The Association Between IL-6 And TGF-β1 And Resting-state FMRI In Patients With Bipolar Disorder

Objective:To investigate the correlation between peripheral cytokine,spontaneous brain activities and clinical symptoms in patients with bipolar disorder(BD)by using functional magnetic resonance imaging(fMRI),in order to explore a reliable theoretical basis for dysfunction of immunity and changes of brain function in BD.Method:A case-control study was conducted.Thirty-two patients with bipolar disorder who have stopped taking medication for more than 4 weeks were enrolled,according to The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition(DSM-5).The demographic characteristics,clinical data,blood specimens,and fMRI data were collected before beginning treatment.After 6-week treatment,relevant indexes were recollected.Simultaneously,thirty healthy controls who shares the same age,gender,and years of studies and research on patients were enrolled for the same experimentation indexes whose data were already collected.The plasma level of interleukin-6(IL-6)and transforming growth factor β1(TGF-β1)were measured by enzyme-linked immunosorbent assay(ELISA).The regional homogeneity(Reho),the amplitude of low frequency fluctuation(ALFF)and the fractional amplitude of low frequency fluctuation(fALFF)were used to analyze fMRI data.SPSS(version 23.0)was used to statistically analysis the difference between cytokines,demographic characteristics and clinical data,and the relationship between cytokines and Reho values,ALFF values and fALFF values.One-sample Kolmogorov-Smirnov test,t-test,chi-square test,Mann-Whitney U test,Wilcoxon signed-rank test,Pearson correlation analysis,Spearman correlation analysis and multiple linear regression were conducted to analyze the results.All P values were 2 tailed with significance level at 0.05.Preparation for the data of fMRI for analysis was handled by using DPARSF and analyzed by using REST v1.8.One-sample t test was used to analysis the data between two groups,the paired t test was used to analysis the date in patients before and after treatment.An uncorrected threshold of P<0.01 was used for the initial comparisons.Using AlphaSim to correct for multiple comparisons.Only the clusters with a significance threshold of P<0.05 at the cluster level were reported.Results:1.There were significant differences in serum IL-6 and TGF-β1 levels between the control group and the patient group at baseline(P<0.05).After 6-week treatment,there was no significant difference in IL-6 levels between the patients and the control group.A significant difference was found in level of TGF-β1 between two groups(P<0.05).The difference of IL-6 and TGF-β1 levels in the patient group before and after treatment was statistically significant(P<0.05).2.The levels of IL-6 and TGF-β1 in the baseline period were not correlated with the demographic characteristics,(P>0.05).After 6-weeks treatment,IL-6 levels were positively correlated with age and marital status(P<0.05),and TGF-β1 levels were negatively correlated with years of education(P<0.05).After the control of age,there was no correlation between IL-6 and TGF-β1 levels after 6-weeks treatment was found(P>0.05).After controlling for age,the level of TGF-β1 in the baseline was positively correlated with the age of onset(P<0.05).The levels of IL-6 and TGF-β1 in the baseline and after 6-weeks treatment were correlated with the state of first-episode(P<0.05).IL-6 levels after 6-weeks treatment were positively correlated with CGI-SI and CGI-EI scores.Multiple linear regression showed that there was a significant correlation between IL-6 and TGF-β1 levels at baseline and the state of first-episode t(P<0.05).There was a significant correlation between the levels of TGF-β1 and PSP scores at baseline(P<0.05).There was a significant correlation between IL-6 levels and the state of first-episode after 6-weeks treatment(P<0.05).There was a significant difference the levels of IL-6 and TGF-β1 between the patients first-episode is manic and the patients first-episode is depression(P<0.05).3.Compared with healthy controls,the Reho value of left Putamen was significantly higher than that of healthy controls.There was no significant difference in the Reho value of the whole brain before and after treatment.The Reho value of left putamen was related to age and current status(P<0.05).The Reho value of left putamen of patients with bipolar disorder was positively correlated with the level of TGF-β1(P<0.05),and was not correlated with IL-6 level.4.The ALFF value of the left inferior frontal gyrus in the patients with bipolar disorder was significantly higher than that in controls.There was no significant difference in the ALFF values of the whole brain between the patients before and after treatment.There was no correlation between the ALFF values in the left inferior frontal and the levels of TGF-β1 and IL-6(P>0.05).Conclusions:1.The plasma level of IL-6 and TGF-β1 in patients with bipolar disorder are significantly higher than those in healthy controls,and the levels of serum IL-6 and TGF-β1 in patients with bipolar disorder with first episode is mania are significantly higher than those in depression,cytokine levels are also associated with the severity of clinical symptoms.2.The Reho value of the left Putamen of the patients with bipolar disorder was significantly changed compared with the healthy controls.The ALFF value of the left inferior frontal was significantly changed compared with the healthy controls.It is suggested that patients with bipolar disorder have spontaneous activity and intensity changes in the neurons of cortico-limbic pathways.3.The Reho value of the left Putamen of bipolar disorder was significantly correlated with the level of TGF-β1,suggesting that cytokine levels are associated with changes in spontaneous neurons activity of limbic system.Some cytokines may be involved in the pathological process of neuronal changes in specific brain regions of bipolar disorder.