Studies On Characteristics Of Brain Structure And Function In Adolescents With Generalized Anxiety Disorder

Objective:Generalized anxiety disorder (GAD) is a common anxiety disorder. However, the neural pathophysiology of GAD is less studied till now. There are three aims in this study. First, high-resolution structural magnetic resonance imaging (sMRI) technique and a voxel-based morphometry (VBM) analysis approach were employed to explore gray matter volume alterations in first-episode, naive-medicated, adolescent GAD patients and the impact of gender and childhood maltreatment on gray matter volumes in GAD patients. Second, diffusion tensor imaging (DTI) technique and voxel-based analysis (VBA) were employed to test abnormalities of white matter integrity in first-episode, naive-medicated, adolescent GAD patients and the impact of gender and childhood maltreatment on white matter integrity in GAD patients. Third, functional magnetic resonance imaging (fMRI) technique and a dot probe task were employed to examine characteristics of selective attentional bias in first-episode, naive-medicated, adolescent GAD patients and the possible brain neural pathological mechanism associated with selective attentional bias.Methods:The Screen for Child Anxiety Related Emotional Disorders (SCARED) and the Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime (K-SADS-PL) were adopted to screen and evaluate. All patients met the criteria for GAD in American Diagnostic and Statistical Manual Version-â…£ (DSM-â…£). Healthy controls free of mental disorders or physical disorders were selected to match patients in age, gender, and education level. All subjects enrolled fulfilled a series of cognitive tests and the Childhood Trauma Questionnaire (CTQ). All patients also completed Beck Depression Inventory (BDI) and the Penn State Worry Questionnaire (PSWQ). Then, all subjects underwent magnetic resonance scan, including sMRI, DTI and fMRI. While under fMRI scan, all subjects were demanded to execute a dot probe task. Finally, all data were processed with softwares of Statistical Parametric Mapping (SPM) and Statistical Product and Service Solutions (SPSS).Results:1. Thirty adolescent GAD patients and27healthy controls finished high-resolution sMRI. However, for poor image data quality and incomplete clinical data only26adolescent GAD patients and25healthy controls were finally enrolled in analysis. Compared to healthy controls, adolescent GAD patients showed larger gray matter volumes in the right putamen, right insula, as well as the left lingual gurus and hippocampus. The results from gender-by-diagnosis general linear model showed diagnosis main effects on the right putamen, gender main effects on the left precuneus/posterior cingulate cortex, bilateral caudate, right orbitofrontal cortex and left cerebellum posterior lobe, as well as no diagnosis-gender interaction effect. Further analysis exhibited that:1) Larger right putamen gray matter volumes in GAD patients compared to healthy controls,2) Larger left precuneus/posterior cingulate cortex in males compared to females,3) Decreased bilateral caudate, right orbitofrontal cortex and left cerebellum posterior lobe in males compared to females. The results from maltreatment-by-diagnosis general linear model showed diagnosis main effects on the right putamen, maltreatment-by-diagnosis interaction effect in the left thalamus, and no maltreatment main effect. Further analysis found larger right putaminal gray matter volumes in GAD patients compared to healthy controls and only adolescent GAD patients with a history of childhood maltreatment having larger left thalamic gray matter volume. Besides, a positive correlation between childhood maltreatment and the left thalamic gray matter volume was found only in GAD patients.2. Twenty-eight adolescent GAD patients and27healthy controls finished DTI. However, for poor image data quality and incomplete clinical data only25adolescent GAD patients and24healthy controls were finally enrolled in analysis. Compared to healthy controls, adolescent GAD patients showed decreased FA in the bilateral frontal white matter and the right occipital white matter. The results from gender-by-diagnosis general linear model showed diagnosis main effects on the bilateral frontal white matter and the right occipital white matter, no gender main effect and gender-by-diagnosis interaction effect. The results from maltreatment-by-diagnosis general linear model showed diagnosis main effects on the bilateral frontal white matter and the right occipital white matter and maltreatment main effect on the right parietal white matter. Further analysis showed increased FA of the right parietal white matter in subjects with histories of childhood maltreatment compared to subjects without histories of childhood maltreatment.3. Twenty-eight adolescent GAD patients and26healthy controls finished fMRI. However, for poor image data quality, incomplete clinical data and poor response to the dot probe task only23adolescent GAD patients and21healthy controls were finally enrolled in analysis. Behavior data suggested adolescent GAD patients showed longer average response latencies compared to healthy controls. The average response times in trials containing threat pictures were longer than that in trials containing happy pictures. Relative to healthy controls, adolescent GAD patients showed higher disengaging index score in trials containing threat pictures. FMRI results showed adolescent GAD patients manifested decreased activation in the left dorsolateral prefrontal cortex, right anterior cingulate cortex and left middle temporal cortex compared to healthy controls when finishing trials containing threat pictures. Besides, the activation in the left dorsolateral prefrontal cortex was negatively correlated with anxiety level in GAD patients.Conclusions:1. This study support the hypothesis that the occurrence of GAD is based on abnormal interaction between cortical and subcortical structures. The frontal cortex and the putamen might be involved in the neural circuitry associated with GAD.2. There are gender differences in gray matter volumes, while no gender differences in white matter integrity. However, these gender differences of gray matter volumes have no impact on GAD.3. The impact of childhood maltreatment on GAD might be associated with structural alterations in the thalamus. The alteration in the parietal white matter in subjects with histories of childhood maltreatment suggests over processing of the environmental information, which could increase the risk of developing mental disorders.4. Adolescent GAD patients have a difficulty in disengaging from threat information, which might be associated with the dysfunction of higher-order cortical structures, such as the prefrontal cortex and anterior cingulate cortex.