| Objective: Major depressive disorder(MDD)is a mental illness involving various systems in the body.The core symptoms are low mood,reduced interest,and decreased energy.Patients often have cognitive impairment and behavioral changes,accompanied by psychotic symptoms such as hallucinations and delusions.Some patients also experience strong suicidal ideation and behavior which can lead to death and disability.Current treatment for depression mainly involves pharmacotherapy.However,research has shown that the current effective rate of drug treatment is less than 50%,which makes patients lose confidence in seeking treatment and affects their normal work and life.It is therefore important to explore the mechanisms underlying individual responses to medications,so that patients can identify medication effectiveness early,reduce the probability of trial and error,and increase the success rate and compliance of treatment.The pathophysiological basis of MDD is not yet clear,and there are studies suggesting that it involves abnormalities in the central nervous system,including neurotransmitter imbalances,impaired neurogenesis,and decreased neural plasticity.In recent years,magnetic resonance imaging(MRI)technology has been widely used in neuroimaging studies of psychiatric disorders due to its non-invasive and safe nature.Previous studies have found that in adolescents with depressive disorders,after 8 weeks of treatment with SSRIs(selective serotonin reuptake inhibitors).In addition,previous studies using diffusion tensor imaging(DTI)have found that effective antidepressant treatment can significantly improve the damage to neural fiber in the frontal and cingulate gyrus regions.The fractional anisotropy(FA)values in the bilateral frontal white matter areas of patients with depressive disorders are also related to the degree of improvement after treatment.However,these studies mainly focus on the functional connectivity between a single brain region and other brain regions,or the functional and structural changes in a single brain region.Previous research has shown that the activity of the human brain is not the independent activity of a single brain region,but requires the collaborative cooperation of various brain regions.Similarly,MDD is not a disease that involves only a single brain region,but rather a disease with abnormal connectivity in the whole brain circuit.Therefore,exploring the damage to a single brain region alone may not be sufficient to reveal its biological mechanism.We need to study the brain function and structure of MDD at the level of brain networks,and explore the changes in connectivity between various brain regions.The complex network theory based on graph theory is an emerging interdisciplinary subject that integrates multiple methods to study complex systems.It can be used to describe and evaluate complex brain structural and functional networks,and provides new approaches to explore the mechanisms of the brain.This method has also been widely applied in the research of psychiatric and neurological brain diseases.However,there have been relatively few studies using this method to explore the efficacy of antidepressant drugs.Some studies have found a negative correlation between the shortest path length of MDD brain functional network features and HAMD-24 rating scale reduction,while others have suggested a positive correlation between the node efficiency of the left hippocampus and the reduction in HAMD score.Results are inconsistent,and direct comparison by efficacy groups has not been conducted,which requires further research.With the development of gut microbiota research,studies have found that individual differences in drug efficacy are related to gut microbiota.The individualized gut microbiota characteristics of patients may affect their drug efficacy.Additionally,the concept of the "microbiota-gut-brain axis" has attracted increasing attention in the medical and biological fields.Gut microbiota may participate in changes in brain function and structure via the "gut-brain axis",thus triggering depression.However,the relationship between drug efficacy and the characteristics of individual gut microbiota is still unclear,and previous studies have mostly been animal experiments with few human population studies.Follow-up studies have found a correlation between the decreasing trend of Klebsiella in MDD and HAMD scores at three time points(day 1,day 15,and day 29),suggesting a relationship between microbiota changes and symptom improvement.Other studies have explored the differences in gut microbiota between completely and incompletely remitted MDD patients and healthy individuals and found a negative correlation between the Bacteroides genus and the severity of depressive symptoms.Overall,there is little research on the relationship between antidepressant drug efficacy and gut microbiota,and the relationship between the two is still not clear,requiring further research.It is also worth considering how to more intuitively observe the relationship between MDD gut microbiota and antidepressant drug efficacy.Neuroimaging can provide a more intuitive observation of brain activity and structural changes in MDD patients with different treatment outcomes compared to healthy individuals.By studying the relationship between gut microbiota dysbiosis characteristics and abnormal brain function and structure,it may be possible to better explore the connection between microbiota and the brain and further help explain the bidirectional communication mechanism between the two.At the same time,by studying the dysbiosis characteristics of gut microbiota in MDD patients with different treatment outcomes,as well as the correlation between abnormal brain functional and structural network topology and gut microbiota dysbiosis characteristics,it may be possible to better investigate the biological mechanisms associated with antidepressant drug efficacy.This proposed study aims to combine brain functional and structural networks with gut microbiota to explore potential factors affecting antidepressant drug efficacy,providing theoretical guidance for investigating individualized differences in treatment efficacy.Additionally,by exploring the relationship between gut microbiota and brain structure and networks,we aim to investigate the possible interactions between gut microbiota and the brain network,providing a theoretical basis for subsequent investigations into the mechanisms underlying drug efficacy.Methods:Part I: A total of 74 participants aged 18-50,including 39 MDD patients and 35 healthy controls(HC),were recruited for this study.General information was collected from participants,and clinical assessments were