Article

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.

Full-text

Available from: Heinz Boeker
Ketamine Decreases Resting State Functional Network
Connectivity in Healthy Subjects: Implications for
Antidepressant Drug Action
Milan Scheidegger
1,2
*
.
, Martin Walter
3,4,5
*, Mick Lehmann
1
, Coraline Metzger
3,5
, Simone Grimm
2,6,7
,
Heinz Boeker
2
, Peter Boesiger
1,9
, Anke Henning
1,8
, Erich Seifritz
2,8,9
1 Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland, 2 Clinic of Affective Disorders and General Psychiatry, Psychiatric University Hospital,
Zurich, Switzerland, 3 Department of Psychiatry, Otto-von-Guericke University, Mag deburg, Germany, 4 Department of Behavioral Neurology, Leibniz Institute for
Neurobiology, Magdeburg, Germany, 5 Clinical Affective Neuroimaging Laboratory (CANLAB), Center for Behavioral and Brain Sciences, CBBS, Magdeburg, Germany,
6 Cluster Languages of Emotion, Freie Universita
¨
t Berlin, Berlin, Germany, 7 Department of Psychiatry, Charite
´
, CBF, Berlin, Germany, 8 Zurich Center for Integrative Human
Physiology (ZIHP), University of Zurich, Zurich, Switzerland, 9 Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
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.
Citation: Scheidegger M, Walter M, Lehmann M, Metzger C, Grimm S, et al. (2012) Ketamine Decreases Resting State Functional Network Connectivity in Healthy
Subjects: Implications for Antidepressant Drug Action. PLoS ONE 7(9): e447 99. doi:10.1371/journal.pone.0044799
Editor: Stefano L. Sensi, University G. D’Annunzio, Italy
Received April 18, 2012; Accepted August 14, 2012; Published September 24, 2012
Copyright: ß 2012 Scheidegger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Imaging was carried out using an MR scanner financed by the ‘‘highly speci lized medicine’’ grant of the canton of Zurich. The funders had no role in
study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: scheidegger@biomed.ee.ethz.ch (MS); martin.walter@med.ovgu.de (MW)
. These authors contributed equally to this work.
Introduction
Based on the increasing evidence of glutamate-modulating
agents having strong and rapid antidepressant properties [1,2], the
NMDA receptor antagonist ketamine has been firmly established
as a research tool for the investigation of the neurobiology of the
glutamatergic system in major depressive disorder (MDD) and
novel molecular targets associated with rapid onset of antidepres-
sant drug action [3–7]. Although its exact mechanism of action is
still unknown, various neuronal and molecular pathways have
been investigated in animal models and are proposed to critically
mediate its antidepressant effects [8–11]. Here, we aim to
investigate pharmacological changes in functional connectivity in
the healthy human brain as a model for ketamine’s antidepressant
action in order to elucidate its systems level biomechanisms. In the
following sections, we briefly review glutamatergic mechanisms
that are relevant to ketamine’s drug action and that constitute a
theoretical framework for the understanding of the neuronal
adaptations that are accessible by pharmacological resting state
functional magnetic resonance imaging (rsfMRI).
1. The gluta matergic system as a target for
antidepressant intervention
In general, we hypothesize that the therapeutic potential of
ketamine may be explained by reversing disturbances in the
glutamatergic system [12] and thus restore parts of a disrupted
neurobehavioral homeostasis in MDD, where several structural,
metabolic, and functional abnormalities have been described
previously [13–20]. Based on converging evidence from neuroim-
aging, neuropathological, and therapeutic intervention studies, the
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depressed state can be characterized by the tendency to enter and
to remain in an inappropriate mode of information processing in
limbic-cortico-striato-pallido-thalamic circuits that subserve the
regulation of mood [21–23]. Since glutamate is the most abundant
and major excitatory neurotransmitter in the human brain,
pathophysiological changes in glutamatergic signaling associated
with chronic stress exposure and disease progression emerge as a
powerful explanatory framework to integrate the observed findings
into a comprehensive disease model and provide novel molecular
targets for therapeutic interventions [1]. This notion is further
supported by several findings at different levels of neuronal
organization, demonstrating beneficial effects of ketamine on
glutamatergic signaling [24–28], AMPA-to-NMDA-receptor
throughput [11,29], intracellular signaling [8,10], and neuro-
trophic factors [30,31]. In conclusion, those findings indicate that
ketamine may have a stimulating effect on overall glutamate-
glutamine-cycling, which is supposed to be reduced in MDD
[12,17,32].
