Ketamine Treatment and Global Brain Connectivity in Major Depression

Abstract

Capitalizing on recent advances in resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) and the distinctive paradigm of rapid mood normalization following ketamine treatment, the current study investigated intrinsic brain networks in major depressive disorder (MDD) during a depressive episode and following treatment with ketamine. Medication-free patients with MDD and healthy control subjects (HC) completed baseline rs-fcMRI. MDD patients received a single infusion of ketamine and underwent repeated rs-fcMRI at 24 h posttreatment. Global brain connectivity with global signal regression (GBCr) values were computed as the average of correlations of each voxel with all other gray matter voxels in the brain. MDD group showed reduced GBCr in the prefrontal cortex (PFC) but increased GBCr in the posterior cingulate, precuneus, lingual gyrus, and cerebellum. Ketamine significantly increased GBCr in the PFC and reduced GBCr in the cerebellum. At baseline, 2174 voxels of altered GBCr were identified, but only 310 voxels significantly differed relative to controls following treatment (corrected α<0.05). Responders to ketamine showed increased GBCr in the lateral PFC, caudate, and insula. Follow-up seed-based analyses illustrated a pattern of dysconnectivity between the PFC/subcortex and the rest of the brain in MDD, which appeared to normalize postketamine. The extent of the functional dysconnectivity identified in MDD and the swift and robust normalization following treatment suggest that GBCr may serve as a treatment response biomarker for the development of rapid acting antidepressants. The data also identified unique prefrontal and striatal circuitry as a putative marker of successful treatment and a target for antidepressants' development.

Figure 1

GBCr alterations in MDD at baseline and following ketamine treatment. Clusters mark brain regions with significant GBCr reduction (blue) or increase (red–yellow) in MDD compared with HC prior to ketamine treatment (a) and 24 h after intravenous infusion of ketamine (b) (whole-brain voxel-wise independent t-test with corrected α<0.05). The prefrontal cortex region is labeled with a black line. HC, healthy controls; GBCr, global brain connectivity with global signal regression; MDD, major depressive disorder. A full color version of this figure is available at the Neuropsychopharmacology journal online.

Figure 2

Individual variation in delta GBCr. This figure depict the spread at the subject level of both the percentage of improvement of depressive symptoms and the average GBCr changes in each of the five clusters identified in the responders vs non-responders analysis. The gray area is the 95% confidence band of the best-fit line. Clusters' locations are shown in right lower panel. GBCr, global brain connectivity with global signal regression; lPFC, lateral prefrontal cortex; MADRS, Montgomery–Åsberg Depression Rating Scale.

Figure 3

Distributions of GBCr at baseline and following ketamine treatment. (a) Distributions of absolute z-values of voxels showing significant reduction or increase of GBCr in MDD compared with HC prior to ketamine treatment (red) or 24 h after intravenous infusion of ketamine (blue). Although both distributions largely overlapped, the numbers of altered GBCr were numerically higher preketamine in each bin of the absolute z-values up to z~3.5. Of the 310 significant voxels postketamine, 123 were altered at baseline and 187 differed between groups only at the 24 h time point. (b) Distributions of GBCr in the anatomically defined PFC (delineated in Figure 1) in MDD and HC prior to ketamine treatment. The histograms depict comparable normal distributions in both groups with large effect size left shift in MDD reflecting overall reduction in PFC GBCr. (c and d) Distributions of PFC GBCr in HC and MDD responders (c) or MDD non-responders (d) 24 h after infusion of ketamine. The histograms reveal large overlap between the PFC GBCr distributions of HC and MDD responders (c). However, MDD non-responders continued to show large effect size left shift, suggesting a lack of normalization of PFC GBCr in this subgroup. GBCr, global brain connectivity with global signal regression; HC, healthy controls; MDD, major depressive disorder; PFC, prefrontal cortex. A full color version of this figure is available at the Neuropsychopharmacology journal online.

Figure 4

Seed-based connectivity alteration in the affective (AN), cognitive Control (CCN), and default mode networks (DMN). (a–c): Clusters mark brain regions with significant connectivity reduction (blue) or increase (red–yellow) in MDD compared with HC at baseline. (d–f) Clusters mark brain regions with significant connectivity reduction (blue) or increase (red–yellow) in following ketamine treatment. The prefrontal cortex region is labeled with a black line. The seeds' locations are marked with green circles. The empty black circles locate the dorsal nexus area. DLPFC, dorsolateral prefrontal cortex; HC, healthy controls; MDD, major depressive disorder; PCC, posterior cingulate and precuneus area; sgACC, subgenual anterior cingulate cortex. A full color version of this figure is available at the Neuropsychopharmacology journal online.