Magnetoencephalographic Correlates of Suicidal Ideation in Major Depression

Abstract

Background: Defining the neurobiological underpinnings of suicidal ideation (SI) is crucial to improving our understanding of suicide. This study used magnetoencephalographic gamma power as a surrogate marker for population-level excitation-inhibition balance to explore the underlying neurobiology of SI and depression. In addition, effects of pharmacological intervention with ketamine, which has been shown to rapidly reduce SI and depression, were assessed.

Methods: Data were obtained from 29 drug-free patients with major depressive disorder who participated in an experiment comparing subanesthetic ketamine (0.5 mg/kg) with a placebo saline infusion. Magnetoencephalographic recordings were collected at baseline and after ketamine and placebo infusions. During scanning, patients rested with their eyes closed. SI and depression were assessed, and a linear mixed-effects model was used to identify brain regions where gamma power and both SI and depression were associated. Two regions of the salience network (anterior insula, anterior cingulate) were then probed using dynamic causal modeling to test for ketamine effects.

Results: Clinically, patients showed significantly reduced SI and depression after ketamine administration. In addition, distinct regions in the anterior insula were found to be associated with SI compared with depression. In modeling of insula-anterior cingulate connectivity, ketamine lowered the membrane capacitance for superficial pyramidal cells. Finally, connectivity between the insula and anterior cingulate was associated with improvements in depression symptoms.

Conclusions: These findings suggest that the anterior insula plays a key role in SI, perhaps via its role in salience detection. In addition, transient changes in superficial pyramidal cell membrane capacitance and subsequent increases in cortical excitability might be a mechanism through which ketamine improves SI.

Trial registration: ClinicalTrials.gov NCT00088699.

Keywords: Depression; Gamma; Insula; Ketamine; Magnetoencephalography; Suicidal ideation.

Conflict of interest statement

Disclosures

Dr. Zarate 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. All other authors report no biomedical financial interests or potential conflict of interests.

Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. Study Design and Clinical Outcomes.

A) The study included a double-blind, placebo-controlled, crossover design. During Phase I, patients tapered off their medications and completed a 14-day drug-free period prior to entering Phase II. A baseline (BL) MEG recording was collected during this time-period (specifically, 2 to 4 days prior to the first infusion). During Phase II, patients received both ketamine (KET) and placebo saline (PCB) infusions, with a 14-day period between crossover. MEG recordings were collected 6–9 hours following each infusion. B) Clinically, patients showed significant reductions in suicidal ideation and depression scores following ketamine administration compared to baseline. In addition, patients showed significant reductions in depression scores between the ketamine and placebo sessions.

Figure 2.. Gamma Power and Suicidal Ideation and Depression.

Images of normalized, root mean square gamma power (30–50 Hz) estimates associated with suicidal ideation (SI) and depression (MADRS – without SI) from the linear mixed-effects model are superimposed on a high-resolution structural scan. Images are thresholded at pFDR<0.05. A network of regions centered in the insular cortex showed associations with SI scores, while a more dorsal, distributed network of regions showed associations with MADRS (without SI) scores in our patients. In addition, within insular cortex, bilateral anterior regions showed significant associations with SI, while more dorsal, posterior (and left-lateralized) regions were associated with MADRS (without SI) scores.

Figure 3.. Models of Connectivity: Insula to Anterior Cingulate.

A). The CMM_NMDA model includes four distinct cell layers: superficial pyramidal cells, spiny stellates, inhibitory interneurons, and deep pyramidal cells. Forward connections originate from superficial pyramidal cells to excitatory spiny stellate cells, while backward connections originate from deep pyramidal cells to both superficial pyramidal cells and inhibitory interneurons. B) We constructed three plausible models of message-passing between insula (IN) and anterior cingulate (AC). Model 1 included lateral connections between IN and AC, while Model 2 included feedforward connections from IN to AC and feedback connections from AC to IN, and Model 3 included feedforward connections from AC to IN and feedback connections from IN to AC. C) Bayesian Model Selection (BMS) was used to adjudicate between models, demonstrating that Model 1 with fully interconnected feedforward and feedback connections between each region had the largest exceedance probability.

Figure 4.. Model Fits.

A) Spectral densities from Model 1 for the insula and anterior cingulate from the baseline (BL), placebo (PCB), and ketamine (KET) sessions for three example subjects. Solid lines indicate the data, while dashed lines represent the model fit. B) Model fits were compared across sessions in terms of the percent of the variance explained. No biasing in model fits was found between sessions.

Figure 5.. AMPA Connectivity and Depression.

We compared NMDA and AMPA extrinsic connectivity estimates following ketamine (KET) administration with changes in both suicidal ideation (SI) and depression (MADRS – without SI) scores. Only MADRS (without SI) scores showed an association with connectivity – lower AMPA connectivity for the backward connection from insula to anterior cingulate was associated with lower depression symptomatology.