Psychiatry - Theses
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Williams Syndrome: links between brain, cognition, and behaviour
The interrelationships between brain, cognition, and behaviour are complex but can be more clearly characterised by studying disorders with an underlying genetic basis. This thesis examined these interrelationships in the context of Williams syndrome (WS), a neurodevelopmental genetic disorder that affects aspects of cognition, behaviour, and brain structure. The principal aims of this thesis were to evaluate the cognitive, behavioural, and neuroanatomical profile of WS individuals and to explore the relationships between aspects of the cognitive and behavioural profile and the neuroanatomical changes that are evident in WS. Three general hypotheses, and 10 specific hypotheses, were postulated as a means of exploring these aims. The first general hypothesis predicted that WS individuals would demonstrate distinct features within their cognitive and behavioural profile. Specifically, it was predicted that WS individuals would show relative strengths on verbal tasks and significant deficits on visuospatial and mathematical tasks, in contrast to control participants who were predicted to show a more even profile. It was also predicted that WS individuals would show evidence of heightened affect in response to music and demonstrate hypersociability as compared to control participants
What are the special characteristics of families who provide long term care for children of parents with mental illness?
This project investigated characteristics relating to family functioning and attitudes to mental illness, and caregiving, which distinguish families choosing to care for children of parents with mental illness (CPMI) from families who choose not to but do care for other children (NCPMI), and from families not involved in the adoptive care system (COMM). Welfare agencies seeking long term home based care for children of parents with mental illness (among other groups of children) report that potential caregivers are concerned about the child’s genetic risk, and the requirement that they facilitate access visits with the birth parent. Consequently it is more difficult to recruit caregivers to care for children of parents with mental illness. Previous studies found that families who adopt children with special needs had family systems that were flexible and able to adapt to changing needs, and in which family members felt close to one another. It was not known if the functioning of families who care for children of parents with mental illness would differ from other family groups. Nor was it known if these families would differ in motivation to be caregivers and attitudes to mental illness from other family groups. Forty four families completed a questionnaire providing background information, and a family functioning questionnaire which included the FACES II measure (Family Adaptability and Cohesion Evaluation Scale) and questions assessing level of altruism, and tendency to respond in a socially desirable manner. Data from the FACES II measure was used to classify families according to the Circumplex Model of Marital and Family Systems. Q-methodology was used to assess participants’ attitudes to eight issues related to the research question: mental illness, children of parents with mental illness, parents having a mental illness, family environment, motivation to be caregivers, ongoing contact between child in care and parent, approval of others when deciding to be a caregiver, and flexibility in deciding to accept a certain child for placement. The Q-method required participants to rate 42 statements (a Q-set), concerning these issues, according to a fixed distribution, from statements with which they strongly agreed to statements with which they strongly disagreed. Participants could also give open-ended responses to questions addressing the same issues in a semi-structured interview. The CPMI group were found to have a lower level of income and education than the other two groups, and were more likely to be full time caregivers. Both caregiver groups were unlikely to have children of their own. The profiles of the three groups on the cohesion and flexibility sub-scales of FACES II were similar. The classification of the family groups on the Circumplex model showed that the CPMI group were located in the balanced and mid-range levels of the model more so than the other two groups. Responses to the Q-sort and interview questions suggested that the CPMI families were more understanding of mental illness, and of the needs of the children and capacity of their parents. It is suggested that future studies increase the number of participants, and investigate in more detail the factors which motivate families who provide long term care for children of parents with mental illness.
