Psychiatry - Theses

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    Healthy Ageing in Older Veterans: A Mixed-Methods Study
    Watson, Loretta Ann ( 2023-10)
    Older military veterans are a unique population whose experiences of ageing may be different from those of their non-veteran peers in terms of physical, mental, and social health. Healthy ageing, however, has yet to be sufficiently well conceptualised for older veterans. Increased understanding of veteran healthy ageing is necessary to inform the development of health and social policy and practice that aims to support veterans to age well. This mixed-methods research aimed to extend the knowledge of healthy ageing in older veterans by exploring their perceptions of ageing well in order to examine heterogeneity in terms of their health. Study I aimed to gain an understanding of the meaning older veterans ascribed to ageing well, which was used to define health in Study II. Study II aimed to identify and examine health patterns of older veterans. Study I utilised interview data from 38 Australian veterans aged 60-75 years and reflexive thematic analysis to develop two themes, namely “Able to do what matters”, capturing autonomy, and “Caring, sharing, and being understood”, capturing connectedness. It was concluded that ageing well for the veterans in Study I meant living with expressed autonomy and sustained connectedness. Study II utilised latent profile analysis and survey data from 374 Australian veterans (M = 69.1 years; SD = 4.4) to estimate four groups with distinct health patterns. These were High Capacity (45%), Low Capacity (15%), Low Physical/High Mental Capacity (20%), and High Physical/Low Mental Capacity (20%). The health groups demonstrated a level of complexity not previously identified by past variable-level analyses. A secondary aim of Study II was to determine whether certain antecedents predicted the health patterns using multinomial logistic regression analysis. Significant predictors were educational attainment, self-efficacy, and attitudes to ageing. Specifically, higher educational attainment, greater self-efficacy, and more positive attitudes to ageing increased the likelihood of belonging to the High Capacity group compared to the other groups. The combined findings were used to develop a new framework for veteran healthy ageing, comprising a conceptual model and descriptions of four health patterns that characterise the variability in veteran health. Thus, this research developed a conceptual and empirical base for understanding veteran healthy ageing, offering future direction for expanding the evidence base in this emerging area. Findings may have practical utility for health and social policy and service provision, and implications for models of healthy ageing.
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    Characterising relationships between adolescent sleep, brain development and psychopathology
    Cooper, Rebecca Elizabeth ( 2023-07)
    Background. Sleep is critical for cognitive, emotional, behavioural and physiological wellbeing, particularly during the adolescent period. Adolescents experience substantial changes in sleep behaviour, such as delays in timing, decreases in duration, changes in sleep staging and sleep-related preferences. When combined with external psychosocial demands, however, such changes often result in sleep that is chronically insufficient and of poor quality. While the relationship between poor and insufficient sleep and psychopathology is well established, little is known about the role of changes in sleep on long-term mental health outcomes. Further, little work has accounted for the comorbidity of sleep behaviours, and especially the role of comorbid sleep problems, when examining relationships between sleep and psychopathology. In addition, cross-sectional evidence suggests that relationships between sleep and psychopathology may be anchored or mediated by changes in brain structure, and substantial evidence from preclinical studies suggests insufficient and poor sleep may negatively impact the developing brain. However, little prospective work has investigated this hypothesis in humans. The general aim of this thesis was to characterise longitudinal relationships between sleep, psychopathology and brain development across adolescence. Methods. Subjective questionnaires of sleep behaviour and psychopathology, combined with structural magnetic resonance imaging data from two longitudinal studies, was used to examine prospective relationships between sleep, psychopathology and brain structure and development across adolescence. Results. In our first study, we showed that diurnal preference, a sleep-related behaviour that indexes an individual’s preferred timing of sleep, underwent non-linear delays during adolescence. This delay resulted in an overall increase in eveningness preference across the entire sample. In turn, individuals with a greater shift towards eveningness were more likely to experience externalizing psychopathology symptoms, and also evinced an attenuated trajectory of white matter development in late adolescence. In our second study, we observed substantial diversity in the types and patterns of sleep problems experienced by pre-adolescents, which further diversified in the transition into young adolescence. Changes in sleep problems over time were in turn associated with significant changes in psychopathology. In the third study, we identified associations between brain structure, insomnia and psychopathology symptoms, and that these associations showed significant overlap cross-sectionally and prospectively, indicating that similar neural regions are associated with both insomnia and psychopathology. Conclusions. This thesis demonstrates that sleep, psychopathology and brain structure and development are tightly interconnected. Sleep- and sleep-related behaviours were found to predict changes in psychopathology, and may also influence brain development and structure. Further, structural alterations associated with specific sleep behaviours are shared with psychopathology, which may indicate shared neurobiological mechanisms underpinning their established comorbidity. Taken together, findings from this thesis provide further evidence for the critical importance of sleep for adolescent mental health, and also suggest that sleep may also be important for optimal brain development.
