Replicating Global Brain Connectivity As an Imaging Marker for Depression - Influence of Preprocessing Strategies and Placebo-Controlled Ketamine Treatment

Abstract

Background: Major depressive disorder (MDD) is associated with altered global brain connectivity (GBC), as assessed via resting state functional magnetic resonance imaging (rsfMRI). Antidepressant treatment with ketamine normalized aberrant GBC changes in the prefrontal and cingulate cortices, warranting further investigations of GBC as a putative imaging marker. However, results were only obtained via global signal regression (GSR). This study is an independent replication of that analysis using a separate dataset. Methods: GBC was analyzed in 28 individuals with treatment-resistant MDD and 22 healthy controls (HCs) at baseline, post-placebo, and post-ketamine. To investigate the effects of preprocessing, three distinct pipelines were used: 1) regression of white matter (WM)/cerebrospinal fluid (CSF) signals only (BASE); 2) WM/CSF+GSR (GSR); and 3) WM/CSF+physiological parameter regression (PHYSIO). Outcomes: Compared to PHYSIO and BASE regression, GSR reduced Fisher Z-scores (Fz-scores) in large clusters. PHYSIO did not resemble GBC preprocessed with GSR (GBCr). Reduced GBCr was observed in MDD participants at baseline in the anterior and medial cingulate cortices, as well as in the prefrontal cortex. Significant results were only found with GSR. Ketamine had no effect compared to baseline or placebo in either group. Interpretation: These results concur with several studies that used GSR to study GBC. Altered GBCr was observed in the cingulate and prefrontal cortices, but ketamine treatment had no effect. Further investigations are warranted into disease-specific components of global fMRI signals that may drive these results and of GBCr as a potential imaging marker in MDD. Funding Statement: Funding was supported by the NIMH-NIH (ZIAMH002857;NCT00088699). Declaration of Interests: Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)- hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. Dr. Kraus received travel support from Roche and AOP Orphan. All other authors have no conflict of interest to disclose, financial or otherwise. Ethics Approval Statement: Participants included in this study were part of a larger protocol at the National Institute of Mental Health (NIMH) in Bethesda, Maryland, USA (NCT00088699, National Institutes of Health (NIH) Protocol No. 04-M-0222). All participants provided written informed consent after oral explanation of study procedures, which were approved by the NIH Combined Central Nervous System Institutional Review Board.