Psychiatry - Theses
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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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ItemEffective connectivity in major depressive disorder and its association with treatment response: a functional magnetic resonance imaging investigation( 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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ItemThe influence of parenting and genetic variants on internalising symptoms during late childhood: neural mechanisms and the HPA-axis( 2019)Background: Greater levels of internalising symptoms during childhood and adolescence increase the risk of developing depression later in life. As such, investigating risk factors for depression in young people is important for understanding the aetiology of the disorder and for informing prevention strategies. Whilst it is known that extreme forms of childhood adversities, such as childhood trauma and abuse, represent a risk factor for depression, less has been done in investigating the effect of parenting behaviour. Emerging research suggests that negative parenting practices (e.g., parental rejection), as well as the lack of positive parental behaviours, increase the risk of internalising symptoms during childhood and adolescence. One of the proposed mechanisms linking poor parenting practices and depression is the effect of parenting behaviour on brain function and brain structure, particularly in regions involved in processing and regulating responses to emotional stimuli, such as the amygdala, prefrontal cortex and hippocampus. Animal studies suggest that parenting may affect the brain via effects on the hypothalamic-pituitary-adrenal (HPA) axis, which has a central role in the response to stress. Genetic factors are also likely to play a role, whereby genetic variants in HPA axis genes may contribute to the regulation/dysregulation of the system. To date, however, there is a lack of research focusing on genes related to HPA axis function, and their interaction with environmental factors (including parenting) in predicting internalising symptoms. Further, no research has investigated the neural mechanisms by which parenting behaviours, HPA genes, and their interaction, exert their influence on internalising symptoms. The aim of this thesis was to investigate a) whether parenting behaviour interacts with HPA genes to influence internalising symptoms in children/adolescents, and b) whether brain structure/function of regions involved in emotion processing (particularly the amygdala and hippocampus) mediates this link. Method: Data from two longitudinal studies were used in this thesis: the Adolescent Development Study (ADS) and the Families and Childhood Transitions Study (FACTS), to explore aims across three experimental chapters. The first study included 98 adolescents from the ADS, for whom hippocampal structural development was measured from magnetic resonance imaging (MRI) scans performed across three waves (W): W1 (mean age =12.6 years), W2 (mean age=16.5 years), W3 (mean age =18.8 years). Maternal negative behaviour was measured at W1 from an observed interaction task. Adolescents’ depressive symptom severity was measured at W1 and W3 with self-reported questionnaires, and genetic risk was calculated using a composite HPA genetic risk score. The second and third studies included 86 (mean age=10.1 years) and 80 (mean age=10.0 years) children, respectively, from FACTS. Observational measures of maternal parenting behaviour were collected during mother-child interactions. Children underwent functional MRI (fMRI) while performing an implicit emotion-processing task. Self-reported and parent-reported measures of child internalising symptoms were also collected. HPA genetic risk was calculated in a similar fashion to the first study. Results: Across both studies, neither HPA genetic risk score nor the interaction between HPA genetic risk score parenting behaviour predicted internalising symptoms in children/adolescents. For study 1, we did not find support for a mediating role of hippocampal structure in the relationship between parenting behaviour and internalising symptoms. Rather, we found a moderation effect such that negative maternal parenting behaviour predicted depressive symptoms longitudinally in adolescents with flattened hippocampal growth and HPA genetic risk. While maternal behaviour was not associated with hippocampal development, in study 2 it was associated with activity/connectivity in brain regions involved in emotion processing. In particular, maternal negative behaviour during a problem-solving interaction was associated with increased amygdala reactivity and connectivity with parietal cortex in children. Maternal negative behaviour during an event-planning interaction was associated with decreased activity in the lingual gyrus in girls. Maternal communicative behaviour was associated with increased medial orbitofrontal cortex activity. These parenting-related neural findings were not associated with child internalising symptoms. In study 3, HPA genetic risk predicted increased amygdala-precuneus connectivity, which in turn was associated with greater internalising symptoms in children. Moreover, HPA genetic risk interacted with negative maternal parenting behaviour to predict increased connectivity between amygdala and superior frontal gyrus, anterior cingulate cortex and parietal cortex. Conclusion: These results suggest that there is a complex interplay between neurobiological, environmental and genetic factors in predicting internalising symptoms in children and adolescents. Neurobiological factors (e.g., hippocampal development) may act as an independent risk factor for depressive symptom severity, but they may also be influenced by environmental and genetic factors. Parenting behaviour, particularly maternal negative and communicative behaviour, may influence brain activity and connectivity in regions involved in emotion processing. The lack of association with internalising symptoms hampers our ability to draw conclusions on the significance of the parenting-related neural findings for children’s mental health. However, given that depression is characterised by impaired emotion processing, including increased sensitivity towards negative stimuli, we speculate that differences associated with negative parenting behaviour, such as amygdala heightened reactivity to negative stimuli, may represent a risk factor for the disorder. HPA genetic variants may moderate the effect of parenting behaviour on these circuits (particularly the frontoamygdala circuitry), such that not all children are sensitive to parenting effects on neurobiology, and may confer risk for depression via altering corticolimbic connectivity. This study highlights the importance of parenting behaviour for children emotional neurocircuitry development and demonstrates the moderating role of genetic factors.