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.

BACKGROUND: The brain and retina are derived from the neuroectoderm and have structural and functional similarities. Researchers have separately analyzed brain and retinal perfusion in psychosis patients, but few studies have investigated the relationship between them. While the retina can serve as a proxy for brain disorders such as Alzheimer’s or Parkinson’s, less is known for psychosis. Thus, this study aims to examine the connection between retinal and brain perfusion in patients with psychosis. METHODS: A total of 48 participants, 17 healthy control and 31 probands, took part in the Bipolar and Schizophrenia Network on Intermediate Phenotype-2 (BSNIP-2) study at the Boston location at Beth Israel Deaconess Medical Center. Participants underwent arterial spin labeling MRI (magnetic resonance imaging) and retinal OCTA (optical coherence tomography angiography) imaging to determine brain and retinal perfusion, respectively. Whole retinal layer (superficial, deep, and choriocapillaris) and lobe-wise brain perfusion (frontal, temporal, parietal, occipital, and cingulate cortices) was used for analyses. Statistical analysis was performed in R and results were summarized using basic descriptive statistics. RESULTS: In probands, there was a significant positive correlation between vessel diameter index (VDI) and frontal lobe perfusion (r=0.74, p=0.000027) and between vessel diameter (VD) and frontal lobe perfusion (r=0.64, p=0.00077), but not for healthy controls. There was a significant negative correlation between VDI and temporal lobe perfusion (r=-0.56, p=0.0046), but not for healthy controls. There were no significant results for healthy controls or probands between retinal perfusion and occipital lobe perfusion. CONCLUSION: This study demonstrates that retinal perfusion may be a proxy marker for frontal lobe perfusion and could be used for predicting cognitive performance in a psychosis population given that the frontal lobe is primarily involved in executive functioning. There was an absence of a relationship between retinal perfusion and the occipital perfusion which suggests that retinal perfusion does not match visual neuronal pathway connections to the occipital cortex. These findings demonstrate a step towards appreciating how the retina can be leveraged to understand brain dysfunction in psychosis.

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