Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action

Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland
PLoS ONE (Impact Factor: 3.23). 09/2012; 7(9):e44799. DOI: 10.1371/journal.pone.0044799
Source: PubMed

ABSTRACT Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the "dorsal nexus "(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.

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Available from: Heinz Boeker, Sep 01, 2015
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    • "Although inhibitory GABA has recently been shown to mediate EEG task-evoked measures like gamma band oscillations (Muthukumaraswamy et al. 2009, 2013; Lally et al. 2014; Barr et al., 2013), studies on excitatory glutamate modulation of EEG measures have been reported less widely (for exceptions, see Lally et al. 2014; for animal studies, see Morales-Villagrán et al., 2008). Glutamate is an excitatory transmitter that fMRI and MRS analyses have shown to mediate resting state activity, including both intra-regional activity levels and trans-regional functional levels (Enzi et al. 2012; Duncan et al., 2011, 2013; also see Falkenberg et al., 2012; Scheidegger, 2012). Such glutamatergic modulation of the resting state suggests that glutamate might mediate the influence of pre-stimulus state activity on stimulus-related activity. "
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    ABSTRACT: Recent studies have demonstrated neural overlap between resting state activity and self-referential processing. This "rest-self" overlap occurs especially in anterior cortical midline structures like the perigenual anterior cingulate cortex (PACC). However, the exact neuro-temporal and biochemical mechanisms remain to be identified. Therefore, we conducted a combined EEG-MRS study. EEG focused on pre-stimulus (e.g., prior to stimulus presentation or perception) power changes to assess the degree to which those changes can predict subjects' perception (and judgment) of subsequent stimuli as high or low self-related. Magnetic resonance spectroscopy (MRS) measured resting state concentration of glutamate, focusing on PACC. High pre-stimulus (e.g., prior to stimulus presentation or perception) alpha power significantly correlated with both perception of stimuli judged to be highly self-related, and with resting state glutamate concentrations in the PACC. In sum, our results show (i) pre-stimulus (e.g., prior to stimulus presentation or perception) alpha power and resting state glutamate concentration to mediate rest-self overlap which (ii) dispose or incline subjects to assign high degrees of self-relatedness to perceptual stimuli.
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    • "Particularly, this technique provides a promising tool to map intrinsic functional connectome of the human brain [Van Dijk et al., 2010; Wang et al., 2010], whose architectures are consistently reported to be disrupted in MDD [Greicius et al., 2007; Sheline et al., 2010; Zhang et al., 2011] and, more importantly, provide object biomarkers for the diagnosis of the disease [Zeng et al., 2012]. Furthermore , a growing body of evidence has shown that antidepressant drugs could significantly reverse MDDrelated disruptions of network connectivity in healthy brains [McCabe et al., 2011; Scheidegger et al., 2012]. These findings collectively suggest that a network analysis of R-fMRI data is promising to address the issue of interest in the current study. "
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    • "Adults with early life stress, but without psychiatric illness, have demonstrated reduced DMN connectivity compared with healthy controls (Philip et al., 2013), suggesting that avoiding the process of selfreferential rumination may be a stress coping mechanism. One mechanism by which Ketamine, an NMDA antagonist with antidepressant properties, may exert its effects is by decoupling DMN connectivity with the dorsal nexus (Scheidegger et al., 2012). CT may increase subgenual cingulate and MPFC reactivity to positive stimuli, while attenuating reactivity to negative stimuli, a neural activity change that accounts for reductions in depressive symptoms (Yoshimura et al., 2014). "
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