# Specific properties changes of traumatic memory in PTSD patients after multiple reactivations of this memory under propranolol or placebo: An exploratory study

S. Taib, P. Birmes, W. El Hage, C. Thalamas, Guillaume Vaiva, A. Yrondi, Pascal Roullet

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## ► To cite this version:

S. Taib, P. Birmes, W. El Hage, C. Thalamas, Guillaume Vaiva, et al.. Specific properties changes of traumatic memory in PTSD patients after multiple reactivations of this memory under propranolol or placebo: An exploratory study. European Journal of Trauma and Dissociation, 2025, European Journal of Trauma & Dissociation, 9 (2), pp.100532. 10.1016/j.ejtd.2025.100532. hal-05139522

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Research Paper

# Specific properties changes of traumatic memory in PTSD patients after multiple reactivations of this memory under propranolol or placebo: An exploratory study ☆

<figure><img src="image_3.png" /></figure>

Simon Taïb<sup>a,b</sup>, Philippe Birmes<sup>a,b</sup>, Wissam El Hage<sup>c</sup>, Claire Thalamas<sup>d</sup>, Guillaume Vaiva<sup>e</sup>, Antoine Yrondi<sup>b</sup>, Pascal Roullet<sup>a,f,*</sup>

ARTICLE INFO

Keywords:

PTSD

Intrusive memory

Reactivation

Propranolol

Traumatic memory

ABSTRACT

**Introduction:** Intrusive memories from a traumatic event are a core criterion for a PTSD diagnosis. Very few studies have assessed the specific properties of traumatic memories and their evolution over time in patients with PTSD. The aim of this study was to compare the evolution of trauma-related memory features before and after treatment by traumatic memory reactivation under propranolol and placebo.

**Methods:** In this randomized controlled trial, 46 adults diagnosed with longstanding PTSD had an evaluation of the specific properties of their trauma-related memory using the autobiographical memory questionnaire, as well as the PTSD Checklist and Beck's Depression Inventory-II. Each of them underwent six consecutive weeks of traumatic memory reactivation under propranolol and placebo before reassessment of the psychometric properties mentioned above.

**Results:** After the six-treatment sessions, we did not observe any effect on the 19 questions on the memory of the traumatic event between patients with placebo or propranolol treatment.

However, in all patients, we found a significant positive association between PTSD symptom improvement after traumatic reactivation treatment and the reduction of emotional intensity of the memory event but also on the fact that patients felt less like returning to the past

**Discussion:** A consecutive six-week reactivation treatment in patients with PTSD led to changes in the properties of the core-features of trauma-related memories but these changes are the same in the propranolol or placebo groups.

# 1. Introduction

## 1.1. Traumatic memories

Post-traumatic stress disorder (PTSD) is a common psychiatric condition that occurs after an exposure to a traumatic event. The characteristic symptoms of the disorder include re-experiencing of trauma memories, avoidance of cues that remind the individual of the trauma,

negative emotions and thoughts, and hyperarousal (American Psychiatric Association, 2013; Ressler et al., 2022). PTSD is often associated with comorbid psychiatric diseases, such as major depressive disorder, dissociative symptoms, anxiety disorders, or substance abuse disorders (Shalev et al., 2017).

The most disabling symptom of PTSD is certainly recurrent and intrusive traumatic memories (Herzog et al., 2025; Iyadurai et al., 2019). These intrusive memories have specific properties as

<footnote><sup>a</sup> Centre Régional Psychotraumatisme Occitanie, CHU Toulouse, Toulouse, France</footnote>

<footnote><sup>b</sup> Toulouse NeuroImaging Centre, University of Toulouse, Inserm, UPS, Toulouse, France</footnote>

<footnote><sup>c</sup> University of Tours, iBrain, INSERM U1253, CHRU Tours, CIC 1415, Tours, France</footnote>

<footnote><sup>d</sup> Clinical Investigation Center 1436, Toulouse University Hospital, INSERM, Toulouse, France</footnote>

<footnote><sup>e</sup> University Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, Centre National de Ressources et Résilience pour les psychotraumatismes (Cn2r Lille - Paris), Lille, France</footnote>

<footnote><sup>f</sup> University of Toulouse, UPS, Toulouse, France</footnote>

<footnote>* Traumatic memory in PTSD patients</footnote>

<footnote>* Corresponding author at: Centre Hospitalier Léon-Jean Grégory, Pôle Nord-Ouest de Psychiatrie Adulte, Avenue du Roussillon, BP22, 66301 Thuir Cedex, France.
E-mail address: pascal.roullet@univ-tlse3.fr (P. Roullet).</footnote>
recollection, belief in the memory's accuracy, vividness, linguistic/narrative form and, rehearsal. Previous studies described property changes of traumatic memories in individuals with PTSD. For example, the patients describe them as relatively brief sensory fragments of the experience (Ehlers et al., 2002; Rubin, 2011); visual intrusions are more frequently reported than simple thoughts (Ehlers et al., 2002; Schönfeld & Ehlers, 2017) and are accompanied by a sense of present threat and "nowness", i.e., the feeling that the sensations are experienced in the present rather than in a memory of the past (Ehlers & Clark, 2000). This leads to an extremely vivid experience, associated with a high emotional intensity (Berntsen et al., 2003; Megías et al., 2007). Moreover, the traumatic memory is decontextualized and plays a leading role in the organization of the autobiographical knowledge of the patients (Brewin, 2011), resulting in a loss of episodic features of other unrelated memories in a phenomenon called "overgeneralized memory" (Moore & Zoellner, 2007). A recent review sought to investigate the accuracy of traumatic memories in persons with a diagnosis of posttraumatic stress disorder. Eleven studies were included. Most of them concluded that the memory of trauma is as accurate in people with as in those without PTSD. The only recurring difference identified across studies was in recollection of trauma over time (Mattsson et al., 2021).

