Interaction Mechanism Between Low-level And High-Level Brain Function Systems In Schizophrenia

Schizophrenia is a serious chronic mental illness,which usually begins at the stage of young adults.So far,the underlying cause is still not clear.Even if there are many treatments such as drugs,the disease is often accompanied for a lifetime.The main psychological characteristics of this disorder are disturbances in thinking,perception,emotion,and behavior,and serious uncoordinated mental activities.The prevalence of schizophrenia in the population is about 1% worldwide,and its prevalence in China has reached to 1.5%.Due to its high disability,it brings a huge economic and spiritual burden to patients,their families,nursing staff and the entire society.Deepening the understanding of the pathophysiological mechanism of schizophrenia has become the key to the development of effective treatment and rehabilitation methods.At the end of the 19 th century,when Kraeplin first proposed the use of "dementia praecox" to describe schizophrenia,high-order cognitive dysfunction has been considered to be a core component of schizophrenia.So far,most of studies for investigating the neuropathological mechanisms of schizophrenia have focused on high-order cognitive brain function systems.Less attention has been paid to the role of low-level perceptual systems in the neuropathological mechanism of schizophrenia.However,in recent years,more and more studies have emphasized that the low-level perception system of schizophrenia and its abnormal interaction with the high-level cognitive function system are indispensable for understanding the neuropathological mechanism of schizophrenia.Based on this,this study used functional magnetic resonance imaging as the carrier and functional connectivity as the core analysis method to serially investigate the low-level perception system of schizophrenia and its interaction mechanism with the higher-order cognitive function system.The main research contents of this thesis are as follows:1.Using meta-analysis statistical technique,we systematically integrated the literature of schizophrenia reporting the seed-based functional connectivity abnormality and the abnormal structure connectivity of the white matter based on voxel fractional anisotropy(FA),and then obtained the relatively consistent conclusion of the large-scale functional connectivity and structural connectivity of schizophrenia.The meta-analysis of functional connectivity highlighted changes of functional connectivity of salience network as the main feature in schizophrenia.These results suggested that schizophrenia has disturbances in the perception and management of salient information in the surrounding environment,and points out the necessity of strengthening the study of perception system in schizophrenia.White matter structural meta-analysis based on unbiased voxel FA found schizophrenia showed reduced structural integrity in right posterior cingulate fiber connecting the visual and parietal cortex of the back part of the brain,and left posterior superior longitudinal beam connecting the front and back of the brain,which suggests there is a functional abnormality in the primary processing of local information in the back of the brain and its abnormal interaction with the higher-order control cortex information in the front of the brain.The results of the two sub-studies can be systematically integrated into the disconnected network model of schizophrenia,and the two sub-studies can complement each other and verify each other.The corresponding white matter changes may lay the foundation for changes in observed abnormality of functional connectivity.This study jointly pointed out the necessity of strengthening research on low-level perception and information interaction between the perception and high-level cognitive systems.2.Adopting a novel dynamic functional connectivity,this study comprehensively investigated the abnormality of dynamic functional connectivity in schizophrenia from voxel-level,brain region-level to network level.Schizophreni patients showed consistent increased variability in low-level perception system across these three different levels of functional connectivity.In addition,higher-order cognitive networks(such as the default mode network and the frontalpareital network)were only found to have a reduction in functional connectivity variability at the level of the whole brain connection rather than the local voxel level in schizophrenia.These findings highlighted the fundamental role of enhanced dynamic communication of low-level perceptual networks(mainly indicating the high instability of perceptual input information in schizophrenia),and the higher-order cognitive network in schizophrenia had weakened the ability to dynamically integrate the whole brain information including information from low-level sensory systems.These findings provided novel evidence of neural correlates for the hypothesis of the disintegratation of schizophrenia’s perceptions and higher-order cognitive processes,and further highlighted the key role of bottom-up processing in understanding the pathological mechanisms of schizophrenia.3.Based on the above two studies,we found a large range of changes of the static and dynamic functional connectiviy in schizophrenia.We speculated that the schizophrenia would show altered macro-level low-level perception-high level cognitive brain function system hierarchy organization that constitutes one of the basic principles of human brain information processing.Starting from the macroscopic functional hierarchical organization,a new combination of gradient functional connectivity and stepwise functional connectivity analysis was used to analyze the complementary characterization of cortical low-level sensorimotor-high-level associative cortical hierarchical organization.The functional connectivity gradient analysis found that the schizophrenia showed a compressed cortical hierarchical organization,in which the sensorimotor area was more compressed,and the higher-order network portion was less compressed,resulting in a reduced differentiation between the lower-level perception and the higher-order cognitive system.Notably,this compression represents an integrated change in functionality,not a compression in brain structure.The stepwise functional connectivity analysis found the compression of cortical hierarchical organization was closely related to reduced integration of low-level perception systems,and reduced separation of low-level perception and high-level cognitive systems.This study provided a new system-level neural correlates for the pathological interaction of low-level early perception and high-level cognitive function in schizophrenia,namely the compression of perceptual system-multifunctional associative cognitive system in the cerebral cortex.Within the framework of compressed cortical hierarchical