Altered Dynamic Functional Connectivity In Schizophrenia And Its Underlying Pathological Mechanism

Background: Schizophrenia is a serious mental disorder with functional disorganization of neural functional networks.However,the strong heterogeneity of schizophrenia symptoms hinders our understanding of its etiology.According to the Research Domain Criteria,mental disorders are caused by injury of specific parts of the brain.These parts are responsible for cognition,emotion,and behavior respectively.Therefore,it will be a great contribution to our understanding of the pathological with the use of a dimensional approach to clarify the neural network function characteristic of schizophrenia.Current analysis methods are limited,the steady-state brain function network analysis methods might not accurately reflect the dynamic characteristics of spontaneous neural network function of schizophrenia as this method only measures the attribute of the average functional connection of the brain over some time.To this end,the key questions to be addressed in the study are（1）to investigate the changes in dynamic functional connectivity complexity among schizophrenic patients,clarified the correlation between the complexity of functional connectivity,mental symptoms,and emotional dysfunction.In addition,the impact of age of onset on the complexity of dynamic functional connectivity will be investigated by classifying patients into early-onset（< 18 years）and adult-onset（>= 18 years）schizophrenia according to the age of onset.（2）To investigate the role of dynamic functional connectivity complexity in the pathological mechanisms of schizophrenia,high-risk populations（including unaffected first-degree relatives with schizophrenia and schizotypal personality traits）were recruited to explore the characteristics of dynamic functional connectivity complexity and the correlation with dysfunctional emotional functioning.Methods: Study Ⅰ recruited 46 schizophrenia patients with the use of DSM-IV criteria for classification and 39 healthy participants;Study Ⅱ included 30 unaffected first-degree relatives,27 schizotypal personality traits participants,and 31 healthy controls.All subjects underwent resting-state functional Magnetic Resonance Imaging（rs-f MRI）.Then were evaluated using the Temporal Experience of Pleasure Scale（TEPS）,and the Emotional Expressivity Scale（EES）.The sliding window method was used to estimate the dynamic functional connectivity patterns between 142 brain regions in each subject.Complexity measure（i.e.,entropy）was applied to quantify functional complexity,and the mean dynamic functional connectivity complexity was calculated for the five-brain functional network（including Default Mode Network,DMN;Executive Control Network,ECN;Salience Network,SN;Visual Network,VN;Sensorimotor Network,SMN）.Finally,a series of hypothesis tests with FDR correction for p-values were performed to determine group differences in complexity at the whole brain,network,and node levels,respectively.Results: The results of Study Ⅰ showed that patients with schizophrenia reported higher social,physical anhedonia;lower anticipatory,consummatory pleasure.The early-onset schizophrenia group reported decreased anticipatory and total pleasure experience,while the adult-onset schizophrenia group did not report emotional dysfunction.Schizophrenia patients had reported an increase in dynamic functional connectivity complexity across the brain on average.At the network level,with increased dynamic functional connectivity complexity in the visual network consistently present among the schizophrenia whole group,early-onset,and adultonset schizophrenia patients.The dynamic functional connectivity complexity of the Sensorimotor networks was significantly higher in the schizophrenia whole group and adult-onset schizophrenia patients,while the dynamic functional connectivity complexity of the salience network was associated with more severe negative symptoms in schizophrenia whole group,and early-onset schizophrenia patients.Area-level analysis revealed that schizophrenia patients showed significantly higher dynamic functional connectivity complexity in the bilateral thalamus（part of the salience network）,right parietal cortex（part of the Sensorimotor network）,and right occipital and posterior occipital cortex（part of the visual network）.Further analysis revealed that elevated dynamic functional connectivity complexity in the right thalamus was mainly present in the early-and adult-onset schizophrenia group.Results from Study Ⅱ showed that unaffected first-degree relatives reported lower anticipatory,and total pleasure scores.The schizotypal personality trait group reported increased levels of social anhedonia,emotional expression,and emotional inhibition.Unaffected first-degree relatives and schizotypal personality trait group showed similar whole-brain average dynamic functional connectivity complexity with health control.At the network level,unaffected first-degree relatives dynamic functional connectivity complexity was no significantly changes,it demonstrated that the dynamic functional connectivity complexity in the salience network was associated with decreased emotional expression and pleasure,while higher dynamic functional connectivity complexity in the visual network was negatively correlated with anhedonia symptoms.The schizotypal personality trait group had significantly enhanced dynamic functional connectivity complexity of the executive control network.Conclusion: Increased dynamic functional connectivity complexity in largescale brain networks（including VN,SMN,SN）was found across schizophrenic patients,suggesting elevated instability in the perceptual processing of internal,external world inputs,and emotion processing in schizophrenia.This may be related to the severity of negative symptoms,which explains the heterogeneity of emotional and cognitive function in schizophrenia to a certain extent and supports the neurodevelopmental hypothesis.Moreover,there is no significantly increased network functional complexity among unaffected first-degree relatives,But it is related to the symptom performance of anhedonia and the dysfunctional emotion expression.It indicates the impaired complexity of dynamic functional connectivity of the brain network may exist before the onset of the disease,suggesting that it may be a candidate endophenotype of schizophrenia.