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


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.

Download full-text


Available from: Heinz Boeker,
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Social neuroscience 07/2015; DOI:10.1080/17470919.2015.1072582 · 2.66 Impact Factor
    • "Ketamine, a dissociative anesthetic at high doses, acts as an N-methyl-D-aspartate (NMDA) receptor antagonist. At lower, subanesthetic doses, ketamine is widely used in both species to investigate mechanisms underlying psychosis and, more recently, as a potential rapid onset antidepressant (Diamond et al. 2014; Niciu et al. 2014; Salvadore et al. 2010; Scheidegger et al. 2012; Vollenweider et al. 1997; Zarate et al. 2013). "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Accumulating evidence suggests that early improvement after two-week antidepressant treatment is predictive of later outcomes of patients with major depressive disorder (MDD); however, whether this early improvement is associated with baseline neural architecture remains largely unknown. Utilizing resting-state functional MRI data and graph-based network approaches, this study calculated voxel-wise degree centrality maps for 24 MDD patients at baseline and linked them with changes in the Hamilton Rating Scale for Depression (HAMD) scores after two weeks of medication. Six clusters exhibited significant correlations of their baseline degree centrality with treatment-induced HAMD changes for the patients, which were mainly categorized into the posterior default-mode network (i.e., the left precuneus, supramarginal gyrus, middle temporal gyrus, and right angular gyrus) and frontal regions. Receiver operating characteristic curve and logistic regression analyses convergently revealed excellent performance of these regions in discriminating the early improvement status for the patients, especially the angular gyrus (sensitivity and specificity of 100%). Moreover, the angular gyrus was identified as the optimal regressor as determined by stepwise regression. Interestingly, these regions possessed higher centrality than others in the brain (P < 10(-3) ) although they were not the most highly connected hubs. Finally, we demonstrate a high reproducibility of our findings across several factors (e.g., threshold choice, anatomical distance, and temporal cutting) in our analyses. Together, these preliminary exploratory analyses demonstrate the potential of neuroimaging-based network analysis in predicting the early therapeutic improvement of MDD patients and have important implications in guiding earlier personalized therapeutic regimens for possible treatment-refractory depression. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Human Brain Mapping 04/2015; 36(8). DOI:10.1002/hbm.22817 · 5.97 Impact Factor
Show more