Wellbeing of firefighters: the impact of individual factors, potentially traumatic event exposure, and operational and organisational factors on mental health outcomes
Aims: This study aimed to investigate the prevalence of the common mental health disorders associated with increased exposure to potentially traumatic events in career and volunteer firefighters, and to identify which individual, acute stressor, operational and organisational factors predict mental health outcomes. Method: Four Australian services participated in a prospective study, with 335 firefighters completing an online survey twice (12-months apart). The survey comprised demographic and fire service information, self-report measures for PTSD, depression, anxiety, alcohol use, exposure to personal trauma and life stressors, number and types of firefighter-related potentially traumatic events experienced in the previous 12-months, job satisfaction related to operational and organisational characteristics of their role, and a measure of the priority their fire service placed on their psychological wellbeing. Structured clinical interviews were conducted with a sample of survey respondents to assess for PTSD, depression, generalised anxiety disorder and alcohol use disorder. Results: From 297 clinical interviews (91 career firefighters and 206 volunteer firefighters), 24% (n = 22) of the career firefighters met diagnosis for any psychiatric disorder. Of these, 3% met criteria for PTSD, 5% for depression, 4% for generalised anxiety disorder, and almost 12% for alcohol use disorder. The primary regression analyses indicated the following findings for the career firefighters. The main variable associated with each of the four disorders was the respective level of symptoms at baseline. In addition, exposure to more potentially traumatic events in the previous 12 months contributed to, and high job satisfaction associated with the operational aspects of their role protected them against the development of PTSD and depression. Finally, the findings indicated that experiencing more recent life events in the previous 12 months and rank (being a firefighter) contributed to more symptoms of Alcohol Use Disorder. From the interviews 17% (n = 35) of the volunteer firefighters met diagnosis for any psychiatric disorder. Of these, 2% met criteria for PTSD, 4% for depression, 5% for generalised anxiety disorder, and 6% for alcohol use disorder. The primary regression analyses indicated that the only predictor of PTSD, generalised anxiety disorder and alcohol use disorder was the respective baseline level for each disorder. The main predictors of depression were baseline level of symptoms of depression and experiencing more recent life events in the previous 12 months. Conclusions: The relatively low prevalence rates for the career and volunteer firefighters in this study indicate their reasonably good mental health across the four disorders. The rates compare favourably with other firefighter studies and are comparable with the rates in the general population for most disorders. An exception to this was volunteer firefighters’ high rate of alcohol dependence and low rate of PTSD. The findings indicate the importance of fire services developing cultures that support and encourage the early identification and management of symptoms and have systems in place to monitor the types of and frequency of firefighters’ exposure to potentially traumatic events. Finally, particularly for the career firefighters, the findings highlight the protective nature of high job satisfaction associated with operational characteristics of their role and reduced mental health symptoms, and the importance for firefighters and managers to recognise and address reductions in job satisfaction.
War experiences: the emotional health and wellbeing of Polish elderly immigrants
Background: Large numbers of Polish refugees arrived in Australia following the end of the Second World War as displaced people, unable to return to their homeland. All had experienced loss of their homeland and many lost loved ones, endured hardship and suffering. Now this group constitutes a significant proportion of the Polish-Australian aged community. The main aim of this thesis is to describe, from a life-span perspective, the relationship between major life events, including war experiences, and psychological and physical health now and in the past. Attention is focused on the factors associated with the longevity of the trauma response. Method: A mixed methods approach was employed using quantitative and qualitative methods along with a detailed historical account of the war and resettlement contexts. The quantitative component involved the recruitment and interview of a convenience sample of 72 Polish elderly migrants from Polish Senior Citizen's clubs across the Melbourne Metropolitan area. Participants who gave informed consent completed a detailed questionnaire and interview about their current physical health, social networks, psychological health, quality of life, posttrauma growth, war-related experiences, traumatic events, migration, and post war life events. Categorical and continuous variables were analysed using a combination of parametric and nonparametric statistics. The qualitative component involved a narrative interview with a subset of 18 people about the war years and early life in Australia. In addition, detailed field notes were compiled from the quantitative questions with the remaining 54 people supplementing their responses with stories and accounts while filling out the questionnaires. This produced a rich source of data that was analysed thematically. Results: Fifty-three per cent of participants were women. Most were aged 75 or older (71%). Just over half were married and a third were living alone. The majority had children (90%). Twenty-one per cent described their physical health and seven per cent their emotional health as poor. During the war, 42% were in Germany as forced labourers, 26% had been exiled to the former Soviet Union, 15% had participated in