Ketamine Treatment and Global Brain Connectivity in Major Depression

This open-label, counterbalanced, between-subjects study (n=43) compared brain activity before and after ketamine (35mg/70kg) administration across healthy control and patients with major depression. The treatment normalized restored abnormally low brain connectivity levels in the prefrontal cortex of patients with depression, which may be indicative of a potential mechanism whereby ketamine restores synaptic dysconnectivity related to chronic stress and increased extracellular glutamate in the prefrontal cortex. The authors highlight the method of global brain connectivity with signal regression as a useful biomarker for quantifying treatment response to rapid-acting antidepressants.

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Discussion: 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.”

Authors: Chadi G. Abdallah, Lynnette A. Averill, Katherine A. Collins, Paul Geha, Jaclyn Schwartz, Christopher Averill, Kaitlin E. DeWilde, Edmund Wong, Alan Anticevic, Cheuk Y Tang, Dan V Iosifescu, Dennis S Charney & James W. Murrough

Summary

INTRODUCTION

Resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) measures whole-brain connectivity and can be used to identify altered networks in major depressive disorder (MDD). A novel graph-based measure, termed global brain connectivity with global signal regression (GBCr), can be used to quantify functional dysconnectivity in MDD.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exerts rapid antidepressant effects in treatment-resistant MDD patients, offering a unique pharmacoimaging paradigm to investigate the neural correlates of antidepressant response. Preclinical models of depression and chronic stress show impaired prefrontal synaptic connectivity and homeostasis, which rapidly normalize within 24 h of ketamine treatment. This may explain the rapid enhancement of synaptic structure and function observed in humans following ketamine treatment.

Studies in depression have reported functional connectivity abnormalities within the prefrontal cortex (PFC) and other cortical and subcortical regions. GBCr can be used to quantify brain dysconnectivity in MDD and to relate these abnormalities to rapid mood normalization following treatment.

Based on the data, we hypothesize that patients with MDD will show altered GBCr, in particular, reduced PFC GBCr, following ketamine treatment.

Subjects

The current study enrolled male and female individuals aged 21 – 65 years with MDD and healthy control volunteers. Patients had to be drug-free for at least 1 week prior to imaging and have a current major depressive episode with MDD diagnosis.

Study Procedures

Patients with MDD underwent baseline structural MRI and rs-fcMRI scans, and ketamine 0.5 mg/kg infusion over 40 min was administered intravenously. Patients were divided into responders and non-responders to treatment based on MADRS scores.

Neuroimaging Data Acquisition

Philips Achieva 3.0 T X-series MRI was used for the imaging study. Resting-state functional data was acquired using a T2*-weighted gradient echo-planar imaging sequence, and task-based fMRI and diffusion tensor imaging scans were acquired during the same session.

GBCr Values

Global Brain Connectivity (GBCr) is a measure of nodal strength of a voxel in the whole brain network, determining brain hubs and examining the coherence between a local region and the rest of the brain.

Statistical Analyses

Demographic differences between the study groups were examined using t-test and chi-square, and treatment effects were assessed using paired t-test and independent t-tests.

Clinical Characteristics

18 patients with MDD and 25 patients with HC successfully completed all study procedures. 10 patients with MDD achieved response to ketamine treatment.

GBCr Values Preketamine and Postketamine

Prior to treatment, whole-brain comparison revealed widespread dysconnectivity in MDD, with seven clusters showing significant reduction in GBCr in MDD compared with HC. Following treatment, three small clusters showed increased or reduced GBCr in MDD.

GBCr and Treatment Response

Responders showed higher delta GBCr values in the right lateral PFC and left anterior insula compared to non-responders.

Five clusters of significantly higher GBCr were found in responders compared with non-responders in the left and right caudate, left and right lateral PFC, and left middle temporal (Figure 2).

