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)

The number of reported students with psychiatric disabilities who are seeking services and/or accommodations is steadily increasing on college campuses. Much of the research and documentation that surround the study of college students with psychiatric disorders is extremely broad in focus and tends to group all psychiatric diagnoses together when reporting outcome studies. The research literature that is devoted to the study of the college student diagnoses with Panic Disorder with Agoraphobia is limited in scope and nature. The majority of the literature is devoted to the physiological and behavioral ramifications of the disorder or treatment modalities. a review of the extant literature reveals that there is no substantive research available that provides insight into the college experiences of the student diagnoses with Panic Disorder with Agoraphobia. In summary, it is safe to say that there is not enough pertinent information readily available to enlighten college and university faculty and staff about the experiences of college students diagnosed with Panic Disorder with Agoraphobia. specifically, little is known about: (1) the academic, psychosocial, and environmental needs of these students (2) what disability related barriers these student may have experienced (3) what coping mechanisms are typically employed, and (4) what services and accommodations these students have found to be the most effective while they were enrolled in college. The purpose of this study was to examine the nature and the scope of the college experiences of students who were diagnosed with Panic Disorder with Agoraphobia. The subjects for this study consisted of a select group of upperclassmen at Virginia Tech. Gender or age was not a factor in the selection process. For purposes of this study, the qualitative in-depth interview method was considered the most appropriate form of data collection. Analysis of the data revealed the following common experiences among the subjects in the study: (1) All subjects experienced difficulties in the classroom due to their Panic Disorder. (2) All of the subjects had concerns with the physical setting of the campus (i.e. preferential seating, avoidance of large classrooms and auditoriums, and anxiety-like symptoms as the result of bright or fluorescent lighting). (3) A lack of social contacts both in and out of the classroom was a common experience. (4) While all subjects had tried medication to control their Panic Disorder, two of the subjects stopped their medication even though they reported an improvement I their symptoms. The majority of the subjects stated that they did not want to remain on the medication for fear of addiction or using the medication as a "crutch." (5) All of the subjects sought out counseling while attending Virginia Tech. All of the subjects, with the exception of one, did not seek any treatment for their anxiety of Panic Attacks until after they arrived at Virginia Tech. (6) All of the subjects, with the exception of one suffered with either chronic anxiety, or Panic Attacks for over one year before seeking any medical relief or counseling. (7) All of the subjects reported that counseling was helpful and for the most part, they all tried to use relaxation techniques when experiencing a Panic Attack. (8) All of the subjects are still having difficulty with chronic anticipatory anxiety and occasional Panic Attacks. (9) While the majority of the subjects interviewed were optimistic about their career options, it was evident that all of the subjects have encountered significant anxiety-related barriers that have impacted their choice of major and possible future jobs. the majority of the subjects reported that it was important to have a job where the workload was not too stressful and the workplace was viewed as a "safe" environment. / Ph. D.

Research assessing the diagnostic criteria for hoarding disorder has firmly differentiated hoarding disorder from normative collecting. However, there has been no examination of non-normative collecting – that is, collectors that experience elevated hoarding symptoms. The current study utilized an online survey to explore differences between self-identified collectors (n = 140) and non-collectors (n = 169) in externalized hoarding symptoms, saving cognitions, and psychosocial functioning. Collectors reported higher general self-efficacy and higher need for control of items than non-collectors. Hoarding symptoms were not significantly different between collectors and non-collectors. These results suggest that identifying as a collector does not significantly change the outward presentation of hoarding symptoms in this sample. However, the differences in internal cognitions imply that there are factors related to collecting behaviors that could influence treatment seeking behaviors and treatment outcomes. Future studies should consider whether identifying as a collector influences the efficacy of established treatments for hoarding disorder.

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.

