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.
Authors
- James Murrough
- Lauren Averill
- Dennis Charney
Published
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.
Research Summary of 'Ketamine Treatment and Global Brain Connectivity in Major Depression'
Introduction
Resting-state functional connectivity MRI (rs-fcMRI) has revealed widespread alterations of large-scale brain networks in major depressive disorder (MDD), but most prior work used seed-based approaches that require preselecting regions of interest. Abdallah and colleagues adopted a fully data-driven, graph-based metric—global brain connectivity with global signal regression (GBCr)—to quantify whole-brain functional dysconnectivity without a priori seeds. GBCr indexes the average correlation of each voxel's BOLD time series with all other grey-matter voxels and has been related to regional cerebral blood flow and normal cognitive function in earlier studies. This study set out to compare GBCr in medication-free patients with MDD during a depressive episode versus healthy controls, and to test whether a single subanaesthetic infusion of ketamine (0.5 mg/kg) would rapidly normalise GBCr abnormalities. The investigators hypothesised that MDD patients would show reduced prefrontal cortex (PFC) GBCr at baseline and that ketamine's rapid antidepressant effects—typically evident within 24 hours—would parallel increases in PFC GBCr, with greater GBCr change in clinical responders.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Abdallah, C. G., Averill, L. A., Collins, K. A., Geha, P., Schwartz, J., Averill, C., DeWilde, K. E., Wong, E., Anticevic, A., Tang, C. Y., Iosifescu, D. V., Charney, D. S., & Murrough, J. W. (2017). Ketamine Treatment and Global Brain Connectivity in Major Depression. Neuropsychopharmacology, 42(6), 1210-1219. https://doi.org/10.1038/npp.2016.186
References (4)
Papers cited by this study that are also in Blossom
Ari, A., Abdallah, C. G., Sanacora, G. et al. · Annual Review of Medicine (2014)
Bobo, W. V., Vande Voort, J. L., Croarkin, P. E. et al. · Depression and Anxiety (2016)
Murrough, J. W., Collins, K. A., Fields, J. et al. · Translational Psychiatry (2015)
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
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Li, W. C., Chen, L. F., Su, T. P. et al. · Journal of Affective Disorders (2023)
Zavaliangos-Petropulu, A., Mcclintock, S. M., Khalil, J. et al. · Journal of Affective Disorders (2023)
Meshkat, S., Cao, B., Teopiz, K. M. et al. · Journal of Affective Disorders (2023)
Shiroma, P. R., Velit-Salazar, M. R., Vorobyov, Y. · Clinical Drug Investigation (2022)
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Alexander, L., Jelen, L. A., Mehta, M. A. et al. · Neuroscience and Biobehavioral Reviews (2021)
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Kohtala, S., Alitalo, O., Rosenholm, M. et al. · Pharmacology and Therapeutics (2020)
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Ionescu, D. F., Felicione, J. M., Gosai, A. et al. · Harvard Review of Psychiatry (2018)
Preller, K. H., Burt, J. B., Adkinson, B. et al. · eLife (2018)
Abdallah, C. G., Sanacora, G., Duman, R. S. et al. · Chronic Stress (2018)
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Niciu, M. J., Shovestul, B. J., Jaso, B. A. et al. · Journal of Affective Disorders (2018)
Abdallah, C. G., Averill, C. L., Salas, R. et al. · Biological Psychiatry (2017)
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