the Armed Forces, 11% were civilians in Poland and 5% were Concentration Camp Survivors. Every person interviewed had experienced at least two traumatic events during the war. The most commonly reported events were the loss of home and belongings (81%), lack of food and water (79%), bombardment (78%) and forced separation from family (74%). People who had survived the concentration camps and ex-service men experienced the highest number of traumatic events. Number of traumatic events during the war was correlated with life-time PTSD symptoms (r=0.46 p=0.01), current PTSD symptoms (r=0.36) and physical health conditions (r=0.37 p=0.01) but was not associated with current quality of life. Negative worldview was associated with PTSD (lifetime and current), physical health conditions and impact of illness. Trait anxiety and years of residency were associated with depression, anxiety, PTSD (lifetime and current) scores and physical health conditions. Negative worldview, Trait anxiety and years of residency were all independent predictors of psychological distress accounting for 51% of the variance in psychological distress. During their-lifetime, 75% of people identified a period of fear, anxiety and panic, 47% of participants reported feeling depressed, while 7% met criteria for PTSD. In the last six months, 33% reported clinically significant anxiety symptoms, 3% had moderate-severe depressive symptoms and 3% met criteria for current PTSD. Coping strategies mentioned most frequently were use of religion (54%) talking to family and friends (32%) and avoiding any reminders (18%) although none of these strategies were associated with emotional or physical health. Thematic analysis revealed that Polish elderly described their accounts of trauma and physical deprivation in the context of individual, familial and community suffering. Individuals described a range of emotional responses to trauma such as fear, grief and humiliation. These emotions were also experienced by family and community. Survival mechanisms such as acts of defiance, using one’s own skills and having hope were described at an individual level. Family was identified as an important survival resource - a central component to this theme was that of the ‘strong mother’ fending for her children. Community was another resource identified by study participants such as the ‘acts of kindness by strangers’ that often made the difference between life and death. The theme of community and family suffering meant that the individual was not alone in trauma but surrounded by others in a similar situation. Community structures were an important part of the recovery and healing that took place after the war. The cohesive nature of Polonia (Poles abroad) may explain why people who did not return to Poland and migrated to Australia in the late 1940’s and 1950’s had lower rates of psychological distress compared with those who returned to communist Poland and only arrived relatively recently. Conclusions: More than 60 years on from the end of the Second World War Polish elderly people were still affected by these events in some way and that in a small number of cases these events were associated with current emotional and physical health. The main determinant of current emotional and physical health was the type of main experience people endured, the number of traumatic events experienced, having a negative world-view, fewer years of residency and higher Trait-Anxiety scores. The thematic analysis revealed that there is a complex relationship between individuals, families and communities in how they experienced trauma and its aftermath and the resources and mechanisms they used in order to survive.
Understanding the role of frontotemporal brain structures in schizophrenia through magnetic resonance imaging and neuropathological studies
Section 1: The first two chapters describe my initial hippocampal volumetric work in patients with first-episode psychosis and chronic schizophrenia that identified hippocampal changes early in the course of psychosis. Chapter 3 explores in detail the theoretical basis for hippocampal involvement in schizophrenia and introduces for the first time the concept that the hippocampal volume changes observed in patients with first episode psychosis and chronic schizophrenia may not be present in patients at high risk of psychosis. Chapters 4 to 6 describe a series of cross sectional studies showing that hippocampal volumes are normal in high risk patients who later develop psychosis (Chapter 4 and 6), normal in patients with schizophreniform psychosis (Chapter 6), reduced on the left side in patients with first-episode schizophrenia (Chapter 6) and bilaterally reduced in patients with chronic schizophrenia (Chapter 6). These findings suggest that right hippocampal volume reduction occurs with increased illness duration, a finding supported by a voxel based morphometry study of patients with chronic schizophrenia (Chapter 5). Finally in contrast to our original findings (Chapter 1) that hippocampal volumes were equally reduced in patients with first-episode schizophrenic and non schizophrenic psychoses, our study of a much larger first-episode cohort (Chapter 6) showed that hippocampal volume reduction was specific to schizophrenic psychoses while amygdala enlargement was specific to non schizophrenic first-episode psychoses. These findings suggested either that (i) patients who make the transition from high-risk to first-episode or first-episode to chronic schizophrenia already have hippocampal changes and/or (ii) that hippocampal volume changes occurred progressively over the course of the illness. Section 2: Chapters 7 and 8 describe follow-up longitudinal imaging studies in a first-episode cohort and a high-risk cohort respectively. We did not identify hippocampal volume change over a two-year period (Chapter 7) but observed whole brain changes over time in first-episode and chronic schizophrenia cohorts. We hypothesised that structural changes may have occurred prior to or over the transition to active psychotic