The Brain Network Mechanism Of Anhedonia And Gene Polymorphism Of Dopamine Pathway In Major Depressive Disorder

Part 1: The anhedonia and reward circuit abnormal features in major depressive disorderChapter 1: The modulating role of regulatory focus on the relationship between early life stress and anhedonia in patients with depressionObjective: This study aimed to investigate the moderating role of regulatory focus on the relationship between early life stress(ELS)and anhedonia in major depressive disorder(MDD).Methods: Sixty-four MDD patients and forty-one matched cognitively normal(CN)subjects were recruited and underwent a series of behavioral evaluations,including of physical anhedonia(PA)and social anhedonia(SA),the Childhood Trauma Questionnaire,and regulatory focus.Partial correlation analyses and moderation analyses were conducted to investigate the association between ELS,regulatory focus and anhedonia.Results: Compared to the CN group,the MDD group showed higher ELS,PA and SA scores and lower promotion focus scores.In the MDD group,ELS was positively correlated with PA and SA scores,while promotion focus scores were negatively correlated with PA scores.Importantly,promotion focus negatively moderated the relationship between ELS and PA scores in MDD patients(R2 = 0.08,F(1,60)= 6.49,p = 0.01).Conclusion: The present study demonstrated the influence of ELS on physical anhedonia and that promotion focus would moderate ELS-related anhedonia in MDD patients.Chapter 2: The association between disrupted reward circuits and cognitive deficits and depression severity in major depressive disorderObjective: To investigate the neural correlates of cognitive function and depression severity on reward circuits in MDD patients.Method: Seventy-five drug-naive MDD patients and 42 cognitive normals(CN)subjects underwent a resting-state functional magnetic resonance imaging(rs-f MRI)scan.Bilateral nucleus accumbens(NAc)were selected as seeds to construct reward circuits across all subjects.Multivariate linear regression analysis was employed to investigate neural substrates of cognitive function,depression severity,age,education,and course of disease on the reward circuits in MDD patients.The common pathway underlying cognitive deficits and depression was identified with conjunction analysis.Results: Compared with CN subjects,MDD patients showed decreased reward network connectivity was primarily located in the prefrontal-striatal regions.Importantly,distinct and common neural pathways underlying cognition and depression were identified,implying the independent and synergistic effects of cognitive deficits and depression severity on reward circuits.Additionally,right NAc and middle cingulate cortex connectivity positively correlated with education level was found in CN subjects but not in MDD patients,while decreased connectivity in bilateral rostral anterior cingulate cortex was negatively correlated with the course of disease in MDD patients.Conclusion: This study identified that disrupted functional connectivity within reward circuits was significantly associated with cognitive deficits,depression severity,and trait property in MDD patients.These findings suggested that besides antidepressant treatment,normalized reward circuits should be focused and may improve depression and cognitive deficit for MDD patients.Chapter 3: The network features of reward and cognitive control networks in major depressive disorder with anhedoniaObjective: To explore whether and how the reward network(β-network)and cognitive control network(δ-network)are linked to biasing anhedonia in MDD patients.Methods: Sixty-eight MDD patients and 64 cognitively normal(CN)subjects underwent a resting-state functional magnetic resonance imaging scan.2*2 ANCOVA analysis was used to explore the difference of nucleus accumbens-based voxel-wised functional connectivity(FC)between groups.Then,the β-and δ-networks were constructed and compared the FC intensity within and between β-and δ-networks across all subjects.Multiple linear regression analysis was also employed to investigate the relationships between neural features of β-and δ-networks and anhedonia in MDD patients.Results: Compared to CN subjects,MDD patients showed the synergistically functional decoupling in both β-and δ-networks,as well as the decreased FC intensity in intra-and inter-β-and δ-networks.In addition,the FC in both β-and δ-networks were significantly correlated with anhedonic severity in MDD patients.Importantly,the integrated neural features of β-and δ-networks would more precisely predict anhedonia symptom.Conclusion: These findings initially demonstrated that the imbalanced β-and δ-networks activity successfully predicted anhedonia severity,and suggested that the neural features in both β-and δ-networks would represent a fundamental mechanism underlying anhedonia in the MDD patients.Part 2: Imaging genetics study on the relationship between gene polymorphism of dopamine pathway and depressionChapter 4: Catechol-O-methyltransferase(COMT)polymorphism effect on brain function in major depressive disorder and healthy controlObjective: To investigate the main effects and interactions of disease states and COMT rs4680 on brain function in patients with major depressive disorder and cognitively normal participants by using data-driven analysis.Methods Fifty patients with MDD and 35 cognitively normal participants underwent a resting-state functional magnetic resonance imaging scan.A voxelwise and data-driven global functional connectivity density(g FCD)analysis was used to investigate the main effects and interactions of disease states and COMT rs4680 on brain function.Results We found significant group differences on the g FCD in bilateral fusiform area(FFA),postcentral and precentral cortex,left superior temporal gyrus(STG),rectal gyrus,right ventrolateral prefrontal cortex(vl PFC),and the abnormal g FCDs in left STG was positively correlated with severity of depression in MDD group.Significant disease × COMT interaction effects were found in the bilateral calcarine gyrus,right vl PFC,hippocampus,and thalamus,and left SFG and FFA.Further post-hoc tests showed a nonlinear modulation effect of COMT on g FCD in the development of MDD.Interesting,an inverted U-shaped modulation was showed in the prefrontal cortex(control system),while U-shaped modulations were found in the hippocampus,thalamus and occipital cortex(processing system).Conclusion Our study manifested a nonlinear modulation of interacting between COMT and depression on brain function.These findings expand our understanding of the COMT effect underlying pathophysiology in MDD patients.Chapter 5: Dopamine multilocus genetic profile effects on depressive traits and reward circuit in major depressive disorderObjective: To investigate the neural mechanism underlying the polygenic effects in dopamine pathway on the reward network in major depressive disorder(MDD)using imaging genetic approach.Method: Fifty-three MDD patients and 37 cognitively normal(CN)subject were recruited and completed the resting-state functional MRI scan.Multivariate linear regression analysis was employed to investigate the effects of disease and multilocus genetic profile scores(MGPS)on the reward network,which constructed by nucleus accumbens(NAc)functional connectivity(NAFC)network.Results: DA-MGPS was widely association within NAFC network,mainly in inferior frontal cortex,insula,hypothalamus,superior temporal gyrus,and occipital cortex.The pattern of DA-MGPS effects in fronto-striatal pathway was opposite in MDD patients compared with CN subjects.More importantly,the NAc-putamen connectivity mediates the association between DA MGPS and anxious depression traits in MDD patients.Conclusion: DA multilocus genetic profile makes a considerable contribution to reward network and anxious depression in MDD patients.This finding expands our understanding of the pathophysiology of polygenic effects underlying the brain network in MDD patient.