Exploration of GBCr Distributions Preketamine and Postketamine

We extracted the absolute z-values of all brain voxels showing GBCr abnormalities in MDD at baseline and following treatment, and found 2174 voxels with reduced or increased GBCr in MDD.

We plotted the average GBCr of each PFC voxel across all subjects in each study group, and noticed a large effect size of left shift in the PFC GBCr distribution in MDD group compared with HC group.

Exploratory Seed-Based Analyses

We conducted two follow-up seed-based analyses to provide preliminary data illustrating the circuitry underlying GBCr alterations. The results showed that MDD patients had increased connectivity within the PFC, but reduced connectivity between the PFC and other brain regions.

Postketamine responders showed increased connectivity in the lPFC and caudate with several brain regions outside the PFC/subcortex compared with non-responders.

DISCUSSION

We found reduced GBCr in the PFC of patients with MDD compared with healthy subjects, and this largely normalized 24 h following ketamine treatment. Responders to ketamine treatment demonstrated more robust increases in GBCr compared with non-responders.

A working model of depression and chronic stress proposes that prefrontal glutamate synaptic dysconnectivity is a key underlying neural correlate of depression. Ketamine treatment normalized large-scale GBCr abnormalities, suggesting that these abnormalities are state dependent or partially trait dependent.

Ketamine treatment normalized the GBCr, but traditional antidepressants may also reverse some intrinsic network abnormalities.

The current study found that GBCr abnormalities were associated with chronic stress-induced synaptic dysconnectivity in the PFC. This finding is consistent with prior evidence that synaptic connectivity is necessary for successful antidepressant treatments.

Chronic stress has been found to reduce prefrontal GBCr in several chronic psychiatric disorders, including bipolar, obsessive-compulsive, and schizophrenia. Early-course schizophrenia patients had increased PFC GBCr, which suggests that glutamatergic activation may contribute to increased synaptic strength.

GBCr abnormalities were observed in the frontal region of various stress-related psychiatric disorders, but there appeared to be limited overlap between the locations of abnormal clusters, and some regional abnormalities may be disease specific, eg, posterior cingulate and precuneus clusters in MDD.

Ketamine induced changes in GBCr were observed at a single time point and may last for about 10 days. Frequent daily administration of ketamine may lead to repeated glutamate surge, increased extracellular glutamate, excito-toxity, and synaptic dysconnectivity comparable to chronic stress models of depression.

We found increased sgACC and DLFPC connectivity with the dorsomedial PFC, which normalized following treatment. This suggests that the enhanced engagement of the frontostriatal regions underlies the behavioral shift from depression, withdrawal, and rumination to exploratory and externally focused behavior following recovery.

Limitations

This study has several limitations, such as comorbid anxiety disorders and short medication-free period, and it cannot rule out residual effects from prior antidepressant use.

The current study used short resting-state acquisition, and the sample size was relatively small, so future studies should consider using longer acquisition times and using a multimodal approach to investigate the underlying mechanisms of GBCr abnormalities and normalization.

FUNDING AND DISCLOSURE

This research was supported by the National Institute of Mental Health, the Iris & Junming Le Foundation, the Brain and Behavior Research Foundation, the Patterson Trust Award, the US Department of Veterans Affairs, and the Office of Academic Affairs. The content of this article is solely the responsibility of the authors, and the National Institutes of Health has no role in the design, conduct, collection, management, analysis, and interpretation of the data, or preparation, review, or approval of the manuscript.

Dr. Abdallah has received funding from the National Institutes of Health, the Brain and Behavioral Research Foundation, the Department of Defense, the American Psychiatric Foundation, and the Robert E. Leet and Clara Guthrie Patterson Trust. Dr. Iosifescu has received funding from Roche. Dennis Charney, Dean of Icahn School of Medicine at Mount Sinai, has been named on a use patent for ketamine for the treatment of depression. He has received funding from the US Department of Defense.

Study details

Topics studied
Neuroscience Depression

Study characteristics
Open-Label Bio/Neuro

Participants
43

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