The Study Of Brain Connectivity In Schizophrenia Patients With Auditory Verbal Hallucinations

Schizophrenia(SZ)is a serious mental disorder that associates with abnormalities of brain structure and functions.As important indicators to evaluate the severity and clinical efficacy of schizophrenia,auditory verbal hallucinations(AVHs)are the most common symptoms of SZ,with an incidence of 60%-80%.Auditory content often threatens the patient,commands the patient,or talks about the patient's mind,comments the patient's behavior,and gives the patient great pain.Especially in the command of self-injury,wounding or other violent behavior,patients will bring serious harm to them self,their family and society.At present,the neural mechanism of schizophrenia auditory verbal hallucinations is not clear.Revealing the mechanism of AVHs,not only has great significance in AVHs clinical,but also in the pathophysiology of SZ.Previous neuroimaging studies on AVHs have revealed structural and functional alterations in-the language network,including brain regions associated with speech generation and perception.Among them,several studies have demonstrated main effects of auditory hallucinations are related to left middle temporal gyrus(LMTG),left temporo-parietal regions and left inferior frontal gyrus(LIFG).Recent studies further indicate that patients with AVHs had lower GMV in frontal and temporal cortical regions and thinner cortical thickness in the temporal gyrus.Voxel-based morphometry study reported that severity of auditory hallucinations correlated with superior temporal areas including primary and secondary auditory cortices.Besides,experience of AVHs has been associated with increased activation in the left inferior frontal cortex and left middle temporal cortex.A quantitative meta-analysis revealed that AVHs were highly associated with left inferior frontal gyrus and the left inferior parietal lobule(LIPL).The substantial neuroimaging studies suggest that brain disorders associated with aberrant cognitive functions are not involved in a single brain region,but a more diffuse cognitive dysfunction depending on connectivity between regions.Locating specific brain regions that behave abnormally in schizophrenia with AVHs might be insufficient to understand the underlying basis.Diffusion tensor imaging(DTI)study revealed reduced integrity of the fiber connecting frontal and temporo-parietal language regions.It's further supported by neuroimaging studies revealing that auditory hallucinations in schizophrenia associated with dysconnectivity in the language network of cortical areas.Study of f MRI showed that the emergence of AVHs was the result of mild disruption of function connectivity along the fronto-temporal pathway.Reduced fronto-temporal functional connectivity has also been demonstrated in SZ patients with AVHs during sentence-completion task,external speech processing,and speaking aloud task.Resting state f MRI study showed that disrupted intrinsic connectivity of the language network could underlie persistent AVHs in patients with SZ.It was also suggested that AVHs may be traced back to abnormally elevated resting state activities in auditory cortex.Based on a comprehensive review of a large number of case studies on AVHs,it has been found that the lesion is almost always located in the brain pathway of the language network.Although previous studies have shown that the emergence of auditory hallucinations is associated with changes in the connectivity of brain language network,there is no systematic study of structural connectivity,functional connectivity,and effective connectivity within language network.Structural connectivity is the relationship of structure and anatomy between the brain regions.It is the material basis of functional connectivity and effective connectivity.Functional connectivity refers to the interrelationship in the brain areas of the dynamic physiological activities,clarifying whether there is a connectivity relationship between the brain areas and the strength of the connection relationship.Effective connectivity is to describe how a brain area acts on another brain area.That is to explain the causal pattern of information transmission in the brain interval.We believe that only the systematic study of the connectivity of the brain language network can really reveal the mechanism of AVHs.And it also has a very important significance for the diagnosis and treatment of schizophrenia.This paper studies the relationship between AVHs and abnormal brain connection based on MRI data.In study one,we use the DTI technology research the integrity of white matter fiber three groups of subjects(18 SZ with AVHs,18 SZ without AVHs,37 healthy controls).The results showed that the FA value of temporal lobe was abnormal in SZ without AVHs.In SZ with AVHs group,FA value is lower in temporal,frontal,cingulate,cerebellum,especially in the frontal and temporal lobe of the language areas.The arcuate fasciculus contains fibers connecting the frontal,parietal,and temporal language areas.Compared with healthy control subjects,SZ with AVHs showed lower FA value in those areas.This