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

Abstract

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 depressed and 10 healthy controls - HC) were exposed to a one-hour single session of EMONO and followed for one week. Cerebral connectivity of the Anterior Cingulate Cortex (ACC, seed based resting state blood oxygen level dependent) and BTP (as assessed with ultrasound Tissue Pulsatility Imaging) were compared before and after exposure (as well as during exposure for BTP) among HC, non-responders and responders. Response was defined as a reduction of at least 50% in the MADRS score one week after exposure. 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 3 groups between baseline and gas exposure, but the increase in BTP within the first ten minutes was only significant in responders. We found that a single session of EMONO can rapidly modify the functional connectivity in the ACC, especially in the subgenual region, which appears to contribute to the antidepressant response. 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.