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    Emotion Regulation in Post-Traumatic Stress Disorder
    O'Brien, Hope ( 2023-05)
    Emotion processing theory is the prevailing model which explains the development and maintenance of post-traumatic stress disorder (PTSD). While it contends that emotional engagement with the feared stimulus is paramount for recovery, emotional engagement has largely been indexed through subjective distress ratings rather than detailing the process (i.e., what is actually happening). The primary aim of this thesis is to use the Extended Process Model of Emotion Regulation to understand 1) how deficits in emotion regulation in PTSD may impair emotion processing through difficulties with emotional engagement, and 2) how these learnings could improve treatment for PTSD. To do so, this thesis builds on previous research on emotion regulation in PTSD through three papers. The first study mapped existing knowledge of emotion regulation in PTSD onto Gross’ Extended Process Model of Emotion Regulation. It identified areas in need of further research, including the integration of a more holistic model through empirical research on attitudes, beliefs, and norms in emotion regulation as well as advancing measurement techniques. These became the foundation for the second and third studies. The second paper looked at three understudied aspects of emotion regulation in PTSD: emotion perception, beliefs about emotion(s), and attitudes about emotion(s). Structural equation modelling (N=104) demonstrated that emotion perception and fixed beliefs about emotion are significantly and uniquely associated with PTSD severity, suggesting that as difficulties with the identification, clarification, and awareness of emotions and fixed beliefs about emotion increase, PTSD severity increases. Finally, the third paper used an ecological momentary assessment (EMA) design to investigate the impact of PTSD on emotion regulation strategy choice in daily life. Using data from an experience sampling study in a trauma exposed sample (N=70; 7 days; 423 observations), the results revealed that PTSD severity was linked to greater use of suppression, distraction, and rumination to manage negative emotions independent of emotional intensity. Altogether, the patterns of emotion regulation difficulties in PTSD demonstrated by this research (deficits in emotion perception, fixed beliefs about the malleability of emotions, and an overreliance on maladaptive strategies) seem to block emotional engagement thus impairing emotion processing. All in all, findings from this research suggest that emotion dysregulation is at the core of PTSD.
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    The Effect of Alexithymia on Posttraumatic Stress Disorder Presentation and Treatment Response
    Putica, Andrea ( 2022)
    Fear extinction learning is the dominant mechanism underlying the development of trauma-focused treatments for PTSD. Fear extinction learning fails to account for all PTSD presentations and treatment variance. As a result, treatment non-response among frontline treatments continues to be approximately 50%. This thesis will explore the role of emotional agency, i.e., alexithymia, on PTSD presentations, fear memory processing, and treatment outcomes, working towards the development of a parsimonious account of PTSD where the self is viewed as an object and an agent to inform precision treatments.
