Objective: Primarily, to determine if affective Theory of Mind (ToM) decoding differs between patients with bipolar disorder who are experiencing mania, euthymia, or depression. Secondarily, to determine if a bias in ToM in patients experiencing different affective episodes is related to a positive, negative, or neutral valence of the target. Finally, to determine if mental state decoding is related to the severity of depressive, manic, or anxious symptoms Methods: A prospective, cross-sectional, study of ToM in patients with bipolar disorder experiencing mania (n = 14), depression (n = 25), or euthymia (n = 20), using the “Reading the Mind in the Eyes Task” (Eyes Task) and the Animal Task developed to control for nonsocial response demands of the Eyes Task. Measures of depressive and anxious symptoms were taken using self-report scales. Interview measures of depressive and manic symptoms were also conducted. A review of patient records was conducted to collect information regarding medications, and course of illness variables. Results: Patients experiencing mania were significantly impaired in mental state decoding compared to euthymic and depressed patients with bipolar disorder. No significant difference was observed between the depressed and euthymic groups. These relationships were maintained when controlling for age of illness onset and Animal Task accuracy. No effect of valence was found. Manic symptom severity was negatively correlated to Animal Task accuracy but no other relationships between Eyes and Animal Tasks and the severity of manic, depressive, or anxious symptoms were found. Group differences in Eyes Task performance were not due to differences in demographics, axis I comorbidities, history of psychosis, or course of illness measures. Limitations: The sample was too small to assess differences between acutely and chronically ill patients. There was no assessment of neurocognition or intelligence using tasks previously validated with manic patients. Conclusions: Patients with bipolar disorder experiencing mania were significantly impaired in mental state decoding compared to patients who were depressed or euthymic. The deficit in ToM decoding in manic patients independent of indicators of illness severity may be indicative of qualitative differences in interpersonal dysfunction between mania, depression, and euthymia in patients with bipolar disorder. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2011-02-10 13:18:17.667

Almost all neuropsychological studies of adult bipolar disorder (BP) have failed to control for the established cognitive effects of attention deficit hyperactivity disorder (ADHD), and often other covariates. ADHD comorbidity in BP is common, and has already been shown to significantly worsen the clinical presentation of BP. This study of young adults (16 - 34 years) aimed to establish whether ADHD and BP with childhood ADHD groups had more impaired cognitive profiles (after controlling for numerous covariates) relative to BP without childhood ADHD and control groups. Using recognised structured and semi-structured clinical interviews and symptom rating scales, BP with (n = 18) or without (n = 66) childhood ADHD groups were recruited from a therapy study, and ADHD (n = 27) and control (n = 26) groups were recruited from the community. Participants completed tests (some from the Cambridge Neuropsychological Test Automated Battery) of executive functioning, memory, attention and psychomotor speed. MANCOVA results for cognitive performance indicated that the BP with childhood ADHD group did not differ significantly from the other three groups (except on a test of visual object memory, where it outperformed the ADHD group). The ADHD group was impaired relative to the BP without childhood ADHD and control groups on measures of verbal and visual memory. It was also more impaired than controls on a measure of attention. The BP without childhood ADHD group had visual memory and attention difficulties relative to controls. Compared to BP (controlling for ADHD), ADHD is associated with a more diverse range of cognitive impairment. Nevertheless, individuals with BP may independently demonstrate memory and attention difficulties which have the potential to interfere with treatment and day-to-day functioning.

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Bipolar Disorder (BD) is a debilitating mental illness that presents as mood alterations between manic and depressive states. There remain large gaps in the knowledge surrounding the disease, due to three main issues in understanding the illness. First is a lack of an appropriate animal model that mimics both manic and depressive symptoms. Second is a lack of knowledge on the biological cause of the disease. Finally, a lack of knowledge on the precise mechanism of action of lithium (Li), the main treatment for BD prevents more progressive research into the disease. Inflammation and a subsequent disruption of the blood-brain barrier (BBB) have recently been demonstrated in other psychiatric conditions, such as Alzheimer’s Disease (AD) and Schizophrenia (SZ). This mechanism remains to be fully investigated in BD. This thesis presents an inflammatory model of BBB disruption in rodents. A study examining gene expression in discordant sibling pairs with SZ or BD discovered that the Max gene was elevated two-fold in bipolar patients as compared to their non-BD siblings. We aim to elucidate on these findings and examine the effect of common BD treatments on Max gene expression. The first study utilized lipopolysaccharides (LPS) to induce an inflammatory response in the BBB, and sodium fluoroscein (NaF) to measure the levels of resulting disruption. It was shown that Li is unable to attenuate disruption of the BBB, and an LPS administration with Li pretreatment causes higher disruption than either substance alone in several brain regions. The second study examined Max gene expression levels in naïve rats as a result of Li or valproate (VPA) treatment. VPA was shown to significantly downregulate the expression of Max in a rodent model. These studies may provide insight into understanding the pathophysiology of BD, leading to better, more accurate animal models and more targeted therapies for the disorder. / Thesis / Master of Science (MSc)