## 1.2. Can traumatic memories change?

Very few studies assessed the evolution of property features of the traumatic memory after the treatment of the PTSD. The representation and details of traumatic memory may evolve after trauma-focused therapies since after treatment, only 38 % of the details were consistent with the pre-treatment narrative, 38 % were omitted, 21 % were new details and 2 % were changes (Memon et al., 2021). After Cognitive-behavioral therapy (CBT), patients with PTSD had diminished frequency of the intrusions, less vivid memories, lower associated emotional distress and lost the feeling of "nowness" associated with the flashbacks (Hackmann et al., 2004; Speckens et al., 2006). Using prolonged-exposure CBT, memory fragmentation seemed to be less important after treatment of the PTSD, and correlated with a decrease in depressive symptoms (Foa et al., 1995; van Minnen et al., 2002). However, these results remain inconsistent because Kindt and colleagues (Kindt et al., 2007) failed to replicate any change of the narrative of the traumatic event over the treatment course.

Soon after experiencing trauma, the memory is in an active state in short-term memory until it gets consolidated and stabilized into long-term memory. The retrieval of a consolidated memory at later time points returns the memory from an inactive state in long-term memory to an active state. It is well established that a reactivated memory becomes temporarily labile and requires stabilization, referred to as reconsolidation (Nader et al., 2000; Przybyslawski et al., 1999; Sara, 2000). Reconsolidation most readily takes place after brief reactivation, thereby strengthening the long-term memory. During reconsolidation events, the active memory traces are potentially susceptible to modification (Maddox et al., 2019; Milton, 2023).

## 1.3. Can treatment change traumatic memories?

Thus, as the reaction to traumatic memory is a core feature of PTSD, a novel therapeutic strategy is to block reconsolidation after memory reactivation under the influence of propranolol, a noradrenergic beta-receptor blocker (Brunet et al., 2018). In a previous study (Roullet et al., 2021), we showed that a traumatic memory reactivation treatment, associated with propranolol or placebo, was useful in treating PTSD. Even if there was no significant difference at one week post-treatment, at three months posttreatment, patients who had propranolol maintained their improvement compared to those who had placebo.

Because of these scientific premises underlying a traumatic reactivation treatment, we hypothesize that specific property changes might be observed in patients with PTSD after their treatment.

Thus, this ancillary study aims to compare the evolution of trauma-related memory features before and after the traumatic memory reactivation procedure and to analyze whether this evolution was impacted by propranolol treatment and the initial level of severity of PTSD.

As nowness, distress and lack of context predicted PTSD severity at 6 months (Michael et al., 2005) and as the emotional intensity and rehearsal were the more important properties of autobiographical memories associated with PTSD (Rubin, 2011), we expect a significant evolution on these specific measures after memory reactivation procedure.

# 2. Materials and methods

The main results for this clinical trial are presented elsewhere (Roullet et al., 2021).

## 2.1. Subjects and study design

Participants were recruited from three different university hospitals (Toulouse, Lille, Tours), in France. To be included, participants had to have a primary diagnosis of PTSD according to DSM-IV criteria with the Structured Clinical Interview for DSM (SCID) (First et al., 2007). Participants provided written informed consent after receiving a full explanation. This trial received approval from an ethics committee (CPP 2009-012,976-29) and was registered on clinicaltrials.gov (NCT01713556). Following inclusion, participants were assigned by randomised complete block, to either the "traumatic memory reactivation+propranolol" group, hereafter referred to as the propranolol group or the "traumatic memory reactivation+placebo" group, referred to as the placebo group.

The general design of the study is summarized in Fig. 1. Propranolol or placebo was administered 90-minutes before the memory reactivation session. This reactivation was performed in the center once a week for six consecutive weeks. For the first session (W1), 90 min after ingesting the propranolol or a placebo, participants wrote a one-page trauma narrative in the present tense, first person singular, focusing on the event's most disturbing moments. This task took up to 30 min. The therapist asked the patient to add some emotional details, if possible. Prior to the second session, a "traumatic script" was prepared. In subsequent treatment sessions (W2 to W6), 90 min after receiving the medication, participants read their trauma script. Participants did not receive any additional intervention.

For this present ancillary study, we kept only the patients who answered the Autobiographical Memory Questionnaires (AMQ) both before and one week after treatment (n = 46), 24 patients in the placebo group and 22 patients in the propranolol group (Fig. 2).

## 2.2. Assessment

**_The Posttraumatic stress disorder Checklist Scale (PCL-S)_** (Ventureyra et al., 2002) was used to assess PTSD symptoms. Scores ranged from 17 to 85, with higher scores reflecting increased levels of PTSD symptoms. Scores ≥ 45 reflect a condition that warrants clinical attention. We used PCL-S and not PCL-5 because at the beginning of this study, the DSM-5 was not yet published and the PCL-5 was not validated in French and so, the PCL-S was the standard measure for measuring PTSD.