Boston University. University Professors Program Senior theses. / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2999-01-01

Boston University. University Professors Program Senior theses. / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2999-01-01

Introduction: Bipolar disorder (BD) is a recurrent and chronic mood disorder. BD type I (BD-I) is associated with high disability, lower quality of life, and excess mortality. Importantly, BD is also associated with severe functional impairment. Staging models suggest BD is a progressive illness and use episode recurrence and functional impairment in euthymia as main proxy measures. Research has identified deficits in functioning in BD compared to healthy controls (HC) and suggest that impairment may be sustained in periods of euthymia and related to episode recurrence. The current research uses data from a larger longitudinal neuroimaging study to investigate psychosocial and subjective cognitive function, as measured by the Functional Assessment Short Test (FAST) and the Cognitive Failures Questionnaire (CFQ), in individuals with BD-I who experienced an episode relapse (BDR) compared to those who did not (BDNR) and healthy controls (HC). Methods: Participants completed up to 3 visits over 2 years, that took place approximately 1 year apart. The final sample consisted of 61 HC, 21 BDR, and 26 BDNR participants. Three analyses were conducted to explore between and within-subject differences: mixed-effects analysis of variance (ANOVA), one-way Kruskal-Wallis tests, and simple linear growth analyses. Missing data precluded using three time points for some analyses, so the mixed-effects ANOVA and one-way Kruskal-Wallis tests used two re-binned timepoints (baseline and follow-up) and the growth curve analysis used all three timepoints. Results: Significant differences were found between the HC group and both BD groups (BDR and BDNR) for both the FAST and CFQ at baseline and follow-up visits. No significant differences were found between the BDR and BDNR groups, neither differences at timepoints nor differences in change across timepoints. The BDNR group demonstrated a significant decrease in CFQ scores over the 3 timepoints. Conclusion and Future Directions: The results suggest that individuals with BD-I experience sustained impairment in psychosocial and subjective cognitive function over time compared to HC, but relapse does not have a significant effect on this impairment. Since the BDNR group demonstrated a decrease in CFQ scores over time, not experiencing relapse may be implicated in the improvement of subjective cognitive functioning. Future studies with longer measurement windows and larger sample sizes could further clarify these findings. / Thesis / Master of Science (MSc) / Bipolar disorder type I (BD-I) is a debilitating mood disorder involving manic episodes (e.g. heightened mood, excessive energy, impulsivity) and oftentimes depressive episodes as well (e.g. low mood, little interest in activities, sleep problems). BD-I is associated with high rates of functional impairment. Some models suggest that BD-I is a progressive illness wherein a longer duration of illness, a higher number of mood episodes, and lingering impairment at times outside of mood episodes can be indicators of the illness getting worse overtime and affecting individuals more negatively. Using data from a larger study, the current study aimed to investigate functional impairment in individuals with BD-I who experienced an episode relapse (BDR) compared to those who did not (BDNR) and healthy controls (HC). Two measures of function were used: psychosocial functioning was measured by the Functional Assessment Short Test (FAST) and subjective cognitive functioning was measured by the Cognitive Failures Questionnaire (CFQ). Participants completed up to 3 visits over 2 years, spaced approximately 1 year apart. Differences between both BD groups and the HC group were found for both scales, suggesting a sustained functional deficit in BD over time. No differences between the BDR and BDNR groups were found, but the BDNR group demonstrated improvement in subjective cognitive functioning over the 2-year period. These findings suggest that BD-I shows impairment in psychosocial and subjective cognitive functioning as compared to HC but that relapse status did not have an effect. This research suggests that perhaps mood episode relapse may not influence functioning negatively, but a lack of relapse may have positive effects on subjective cognitive functioning.