Bipolar disorder (BD) is a chronic and often progressive illness that has a significant impact on quality of life and functioning. Pharmacological treatments are not effective for all patients, emphasizing the need to better understand the pathophysiology of the disorder. It is well known that patients with BD present with increased levels of inflammatory markers during mood episodes and often exhibit chronic low grade inflammation, implicating the immune system in the etiology of the disorder. Furthermore, patients with BD show deficits in neurotrophic factors suggesting that alterations in neurogenesis may precipitate clinical features. Recent evidence indicates that accelerated aging processes may underlie the pathophysiological changes observed in BD, implicating biomarkers related to aging. The chemokine C-C motif chemokine 11 (CCL11) and the cytokine growth differentiation factor 11 (GDF11) have been identified as proteins that increase and decrease with age, respectively. As such, this thesis presents research examining serum levels of these proteins in drug-naive young adults with BD and a matched healthy control group. We analyzed serum levels of CCL11 and GDF11 using enzyme linked immunosorbent assay (ELISA). Our results indicate that serum levels of CCL11 and GDF11 do not differ between the BD group and the healthy control group, however CCL11 levels were elevated in males and in individuals with tobacco abuse/dependence when considering the entire sample. Our results suggest that serum levels of these proteins do not differ between drug-naive young adults with BD and healthy controls, but that alterations may be due to demographic and lifestyle factors. Small sample size and low power should be considered when interpreting these results. / Thesis / Master of Science (MSc)

A Thesis Submitted to the School of Graduate Studies in Partial Fulfilment of the Requirements for the Degree Doctor of Philosophy in Neuroscience / Bipolar disorder (BD) is increasingly being recognized as a neuroprogressive illness characterized by progressively worsening cognitive function and structural brain changes. Although lithium remains the gold standard treatment for BD, its ability to halt neuroprogression is a crucial, yet not fully understood aspect of its therapeutic benefit. Accumulating evidence suggests that lithium may be neuroprotective through alleviating ER stress, a feature highly implicated in the pathogenesis of BD. Over the last 20 years, Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF), an ER resident protein, has gained significant attention due to its ability to alleviate ER stress, reduce inflammation, and enhance cellular survival. In this thesis, we investigated the relationship between lithium and MANF using in vitro cellular models and in vivo rodent models. We establish that lithium upregulates MANF expression via the AP-1 signalling pathway. Moreover, we show that MANF plays a crucial functional role in lithium’s neuroprotective effects, as inhibiting the AP-1 pathway negated lithium’s protection against ER stress-induced neurotoxicity and reduced MANF expression. Furthermore, we demonstrate that MANF deficiency increases striatal cell susceptibility to amphetamine-induced neurotoxicity, highlighting its protective function in preclinical models of mania. In vivo experiments further showed that overexpressing MANF in amphetamine-treated rats reduced hyperlocomotion, prevented the upregulation of ER stress markers, and prevented amphetamine-associated death. Collectively, these findings suggest that MANF may be a critical mediator of lithium’s ability to halt neuroprogression in BD and advance our understanding of BD pathophysiology. Importantly, we present MANF as a promising therapeutic candidate for future therapeutic interventions aimed at halting neuroprogression in BD and preventing fatality due to amphetamine overdose. / Dissertation / Doctor of Philosophy (PhD) / Bipolar disorder (BD) is a psychiatric condition characterized by extreme episodic mood swings of highs (mania) and severe lows (depression). Over time, BD patients can experience changes in the brain, worsening symptoms, and cognitive decline – a process understood as neuroprogression. Lithium, a common treatment for BD, has been shown to slow down this detrimental progression, although exactly how it is accomplished is not fully understood. This thesis focused on a protein called MANF, which has been shown to protect and keep brain cells healthy by reducing stress within cells. We found that lithium increases MANF levels in brain cells, and this increase is crucial for lithium’s neuroprotective effects. Furthermore, we show that MANF is protective against the toxic drug amphetamine in brain cells and stops overdose- mediated death from occurring. By understanding how MANF works, we propose a new treatment intended to prevent the progression of BD and potential treatment for amphetamine overdose.

