Salience Network Functional Connectivity Predicts Placebo Effects in Major Depression

Abstract

Background: Recent neuroimaging studies have demonstrated resting-state functional connectivity (rsFC) abnormalities among intrinsic brain networks in Major Depressive Disorder (MDD); however, their role as predictors of treatment response has not yet been explored. Here, we investigate whether network-based rsFC predicts antidepressant and placebo effects in MDD.

Methods: We performed a randomized controlled trial of two weeklong, identical placebos (described as having either "active" fast-acting, antidepressant effects or as "inactive") followed by a ten-week open-label antidepressant medication treatment. Twenty-nine participants underwent a rsFC fMRI scan at the completion of each placebo condition. Networks were isolated from resting-state blood-oxygen-level-dependent signal fluctuations using independent component analysis. Baseline and placebo-induced changes in rsFC within the default-mode, salience, and executive networks were examined for associations with placebo and antidepressant treatment response.

Results: Increased baseline rsFC in the rostral anterior cingulate (rACC) within the salience network, a region classically implicated in the formation of placebo analgesia and the prediction of treatment response in MDD, was associated with greater response to one week of active placebo and ten weeks of antidepressant treatment. Machine learning further demonstrated that increased salience network rsFC, mainly within the rACC, significantly predicts individual responses to placebo administration.

Conclusions: These data demonstrate that baseline rsFC within the salience network is linked to clinical placebo responses. This information could be employed to identify patients who would benefit from lower doses of antidepressant medication or non-pharmacological approaches, or to develop biomarkers of placebo effects in clinical trials.

Keywords: Major Depression; biomarkers of treatment response; large-scale connectivity networks; placebo effects; resting-state functional connectivity.

Figures

Figure 1. Experimental Design

A) After pre-randomization (screening), subjects are randomized into one of two conditions each lasting seven days: 1) Active: placebo administration with disclosure that it may provide antidepressant-like treatment effects; 2) Inactive: placebo administration with disclosure that it is an inactive agent. B) A three day washout occurs during which the patient receives no medication. C) Subjects cross-over to the alternative condition. D) Resting-state fMRI scans are obtained immediately after each condition. E) After full completion of the placebo trial, subjects undergo ten weeks of open-label antidepressant treatment. Depression measures are administered (* marks QIDS-16SR administration) at pre-randomization, pre- and post-active, pre- and post-inactive, and week 0, 2, 4, 8, 10 of the antidepressant trial.

Figure 2. Functional Connectivity of Networks

One-sample t-tests including baseline (inactive condition) resting-state fMRI scans for all 29 subjects for each ICA-component corresponding to the network: A) Default-mode, B) Salience, C) Left (left-side) and right (right-side) executive networks. The t-score bars are shown at the right; all images are displayed at a threshold of p

Figure 3. Baseline Functional Connectivity of the Salience Network Predicts Response to Placebo Administration

N=29. (Top left and right): Voxel-by-voxel correlational analysis between baseline functional connectivity of the SN and decreases in depression symptoms in response to placebo administration. Clusters passing significance threshold are labeled. Image display is at p

Figure 4. Multivariate Relevance Vector Regression

Left: Mean predictor map with an arbitrary threshold of >50% of minimum and maximum voxel weight values. The map shows the relative contribution of each voxel to the regression function in relation to all other voxels. Color bar signifies weight value for all voxels. Right: Scatter plot showing the predicted placebo response value derived from each subject’s baseline SN functional connectivity using RVR leave-one-out cross validation versus their actual placebo response value (r = 0.41; p-value = 0.018).