Frequency-specific functional connectivity density as an effective biomarker for adolescent generalized anxiety disorder

Several neuropsychiatric diseases have been found to influence the frequency-specific spontaneous functional brain organization (SFBO) in resting state, demonstrating that the abnormal brain activities of different frequency bands are associated with various physiological and psychological dysfunctions. However, little is known about the frequency specificities of SFBO in adolescent generalized anxiety disorder (GAD). Here, a novel complete ensemble empirical mode decomposition with adaptive noise method was applied to decompose the time series of each voxel across all participants (31 adolescent patients with GAD and 28 matched healthy controls; HCs) into four frequency-specific bands with distinct intrinsic oscillation. The functional connectivity density (FCD) of different scales (short-range and long-range) was calculated to quantify the SFBO changes related to GAD within each above frequency-specific band and the conventional frequency band (0.01-0.08 Hz). Support vector machine classifier was further used to examine the discriminative ability of the frequencyspecific FCD values. The results showed that adolescent GAD patients exhibited abnormal alterations of both short-range and long-range FCD (S-FCD and L-FCD) in widespread brain regions across three frequency-specific bands. Positive correlation between the State Anxiety Inventory (SAI) score and increased L-FCD in the fusiform gyrus in the conventional frequency band was found in adolescents with GAD. Both S-FCD and L-FCD in the insula in the lower frequency band (0.02-0.036 Hz) had the highest classification performance compared to all other brain regions with inter-group difference. Furthermore, a satisfactory classification performance was achieved by combining the discrepant S-FCD and L-FCD values in all frequency bands, with the area under the curve (AUC) value of 0.9414 and the corresponding sensitivity, specificity, and accuracy of 87.15, 92.92, and 89.83%, respectively. This study indicates that the alterations of SFBO in adolescent GAD are frequency dependence and the frequencyspecific FCD can potentially serve as a valuable biomarker in discriminating GAD patients from HCs. These findings may provide new insights into the pathophysiological mechanisms of adolescent GAD.