result demonstrated decreased fiber integrity and imbalance in directionality of the arcuate fasciculus.This pattern could not be demonstrated for SZ without AVHs.The arcuate fasciculus provides a pathway by which frontal speech-production areas can influence auditory and speech perception areas during overt and inner speech.A disruption of the arcuate fasciculus leads to a disturbance of the neuronal connection from the frontal Broca area to the temporal Wernicke area,which results in a disturbance of the stream of speech.One link between AVHs and inner speech is the common clinical observation that the content of AVHs is often closely related to the content of the patient's own thought.Most studies investigating FA values suggest that disturbances of FA values are related to the integrity of the fiber.This may facilitate the dysfunctional coactivation of the language-related areas.We also found that patients with AVHs have abnormal FA value in the cingulated.The cingulated gyrus is discussed as an ‘interface between emotion and cognition',and impairment is found in several psychiatric disorders such as schizophrenia,obsessive-compulsive disorder,and major depression.Our results are consistent with earlier studies.In this experiment,we performed fiber tracing analysis using LIFG,LMTG and LIPL as the ROIs in the language area.The results showed that there were many disordered connections and crossovers in the fiber connection of the schizophrenia patients,reflected the decreased integrity of fiber in the language area.Compared to healthy controls,we found that the largest change of fiber structure in SZ with AVHs were the frontal and temporal lobes in the language network.These changes are likely to be the source of auditory hallucinations and help to understand how the signals generated inside the brain are thought to be external.We believe that abnormal connections result in abnormal activation of external sounds and language stimuli,making it impossible for patients to distinguish signals generated within their own brain from external stimuli.In order to confirm this conclusion,we further study the function connection of the same subjects.In study two,we used the method of independent component analysis to research the functional connectivity of language network in the same three group subjects.Statistical analysis showed that compared with the healthy controls,both patient groups showed decreased functional connectivity in the left region of the language network.At the same time,SZ with AVHs showed increased functional connectivity in multiple brain regions on the right side of the language network relative to the SZ without AVHs.In this study,we found that the two groups of patients showed decreased function connection in the left middle temporal gyrus,superior temporal gyrus and inferior frontal gyrus.The results suggest that the reduction of the left side of the language network function may be a common pathological change in schizophrenia patients.The results are consistent with previous studies on schizophrenia.At the same time,we also found that compared with SZ without AVHs and healthy controls,SZ with AVHs showed decreased functional connection in the left middle temporal gyrus and inferior frontal gyrus.The results suggest that abnormal functional connectivity in these brain areas may be associated with the appearance of AVHs.We have found abnormal structural connectivity in those areas in the first study,so the results in study one and study two confirmed each other,and showed that the AVHs are due to the abnormal function and structural connectivity in brain language regions.In study three,we utilized stochastic dynamic causal modeling(DCM)to investigate directed connections within the language network in schizophrenia patients with and without AVHs.the subjects were exactly the same as the first two experiments in the current resting-state f MRI study.Time series of three regions of interest(ROIs),which have been reported to be important in language processing,including the LIFG,LMTG,and LIPL within the language network were extracted.For each subject,a fully-connected DCM model was first built and then a reduced(winning)model was identified using a network discovery scheme.Statistical differences between three groups were characterized by a one way ANOVA,followed with post-hoc t-tests.The results showed that the connection from the LIFG to LMTG was significantly decreased in patients with AVHs compared to those without AVHs.Meanwhile,the effective connection from the LIPL to LMTG was significantly decreased compared to the healthy controls.Our findings suggest that aberrant pattern of causal interactions within the language network in patients with AVHs,indicating that the hypoconnectivity or disrupted connection from frontal to temporal speech areas might be critical for the pathological basis of AVHs.In all the three experiments,we found that there was an abnormality in the regional connection of the brain language network in SZ with AVHs,indicating that the reduction or disruption of connectivity in the language region may be the key to the AVHs pathology.