Multimodal imaging studies combining MR spectroscopy and
fMRI raised the interest for the investigation of the neurochemical
basis of blood oxygen level-dependent (BOLD) signal fluctuations
during activity [17,33,34] and at rest [35,36]. Specifically in
depressed patients, altered negative BOLD responses in the default
mode network (DMN) [37] could be found during emotional
processing tasks [38,39], with decreased negative BOLD signal
amplitudes being positively correlated with lower glutamate
concentrations within the pregenual anterior cingulate cortex
(PACC) [17]. A current investigation by Salvadore et al. (2009)
importantly revealed magnetoencephalographic activation in the
PACC to be predictive of subsequent treatment response to
ketamine in MDD, thus providing a link between ketamine
efficacy and glutamatergic dysfunction in the ACC [40].
Interestingly, altered resting state functional connectivities can be
traced back to specific glutamatergic abnormalities within distinct
neuronal networks in depressed patients as well [35]. In
conclusion, glutamatergic signaling and brain energy metabolism
seem to be altered in MDD and might be reflected in changes of
functional signals up to the systems level and explain some crucial
aspects of depressive symptomatology. Targeting the glutamater-
gic system by glutamate-modulating drugs such as ketamine might
thus hold considerable promise for the development of new
treatments for mood disorders.
2. Resting state functional connectivity as a biological
marker for antidepressant intervention
Recent advances in resting state functional connectivity
neuroimaging techniques suggest their utility for the investigation
of (1) intrinsic brain connections in the healthy human brain, (2)
pathophysiological alterations in disease states and (3) changes in
neuronal network dynamics following therapeutic interventions
[41,42]. The characterization of changes in functional connectivity
between brain networks subserving distinct psychophysiological
functions might explain how various psychiatric symptoms arise
from disrupted connectivities between distinct functional networks.
Several dysfunctions in cortico-limbic neurocircuits [43,44] as well
as task-positive and task-negative systems [45] have been reported
in previous studies of resting state functional connectivity in
depressed patients. Recently, the ’’dorsal nexus’’ (DN) was defined
as a bilateral dorsal medial prefrontal cortex (DMPFC) region
showing dramatically increased depression-associated fMRI con-
nectivity with large portions of the cognitive control network
(CCN), the default mode network (DMN), and affective network
(AN) [46]. Hence, reducing increased connectivity of the DN
might play a critical role in reducing depressive symptomatology
and thus represent a potential therapeutic target for affective
disorders. The hypothesis that decreasing the activity of the DN
might be a potential marker of antidepressant drug intervention
was tested in a recent study in healthy subjects, showing reduced
connectivity between the left DN seed region and the left
hippocampus after selective serotonin reuptake inhibitor (SSRI)
administration (citalopram, 20 mg, given daily for seven days) in a
double-blind placebo-controlled design [47]. Interestingly, in
another study the SSRI citalopram and the selective norepineph-
rine reuptake inhibitor (NARI) reboxetine reduced subcortical-
cortical connectivities between the amygdala and the medial and
orbitofrontal prefrontal cortices [48]. In conclusion, rsfMRI
provides sufficient sensitivity and specificity for clinical applica-
tions including research studies focussing on disease biomarkers
and pharmacological interventions. Recent evidence points to
altered functional connectivity within and between critical
neurocircuits in MDD. Reducing abnormally increased connec-
tivities in those functional networks might represent a general
response pattern to antidepressant drug treatment.
3. Investigating large-scale neural network dynamics
following ketamine administration
Little is known about how ketamine affects large-scale neural
network dynamics in the healthy human brain and whether it has
the potential to restore the aberrant functional connectivities seen
in MDD. Based on previous findings with other antidepressants,
we hypothesized that ketamine at subanaesthetic doses will
decrease the cortico-limbic resting state connectivity in healthy
subjects as a general response pattern. In addition, we aimed to
evaluate the pharmacological effects of ketamine on resting state
connectivities via the DN [46] as a model for antidepressant drug
intervention. To test our hypothesis, we examined 19 healthy
subjects in a randomized, placebo-controlled, double-blind,
crossover study. Every subject underwent four MR scan sessions
including two baseline and two post infusion measurements
24 hours following a subanaesthetic intravenous dose of S-
ketamine, or saline, respectively (Fig. 1). The 24 h follow-up
interval was based on the evidence that ketamine decreases
depressive symptomatology most effectively one day after a single
intravenous infusion [4]. We thus aimed at directly probing the
effect of a glutamatergic antidepressant drug on resting state
functional connectivity in healthy subjects.