**_The Beck Depression Inventory II (BDI-II)_** (Beck et al., 1996) is a 21-item self-report inventory to assess the severity of depressive symptomatology. Each symptom is rated from 0 to 3. The total score can range from 0 to 63 with scores ≥ 29 indicating symptoms of severe depression.

**_The AMQ_** was developed by Greenberg (Greenberg et al., 2005) and we translated it into French for this study. AMQ allows studying variations due to emotion, but also differential effects on specific properties of autobiographical memory.

The nineteen questions of the AMQ were specifically directed at
<figure><img src="image_4.png" /><figcaption>Fig. 1. The general design of the study. (A) Overview of the different sessions with or without treatment with, for each session (W1 to W18), the different scales measured. (B) Course of sessions with propranolol or placebo treatment. W= week; AMQ = Autobiographical Memory Questionnaires; PCL-S = Posttraumatic stress disorder Checklist Scale, BDI-II = The Beck Depression Inventory II; CM = Cardio monitoring (blood pression and heart rate).</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>Fig. 2. Eligible participants were randomly assigned to group treatments (propranolol = "traumatic memory reactivation + propranolol" group; placebo = "traumatic memory reactivation + placebo" group). W= week. At w7, we first analyzed the data by group (propranolol vs placebo) then we pooled all the data for a second analysis.</figcaption></figure>

autobiographical memory properties. The questions investigated recollection and belief, the component processes of the memory, and some of the reported properties of the events (see the different questions and quotations in Table 1).

## 2.3. Statistical analysis

Statistical analyses were performed with Jamovi 1.2.27. Sociodemographic and clinical characteristics were presented using means and standard deviations for continuous variables and frequency distributions for categorical variables. To avoid any interpretation bias, we
**Table 1**

Autobiographic Memory Questionnaire. The French version is the translation of the appendix "A" from Greenberg et al., 2005.

<table><thead><tr><th colspan="2">For the first seven questions, the scales ranged from 1 (not at all), to 3 (vaguely), to 5 (distinctly), to 7 (as clearly as if it were happening right now).</th></tr></thead><tbody><tr><td>Reliving</td><td>As I remember the event, I feel as though I am reliving the original event.</td></tr><tr><td>Hear</td><td>As I remember the event, I can hear it in my mind.</td></tr><tr><td>See</td><td>As I remember the event, I can see it in my mind.</td></tr><tr><td>Talk</td><td>As I remember the event, I or other people are talking.</td></tr><tr><td>Spatial</td><td>As I remember the event, I know its spatial layout.</td></tr><tr><td>Emotions</td><td>As I remember the event, I can feel now the emotional intensity that I felt then.</td></tr><tr><td>Setting</td><td>As I remember the event, I can recall the setting where it occurred.</td></tr><tr><td colspan="2">For the next seven questions, the scales ranged from 1 (not at all), to 3 (vaguely), to 5 (distinctly), to 7 (as much as any memory)</td></tr><tr><td>Remember/ know</td><td>Sometimes people know something happened to them without being able to actually remember it. As I think about the event, I can actually remember it rather than just knowing that it happened.</td></tr><tr><td>In words</td><td>As I remember the event, it comes to me in words.</td></tr><tr><td>Back in time</td><td>As I remember the event, I feel that I travel back to the time when it happened, that I am a subject in it again, rather than an outside observer tied to the present.</td></tr><tr><td>Story</td><td>As I remember the event, it comes to me in words or in pictures as a coherent story or episode and not as an isolated fact, observation, or scene.</td></tr><tr><td>Fragmented</td><td>My memory of the event is fragmented into specific details with missing bits.</td></tr><tr><td>General</td><td>My memory for the event is only as detailed as the general knowledge of this type of event that I would expect most people to have.</td></tr><tr><td>Coherence</td><td>My memory of the event has a personal coherence: it fits easily into a story I would tell about that part of my life.</td></tr><tr><td colspan="2">The remaining questions had unique scales.</td></tr><tr><td>Valence</td><td>Please rate the emotional valence or the kinds of emotions it involves (1 = 100 % negative; 7 = 100 % positive).</td></tr><tr><td>Real/imagine</td><td>I believe the event in my memory really occurred in the way I remember it and that I have not imagined or fabricated anything that did not occur (scale: 1 = 100 % imaginary; 7 = 100 % real).</td></tr><tr><td>Rehearsal</td><td>Since it happened, I have thought or talked about this event (scale: 1 = not at all; 7 = as often as any event in my life).</td></tr><tr><td>Field/observer</td><td>As I remember the event, I imagine it again through my own eyes seeing what I would have seen then, or as an observer from a different perspective than the one I had (1 = own eyes; 2 = observer; 3 = can't tell).</td></tr><tr><td>Once/many</td><td>To the best of your knowledge, is the memory of an event that occurred once at one particular time and place, a summary or merging of many similar or related events, or for events that occurred over a fairly continuous extended period of time lasting more than a day (scale: 1 = once; 2 = merging; 3 = extended).</td></tr></tbody></table>

performed statistical analyses to verify that sociodemographic and clinical characteristics were not different in the two groups before the start of treatment. For this, we used chi-square tests or Fisher's exact test for categorical variables and t-tests for continuous variables.

