Posttraumatic stress disorder (PTSD) is a psychological disorder that develops following exposure to perceived life-threatening trauma. Characteristic features include behavioral changes caused by... Show morePosttraumatic stress disorder (PTSD) is a psychological disorder that develops following exposure to perceived life-threatening trauma. Characteristic features include behavioral changes caused by heightened arousal, including fear and anxiety. Glucocorticoid receptor (GR) hypersensitivity, as defined by strong negative feedback, has been one of the most robust findings of altered HPA axis function in PTSD. In this thesis, we evaluated GR-related changes that were exposed to the three consecutive stressors of the single prolonged stress (SPS) animal model for PTSD. We tested the potential of the GR antagonist RU486 treatment in reversing these stress-induced effects. We found that GR antagonism can normalize some stress-induced parameters. We demonstrated that varying the timing of RU486 administration and evaluation gave different behavioral results and dynamics of gene expression, that revealed complex interactions between stress and RU486 over time. We also tested the GR sensitivity after administered the exogenous corticosterone. Our data suggest the enhanced stress responsiveness after SPS to moderate but not mild stressors and a sensitization of brain GR signaling that extends beyond direct negative feedback regulation. Lastly, we provide evidence for a role of β-arrestin-2 as a modulator of regulating amygdala activity in response to fear/anxious memory of PTSD. Show less
Background: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies... Show moreBackground: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. Methods: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. Results: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for D-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. Conclusion: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable. Show less
Jones, C.; Smith-MacDonald, L.; Veelen, N. van; VanderLaan, A.; Kaneva, Z.; Dunleavy, R.S.; ... ; Bremault-Phillips, S. 2022
Background As provisions of mental healthcare services to military and veteran populations increases the risk to service providers developing secondary traumatic stress (STS), efforts are needed to... Show moreBackground As provisions of mental healthcare services to military and veteran populations increases the risk to service providers developing secondary traumatic stress (STS), efforts are needed to examine the impact of delivering novel interventions which may include 3MDR. As a virtual-reality supported intervention, 3MDR exposes the patient, therapist and operator to graphic and sensory stimuli (i.e. narratives, imagery, smells, and music) in the course of the intervention. 3MDR is actively being researched at multiple sites internationally within military and veteran populations. It is, therefore, crucial to ensure the safety and wellbeing of 3MDR therapists and operators who are exposed to potentially distressing sensory stimuli. Objective The purpose of this study is to qualitatively examine the impact and experiences of STS amongst therapists and operators in delivering 3MDR. For this study, impact will be defined as therapists or operators experiencing perceived STS as a result of delivering 3MDR. Methods This exploratory qualitative study recruited 3MDR therapists and operators (N = 18) from Canada, the Netherlands, the United Kingdom, and the United States who had previously delivered 3MDR therapy. Telephone or video-conferencing interviews were used to gather data that was subsequently transcribed and thematically analyzed. Results Four themes emerged among the therapists (n = 13) and operators (n = 5): (1) personal cost and benefits of 3MDR, (2) professional paradox of a 3MDR therapist, (3) perceived effect of 3MDR on patients, and (4) recommendations for future 3MDR use. Conclusions STS was not noted to be a significant challenge for 3MDR therapists and operators. Future research may investigate optimal means of providing training and ongoing support for 3MDR therapists and operators. Show less
Oprel, D.A.C.; Hoeboer, C.M.; Schoorl, M.; Kleine, R.A. de; Cloitre, M.; Wigard, I.G.; ... ; Does, W. van der 2021
Background: It is unclear whether the evidence-based treatments for PTSD are as effective in patients with CA-PTSD.Objective: We aimed to investigate the effectiveness of three variants of... Show moreBackground: It is unclear whether the evidence-based treatments for PTSD are as effective in patients with CA-PTSD.Objective: We aimed to investigate the effectiveness of three variants of prolonged exposure therapy.Method: We recruited adults with CA-PTSD. Participants were randomly assigned to Prolonged Exposure (PE; 16 sessions in 16 weeks), intensified Prolonged Exposure (iPE; 12 sessions in 4 weeks followed by 2 booster sessions) or a phase-based treatment, in which 8 sessions of PE were preceded by 8 sessions of Skills Training in Affective and Interpersonal Regulation (STAIR+PE; 16 sessions in 16 weeks). Assessments took place in week 0 (baseline), week 4, week 8, week 16 (post-treatment) and at a 6-and 12-month follow-up. The primary outcome was clinician-rated PTSD symptom severity.Results: We randomly assigned 149 patients to PE (48), iPE (51) or STAIR+PE (50). All treatments resulted in large improvements in clinician assessed and self-reported