated with anxiety symptom, nor fMRI signal change, measured at eight weeks. Discussion This research investigated regional brain properties in GAD for biomarker utility, before testing them in a ‘proof of concept’ study using the purported anxiolytic agent, Kava. Metabolic and functional data were successful in producing differences in the dorsal ACC that could be (if replicated in a larger study) be utilised as biomarkers to aid in the management of GAD symptoms. Limitations of the studies were small sample sizes, GABA signal quality and equivocal toolbox results. The neurobiological effects of Kava have not been directly studied using MRI imaging in humans. The findings of a reduction to GABA levels after treatment may potentially reflect a normalising of the GABA system similar to healthy control data observed in the first study. GAD is a prevalent psychiatric disorder that is under-diagnosed and under-treated. While a great deal of work is inherent in establishing biomarkers for clinical benefit, this research contributes MRI evidence of biological differences, and insight into the mechanisms of Kava, together with a translational rationale for the study of novel anxiolytics as potential GAD treatments. The outcomes and findings of this research fit well with the current affective disorder literature and exceed contemporary work in the field of GAD biomarker and treatment research.
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ItemNo Preview AvailableAutism Spectrum Disorder (ASD) and Anaesthesia( 2019)This thesis addresses the question of what is the best evidence-based management for children with ASD (autism spectrum disorder) coming under anaesthetic care in the hospital setting. The increasing prevalence of ASD (1) has meant that most anaesthetists need to become proficient in understanding and managing children with ASD. Children with ASD have higher hospital contact than their neurotypical peers.(2) Behavioural problems, sensory sensitivities, language deficit, and inflexibility with change contribute to the difficulties experienced by children with ASD in the hospital setting. (3)Hospitals may be inherently challenging to children with ASD: being inflexible places, with the sound of crying children, with invasive monitoring techniques and bright lights.(4) One unpleasant anaesthetic experience can lead to heightened anxiety and future refusal to attend hospital. In order to find the context for best anaesthetic care, we have reviewed the existing literature about ASD and its management in chapter one. The first part of chapter two is a review of anxiety and premedication in general terms. The evidence for current best practices in managing children with ASD in the perioperative period is outlined in the second part of chapter two. To further understand the family and staff perspective of optimal care, we conducted a qualitative study of 29 individuals including 15 parents of children with ASD who had had a recent anaesthetic and 14 staff members that had looked after them in different capacities at two hospitals in Melbourne, Australia in chapter three. Chapter four contains discussion and conclusion. It includes discussion about the discontinued preparation/premedication trial (CLOMID). The flaws in the design and obstacles in its execution are examined. Our data showed important organisational, educational and resource matters. Problems such as prolong waiting for an operation date, lack of training of staff including anaesthetists and nurses, lack of availability of simple equipment and private spaces in the recovery rooms- were to be addressed. Good communication, clear explanation, and friendly attitudes as well as flexibility and individualised care of patients were considered useful. The supplementary material includes a protocol for a preparation /premedication study that has not been concluded as well as two social stories that I have designed.
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ItemSex differences in fear learning in juvenile rats( 2020)The present thesis examined the sex differences in fear learning in the developing rat. Traditionally, it has been widely assumed that pre-pubertal sex differences are negligible in developmental studies. However, epidemiological studies and sexual dimorphism in the brain prior to puberty, indicate that sex differences in fear learning may emerge early in life. In chapter 2, I assessed renewal, reinstatement and spontaneous recovery of extinguished fear (i.e. relapse of extinguished fear) in juvenile male and female rats. I found that P18 females showed all three fear relapse behaviors while P18 males did not. This finding implied that P18 female rats were able to form the contextual memories while P18 males could not. However, whether the ability to form a context-shock association contributes to fear extinction in juvenile rats, has not been explicitly tested. Therefore in chapter 3a and 3b, I directly compared renewal with context fear, using identical fear conditioning parameters in the developing rats. In chapter 3a, I found that P18 male rats did not show renewal while P25 male rats did. P18 and P25 male rats displayed comparable contextual freezing immediately after conditioning and after 24 hours delay. In chapter 3b, both P18 and P25 female rats displayed renewal. I also found that P18 female rats displayed a developmental deficit in context fear learning compared to P25 female rats. Together, findings from chapter 2, 3a and 3b strongly suggested that the emergence of context memory may be sex-dependent, where context-specific extinction emerges earlier in females while context fear learning emerges first in males. Given the critical role of the hippocampus in context-dependent learning, I thought the sex differences in the hippocampal function may underlie the observed sex differences in fear learning. In chapter 4, I examined the role of dHPC and vHPC in fear extinction in P18 male and female rats. I showed that temporary inactivation of the dHPC prior to extinction accelerated extinction acquisition in both male and female rats. I also showed that pre extinction inactivation of the vHPC reduced freezing during extinction and impaired extinction recall, regardless of sex. Collectively, these findings strongly suggest sexually dimorphism in fear learning emerges early in life and emphasize the importance of sex as a factor in the field of developmental learning and memory.