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    Supporting the Transition to Parenthood for High-Risk First-Time Mothers in Pregnancy: The STAR Mums Program
    Bellhouse, Clare Elizabeth ( 2022)
    Abstract The transition to parenthood requires significant psychological, social, cognitive and biological adaptation. Successfully navigating this period is critical for maternal mental health, infant development and the development of the parent-infant attachment relationship. In order to have a comprehensive approach to intervention in pregnancy where there are risk factors for difficulties it is important to understand how these domains interact and the consequences for disruption in any of these areas for mothers, infants and their relationship. This thesis thoroughly examines this complex transition and the experiences of this for mothers at a high-risk of experiencing difficulties. Understanding the experience of women at risk in this transition can assist in identifying women who may require intervention in pregnancy to assist in trying to prevent disturbances in the parent-infant relationship. Additionally, this thesis describes a novel psychological intervention, the Supporting Transitions, Attachment and Relationships (STAR Mums) program, a psychodynamic attachment-based group intervention, for pregnant women with risk factors for attachment difficulties. The STAR Mums program aims to provide intervention during pregnancy to assist women identified as having risk factors in the transition to parenthood with the desired outcome to support a healthy transition to parenthood and to reduce some of these risk factors. This study involves a mixed-methods approach incorporating both qualitative and quantitative assessments of sixteen first-time mothers over a 12-month period. The use of qualitative methods allowed a more in-depth exploration of participants’ experiences of the transition to parenthood, their capacity for reflection and their experiences of participating in the program. Participants’ subjective experiences of participating in this intervention and of their transition to parenthood and early parenting can also help us to understand which aspects of this type of intervention are potentially useful and what additional supports may be necessary for subsets of this population. II This thesis highlights the complexity of the transition to parenthood and the need for an increased focus on supporting high-risk women in this period to prevent serious long-term consequences. This work provides an important first step in developing an intervention which provides an opportunity for women at risk to begin to work through issues which may impact their relationship with their infants before they are born, a true form of early intervention.
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    The Brain-Behavioural Basis of Human Safety Learning: An investigation of Pavlovian conditioned inhibition
    Laing, Patrick Alexander Fullerton ( 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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    Knowledge of and Attitudes towards Dementia among Older Chinese Adults: A cross-national comparative study between Melbourne and Beijing
    Zhao, Mei ( 2021)
    Dementia is a public health priority globally. In the absence of effective treatments to reverse or cure dementia to date, targeted information on dementia risk reduction strategies and the importance of a timely diagnosis of cognitive impairment is crucial for ageing people to manage their brain health. However, previous studies indicate that insufficient knowledge of dementia and negative attitudes towards dementia are barriers to engage with available information and help-seeking behaviours. In particular, culturally and linguistically diverse (CALD) populations in Australia, such as Chinese immigrants, often face specific barriers which need more investigation. Therefore, the aim of this thesis is to investigate and compare the knowledge of and attitudes towards dementia between older Chinese adults living in Melbourne, Australia and those in Beijing, China. Based on the socioecological framework, this thesis explored older Chinese adults' knowledge of and attitudes towards dementia on four levels: intrapersonal, interpersonal, community, and sociocultural level. This framework was used in study design, result integration and interpretation. A mixed-method approach was employed and consisted of three sub-studies, including one quantitative study (Study One) and two qualitative studies (Study Two and Study Three). Study One assessed and compared dementia knowledge and its associated factors between older Chinese adults in Melbourne and those in Beijing. A convenience sample of 379 older Chinese adults aged 50 or above were included, 226 from Beijing and 153 from Melbourne. Their level of dementia knowledge was assessed cross-sectionally using the Alzheimer's Disease Knowledge Scale (ADKS). This study found that older Chinese adults in both groups had similar levels of dementia knowledge and knowledge subdomains. Of the seven subdomains, older Chinese adults were most knowledgeable about the life impact of dementia as well as treatment and management, and least knowledgeable about caregiving and risk factors. Younger age and self-reported concerns about dementia were significantly associated with higher levels of dementia knowledge in the Melbourne group. In the Beijing group, a positive family history of dementia was significantly associated with a higher level of dementia knowledge. Study Two explored and compared older Chinese adults' attitudes towards dementia between Melbourne and Beijing. Based on the tripartite model of attitude, semistructured interviews were conducted with 46 Chinese adults aged 50 