A Longitudinal Study Of Structural MRI And Resting-state Functional MRI In Medication Free Patients With Bipolar Depression

Objective:This study is to explore the spontaneous brain activity,the cortex thickness and morphology of brain,the dynamic and static functional connectivity in depressive and euthymia status of bipolar disorder(BD)patients with structural and functional MRI by follow-up study,and to research the correlation between the abnormal structure and function of brain and the clinical symptoms.Through this study,we want to get a comprehensive understanding of the biological characteristics of brain structure and function in BD patients.Methods:In this study,77 medication-free Patients with BD depression and69 Healthy Control(HC)were enrolled at baseline.Patients with BD depression were assessed for clinical symptoms,neurocognitive testing and MRI.After these procedures,the patients received medication treatment and were followed up.Clinical symptoms of these patients were assessed monthly.When the depressed patients were remitted and the euthymia status lasted at least 3 months,with Hamilton Depression Scale 17 items(HAMD-17)<7 and Young manic rating scale(YMRS)<6,these followed up patients were assessed for clinical symptoms,neurocognitive testing and MRI again.Amplitude of low-frequency fluctuation(ALFF)/ratio of fractional ALFF(fALFF)and Regional homogeneity(ReHo)were employed to evaluate the local spontaneous neural activity of the brain,the brain functional connectivity of brain functional networks were evaluated with static functional connectivity(sFC)and dynamic functional connectivity(dFC).Cortical thickness(CT),sulcus depth(SD),fractal dimension and Gyrification index(GI)were calculated by Surface-based morphometry(SBM).Wisconsin card sorting test(WCST),stroop color and word test(SCWT),trail making test A and B(TMT A and TMT B),verbal fluency test(VFT)and Hopkins verbal learning test-revised(HVLT-R)tests were used to test the cognitive ability of BD patients.Results:(1)Spontaneous neural activity of brainResults of fALFF:Compared with HC group,the fALFF values of bilateral postcentral gyrus significantly decreased in depressed BD patients and increased in bilateral middle frontal gyrus(P<0.05,FDR corrected).Compared with depressive state,fALFF values of bilateral temporal pole,right inferior frontal gyrus triangle and bilateral precentral gyrus significantly decreased in euthymic state in BD patients(P<0.05,FDR corrected).Results ofALFF:Compared with HC group,ALFF values of left insula and bilateral postcentral gyrus significantly decreased in depressed BD patients;ALFF values of left rolandic operculum(ROL),left angular gyrus,left supplementary motor and right middle frontal gyrus are significantly increased(P<0.05,FDR corrected).Compared with depressive state,ALFF values of bilateral postcentral gyrus and left precuneus in euthymic state in BD patients significantly increased(P<0.05,FDR corrected).Results of ReHo:Compared with HC group,ReHo values of bilateral precentral gyrus,bilateral postcentral gyrus and right precuneus significantly decreased in depressed BD patients.The ReHo values of bilateral middle frontal gyrus,right inferior frontal gyrus triangle and left ROL significantly increased(P<0.05,FDR corrected),and there was no significance in ReHo between depressive state and euthymic state in BD patients(P>0.05,FDR corrected).The ReHo values of the right middle frontal gyrus were significantly correlated with immediate recall and delayed recall of HVLT-R respectively(P<0.00023,Bonferroni corrected).The regression model of spontaneous neural activity of brain was established as follows:Y=2.948-1.211X2--1.390X4+1.100X7,X2 was ALFF values of the left postcentral gyrus,X4 was fALFF values of the left postcentral gyrus,and X7 was ReHo values of the left middle frontal gyrus.The equation was statistically significant(Hosmer and Lemeshow Test,χ~2=8.147,P=0.320,P>0.05),the area under receiver operating characteristic curve(ROC)in training set and the verification set was0.723 and 0.716 respectively.(2)Functional connectivity of brain networksFC results:Compared with HC group,the sFC of depressed BD patients in the triple network:the sFC between SAN and ECN increased,internal connectivity of SAN and ECN both increased(P<0.01,FDR corrected);the sFC of depressed BD patients between triple network and motor,sensory,language network:the sFC between DMN and AUD,SMN,LAN increased;between ECN and AUD,VIS increased;between SAN and AUD,SMN,LAN increased(P<0.01,FDR corrected);the sFC of depressed BD patients of motor,sensory,language network:the sFC between SMN and VIS,between AUD and LAN increased,The sFC of depressed BD patients between VIS and AUD network both increased and decreased in components(P<0.01,FDR corrected).There was no significant difference in sFC between depressive state and euthymic state in BD patients(P>0.01,FDR corrected).dFC results:Compared with HC group,The dFC of depressed BD patients in state 1,between ECN and SAN decreased(P<0.05,FDR corrected);In state 4,the dFC of triple network:the internal dFC of DMN,SAN increased,ECN decreased;the dFC between DMN and ECN,SAN increased,between SAN and ECN decreased(P<0.05,FDR corrected).The dFC between triple network and motor,sensory,language network:the dFC between DMN and VIS decreased;between ECN and AUD,VIS,SMN,LAN increased;The dFC between SAN and VIS increased(P<0.05,FDR corrected);The internal dFC of AUD decreased(P<0.05,FDR corrected).The dFC between BG and VIS increased(P<0.05,FDR corrected).Compared with depressed BD patients,dFC of euthymic BD patients between ECN and VIS,LAN decreased,internal dFC of VIS increased(P<0.05,FDR corrected).The fraction time(state 1)and mean dwell time(state 1)of dFC between depressed BD patients and HC group were statistically different(P<0.006,Bonferroni corrected,).Fraction time and mean dwell time were significantly correlated with percent conceptual level responses of WCST in dFC state 3(P<0.0006,Bonferroni corrected,).