Psychiatry - Theses

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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.
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    Neural correlates of memory dysfunction across stages of schizophrenia-spectrum disorder
    Wannan, Cassandra Marie Joanne ( 2020)
    Schizophrenia-spectrum disorders are severe mental illnesses characterised by hallucinations, delusions, blunted affect and disorganised thought patterns. A core feature of these disorders is cognitive deficits, which are associated with functional disability. Episodic memory, in particular, is one of the most severely impacted areas of cognitive functioning in schizophrenia-spectrum disorder, and memory deficits predict poorer clinical prognosis and increased functional disability. However, the longitudinal course of episodic memory deficits in schizophrenia-spectrum disorders is currently poorly defined, with the focus to date being on areas of functioning that are already impaired in early illness stages, such as verbal memory. In order to better understand trajectories, it may be important to examine areas of functioning that are preserved early in the illness, such as visual associative memory. Furthermore, there is currently a poor understanding of the neural underpinnings of memory impairment in schizophrenia-spectrum disorders, making it difficult to develop targeted interventions aimed at ameliorating these deficits. It is plausible that episodic memory impairments in these disorders is related to underlying dysfunction in the brain regions and networks that underlie this ability – namely, the hippocampus and its connections to the prefrontal cortex. This thesis utilised longitudinal cognitive assessment and cross-sectional multi modal neuroimaging to address three primary research aims: 1. To investigate the longitudinal course of episodic memory ability over a 5-11-year follow-up period in individuals with first-episode psychosis. 2. To investigate relationships between visual associative memory performance and hippocampal subfield volumes in FEP individuals and individuals with chronic schizophrenia-spectrum disorders. 3. to investigate whether visuospatial associative memory ability is related to white matter microstructure in the hippocampal-prefrontal pathway in FEP individuals and individuals with chronic schizophrenia-spectrum disorders. Results showed that visual associative memory ability was preserved in in individuals who had recently experienced a first psychotic episode, but deteriorated over a 5-11 year follow-up period. Conversely, verbal associative memory ability improved over the follow-up period to the same degree in FEP individuals and healthy controls. In a subsequent cross-sectional study, we found that, while hippocampal subfield volume reductions were present only in individuals with chronic schizophrenia-spectrum disorder, poorer episodic memory performance was associated with reduced subfield volumes in the CA4/dentate gyrus (DG) and in the stratum layers in both FEP individuals and those with chronic schizophrenia-spectrum disorder. Finally, we found that abnormal white matter microstructure in a number of memory-related ROIs and hippocampal-prefrontal pathways was present only in individuals with chronic schizophrenia-spectrum disorder. Furthermore, microstructural abnormalities in the fornix and the hippocampal-thalamic pathway were associated with poorer memory performance in individuals with chronic schizophrenia-spectrum disorder, but not FEP individuals. These findings provide new insights into the neural underpinnings of episodic memory impairment across stages of schizophrenia-spectrum disorder, and suggest that hippocampal structure may be more relevant to memory impairment in FEP individuals, with memory-related white matter abnormalities emerging in later illness stages.