illness. Chapter 8 describes parahippocampal and frontal changes in high-risk patients who developed a psychotic illness and not in those who did not develop a psychotic illness. These findings provided support for the concept that some patients with a psychotic illness exhibit progressive structural brain changes. Section 3: Chapters 1 to 8 describe evidence for the presence of structural brain changes in the hippocampi of patients with schizophrenia. Structural MRI cannot determine the neurobiological correlates of such brain changes i.e what is causing the changes or which elements of brain tissue are involved. The neurobiology of diseases that mimic schizophrenia (‘secondary schizophrenias’) has provided insights into schizophrenia. Chapter 9 describes a previously unrecognised association between young onset frontotemporal dementia and schizophrenia-like psychosis and specific hippocampal pathology in these cases. Chapter 10 describes similar pathological abnormalities in the hippocampus of patients with schizophrenia and bipolar disorder, who had never been suspected of having dementia earlier in life. The identification of clinical and neuropathological associations between FTD and schizophrenia / bipolar disorder is of significant clinical relevance and provide new avenues for research into the underlying neurobiology of major mental disorders. Section 4: The concluding section discusses how the work in this thesis can be understood within the context of neuroimaging work that has emanated from this large dataset and the current schizophrenia literature. The association between schizophrenia and FTD identified in Chapters 9 and 10 is explored further in this final section with reference to the literature and some illustrative case reports.
Understanding the neural basis of the experience of negative moral emotions in healthy and depressed adolescents
Background: Shame and guilt are negative moral emotions that are usually experienced when rules, norms or social agreements are broken. These emotions are associated with punishing feelings of self-blame relating to behaviour and character and are crucial for social development during adolescence. However, there is currently a poor understanding of the neurobiological underpinnings of these emotions. The importance of understanding the neural correlates of these emotions lies in a better understanding of human social functioning and the role they play in particular mental disorders such as depression. Depression is a mood disorder that affects a large number of adolescents. A key component of depression is emotional dysfunction, and it has been recognised that moral emotions such as shame and guilt play an important role in the development and maintenance of depression. Despite extensive knowledge of the neural mechanisms underlying deficits in basic emotional processes in adolescent depression, there is no research to date that has investigated the neural correlates of shame and guilt in a depressed adolescent population. Broad Aim of PhD study: To investigate the common and distinct neural correlates of the experience of negative self-conscious emotions (i.e., shame and guilt) in healthy and depressed adolescents using a novel social moral dilemma paradigm. Methodology: A novel shame and guilt induction paradigm was developed for use with functional Magnetic Resonance Imaging (fMRI). A total of 44 female teenager-relevant social moral dilemmas were created and validated via an online survey. Twenty-two female adolescents with major depressive disorder (MDD) (mean age = 20.19) and 47 healthy female controls (mean age = 18.89) aged 15-24 were recruited from the Melbourne area. Patients were recruited from Orygen Youth Health and Headspace Centres in Melbourne. During fMRI, the adolescents were presented with dilemmas one at a time and were requested to a) make a decision about what they would do if in that situation, and b) reflect upon how they would feel. Ratings of emotional experience were collected post-scan. Analyses were conducted to investigate the neural correlates of self-reported shame and guilt experiences in both depressed and healthy adolescents, and to examine whether the groups differed in their neural response associated with these negative self-blaming emotions. Results: Findings showed marked individual variations in shame and guilt responses to the different dilemmas in both the healthy control and MDD participants. The common experience of shame and guilt in healthy individuals was associated with significant activation in lateral and medial parts of the prefrontal cortex (including the medial and dorsomedial PFC extending to the supplementary motor cortex, the dorsal anterior cingulate cortex and mid-cingulate, the lateral superior, middle and inferior frontal gyri, and the ventrolateral PFC extending to the anterior insula), temporal area (superior temporal sulcus), parietal regions (supramarginal and angular gyri), as well as some subcortical regions (thalamus and caudate nucleus). Adolescents with major depressive disorder showed similar associations between shame and guilt and brain activity compared with healthy participants, but with a lesser extent of activation. In terms of differences between healthy and depressed individuals, the anterior middle temporal cortex was associated with guilt to a greater extent for the control group compared to the patient group. Additionally, results showed activity in the superior parietal cortex extending to the inferior parietal cortex and the precuneus to be associated with shame to a greater extent in patients compared to controls. Significance: The proposed project will advance the understanding of the neural correlates of shame and guilt in healthy individuals as well as the neural basis of these same emotions in depressed adolescents. The information gained from this will be of significant value for the development of prevention and treatment efforts for depression as well as other mental disorders for which these self-conscious emotions play a significant role.