completed.Baseline MRI data were collected,followed by an 8-week follow-up evaluation of changes in symptoms for patients taking sertraline.Based on HAMD scores,patients were categorized into the MDD incompletely remitted group(HAMD > 7)and fully remitted group(HAMD ≤ 7).Ultimately,19 patients were classified into the MDD incompletely remitted group,and20 patients were classified into the MDD fully remitted group.The collected MRI data were preprocessed,and functional and structural brain networks were constructed using the AAL90 template.Network parameters including global and nodal attributes were calculated.Demographic and clinical data were analyzed using Chisquare test,two-sample t-test,analysis of variance(ANOVA),and non-parametric tests to analyze demographic and clinical data.Differences in baseline brain network topological properties between the MDD and healthy control groups,as well as between the MDD fully remitted,MDD incompletely remitted,and healthy control groups at baseline,were compared.Two-sample t-tests and analysis of variance were used to calculate global and nodal topological properties for the two and three groups,respectively.The differences in brain network topological properties were plotted as ROC curves,and Logistic regression was used to integrate multiple imaging indicators and plot the ROC curves.Part II: A total of 54 participants,including 27 MDD patients and 27 healthy controls,were collected for this study,all of whom were from the first study.Inclusion and exclusion criteria were the same as in the first study.While collecting MRI data from participants,we also collected their feces.The same follow-up process as in the first study was performed,and ultimately 13 patients were classified into the MDD incompletely remitted group,and 14 patients were classified into the MDD fully remitted group.Alpha and Beta diversity were calculated based on the 16 S r RNA analysis of the collected fecal samples,and differences in gut microbiota between the MDD and healthy control groups,as well as between the MDD fully remitted,MDD incompletely remitted,and healthy control groups at baseline,were explored at multiple levels including phylum,class,order,family,and genus.Differential species were identified using the LEf Se method.The relationship between differential brain network topological properties and differential gut microbiota was explored using correlation analysis based on the results of study one and differential species.The ROC curves of differential species were drawn separately,and Logistic regression was used to integrate the differential species and differential brain network topological properties from study one to plot ROC curves.ResultsPart 1:(1)There were no significant differences in structural or functional network topological properties between MDD patients and healthy controls.(2)In terms of global attributes of the structural network,the MDD incompletely remitted group showed a significant decrease in shortest path length and a significant increase in global efficiency compared to the MDD completely remitted group and healthy controls.There were no significant differences in functional and structural network topological properties between the MDD completely remitted group and healthy controls.(3)In terms of nodal attributes of the functional network,the MDD incompletely remitted group showed significantly increased betweenness centrality in the right insular and paracingulate gyrus compared to the healthy control group and MDD completely remitted group,and significantly increased betweenness centrality in the right angular gyrus compared to the healthy control group but not the MDD completely remitted group.There were no significant differences in functional network nodal properties between the MDD completely remitted group and healthy controls.(4)The combined ROC curve of multiple imaging indicators had an AUC of 0.889,demonstrating good discriminative ability.Part2:(1)MDD patients showed no significant differences in alpha diversity compared to healthy controls,but significant differences in beta diversity were found.Differential species analysis identified nine differential species,of which seven were enriched in the MDD patients and two were enriched in healthy controls.(2)There were no significant differences in alpha diversity among the MDD incompletely remitted group,MDD completely remitted group,and healthy controls,but significant differences in beta diversity were found among the three groups.Differential species analysis identified 13 differential species,of which eight were enriched in the MDD incompletely remitted group,two were enriched in the MDD completely remitted group,and three were enriched in healthy controls.(3)Correlation analysis found a positive correlation between the betweenness centrality of the functional network in the right insular and paracingulate gyrus of incompletely remitted MDD patients and the abundance of Clostridiaceae and Clostridium.(4)The ROC curves showed that the combination of the gut microbiota and brain imaging indicators had an AUC of 0.896,demonstrating good discriminative ability.ConclusionPart 1: This study found that after 8 weeks of treatment,MDD patients who did not achieve complete remission exhibited abnormal brain structural network integration functions and abnormal brain structural and functional network node properties at baseline,such as the right cingulate gyrus.This suggests that MDD patients who do not respond well to medication may have more significant abnormalities in brain structure and functional networks,and these abnormal topological properties have good abilities to distinguish the effectiveness of Sertraline treatment.Part2: This study found that MDD patients who responded poorly to Sertraline treatment may exhibit more significant differences in gut microbiota compared to healthy individuals at baseline.The microbiota,as well as the distinctive bacteria and brain structural and functional network node properties such as the right cingulate gyrus,may have good abilities to distinguish the effectiveness of Sertraline treatment.This suggests that combining gut microbiota with brain imaging may be a useful approach to study the antidepressant effects of SSRI drugs,especially Sertraline.Overall,this study found that MDD patients who responded poorly to Sertraline treatment may have more specific changes in brain structure,functional networks,and gut microbiota,and these changes are consistent with incomplete remission of MDD.This highlights the potential of combining gut microbiota and brain imaging to investigate the mechanisms underlying drug efficacy. |
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