Obsessive Compulsive Disorder (OCD) is classified as an anxiety disorder characterized by distressing persistent unwanted ideas or impulses (obsessions) and urges and/or compulsion to do something to relieve the associated anxiety caused by the obsession. The thematic content of the obsessions are highly variable, ranging from symmetry, contamination to aggressive concerns. Compulsions tend to be linked to the obsessions, but can also be idiosyncratic to the intrusive thought. According to the cognitive model, Obsessive-compulsive disorder (OCD) is maintained by various belief factors such as an inflated sense of responsibility, overestimation of threat and the over-control of thoughts. Despite much support for this hypothesis, there is a lack of specificity. This series of studies sought to determine the relationship between a number of cognitive beliefs and appraisal processes and obsessive-compulsive symptoms. This thesis presents the results of three studies. The first study was designed to investigate the hypothesis that certain beliefs are more prevalent in OCD, compared with other anxiety disorders. The second study expands on earlier findings by examining whether the six metacognitive beliefs proposed by the Obsessive Compulsive Cognitions Working Group, (OCCWG; 1997, 2001, & 2003) correlate with specific symptom-based OCD subtypes. The final study addresses some of the methodological weaknesses inherent in retrospective self-report measures by replicating the study using experimental techniques. Most importantly, this research was conducted from within the theoretical framework of Rachman (1993) and Salkovskis (1989) models which emphasise the misinterpretation of significance of the intrusive thoughts. The first study explored the relationship between thought-action fusion (TAF) and inflated responsibility beliefs across individuals diagnosed with obsessive compulsive disorder (OCD), an anxiety disorder other than OCD (anxious controls; AC), and a non-anxious control group (NAC). It was hypothesized that the OCD group would evidence significantly higher inflated responsibility and TAF scores, compared to the AC and NAC groups. In this study, non-clinical and clinical participants were recruited for research. The non-clinical group was comprised of undergraduate students (n = 22: mean age = 26.8; SD = 9.2). The clinical groups included 20 participants with OCD as their primary diagnosis (mean age = 32.1; SD = 11.9) and 21 individuals diagnosed with another anxiety disorder (mean age = 32.2; SD = 10.9). To measure inflated responsibility beliefs and thought action fusion, self-report questionnaires were administered to the participants. The results of this study demonstrated that inflated responsibility beliefs, while present in other anxiety disorders, were significantly higher in participants with OCD, even after controlling for depressed mood and TAF levels. No group differences emerged between the OCD and anxious groups on measures of TAF. Thus, it can be tentatively concluded that inflated responsibility beliefs may have a more robust relationship with OCD than TAF beliefs, which appear to act as a general vulnerability factor occurring along a continuum of anxiety disorders. The second study examined the associations between the six OCD-related beliefs: control of thoughts, importance of thoughts, responsibility, intolerance of uncertainty, overestimation of threat and perfectionism and five empirically derived OCD subgroups. Clinical participants with a primary diagnosis with OCD (n = 67: mean age = 38.0; SD = 11.7) were recruited over a period of two years from the Anxiety Disorders Unit. Participant responses were cluster analysed to form five stable groups: aggressive obsessions-checking compulsions (n = 22: mean age = 26.8; SD = 9.2); contamination obsessions-cleaning compulsions (n = 22: mean age = 26.8; SD = 9.2); symmetry concerns-ordering/arranging compulsions (n = 22: mean age = 26.8; SD = 9.2); hoarding obsessions-hoarding compulsions (n = 22: mean age = 26.8; SD = 9.2); and miscellaneous obsessions -miscellaneous compulsions (n = 22: mean age = 26.8; SD = 9.2). The second found that intolerance of uncertainty was significantly related to the contamination subgroup. While responsibility and threat estimation beliefs were higher in the aggressive-checking subgroup, these differences did not reach statistical significance. No other significant results were found, however, there was a non-significant trend for perfectionism beliefs to be higher in symmetry-ordering and hoarding subgroup. Following the results of this study, questions remained about whether the lack of significant findings reflected the generality of these beliefs or were due to methodological differences. This led to the development of the final study presented in this thesis. The purpose of the final study was to investigate whether the second study was limited by the method of assessment (e.g. self-report questionnaires). This study was unique, as it was the first of its kind to experimentally manipulate all six beliefs in empirically derived OCD subtypes. Twenty participants (mean age = 45.0; SD = 11.0) were chosen from the second study to form the following priori groups: contamination (n = 4: mean age = 44.5; SD = 9.5); aggressive (n = 6: mean age = 46.5; SD = 7.2); hoarding (n = 4: mean age = 47.2; SD = 6.9); and symmetry (n = 6: mean age = 41.8; SD = 17.4). Six behavioural experiments designed to reflect one of the six OCCWG beliefs were specifically developed and administered to the groups. Baseline scores were obtained using self-report questionnaires. The study found strong support for the use of experimental paradigms over self-report measures, as several significant interactions between cognitive beliefs and OCD symptom-based subtypes were found. Specifically, the hoarding subgroup evidenced significantly higher overall thought action fusion scores compared to those in the contamination group. The symmetry subgroup exhibited significantly higher anxiety than the aggressive group during the perfectionism task and demonstrated significantly higher scores on several items measuring perfectionism compared to the contamination group. Finally, over-estimation of threat beliefs was significantly higher in the contamination thoughts. No statistically significant group differences were found for controllability of thoughts, responsibility and intolerance of uncertainty. In conclusion, these studies collectively showed that in some cases of OCD certain beliefs appear highly applicable, whereas in others they are not. This finding may explain why some OCD patients have poor treatment outcomes as the beliefs and appraisals were highly variable across groups. These findings are of both theoretical and clinical significance because they add to the growing understanding that OCD may consist of distinct clusters of symptoms with different underlying motivations and beliefs. This finding is of clinical significance because treatment guidelines for OCD can become more specific, factoring into the therapy situation these underlying beliefs and appraisal processes. Lastly, the findings regarding inflated responsibility deserve special mention, given the significance of this construct in contemporary cognitive models. The results of the present studies were mixed with regard to responsibility as only the first study found a significant result. It appears that, like the other belief domains proposed by the OCCWG, responsibility may not be specific to all types of OCD and current cognitive models may benefit was shifting the emphasis to other belief domains.

