The Working Memory Network Study Based On Resting-state Functional Magnetic Resonance Imaging

Human brain is the most complicated organ in our body and the physical basis for high-level cognition. As the core of cognitive function, working memory is a memory system referring to the temporary maintenance and manipulation of information that is essential for higher-order cognitive processing, including comprehension, learning, and reasoning. Furthermore, some common psychiatric disorders(such as schizophrenia) have been suggested to be characterized by working memory deficit. However, the neural correlates of working memory performance are still unclear. Hence, based on praxiology and imageology, this paper studied the interactive mechanism between the working memory-related brain regions in healthy people and compared the differences of this mechanism between healthy controls and schizophrenic patients. Moreover, this paper investigated the influence of schizophrenia risk gene on the prefrontal cortical-striatal circuit and working memory in healthy people. These studies provide novel insight into the neural substrate of working memory, allow a much deeper understanding of the relationship between psychiatric disorders(especially schizophrenia) and working memory deficit, and help to reveal the genetic basis of working memory. The main works of this dissertation are as follows:1. Previous studies suggest that the prefrontal lobe is a key region for working memory performance. Here, in a large sample of healthy young adults, we identified the core working memory regions by linking working memory performance to resting-state functional connectivity with the bilateral dorsolateral prefrontal cortex, the most important region involved in working memory. Then a spectral dynamic causal modeling analysis was performed to quantify the effective connectivity between these regions. Finally, the effective connectivity was correlated with working memory performance to characterize the relationship between these connections and working memory performance. The findings delineated that the functional connections between the bilateral dorsolateral prefrontal cortex and the dorsal anterior cingulate cortex and between the right dorsolateral prefrontal cortex and the left orbital fronto-insular cortex were positively correlated with working memory performance. Furthermore, the effective connectivity from the dorsal anterior cingulate cortex to the bilateral dorsolateral prefrontal cortex and from the right dorsolateral prefrontal cortex to the left orbital fronto-insular cortex could predict individual differences in working memory. Because the dorsolateral prefrontal cortex is a principal region in the central-executive network, and the dorsal anterior cingulate cortex and orbital fronto-insular cortex are core regions of the salience network, we inferred that the inter- and causal-connectivity between core regions within the central-executive and salience networks is functionally relevant for working memory performance. In summary, the current study identified the dorsolateral prefrontal cortex-related resting-state effective connectivity underlying working memory and suggests that individual differences in cognitive ability could be reflected by resting-state effective connectivity.2. Working memory deficit is a core feature of schizophrenia. A number of studies revealed that working memory network is aberrant in schizophrenic patients. Hence, the second work in this paper made a clinical validation of the findings in the first work based on the functional magnetic resonance imaging data of first-episode schizophrenic patients and matched healthy controls. This work revealed that the effective connectivity from the dorsal anterior cingulate cortex to the left and right dorsolateral prefrontal cortex and from the right dorsolateral prefrontal cortex to the left orbital fronto-insular cortex were weaker in patients than in controls. Furthermore, these effective connections displayed positive correlation with working memory performance in controls. However, in patients, the effective connectivity from the dorsal anterior cingulate cortex to the dorsolateral prefrontal cortex was not correlated with working memory performance, and the effective connectivity from the right dorsolateral prefrontal cortex to the left orbital fronto-insular cortex was negatively correlated with working memory performance. These results indicated the aberrant top-down mechanism of working memory process in patients, and support the hypothesis that the working memory-dependent prefrontal dysconnectivity is a common feature of schizophrenic patients.3. Dopamine receptor D3(DRD3) gene is intimately associated with the pathogenesis of schizophrenia. However, the neural mechanism underlying this association is largely unknown. DRD3 rs167771 polymorphism has been recognized to link to the biological activity of DRD3 gene. Thus, based on rs167771 polymorphism, the third work in this paper focused on revealing specific mechanism that links DRD3 gene to the risk of schizophrenia. The left and right striatum, which are the regions most prominently influenced by dopamine, were selected as the seed regions in this work, and created the voxel-wise resting-state functional connectivity maps between the seed regions and the prefrontal cortex in functional imaging data of 283 healthy Chinese participants. Furthermore the spectral dynamic causal modeling estimated the effective connectivity between the regions whose functional connectivity is different between groups, and then the correlation analysis of the effective connectivity and working memory performance was conducted. This study revealed that functional connectivity between the left striatum and right dorsolateral prefrontal cortex in risk group was stronger than in non-risk group, and this connectivity did not display significant correlation with working memory performance in risk group, different from the positive correlation in non-risk group. Further, effective connectivity from the left striatum to the right dorsolateral prefrontal cortex was stronger in risk group than in non-risk group. Moreover, this connectivity did not display correlation with working memory performance in risk population, different from the positive correlation in non-risk group. In all, the current findings obtained in a large sample of healthy participants identified potential neural mechanisms linking DRD3 gene with the risk of developing schizophrenia via the intermediate phenotype of the connectivity between the striatum and the prefrontal cortex.Taken together, based on praxiology, genetics and imageology, the present paper explored the interactive mechanisms not only within the prefrontal cortex but also between the prefrontal cortex and the striatum. These studies revealed the working memory-related brain functional integrations in healthy people, schizophrenic patients and population with schizophrenia risk. These findings help to delineate the neuronal mechanisms of working memory and contribute to the prevention and treatment of schizophrenia.