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      Altered brain activity and functional connectivity after MDMA-assisted therapy for post-traumatic stress disorder

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          Abstract

          Introduction

          3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) for post-traumatic stress disorder (PTSD) has demonstrated promise in multiple clinical trials. MDMA is hypothesized to facilitate the therapeutic process, in part, by decreasing fear response during fear memory processing while increasing extinction learning. The acute administration of MDMA in healthy controls modifies recruitment of brain regions involved in the hyperactive fear response in PTSD such as the amygdala, hippocampus, and insula. However, to date there have been no neuroimaging studies aimed at directly elucidating the neural impact of MDMA-AT in PTSD patients.

          Methods

          We analyzed brain activity and connectivity via functional MRI during both rest and autobiographical memory (trauma and neutral) response before and two-months after MDMA-AT in nine veterans and first-responders with chronic PTSD of 6 months or more.

          Results

          We hypothesized that MDMA-AT would increase amygdala-hippocampus resting-state functional connectivity, however we only found evidence of a trend in the left amygdala—left hippocampus ( t = –2.91, uncorrected p = 0.0225, corrected p = 0.0901). We also found reduced activation contrast (trauma > neutral) after MDMA-AT in the cuneus. Finally, the amount of recovery from PTSD after MDMA-AT correlated with changes in four functional connections during autobiographical memory recall: the left amygdala—left posterior cingulate cortex (PCC), left amygdala—right PCC, left amygdala—left insula, and left isthmus cingulate—left posterior hippocampus.

          Discussion

          Amygdala—insular functional connectivity is reliably implicated in PTSD and anxiety, and both regions are impacted by MDMA administration. These findings compliment previous research indicating that amygdala, hippocampus, and insula functional connectivity is a potential target of MDMA-AT, and highlights other regions of interest related to memory processes. More research is necessary to determine if these findings are specific to MDMA-AT compared to other types of treatment for PTSD.

          Clinical trial registration

          https://clinicaltrials.gov/ct2/show/NCT02102802, identifier NCT02102802.

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          Most cited references119

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest.

            In this study, we have assessed the validity and reliability of an automated labeling system that we have developed for subdividing the human cerebral cortex on magnetic resonance images into gyral based regions of interest (ROIs). Using a dataset of 40 MRI scans we manually identified 34 cortical ROIs in each of the individual hemispheres. This information was then encoded in the form of an atlas that was utilized to automatically label ROIs. To examine the validity, as well as the intra- and inter-rater reliability of the automated system, we used both intraclass correlation coefficients (ICC), and a new method known as mean distance maps, to assess the degree of mismatch between the manual and the automated sets of ROIs. When compared with the manual ROIs, the automated ROIs were highly accurate, with an average ICC of 0.835 across all of the ROIs, and a mean distance error of less than 1 mm. Intra- and inter-rater comparisons yielded little to no difference between the sets of ROIs. These findings suggest that the automated method we have developed for subdividing the human cerebral cortex into standard gyral-based neuroanatomical regions is both anatomically valid and reliable. This method may be useful for both morphometric and functional studies of the cerebral cortex as well as for clinical investigations aimed at tracking the evolution of disease-induced changes over time, including clinical trials in which MRI-based measures are used to examine response to treatment.
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              Advances in functional and structural MR image analysis and implementation as FSL.

              The techniques available for the interrogation and analysis of neuroimaging data have a large influence in determining the flexibility, sensitivity, and scope of neuroimaging experiments. The development of such methodologies has allowed investigators to address scientific questions that could not previously be answered and, as such, has become an important research area in its own right. In this paper, we present a review of the research carried out by the Analysis Group at the Oxford Centre for Functional MRI of the Brain (FMRIB). This research has focussed on the development of new methodologies for the analysis of both structural and functional magnetic resonance imaging data. The majority of the research laid out in this paper has been implemented as freely available software tools within FMRIB's Software Library (FSL).
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                Author and article information

                Contributors
                Journal
                Front Psychiatry
                Front Psychiatry
                Front. Psychiatry
                Frontiers in Psychiatry
                Frontiers Media S.A.
                1664-0640
                12 January 2023
                2022
                : 13
                : 947622
                Affiliations
                [1] 1Department of Computational Biology, Cornell University , Ithaca, NY, United States
                [2] 2MAPS Public Benefit Corporation , San Jose, CA, United States
                [3] 3Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina , Charleston, SC, United States
                [4] 4Wake Forest School of Medicine , Winston-Salem, NC, United States
                [5] 5Ralph H. Johnson VA Medical Center , Charleston, SC, United States
                [6] 6Department of Neurology, University of California , San Francisco, San Francisco, CA, United States
                [7] 7Multidisciplinary Association for Psychedelic Studies , San Jose, CA, United States
                [8] 8Department of Radiology, Weill Cornell Medicine , New York, NY, United States
                Author notes

                Edited by: Peter Schuyler Hendricks, University of Alabama at Birmingham, United States

                Reviewed by: Andrew Burke, Indiana University Bloomington, United States; Manoj Doss, Johns Hopkins University, United States; Haley Dourron, University of Alabama at Birmingham, United States

                *Correspondence: S. Parker Singleton, sps253@ 123456cornell.edu

                This article was submitted to Psychopharmacology, a section of the journal Frontiers in Psychiatry

                Article
                10.3389/fpsyt.2022.947622
                9879604
                36713926
                b1429ee8-a00b-4780-9fa7-0c25ff89ed6c
                Copyright © 2023 Singleton, Wang, Mithoefer, Hanlon, George, Mithoefer, Mithoefer, Coker, Yazar-Klosinski, Emerson, Doblin and Kuceyeski.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 May 2022
                : 19 December 2022
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 113, Pages: 16, Words: 11158
                Funding
                Funded by: National Institutes of Health, doi 10.13039/100000002;
                Award ID: RF1MH123232
                Award ID: R01NS102646
                The clinical trial was sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS), a 501(c)(3) non-profit organization. MAPS provided the MDMA and fully funded this study from private and foundation donations. MAPS Public Benefit Corporation (MAPS PBC), wholly owned by MAPS, was the trial organizer. SPS was supported by the National Science Foundation Graduate Research Fellowship (Grant No. DGE-1650441). AK was supported by the National Institutes of Health (RF1MH123232, R01NS102646, and R21NS104634).
                Categories
                Psychiatry
                Clinical Trial

                Clinical Psychology & Psychiatry
                ptsd,mdma,amygdala,hippocampus,insula,fmri,functional connectivity,autobiographical memory

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