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

Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 06/2010; 35(7):1415-22. DOI: 10.1038/npp.2010.24
Source: PubMed


Pregenual anterior cingulate cortex (pgACC) hyperactivity differentiates treatment responders from non-responders to various pharmacological antidepressant interventions, including ketamine, an N-methyl-D-aspartate 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. This study tested the hypothesis that during the N-back task, a widely used working memory paradigm, low pretreatment pgACC activity, as well as coherence between the pgACC and the amygdala, would be correlated with the clinical improvement after ketamine. Magnetoencephalography (MEG) recordings were obtained from 15 drug-free patients with MDD during working memory performance 1 to 3 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 4 h of ketamine administration (r=0.82, p=0.0002, false discovery rate (FDR) <0.05). Pretreatment 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.

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    • "While we cannot quantitatively align the human and rat exposure-response relationships, the ketamine-induced hyperconnectivity in both species was comparable at different, species-specific, dose and exposure levels. Whereas humans received racemic ketamine (mixture of S(+) and R(−) enantiomers) according to a well-established protocol (Salvadore et al. 2010), rats received S-ketamine, the S(+)-enantiomer of ketamine which is discussed as the main compound responsible for the NMDA-antagonistic effect . As both R-and S-ketamine exhibit a voltage-and usedependent blockade of NMDA receptor currents in cell culture (Zeilhofer et al. 1992), there is no evidence of a strong difference between the effect of racemic or S-ketamine. "
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    ABSTRACT: Aberrant prefrontal-hippocampal (PFC-HC) connectivity is disrupted in several psychiatric and at-risk conditions. Advances in rodent functional imaging have opened the possibility that this phenotype could serve as a translational imaging marker for psychiatric research. Recent evidence from functional magnetic resonance imaging (fMRI) studies has indicated an increase in PFC-HC coupling during working-memory tasks in both schizophrenic patients and at-risk populations, in contrast to a decrease in resting-state PFC-HC connectivity. Acute ketamine challenge is widely used in both humans and rats as a pharmacological model to study the mechanisms of N-methyl-D-aspartate (NMDA) receptor hypofunction in the context of psychiatric disorders. We aimed to establish whether acute ketamine challenge has consistent effects in rats and humans by investigating resting-state fMRI PFC-HC connectivity and thus to corroborate its potential utility as a translational probe. Twenty-four healthy human subjects (12 females, mean age 25 years) received intravenous doses of either saline (placebo) or ketamine (0.5 mg/kg body weight). Eighteen Sprague-Dawley male rats received either saline or ketamine (25 mg/kg). Resting-state fMRI measurements took place after injections, and the data were analyzed for PFC-HC functional connectivity. In both species, ketamine induced a robust increase in PFC-HC coupling, in contrast to findings in chronic schizophrenia. This translational comparison demonstrates a cross-species consistency in pharmacological effect and elucidates ketamine-induced alterations in PFC-HC coupling, a phenotype often disrupted in pathological conditions, which may give clue to understanding of psychiatric disorders and their onset, and help in the development of new treatments.
    Psychopharmacology 07/2015; 232(21-22). DOI:10.1007/s00213-015-4022-y · 3.88 Impact Factor
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    • "The need to improve upon current treatment options is clear, and the identification of biomarkers of response, particularly in a human biomarker of rapid antidepressant effect paradigm (Zarate et al., 2013), will facilitate this goal. Functional brain imaging has been used successfully to discriminate between treatment responders and nonresponders (Korb et al., 2009; Salvadore et al., 2010; Furey et al., 2013) and to begin to characterize pretreatment, brain-based differences among patients that reflect the potential to respond to specific treatments. These findings indicate that biological variables underlie the clinical variability associated with treatment response, supporting the concept that a more personalized approach to treatment has the potential to be successful. "
