Single and repeated ketamine treatment induces perfusion changes in sensory and limbic networks in major depressive disorder

Abstract

Ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depressive disorder (MDD). Yet, how single and repeated ketamine treatment induces brain systems-level neuroplasticity underlying symptom improvement is unknown. Advanced multiband imaging (MB) pseudo-continuous arterial spin labeling (pCASL) perfusion MRI data was acquired from patients with treatment resistant depression (TRD) (N = 22, mean age=35.2 ± 9.95 SD, 27% female) at baseline, and 24 h after receiving single, and four subanesthetic (0.5 mg/kg) intravenous ketamine infusions. Changes in global and regional CBF were compared across time points, and relationships with overall mood, anhedonia and apathy were examined. Comparisons between patients at baseline and controls (N = 18, mean age=36.11 ± 14.5 SD, 57% female) established normalization of treatment effects. Results showed increased regional CBF in the cingulate and primary and higher-order visual association regions after first ketamine treatment. Baseline CBF in the fusiform, and acute changes in CBF in visual areas were related to symptom improvement after single and repeated ketamine treatment, respectively. In contrast, after serial infusion therapy, decreases in regional CBF were observed in the bilateral hippocampus and right insula with ketamine treatment. Findings demonstrate that neurophysiological changes occurring with single and repeated ketamine treatment follow both a regional and temporal pattern including sensory and limbic regions. Initial changes are observed in the posterior cingulate and precuneus and primary and higher-order visual areas, which relate to clinical responses. However, repeated exposure to ketamine, though not relating to clinical outcome, appears to engage deeper limbic structures and insula. ClinicalTrials.gov: Biomarkers of Fast Acting Therapies in Major Depression, https://ichgcp.net/clinical-trials-registry/NCT02165449, NCT02165449.

Keywords: CBF; Fusiform; Insula; Ketamine; MB pCASL; MDD.

Conflict of interest statement

Conflict of interest Authors have no disclosures or any competing financial interests in relation to the work described.

Copyright © 2020. Published by Elsevier B.V.

Figures

Figure 1.

A) Study design showing the timing of MRI sessions and clinical assessments; B) Imaging pre-processing pipeline where wp= white paper mode, and Pvcorr = partial volume correction.

Figure 2.

A) Effect of ketamine treatment after first infusion (TP2vsTP1). Results are displayed on surface, and in B) volume space. Clusters in red correspond to p

Figure 3.

Region of interests (ROIs color coded) used to perform follow-up analysis of relationships between regional CBF and mood variables. The bar plots represent the average CBF in the ROIs across ketamine treatment (*p

Figure 4.

Regional correlates of CBF with clinical variables. A) Baseline (TP1) CBF in the fusiform showed a significant negative relationship with acute change in HDRS (TP1-TP2); B) Acute change in CBF in the cuneus (TP1-TP2) showed a significant positive relationship with serial change (TP1-TP3) in AES, SHAPS and HDRS scores.

Figure 5.

CBF change after fourth infusion of ketamine (TP1vsTP3) (p