To analyze the evolution of the scores for the first seventeen questions of the AMQ between pre (W1) to post (W7) treatment, we used an ANOVA with repeated measures (between factor: treatment (placebo or propranolol); within factor: sessions (pre and post-treatment)). For the two last questions of the AMQ, group comparisons were calculated with Chi-square.

Linear regression models (enter method), adjusted based on gender, were applied to test the association between the dependent variable (scores for the 19 questions of the AMQ) and the independent variables: the intensity of post-traumatic symptoms (PCL) and intensity of depression (BDI). As a low PCLs score at W7 does not necessarily mean a strong improvement in PCLs scores, we performed an additional analysis on the improvement level of PCLs scores during pre-to-post treatment (PCLs score week 7 – PCLs score week 1).

**3. Results**

**3.1. Sociodemographic and clinical characteristics**

Thirty-three patients were randomly assigned to the propranolol group and 33 to the placebo group. Patients who did not answer the Autobiographical Memory Questionnaires before (n = 8) and after (n = 4) the procedure were excluded. Finally, we analyzed the data obtained from 46 patients, 22 in the propranolol group and 24 in the placebo one. The remaining patient characteristics are summarised in Table 2. Groups were equivalent except for the age (propranolol 44.6 (39.5–49.7) years; placebo 36.0 (31.0–41.0) years; t(44)=2.34 *p* = 0.024). Noticeably, patients of these two groups did not differ on any of the assessments measured before the start of the treatment. Indeed, the scores during week 1 are very similar on the PCL-S (t(44)=1.52 *p* = 0.135), on the BDI-II (t(44)=1.23 *p* = 0.225) scores and on the percentage of MDE (χ² (1, N = 46)=2.014 *p* = 0.143). No major adverse event occurred during our study (especially no hospitalization nor suicide attempt). None of the subjects had a significant increase of their depressive symptoms per protocol.

As in the original study (Roulet et al., 2021), we obtained a very significant reduction in the PCLs and BDI scores during the 6-treatment sessions but at the end of the treatment (W7), the propranolol patients did not differ on the level of PCLs score (t(44)=0.67 *p* = 0.419) and the

**Table 2**

Demographic and clinical characteristics.

<table><thead><tr><th></th><th>Total<br>(n = 46)</th><th>Placebo<br>group<br>(n = 24)</th><th>Propranolol<br>group<br>(n = 22)</th><th>p-value<sup>a</sup></th></tr></thead><tbody><tr><td><strong>Age:</strong> (years) Mean (95 % CI)</td><td>40.5<br>(36.7–44.3)</td><td>44.6<br>(39.5–49.7)</td><td>36.0<br>(31.0–41.0)</td><td><strong>0.024</strong></td></tr><tr><td><strong>Gender:</strong> No (%) of women</td><td>26 (56.5)</td><td>15 (62.5)</td><td>11 (50.0)</td><td>0.393</td></tr><tr><td><strong>Education:</strong> College experience No (%)</td><td>20 (43.5)</td><td>13 (54.2)</td><td>7 (31.8)</td><td>0.127</td></tr><tr><td><strong>Duration of trauma<br>before treatment</strong> (years) Mean (95 % CI)</td><td>5.9<br>(2.5–9.3)</td><td>4.85<br>(0.3–9.4)</td><td>7.04<br>(2.0–12.1)</td><td>0.531</td></tr><tr><td><strong>PCL-S score at W1:</strong> Mean (95 % CI)</td><td>64.3<br>(61.5–67.1)</td><td>62.2<br>(58.3–66.1)</td><td>66.5<br>(62.6–70.4)</td><td>0.135</td></tr><tr><td><strong>PCL-S score at W7:</strong> Mean (95 % CI)</td><td>44.4<br>(39.6–49.3)</td><td>42.5<br>(35.9–49.1)</td><td>46.5<br>(39.4–53.7)</td><td>0.419</td></tr><tr><td><strong>BDI score at W1:</strong> Mean (95 % CI)</td><td>27.5<br>(23.8–31.1)</td><td>25.3<br>(20.2–30.4)</td><td>29.9<br>(24.7–35.0)</td><td>0.225</td></tr><tr><td><strong>BDI score at W7:</strong> Mean (95 % CI)</td><td>15.8<br>(12.3–19.3)</td><td>14.6<br>(9.9–19.3)</td><td>17.0<br>(11.7–22.3)</td><td>0.505</td></tr><tr><td><strong>MDE at W1:</strong> No (%)</td><td>22 (47.8)</td><td>9 (37.5)</td><td>13 (59.1)</td><td>0.143</td></tr><tr><td><strong>Index trauma:</strong> No (%)</td><td></td><td></td><td></td><td></td></tr><tr><td style="padding-left: 20px;">Motor vehicle accident, work accident</td><td>16 (34.8)</td><td>10 (41.6)</td><td>6 (27.3)</td><td></td></tr><tr><td style="padding-left: 20px;">Physical assault</td><td>18 (39.1)</td><td>10 (41.6)</td><td>8 (36.4)</td><td></td></tr><tr><td style="padding-left: 20px;">Sexual trauma</td><td>8 (17.4)</td><td>3 (12.5)</td><td>5 (22.7)</td><td></td></tr><tr><td style="padding-left: 20px;">Combat, war zone, captivity</td><td>3 (6.5)</td><td>0 (0)</td><td>3 (13.6)</td><td></td></tr><tr><td style="padding-left: 20px;">Other</td><td>1 (2.2)</td><td>1 (4.2)</td><td>0 (0)</td><td>0.227</td></tr><tr><td><strong>Comorbidities at W1:</strong> No (%)</td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Anxiety disorders</strong></td><td></td><td></td><td></td><td></td></tr><tr><td style="padding-left: 20px;">Social phobia</td><td>4 (8.7)</td><td>1 (4.2)</td><td>3 (13.6)</td><td>0.255</td></tr><tr><td style="padding-left: 20px;">OCD</td><td>4 (8.7)</td><td>2 (8.3)</td><td>2 (9.1)</td><td>0.927</td></tr><tr><td style="padding-left: 20px;">GAD</td><td>17 (36.9)</td><td>8 (33.3)</td><td>9 (40.9)</td><td>0.511</td></tr><tr><td style="padding-left: 20px;">Panic disorder</td><td>4 (8.7)</td><td>2 (8.3)</td><td>2 (9.1)</td><td>0.927</td></tr><tr><td><strong>Substance abuse:</strong> No (%)</td><td>4 (8.7)</td><td>3 (12.5)</td><td>1 (4.5)</td><td>0.339</td></tr></tbody></table>