Topographic organization of the human insular cortex and subcortex in health and neuropsychiatric illness
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.
The specificity of morphological changes of the corpus callosum in schizophrenia and related major mental disorders
Schizophrenia is a disabling major mental illness associated with marked impairments in reality testing, organization of speech and behaviour and cognition. Significant evidence points to functional dysconnectivity between cortical and subcortical regions as the major pathophysiological underpinning of the symptoms and disability associated with schizophrenia. Modern neuroimaging techniques have suggested that this dysconnectivity is driven, at least partially, by neuroanatomical changes to connectivity in the brain at the level of white matter tracts, the main connecting “organs” in the brain. This thesis describes the analysis of the structure of the corpus callosum, the brain’s largest white matter fibre tract, with the aim of determining if changes to anatomical connectivity in schizophrenia are associated with a unique callosal shape “signature”. This was undertaken by using a shape analysis methodology that examined regional callosal thickness, using a non-parametric permutation method to determine between-group differences and the relationship between illness variables and callosal shape. This methodology was applied to multiple illness stages: established illness, first-episode psychosis and pre-psychotic patients. It was then applied to other major mental disorders, including multiple cohorts of patients with bipolar disorder and patients with major depression, to determine if any changes seen in schizophrenia patients were specific to schizophrenia-spectrum illness or were more general markers of major mental illness. The results suggest that patients with schizophrenia-illness show specific thickness reductions at the level of the anterior callosum, connecting frontal cortical regions, that are present during the pre-psychotic phase and with first-episode illness. Furthermore, with established illness, these changes are accompanied by additional changes in the callosum connecting cingulate, temporal and parietal regions. Changes seen in healthy individuals as part of the normal ageing process appeared to be disrupted in schizophrenia patients. In bipolar patients, a very different pattern of results emerged, with more global thickness reductions and disproportionate thinning at the level of the posterior callosum. Depressed patients, by contrast, showed state-specific posterior expansions, which bore some homology to changes seen in patients with depressed first-episode psychotic patients and patients with schizoaffective disorder. Furthermore, in the schizophrenia-spectrum group, changes at the level of the genu were strongly predictive of transition to psychosis in those individuals at high-risk for psychosis, and in first-episode individuals were highly predictive of long-term outcome of their psychotic illness. These changes suggest that there are schizophrenia-specific changes at the level of the callosum, marking a unique callosal “signature” for schizophrenia-spectrum illness. These changes show predictive validity for outcome at the earliest stages of illness, and are distinct from changes seen in major affective disorders. These findings suggest that shape changes to white matter structures may be a useful marker to aid diagnosis, in the identification of individuals who may develop a psychotic illness, and in defining the nature of their future illness course.