Bipolar disorder and borderline personality disorder are common psychiatric diagnoses. One is a mood disorder with a strong genetic basis while the other is a disorder of personality commonly related to abusive experiences in childhood. Despite contrasting aetiologies they can be difficult to differentiate because of overlapping clinical presentations and symptoms. Diagnostic accuracy is important because of their polarised treatment approaches: long term treatment with mood stabilizers for bipolar disorder and psychotherapy for borderline personality disorder. A qualitative study of psychiatrists revealed comprehensive knowledge of the diagnostic criteria however, many expressed the view that diagnostic criteria did not assist diagnostic differentiation. These findings were validated in a large electronic survey of UK psychiatrists. A detailed study of actual diagnostic processes revealed that this scepticism appeared to influence actual practice. Clinicians largely ignored diagnostic criteria but continued to give diagnoses. Age and IQ matched women with bipolar disorder, borderline personality disorder and a healthy control group were compared in a series of cognitive tasks. Borderline personality disorder was associated with a failure to establish and maintain reciprocal cooperation in a game theoretic measure of social exchange. This behavioural change was not seen in euthymic bipolar disorder. Borderline personality disorder was also associated with an insensitivity to reward and losses in a risky decision-making task. Using a simple two-choice reaction task post error slowing was significantly amplified in the borderline group despite overall reaction times and error rates being similar in all three groups. Clinical diagnostic practice as revealed in this study is not adequate to reliably differentiate between bipolar disorder and borderline personality disorder. Laboratory measures of social exchange, decision making and post-error slowing highlight fundamental difficulties in borderline personality disorder not seen in euthymic bipolar disorder. These findings support the differentiation of bipolar disorder from borderline personality disorder and offer translational models for developing and evaluating new treatments for borderline personality disorder.