The data include the No of events (%) or mean (SD). <sup>a</sup> Group comparisons calculated with Chi-square, Fisher's exact test, or the independent t-test. M=mean; SD=standard deviation; No.=number; OCD=obsessive-compulsive disorder; GAD=general anxiety disorder; MDE=major depressive episode.
level of BDI score (t(44)=0.67 p = 0.505).

## 3.2. Propranolol effect on evolution of AMQ between the pre- and post-treatment session

After the six-treatment sessions, we did not observe any effect on the 19 questions on the memory of the traumatic event between patients with placebo or propranolol treatment (Table 3). Moreover, the ANOVA did not reveal any interaction between this factor and the evolution of the score of the 19 questions between W1 and W7.

However, on all patients, we were able to observe that six traumatic memory reactivation sessions modified the quality of their traumatic memory, independently of the treatment (placebo or propranolol) for different questions (Table 3) but the statistics reached the necessary level of significance with Bonferroni corrections (p < 0.0026) only for three questions. Indeed, there was a significant decrease in the emotional intensity [emotions: F(1,44)=20.07 p < 0.001] related to the traumatic event after treatment compared to before treatment. In addition, patients felt less like returning to the past after treatment [back in time: F(1,44)=28.85 p < 0.001] and thought a little less about their traumatic memory after treatment [Rehearsal: F(1,44)=12.03 p = 0.001].

## 3.3. Association between scores of the 19 questions of the AMQ before treatment and severity of PTSD symptoms and depressive symptoms

Before treatment, in a model adjusted for gender, we found no significant association between scores of the 19 questions of the AMQ and PTSD symptom severity and depressive symptom severity (Table 4). Thus before treatment, there seems to be no link between the different memory parameters of the traumatic event and the level of PTSD or depression.

<caption>**Table 4**</caption>

Association between AMQ scores before treatment and severity of PTSD and depressive symptoms.

<table><thead><tr><th rowspan="3">AMQ questions</th><th colspan="2">Before treatment (W1)</th><th colspan="2">After treatment (W7)</th></tr><tr><th colspan="2">predictors</th><th colspan="2">predictors</th></tr><tr><th>PCL p-value</th><th>BDI p-value</th><th>PCL p-value</th><th>BDI p-value</th></tr></thead><tbody><tr><td>Reliving</td><td>0.896</td><td>0.352</td><td>0.009</td><td>0.124</td></tr><tr><td>Hear</td><td>0.201</td><td>0.406</td><td>0.041</td><td>0.287</td></tr><tr><td>See</td><td>0.200</td><td>0.893</td><td>0.111</td><td>0.168</td></tr><tr><td>Talk</td><td>0.027</td><td>0.626</td><td>0.09</td><td>0.423</td></tr><tr><td>Spatial</td><td>0.043</td><td>0.090</td><td>0.221</td><td>0.543</td></tr><tr><td>Emotions</td><td>0.021</td><td>0.953</td><td><strong>&lt;0.001</strong></td><td>0.247</td></tr><tr><td>Setting</td><td>0.644</td><td>0.35</td><td>0.011</td><td>0.059</td></tr><tr><td>Remember/know</td><td>0.464</td><td>0.537</td><td>0.144</td><td>0.038</td></tr><tr><td>In words</td><td>0.802</td><td>0.152</td><td>0.914</td><td>0.591</td></tr><tr><td>Back in time</td><td>0.125</td><td>0.664</td><td><strong>0.002</strong></td><td>0.808</td></tr><tr><td>Story</td><td>0.604</td><td>0.262</td><td>0.482</td><td>0.317</td></tr><tr><td>Fragmented</td><td>0.062</td><td>0.270</td><td>0.281</td><td>0.519</td></tr><tr><td>General</td><td>0.950</td><td>0.256</td><td>0.986</td><td>0.617</td></tr><tr><td>Coherence</td><td>0.484</td><td>0.36</td><td>0.462</td><td>0.348</td></tr><tr><td>Valence</td><td>0.488</td><td>0.136</td><td>0.194</td><td>0.639</td></tr><tr><td>Real/imagine</td><td>0.648</td><td>0.716</td><td>0.94</td><td>0.286</td></tr><tr><td>Rehearsal</td><td>0.425</td><td>0.263</td><td>0.167</td><td>0.872</td></tr><tr><td>Field/observer</td><td>0.733</td><td>0.978</td><td>0.155</td><td>0.221</td></tr><tr><td>Once/many</td><td>0.072</td><td>0.005</td><td>0.802</td><td>0.822</td></tr></tbody></table>

Linear regression to test the association between the score on the 19 questions of the AMQ and the intensity of post-traumatic symptoms (PCL-S) and depression (BDI-II) before and after treatment. W=week.

