The Spatio-temporal Interaction Of The Prefrontal-limbic-striatum Circuit In Major Depressive Disorder And Bipolar Depression

Whether the subcortical pathway was modulated by the emotion stimuli remains unknown during the early stage of emotion processing. Recently, it is still unclear that the spatio-temporal interaction of prefrontal-limbic-striatum circuit during the happy facial emotion processing, as well as the therapeutic effects. In addition, the depressive state of bipolar disorder (BD) was prone to be misdiagnosed with major depressive disorder (MDD), due to the lack of objective assessment biomarker. Thus it is necessary to find an objective biomarker to distinguish the BD from the MDD, which will facilitate the clinical diagnose and treatment of BD and MDD.Objective:1) to assess whether the subcortical pathway was modulated by the emotion stimuli during the early emotion processing stage in the MDD and healthy controls, and whether the MDD showed abnormal effective connectivity of the subcortical pathway.2) to investigate the most superior pattern of the effective connectivity of prefrontal-amygdala circuit in depressed patients, and discuss the possible aberrant mechanism of depression.3) to explore the changes of prefrontal-limbic-striatum circuit after antidepressant in MDD, aiming to find an cue to predict the therapeutic effect.4) to examine whether the prefrontal-striatum circuit could distinguish the BD patients from MDD patients, in order to find an neuroimage biomarker.Methods:The depressive patients from Nanjing Brain Hospital were covered by the DSM-Ⅳ-TR criteria of MDD and BD, who were well matched with the healthy controls’ age, education, sex and the resident location. All the participants were estimated by the Hamilton Depression Scale 17-items (HAMD17) and Bech-Rafaelsdn mania rating scale (BRMS) and scanned by the magnetoencephalograph (MEG) during the recognition of facial emotion task. The MEG data were preprocessed by the SPM8 software and analyzed by the Granger Casual Model (GCM) and Dynamic Casual Model (DCM). The interested effective connectivity of brain areas were extracted and further statistical analysis.Results:1) After the DCM calculation, the bayesain model selection(BMS) hinted that the depressed patients showed different emotion processing pattern. During the 0-100ms, the effective connectivity from the primary visual cortex(V1) to the orbito frontal cortex (OFC) was modulated by the sad facial emotion, while the depressed patients was not until 150-200ms. During the period of 0-100ms, the modulatory connectivity from the left V1 to the left OFC was obviously decreased (P=0.01), as well as the endogenous connectivity from the right pulvinar (Pul) to the right OFC (P=0.04). While the endogenous connectivity from the right V1 to the right OFC was heightened (P=0.01) during the period of the 0-150ms. In addition, the modulatory connectivity of the left Pul-OFC (P=0.04) and the endogenous connectivity of the right Pul-amygdala were also reduced (.P=0.04) between the time period of 0-200ms.2) The BMS indicated that model with top-down modulate connections from the dorsolateral prefrontal cortex (DLPFC) to the anterior cingulate cortex (ACC), from the DLPFC to the Amygala (Amy) and from the ACC to the Amy was the most superior model with exceedance probability of 0.41. In the right hemisphere of the depressed group, the endogenous connectivity from the Amy to the ACC was significantly decreased compared to healthy controls (t=-2.21, P= 0.033), while the endogenous connectivity from the ACC to the DLPFC was enhanced significantly (t= 2.50, P= 0.017), which was the same with the endogenous connectivity from Amy to DLPFC (t= 2.10, P= 0.040).3) The Amy to the DLPFC and the DLPFC to Ventral striatum (P=0.00049, P=0.047) was different among the MDD, BD and healthy controls during the sad facial emotion processing. Compared to the healthy controls, the current-state depressed patients showed reduced effective connectivity of ACC-OFC, and OFC-Ventral striatum (P=0.047, P=0045) under happy facial emotion processing, while it turned to normal after antidepressant. The effective connectivity of Amy-DLPFC and DLPFC-Ventral striatum were decreased in current depressed patients during the sad stimuli (P=0.004,P=0.0084). On the contrary, the effective connectivity of DLPFC-ACC, Ventral striatum-OFC were increased in the depressed patients (P=0.0168,P=0.0044). After the antidepressant, the remitted depression displayed reduced effective connectivity of ACC-DLPFC, ACC-Ventral striatum, DLPFC-Ventral striatum (P=0.022, P=0.025, P=0.035), while the effective connectivity of Ventral striatum-OFC (P=0.045) was still enhanced during the sad facial emotion. The remitted depressed patients showed stronger effective connectivity of Amy-DLPFC (P=0.012) than current depressed patients during sad stimuli.4) The effective connectivity of OFC-ACC could categorize the three group (P=0.023), including the MDD, BD and healthy controls under the sad facial stimuli, while it was the effective connectivity of ACC-Ventral striatum that had the statistical difference during the happy stimuli among the three groups. When compared to the healthy controls, MDD showed decreased effective connectivity of Ventral striatum-ACC, Ventromedial prefrontal cortex (VMPFC)-OFC, OFC-VMPFC, OFC-Ventral striatum when they recognized sad face (P=0.0094, P=0.015,P=0.028, P=0.022), while the connectivity from the ACC to the OFC and the VMPFC were abnormal when they dealt with the happy face (P=0.007, P=0.004, P=0.01). The BD patients had stronger connectivity of the ACC-OFC and the OFC-ACC than the healthy controls during sad face processing (P*=0.016, P=0.038), while they did not show any difference with the healthy controls when they recognized the happy face. Compared to the depressed patients, the BD patients showed increased connectivity of Ventral striatum-ACC and OFC-ACC (P=0.047, P=0.013) when recognized sad facial stimuli, and increased connectivity of Ventral striatum-ACC under happy face (P=0.04).Conclusions:1) During the early period of the emotion processing, the processing pattern in MDD was distinct to the healthy controls. In addition, the depressed patients may exist the pathway that the emotion brains of Amy and OFC may have a feedback to the visual cortex. What’s more, the V1 to the OFC was abnormal in the early stage of emotion processing in depression.2) The endogenous effective connections of prefrontal-amygdala in major depressive disorder are exactly impaired, which may indicate that major depressive disorder has a negative bias. While depressed patients didn’t show abnormality in the modulate connectivity of the circuit under happy stimulus.3) The prefrontal-limic-striatum circuit of the remitted depression did not recovered to the normal state, while the effective connectivity of the Amy-DLPFC may indicating therapeutic effect.4) The BD patients showed normal effective connectivity of prefrontal-striatum when they dealt with the positive stimuli, while the MDD patients decreased, which suggested that the prefrontal-striatum circuit could distinguish the MDD and BD.