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. 2023 Jan 12:13:947622.
doi: 10.3389/fpsyt.2022.947622. eCollection 2022.

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

S Parker Singleton  1 , Julie B Wang  2 , Michael Mithoefer  2   3 , Colleen Hanlon  4 , Mark S George  3   5 , Annie Mithoefer  2 , Oliver Mithoefer  3 , Allison R Coker  2   6 , Berra Yazar-Klosinski  7 , Amy Emerson  2 , Rick Doblin  7 , Amy Kuceyeski  1   8
Affiliations

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

S Parker Singleton et al. Front Psychiatry. .

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.

Keywords: MDMA; PTSD; amygdala; autobiographical memory; fMRI; functional connectivity; hippocampus; insula.

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Conflict of interest statement

MM was paid as a contractor by MAPS PBC. AE, AC, and JW received salary support for full-time employment with MAPS PBC. BY-K and RD received salary support for full-time employment with MAPS. MM is on the Clinical Advisory Board of Awakn Life Sciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Simplified study design. Subjects were assessed and imaged at the start of the study (baseline). All subjects [low dose (LD; 30 mg MDMA), medium dose (MD; 75 mg MDMA), and high dose (HD; 125 mg MDMA)] underwent three non-drug preparatory therapy sessions prior to their first MDMA dosing session. Each MDMA session was followed by three non-drug integration therapy sessions. After MDMA session 2 and the subsequent integration sessions, subjects were assessed and the dosing blind was broken. HD subjects completed their final set of drug and non-drug therapy sessions unblinded, and LD/MD subjects crossed over into the HD arm where they completed three sets of drug and non-drug sessions, now with the higher dose and unblinded. All subjects were assessed and underwent MRI approximately two months following their last HD MDMA session. See “2. Methods” section for a full description of study design and scanning protocols.
FIGURE 2
FIGURE 2
Patient CAPS-IV total severity scores at the baseline (pre-therapy) and two-month follow-up (post-therapy) scanning sessions. Black solid and dashed lines indicate group means and medians, respectively. Blue marker = male. Red marker = female. A significant reduction is PTSD severity was observed after MDMA-AT (baseline > follow-up; N = 9, t = 6.36, p = 0.00022).
FIGURE 3
FIGURE 3
Resting-state functional connectivity between the amygdala and hippocampus before and after MDMA-AT. P-values from a two-sided, paired t-test. Blue = male. Red = female. Black solid and dashed lines indicate group means and medians, respectively (N = 8; t-statistics indicate baseline > follow-up; *uncorrected p < 0.05).
FIGURE 4
FIGURE 4
Group-level activation contrasts for trauma versus neutral script listening tasks (N = 9). All panels show t-statistics for corresponding contrasts. Analyses were performed in 3 mm MNI standard space, however results here are interpolated into 1 mm MNI standard space and clipped to only show t-statistics greater than ± 1 for visualization purposes. Statistics reported below (voxels, volume, t-statistic, corrected p-value) were calculated from original 3 mm results. P-values were corrected using threshold-free cluster enhancement (TFCE; see section “2. Methods”). For panels (A–E), positive t-statistics indicate greater activation to trauma scripts compared to neutral. For panel (F), sign indicates the direction of change in trauma > neutral contrast from baseline (i.e., negative t-statistics indicate the contrast between trauma and neutral scripts was decreased at the two-month follow-up compared to baseline). Crosshairs are located on the center of gravity (c.o.g.) of significant clusters. (A) Cluster 1 for the baseline contrast is located primarily in the right and left isthmus cingulate, with some overlap into the right and left precuneus (c.o.g. MNI152 [0, –48, 24]; 6 voxels (162 mm3); c.o.g. t = 9.61, p(TFCE) = 0.0293). (B) Cluster 2 for the baseline contrast is located in the left caudal middle-frontal gyrus (c.o.g. MNI152 [-36, 21, 51]; 3 voxels (81 mm3); c.o.g. t = 9.01, p(TFCE) = 0.0234). (C) Cluster 3 for the baseline contrast is located in the right medial prefrontal cortex (c.o.g. MNI152 [6, 57, 30]; 2 voxels (54 mm3); c.o.g. t = 7.41, p(TFCE) = 0.0488). (D) Cluster 4 for the baseline contrast is located in the left rostral middle frontal gyrus (c.o.g. MNI152 [-21, 54, 15]; 1 voxel (27 mm3); c.o.g. t = 9.45, p(TFCE) = 0.0312). (E) There were no significant activation contrasts at the two-month follow-up (crosshairs shown at MNI152 [0, 0, 0]). (F) Comparing the group-level contrasts between time points (follow-up > baseline), there exists one significant cluster located primarily in the right and left cuneus, with some overlap into the right and left lingual gyrus (c.o.g. MNI152 [3, –90, 3]; 47 voxels (1,269 mm3); c.o.g t = –9.31, p(TFCE) = 0.0391).
FIGURE 5
FIGURE 5
(A) Paired t-statistics shown for differences in functional connectivity between all brain regions of interest during the task fMRI scan involving neutral and trauma memory audio listening (N = 9; baseline > follow-up; *two-sided uncorrected p < 0.05; **pFDR < 0.05, corrected). (B) Pearson correlation values between changes in ROI functional connectivity and reduction in CAPS scores. Changes were calculated as follow-up values minus baseline values. (N = 9; *uncorrected p < 0.05; **pFDR < 0.05) Age and mean FD difference between baseline and follow-up were included as covariates of non-interest. (C) Scatter plots of the three correlations that remained significant after corrections for multiple comparisons (i.e., pFDR < 0.05). Red marker = female. Blue marker = male.
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