Ketamine and Attentional Bias Toward Emotional Faces: Dynamic Causal Modeling of Magnetoencephalographic Connectivity in Treatment-Resistant Depression

Abstract

The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (TRD) and bipolar disorder. While its underlying mechanism of antidepressant action is not fully understood, modulating glutamatergically-mediated connectivity appears to be a critical component moderating antidepressant response. This double-blind, crossover, placebo-controlled study analyzed data from 19 drug-free individuals with TRD and 15 healthy volunteers who received a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg) as well as an intravenous infusion of saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6-9 h after both drug and placebo infusions. During scanning, participants completed an attentional dot probe task that included emotional faces. Antidepressant response was measured across time points using the Montgomery-Asberg Depression Rating Scale (MADRS). Dynamic causal modeling (DCM) was used to measure changes in parameter estimates of connectivity via a biophysical model that included realistic local neuronal architecture and receptor channel signaling, modeling connectivity between the early visual cortex, fusiform cortex, amygdala, and inferior frontal gyrus. Clinically, ketamine administration significantly reduced depressive symptoms in TRD participants. Within the model, ketamine administration led to faster gamma aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) transmission in the early visual cortex, faster NMDA transmission in the fusiform cortex, and slower NMDA transmission in the amygdala. Ketamine administration also led to direct and indirect changes in local inhibition in the early visual cortex and inferior frontal gyrus and to indirect increases in cortical excitability within the amygdala. Finally, reductions in depressive symptoms in TRD participants post-ketamine were associated with faster α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) transmission and increases in gain control of spiny stellate cells in the early visual cortex. These findings provide additional support for the GABA and NMDA inhibition and disinhibition hypotheses of depression and support the role of AMPA throughput in ketamine's antidepressant effects. Clinical Trial Registration: https://ichgcp.net/clinical-trials-registry/NCT00088699?term=NCT00088699&draw=2&rank=1, identifier NCT00088699.

Keywords: amygdala; dynamic causal modeling; ketamine; magnetoencephalography; major depressive disorder.

Conflict of interest statement

CZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R) -hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Gilbert, Galiano, Nugent and Zarate.

Figures

Figure 1

Gamma power and dynamic causal modeling (DCM). (A) A network of regions showed robust increases in induced gamma power during the task. These included the bilateral early visual cortex, bilateral fusiform cortex, and bilateral inferior frontal gyrus. When directly testing the effect of infusion, higher induced gamma power was found in the left amygdala for the ketamine infusion. (B) The default CMM_NMDA model includes four distinct intrinsic (within region) cell layers: superficial pyramidal cells, spiny stellate cells, inhibitory interneurons, and deep pyramidal cells [adapted from Gilbert et al. (57)]. Intrinsic excitatory connections were mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors while intrinsic inhibitory connections were mediated by gamma aminobutyric acid (GABA) receptors. Each cell population included a self-gain parameter that reflected precision for each cell type. Each receptor also included distinct time constants and dynamics in the model. Between regions, superficial pyramidal cells carry forward extrinsic signals to excitatory spiny stellate cells. Deep pyramidal cells carry backward extrinsic signals to both superficial pyramidal cells and inhibitory interneurons.

Figure 2

Models of connectivity, winning model, and example model fits. (A) Two plausible models were constructed to account for message passing between the early visual cortex (EV), fusiform cortex (Fusi), amygdala (Amy), and inferior frontal gyrus (IFG). Model 1 included reciprocal forward and backward connections from the EV to the Fusi, from the Fusi to the Amy, and from the Amy to the IFG. Model 2 included a direct, reciprocal, forward and backward connection from the EV to the IFG. (B) Bayesian Model Selection (BMS) was used to adjudicate between models, demonstrating that Model 2, with fully interconnected feedforward and feedback connections between each region, had the greatest exceedance probability. RFX, random effects. (C) Example evoked responses (left) and model fits (right) for a healthy volunteer (HV, top) and participant with treatment-resistant major depressive disorder (MDD) (bottom).

Figure 3

Meaningful parameters showing group by drug interactions. The estimated log mean and variance of each meaningful (95% probability or greater) parameter are plotted for participants with treatment-resistant major depressive disorder (MDD) (left) and healthy volunteers (HV) (right) for: (A) the four receptor time constants showing group by drug interactions, and (B) the five intrinsic connectivity parameters showing group by drug interactions. IFG, inferior frontal gyrus, C, baseline/placebo sessions, K, ketamine session, ss, spiny stellate cells; ii, inhibitory interneurons; sp, superficial pyramidal cells; dp, deep pyramidal cells.

Figure 4

Parameter change and antidepressant response. Two parameters showed a significant association between change from baseline (B) to ketamine (K) sessions and associated changes in Montgomery-Asberg Depression Rating Scale (MADRS) scores (B–K). ss, spiny stellate cells; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.