Lu Lu1,2, Hailong Li1, Jeffrey A Mills3, Heidi Schroeder2, Sarah A Mossman2, Sara T Varney2, Kim M Cecil4,5, Xiaoqi Huang1,6, Qiyong Gong1,6, Amir Levine7, Melissa P DelBello2, John A Sweeny1,2, Jeffrey R Strawn2. 1. Department of Radiology, Huaxi MR Research Center (HMRRC), West China Hospital of Sichuan University, Chengdu, China. 2. Department of Psychiatry, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA. 3. Department of Economics, Lindner College of Business, University of Cincinnati, Cincinnati, Ohio, USA. 4. Department of Radiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA. 5. Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. 6. Psychoradiology Research Unit of Chinese Academy of Medical Sciences, West China Hospital of Sichuan University, Chengdu, China. 7. Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York City, New York, USA.
Abstract
Objectives:Placebo response is one of the most significant barriers to detecting treatment effects in pediatric (and adult) clinical trials focusing on affective and anxiety disorders. We sought to identify neurofunctional predictors of placebo response in adolescents with generalized anxiety disorder (GAD) by examining dynamic and static functional brain connectivity. Methods: Before randomization to blinded placebo, adolescents, aged 12-17 years, with GAD (N = 25) underwent resting state functional magnetic resonance imaging. Whole brain voxelwise correlation analyses were used to determine the relationship between change in anxiety symptoms from baseline to week 8 and seed-based dynamic and static functional connectivity maps of regions in the salience and ventral attention networks (amygdala, dorsal anterior cingulate cortex [dACC], and ventrolateral prefrontal cortex [VLPFC]). Results:Greater dynamic functional connectivity variability in amygdala, dACC, VLPFC, and regions within salience, default mode, and frontoparietal networks was associated with greater placebo response. Lower static functional connectivity between amygdala and dorsolateral prefrontal cortex, amygdala and medial prefrontal cortex, dACC and posterior cingulate cortex and greater static functional connectivity between VLPFC and inferior parietal lobule were associated with greater placebo response. Conclusion:Placebo response is associated with a distinct dynamic and static connectivity fingerprint characterized by "variable" dynamic but "weak" static connectivity in the salience, default mode, frontoparietal, and ventral attention networks. These data provide granular evidence of how circuit-based biotypes mechanistically relate to placebo response. Finding biosignatures that predict placebo response is critically important in clinical psychopharmacology and to improve our ability to detect medication-placebo differences in clinical trials.
RCT Entities:
Objectives: Placebo response is one of the most significant barriers to detecting treatment effects in pediatric (and adult) clinical trials focusing on affective and anxiety disorders. We sought to identify neurofunctional predictors of placebo response in adolescents with generalized anxiety disorder (GAD) by examining dynamic and static functional brain connectivity. Methods: Before randomization to blinded placebo, adolescents, aged 12-17 years, with GAD (N = 25) underwent resting state functional magnetic resonance imaging. Whole brain voxelwise correlation analyses were used to determine the relationship between change in anxiety symptoms from baseline to week 8 and seed-based dynamic and static functional connectivity maps of regions in the salience and ventral attention networks (amygdala, dorsal anterior cingulate cortex [dACC], and ventrolateral prefrontal cortex [VLPFC]). Results: Greater dynamic functional connectivity variability in amygdala, dACC, VLPFC, and regions within salience, default mode, and frontoparietal networks was associated with greater placebo response. Lower static functional connectivity between amygdala and dorsolateral prefrontal cortex, amygdala and medial prefrontal cortex, dACC and posterior cingulate cortex and greater static functional connectivity between VLPFC and inferior parietal lobule were associated with greater placebo response. Conclusion: Placebo response is associated with a distinct dynamic and static connectivity fingerprint characterized by "variable" dynamic but "weak" static connectivity in the salience, default mode, frontoparietal, and ventral attention networks. These data provide granular evidence of how circuit-based biotypes mechanistically relate to placebo response. Finding biosignatures that predict placebo response is critically important in clinical psychopharmacology and to improve our ability to detect medication-placebo differences in clinical trials.
Authors: Lu Lu; Hailong Li; William T Baumel; Jeffrey A Mills; Kim M Cecil; Heidi K Schroeder; Sarah A Mossman; Xiaoqi Huang; Qiyong Gong; John A Sweeney; Jeffrey R Strawn Journal: Neuropsychopharmacology Date: 2021-09-27 Impact factor: 8.294