Brain Connectivity In Patients With Generalized Anxiety Disorder Based On Magnetic Resonance Imaging

According to an epidemiological study performed in 2017,the global anxiety disorder patients has exceeded 284 million,which lead to high mental illness burden.Generalized anxiety disorder(GAD)is one of the most common types among all anxiety disorders,which featured by exaggerated and uncontrollable worry about daily events,negative self-related cognition,imbalanced male and female prevalence,high social burden,and low quality of life.However,existing studies on GAD is still relatively small,and the pathological mechanisms of such disease are still unclear.With the application of magnetic resonance imaging(MRI)techniques,growing number of studies in brain research have focused on brain functional and structural alterations of GAD.The available evidences suggest that,GAD is a disease which associated with cognition and emotion dysfunction,accompanied by multiple local and global brain functional and structural alterations.While,the current findings for GAD are not exactly the same due to heterogeneity of patient characteristics and analytical methodologies.Nevertheless,a review has summarized previous neuroimaging studies of GAD published before 2018,and pointed out that GAD is a disease with abnormal brain connections.Therefore,brain connectivity may be an essential component in understanding the pathological basis for GAD.This article focuses on the neural mechanisms of brain connections in GAD and performed several aspects of studies.First,we combined multi-modal functional neural imaging and the sex differences to explore the basic neural mechanisms of brain connections in GAD.Second,we employed dynamic brain functional connectivity and psychophysiological interaction(PPI)analyses to investigate the dynamic brain functional integration of GAD.Finally,we utilized the morphological brain structural connectivity to detect the brain anatomical degeneration mechanism of GAD.The main research contents include the following parts:1.Neurovascular coupling analysis between functional connectivity strength(FCS)and cerebral blood flow(CBF)was performed to investigate the relationship between brain functional connectivity and brain blood supply in patients with GAD.The voxelwise CBF-FCS correlation was used to reflect the global neurovascular coupling,while the CBF/FCS ratio was applied to denote the local neurovascular coupling.The results showed that,the global neurovascular coupling was reduced in GAD,which implicated the imbalance between brain functional connectivity and blood perfusion.Moreover,the local neurovascular coupling was increased in the right superior parietal gyrus(SPG)in GAD,and negatively associated with the self-esteem scores of GAD,which may correlated with aberrant self-related processing of GAD.These findings may provide metabolism basis for aberrant brain functional connectivity in GAD from the perspective of neurovascular coupling.2.According to imbalanced male/female ratio in GAD,we explored the effects of sex on brain functional connectivity alterations in GAD.First,the CBF was utilized as the surrogate of local brain function.During CBF-related analysis,regions simultaneously influenced by diagnosis(GAD vs.healthy control)and sex(males vs.females)were subjected to subsequent functional connectivity analysis to search the different brain functional connectivity patterns between male and female patients.The results showed that,the CBF of the left orbital frontal cortex,left fusiform gyrus,and the right middle temporal gyrus(MTG)was simultaneously influenced by diagnosis and sex.The functional connectivity between the MTG and inferior parietal lobule was different between male and female patients.Intriguingly,the moderation effect of illness duration on brain dysfunction was identified in male patients but not observed in female patients.These findings revealed different functional connectivity patterns in male and female GAD patients,which offer more subtle information in revealing neuropathological basis of GAD,and may also provide some potential clues for sex-specific intervention in GAD.3.In accordance with temporal variability feature of functional connectivity pattern,dynamic functional connectivity density(d FCD)approach was employed to identify the dynamic changes of local functional integration in GAD.The bilateral dorsomedial prefrontal cortex(dm PFC)and left hippocampus of patients exhibited increased d FCD variability,whereas the right postcentral gyrus of GAD showed decreased d FCD variability.The increased d FCD variability in the left dm PFC could predict the anxiety symptom severity of patients.The dynamic functional integration of the frontolimbic system and sensorimotor cortex may provide brain dysfunctional information of GAD in subtle time scale,and offer critical biomarker for anxiety symptom prediction in GAD.4.Leveraging self-related task and PPI analysis,we tracked the functional connectivity basis for abnormal self-related cognition in GAD.During the task,patients with GAD exhibited abnormal self-related processing,manifested as lower biased selfrelated rating scores on personality traits(decreased superiority illusion),and decreased brain activation in the left dm PFC,inferior frontal gyrus,superior temporal sulcus(STS),and the bilateral lingual gyrus.Regions with attenuated brain activation exhibited abnormal functional connectivity with regions relevant to reward,emotion,and theory of mind processing.These findings provide evidences for aberrant self-related processing in GAD,and reveal the influences of external stimulation on brain functional integration in GAD.5.We combined the illness duration-related gray matter volume(GMV)changes and the morphological causal structural covariance,to map the time information and causality of anatomical alterations in GAD.The results indicated that,along with increasing illness duration,the GMV reduction in GAD was step from the subgenual anterior cingulate cortex(sg ACC)and gradually expanded to the prefrontal cortex,temporal cortex,and the right insula.The sg ACC and the right insula may separately correlate with the origin and the maintenance of anxiety.The sg ACC and right insula-based causal analyses in GAD group suggest that,the sg ACC and the right insula had positive causal effects on each other.Additionally,these two regions jointly promote the GMV reduction of the parietal cortex,and simultaneously inhibit the GMV reduction of the posterior cingulate cortex,dorsolateral prefrontal cortex,and some regions of the temporal lobe and visual cortex.They also project opposite causal effects on the GMV changes of the somatosensory cortex and the ventrolateral prefrontal cortex.These results may indicated that,patients with GAD suffered from progressive GMV reduction when illness duration increased,and these structural alterations had causal relationships.In summary,this thesis reflect the basic neural mechanisms of GAD from the perspective of neurovascular coupling and sex differences;reveal the dynamic changing patterns of brain functional integration in GAD by combining resting-state and task MRI;tracking the brain structural degeneration circuits in GAD with increasing illness duration.In accordance with aforementioned studies,we may understand the neuropathological basis of GAD more comprehensive.