Genetic Susceptibility And Diagnosis Specificity Of Thalamo-cortical Functional Abnormality In Schizophrenia

Objectives:Previous resting-state MRI studies have been consistently identified functional abnormalities in the thalamocortical circuit of schizophrenias,suggesting that the abnormal thalamocortical functional connectivity is a key neurobiological basis for schizophrenia.Schizophrenia is a mental disorder charactered with a heritability of about80%.Previous studies have provided some evidences that abnormalities in the thalamocortical circuit may be presented during early neurodevelopment process of schizophrenia,suggesting that this circuit is associated with genetic susceptibility of this disease,but there is still no evidence to clarify this issue.Furthermore,cognitive deficits are core features in schizophrenia,such as abnormal attention,memory,and executive function.And there were evidences showed that abnormalities in the thalamocortical circuit may play an important neuropathological role in cognitive deficits of schizophrenias.Another scientific question that needs to be answer is whether schizophrenias will show specific pattern of abnormal thalamocortical functional connectivity when they are performing the cognitive task.To answer these questions,we investigated whether abnormalities in abnormal thalamocortical resting-state functional connectivity are influenced by genetic susceptibility of schizophrenia and whether there is a specific pattern of abnormal thalamocortical functional connectivity in schizophrenia during cognitive tasks in two studies,respectively.We aim to provide scientific evidences to further verify whether abnormal thalamocortical functional connectivity is a specific neurobiological marker for schizophrenia.Methods:Study one:Eighty-seven schizophrenia patients,92healthy siblings of schizophrenia patients,and 98 healthy controls were included in this study,and resting-state MRI data were collected from all subjects.A functional connectivity analysis based on brain regions of interest（each subdivision of the thalamus）was used to identify the functional characteristics of the thalamocortical circuit in schizophrenias and their healthy siblings.Correlations between abnormalities in thalamic-cortical loop function and demographic information and clinical characteristics were examined by correlation analysis.Study two:One hundred and twelve patients with schizophrenia,58patients with bipolar disorder,41 patients with depression and 78 healthy controls were included in this study,and task-state MRI data were collected from all subjects when they are completing the N-BACK task.Whole-brain functional connectivity analysis was performed based on brain regions of interest（each subdivision of the thalamus）to identify the functional characteristics of the thalamocortical circuit in patients with schizophrenia,bipolar disorder and depression.Correlations between abnormalities in thalamic-cortical loop function and demographic data,clinical symptom and cognitive performance were examined by correlation analysis.Results:Study one:（1）Compared to healthy controls,schizophrenia patients and their healthy siblings both showed reduced thalamic-prefrontal-cerebellar connectivity（p<0.001,FDR corrected）,with the reduced connectivity areas located mainly in the medial dorsal nucleus of thalamus.（2）Only patients with schizophrenia showed enhanced thalamic-sensory-motor area connectivity（p<0.001,FDR corrected）,and the enhanced connectivity was mainly located in the dorsal and ventral lateral nuclei of the thalamus.（3）In schizophrenias,both enhanced thalamic-sensory-motor area connectivity and reduced thalamic-prefrontal-cerebellar connectivity were associated with the severity of clinical symptoms（p<0.05,FDR corrected）.Study two:（1）In the 0-BACK task condition,the accuracy was significantly lower in the schizophrenia group than in the healthy control group,the depression group and the bipolar disorder group（p<0.05）.In the 2-BACK task condition,the accuracy was significantly lower in the schizophrenia group than in the healthy control and depression groups（p<0.05）.（2）Among patients with schizophrenia,bipolar disorder,and depression,an abnormal pattern characterized by increased sensorimotor-thalamic connectivity and decreased prefronto-thalamic connectivity under working memory load was only presented in schizophrenia group（p<0.05,FDR corrected）.（3）Under working memory load,there was a significant negative correlation between the mean functional connectivity of brain areas with increased sensorimotor-thalamic connectivity and those with decreased prefronto-thalamic connectivity in schizophrenia(0-BACK:r=-0.57,p=8.37×10^-11;2-BACK:r=-0.31,p=1.09×10^-3).Conclusions:Schizophrenia patients showed similar abnormal thalamic-cortical functional connectivity to their healthy siblings during the resting state,suggesting that the abnormal thalamic-cortical functional connectivity is influenced by genetic susceptibility of schizophrenia.The abnormal pattern of increased sensorimotor-thalamic connectivity and decreased prefronto-thalamic connectivity under working memory load may be a neurophysiological feature specific to schizophrenia,and not shown in patients with bipolar disorder and depression.