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ItemFunctional connectivity alterations in brain networks relevant to self-awareness in chronic cannabis users(PERGAMON-ELSEVIER SCIENCE LTD, 2014-04)BACKGROUND: Recreational drugs are generally used to intentionally alter conscious experience. Long-lasting cannabis users frequently seek this effect as a means to relieve negative affect states. As with conventional anxiolytic drugs, however, changes in subjective feelings may be associated with memory impairment. We have tested whether the use of cannabis, as a psychoactive compound, is associated with alterations in spontaneous activity in brain networks relevant to self-awareness, and whether such potential changes are related to perceived anxiety and memory performance. METHODS: Functional connectivity was assessed in the Default and Insula networks during resting state using fMRI in 28 heavy cannabis users and 29 control subjects. Imaging assessments were conducted during cannabis use in the unintoxicated state and repeated after one month of controlled abstinence. RESULTS: Cannabis users showed increased functional connectivity in the core of the Default and Insula networks and selective enhancement of functional anticorrelation between both. Reduced functional connectivity was observed in areas overlapping with other brain networks. Observed alterations were associated with behavioral measurements in a direction suggesting anxiety score reduction and interference with memory performance. Alterations were also related to the amount of cannabis used and partially persisted after one month of abstinence. CONCLUSIONS: Chronic cannabis use was associated with significant effects on the tuning and coupling of brain networks relevant to self-awareness, which in turn are integrated into brain systems supporting the storage of personal experience and motivated behavior. The results suggest potential mechanisms for recreational drugs to interfere with higher-order network interactions generating conscious experience.
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ItemDietary intake of fish and PUFA, and clinical depressive and anxiety disorders in women(CAMBRIDGE UNIV PRESS, 2013-06-14)Fish and PUFA consumption are thought to play a role in mental health; however, many studies do not take into account multiple sources of PUFA. The present study analysed data from a sample of 935 randomly selected, population-based women aged 20–93 years. A validated and comprehensive dietary questionnaire ascertained the consumption of n-3 and n-6 PUFA. Another assessed fish and energy intake and provided data for a dietary quality score. The General Health Questionnaire-12 (GHQ-12) measured psychological symptoms and a clinical interview (Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition) assessed depressive and anxiety disorders. Median dietary intakes of long-chain n-3 fatty acids (310 mg/d) were below suggested dietary target levels. The only PUFA related to categorical depressive and anxiety disorders was DHA. There was a non-linear relationship between DHA intake and depression; those in the second tertile of DHA intake were nearly 70% less likely to report a current depressive disorder compared to those in the first tertile. The relationship of DHA to anxiety disorders was linear; for those in the highest tertile of DHA intake, the odds for anxiety disorders were reduced by nearly 50% after adjustments, including adjustment for diet quality scores, compared to the lowest tertile. Those who ate fish less than once per week had higher GHQ-12 scores, and this relationship was particularly obvious in smokers. These are the first observational data to indicate a role for DHA in anxiety disorders, but suggest that the relationship between DHA and depressive disorders may be non-linear.
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ItemNo Preview AvailablePsychological trajectories in the year after a newly diagnosed seizure(WILEY-BLACKWELL, 2012-10)PURPOSE: Underdiagnosed depression and anxiety are well-recognized issues in chronic epilepsy, but the evolution of these symptoms after diagnosis is not well understood. We aimed to identify mood trajectories after a first seizure, and to examine factors impacting these trajectories. METHODS: Seventy-four patients were evaluated at 1, 3, and 12 months with (1) the Hospital Anxiety and Depression Scale, and (2) a semistructured interview assessing patients' initial psychological reaction to the seizure at 1 month (limited vs. pervasive loss of control). The SAS Institute's TRAJ data modelling procedure was employed to delineate trajectories. KEY FINDINGS: Two depression and three anxiety trajectories were identified, with significant overlap. The majority of patients (≈ 74%) followed a trajectory with low depression throughout the study, and either low or moderate anxiety. A minority followed trajectories with high depression and anxiety from diagnosis (≈ 16%). Patients with high levels of distress were adversely affected by seizure recurrence and antiepileptic drugs (AEDs), whereas those with low levels were not. Trajectories were predicted by the patient's sense of loss of control early after diagnosis and were weakly related to demographic and medical variables (age, gender, education, relationship status, psychiatric history, and prior epileptic events). SIGNIFICANCE: Methods that account for heterogeneity in patient responses are critical for developing a clinically relevant understanding of adjustment after a newly diagnosed seizure. Most patients appear to be resilient in the face of early seizures, whereas those at risk of longer-term psychological difficulties may be evident from diagnosis. Early screening for depression and anxiety is warranted.
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ItemMoving towards a population health approach to the primary prevention of common mental disorders(BMC, 2012-11-27)There is a need for the development of effective universal preventive approaches to the common mental disorders, depression and anxiety, at a population level. Poor diet, physical inactivity and smoking have long been recognized as key contributors to the high prevalence noncommunicable diseases. However, there are now an increasing number of studies suggesting that the same modifiable lifestyle behaviors are also risk factors for common mental disorders. In this paper we point to the emerging data regarding lifestyle risk factors for common mental disorders, with a particular focus on and critique of the newest evidence regarding diet quality. On the basis of this most recent evidence, we consequently argue for the inclusion of depression and anxiety in the ranks of the high prevalence noncommunicable diseases influenced by habitual lifestyle practices. We believe that it is both feasible and timely to begin to develop effective, sustainable, population-level prevention initiatives for the common mental illnesses that build on the established and developing approaches to the noncommunicable somatic diseases.