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    The Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL) Veterans study - Post traumatic stress disorder and risk of Alzheimer's disease
    Elias, Alby ( 2020)
    Background Epidemiological studies have suggested an association between posttraumatic stress disorder (PTSD) and Alzheimer’s dementia in Vietnam veterans. These studies, however, did not use biomarkers of Alzheimer’s disease (AD) to either confirm the diagnosis or assess the relative prevalence of AD pathology when investigating the risk of dementia in PTSD. Aim This study aimed at testing the hypothesis that Vietnam veterans with combat PTSD have an increased risk for Alzheimer’s disease in comparison with veteran controls as measured by biomarkers such as amyloid-beta and tau retention in the brain and regional hypometabolism and atrophy. Method Vietnam veterans with a history of PTSD as defined by the Clinicians-Administered PTSD scale (CAPS) score of 40 or above and veteran control subjects as defined by CAPS score of 30 or below and with no current clinical evidence of dementia participated in the study. Outcome measurements were amyloid-beta and tau deposition and regional brain metabolism and volumetry. Amyloid-beta and tau burden was estimated by the Specific Uptake Value Ratio (SUVR) of 18F-florbetaben, and 18F-AV-1451 respectively. 18F-fluorodeoxyglucose positron emission tomographic (PET) scan measured regional brain metabolism, and 3-Tesla T1 MP-RAGE Magnetic Resonance Imaging (MRI) estimated regional volumetry. Comprehensive neuropsychological battery measured cognitive function. Results Between March 2014 and June 2017, 83 male Vietnam Veterans (controls, n=30, CAPS=4; lifetime PTSD, n=53, CAPS=73.95; lifetime and current PTSD, n=30, CPAS=52.50) completed the assessments. There was no significant difference between the two groups in the uptake of 18F-florbetaben, 18F-AV-1451 or 18F-fluorodeoxyglucose, or regional brain volumetry. The rate of apolipoprotein E e4 allele was not significantly different between the groups. Compared with control veterans, the PTSD participants had a significantly lower level of education, predicted premorbid Intelligent Quotient (IQ), and total intracranial volume and higher depression rating score. The Montreal Cognitive Assessment score was significantly lower in the PTSD group than in controls. The group differences in Montreal Cognitive Assessment did not remain, however, when adjusted for premorbid IQ or depression in a multilinear regression model analysis. Conclusions Posttraumatic stress disorder is not associated with an increased prevalence of biomarkers of Alzheimer’s disease. The proxy measures of cognitive reserve, a factor that may delay the onset of Alzheimer’s dementia, were relatively low in subjects with PTSD, and this may explain the previously reported higher incidence of dementia in subjects with PTSD compared to age-matched controls.
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    Topographic organization of the human insular cortex and subcortex in health and neuropsychiatric illness
    Tian, Ye ( 2020)
    The structure, function and connectivity of the human brain are topographically organized. This topographic organization provides profound insight into cortical information processing, representation of mental states, and accounts for individual variation in behavioral traits and cognition. Whereas classical models of brain topography focus on distinct cortical patches defined by discrete boundaries, contemporary evidence from neuroimaging suggests that topographic variation may be better conceptualized in terms of a set of continuous gradients of gradual change that overlap in space. My work aims to reconcile these two conceptualizations of brain topography, particularly with respect to the insular cortex, a topographically complex and functionally heterogeneous cortical lobe whose organization has remained disputed for centuries. Using modern functional neuroimaging techniques, I showed that the insula’s topography is best conceptualized as a continuum of gradual change oriented along an anterior-posterior axis. I found that individual variation in the insula’s functional topography associates with human cognitive and emotional traits as well as somatosensory functions. Having characterized the functional architecture of the insular cortex in healthy adults, my next aim was to investigate whether neuropsychiatric illness is associated with alterations in the insula’s functional organization. To this end, I compared the insula’s functional connectivity gradients between individuals with schizophrenia and healthy controls. I found evidence suggesting subtle reorganization of the insula’s functional topography in schizophrenia. In particular, the connectivity profile along the anterior-posterior topographic axis of the insular cortex was altered and less differentiated in individuals with schizophrenia. I showed that the extent of reorganization of the insula’s functional topography significantly associates with the severity of clinical symptoms, particularly negative symptoms of psychosis and intellectual impairment. Finally, I applied the new methodology that I developed to map the insula’s topography to study other brain regions, including the entire human subcortex. This unveiled four hierarchical scales of subcortical organization, recapitulating well-known anatomical nuclei at the coarsest scale and delineating 27 new bilateral regions at the finest. Based on this work, I developed a new MRI subcortical atlas to enable holistic connectome mapping and characterization of cortico-subcortical circuits. The new subcortex atlas was personalized to account for connectivity differences across individuals and utilized to uncover a reproducible association between subcortical functional connectivity and tobacco use. Overall, this thesis provides fundamental insight into the functional organization of the human insular cortex and subcortex in health and neuropsychiatric illness, particularly focusing on the distinction between classical models of topographic variation based on discrete regions and contemporary representations involving continuous gradients. The new methodology that I developed is not limited to the insular cortex and the subcortex and can be applied to other cortical and subcortical regions in humans as well as other species.
