Anterior Cingulate Desynchronization and Functional Connectivity with the Amygdala During a Working Memory Task Predict Rapid Antidepressant Response to Ketamine

Abstract

Pregenual anterior cingulate (pgACC) hyperactivity differentiates treatment responders from non-responders to various pharmacological antidepressant interventions, including ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist. Evidence of pgACC hyperactivition during non-emotional working memory tasks in patients with major depressive disorder (MDD) highlights the importance of this region for processing both emotionally-salient and cognitive stimuli. However, it is unclear whether pgACC activity might serve as a potential biomarker of antidepressant response during working memory tasks as well, in line with previous research with emotionally-arousing tasks. The present study tested the hypothesis that during the N-back task, a widely-used working memory paradigm, low pre-treatment pgACC activity, as well as coherence between the pgACC and the amygdala, would be correlated with the clinical improvement following ketamine. Magnetoencephalography (MEG) recordings were obtained from 15 drug-free patients with MDD during working memory performance one to three days before receiving a single ketamine infusion. Functional activation patterns were analyzed using advanced MEG source analysis. Source coherence analyses were conducted to quantify the degree of long-range functional connectivity between the pgACC and the amygdala. Patients who showed the least engagement of the pgACC in response to increased working memory load showed the greatest symptomatic improvement within four hours of ketamine administration (r = 0.82, p = 0.0002, FDR < 0.05). Pre-treatment functional connectivity between the pgACC and the left amygdala was negatively correlated with antidepressant symptom change (r = −0.73, p = 0.0021, FDR <0.05). These data implicate the pgACC and its putative interaction with the amygdala in predicting antidepressant response to ketamine in a working memory task context.

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

“…This would also correspond to the time when ketamine increases levels of glutamate [47], which could underlie the increased activity observed in the FST. As pointed out by the authors [46], rapamycin would not be expected to block the effects of ketamine at this time point since the induction of synaptic proteins and synaptogenesis is delayed by approximately 2 h. This later time point corresponds more closely to the initial antidepressant response observed in depressed patients [36,40].…”

“…This is critical as mTOR is expressed in neuronal and glial cell bodies, which could mask changes in the smaller dendritic compartment. Second, the behavioural analysis was conducted 30 min after ketamine administration, when ketamine levels are still high in brain and corresponds to the time when patients experience mild psychotomimetic and dissociative effects of ketamine [36,40]. This would also correspond to the time when ketamine increases levels of glutamate [47], which could underlie the increased activity observed in the FST.…”

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

“…It has been suggested that the psychotropic effects of ketamine might also be related to alterations in the connectivity between specific brain regions, which has been demonstrated both in animal (Bolton et al, 2012) and in human studies (Salvadore et al, 2010).…”

Psychiatric Stress Testing: Novel Strategy for Translational Psychopharmacology

“…Information processing by these circuits following such a provocative load can then be quantified using various imaging (Fineberg et al, 2010;Stahl, 2008;Bush et al, 2005) or electrophysiological techniques (Salvadore et al, 2009(Salvadore et al, , 2010. The N-back cognitive load, for example, is a 'stress test' generally used to tax the functioning of the dorsolateral prefrontal cortex (DLPFC); the Stroop task tests the function of the dorsal anterior cingulate cortex; facial expressions test the amygdala and perigenual anterior cingulate cortex (pgACC); gambling tasks test the orbital frontal cortex; and so on (Salvadore et al, 2009(Salvadore et al, , 2010Fineberg et al, 2010;Stahl, 2008;Bush et al, 2005). The reaction of a brain circuit to the specific load placed upon it can be used as a measure of the efficiency of information processing in that brain circuit.…”

“…The study of Salvadore et al (2010) provides a glimpse into how such 'psychiatric stress tests' may also translate into predictors of who will respond to a specific drug.…”