The role of lifestyle, cardiovascular factors and biomarkers on health status in older adults at risk of cognitive deterioration
Recent developments in neuroscience have heightened the possibilities to tackle the prodromal stage of dementia. The purpose of this thesis is to identify the relationships between physical health, cognitive function, vascular risk burden and peripheral biomarker candidates in 108 older adults at risk of cognitive decline. The AIBL Active trial participants, aged 60 years and older (32 cases of MCI, 76 cases of SMC) with at least one cardiovascular risk factor present, completed a neuropsychological test battery and provided cross-sectional health data and physical activity information using a validated questionnaire and pedometer recordings. Cardiovascular parameters and blood tests determined if the participants met the clinical definition of metabolic syndrome that referred to a cluster of vascular and metabolic disturbances due to obesity and insulin resistance. This thesis utilised a preferred statistical standardisation of metabolic syndrome factors and obtained continuous variable (z-scores) to indicate the composite cardiovascular risk burden that addressed the progressive nature of the syndrome. Regression models adjusted for covariates examined the associations between the parameters and cognitive function. Almost two-thirds of participants met the national physical activity guidelines for older Australians with MCI or SMC (moderate-to-vigorous physical activity (MVPA) over 150 minutes per week), according to self-report (average 317 minutes/week). The pedometer estimated a mean of 6,926 steps/day for all participants. Participants with lower body mass index (BMI) and higher self-efficacy were 18% and 24% respectively more likely to meet the guideline recommendations. The risk severity of metabolic syndrome was inversely associated with pedometer tracked physical activity and the six-minute walk test, independent of global cognitive performance. The six-minute walk test has a stronger association with metabolic syndrome and may be a preferable assessment tool to evaluate exercise capacity compared to the timed-up-and-go test in participants at risk of cognitive decline. The metabolic syndrome components are traditional vascular and metabolic risk factors, but few cognitive studies have examined the combined risk severity. While cognitive tests scores were similar between the two groups with or without a clinical diagnosis of a metabolic syndrome, the continuous standardised z-scores for metabolic syndrome were associated with lower cognitive performance for global cognition and executive functions. Therefore, the combined risk burden (z-score) was more sensitive to cognitive associations than the presence or absence of the clinical syndrome. Multivariate regression analyses showed separate linear associations between vascular risk factors (fasting homocysteine, glucose and Framingham scores) and lower cognitive functions. The importance and originality of this thesis are that several peripheral biomarkers showed significant associations with cognition, including between increasing plasma tumour necrosis factor (TNF-alpha) and executive dysfunction and between increasing brain-derived neurotrophic factor (BDNF) and better global cognition. A model hypothesising the relationship between physical health, cognition, vascular risk factors and biomarkers is proposed. A higher cardiometabolic risk burden may point to opportunities for cognitive testing and lifestyle modification recommendation in older adults as individuals may experience cognitive changes. The findings in the peripheral biomarker analyses add to the evidence of associations between TNF-alpha, BDNF and cognitive deficits. Future longitudinal research will be needed to establish a direct link between health factors, biomarkers and cognitive decline in older adults at risk of cognitive deterioration.
The role of cholinergic muscarinic receptor 2 and 3 in mood disorders
Variation in cholinergic muscarinic receptor (CHRM) levels is thought to be involved in the pathophysiology of bipolar disorder (BPD) and major depressive disorder (MDD). Lower levels of CHRM2/CHRM4 protein in the human dorsolateral frontal cortex (Brodmann’s area (BA) 46) from subjects with BPD and MDD, and CHRM3 in the human orbitofrontal cortex (BA 10) from subjects with BPD have previously been reported by my laboratory. I sought to confirm those findings in BA 10 and 46 in a larger cohort from subjects with BPD (n = 15), MDD (n = 15) and controls (n = 20) as well as see whether these changes occur in other cortical regions by examining BA 17, 24 and 47, which are also thought to be affected in mood disorders. I investigated whether the binding densities of the CHRM selective radioligands [3H]4-DAMP, [3H]pirenzepine and [3H]AF-DX 384 are altered in mood disorders. Findings from the binding data were confirmed using Western blot and quantitative Real-Time PCR (qPCR), and oxotremorine M stimulated-[35S]GTPγS binding was used to see whether changes in protein levels affected the receptor activity. I also investigated whether muscarinic receptor levels, using [3H]AF-DX 384 and [3H]pirenzepine binding, are altered in the rat brain regions 24 hours after the last acute or chronic treatment with mood stabilisers or antidepressant drugs (n = 20 per group) as part of potential confounding factors. Previous protocols used to measure [3H]4-DAMP binding measured both CHRM3 and CHRM1. I adapted this protocol