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Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study

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Abstract

Nitrous oxide (N2O) has recently emerged as a potential fast-acting antidepressant but the cerebral mechanisms involved in this effect remain speculative. We hypothesized that the antidepressant response to an Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) would be associated with changes in cerebral connectivity and brain tissue pulsations (BTP). Thirty participants (20 with a major depressive episode resistant to at least one antidepressant and 10 healthy controls—HC, aged 25–50, only females) were exposed to a 1-h single session of EMONO and followed for 1 week. We defined response as a reduction of at least 50% in the MADRS score 1 week after exposure. Cerebral connectivity of the Anterior Cingulate Cortex (ACC), using ROI-based resting state fMRI, and BTP, using ultrasound Tissue Pulsatility Imaging, were compared before and rapidly after exposure (as well as during exposure for BTP) among HC, non-responders and responders. We conducted analyses to compare group × time, group, and time effects. Nine (45%) depressed participants were considered responders and eleven (55%) non-responders. In responders, we observed a significant reduction in the connectivity of the subgenual ACC with the precuneus. Connectivity of the supracallosal ACC with the mid-cingulate also significantly decreased after exposure in HC and in non-responders. BTP significantly increased in the three groups between baseline and gas exposure, but the increase in BTP within the first 10 min was only significant in responders. We found that a single session of EMONO can rapidly modify the functional connectivity in the subgenual ACC-precuneus, nodes within the default mode network, in depressed participants responders to EMONO. In addition, larger increases in BTP, associated with a significant rise in cerebral blood flow, appear to promote the antidepressant response, possibly by facilitating optimal drug delivery to the brain. Our study identified potential cerebral mechanisms related to the antidepressant response of N2O, as well as potential markers for treatment response with this fast-acting antidepressant.

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Fig. 1: Voxel-wise results and plots.
Fig. 2: Changes in MeanBTP (upper graph) and in MaxBTP (lower graph) between pre-exposure (baseline), per-exposure, and post-exposure (24 h post N2O) among responders (blue, n = 9), non-responders (red, n = 11) and healthy controls (green, n = 10).

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Acknowledgements

The PROTOBRAIN study was supported by grants from “La Fondation de l’Avenir pour la Recherche Médicale (grant no. DLAM_2017251)” and from “La Fondation Planiol pour la Recherche sur le Cerveau.”

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Authors and Affiliations

  1. UMR 1253, iBrain, Université de Tours, Inserm, Tours, France

    Thomas Desmidt, Frédéric Andersson, Bruno Brizard, Jean-Pierre Réméniéras, Nicolas Arlicot, Laurent Barantin, Fabien Espitalier, Catherine Belzung, Arnaud Tanti, Vincent Camus & Wissam El-Hage

  2. CHU de Tours, Tours, France

    Thomas Desmidt, Nicolas Arlicot, Fabien Espitalier, Sandrine Cognet, Vincent Camus, Wissam El-Hage & Pierre Poupin

  3. CIC 1415, CHU de Tours, Inserm, Tours, France

    Thomas Desmidt, Paul-Armand Dujardin, Valérie Gissot & Wissam El-Hage

  4. Behavior and Basal Ganglia Host Team 4712, University of Rennes 1, Rennes, France Department of Psychiatry, Rennes University Hospital, Guillaume Régnier Hospital Centre, Rennes, France

    Gabriel Robert

  5. Addictology and Liaison Psychiatry Department, CHU de Nantes, 44000, Nantes, France

    Samuel Bulteau

  6. Department of Psychiatry, University Hospital, Angers, France

    Quentin Gallet & François Kazour

  7. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Helmet T. Karim

  8. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    Helmet T. Karim

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  1. Thomas Desmidt
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Contributions

TD designed the study, enrolled the depressed participants and wrote the manuscript. PAD performed the ultrasound recording and signal processing and wrote the manuscript. FA performed the MRI pre-processing and wrote the manuscript. BB performed the ultrasound recording. JPR designed the ultrasound signal processing and wrote the manuscript. VG enrolled the healthy volunteers and supervised the gas exposure. NA supervised the provision of the gas. LB supervised the MRI acquisitions. FE advised for the gas exposure. PP performed the statistics. HTK performed the MRI pre- and post-processing, analyzed the MRI data and wrote the manuscript. All authors critically reviewed the manuscript.

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Correspondence to Thomas Desmidt.

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Competing interests

TD reports personal fees from Janssen and Lundbeck. WEH reports personal fees from Air Liquide, Eisai, Janssen, Lundbeck, Otsuka, UCB and Chugai. VC reports personal fees from Janssen, Bristol Myers Squibb and AA Pharma. All other authors declare no competing interests.

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Desmidt, T., Dujardin, PA., Andersson, F. et al. Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study. Mol Psychiatry 28, 3900–3908 (2023). https://doi.org/10.1038/s41380-023-02217-6

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