Neuroimaging Study On The Emotion Regulation System Of Major Depressive Disorder

Major depressive disorder(MDD)is a significant public health problem.It is associated with increased morbidity and mortality.Based on estimates from the World Health Organization(WHO),MDD is the third leading cause of disability across the world,and responsible for the greatest proportion of burden associated with non-fatal health outcomes and accounts for approximately 12% total years lived with disability.The classic pathopsychological model of depression proposes that the emotional regulation have been consistently linked with the onset and maintenance of depression.The dysfunction of emotional regulation is mainly manifested as negative biases in emotional information processing,failing in cognitive control of emotion and reward processing.Previous studies suggested that the prefrontal cortex(PFC),limbic system,some subcortical nuclei,such as striatum are dramatically implicated in emotionality and emotional processing.There is a hierarchy of brain regions recruited where the PFC is at the top of the hierarchy and exerts cognitive control of regions at the bottom of the hierarchy that engage in automatic reactivity/emotion responding,such as striatum and limbic regions.In particular,the PFC modulates emotional responses via their impact on affect systems like the amygdala and ventral striatum.It involves top-down intervention and volitional regulation to emotion.By contrast,some limbic regions and striatum intermediate the bottom-up emotion processing,respectively.Disrupted brain functions within this system could be related to dysfunction in sustaining adaptive emotional response and may serve as an important pathological feature underlying depression.In recent years,the development of neuroimaging technology and brain network analysis methods in the field of brain science provides new approach for studying brain neural mechanism of neuropsychiatric diseases.For example,functional magnetic resonance imaging(f MRI)techniques are used to investigate the pathophysiology of MDD and identify biomarkers,which would be helpfull to diagnose and predict treatment responses.This study focused on the abnomal "emotional regulation system" of MDD and employed the resting state f MRI to explore the neuropathphysiological abnormalities of brain regions which are distributed in emotion regulation system and associated with depressive epidode.we try to depict the intrinsic neural activity and characterize the dysconnectivity pattern within this system at resting state,which might help us better investigate the neuro-pathophysiological mechanisms underlying MDD.The main research content includes the following four parts:1.The neuro-pathphysiological abnormalities of major depressive disorder(MDD)have been reported to be distributed in emotion regulation system.Firstly,to explore the significant functional connectivity(FC)abnormalities of emotion regulation system in MDD,the regions of interest located in the key areas of this system,which composed of the prefrontal cortex-limbic-subcortical nucleus system,were selected in prior.We further measured the relationships between aberrant FC and core affective symptoms of MDD(decrease of positive affect and increase of negative affect).We found that compared with healthy controls(HCs),patients with MDD exhibited significant aberrant FC within this system.Importantly,deceased FC was mainly involved in the prefrontal-limbic system,while elevated FC was observed in the prefrontal-striatum system.In the MDD group,decreased FC of right posterior hippocampus-left dorsolateral prefrontal cortex(dl PFC)was negatively associated with the negative affect scores,the FC of left ventral striatum-left dl PFC was significantly negatively related with the positive affect scores.These findings demonstrated that MDD showed characteristic pathological alterations of the emotion regulation system.Dysconnectivity within prefrontal-limbic system might be more related to the dysregulation of negative affect,whereas dysconnectivity within prefrontal-striatum system might influence more on positive affect processing.The decrease of positive affect and increase of negative affect in MDD might have different pathological basis,respectively.These results could help better understand the dysconnectivity pattern in the emotion regulating system underlying depression.2.Secondly,MDD is a multidimensional and heterogeneous disease.Its heterogeneity may be reflected in the trait characteristics related to personality trait and the state characteristics related to clinical symptoms,which may be involved in the functional abnormalities of the emotional regulation system.Therefore,uing the spatial pairwise clustering(SPC)analysis combined with network-based statistic(NBS)method,we aimed to explore the neuropathological alterations in the emotion regulation system of MDD from voxel level to network level.We further identified the subnetworks with differences between groups and built the prediction model based on support vector regression(SVR)methods to predict depression-related trait characteristics and state characteristics.Our results showed that the aberrant FC subnetworks within the emotion regulation system involved in prefrontal-limbic system,prefrontal-striatum system and within the limbic system.In addition,the disruptions of subnetworks of prefrontal cortex-anterior cingulate cortex and amygdala-hippocampus can predict the anhedonia symptoms.While the impairments of subnetworks of bilateral amygdala and hippocampus can predict the sadness affective personality traits factor.The current study implied that MDD is a heterogeneous disease,the abnomalities in emotion regulation system may correspond to the different pathological dimension of MDD,thus could provide new ideas for understanding the pathological mechanisms underlying depression.3.Thirdly,depression can be divided into different subtypes according to their clinical responses to medication,which may have different pathological impairments in terms of brain functional connectivity.In this study,we explored the FC abnormalities in different subtypes of MDD including the treatment-resistant depression(TRD)and treatment-sensitive depression(TSD)at different frequency bands by using the NBS method.The brain was divided into 90 regions of interest using an automated anatomical labeling atlas to construct the large-scale brain functional networks.In the slow-5 frequency band,the dysconnected subnetwork of TSD mainly lies in the fronto-parietal top-down control network.Moreover,the abnormal neural circuits of TRD are more extensive and complex.These circuits not only confined to the abnormal affective network but also involved in other networks such as salience network,auditory network,visual network,and language processing cortex.In slow-4 frequency band,no significant dysfunction network was found in TSD,and the dysfunction subnetwork of TRD was not completely overlapped with that in slow-5 frequency band.These findings reflected that the FC abnormalities of both TSD and TRD were frequency-specific and they showed distinct pathophysiological mechanisms.This study would be helpful in differentiating two subtypes of MDD and predicting treatment responses.4.Finally,depressive symptoms during depressive episode are similar to those of bipolar disorder(BD),and it’s difficult to clinical distinguish BD from MDD.There is a lack of reliable neural markers that can be used to distinguish between these two subtypes of depression(unipolar and bipolar)Thus,to explore the different pathological mechanisms underlying MDD and BD,we examined the striatum cerebral blood flow and its FC by using the arterial spin labeling technology(ASL)imaging and resting state f MRI.Depressive patients with BD and MDD and HCs were recruited in the current study.The CBF and FC values were then estimated by using ASL imaging data and resting-state f MRI data respectively,and the results of the three groups were compared.The patients with BD and those with MDD both had higher CBF values than the HCs in the right caudate and right putamen.The hyper-metabolism of right striatum in BD patients was associated with increased average duration per depressive episode.The two disorders showed commonly increased FC between the striatum and dorsolateral prefrontal cortex,whereas the altered FC of the striatum with precuneus/cuneus was observed only in patients with BD.These findings supported that,patients with BD and those with MDD had a common deficit in their prefrontal-limbic-striatal circuits.The altered striatoprecuneus FC can be considered as a marker for the differentiation of patients with BD from those with MDD.