Greater Dynamic and Lower Static Functional Brain Connectivity Prospectively Predict Placebo Response in Pediatric Generalized Anxiety Disorder

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.

Keywords: anxiety disorder; functional connectivity; neuroimaging; placebo.

Conflict of interest statement

Dr. Strawn has received research support from Allergan, Neuronetics, Lundbeck, Otsuka and the National Institutes of Health. He receives royalties from Springer Publishing for two texts and has received material support from Myriad. He has consulted to the Food and Drug Administration and Myriad Genetics. Dr. Mills has received research support from the Yung Family Foundation and Dr. Cecil receives support from National Institute of Environmental Health Sciences (R01 ES027224, K.M.C.). Dr. DelBello receives research support from NIH, PCORI, Acadia, Allergan, Janssen, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, and Sunovion. She is also a consultant, on the advisory board, or has received honoraria for speaking for Alkermes, Allergan, Assurex, CMEology, Janssen, Johnson and Johnson, Lundbeck, Myriad, Neuronetics, Otsuka, Pfizer, Sunovion, and Supernus. The remaining authors have nothing to disclose. The views expressed within this article represent those of the authors and are not intended to represent the position of NIMH, NICHD, the National Institutes of Health (NIH), or the Department of Health and Human Services.

Figures

FIG. 1.

Increased dynamic FC associated with placebo response in adolescents with generalized anxiety disorder. For each seed (left column, red) significant whole-brain dynamic FC associations are shown (middle column). Placebo response (right column) was associated with decreased dynamic FC between the left amygdala and left IPL, between the left amygdala and right insula, and between the left amygdala and right angular (A). For the right amygdala, placebo response was associated with decreased dynamic FC to the left fusiform (B). Placebo response was also associated with decreased dynamic FC between left dACC and left angular gyrus (C), between the right dACC and left mPFC (D), and between the left VLPFC and IPL (E). dACC, dorsal anterior cingulate cortex; FC, functional connectivity; IPL, inferior parietal lobule; mPFC, medial prefrontal cortex; VLPFC, ventrolateral prefrontal cortex. Color images are available online.

FIG. 1.

Increased dynamic FC associated with placebo response in adolescents with generalized anxiety disorder. For each seed (left column, red) significant whole-brain dynamic FC associations are shown (middle column). Placebo response (right column) was associated with decreased dynamic FC between the left amygdala and left IPL, between the left amygdala and right insula, and between the left amygdala and right angular (A). For the right amygdala, placebo response was associated with decreased dynamic FC to the left fusiform (B). Placebo response was also associated with decreased dynamic FC between left dACC and left angular gyrus (C), between the right dACC and left mPFC (D), and between the left VLPFC and IPL (E). dACC, dorsal anterior cingulate cortex; FC, functional connectivity; IPL, inferior parietal lobule; mPFC, medial prefrontal cortex; VLPFC, ventrolateral prefrontal cortex. Color images are available online.

FIG. 2.

Static FC signatures associated with placebo response in adolescents with generalized anxiety disorder. For each seed (left column, red) significant, whole-brain static FC associations are shown (right column). (A). For the dACC (B), placebo response was associated with increased static FC to the PCC and for the VLPFC (C), placebo response was associated with decreased static FC to the IPL. dACC, dorsal anterior cingulate cortex; FC, functional connectivity; IPL, inferior parietal lobule; PCC, posterior cingulate cortex; VLPFC, ventrolateral prefrontal cortex. Color images are available online.