and over, including 21 from Melbourne and 25 from Beijing. The study found that older Chinese adults in both groups reported stigma and stereotypes associated with dementia. Most of them reported being afraid of developing dementia and thought it was a tragedy for families, particularly for adult children. However, they believed there was nearly no impact on patients themselves and the community in general. Most participants preferred home care, but acknowledged that formal care might be an alternative needed in the future. In the Beijing group, older adults perceived dementia as a common chronic disease in later life and called for more support in response to dementia from the community, government and society as a whole. Most of them expressed concerns about developing dementia in the future and considered the financial situation as a key determinant for the type of dementia care they would select. In terms of risk factors, they highlighted the important role of physical health conditions in the development of dementia. Older Chinese immigrants in the Melbourne group perceived dementia as an unpleasant topic, but not of many concerns to them specifically. Most of them expressed less concern about developing dementia in the future. Not many of them expressed interest in learning more about dementia. The majority stated they would consider their children's advice about participating in dementia education programmes. Meanwhile, they would be worried about language barriers and transportation limitations when considering participation in such programmes. Study Three explored and compared attitudes towards dementia from older Chinese adults' significant others' perspectives, including adult children, health professionals and community service providers. In total, 25 adult children (13 from Melbourne and 12 from Beijing), 13 health professionals (five from Melbourne and eight from Beijing) and ten community services providers (five from Melbourne and five from Beijing) were interviewed. Results indicated that across Melbourne and Beijing, all three groups of significant others reported that older Chinese adults usually avoided the topic of dementia or people living with dementia (PwD). They preferred home care if they developed dementia in the future. Adult children participants from Melbourne reported more proactive and positive attitudes towards dementia among older Chinese adults as compared to adult children from Beijing. Specific findings were reported regarding the impact of the migration experience in the Melbourne group, including language barriers, transportation limitations, limited social networks and the more independent parent-child relationship than the traditional Chinese parent-child relationship. These barriers influenced help-seeking behaviours not only in relation to cognitive concerns and dementia but also for other health concerns. With the specific comparison between immigrants and non-immigrants in older Chinese people, this thesis contributes new knowledge on the impact of the migration experience and the sociocultural environment on participants' knowledge of and attitudes towards dementia. With this, the results of this thesis have the potential to inform the development of targeted strategies to enable and maintain dementia health promotion for older Chinese adults living with or without migration experience.
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    Associations between early adversity, brain development, and mental health during adolescence
    Rakesh, Divyangana ( 2022)
    Early adverse experiences, like childhood maltreatment and socioeconomic disadvantage, are associated with lifelong consequences for mental health. However, the underlying neurobiological mechanisms of these associations are yet to be characterized. It has been suggested that adverse experiences may shape mental health via alterations in neurodevelopment. The aim of this thesis was to investigate how childhood maltreatment and socioeconomic disadvantage (which are both highly prevalent in the general community and are strong predictors of poor mental health outcomes), influence brain development during childhood and adolescence, and how those changes, in turn, contribute to mental health outcomes. An additional aim of the thesis was to examine environmental and psychological factors that may buffer the effects of adversity on brain development and mental health. This thesis used structural magnetic resonance imaging and resting state functional magnetic resonance imaging data from two studies, the Orygen Adolescent Development Study, and the Adolescent Brain Cognitive Development Study, in order to comprehensively characterize associations between childhood maltreatment, socioeconomic status (SES), and brain structure and functional connectivity as well as mental health. In the first and second study we investigated associations between childhood maltreatment (as well as specific dimensions of maltreatment) and longitudinal development of functional connectivity during adolescence, and showed that total maltreatment, abuse, and neglect, are associated with deviations in typical patterns of functional connectivity development. We also showed that these alterations in functional connectivity development are associated with mental health outcomes. Next, in the third study, we systematically synthesized the association between SES and brain structure, function, and connectivity, and showed that while there were some consistencies in findings, results were often mixed (especially at the level of individual SES indices). In the fourth and fifth study, we focused specifically on neighborhood disadvantage given that our review (third study) identified this to be a relatively unexplored SES indicator. In the fourth study, we