Methods
Ethics Statement
The study was approved by the University of Zurich
institutional review board, and all subjects gave written informed
consent before screening.
Subjects
Healthy subjects (n = 19, mean age, 40.5+7.5 [standard
deviation]; body mass index, 24+4.1; 9 males) without any
psychiatric, neurological, or medical illness were self-referred from
online study advertisements. All subjects underwent a psychiatric
interview and medical examination. Only medication-free subjects
that were healthy according to physical examination, electrocar-
diogram, blood and urine analyses were included in the study.
Exclusion criteria were a history of psychiatric/neurological
diseases, drug abuse, concurrent medication, cardiovascular
disease, anaemia, thyroid disease, any somatic disease affecting
drug metabolism and excretion (e.g. renal or liver disease), MR
exclusion criteria, pregnancy, and left handedness.
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Study design
17 out of 19 subjects (one study dropout per ketamine or
placebo run due to personal reasons) completed a total of four
rsfMRI sessions in a double-blind, randomized, crossover study
design (Fig. 1). The order of placebo and ketamine administration
was assigned by an external third party. Participants were stratified
for sex and age and randomly assigned to both groups (ketamine-
placebo or placebo-ketamine) with a randomization ratio of 1:1 to
assertain matched groups. The baseline rsfMRI scan was followed
by an intravenous (i.v.) infusion (45 mins) of either S-ketamine
(0.25 mg/kg, KetanestH S, Pfizer, Zurich, Switzerland) or saline
(0.90% w/v of NaCl) outside the scanner. Previous clinical trials
mostly used an i.v. dose of 0.5 mg/kg of racemic ketamine (R/S
enantiomer ratio of 1:1). The S(+)-isomer of ketamine is
characterized by a 3–4 times higher affinity or potency at specific
receptors, so that a dose reduction of 50% is recommended [49].
Since the antidepressant effect of ketamine is most prominent after
one day [4], the follow-up fMRI scans were scheduled 24 hours
after the ketamine or placebo infusion in order to assess the related
effects on neuronal network dynamics that might contribute to the
understanding of its antidepressant efficacy. To avoid possible
carry-over effects, the time lag between the two baseline
measurements was set to at least ten days. The time of day for
all the imaging sessions was kept constant for every participant.
Psychometric measures
Psychotomimetic side effects during ketamine infusion were
assessed post hoc using the Altered States of Consciousness rating
scale ‘5D-ASC’ [50]. The state-trait anxiety inventory (STAI X1)
[51] and the Snaith–Hamilton Pleasure Scale (SHAPS) [52] were
repeatedly used to assess subjective state and mood during the
experiments (ratings before, 15 min, and 24 h after pharmacolog-
ical intervention).
fMRI data acquisition and analysis
Measurements were performed on a Philips Achieva TX 3-T
whole-body MR unit equipped with an 8-channel head array. The
subjects were told to lie still in the scanner with their eyes closed
during the acquisition of resting state data. The functional images
were collected in 10 min runs (200 volumes) using a sensitivity-
encoded single-shot echo-planar sequence (TE = 35 ms; field of
view = 22 cm; acquisition matrix = 80680, interpolated to
1286128, 32 contiguous slices, voxelsize = 2.7562.7564 mm,
and sensitivity-encoded acceleration factor R = 2.0) sensitive to
BOLD contrast (T2* weighting). Using a midsagittal scout image,
32 contiguous axial slices were placed along the anterior-posterior
commissure plane covering the entire brain and acquired with a
repetition time of 3000 ms (h =82u) in ascending slice order. A 3-
dimensional T1-weighted anatomical scan was obtained for
structural reference.
Data were analyzed using the SPM8 (Wellcome Trust Center
for Neuroimaging, London, England) based data processing
assistant for resting state fMRI (DPARSF, Yan Chao-Gan, State
Key Laboratory of Cognitive Neuroscience and Learning, Beijing
Normal University, China [53]) which includes a rsfMRI data
analysis toolkit (REST, by Song Xiao-Wei et al. [54]). The
preprocessing steps followed the standard protocol described by
Yan and Zang [53]. Functional data was corrected for differences
in slice acquisition time, motion-corrected using a least squares
approach and a six-parameter (rigid body) linear transformation,
spatially normalized (to 36363 mm isovoxels in standard space)
and smoothed using a 4-mm full-width-at-half-maximum Gauss-
ian kernel. The data was linearly detrended and filtered by a band
pass filter (0.01–0.08 Hz) to suppress cardiac and respiratory
motion induced effects. An additional regression of nuisance
covariates was applied during which the functional data was
corrected for the six head movement parameters and for global
mean signal as well as for white matter and cerebrospinal fluid
signal (defined according to Yan and Zang, 2010) [53].