to make the [3H]4-DAMP binding assay more selective to CHRM3. Contrasting previous findings, there was no difference in levels of CHRM3 protein in any cortical region from subjects with BPD and MDD compared to controls. [3H]pirenzepine binding was lower in the outer layer of BA 17 and BA 24 in BPD and MDD, and in BA 47 from subjects with MDD, but not BPD. [3H]AF-DX 384 binding was lower in the outer layer of BA 17 and BA 24 from subjects with BPD and MDD, and in the inner layer of BA 17 and BA 46 from subjects with BPD, but not MDD, compared to controls. I subsequently examined levels of CHRM2 and CHRM3 protein using Western blotting. Two CHRM2-specific immunogenic bands were detected on the western blots. CHRM2 protein levels were significantly lower in the upper band (71 kDa), but not the lower band (67 kDa), in BA 24 in BPD only compared to controls. By contrast, there was no change in BA 46 from subjects with BPD and MDD. Moreover, levels of CHRM3 protein were not changed in BA 10 from subjects with BPD and MDD compared to control subjects. Similarly, the levels of CHRM3 mRNA using qPCR in BA 10 were also not altered. Levels of specific [35S]GTPγS binding stimulated by oxotremorine M were significantly lower in BA 24 from subjects with BPD, but not MDD, compared to controls. However, there was no change in oxotremorine M stimulated-[35S]GTPγS binding in BA 46. In neuropsychopharmacological studies, there were widespread regions-specific increases in levels of [3H]AF-DX 384 and [3H]pirenzepine binding in rats following chronic treatment lithium and sodium valproate. Chronic lithium administration resulted in a significant increase in the densities of [3H]AF-DX 384 binding in the cingulate, parietal cortices, caudate putamen, nucleus accumbens and olfactory tubercle, but not the frontal cortex. Interestingly, there were significantly higher levels of [3H]pirenzepine binding in all rat brain regions examined after treatment with lithium. Moreover, treatment with sodium valproate for 28 days caused an increase in levels of [3H]AF-DX 384 binding in the caudate putamen, nucleus accumbens and olfactory tubercle of rats and an increase in [3H]pirenzepine binding densities in the cingulate cortex, caudate putamen and nucleus accumbens. By contrast, acute and chronic antidepressant drugs, fluoxetine and imipramine, administration resulted in no change in the levels of [3H]AF-DX 384 binding in any brain region of rats. No change in [3H]pirenzepine binding was found in any rat brain region following acute and chronic administration of antidepressant drugs. These findings suggest that regionally specific decreases in the level of cortical muscarinic receptors are involved in the pathophysiology of mood disorders.
The role of adrenarche in shaping the mind: how adrenarcheal hormones contribute to the development of brain connectivity and internalising symptoms
The transition from childhood to adolescence is a particularly vulnerable period for the development of internalising symptoms and disorders. Hormonal changes as well as changes in brain structure and function may play a role in this increased vulnerability. Most of the research to date has focused on the hormonal and brain changes during gonadarche, whereas the literature is much more limited for adrenarche, an earlier pubertal phase that takes place prior to gonadarche. Therefore, this thesis aimed to examine how (changes in) adrenarcheal hormones relate to the development of brain structural and functional connectivity, and how that in turn affects internalising symptoms in late childhood to early adolescence. Data were used from two longitudinal community-based samples with two time points each (sample 1 M ages 9.5 and 12.2 years; sample 2 M ages 8.5 and 10 years). At each time point in each study, levels of dehydroepiandrosterone (DHEA), its sulfate (DHEAS) and testosterone were measured and averaged from morning saliva samples collected across several days. Participants also underwent Magnetic Resonance Imaging (MRI) scans, and completed self-report questionnaires, at both time points. Diffusion-weighted imaging scans were analysed to examine white matter structural connectivity. Functional Magnetic Resonance Imaging (fMRI) scans during an affective face processing paradigm were analysed to examine functional connectivity. Levels of internalising symptoms were based on self-report questionnaires: the Spence Children’s Anxiety Scale, the Children’s Depression Inventory, and the Positive And Negative Affect scale. Analyses were conducted to investigate associations between hormone levels (initial levels and changes in levels over time) and brain structural and functional connectivity (baseline and change over time). Analyses were also conducted to investigate whether hormone-related changes in structural/functional connectivity were associated with symptoms. The results showed that children with high DHEA levels at age 9 had higher mean diffusivity (cross-sectionally) in a wide range of white matter tracts, suggesting that relatively early exposure to DHEA might be negatively associated with white matter microstructure. Changes in testosterone from age 8.5 to 10 years were negatively associated with the development of white matter structure as quantified by fibre cross-section in posterior white matter tracts. Higher levels of testosterone at age 8.5 years, however, were related to stronger development of fibre cross-section from age 8.5 to age 10 years. These hormone-related changes in white matter