Identifying Abnormal Brain Network In Auditory Processing Of Schizophrenia And Preliminary Verification With RTMS Intervention

Objective:We aimed to explore the mechanism of parietal memory network(PMN),default network(DMN)and auditory network(AN)in contribution to auditory hallucinations(AHs)in first episode schizophrenia,and to identify the neurobiological indexes to distinguish schizophrenia patients with AHs from those with out AHs.And,with a randomized controlled double-controled trial,we investigated the efficacy and safety of high frequency repetitive transcranial magnetic stimulation(rTMS)in the treatment of schizophrenia patients with auditory hallucinations.Subjects and methods:65 healthy controls,36 first-episode schizophrenic patients without auditory hallucinations(AH-),29 first-episode schizophrenic patients with auditory hallucinations(AH+)were firstly recruited to complete the rest state MRI scan,clinical scale and cognitive function evaluation.Clinical symptoms were assessed with Brief Psychiatric Rating Scale(BPRS-E)Expanded Version and and the Scale for Assessment of Negative Symptoms(SANS).The severity of AHs was assessed with auditory hallucination Rating Scale(AHRS).The cognitive function level of all subjects was assessed by the MATRICS Consensus Cognitive Battery(MCCB).After preprocessing of the resting-state fMRI data,the independent component analysis was carried out to extract the functional connection maps of AN,PMN and DMN for the participants of three group.The network-level,node-level and voxel-based analyses in above three networks were carried out across the three groups respectively.The among-group differences of fMRI data were further correlated with the results of clinical scale and cognitive assessment.Then,a total of 23 schizophrenia or schizophreniform patients were enrolled in the intervention study,and were randomly assigned to real and sham repetitive transcranial magnetic stimulation(rTMS)intervention for 4 weeks.Meanwhile,19 normal controls matched with age,gender and education level of patients were recruited.The patients were assessed with PANSS and AHRS.The cognitive function level of all subjects was assessed by the MCCB.After preprocessing the resting-state fMRI data,independent component analysis was carried out to extract the functional connectivity maps of auditory network(AN)and parietal memory network(PMN)for all the subjects of three groups,and the inter-group analyses of network level and node level in AN and PMN were conducted respectively.The among-group differences were correlated with the results of clinical scale and cognitive assessment.Results:In the section of cross-sectional study,we found that only AH+patients showed decreased connectivity in PMN,with significantly lower connecting strength than HC group(t=3.51,p<0.001)and AH-group(t=2.52,p=.015).Both AH+(t=2.44,p=.017)and AH-(t=2.57,p=.012)patients showed abnormal function connectivity in AN,which was significantly lower than that of HC group.However,there was no difference in functional connectivity in DMN among the three groups(F= 1.63,p=.200).Analysis of variance based on voxel level showed that there were significant differences among the three groups in the core regions of PMN and AN,including the bilateral precuneus gyrus(lPcu and rPcu),the left posterior cingulate gyrus(lPCC)in PMN,as well as the right Heschl’s gyrus(rMG),the right superior temporal gyrus(rSTG)and the right superior temporal gyrus(rpSTG)in AN network(P<0.05,FWE correctted).Among them,AH+patients showed a specific decrease in overall functional connectivity in the right precuneus gyrus(rPcu)(compared with HC:t=5.30,P<0.001;compared with AH-:t=3.36,P=0.001).Further analysis among time courses of ROIs confirmed that there was abnormal internal functional connection in the core regions of PMN in AH+group,that is,the reduced functional connection between the left posterior cingulate gyrus and the left precuneus.In the exploratory correlation analysis,the functional connectivity between the posterior and left precuneus was significantly correlated with the severity of auditory hallucination symptom(r=-.42,p=.044).In addition,the functional connecting strength of PMN was statistically correlated to the memory function of patients.In the part of rTMS intervention study,repeated measurement analysis of variance showed that there was no significant statistical difference in the interaction of time by group(real and sham rTMS)in clinical messures including total score of PANSS,subscale scores of positive symptom,negative symptom,general pathological symptom,and total score of AHRS.Considering the small sample size in current study,we conducted paired t-test analysis on the scale scores at baseline and the scores after 4 weeks in the two groups respectively.The results showed that the total score of PANSS,subscale scores of positive symptom scale,general pathological symptom as well as score of AHRS scale decreased significantly in both in real and sham rTMS groups.Further analysis of the each item of AHRS showed that the scores of almost all items in real rTMS group were significantly decreased after treatment except for the reality of auditory hallucination.However,the sham rTMS group only showed significantly reduced scores in items of attentional salience and distress level of AHRS.At the level of network node in resting-stae fMRI,the functional level of precuneus node in PMN was significantly increased only in real rTMS group(t=-2.55 p= 0.044),which is absent in sham rTMS group.Furthermore,by defining 25%reductions of AHRS score as treatment responder,we divided all patients into two groups(responder and non-responder)according to the score reduction rate.The results showed that there was a trending time-by-group difference in ACC node of PMN between the two groups(F=3.54,p=0.086).Post-hoc analysis inllustrated that there was no significant change of AN node of PMN in the responding patients(t=0.47,p=0.659),but the functional level of AN node in the non-responding patients decreased significantly(t=0.47,p=0.042).In the correlation analysis,the functional connectivity of precuneus in healthy subjects at baseline was significantly correlated with the working memory(r= 0.59,p= 0.014),visual learning(r= 0.71,p=0.001),reasoning and problem solving(r = 0.54,P = 0.029),comprehensive score(r=0.60,P=0.010)in the MCCB scale.Conclusion:The functional connection defect of PMN is related to auditory hallucination symptom and language memory function in schizophrenia.The results showed that the separation between PMN and DMN is of great importance in finding the neuroimaging biomarkers of auditory hallucination.Overall,the application of high frequency rTMS over the precuneus treat AHs in schizophrenic patients is practical and safety.The preliminary results of the study showed that the functional connectivity level in precuneus of PMN network was significantly improved after real rTMS intervention,suggesting that the function of the region can be improved by the treatment of 10 Hz rTMS for 4 weeks.However,in terms of efficacy,the study has not found significant difference between the real and sham rTMS groups,which may be accounted to the small sample size and treatment-resistant features in in some patients with AHs.It is also necessary to expand the sample and applied subgroup analysis to determine whether this intervention is effective.