Seed region selection
We limited our analysis to a priori determined seed regions
based on functional-anatomical network hypotheses and fMRI
studies that yielded differential patterns of functional activation
and connectivity in depressed patients and healthy subjects
[21,44,46,48]. Primarily, we focused on seed regions of interest
(ROI: x, y, z, in Montreal Neurological Institute (MNI) space) in
the cognitive control network (CCN), the default mode network
(DMN), and affective networks (AN) that have been shown to
exhibit increased resting state connectivity via the DN in depressed
patients (s. Fig. 2): the left and right DLPFC (sphere at 636 27 29
with 10 mm radius), the left and right PCC (sphere at 66–50 24
with 7 mm radius), and the sgACC (sphere at 2 28–5 with 5 mm
radius). Since in a recent study, decreased connectivity of the
amygdala to prefrontal areas has been shown following antide-
pressant treatment [48], we further included anatomically defined
ROIs for left and right amygdala, taken from the Automated
Anatomical Labeling (AAL) atlas [55].
Statistical analysis
Using the DPARSF toolbox, whole brain functional connectiv-
ity (FC) maps were obtained from the a priori determined seed
regions of interest for each subject and every session separately.
Statistical tests on regional functional connectivity maps were
computed after application of Fisher’s r-to-z transform, which
yields variates that are approximately normally distributed. Paired
t-test significance maps were computed in SPM8, based on the
individual FC maps of the sessions baseline (ketamine) vs. follow-
Figure 1. The randomized, double-blind, placebo controlled
crossover design. Session 1 and 2 were completed by n = 19, session
3 and 4 by n = 17 (1 dropout per group). The blue and the red path
indicate the randomly assigned order of administration.
doi:10.1371/journal.pone.0044799.g001
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up (ketamine) and baseline (placebo) vs. follow-up (placebo). For
the three seed-based comparisons, the correction of the t contrasts
was made with a voxelwise threshold of p,0.001 and 15 voxels,
achieving a corrected cluster threshold of p,0.05, as determined
by the Monte Carlo simulations via AlphaSim (http://afni.nimh.
nih.gov/afni) across whole brain (Gaussian filter width (FWHM)
computed from the estimation of spatial smoothness of the
residuals using AFNI (http://afni.nimh.nih.gov/afni): sig-
max = 2.70, FWHMx = 6.36; sigmay = 2.70, FWHMy = 6.35;
sigmaz = 2.78, FWHMz = 6.54; cluster connection radius
(rmm) = 5.2 mm, individual voxel threshold probability = 0.001,
1000 iterations). Using the DPARSF toolbox, functional time
series were extracted within each of the seed regions and in the
target ROI of the dorsal nexus and in the MPFC/PACC voxel
cluster, which was determined from the paired t-test significance
maps. To quantify changes in functional connectivity of the seed
regions to the target voxel clusters, correlation coefficients between
the extracted functional time series were computed in Matlab
R2009b (The MathWorks, Inc., Natick, MA, USA) for each
subject and every session separately. Paired t-tests were applied to
compare differences in Fisher z-transformed correlation values
between baseline and follow-up sessions. Graphs of the mean
changes in z-transformed correlation values were created using
SigmaPlot (Systat Software Inc.). Whole brain paired t significance
images were thresholded in SPM8 and visualized with the
BrainNet Viewer (http://www.nitrc.org/projects/bnv/).
Results
Psychometric measures
Compared to placebo, subjects reported a significant increase in
psychotomimetic symptoms following ketamine administration as
assessed by the 5D-ASC questionnaire [50]. Ketamine treatment
caused the most pronounced increase of scores in the scales of
reduction of vigilance (n = 17, paired t-test: p,0.001), oceanic
boundlesness (p = 0.005), anxious ego-dissolution (p,0.009), and
visionary restructuralization (p,0.022). There was no significant
correlation between psychotomimetic side effects and changes in
functional connectivity of the AN und DMN seed regions to the
DN. Ketamine or placebo treatment also did not affect subjective
state and mood measured over the experimental period using the
STAI X1 [51] and the Snaith-Hamilton Pleasure Scale (SHAPS)
[52].
