The impact of an acute L-DOPA administration on corticostriatal functional connectivity and symptoms of anhedonia in patients with depression Restricted; Files Only

Abstract

Inflammation is thought to affect dopaminergic neurotransmission and reward circuitry in the brain that regulate behaviors related to motivation, leading to anhedonia, a core depressive symptom. In patients with major depressive disorder (MDD), high inflammation indexed by increased plasma C-reactive Protein (CRP) has been shown to associate with lower functional connectivity (FC) within the reward circuitry involving ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC) in association with increasing anhedonia severity. However, it is unknown whether administering the precursor of dopamine L-DOPA can reverse the effects on inflammation on VS-vmPFC connectivity and anhedonia in MDD. In this double-blind, crossover, randomized placebo-controlled trial, 56 patients with MDD underwent fMRI to assess VS-vmPFC FC, along with objective and self-reported measures of anhedonia following an acute dose of L-DOPA/carbidopa (250/50mg) or placebo administered one week apart. We hypothesized that following L-DOPA, patients with high inflammation (CRP>2mg/L) would display greater VS-vmPFC FC compared to those with low inflammation (≤2mg/L). Furthermore, we expected that greater VS-vmPFC FC following L-DOPA would associate with lower anhedonia among patients with high, but not low, inflammation. Neuroimaging, clinical, and behavioral data were analyzed for 40 patients with complete datasets (n=21 Low, n=19 High inflammation). Following L-DOPA, patients with high inflammation had greater VS-vmPFC FC at resting state (F(1,33)=7.4, p=0.01, partial η²=0.183) and during reward anticipation (F(1,24)=6.27, p=0.019, partial η²=0.207) while controlling for age, sex, race, BMI, and FC during the placebo condition. Regardless of inflammation level, higher resting FC following L-DOPA associated with greater reward motivation as measured by the effort expenditure task (EEfRT) (β=0.67, SE=0.23, p=0.008; controlling for age, sex, race, and BMI). Furthermore, among patients with high inflammation, greater resting FC following L-DOPA tended to associate with lower self-reported anhedonia measured by Snaith-Hamilton Pleasure Scale (SHAPS-SR) (β=-11.35, SE=6.05, p=0.087). Our findings suggest that L-DOPA affects reward circuitry only in MDD patients with high inflammation, supporting the hypothesis that these patients have dopamine deficits which can be restored by dopaminergic drugs including L-DOPA. Moreover, our results suggest that corticostriatal connectivity within reward circuitry is a sensitive and reliable brain biomarker for the effects of inflammation on dopamine.

Table of Contents

TABLE OF CONTENTS

Introduction.................................................................................................................. 1

Background.................................................................................................................. 3

Methods....................................................................................................................... 8

Results......................................................................................................................... 15

Discussion.................................................................................................................... 19

References................................................................................................................... 23

 

TABLE OF FIGURES AND TABLES

Fig 1............................................................................................................................. 31

Fig 2............................................................................................................................. 32

Fig 3............................................................................................................................. 33

Fig 4............................................................................................................................. 34

Table 1......................................................................................................................... 35

Table 2......................................................................................................................... 36

Table 3......................................................................................................................... 38

Table S1....................................................................................................................... 39

Table S2....................................................................................................................... 40

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Biology, Neuroscience
Keyword	Inflammation Depression Anhedonia Dopamine
Committee Chair / Thesis Advisor	Jennifer C. Felger, Emory University
Committee Members	Matthew J. Magee, Emory University Jennifer S. Stevens, Emory University Andrew H. Miller, Emory University

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