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    Neuroimaging Biomarkers in Generalised Anxiety Disorder, and Associated Modulations Following an Anxiolytic Intervention
    Savage, Karen Maree ( 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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    Brain network communication models
    Pimentel Seguin, Caio ( 2020)
    Communication between neural elements underpins all aspects of brain functioning. Large-scale neural signalling unfolds atop the human connectome, the complex network that describes how gray matter regions are interconnected by white matter projections. The mechanisms governing the propagation and communication of signals across the connectome remain unknown. The main focus of this thesis is the investigation of network communication models aimed at elucidating how the anatomical substrate of nervous systems facilitates and constrains functional interactions between gray matter regions. To date, the vast majority of network neuroscience studies have assumed neural signalling occurs via topological shortest paths. This is reflected by the widespread use of graph measures such as global efficiency, betweenness centrality and the small world coefficient. In recent years, researchers have begun to question this assumption on the basis that communication via shortest paths is contingent on centralized knowledge of connectome topology, and thus may not be a biologically realistic signalling model. This has led to the exploration of decentralized strategies of network propagation. Most efforts in this direction are focused on diffusive communication, which typically models neural signalling from the perspective of random walk processes. While these approaches do not mandate knowledge assumptions about network organization, they fail to promote efficient and energetically frugal neural information transfer. Therefore, the literature on brain network communication models is currently concentrated on the opposing strategies of shortest path routing and diffusive communication. This thesis aims to reconsider this dichotomous state by investigating alternative brain network communication models. In Chapter 3, we explore the concept of navigation in mammalian connectomes. Navigation is a greedy routing strategy in which information is propagated based on the spatial positioning of brain regions. Using human, macaque and mouse brain networks, we provide evidence that connectome organization is conducive to decentralized efficient communication under navigation. Specifically, the combination of empirical connectome topology and geometry was necessary for successful network navigation, with disruptions to either attribute resulting in marked decreases of navigation efficiency. These findings suggest that brain network architecture may have evolved to facilitate efficient decentralized information transfer, and indicate a three-way relationship between topology, geometry and communication in nervous systems. Decentralized network communication models can be asymmetric. This means that the efficiency of signalling paths may vary depending on the direction of information flow. Importantly, this behaviour occurs even in undirected networks. This unexplored facet of network communication provides the opportunity to study directional patterns of signalling in the human structural connectome, in which all connections are considered bidirectional due to the inability of diffusion imaging to resolve axonal directionality. In Chapter 4, we develop the statistical framework of send-receive asymmetry and demonstrate that it contributes novel insight into large-scale neural signalling directionality. Crucially, this chapter provides cross-modal evidence for the utility of decentralized communication models by demonstrating a statistical association between send-receive asymmetry and the directionality of effective connectivity. Lastly, in Chapter 5 we perform a systematic evaluation of the main neural signalling models proposed in the network neuroscience literature. We evaluate models in terms of their (i) predictive utility of interindividual variation in human behaviour and (ii) structure-function coupling strength. We hypothesize that communication models performing better in these criteria may provide more parsimonious characterizations of information transfer mechanisms in the human brain. Importantly, we benchmark communication models against structural connectivity, and provide evidence that accounting for polysynaptic communication improves the behavioural and functional predictions derived from direct anatomical connections alone. Combining behavioral and functional results into a single ranking of communication models positioned navigation as the top model, suggesting that it may more faithfully recapitulate biological neural signalling patterns. The results in this chapter contribute to elucidating the relationship between human behaviour, functional connectivity and connectome communication. Collectively, the findings reported in this thesis further our knowledge of large-scale neural signalling, promoting a unified understanding of brain structure, function and communication.