Default mode network
At the whole brain level, we observed a focal decrease in
functional connectivity between the left and right PCC seed region
and the bilateral dorsal medial prefrontal cortex (DMPFC), the
pregenual anterior cingulate (PACC) and the medioprefrontal
cortex (MPFC) following ketamine administration (n = 17, paired
t-test: p
uncorr
,0.001, extent threshold of k.15, resulting in a
cluster-level p
corr
,0.05; Fig. 3). There were no other brain regions
showing significant reductions in functional connectivity to the
PCC seed regions. The difference in mean Fisher z-transformed
correlation values extracted from the corresponding seed (PCC)
and projection region in the bilateral DMPFC and MPFC/PACC
was significant for the ketamine condition (n = 17, paired t-test
(baseline-follow-up): p,0.001), with no change after placebo
administration (Fig. 3 and 5).
Affective network
At the whole brain level, we observed a statistical trend for a
reduction in functional connectivity between the sgACC seed
region and the right dorsal medial prefrontal cortex (DMPFC)
following ketamine administration compared to placebo (n = 17,
paired t-test: p
uncorr
,0.001, extent threshold of k.13, resulting in
a cluster-level p
corr
,0.1; Fig. 4). The difference in mean Fisher z-
transformed correlation values extracted from the corresponding
seed (sgACC) and projection region (DMPFC) was significant for
the ketamine condition (n = 17, paired t-test (baseline-follow-up):
p = 0.001), with no significant change after placebo administration
(Fig. 4 and 5).
Other networks
No focal changes in functional connectivity with DLPFC were
found in the whole brain paired t-test thresholded at p
uncorr
,0.001
(extent threshold of k.15, resulting in a cluster-level p
corr
,0.05)
following ketamine administration. Likewise, no significant differ-
ences in functional connectivity between amygdala and prefrontal
cortical areas could be observed after drug administration.
Additional reductions in functional connectivity were found
between amygdala and posterior parietal and premotor areas
but the pattern was similar for both the drug and placebo
condition.
Whole brain dorsal nexus connectivity
In order to assess the specificity of our findings, we created an
additional ’’dorsal nexus ‘‘seed (x: 6, y: 51, z: 24, volume:
Figure 2. Seed region selection. Each of the four solid circles
corresponds to a seed region in the Cognitive Control Network (CCN;
purple): dorsolateral prefrontal cortex (DLPFC); in the Default Mode
Network (DMN; green): posterior cingulate cortex (PCC); in the Affective
Network (AN; orange): subgenual anterior cingulate cortex (sgACC); and
in the amygdala (red).
doi:10.1371/journal.pone.0044799.g002
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513 mm
3
) based on the overlapping voxels that showed significant
changes in functional connectivity to both the posterior and
subgenual cingulate cortices after ketamine administration. At the
whole brain level (using the same threshold as above), functional
connectivity was reduced exclusively to the PCC but nowhere else
in the brain.
Discussion
While pharmacological effects of ketamine on task-induced
fMRI BOLD signals have been studied extensively [56–62], this is
the first randomized, placebo-controlled, double-blind, crossover
study demonstrating changes in resting state functional connec-
tivity in response to ketamine administration in healthy subjects.
As our key finding we report a marked reduction of resting state
functional connectivity between functional nodes of the default
mode network (PCC) via the dorsal nexus (DN), pregenual
anterior cingulate (PACC), and medioprefrontal cortex (MPFC) in
healthy subjects 24 hours after ketamine administration compared
to placebo. The term ’’dorsal nexus’’ was created recently by
Sheline and colleagues (2010) to describe a functional node in the
bilateral DMPFC with dramatically increased resting state
connectivity to three important functional networks - the CCN,
DMN, and AN - in patients suffering from major depression [46].
In our study, we aimed to model and identify ketamine-associated
adaptations in healthy subjects within neural circuits that are
Figure 3. Functional connectivity of the default mode network (DMN). Significant voxels of the dorsal nexus (DMPFC) and pregenual
anterior cingulate cortex (PACC) and medial prefrontal cortex (MPFC) showing reduced functional connectivity to the left posterior cingulate cortex
(PCC) seed region (green) 24 hours after ketamine administration (n = 17, whole brain paired t-test: baseline(ketamine)-follow-up(ketamine);
p
uncorr
,0.001, extent threshold of k.15, corresponds to a cluster-level p
corr
,0.05). The color bar indicates z values. The bar diagrams represent the
change in functional connectivity (Fisher z-transformed correlation values) of the dorsal nexus (left) and the MPFC/PACC (right) to the left PCC from
baseline to follow-up for the ketamine (red) and placebo condition (blue) (n = 17, paired t-test: p,0.001; error bars = s.e.m.).
doi:10.1371/journal.pone.0044799.g003
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relevant to the pathophysiology of MDD. Thus, the observed
decrease in functional connectivity via the DN following ketamine
administration in healthy subjects might have some implications
for its therapeutic action in MDD patients. In light with the peak
of ketamine’s antidepressant effect 24 hours after intravenous
administration [4], our findings suggest that this effect may be
mediated by reducing the hyperconnectivity of the DN as shown
here. Importantly, this action differs from previously reported
effects of acute administration.