organization,cascading damage caused by low-level primary sensorimotor systems and less inefficient intergaration between bottom-up perceptual information and top-down attention requirements and control processes may partly explain the higher-order cognitive deficits in schizophrenia.4.Theoretical and empirical studies have pointed out the important role of the cerebellum in the pathogenesis of schizophrenia.In this study,we took the cerebellum as the research model.Starting from the macroscopic functional hierarchical organization,the functional connectivity gradient analysis was adopted to test whether the compression hierarchy pattern observed in cerebral cortex would be similarly observed in intracerebellar cortex connectivity and connectivity between cerebellar cortex and cerebral cortex.By constructing the functional hierarchy gradient in the cerebellum,the cerebellum-cerebral cortex and the cerebral cortex-cerebellar functional connectivity,compared to heathy controls,schizophrenia patients showed consistent compressed lowlevel sensorimotor-high-level cognitive hierarchtical organization in functional conectivity within the cerebellum,functional connectivity between cerebellar cortex and cerebral cortex,and functional connectivity between the cerebral cortex and cerebellar cortex.Further network investigation observed the increased functional connectivity between the cerebellar sensorimotor network and cerebellar higher-order cognitive network,between the cerebellar perceptual network and cerebral higher-order cognitive network,and between the cerebellar higher-order cognitive network and cerebellar perceptual network in patients with schizophrenia These observations suggested that the separation between the low-level network and the high-level network function network was reduced in schizophrenia,further supporting the compressed functional hierarchy organization.This compression mode was most prominent in the sensorimotor network,which may indicate the presence of cascading effect caused by low-level sensorimotor system damage,which would in turn upstream the low quality information from the lowlevel perceptual system to destroy the function of higher-level systems,which may partially explain the high level cognitive impairment in schizophrenia.Therefore,the compressed functional hierarchical gradient may represent a neurobiological framework that can help us understand the coexistence and interaction of low-level and high-level functional system abnormalities within the cerebellar cortex,cerebellar-cerabral cortex,and cerebral cortex-cerebellar cortex circuits in schizophrenia.5.Based on the perspective of macroscopic functional hierarchical organization and transdiagnositic dimension approaches,we tested whether the low-level sensorimotorhigh-level associative hierarchical organization can index transdiagnostic clinical and behavioral dimensions.To address this question,we also took the cerebellum as the research model and used multivariate partial least squares statistical technique to construct the multivariate correlations between cerebellar low-level sensorimotor-highlevel cognitive hierarchy organization and transdiagnostic dimensions of psychopathology.For the first time,we found there was significant correlation between the connectivity gradient of cerebellar function hierarchy and the multiple behavioral dimensions across psychiatric diagnoses.Relationships can be characterized by four dimensions: general psychopathology,general lack of attention regulation,internalization symptoms and memory dysfunction.Each behavioral dimension was associated with a unique pattern of cerebellar connectivity gradients,supporting individual variability in the organization of the low-level sensorimotor-high-level cognitive function hierarchy can capture the variability of multiple behavioral dimensions across psychiatric diagnoses,which suggested that the abnormal interaction between the low-level brain function system and the high-level brain function system may be a potential core mechanism across the transdiagnostic diemnsions of psychopathology.These findings also highlighted the importance of cerebellar function in the transdiagnostic behavior dimension of psychopathology and thus contributed to the call for development of cerebellar neuroscience,which may greatly contribute to the diagnosis,prognosis,treatment and prevention of cognitive and emotional diseases.In summary,the results of this thesis provided a macro and concise neurobiological framework for the low-level and high-level brain function system interaction mechanism of schizophrenia,that is,the compressed low-level sensorimotor-high-level associative cognitive hierarchical organization.The change of white matter structure provides a structural basis for the change of compression of functional hierarchical organization.Within the framework of the compressed functional hierarchy,schizophrenia manifests in the low-level perception system as the abnormal processing of the salient information from the surrounding environment and the high instability of information coding.It is worth noting that the damage in the low-level perception system would produce a cascading effect to upsteam to higher-level brain function system,and further disrupts subsequent information processing.Moreover,the internal functional structure of the high-level brain function systems is loose,which makes them unable to function their cognitive control ability normally and efficiently,and then the dynamic integration ability to the real-time information from the low-level sensory system is weakened.More importantly,the functional differentiation of the low-level perception system and the high-level cognitive system is reduced in schizophrenia patients,which would lead to the blurring of the boundary between the two systems,and the information processed at different processing stages is easily confused.The compressed functional hierarchical structure model further emphasizes the role of damage of the perceptual system itself and its inefficient information integration with the higher-order cognitive system in understanding the pathophysiology of schizophrenia,and hints at that,in order to improve higher-order cognition of schizophrenia in functional training,at least in the early training stage,low-level perception-based training is necessary to improve the impaired low-level perceptual system.Most importantly,our research extends the low-level sensorimotorhigh-level cognitive function hierarchical organization to a close relationship with multiple psychopathological dimensions across psychiatric disorders,and thus verifies that the changes in this basic functional hierarchy have the ability to generalize,implying the abnormal interaction between the low-level brain function system and the high-level brain function system may be a potential core mechanism across the transdiagnostic dimensions of psychopathology.