(3)Results of brain structureCortical thickness(CT)results:Compared to the HC group,the Cortical thickness on the left side brain of depressed BD patient including cluster 1(Lateral occipital,superior frontal,precuneus,inferior parietal,insula,superior temporal,fusiform,inferior temporal,middle temporal,lingual,lateral orbitofrontal,rostral middle frontal,posterior cingulate),cluster 2(Caudal middle frontal,pars opercularis),cluster 3(Precentral,postcentral)increased significantly(P<0.01,FWE corrected).Age was significantly correlated with CT of lateral orbitofrontal and insula on the left side brain(P<0.00029,Bonferroni corrected).Sulcal depth(SD)results:compared with HC group,the SD on the left side of brain of depressed BD patients including cluster 1(Fusiform,lingual,superior frontal),cluster 2(middle temporal,inferior temporal)and cluster 3(lateral orbitofrontal)decreased significantly(P<0.01,FWE corrected).Compared with depressed BD patients,the SD of euthymic BD patients on the left side of brain including cluster 1(fusiform,superior frontal,lingual),cluster 2(insula),cluster 3(middle temporal,inferior temporal)and cluster 4(lateral orbitofrontal)increased significantly(P<0.01,FWE corrected).Fractal dimension(FD)results:Compared with the HC group,FD of the left side of brain in depressed BD patient including cluster 1(Isthmuscingulate)and cluster 2(paracentral)increased significantly(P<0.01,FWE corrected),and Cluster 3(Fusiform,lingual,parahippocampal),cluster 4(Medialorbitofrontal,superiorfrontal,lateralorbitofrontal),cluster 5(posteriorcingulate,precuneus)and cluster6(inferior temporal)decreased significantly(P<0.01,FWE corrected).Compared with depressed BD patients,the FD on the left side of brain including cluster 1(isthmuscingulate),cluster 2(insula)and cluster3(paracentral)in euthymic BD patients decreased significantly(P<0.01,FWE corrected).Compared with depressed BD patients,the FD of left side of brain including Cluster 4(fusiform,parahippocampal,lingual),cluster 5(medialorbitofrontal,lateralorbitofrontal),Cluster 6(inferiortemporal),Cluster 7(precuneus),cluster 8(caudalanterior cingulate),Cluster 9(parsopercularis),Cluster 10(posteriorcingulate)and cluster 11(rostral middle frontal)in euthymic BD patients increased significantly(P<0.0 1,FWE corrected).Gyrification index(GI)results:There was no significant difference in GI between the depressed patients and HC(P>0.01,FWE corrected).There was no significant difference in GI between depressive state and euthymic state in BD patients((P>0.01,FWE corrected).The regression model of the brain structure was established as follows:Y=-60.847+2.105X2+18.996X3+19.036X5-3.525X8-1.920X9-3.403X10-3.724X12+2.450X13,X2 is SD of left middle temporal gyrus,X3 is SD of left inferior temporal gyrus,X5 wasFD of left lateral orbitofrontal lobe,X8 was CT of left insula,X9 was CT of left lateral orbitofrontal lobe,X10 was CT of left posterior cingulate,X12 was CT of island lid of left inferior frontal gyrus,and X13 was CT of left precentral gyrus.The equation was statistically significant(Hosmer and Lemeshow Test,chi-square value=4.634,P=0.705,P>0.05),The area under ROC curve in training set and the verification set was 0.962 and 0.949respectively.(4)Cognitive functionThere were significant differences in trials administered,total errors,percent errors,perseverative errors,percent non-perseverative errors,failure to maintain set,percent conceptual level responses of WCST,the time of color word interference of SCWT,immediate recall and delayed recall of HVLT-R,and VFT test between HC and depressed BD patients(P<0.05).There were significant differences in the total errors,percent errors,perseverative errors,percent non-perseverative errors,percent conceptual level responses of WCST,color word interference time in SCWT between depressive state and euthymic state in BD patients(P<0.05).Conclusions:(1)The abnormal brain regions of brain spontaneous activity and brain structure mainly located in the cortic-limbic system in depressed BD patients,The results suggested that some of the brain structure and function in depressed BD patients were pathological changed,which were related to the generation and processing of emotion.(2)Compared with depressive states,the spontaneous brain activity and brain structure of euthymic BD patients were changed,and the involved brain areas were mainly located in the cortical limbic system.However,some structures and functions were still not fully recovered,which suggested that these structures and functions may be biological markers of BD patients and risk factors for recurrence(3)The sFC and dFC of brain network in depressed patients mainly increased,which caused the patients unable to deal with information and participate in emotional and cognitive tasks effectively;In euthymic state,these high FC decreased,leading to a corresponding improvement of depressive symptoms.(4)In depressive states,there were cognitive impairment in executive function,speech learning,memory ability,long-term memory extraction in BD patients.With the remission of the disease,executive function,speech learning and memory function were partially improved,long-term memory extraction was not improved.The right middle frontal gyrus was associated with verbal learning and memory.(5)Some of the abnormal brain areas of BD patients detected by structural MRI and functional MRI were partially the same,but not completely identical,which may be due to the brain structure being more affected by the course of disease,genes and other factors.It suggested that we should combine the function and structure of the brain to explore the pathogenesis of mental diseases.