Antagonism at NMDA receptors has been shown to induce
behavioral and neuroplastic changes in animal models relevant to
certain aspects of the pathophysiology of depressive disorders [8–
10]. The changes in resting state connectivity that we observed
24 hours post-infusion might thus result from adaptive changes in
neuroglial glutamatergic throughput, neuroplasticity and informa-
tion processing in specific neurocircuits. In strong support for such
a glutamatergic mechanism of action a recent study reported a
direct relationship between aberrant resting state functional
connectivities and glutamatergic imbalance in depressed patients
across distinct functional networks [35]. This supports our
hypothesis that glutamatergic modulation by specific drugs like
ketamine exerts its antidepressant effects via reconfiguration of
resting state functional connectivity.
The psychophysiological relevance of reducing functional
hyperconnectivities within and between resting state networks like
the DMN or the AN is given by their involvement in
circumscribed aspects of the depressive psychopathology. Regions
of the DMN commonly show the greatest activity at rest and
decrease their level of activity during goal-directed tasks [37] and
are thought to be involved in self-referential processes such as
introspection, remembering, and planning [63]. In patients with
major depression, a failure to normally down-regulate activity
Figure 4. Functional connectivity of the affective network (AN). Significant voxels of the dorsal nexus (DMPFC) showing reduced functional
connectivity to the subgenual anterior cingulate cortex (sgACC) seed region (blue) 24 hours after ketamine administration (n = 17, whole brain paired
t-test: baseline(ketamine)-follow-up(ketamine); p
uncorr
,0.001, extent threshold of k.13, corresponds to a cluster-level p
corr
,0.1 indicating trend-
level significance). The color bar indicates z values. The bar diagram represents the change in functional connectivity (Fisher z-transformed correlation
values) of the dorsal nexus to the sgACC from baseline to follow-up for the ketamine (red) and placebo condition (blue) (n = 17, paired t-test:
p = 0.001; error bars = s.e.m.).
doi:10.1371/journal.pone.0044799.g004
Figure 5. Functional connectivity across the whole experiment. The bar diagrams represent the functional connectivity (Fisher z-transformed
correlation values after global mean regression) for the following experimental conditions: baseline and follow-up (ketamine; red); baseline and
follow-up (placebo; blue). From left to right: Dorsal nexus (DN) connectivity to the left posterior cingulate cortex (PCC); medioprefrontal cortex
(MPFC) and pregenual anterior cingulate cortex (PACC) connectivity to the left PCC; subgenual anterior cingulate cortex (sgACC) connectivity to the
DN (n = 17, paired t-tests; error bars = s.e.m.).
doi:10.1371/journal.pone.0044799.g005
Functional Connectivity after Ketamine Challenge
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Page 6
within the DMN during external stimulation was found [38,39],
with increasing levels of DMN dominance being associated with
higher levels of maladaptive, depressive rumination and lower
levels of adaptive, reflective rumination [64]. Thus, the reduction
in functional connectivity between anterior (PACC/MPFC) and
posterior parts of the DMN (PCC) that we observed after ketamine
administration in healthy subjects may have implications for
antidepressant treatment in terms of a reduction of the increased
level of DMN dominance (s. Fig. 6).
Moreover, the sgACC as a critical hub of the AN plays an
important role in emotion processing and the pathogenesis of
mood disorders and has become a promising target for deep brain
stimulation in patients with severe, refractory depression [65]. A
number of structural, metabolic and functional abnormalities has
been identified in the sgACC of MDD patients [66]. Resting state
sgACC functional connectivity with the DMN was significantly
greater in depressed subjects and correlated positively with the
length of the current depressive episode [44]. As proposed by
Sheline et al. (2010) an attentional shift with increased self-focus
might interfere with task performance in the CCN through
increased resting state DMN connectivity with the DN [46]. The
hot-wiring of the sgACC to those systems might further explain its
maladaptive contribution to negative self-monitoring and reduced
task-performance in MDD, given its role in the regulation of
visceral functions and sad mood [66]. Compared to the reduction
in DMN to DN connectivity after ketamine administration in
healthy subjects, the reduction of AN to DN connectivity was less
pronounced reaching statistical trend-level only and has therefore
to be considered preliminary. The absence of a pre-existing
hyperconnectivity of the sgACC to the DN in healthy subjects
might explain the limited dynamic range in terms of a reduction in
functional connectivity in our study, while this mechanism may
become relevant in a clinical population (s. Fig. 6).
