Triple-network model-based graph theory analysis of the effectiveness of low-dose ketamine in patients with treatment-resistant depression: two resting-state functional MRI clinical trials.

Dysfunction in the default mode, salience, and frontoparietal networks—the triple network model—may underlie treatment-resistant depression. Analyzing resting-state functional connectivity MRI data from two clinical trials, researchers found that a single low-dose ketamine infusion altered network properties. In one trial, ketamine changed degree centrality and cluster coefficient in the right posterior cingulate cortex (default mode network) and cluster coefficient in the right supramarginal gyrus (salience network), compared to saline. In another trial, ketamine altered characteristic path length in the left posterior cingulate cortex (default mode network) compared to midazolam. A time effect on cluster coefficient in the right dorsolateral prefrontal cortex (frontoparietal network) appeared for both ketamine and saline. These findings suggest the triple-network model helps explain ketamine's antidepressant effects.

Study at a glance

Abstract

Evidence suggests the crucial role of dysfunctional default mode (DMN), salience and frontoparietal (FPN) networks, collectively termed the triple network model, in the pathophysiology of treatment-resistant depression (TRD). Using the graph theory- and seed-based functional connectivity analyses, we attempted to elucidate the role of low-dose ketamine in the triple networks, namely the DMN, salience and FPN. Resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) data derived from two previous clinical trials of a single, low-dose ketamine infusion were analysed. In clinical trial 1 (Trial 1), patients with TRD were randomised to either a ketamine or normal saline group, while in clinical trial 2 (Trial 2) those patients with TRD and pronounced suicidal symptoms received a single infusion of either 0.05 mg/kg ketamine or 0.045 mg/kg midazolam. All participants underwent rs-fcMRI pre and post infusion at Day 3. Both graph theory- and seed-based functional connectivity analyses were performed independently. Trial 1 demonstrated significant group-by-time effects on the degree centrality and cluster coefficient in the right posterior cingulate cortex (PCC) cortex ventral 23a and b (DMN) and the cluster coefficient in the right supramarginal gyrus perisylvian language (salience). Trial 2 found a significant group-by-time effect on the characteristic path length in the left PCC 7Am (DMN). In addition, both ketamine and normal saline infusions exerted a time effect on the cluster coefficient in the right dorsolateral prefrontal cortex a9-46v (FPN) in Trial 1. These findings may support the utility of the triple-network model in elucidating ketamine's antidepressant effect. Alterations in DMN, salience and FPN function may underlie this effect.