Brain Imaging Study On The Stress Processing Characteristics Of Adolescent Major Depressive Disorder

Objective:Stress processing-related damage constitutes a significant component of the pathological underpinnings of Major Depressive Disorder（MDD）.However,the stress processing characteristics and physiological mechanisms underlying the pathology of adolescent MDD remain elusive.This study aims to investigate the stress processing characteristics and physiological neurobiological mechanisms of adolescent MDD by means of analyzing the physiological,behavioral,and brain imaging characteristics of adolescent MDD patients within the context of psychological and social stress processing.Moreover,dynamic changes of each index will be analyzed from the perspective of stress exposure time effect,with the ultimate aim of providing empirical evidence to further elucidate the role of stress processing damage in the occurrence and progression of adolescent MDD.Methods:A total of 58 drug-na?ve first-episode depressed patients aged 12-17 years and 70 age-,gender-,and education-matched healthy controls（HC）were recruited for the study.Study 1 collected functional magnetic resonance imaging（f MRI）data of the subjects as they completed the Montreal Imaging Stress Test（MIST）.The subjective stress level of the subjects was evaluated at different time points before and after completing the MIST task,and salivary cortisol samples were collected at 8 different time points before,during,and after the MIST task,which included three repeated stress task sequences.Independent sample t-tests were used to analyze the physiological and behavioral differences between the adolescent MDD group and HC group during stress processing.Data analysis methods,such as the region of interest analysis and psychophysiological interaction（PPI）analysis,were used to analyze the brain functional activation and functional connectivity differences of key nodes in the three core neural networks（the default network,DMN;salience network,SN;and central executive network,CEN）of the adolescent MDD group and HC group during stress processing.The study also used a repeated-measures analysis of variance to examine the changes in various indicators of the adolescent MDD group and HC group at different time points of stress exposure.Finally,Pearson correlation analysis was used to examine the relationship between brain imaging indicators and physiological and behavioral indicators during stress processing for each group.Study 2 collected resting-state functional magnetic resonance imaging data from the participants（including static and dynamic low-frequency amplitude intensity,as well as functional connectivity）,and used a brain region with abnormal activation in Study 1as the seed point and the key nodes of the three core neural networks as regions of interest to compare the differences in static and dynamic brain activation,as well as brain functional connectivity between the adolescent MDD group and HC group in the three network nodes in a non-stressful state using independent sample t-test.Results:（1）Compared to the HC group,the subjective and cortisol stress responses of the adolescent MDD group were significantly enhanced before and after psychological and social stress processing（both p<0.05）.In addition,the results of the analysis of stress exposure time effect showed that compared to the HC group,the cortisol response of the adolescent MDD group was significantly stronger,and the magnitude of increase became greater with longer stress exposure time,especially with a sustained rapid increase even after the stress task ended.（2）The analysis of the MIST task state brain imaging data showed that during the psychological and social stress processing,the hippocampal activation of the adolescent MDD group was significantly enhanced compared to the HC group(p_FWE<0.05).Furthermore,the results of the analysis of stress exposure time effect showed that as stress exposure time increased,the hippocampal activation of the adolescent MDD group gradually decreased,and the magnitude of decrease was more significant than that of the HC group,but the hippocampal activation of the adolescent MDD group was always higher than that of the HC group in all stress task sequences.Moreover,the activation of anterior cingulate gyrus（ACC）and amygdala in the adolescent MDD group during psychological and social stress processing was significantly reduced compared to the HC group(p_FWE<0.05).Furthermore,the results of the analysis of stress exposure time effect showed that the activation level of the HC group increased gradually with longer stress exposure time.At the same time,the activation of ACC in the adolescent MDD group was always lower than that of the HC group in all stress task sequences.In addition,there was no significant difference in brain activation between the two groups in middle frontal gyrus（MFG）,but further analysis of stress exposure time effect showed that as stress exposure time increased,the activation of MFG in the adolescent MDD group gradually decreased.Finally,Pearson correlation analysis showed a significant positive correlation（p<0.05）between the average hippocampal activation value of the adolescent MDD group and changes in cortisol concentration.