Sex Differences In Stress-related Brain Function In Major Depressive Disorder

Objective:Sex differences in epidemiological and clinical characteristics in major depressive disorder（MDD）may implicate the sex differences in the brain function of MDD.So far,the sex differences in the brain function of MDD are still unclear.Psychosocial stress is an important precipitating factor for the onset and relapse of MDD,and it is of great clinical and theoretical significance to elucidate the sex differences in the brain function of MDD from the perspective of stress responses.Hence,the current study aimed to reveal the sex differences in stress-related characteristics（i.e.,subjective stress response,cortisol stress response,and stress-related brain activation）in MDD patients,as well as the effects of sex on the prediction of future relapse of MDD by stress-related characteristics,clarifying the sex differences in neural stress responses in MDD patients and providing insights for the psychopathology of MDD.Methods:Seventy-six unmedicated first-episode female MDD patients,48 unmedicated first-episode male MDD patients,106 male healthy controls（HCs）,and 137 female HCs completed the Montreal Imaging Stress Task（MIST）during functional magnetic resonance imaging.Self-report subjective stress ratings and saliva cortisol samples were collected across the MIST.（1）Group differences in subjective stress response and cortisol stress response were evaluated in study 1.（2）Group differences in stress-related activation in the amygdala,hippocampus,nucleus accumbens（NAc）,medial orbitofrontal cortex（m OFC）,and dorsolateral prefrontal cortex（dl PFC）were evaluated using the region of interest analysis in study 2.（3）Independent component analysis was used to extract the contrast estimates of default mode network,salience network,central executive network,and limbic network.Group differences in contrast estimates of several brain networks were detected in study 3.（4）The follow-up interviews on the unmedicated first-episode MDD patients were conducted approximately to assess whether the patients with subsequent episodes or not within 2 years,resulting in 15 male MDD patients with relapse,16 female MDD patients with relapse,17 male MDD patients without relapse and 26 female MDD patients without relapse.Stress-related characteristics associated with relapse were detected and then submitted to evaluate whether sex modulates the predictive effects of relapse-related stress responses on the relapse of MDD within 2 years using logistic regression analyses in study 4.Results:（1）The male MDD group and the female MDD group did not differ in subjective stress response and cortisol stress response during psychosocial stress processing（p>0.05）;the MDD group exhibited higher saliva cortisol concentration relative to the HC group during the stress recovery period（p<0.05）.（2）A significant Diagnosis×Sex interaction effect emerged for the amygdala,hippocampus,and NAc（p<0.05）.Bonferroni-corrected simple effects analyses clarified that the female MDD group exhibited significantly less deactivation relative to the female HC group in the amygdala,hippocampus,and NAc(p _Bonferroni<0.05),whereas the male MDD and HC groups did not differ(p _Bonferroni>0.05).For the females-but not the males-significant Time×Diagnosis interaction effects emerged for the amygdala,m OFC,and NAc（p<0.05）.Bonferroni-corrected simple-effect analyses of the Time×Diagnosis interaction effects observed in females revealed that healthy females were characterized by a significant increase of deactivation over stress exposure time in the amygdala,m OFC,and NAc(run1>run2,run1>run3;p _Bonferroni<0.05).In contrast,MDD females showed no stress-related increase of deactivation over stress exposure time in these regions(p _Bonferroni>0.05).（3）A significant Diagnosis×Sex interaction effect was observed in the limbic network（p<0.05）.Bonferroni-corrected simple effects showed the female MDD group exhibited less deactivation in this network in comparison to the female HCs(p _Bonferroni<0.05),whereas the male MDD and HC groups did not differ in this network(p _Bonferroni>0.05).A significant Time×Diagnosis interaction effect emerged for the limbic network（p<0.05）.Bonferroni-corrected simple effects analyses revealed there was a significant reduction of deactivation in MDD over stress exposure time(run3>run1,run3>run2;p _Bonferroni<0.05),but not in the HC group(p _Bonferroni>0.05).In addition,the MDD group exhibited higher activation in the salience network relative to the HC group（p<0.05）.（4）The male MDD group with relapse exhibited higher activation in comparison to the male MDD group without relapse,whereas the female MDD group with relapse exhibited a decrease of deactivation over stress exposure in NAc relative to the MDD group without relapse.In the whole sample,the MDD group with relapse exhibited a higher BDI score than the MDD group without relapse.The above relapse-related variables were then included as predictors of logistic regression analysis.Logistic regression analysis revealed that the activation of the dl PFC,sex×dl PFC activation,and BDI score significantly predict the relapse of MDD within two years（p<0.05）.The follow-up analyses revealed that the dl PFC activation can only predict the relapse in the male MDD patients.Conclusions:（1）The male and female MDD patients exhibit similar subjective and cortisol stress responses,but the underlying neural mechanism differs,as revealed by brain activation and activation changes over stress exposure.（2）The MDD patients exhibited sex-nonspecific neurobiological abnormalities during stress processing:both female and male MDD patients exhibited atypical lower activation in the salience network as well as decreased deactivation in the limbic network over stress exposure.（3）The MDD patients exhibited sex-specific neurobiological abnormalities during stress processing:the female MDD patients,but not the male MDD patients,exhibited a reduced ability to deactivate the activation of threat and reward-related brain regions and failed to generate adaptive stress responses in the amygdala,NAc,and m OFC over stress exposure.（4）The relapse of male MDD patients is more related to the dl PFC activation,whereas the relapse of the female MDD patients is more related to the decreased deactivation in NAc over stress exposure.