Large family studies of complex disorders can be used to detect a genomic region linked with a particular illness. Where multiple families are found with common regions of linkage, this could be due to an ancestral mutation common to these families. In this thesis, I describe a method for studying allele sharing in families that share a linkage region, to identify a common founder mutation, thus maximising the results of replicated linkage studies. The method tests the hypothesis that the evidence for shared linkage is derived from the sharing of a common affected ancestor. By comparing the allelic similarity of haplotypes across common linkage regions, it is possible to identify any regions that are identical by descent between the families. A method of permutation analysis followed by a nested permutation technique have been developed to assess the statistical significance of allele sharing scores. Chapter 3 describes the proof of principle of the method through its application to known cystic fibrosis mutations and through simulated datasets. This provides both a real dataset and a much more diverse range of simulated conditions on which to test the method. The range of simulated data was also used to develop a set of criteria for the effective us of the method. In Chapter 4, the allele sharing method was applied to two replicated linkage regions on chromosome 4p15-16 that segregate with bipolar affective disorder. This was done over two phases, first taking in markers covering the genic regions of the shared linkage region and then followed up with a complete coverage of the region. This analysis identified a 200kb region with significant confidence within the 8Mb of the two linkage regions. The study of this region presents a clear example of how replicated linkage results that are caused by some founder effect, can be examined, and refined using this allele sharing method to vastly reduce the region under investigation.

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The global burden of mental health disorders is rising with the world health organization recently having recognized major depressive disorder as the leading cause of disability worldwide. Nearly one in five Canadians are now estimated to struggle with a mental health disorder and Generalized Aanxiety Ddisorder (GAD) Mmajor Ddepressive Ddisorder (MDD) and Bbipolar Ddisorder are three of the most prevalent. Despite significant research into the disorders’ cause, the pathophysiology and underlying etiology of these diseases remains largely undiscovered. Recent research has highlighted the potential role of the gut microbiota in mental health, in particular in connection with anxiety. Our research aims to investigate this link in a cohort of GAD, MDD and bipolar patients recruited through the Anxiety Treatment and Research Centre at St. Joseph’s Healthcare in Hamilton, as well as through the University Health Nnetwork in Toronto. 71 GAD, 18 MDD, 17 euthymic MDD and 23 Bipolar patients provided fecal samples from which DNA was extracted, following which the V3 region of the 16S rRNA gene was amplified and sequenced using the Illumina Miseq platform. Sequencing data was analyzed through an in-house pipeline to construct community profiles of patients and age and sex matched healthy controls. My work involved analyzing the data to identify signature organisms that might identify putative disease associated microbial communities for further hypothesis generation about possible roles in disease. Furthermore, an extensive culturing effort was undertaken to identify and characterize some of the Bacteroides strains which were enriched in the GAD patient population. This study presents novel insights into some of the organisms that may be markers for a number of different diseases as well developing a better understanding of the Bacteroides that were correlated with anxiety. / Thesis / Master of Science (MSc) / Mental hHealth disorders including Ggeneralized Aanxiety Ddisorder (GAD), Mmajor Ddepressive Ddisorder (MDD) and Bbipolar Ddisorder (BD) affect somewhere between five and ten percent of Canadians, with the Wworld Hhealth Oorganization recently labeling MDD the leading cause of disability worldwide. Despite decades of research, on these disorders we still have a poor understanding of what factors may contribute to causing these disorders their underlying mechanisms of actionetiology. Another hallmark of many mental health conditions are increased rates of gastrointestinal symptomsor digestive distress relative to the healthy populatioindividualsn. Recently, there has been a great deal of research about how the trillions of bacteria that live in the digestive tract play a role in neuronal brain development and behaviour. This study aimed to better understand which the organisms reside iinn the digestive tract of mental health patients in hopes of better understanding how some of these organisms could be contributing to patients’ poor mental health. Additionally, through better understanding the nature of these communities, recommendations could potentially be made about therapeutic interventions to restore a healthy community.