Species-conserved reconfigurations of brain network topology induced by ketamine

Abstract

Species-conserved (intermediate) phenotypes that can be quantified and compared across species offer important advantages for translational research and drug discovery. Here, we investigate the utility of network science methods to assess the pharmacological alterations of the large-scale architecture of brain networks in rats and humans. In a double-blind, placebo-controlled, cross-over study in humans and a placebo-controlled two-group study in rats, we demonstrate that the application of ketamine leads to a topological reconfiguration of large-scale brain networks towards less-integrated and more-segregated information processing in both the species. As these alterations are opposed to those commonly observed in patients suffering from depression, they might indicate systems-level correlates of the antidepressant effect of ketamine.

Figure 1

Study protocols and methods. (a) Human (light blue): the subjects received either saline, ketamine or scopolamine via infusion over 45 min, 20 min before each scanning session. BOLD fMRI resting-state data were acquired and the time series of 270 brain regions were extracted. Correlated, these yielded two correlation matrices for each subject. (b) Rats (light green): the two groups of animals received either ketamine or saline injection. BOLD resting-state data were acquired before and 15 min after the injection. The time series of 90 brain regions were extracted and correlated, resulting in one correlation matrix for each animal. (c) Both human and animals matrices were thresholded and binarized to extract the underlying topological network structure. Subsequently, graph metrics such as degree (green lines in the depicted network), path length (red lines) and clustering coefficient (blue) were computed. BOLD, blood-oxygen-level dependent; fMRI, functional magnetic resonance imaging.

Figure 2

Topological reconfigurations after ketamine application. Means of area under curve (AUC) for each calculated graph metrics for humans (a) and rats (b) after saline application (blue) and ketamine (red). Asterisks denote statistically significant differences (P<0.05, FDR corrected) between saline and ketamine. C, clustering coefficient; E_glob, global efficiency; E_loc, local efficiency; FDR, false discovery rate; L, path length; σ, small-worldness coefficient.

Figure 3

Area under curves of network motif frequencies for undirected three- and four-node motifs. For both humans (a) and rats (b), red bars indicate mean values for the ketamine groups, and blue bars indicate mean values for the controls; asterisks denote statistically significant differences between the groups (P<0.05, FDR corrected). AUC, area under the curve; FDR, false discovery rate.

Figure 4

Alterations of functional connectivity after ketamine application. Ketamine-related increase in connectivity in humans (left) and rats (right). The line color represents the statistical significance as indicated by the respective T-statistics. The color of nodes indicates the number of altered connections for the respective node. The outer colored circle represents the brain region's assignment: blue=frontal cortex, yellow=temporal, red=orbital cortex, green=parietal cortex, magenta=hippocampal formation. The areas colored in lighter blue stretch along an anterior-posterior axis compassing multiple brain regions. Human: Cal, calcarine sulcus; F Mid, frontal middle cortex; O Inf, occipital cortex inferior sulcus; O Mid, occipital cortex middle sulcus; PaL, paracentral lobule; PCun, precunes; poC, postcentral sulcus; prC, precentral sulcus; SMA, supplemental motor area; T inf, temporal cortex inferior sulcus; T sup, temporal cortex superior sulcus. Rat: Au, auditory cortex; Cg1, cingulate cortex; HcSDG, hippocampus subiculum/dentate gyrus; I, insular cortex; IL, infralimbic cortex; M2, secondary motor cortex; OF, orbitofrontal cortex; Pir, piriform cortex; PL, prelimbic cortex; S2, secondary somatosensory cortex; TeA, temporal association area; V, visual cortex. Subscript indicates left (l) or right (r) hemisphere.