Our findings suggest that intravenous ketamine in healthy
subjects affects primarily the DMN (PCC) connectivity via the DN
and PACC/MPFC one day after infusion. We could not find any
focal change in connectivity to the CCN following ketamine
administration and contrary to resting state studies with seroto-
nergic and noradrenergic antidepressants including citalopram
and reboxetine [48], functional connectivity of the prefrontal
cortex to the amygdala remained unaffected by ketamine. Hence,
the circumscribed effect of ketamine on DMN connectivity to the
DN supports the hypothesis that effective antidepressant treatment
involves systematic alterations in connections among higher-order
functional networks via nodes such as the DN. However, those
putative implications for MDD have to be regarded as preliminary
since the results reported here are based on healthy subjects. Apart
from this limitation, our aim of addressing systems level
mechanisms of ketamine’s antidepressant action is reflected in
our elaborate study design including a 24 h post-infusion interval,
appropriate dosage and duration of the ketamine infusion, and the
selection of seed regions that are relevant to MDD. Therefore, our
findings may serve as a model to elucidate potential biomechan-
isms of drug action in the absence of any pre-existing homeostatic
dysregulation as part of the disease process, medication status, or
comorbidity. In a next step, the explanatory power of our
observation has to be further confirmed in a randomized-
controlled clinical trial in MDD patients receiving ketamine.
Moreover, our results do not allow any conclusions to be drawn
for the action of ketamine on the healthy human brain in general
or in the context of ketamine as a model for schizophrenia.
In conclusion, we report a reduction of functional connectivity
in networks that play a critical role in the pathophysiology of
MDD in healthy subjects 24 hours after receiving an antidepres-
sant dose of ketamine. Based on those findings we raise the
hypothesis that reducing functional connectivity of the dorsal
nexus reflects underlying molecular mechanisms relevant to the
antidepressant efficacy of ketamine. Whether this circuit-level
glutamatergic effect is likely to be associated with reversing aspects
of emotional and behavioral dysregulation has to be further
investigated in a clinical study involving MDD patients. This is in
further support of the notion of using ketamine as a research tool
into the neurobiology of mood disorders and to delineate potential
biomarkers and action mechanisms of antidepressant treatment
response.
Acknowledgments
We thank Rosilla Bachmann and Ulrich Heidecke for their support with
ketamine administration, Philipp Staempfli and Jutta Ernst for their
assistance with MR scanning, and Meng Li for his help with data analysis.
Author Contributions
Conceived and designed the experiments: MS MW SG HB PB AH ES.
Performed the experiments: MS ML. Analyzed the data: MS MW CM.
Wrote the paper: MS MW CM SG AH ES.
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    • "BOLD signals normally exhibit a wellordered temporal correlation structure that reflects functional organization (widely referred to as functional con- nectivity [FC]) [20] , and defines interconnected restingstate networks (RSNs). The importance of spontaneous activity to brain development and function is exemplified by the persistence of organized spontaneous activity (i.e., FC) in healthy individuals during task performance and sleep [46] , by the preservation of RSN structure in substantially altered brain states (e.g., sedation [22], surgical anesthesia [33, 40], and prolonged vegetative states [7]), and the observation that early changes in FC may be seen in individuals with neurodegenerative dementing illnesses (e.g., Alzheimer [9] and frontotemporal dementia [14]). Despite its importance, few opportunities exist to study the effects of focal (e.g., well-circumscribed lesions) or specific (e.g., inhibition of a single receptor system) insults on spontaneous activity. "
    [Show abstract] [Hide abstract] ABSTRACT: Spontaneous brain activity is required for the development and maintenance of normal brain function. Many disease processes disrupt the organization of intrinsic brain activity, but few pervasively reduce the amplitude of resting state blood oxygen level dependent (BOLD) fMRI fluctuations. We report the case of a female with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, longitudinally studied during the course of her illness to determine the contribution of NMDAR signaling to spontaneous brain activity. Resting state BOLD fMRI was measured at the height of her illness and 18 weeks following discharge from hospital. Conventional resting state networks were defined using established methods. Correlation and covariance matrices were calculated by extracting the BOLD time series from regions of interest and calculating either the correlation or covariance quantity. The intrinsic activity was compared between visits, and to expected activity from 45 similarly aged healthy individuals. Near the height of the illness, the patient exhibited profound loss of consciousness, high-amplitude slowing of the electroencephalogram, and a severe reduction in the amplitude of spontaneous BOLD fMRI fluctuations. The patient's neurological status and measures of intrinsic activity improved following treatment. We conclude that NMDAR-mediated signaling plays a critical role in the mechanisms that give rise to organized spontaneous brain activity. Loss of intrinsic activity is associated with profound disruptions of consciousness and cognition.