showed that neighborhood disadvantage is associated with longitudinal alterations in brain-predicted-age trajectory, which was found to be moderated by temperamental effortful control. In the sixth study, we demonstrated cross-sectional alterations in functional connectivity as a function of disadvantage. We also showed that some of these alterations were associated with poor mental health. However, some associations between neighborhood disadvantage and functional connectivity were found to be moderated by positive parenting and favorable school environments. Finally, in studies six and seven, we demonstrate the independent and interactive effects of different SES indicators on brain structure and connectivity. We show that household income moderated the association between neighborhood disadvantage/low parent educational attainment and connectivity/brain structure. Overall, the findings of this thesis build knowledge around the impact of early adverse experiences on brain structure and functional connectivity, as well as mental health, during childhood and adolescence. Using whole-brain approaches, longitudinal data, and large samples, we were able to demonstrate that both childhood maltreatment and low SES are associated with widespread alterations in brain structure and function. These findings bring us one step closer to understanding the neurobiological pathways through which adversity ‘gets under the skin’ and impacts children’s mental health and wellbeing, and opens up exciting avenues for future research.
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    Effective connectivity in major depressive disorder and its association with treatment response: a functional magnetic resonance imaging investigation
    Jamieson, Alec John ( 2021)
    Despite effective first-line treatments for major depressive disorder (MDD), prognostic outcomes for many young people remain poor. Recent investigations into the interactions between brain regions, both at rest and during specific tasks, appear to suggest that abnormalities in these connections may contribute to the manifestation of depressive symptoms. An improved characterisation of brain associated dysfunction in MDD may elucidate contributing factors to this heterogeneity in treatment response. This thesis used functional magnetic resonance imaging and dynamic causal modelling across three studies to characterise abnormalities in the directional interactions between brain regions. Due to the lack of research examining how different emotional expressions modulate these directional interactions, Study 1 aimed to explore changes to effective connectivity present during the implicit processing of negatively valenced emotional expressions in a sample of healthy adolescents and young adults (N = 92, Mean age = 20.1 +/- 2.9 years). Processing sad and fearful facial expressions were associated with greater positive connectivity from the amygdala to dorsolateral prefrontal cortex (dlPFC). Compared with processing sad faces, processing fearful faces was associated with significantly greater connectivity from the amygdala to dlPFC. Study 2 aimed to examine whether there were differences in effective connectivity between MDD patients and healthy controls during the processing of facial expressions. The healthy controls from Study 1 were compared with a sample of MDD patients (N = 88, Mean age = 19.8 +/- 2.7 years). Following their scan, these patients were randomised to receive cognitive behavioural therapy for 12 weeks, plus either fluoxetine or placebo. Depressed patients demonstrated reduced inhibition from the dlPFC to ventromedial prefrontal cortex (vmPFC) and reduced excitation from the dlPFC to amygdala during sad expression processing. During fearful expression processing patients showed reduced inhibition from the vmPFC to amygdala and reduced excitation from the amygdala to dlPFC. Treatment responders demonstrated greater excitation from the amygdala to dlPFC during sad expression processing and reduced excitation from the amygdala to vmPFC connectivity during fearful expression processing. Finally, Study 3 aimed to examine differences in the effective connectivity at rest between regions commonly implicated in the neurobiology of depression, using the healthy controls (N = 90; Mean age = 20.1 +/- 2.7) and MDD patients (N = 94; Mean age = 19.7 +/- 2.8) from Study 2. Depressed patients demonstrated greater inhibitory connectivity from the rostral anterior cingulate (rACC) to the dlPFC, anterior insular cortex, dorsal anterior cingulate (dACC) and left amygdala. Moreover, treatment responders illustrated greater inhibitory connectivity from the rACC to dACC, greater excitatory connectivity from the dACC to subgenual anterior cingulate (sgACC) and reduced inhibitory connectivity from the sgACC to amygdalae at baseline. Together the findings from these studies detail widespread but distinct alterations associated with MDD which occur at rest and during the implicit processing of sad and fearful facial expressions. These results commonly suggest that MDD is marked by abnormal interactions between regions of the salience, central executive and default mode networks. Across both of our tasks, treatment responders did not demonstrate connectivity which was more similar to healthy controls, but rather illustrated unique alterations that may have predicated their enhanced treatment response. Moreover, while these parameters were shown to be overall predictive of treatment response, in both tasks this was particularly strong for those treated with CBT and placebo. We suggest that this effect may be due to treatment with selective serotonin reuptake inhibitors altering connectivity variability in such a way that this baseline configuration is less informative of future response.
