| Schizophrenia(SZ)is a psychiatric disorder.The etiology of schizophrenia is not yet clear.Schizophrenic subject often mainly depends on drug treatment.Schizophrenia often occurs in young adults(15-35 years old).Schizophrenia suffered from deficient emotion,attention,behavior,thinking and other cognitive impairments,accompanied by positive symptoms,such as auditory hallucinations and delusions.Nearly 1% of the world’s population is suffering from schizophrenia.It imposes a heavy burden on the family and society.In china,the prevalence of schizophrenia is higher than world average level,while its pathophysiological mechanism is still unclear.In recent years,with the rapid development and application of magnetic resonance imaging(MRI),it provides an effective way to explore the pathological mechanism of schizophrenia.In this paper,based on MRI we assessed the brain functional network of schizophrenia through static and dyanmci functional connectivity(FC)analyses.Furthermore,music intervention is commonly used to improve psychiatric symptoms of schizophrenic subjects.To verify the neuropathological mechanism of schizophrenia,we conducted a longitudinal design to investigate the effects of music intervention on the clinical symptoms and functional network in schizophrenic subjects.The main research includes the following seven parts:1.We investigated how reduction change in the cerebellum affects the static and the dynamic FC between the cerebellum and cortical/subcortical networks in schizophrenia.Reduction of gray matter in the cerebellum was confirmed across the cognitive and motor cerebellar modules in schizophrenic subjects.Results from this study demonstrates that the extent of reduction of gray matter within cerebellum correlated with altered static and dynamic FCs between cerebellum and cortical/subcortical netowrks.The severity of patients’ positive symptom was related to these structural-functional coupling score of cerebellums.A post hoc analysis exploring the effect of changed FC within cerebellum,confirmed that a significant positive relationship,between dynamic FCs of cerebellum–thalamus and intracerebellum existed in patients,but not in controls.The reduction of GM within the cerebellum might be associated with modulation of cerebellum–thalamus,and contributes to the dysfunctional cerebellar-cortical communication in schizophrenia.Our results provide a new insight into the role of cerebellum in understanding the pathophysiological of the deficient integration schizophrenia.2.Based on the hypothesis from first part of this paper,we assessed the abnormalities of the static hierarchical network of the eight subreions of thalamus in schizophrenia through step wise functional connectivity(swFC).Furthermore,we calculated the dynamic amplitude of low-frequency fluctuation(ALFF)through sliding window analysis.Then,we also investiaged the hierarchical network of eight subregions of thalamus in schizophrenia through dynamic ALFF time series of voxels.Compared to controls we found that the difference of static hierarchical functional network of eight subregions of thalamic gradually converged to the increased cerebellum-basal ganglia-prefrontal cortex circuit,and the decreased swFC in primary sensorimotor and visual cortex in schizophrenic subjects.In addition,the hierarchical network of dynamic ALFF analysis found that the difference of eight thalamic subareas in schizophrenic subjects converge to the increased swFC in cerebellum,and decreased swFC the sensorimotor and visual cortex.These findings might reveal the neuropathological mechanism of schizophrenia from hierarchical functional networks.3.We investigated the abnormalities of static and dynamic FC in schizophrenic subjects from a large-scale brain network.We calculated a sliding-window based dynamic functional connectivity strength(FCS)and ALFF maps.Then using group independent component analysis(ICA)we characterized dynamic functional covariance network across the various time windows(dFCNW).Furthermore,we assessed individual variability of dFCNW in schizophrenia through inter-subject correlation analysis(ISC)and compared it to healthy controls.The spatial architectures of FCS/ALFF-dFCNW were similar with the traditional resting-state functional networks.Moreover,schizophrenic subjects demonstrated reduced dynamic FC within sensory and perceptual dFCNWs and also decreased connectivity between these dFCNWs and high-order frontal-dFCNWs.The severity of patients’ positive and total symptoms were related to these abnormal dFCs.Furthermore,schizophrenic group showed reduced ISC score of visual-dFCNW compared to healthy controls.The dFCNW during rest might form the intrinsic functional architecture and functional changes associated with psychotic symptom deficit.Our results support the hypothesis that dynamic functional covariance network may influence the aberrant sensory and cognitive function in schizophrenia,further highlight that targeting perceptual deficits could extend our understanding of schizophrenia’s pathophysiology.4.We first calculated the static and dynamic functional convariance network(FCN)in healthy and schizophrenic subjects.Then,we assessed the correlation of static and dynamic FCN between subjects through Pearson correlation analysis.Connectivity was also measured between dynamic FCN through Pearson correlation.It was found that increased similarity of primary perceptual FCN,and decreased similarity of high-order FCN in schizophrenic subjects compared to controls.Moreover,altered connectivity of FCN was observed in schizophrenic