## 3.4. Association between scores of the 19 questions of the AMQ after treatment and severity of PTSD symptoms and depressive symptoms

This time, one week after treatment (Table 4), we found a significant positive association between PTSD symptom severity (PCL-S W7) and the emotional intensity of the memory event [emotions: β = 0.099; SE = 0.018; t = 5.36 p < 0.001]. We also found a positive association between PTSD symptom severity (PCL-S W7) and the fact that patients felt more

<table><caption>**Table 3**
Propranolol effect on evolution of AMQ between the pre- and post-treatment session.</caption><thead><tr><th rowspan="2">AMQ questions</th><th colspan="4">Before treatment (W1)</th><th colspan="4">After treatment (W7)</th><th colspan="3">ANOVA<sup>a</sup></th></tr><tr><th colspan="2">Placebo</th><th colspan="2">Propranolol</th><th colspan="2">Placebo</th><th colspan="2">Propranolol</th><th rowspan="2">Treatment</th><th rowspan="2">Session</th><th rowspan="2">Interaction</th></tr><tr><th></th><th>Mean</th><th>CI</th><th>mean</th><th>CI</th><th>mean</th><th>CI</th><th>mean</th><th>CI</th><th>effect p-value</th><th>effect p-value</th><th>p-value</th></tr></thead><tbody><tr><td>Reliving</td><td>6.08</td><td>5.51-6.66</td><td>5.91</td><td>5.33-6.48</td><td>5.17</td><td>4.29-6.05</td><td>5.27</td><td>4.71-5.84</td><td>0.930</td><td>0.011</td><td>0.636</td></tr><tr><td>Hear</td><td>5.54</td><td>4.89-6.20</td><td>5.36</td><td>4.48-6.24</td><td>4.92</td><td>4.22-5.61</td><td>4.59</td><td>3.74-5.44</td><td>0.602</td><td>0.017</td><td>0.794</td></tr><tr><td>See</td><td>6.33</td><td>5.84-6.83</td><td>6.00</td><td>5.45-6.55</td><td>5.58</td><td>4.95-6.22</td><td>5.55</td><td>4.92-6.17</td><td>0.574</td><td>0.025</td><td>0.512</td></tr><tr><td>Talk</td><td>5.21</td><td>4.48-5.94</td><td>4.55</td><td>3.59-5.50</td><td>4.54</td><td>3.71-5.38</td><td>4.14</td><td>3.28-4.99</td><td>0.290</td><td>0.129</td><td>0.713</td></tr><tr><td>Spatial</td><td>6.42</td><td>6.03-6.81</td><td>6.36</td><td>6.01-6.72</td><td>6.17</td><td>5.67-6.66</td><td>6.09</td><td>5.63-6.55</td><td>0.789</td><td>0.198</td><td>0.955</td></tr><tr><td>Emotions</td><td>5.46</td><td>4.75-6.17</td><td>5.41</td><td>4.70-6.12</td><td>3.75</td><td>2.94-4.56</td><td>4.18</td><td>3.43-4.93</td><td>0.658</td><td><strong>&lt;0.001</strong></td><td>0.467</td></tr><tr><td>Setting</td><td>6.75</td><td>6.26-7.24</td><td>6.77</td><td>6.46-7.09</td><td>6.29</td><td>5.74-6.84</td><td>6.36</td><td>5.99-6.74</td><td>0.870</td><td>0.006</td><td>0.870</td></tr><tr><td>Remember/know</td><td>6.13</td><td>5.59-6.66</td><td>6.23</td><td>5.75-6.71</td><td>6.17</td><td>5.78-6.55</td><td>5.91</td><td>5.35-6.47</td><td>0.786</td><td>0.520</td><td>0.403</td></tr><tr><td>In words</td><td>5.08</td><td>4.29-5.87</td><td>4.45</td><td>3.53-5.38</td><td>5.25</td><td>4.50-6.00</td><td>4.32</td><td>3.56-5.07</td><td>0.124</td><td>0.960</td><td>0.618</td></tr><tr><td>Back in time</td><td>5.29</td><td>4.64-5.94</td><td>5.32</td><td>4.46-6.18</td><td>3.42</td><td>2.55-4.28</td><td>3.86</td><td>2.95-4.78</td><td>0.644</td><td><strong>&lt;0.001</strong></td><td>0.501</td></tr><tr><td>Story</td><td>5.79</td><td>5.26-6.32</td><td>5.32</td><td>4.52-6.12</td><td>5.46</td><td>4.79-6.13</td><td>5.23</td><td>4.70-5.76</td><td>0.328</td><td>0.473</td><td>0.681</td></tr><tr><td>Fragmented</td><td>4.25</td><td>3.25-5.25</td><td>3.86</td><td>2.81-4.91</td><td>3.08</td><td>2.20-3.97</td><td>3.23</td><td>2.38-4.07</td><td>0.839</td><td>0.012</td><td>0.446</td></tr><tr><td>General</td><td>3.75</td><td>2.98-4.52</td><td>3.5</td><td>2.76-4.24</td><td>3.54</td><td>2.70-4.38</td><td>3.32</td><td>2.61-4.03</td><td>0.602</td><td>0.553</td><td>0.968</td></tr><tr><td>Coherence</td><td>5.00</td><td>4.08-5.92</td><td>4.27</td><td>3.29-5.26</td><td>5.63</td><td>5.00-6.25</td><td>5.23</td><td>4.55-5.91</td><td>0.270</td><td>0.013</td><td>0.592</td></tr><tr><td>Valence</td><td>2.33</td><td>1.49-3.17</td><td>1.68</td><td>1.01-2.36</td><td>2.54</td><td>1.83-3.25</td><td>2.41</td><td>1.73-3.09</td><td>0.307</td><td>0.213</td><td>0.487</td></tr><tr><td>Real/imagine</td><td>6.75</td><td>6.41-7.09</td><td>6.86</td><td>6.67-7.06</td><td>6.88</td><td>6.74-7.01</td><td>6.55</td><td>6.21-6.88</td><td>0.473</td><td>0.428</td><td>0.073</td></tr><tr><td>Rehearsal</td><td>6.42</td><td>5.99-6.84</td><td>6.64</td><td>6.36-6.91</td><td>5.83</td><td>5.18-6.49</td><td>5.55</td><td>4.84-6.25</td><td>0.913</td><td><strong>0.001</strong></td><td>0.299</td></tr></tbody></table><table><thead><tr><th></th><th>N</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th><th>Traiment effect<br/>Session effect</th><th>χ<sup>2</sup><br/>p-value</th><th>χ<sup>2</sup><br/>p-value</th></tr></thead><tbody><tr><td>Field/observer<sup>a</sup></td><td>17</td><td>70.8</td><td>15</td><td>68.2</td><td>13</td><td>54.2</td><td>14</td><td>63.6</td><td>0.733</td><td>0.277</td><td>0.65</td></tr><tr><td>Once/many<sup>b</sup></td><td>17</td><td>70.8</td><td>14</td><td>63.6</td><td>16</td><td>66.7</td><td>17</td><td>77.2</td><td>0.859</td><td>0.277</td><td>0.65</td></tr></tbody></table>