structure were not significantly associated with levels of internalising symptoms. Analyses of functional connectivity during affective face processing focused on connectivity of the amygdala to the rest of the brain, because of the crucial role of the amygdala in emotion processing and consistent findings of its involvement in internalising disorders. Indirect effects were found of adrenarcheal hormone levels (controlled for age, potentially indicating a timing effect, i.e. maturation relative to same-age peers) on anxiety symptoms at age 9 years, mediated by amygdala connectivity to visual and limbic areas. Timing of adrenarcheal hormone exposure was also found to have indirect effects on anxiety symptoms longitudinally. Specifically, higher DHEA at age 9 years was indirectly related to more anxiety symptoms at age 12 years, controlling for symptoms at age 9 years, via more positive amygdala to inferior frontal gyrus connectivity. Thus, the findings in this thesis have demonstrated that elevated adrenarceal hormone levels (potentially reflecting early timing of adrenarche) are both cross-sectionally and longitudinally associated with anxiety symptoms through an effect on amygdala functional connectivity. We also showed that the hormonal processes of adrenarche have an impact on white matter microstructure development. These findings have implications for the understanding of how individual variation in adrenarcheal processes can impact children’s brain development and mental health. Future studies should examine whether effects of variation in adrenarcheal processes on brain development and mental health are persistent, as well as establish whether predictors found in the current thesis are also relevant in clinical samples.
The relationship between anxiety vulnerability and stress in the cognitive processing of threat-related information
In order to clarify the relationship between anxiety vulnerability and clinical anxiety, information-processing models have been employed to examine the cognitive biases of anxious individuals for threat-related information. At the core of these models are research findings indicating that anxiety-linked attentional biases render high trait anxious individuals disproportionately vulnerable to the effects of stress. The current research, following the model of Williams, Watts, MacLeod, and Matthews (1988), tested the hypothesis that attention to threat-related information is due to the interaction of trait anxiety and state anxiety. Five comparable studies employed emotional Stroop and probe-detection paradigms to assess the attentional biases of high and low trait anxious individuals to threat-related words in response to elevations of stress. Four of the studies assessed the preconscious and conscious attentional biases of adults and one study investigated the attentional biases of children. This focus allowed developmental comparisons that had not been undertaken previously. The studies were comparable to each other and to previous research. The studies sought to clarify the effects of different forms of stress on the anxiety-linked attentional biases and to assess the effects of these stressors on domain-specific stimuli. The hypotheses were that, in response to elevations in state anxiety, high trait anxious individuals show increased attention to threat and low trait anxious individuals show avoidance of threat. It was expected that these threat-related attentional biases are identified at both preconscious and conscious levels of processing, and more when the stimuli are related to the individuals’ domain of concern. Contrary to expectations, only one study found the predicted pattern and this result occurred at a conscious level of processing. In addition to the lack of support for the hypotheses, a counter-intuitive alternative pattern that was the converse of predictions was identified in four of the five studies. In this pattern, in response to elevated stress, there was a trend for high trait anxious individuals to show decreased attention to threat and low trait anxious individuals to show increased attention to threat. The pattern was identified, in various studies, at conscious and preconscious levels of processing, and more in response to domain-specific stimuli. Adults and children showed similar levels and types of attentional biases. The results of the current studies show some convergence with previous research. The findings are discussed in the context of a proposed model that incorporated aspects of Williams et al’s theories (1988; Williams, Watts, MacLeod, & Mathews, 1977) and Mogg and Bradley’s (1988) theory. This model suggests that high and low trait anxious individuals’ patterns of threat-related attentional biases vary according to their different levels of reactivity to stress, which affects their threat threshold. Due to differences in this threat threshold, high and low trait anxious individuals show divergent attentional responses under the same level of external stress. The model incorporates the avoidance effects identified in previous research and theory. This model may explain both the current counter-intuitive findings and past inconsistencies in the literature. It may also clarify how individuals with different levels of anxiety vulnerability show divergent attentional responses to stress elevations. It is suggested that inclusion of the notion of subjective stimulus threat value into the cognitive processing paradigm may clarify some of the unresolved issues raised in this research.