    No preview · Article · Mar 2016 · Journal of Neurology
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    • "" Quite consistently, we also found a reduction of connectivity between pgACC and dmPFC, close to the previously reported dorsal nexus region. That such changes of RSFC after interventions of antidepressant action can also be observed in healthy subjects was recently supported by a finding from Scheidegger and colleagues [68], who showed that, similar to our finding, a connectivity decrease of anterior and posterior DMN components, located in pgACC and PCC, was observed after 24 hrs of ketamine injection, mirroring the substances' maximum antidepressant effects in patients. In other words, the neuronal effects observed after 40 days of meditation, which was shown to affect depression-related psychometry, also reduced connectivity in a network that is hyperconnected in MDD, and, given the predominance of pgACC findings, this further suggests some specificity given the overall role of its dysfunction and abnormal connectivity in depression [29]. "
    [Show abstract] [Hide abstract] ABSTRACT: The topic of investigating how mindfulness meditation training can have antidepressant effects via plastic changes in both resting state and meditation state brain activity is important in the rapidly emerging field of neuroplasticity. In the present study, we used a longitudinal design investigating resting state fMRI both before and after 40 days of meditation training in 13 novices. After training, we compared differences in network connectivity between rest and meditation using common resting state functional connectivity methods. Interregional methods were paired with local measures such as Regional Homogeneity. As expected, significant differences in functional connectivity both between states (rest versus meditation) and between time points (before versus after training) were observed. During meditation, the internal consistency in the precuneus and the temporoparietal junction increased, while the internal consistency of frontal brain regions decreased. A follow-up analysis of regional connectivity of the dorsal anterior cingulate cortex further revealed reduced connectivity with anterior insula during meditation. After meditation training, reduced resting state functional connectivity between the pregenual anterior cingulate and dorsal medical prefrontal cortex was observed. Most importantly, significantly reduced depression/anxiety scores were observed after training. Hence, these findings suggest that mindfulness meditation might be of therapeutic use by inducing plasticity related network changes altering the neuronal basis of affective disorders such as depression.
    Full-text · Article · Feb 2016
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    • "The residual time-series was then de-trended and band-pass filtered (frequency range 0.01–0.08 Hz) and a signal time-series was extracted from the sgACC seed (10 mm sphere at [2, 28, −5] based upon a previous publication (Scheidegger et al., 2012)). The 15-minute time series was separated into three 5-minute time-series segments of pre-infusion, early-infusion and late-infusion. "
    [Show abstract] [Hide abstract] ABSTRACT: Ketamine has been reported to have efficacy as an antidepressant in several studies of treatment-resistant depression. In this study, we investigate whether an acute administration of ketamine leads to reductions in the functional connectivity of subgenual anterior cingulate cortex (sgACC) with other brain regions. Methods. Thirteen right-handed healthy male subjects underwent a 15 min resting state fMRI with an infusion of intravenous ketamine (target blood level = 150 ng/ml) starting at 5 min. We used a seed region centred on the sgACC and assessed functional connectivity before and during ketamine administration. Results. Before ketamine administration, positive coupling with the sgACC seed region was observed in a large cluster encompassing the anterior cingulate and negative coupling was observed with the anterior cerebellum. Following ketamine administration, sgACC activity became negatively correlated with the brainstem, hippocampus, parahippocampal gyrus, retrosplenial cortex, and thalamus. Discussion. Ketamine reduced functional connectivity of the sgACC with brain regions implicated in emotion, memory and mind wandering. It is possible the therapeutic effects of ketamine may be mediated via this mechanism, although further work is required to test this hypothesis.
    Full-text · Article · Feb 2016 · PeerJ
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