<footnote><sup>a</sup> No. and % of answer "own eyes" (As I remember the event, I imagine it again through my own eyes seeing what I would have seen then).</footnote>

<footnote><sup>b</sup> No. and % of answer "once" (it is the memory of an event that occurred once at one particular time and place).</footnote>
like returning to the past after treatment [back in time: $\beta$ = 0.082; SE = 0.024; $t$ = 3.27 $p$ = 0.002]. For other questions, statistics did not reach the necessary level of significance with Bonferroni corrections ($p$ < 0.0026).

Now, on to the changing scores during pre-to-post treatment, we found a significant positive association between PTSD symptom improvement (PCL-S W7-W1) and the reduction of emotional intensity of the memory event [emotions: $\beta$ = 0.095; SE = 0.017; $t$ = 5.58 $p$ < 0.001] and a positive association between PTSD symptom improvement (PCL-S W7-W1) and the fact that patients felt less like returning to the past [back in time: $\beta$=0.076; SE=0.023; $t$ = 3.23 $p$ = 0.002].

On the other hand, after treatment, we found no significant association between scores of the 19 questions of the AMQ and depressive symptom severity (Table 4).

## 4. Discussion

In this ancillary study, we aimed to compare the evolution of trauma-related memory features before and after the traumatic memory reactivation procedure. In this study, propranolol did not seem to interfere with the properties of the traumatic memories. In fact, treatment with propranolol has no effect on the level of responses to the various questions after treatment or on the evolution of these responses during the procedure. However, the characteristics of the traumatic memories evolve during the six traumatic memory reactivation sessions, independently of the treatment (placebo or propranolol) for different questions. Indeed, the emotional intensity related to the traumatic event decreased, patients felt less like returning to the past and thought less about their traumatic memory after treatment. Moreover, a larger improvement of the PCL-S score was associated with a reduced emotional intensity associated with the trauma and a lesser "time travel" feeling. These results are in line with previous studies which described, as stated before, traumatic memories as being of high emotional intensity (Berntsen et al., 2003; Megías et al., 2007; Rubin, 2011) and with a disrupted sense of time experiencing, with common flashbacks and "nowness" feelings associated to them (Brewin, 2011; Ehlers & Clark, 2000; Michael et al., 2005). These characteristics tend to alleviate in our procedure or with an appropriate treatment such as cognitive behavioral therapy with a trauma focus (Hackmann et al., 2004; Rauch et al., 2004; Speckens et al., 2006).

In the main study (Roullet et al., 2021), we obtained the same improvements in PCL-S and BDI scores in patients treated with propranolol or placebo. In this study, we obtained an evolution of traumatic memory features after the six-memory reactivation sessions, but again, no difference between patient treated by propranolol or placebo. This improvement in the placebo group could be attributed to the exposure procedure (traumatic script) which was repeated six times and to the fact that patients completed seven times the same self-report (PCL) which could also have served as a form of exposure with some emotional engagement. Brief exposure, as the written exposure therapy, a five-session treatment, treatment efficacy (Roullet et al., 2021; Shayani et al., 2024). However, a prospective study comparing the effect of reactivation only versus reactivation plus placebo pill is needed to demonstrate this. If confirmed, this might be a novel argument pointing that trauma-focused psychotherapies (cognitive behavioral therapy, prolonged exposure, or the traumatic memory reactivation treatment for example) affects phenomenological features of traumatic memories in patients with PTSD.