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    ABSTRACT: Faster acting antidepressants and biomarkers that predict treatment response are needed to facilitate the development of more effective treatments for patients with major depressive disorders (MDD). Here we evaluate implicitly and explicitly processed emotional faces using neuroimaging to identify potential biomarkers of treatment response to the antimuscarinic, scopolamine. Healthy participants (n=15) and unmedicated-depressed MDD patients (n=16) participated in a double-blind, placebo-controlled crossover infusion study using scopolamine (4ug/kg). Before and following scopolamine, blood oxygen-level dependent (BOLD) signal was measured using fMRI during a selective attention task. Two stimuli comprised of superimposed pictures of faces and houses were presented. Participants attended to one stimulus component and performed a matching task. Face emotion was modulated (happy/sad) creating implicit (attend-houses) and explicit (attend-faces) emotion processing conditions. The pre-treatment difference in BOLD response to happy and sad faces under implicit and explicit conditions (emotion processing biases) within a-priori regions-of-interest (ROIs), was correlated with subsequent treatment response in MDD. Correlations were observed exclusively during implicit emotion processing in the ROIs, which included the subgenual anterior cingulate (sgACC) (p<0.02) and middle occipital cortices (MOC) (p<0.02). The magnitude and direction of differential BOLD response to implicitly processed emotional faces prior to treatment reflect the potential to respond to scopolamine. These findings replicate earlier results, highlighting the potential for pre-treatment neural activity in the MOC and sgACC to inform us about the potential to respond clinically to scopolamine. Published by Oxford University Press on behalf of CINP 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
    The International Journal of Neuropsychopharmacology 03/2015; 18(8). DOI:10.1093/ijnp/pyv028 · 4.01 Impact Factor
    • "Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, has shown to produce a rapid and efficacious antidepressant response within hours of a 0.5 mg/kg intravenous dose and maintained throughout the following week post-infusion (Carlson et al., 2013; Diazgranados et al., 2010a, 2010b; Zarate et al., 2010). Research efforts have focused on replicating data in both MDD and bipolar depression, alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms, and understanding the neural basis for antidepressant action as well as its effect on neurocognition (Carlson et al., 2013; Ibrahim et al., 2011; Murrough, 2012; Nugent et al., 2014; Salvadore et al., 2010; Zarate et al., 2012). Electroconvulsive therapy (ECT) has consistently been shown to be the most efficacious treatment for patients with severe MDD (Berlim et al., 2014; George et al., 1995; Heijnen et al., 2010; Nahas et al., 2005; Pagnin et al., 2004; Rush et al., 2005). "
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    ABSTRACT: Despite a wide variety of therapeutic interventions for major depressive disorder (MDD), treatment resistant depression (TRD) remains to be prevalent and troublesome in clinical practice. In recent years, deep brain stimulation (DBS) has emerged as an alternative for individuals suffering from TRD not responding to combining antidepressants, multiple adjunctive strategies and electroconvulsive therapy (ECT). Although the best site for TRD-DBS is still unclear, pilot data suggests that the medial forebrain bundle (MFB) might be a key target to accomplish therapeutic efficacy in TRD patients. To explore the anatomic, electrophysiologic, neurocognitive and treatment data supporting the MFB as a target for TRD-DBS. The MFB connects multiple targets involved in motivated behavior, mood regulation and antidepressant response. Specific phenomenology associated with TRD can be linked specifically to the superolateral branch (sl) of the MFB (slMFB). TRD patients who received DBS-slMFB reported high response/remission rates with an improvement in functioning and no significant adverse outcomes in their physical health or neurocognitive performance. Discussion The slMFB is an essential component of a network of structural and functional pathways connecting different areas possibly involved in the pathogenesis of mood disorders. Therefore, the slMFB should be considered as an exciting therapeutic target for DBS therapy to achieve a sustained relief in TRD patients. There is an urgent need for clinical trials exploring DBS-slMFB in TRD. Further efforts should pursue measuring baseline pro-inflammatory cytokines, oxidative stress, and cognition as possible biomarkers of DBS-slMFB response in order to aid clinicians in better patient selection. Copyright © 2014 Elsevier Inc. All rights reserved.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 12/2014; 58. DOI:10.1016/j.pnpbp.2014.12.003 · 3.69 Impact Factor
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