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.
Figure 2.
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).
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); puncorr<0.001, extent threshold of k>15, corresponds to a cluster-level pcorr<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.).
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); puncorr<0.001, extent threshold of k>13, corresponds to a cluster-level pcorr<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.).
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.).
Figure 6.
Proposed hypothetical model of ketamine-associated changes in functional connectivity.
In the healthy human brain, a single antidepressant dose of ketamine reduces functional connectivity of the dorsal nexus (DN) to the Default Mode Network (DMN; green). The reduction in functional connectivity of the Affective Network (AN; orange) to the DN reached trend-level significance only (s. Fig. 4), possibly due to the absence of any pre-existing hyperconnectivity in healthy subjects. This action may serve as a model for the discovery of novel antidepressant biomechanisms in major depression where functional connectivity of the DMN and AN via the DN is increased. The solid circles correspond to seed regions in the posterior cingulate cortex (PCC; green) and subgenual anterior cingulate cortex (sgACC; orange). The correspondingly colored open circles and dotted lines represent regions with decreased connectivity with the respective seed regions after ketamine administration. This hypothetical model is based on results from previous rsfMRI studies in MDD patients and on data obtained in healthy subjects after ketamine administration and needs to be further verified in MDD patients receiving ketamine.