Four trauma-focused treatments received a strong recommendation from the international society for traumatic stress studies: cognitive processing therapy, cognitive therapy for PTSD, eye movement desensitization and reprocessing therapy and prolonged-exposure (Bisson et al., 2019). These four technics shared three core elements: addressing engagement with and activation of the trauma memory, addressing trauma-related cognitions, and finally addressing experiential avoidance (Forbes et al., 2020). Our results seem in line with the first core

element. During the procedure, by repeatedly reactivating the traumatic memory, we can argue that patients who respond to the therapy progressively change the way they engage with this memory and thus modify some of its properties. Moreover, this mechanism is coherent with the theory promoted by some authors who consider that PTSD is more an inappropriate reaction to a traumatic autobiographical memory rather than to the traumatic event itself (Rubin et al., 2008).

A high number of factors have been identified as predictors of treatment outcome for patients with PTSD. For example, some socio-demographical characteristics such as a young age, female gender, being married, or being Caucasian predict a better outcome in treatment (Dewar et al., 2020). On a more clinical basis, symptoms cluster analysis tends to demonstrate that hyperarousal and severe anger were more consistently linked to poorer treatment responses (Elliott et al., 2005; Fletcher et al., 2021; Stein et al., 2012). We found only one study investigating whether characteristics of traumatic memory could be predictors of treatment outcome (Mota et al., 2015). Mota and colleagues showed that the vividness of the traumatic memory was anti-correlated to the post-treatment symptoms severity after a prolonged-exposure cognitive-behavioral therapy. Our results did not support that claim as shown in Table 3. We believe that it is unlikely that this is due to a lack of statistical relevance because no p-value was even remotely close to the significance threshold. However, the authors draw attention to the fact that gender might influence the relationship between treatment response and vividness with mixed and insignificant results when pooling the data all-together.

In our study, results did not show whether comorbid conditions such as anxiety, depression or substance abuse disorders influenced the quality or not of the narrative of the traumatic memory. Cognitive disorders are associated with each of them (Castaneda et al., 2008; Gould, 2010; Rock et al., 2014). Moreover, for example, depressed patients present more often deficits in their memory functioning than healthy subjects, presenting with changes of the declarative memory: poorer memory for positive events, potentiated memory for negative ones, and impaired recollection (Dillon & Pizzagalli, 2018). Therefore, controlling for these potential confounding factors may be important when trying to quantify the quality of traumatic memories in patients with PTSD because of the high rate of comorbidity. However, our results did not demonstrate or impact any of these conditions based on the specific properties of the trauma-related memory.

Our exploratory study has several limitations. The study began in 2013 January. At that time the DSM-5 was not yet published and not translated in French. Thus, we have used PTSD tools adjustable in accordance with DSM-IV-TR criteria. However, there are no differences in the Criterion B symptoms between DSM-IV-TR (re-experiences) and DSM-5 (intrusion symptoms). Moreover, during the validation of the PCL-5, several studies have shown the very high convergence between the PCL-S and PCL-5 scores (Blevins et al., 2015). As it is an ancillary analysis, it was not specifically designed to assess the changes of the traumatic memory features after the six treatment memory reactivation sessions. One must be very cautious and not over-interpret the changes we described as general markers for remission in PTSD. To confirm that hypothesis, future studies implicating the use of different treatment (antidepressants, prolonged-exposure therapy, EMDR...) are needed, with a controlled design versus placebo. Another limitation might be the lack of statistical significance of our study, may be due to the small simple size. Several studies showed that traumatic memories in patients with PTSD were considered vivid (Berntsen et al., 2003) and fragmented (Ehlers et al., 2002; Rubin, 2011) by the patients. We did not reach statistical significance for any items of the AMQ that could refer to these features ("Reliving", "Remember/know", "Fragmented" and "Coherence").

## 5. Conclusion

After the memory reactivation procedure, patients with
improvement of PTSD symptoms had different changes in the features of their trauma-related memories. However, it remains unclear if these changes are due to the remission itself or to a specific process common to traumatic memory reactivation and, on a broader level, all trauma-focus therapies. We need further studies to elucidate this question, focusing on patients treated with different approaches, such as antidepressants for example.

## Funding and disclosure

None of the authors reported any financial interests or potential conflicts of interest.

## CRediT authorship contribution statement

**Simon Taïb:** Writing – original draft, Resources, Formal analysis.
**Philippe Birmes:** Writing – original draft, Supervision, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization.
**Wissam El Hage:** Writing – review & editing, Validation, Investigation, Data curation. **Claire Thalamas:** Writing – review & editing, Conceptualization.
**Guillaume Vaïa:** Writing – review & editing, Validation, Investigation, Data curation.
**Antoine Yrondi:** Writing – review & editing, Validation, Conceptualization.
**Pascal Roullet:** Writing – original draft, Validation, Supervision, Software, Investigation, Formal analysis.

## Declaration of competing interest

None.

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