INTRODUCTION: 3 in 100 people in the United States will experience psychosis in their lifetime. Psychosis is a disease state that occurs in several psychiatric illness, including schizophrenia and bipolar disorder. Psychosis is characterized by the heterogeneity of its symptoms, clinical manifestations, and underlying biology. The Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium was established to identify more homogenous subtypes of psychosis. Recent studies have investigated inflammatory subtypes of psychosis and elucidated the cognitive deficits and structural effects associated with elevated inflammation. Previous studies using fMRI have also elucidated the decreased connectivity of the Default Mode Network (DMN) in psychosis. In this thesis, the functional and cognitive effects of inflammatory subtypes of psychosis are further investigated by incorporating resting state fMRI functional connectivity analysis.
METHODS: Blood samples and fMRI data were collected from individuals with psychosis and healthy participants recruited at the Chicago site of the B-SNIP study. Blood sample peripheral marker assays were performed for IL1β, IL6, IL8, IL10, IL12/IL23p40, interferon gamma (IFNγ), TNFα, TNFβ, CRP, Fms Related Receptor Tyrosine Kinase 1 (Flt-1), VEGF, VEGFD and Complement 4 (C4a). Principal component analysis and hierarchical clustering of peripheral marker data resulted in a two cluster solution of high and low inflammatory subtypes. Resting state networks were adapted from the literature. Network connectivity was investigated using group independent component analysis and inter-network connectivity was determined through Fisher z transformation of network loading coefficients. Mediation analysis of the DMNa on the effects of inflammation and cognition was performed using a statistical model.
RESULTS: 32% (n= 30) of psychosis probands were included in the high inflammation subtype. The Proband High inflammation subtype had higher levels of TNFα, C4a, IL8, IL10 and IFNγ than the Proband Low subtype. The Proband high group had decreased activity in the DMNa compared to the Proband Low group. Inter-network connectivity analysis found a decreased connectivity between the DMNa and the Right Attentional Working Memory Network in Proband High compared to Proband Low. Mediation analysis across the whole sample revealed the DMNa has a mediating effect on inflammation and the following cognitive measures: BACS composite score, BACS verbal memory and tower subscores, Percent Correct and Weschler Memory Scale. The DMNa was also validated as a mediating variable of CRP, IL1β, IL6 separatedly for the indicated cognitive measures above.Mediation analysis across the proband sample revealed DMNa mediated inflammation and BACS composite, BACS tower subscore, and Percent Correct.
CONCLUSION: Inflammatory subtypes of psychosis have proved to identify homogenous subsets of patients with unique characteristics. The high inflammation proband group had decreased DMNa activity and inter-network connectivity between the DMNa and several other resting state networks. Mediation analysis has proved that the DMNa, which is affected by inflammation, mediates cognition.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/45579 |
| Date | 04 February 2023 |
| Creators | Kiely, Chelsea |
| Contributors | Brown, Hannah, Lizano, Paulo |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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