subjects compared to controls,including decreased connectivity between primary perceptual FCNs,decreased connectivity between high order FCNs,and increased connectivity between primay and high order FCNs.These findings indicated that the deficient perceptual network is similar between schizophrenic subjects,while the similarity of abnormal high order network is low between patients.Moreover,there is a high similarity of monitor system(salience and basal ganglia networks)in schizophrenic subjects.Our results support the hypothesis that schizophrenia have abnormal primary and high order brain networks,and reveal abnormal primary and high order information integration in schizophrenia from FCN.These results suggest that the abnormal primary perceptual network of schizophrenia,as well as its integration and transmission system,may be preferentially selected as therapeutic targets.5.We construct voxel-based large-scale dynamic FCS maps at low frequency(slow-4 and slow-5)by data-driven analysis,and investigated the frequency-dependent differences of brain dynamic FC in schizophrenia through repeated measurement ANOVA analysis.It was found that the several regions have higher dynamic FCS at slow-4 frequency,such as cerebellum,dorsolateral prefrontal lobe(DLPFC),visual cortex and posterior parietal lobe.Several regions also have higher dynamic FC at slow-5 frequency,such as caudate,rectus and inferior temporal regions.In addition,the group and frequency interaction effects were found in visual cortex and the key reions of salience network in schizophrenic subjects.The altered frequency-dependent dFC of primary and salience network may be related to the abnormalities of functional integration from different frequency bands in schizophrenia.These regults provide a new way to understand the physiological mechanism of schizophrenia from the frequency dFC.6.To verify the neuropathological mechanism of schizophrenia,we investigated the effects of music intervention in neural circuits through functional magnetic resonance imaging(fMRI)study in schizophrenic subjects.Under the standard care,patients were randomly assigned to music and non-music intervention(MTSZ,UMTSZ)for 1-month.Resting-state fMRI were acquired over three-time points(baseline,1-month and 6-month later)in schizophrenic subjects,analyzed using static and dynamic functional connectivity strength(FCS)and seed-based FC approaches.We found music intervention could positive normalized the static visual network and dynamic motor-cerebellum FC in schizophrenia.Longitudinal statistics showed that the effects of music intervention vanished 6-month later.The neuroimaging evidence provided by this study suggests that music intervention may lead to short-term positive effects on schizophrenic subjects by normalizing the impaired primary perception network of schizophrenic subjects.Importantly,these findings verified the neuropathological mechanism of schizophrenia.7.To verify the neuropathological mechanism of insular network in schizophrenia,we used both seed-based FC and machine learining analyses in this study.After 1-month of music intervention,we found music intervention could normalized the dorsal anterior(dAI)and posterior insula static functional network of schizophrenic subjects.Music intervention could also normalize the dynamic FC of three subregions of insula in schizophrenic subjects.While these improved static and dynamic FCs had vanished 6 months later.Important,support vector regression analysis revealed that baseline-static FC between dAI and anterior cingulate cortex could predict positive symptom remission of MTSZ.Our results indicated that insula region may be the important target of music intervention in schizophrenic subjects.Moreover,these findings verified the neuropathological mechanism of schizophrenia.Altogether,this study systematically explored the neuropathological mechanism of schizophrenia.The main findings of this study as follows: 1.The results of first and second part reveal that the altered FC of cerebellum and basal-ganglia network may be related with the neuropathological mechanism of primary perceptual information integration in schizophrenia;2.The results of third part indicated that abnormal dFCNW is the basis of these deficient integration processing in schizophrenia.The results of fifth part showed that these abnormal processing are also frequency dependent in schizophrenia;3.The results of fourth part revealed that deficient perceptual network is similar between schizophrenic subjects,while the similarity of abnormal high order network is low between patients.Moreover,there is a high similarity of abnormal monitor system(salience and basal ganglia networks)in schizophrenic subjects.These results suggest that the abnormal primary perceptual network of schizophrenia,as well as its integration and transmission system,may be preferentially selected as therapeutic targets;4.The results of six and seven part of this study,indicated that music intervention could improve the integration and regulation of schizophrenic subjects’ primary perceptual to achieve the effect of improving clinical sympoms.These findings validated the neuropathological mechanism of schizophrenia.In conclusion,our findings revealed that the core pathological mechanism of schizophrenia may largely related with primary cortex-regulation network-high order regions loops.This study could promote our understanding of the pathological mechanism of schizophrenia,and is important for clinical intervention and treatment. |
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