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Neuroimaging correlates and predictors of response to repeated-dose intravenous ketamine in PTSD: preliminary evidence

Neuropsychopharmacology volume 46, pages 2266–2277 (2021)Cite this article

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Abstract

Promising initial data indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may be beneficial in post-traumatic stress disorder (PTSD). Here, we explore the neural correlates of ketamine-related changes in PTSD symptoms, using a rich battery of functional imaging data (two emotion-processing tasks and one task-free scan), collected from a subset of participants of a randomized clinical trial of repeated-dose intravenous ketamine vs midazolam (total N = 21). In a pre-registered analysis, we tested whether changes in an a priori set of imaging measures from a target neural circuit were predictive of improvement in PTSD symptoms, using leave-one-out cross-validated elastic-net regression models (regions of interest in the target circuit consisted of the dorsal and rostral anterior cingulate cortex, ventromedial prefrontal cortex, anterior hippocampus, anterior insula, and amygdala). Improvements in PTSD severity were associated with increased functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala during emotional face-viewing (change score retained in model with minimum predictive error in left-out subjects, standardized regression coefficient [β] = 2.90). This effect was stronger in participants who received ketamine compared to midazolam (interaction β = 0.86), and persisted following inclusion of concomitant change in depressive symptoms in the analysis model (β = 0.69). Improvement following ketamine was also predicted by decreased dorsal anterior cingulate activity during emotional conflict regulation, and increased task-free connectivity between the vmPFC and anterior insula (βs = −2.82, 0.60). Exploratory follow-up analysis via dynamic causal modelling revealed that whilst improvement in PTSD symptoms following either drug was associated with decreased excitatory modulation of amygdala→vmPFC connectivity during emotional face-viewing, increased top-down inhibition of the amygdala by the vmPFC was only observed in participants who improved under ketamine. Individuals with low prefrontal inhibition of amygdala responses to faces at baseline also showed greater improvements following ketamine treatment. These preliminary findings suggest that, specifically under ketamine, improvements in PTSD symptoms are accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat.

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Fig. 1: Description of study procedures, clinical measures, and functional imaging measures.
Fig. 2: Neuroimaging correlates of PTSD symptom change.
Fig. 3: Dynamic causal modelling of task-modulated effective connectivity during the emotional face-processing task.
Fig. 4: Baseline predictors of PTSD symptom change.

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Acknowledgements

This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.

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Authors and Affiliations

  1. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Agnes Norbury, Sarah B. Rutter, Abigail B. Collins, Sara Costi, Manish K. Jha, Sarah R. Horn, Marin Kautz, Morgan Corniquel, Katherine A. Collins, Dennis S. Charney, James W. Murrough & Adriana Feder

  2. Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    Katherine A. Collins

  3. Department of Anesthesiology, Perioperative and Pain Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Andrew M. Glasgow & Jess Brallier

  4. Department of Psychology, Tufts University, Medford, MA, USA

    Lisa M. Shin

  5. Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

    Lisa M. Shin

  6. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Dennis S. Charney & James W. Murrough

  7. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Dennis S. Charney

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  1. Agnes Norbury
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Contributions

Contribution to the conception or design of the work: MKJ, LMS, DSC, JWM, AF. Contribution to the acquisition, analysis, or interpretation of data for the work: AN, SBR, ABC, SC, SRH, MK, MC, KAC, AMG, JB, JMW, AF. Drafting the work or revising it critically for important intellectual content: AN, SC, MKJ, LMS, JMW, AF. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: AN, AF. Final approval of the version to be published: All authors.

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Correspondence to Adriana Feder.

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Norbury, A., Rutter, S.B., Collins, A.B. et al. Neuroimaging correlates and predictors of response to repeated-dose intravenous ketamine in PTSD: preliminary evidence. Neuropsychopharmacol. 46, 2266–2277 (2021). https://doi.org/10.1038/s41386-021-01104-4

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