（3）Brain network analysis showed that the adolescent MDD group had functional connectivity abnormalities within DMN,as well as between SN and DMN,SN and CEN(both p_FWE<0.05).During psychological and social stress processing,the functional connectivity strength of hippocampus and posterior cingulate cortex（PCC）was significantly enhanced in the adolescent MDD group compared to the HC group(p_FWE<0.05).Furthermore,the results of the analysis of stress exposure time effect showed that the functional connectivity strength of hippocampus and PCC in the adolescent MDD group was consistently higher than that of the HC group in all stress task sequences,while both groups showed a gradual weakening of functional connectivity with longer stress exposure time.Additionally,the functional connectivity strength of the ACC and MFG,ACC and precuneus during psychological and social stress processing was significantly reduced in the adolescent MDD group compared to the HC group(p_FWE<0.05).Furthermore,the results of the analysis of stress exposure time effect showed that the functional connectivity strength of the ACC and MFG in the adolescent MDD group was consistently lower than that of the HC group in all stress task sequences,and only showed an increase in functional connectivity strength in the later stages of the task,while the functional connectivity strength of the adolescent HC group increased gradually with longer stress exposure time.The functional connectivity strength of ACC and precuneus in the adolescent MDD group was consistently lower than that of the HC group,but both groups showed a gradual increase in functional connectivity strength with longer stress exposure time.In addition,there was no significant difference in functional connectivity between the two groups in the MFG and hippocampus,but further analysis of stress exposure time effects showed that the functional connectivity strength of the adolescent MDD group decreased with longer stress exposure time.Finally,Pearson correlation analysis showed a significant positive correlation（p<0.05）between the functional connectivity strength of hippocampus and PCC in the adolescent MDD group and changes in cortisol concentration.（4）The results of resting-state f MRI data analysis indicate that compared to the HC group,the low-frequency amplitude intensity of the amygdala and hippocampus in the adolescent MDD group was significantly higher,while the low-frequency amplitude intensity of the ACC was significantly lower(both p_FWE<0.05).Meanwhile,the adolescent MDD group displayed abnormal functional connectivity patterns compared to the HC group.Specifically,the MDD group exhibited significantly enhanced functional connectivity between hippocampus and PCC as well as precuneus(both p_FWE<0.05).Moreover,the functional connectivity between MFG and hippocampus,ACC and precuneus,amygdala and precuneus,as well as medial orbitofrontal cortex,was significantly decreased in the MDD group(both p_FWE<0.05).In addition,the results of resting-state dynamic brain activation analysis showed that the dynamic low-frequency amplitude intensity of the ACC in the adolescent MDD group was significantly lower than that in the HC group(p_FWE<0.05).Conclusion:（1）During psychosocial stress,MDD adolescents exhibit abnormal physiological,behavioral,and neuroimaging characteristics.Psychologically,they manifest a significant augmentation in subjective stress.Physiologically,they evince a significant elevation in cortisol stress reactivity.In terms of brain function,they demonstrate activation of critical nodes within DMN and heightened functional connectivity within this network.However,they also exhibit attenuated activation of critical nodes within SN and reduced functional connectivity between SN and DMN,as well as CEN.（2）The psychosocial stress processing characteristics of adolescent depression exhibit time effect,with non-adaptive dynamic functional changes in both the hypothalamic-pituitary-adrenal（HPA）axis and brain activation patterns.These stress-related non-adaptive dynamic functional changes play a crucial role in the onset and development of adolescent MDD.（3）Adolescents MDD patients exhibit aberrant network nodes during stress processing,along with distinctive alterations in brain functional activity among nodes during non-stress resting states.These changes may be the neurophysiological basis for the occurrence and development of adolescent depression.