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    The neural basis of threat and safety reversal learning in healthy subjects and patients with Social Anxiety Disorder
    Savage, Hannah Sylvia ( 2021)
    Responding flexibly to changing sources of threat and safety is critical to the adaptive regulation of emotions, including fear. Anxiety disorders, including social anxiety disorder (SAD), have been linked to maladaptive forms of fear regulation. At a neural systems level, such flexibility is thought to rely on an extended neural circuitry involving the dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortices (vmPFC), although precisely how this occurs remains unclear. Furthermore, few studies have examined this in young, unmedicated SAD patients. To address this, this thesis used functional magnetic resonance imaging (fMRI), and autonomic and subjective measures during a threat and safety reversal learning task, in three studies. Study 1 examined the neural correlates of threat and safety reversal learning and their associations with individual differences in anxious responding in a large sample of healthy adolescents and young adults (N=94; 21.31 years). Overall, participants demonstrated successful threat and safety reversal learning. At a whole-brain level, threat reversal was associated with significant activation of the bilateral anterior insular cortex and dACC, in particular its rostral subregion. Conversely, safety reversal led to significant activation of the anterior vmPFC, together with posterior mid-line regions. Study 2 aimed to characterise the neural, subjective, and autonomic correlates of reversal learning in patients with SAD (N=41; 19.85 years), and compare them to matched patients with major depressive disorder (N=19; 19.42 years) and to healthy controls (N=60; 20.3 years). No significant differences were observed between groups at either a neural, subjective, or autonomic level. Threat learning elicits robust changes across multiple affective domains. It has been argued that the underlying causes of such changes may be dissociable at a neural level, but there is currently limited evidence to support this notion. To address this, Study 3 examined the neural mediators of trial-by-trial skin conductance responses (SCR), and subjective reports of anxious arousal and valence in participants performing the threat and safety reversal learning task during ultra-high field fMRI (N=27; 21.93 years). Our results suggest the broad neurocircuitry of threat learning, including the dACC, anterior insula and vmPFC, mediated the experience of subjective arousal, while only a subset of these regions mediated threat-related SCR and valence. Furthermore, our data suggest dual vmPFC mechanisms modulate SCR during threat learning. Conversely during safety reversal, positive mediators were located in the vmPFC for all domains. We therefore conclude that appropriate responding during safety reversal learning is facilitated by participants engaging self- and valence-based processes. Taken together, our findings complement existing neurocircuitry models of human fear regulation and provide further insights into regional contributions to flexible threat-safety signal processing. We add novel evidence to support distinct underlying neural processes within these regions facilitating autonomic and subjective responding during threat learning and safety reversal. I discuss the implications of these findings for our understanding of brain function and affective processing more broadly. We showed that patients with SAD did not show impairments in threat and safety reversal learning. I discuss how we may otherwise approach studying hypothesised maladaptive fear regulation in future studies.