All ETDs from UAB

Advisory Committee Chair

Adrienne C Lahti

Advisory Committee Members

David C Knight

Edwin W Cook III

Jarred W Younger

Kristina M Visscher

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Schizophrenia is a heterogeneous mental illness and even though it has been studied for over a century, the neuropathology of the disease is still not fully under-stood. Only 1/3 of patients respond well to antipsychotic drug (APD) treatment while another 1/3 show only a partial response and yet another 1/3 of patients are non-responsive, exhibiting little to no change in positive symptoms and a general reduction in quality of life. In order to develop treatments that better serve non-responding and partial re-sponse patients, a greater understanding of APD neuromechanisms is needed. In order to provide a more comprehensive assessment of the effects of APD this project focused on assessing the neurological abnormalities in schizophrenia free of the confounds of APD, as well as the non-dopaminergic mechanisms of APD. We employed a prospective de-sign; recruiting and acquiring data from unmedicated patients with schizophrenia (SZ) and APD naïve first episode psychosis (FEP) patients both before and after a 6 week APD trial. We also utilized a multimodal brain imaging approach, investigating struc-tural and functional magnetic resonance imaging, magnetic resonance spectroscopy (MRS), and connectome analysis. SZ showed widespread reductions in cortical thickness (CT) and local gyrifica-tion index (LGI). Reduced baseline CT, as well as increased CT after 6 weeks of APD treatment were associated with better clinical response. SZ also showed increased net-work segregation in LGI based connectomes at baseline, a difference that normalized after 6 weeks of APD. 2 distinct patient cohorts (antipsychotic-naïve FEP, and unmedicated SZ) presented a pattern of hippocampal hypoconnectivity to other regions of the default mode network (DMN) and hyperconnectivity to the lateral occipital cortex. Though hippocampal glutamate did not differ between FEP and controls, higher glutamate concentrations were predictive of reduced connectivity to anterior DMN in FEP. Both cohort’s also showed that greater baseline hippocamapal-occiptal connectivity was predicitive of clinical response, as was greater reduction in connectivity after 6 weeks. This project shows a pattern of widespread neurological abnormality across mul-tiple neuroimaging modalities prior to treatment. It also provides evidence that a short trial of APD treatment influences morphological, functional, and network aspects of the brain, suggesting that these initial abnormalities may show potential as biomarkers for APD treatment outcome.

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