PTSD symptoms from baseline to 1-year follow-up (Cohen's d > 1.6), with no significant differences among treatments. iPE led to faster initial symptom reduction than PE for self-report PTSD symptoms (t(135) = -2.85, p = .005, d = .49) but not clinician-assessed symptoms (t(135) = -1.65, p = .10) and faster initial symptom reduction than STAIR+PE for self-reported (t(135) = -4.11, p < .001, d = .71) and clinician-assessed symptoms (t(135) = -2.77, p = .006, Cohen's d = .48) STAIR+PE did not result in significantly more improvement from baseline to 1-year follow-up on the secondary outcome emotion regulation, interpersonal problems and self-esteem compared to PE and iPE. Dropout rates did not differ significantly between conditions.Conclusions: Variants of exposure therapy are tolerated well and lead to large improvements in patients with CA-PTSD. Intensifying treatment may lead to faster improvement but not to overall better outcomes.The trial is registered at the clinical trial registry, number NCT03194113, Show less
Gelderen, M.J. van; Nijdam, M.J.; Vries, F. de; Meijer, O.C.; Vermetten, E. 2020
Background: Hypothalamic-pituitary-adrenal axis functioning has been related to treatment outcome in posttraumatic stress disorder (PTSD). Previous studies have primarily focused on cortisol levels... Show moreBackground: Hypothalamic-pituitary-adrenal axis functioning has been related to treatment outcome in posttraumatic stress disorder (PTSD). Previous studies have primarily focused on cortisol levels before and after a course of therapy and findings have not been fully consistent. This study investigated session-related cortisol levels in veterans with treatment-resistant PTSD over the course of a novel motion-assisted virtual reality exposure therapy and aimed to determine whether cortisol levels were related to changes in PTSD symptom severity.Methods: Veterans (N = 22) received six exposure sessions during which salivary cortisol samples were collected pre-session, post-session and in the late afternoon following sessions. PTSD symptom severity was assessed by structured clinical interviews at pre- and post-treatment. Average cortisol levels were compared between responders and non-responders. Linear regression analyses were conducted with PTSD symptom change as criterion variable, average cortisol levels as predictor, and timing of sampling and baseline PTSD symptoms as covariates.Results: Responders to treatment tended to have higher average cortisol levels at pre-session (p = 0.064) and postsession (p = 0.050) compared to non-responders. Higher average pre-session and post-session cortisol levels predicted greater PTSD symptom improvement (pre: b = 1.83, p = 0.009; post: b = 3.57, p = 0.004).Conclusion: This study provides preliminary evidence for session-related cortisol as biomarker of response to exposure-based therapies for PTSD. Higher cortisol levels may have facilitated fear extinction and reconsolidation, and may indicate increased physiological stress activation necessary for appropriate treatment engagement. Further work involving comparable methodology is encouraged to establish session-related cortisol as biomarker and to determine the mechanisms through which it interacts with treatment outcome. Show less
Gelderen, M.J. van; Nijdam, M.J.; Haagen, J.F.G.; Vermetten, E. 2020
Background:Veterans with posttraumatic stress disorder (PTSD) tend to benefit less from evidence-based treatments than other PTSD populations. A novel virtual reality and motion-assisted exposure... Show moreBackground:Veterans with posttraumatic stress disorder (PTSD) tend to benefit less from evidence-based treatments than other PTSD populations. A novel virtual reality and motion-assisted exposure therapy, called 3MDR, provides treatment in an immersive, personalized and activating context.Objective:To study the efficacy of 3MDR for veterans with treatment-resistant PTSD.Method:In a randomized controlled trial (n= 43) 3MDR was compared to a non-specific treatment component control group. Primary outcome was clinician-rated PTSD symptoms at baseline, after 3MDR, and at the 12-week and 16-week follow-up (primary end point). Intention-to-treat analyses of covariance and mixed models were applied to study differences between groups at the end point and over the course of intervention, controlling for baseline scores.Results:The decrease in PTSD symptom severity from baseline to end point was significantly greater for 3MDR as compared to the control group, with a large effect size (F[1, 37] = 6.43,p= 0.016,d= 0.83). No significant between-group difference was detected in the course of PTSD symptoms during treatment when including all time points. The dropout rate was low (7%), and 45% of the patients in the 3MDR group improved clinically. The number needed to treat was 2.86.Conclusions:In this trial, 3MDR significantly decreased PTSD symptoms in veterans with, on average, a history of 4 unsuccessful treatments. The low dropout rate may be indicative of high engagement. However, a lack of significant differences on secondary outcomes limits conclusions that can be drawn on its efficacy and underlines the need for larger phase III trials. These data show emerging evidence for 3MDR and its potential to progress PTSD treatment for veterans (Dutch Trial Register Identifier: NL5126). Show less
Oprel, D.A.C.; Hoeboer, C.M.; Schoorl, M.; Kleine, R.A. de; Wigard, I.G.; Cloitre, M.; ... ; Does, W. van der 2018
