Genetic variation is associated with PTSD risk and aversive memory : Evidence from two trauma-Exposed African samples and one healthy European sample
2018-11-22, Wilker, Sarah, Schneider, Anna, Conrad, Daniela, Pfeiffer, Anett, Boeck, Christina, Lingenfelder, Birke, Freytag, Virginie, Vukojevic, Vanja, Elbert, Thomas, Kolassa, Iris-Tatjana
The probability to develop posttraumatic stress disorder (PTSD), characterized by vivid, intrusive emotional memories of the encountered traumatic events, depends - among other factors - on the number of previous traumatic experiences (traumatic load) and individual genetic vulnerability. So far, our knowledge regarding the biological underpinnings of PTSD is relatively sparse. Genome-wide association studies (GWAS) followed by independent replication might help to discover novel, so far unknown biological mechanisms associated with the development of traumatic memories. Here, a GWAS was conducted in N = 924 Northern Ugandan rebel war survivors and identified seven suggestively significant single nucleotide polymorphisms (SNPs; p ≤ 1 × 10-5) for lifetime PTSD risk. Of these seven SNPs, the association of rs3852144 on chromosome 5 was replicated in an independent sample of Rwandan genocide survivors (N = 370, p < .01). While PTSD risk increased with accumulating traumatic experiences, the vulnerability was reduced in carriers of the minor G-allele in an additive manner. Correspondingly, memory for aversive pictures decreased with higher number of the minor G-allele in a sample of N = 2698 healthy Swiss individuals. Finally, investigations on N = 90 PTSD patients treated with Narrative Exposure Therapy indicated an additive effect of genotype on PTSD symptom change from pre-treatment to four months after treatment, but not between pre-treatment and the 10-months follow-up. In conclusion, emotional memory formation seems to decline with increasing number of rs3852144 G-alleles, rendering individuals more resilient to PTSD development. However, the impact on therapy outcome remains preliminary and further research is needed to determine how this intronic marker may affect memory processes in detail.
Does trauma event type matter in the assessment of traumatic load?
2017-07-06, Conrad, Daniela, Wilker, Sarah, Pfeiffer, Anett, Lingenfelder, Birke, Ebalu, Tracie, Lanzinger, Hartmut, Elbert, Thomas, Kolassa, Iris-Tatjana, Kolassa, Stephan
The likelihood of developing Posttraumatic Stress Disorder (PTSD) depends on the interaction of individual risk factors and cumulative traumatic experiences. Hence, the identification of individual susceptibility factors warrants precise quantification of trauma exposure. Previous research indicated that some traumatic events may have more severe influences on mental health than others; thus, the assessment of traumatic load may be improved by weighting event list items rather than calculating the simple sum score.
We compared two statistical methods, Random Forests using Conditional Interference (RF-CI) and Least Absolute Shrinkage and Selection Operator (LASSO), based on their ability to rank traumatic experiences according to their importance for predicting lifetime PTSD.
Statistical models were initially fitted in a sample of N1 = 441 survivors of the Northern Ugandan rebel war. The ability to correctly predict lifetime PTSD was then tested in an independent sample of N2 = 211, and subsequently compared with predictions by the simple sum score of different traumatic event types experienced.
Results indicate that RF-CI and LASSO allow for a ranking of traumatic events according to their predictive importance for lifetime PTSD. Moreover, RF-CI showed slightly better prediction accuracy than the simple sum score, followed by LASSO when comparing prediction results in the validation sample.
Given the expense in time and calculation effort by RF-CI and LASSO, and the relatively low increase in prediction accuracy by RF-CI, we recommend using the simple sum score to measure the environmental factor traumatic load, e.g., in analyses of gene × environment interactions.
Endocannabinoid concentrations in hair are associated with PTSD symptom severity
2016-05, Wilker, Sarah, Pfeiffer, Anett, Elbert, Thomas, Ovuga, Emilio, Karabatsiakis, Alexander, Krumbholz, Aniko, Thieme, Detlef, Schelling, Gustav, Kolassa, Iris-Tatjana
The endocannabinoid system has been implicated in the regulation of the stress response, fear memory formation, and inflammatory processes. Posttraumatic stress disorder (PTSD) can result from exposure to extreme stress and is characterized by strong, associative memories for the traumatic events experienced. Furthermore, an elevated physical disease risk has been observed in PTSD, likely to be mediated by inflammatory processes. Therefore, altered endocannabinoid regulation can be expected in individuals with PTSD. However, attempts to assess PTSD-associated differences in the endocannabinoid system from human blood samples have provided inconsistent results, possibly due to fluctuating levels of endocannabinoids. In hair, these neuromodulators are accumulated over time and thus give access to a more stable and reliable assessment. We therefore investigated PTSD-associated differences in hair concentrations of endocannabinoids (N-acyl-ethanolamides palmitoylethanolamide [PEA], oleoylethanolamide [OEA] and stearoylethanolamide [SEA]) in 38 rebel war survivors from Northern Uganda suffering from PTSD and N=38 healthy rebel war survivors without current and lifetime PTSD. PTSD diagnosis and symptom severity were assessed in structured clinical interviews employing the Posttraumatic Diagnostic Scale (PDS). A significant group difference was observed for OEA, with PTSD patients showing reduced hair concentrations. Regression analyses further revealed strong negative relationships between all investigated N-acyl-ethanolamides and symptom severity of PTSD. The observed reductions in endocannabinoids might account for the increased inflammatory state as well as for the failure to extinguish fear memories observed in PTSD. Our findings add to the accumulating evidence suggesting the endocannabinoid system as a target for pharmacological enhancement of exposure-based psychotherapy for PTSD.
Gains in cognition through combined cognitive and physical training : the role of training dosage and severity of neurocognitive disorder
2015, Bamidis, Panagiotis D., Fissler, Patrick, Papageorgiou, Sokratis G., Zilidou, Vasiliki, Konstantinidis, Evdokimos I., Billis, Antonis S., Romanopoulou, Evangelia, Karagianni, Maria, Beratis, Ion, Tsapanou, Angeliki, Tsilikopoulou, Georgia, Grigoriadou, Eirini, Ladas, Aristea, Kyrillidou, Athina, Tsolaki, Anthoula, Frantzidis, Christos, Sidiropoulos, Efstathios, Siountas, Anastasios, Matsi, Stavroula, Papatriantafyllou, John, Margioti, Eleni, Nika, Aspasia, Schlee, Winfried, Elbert, Thomas, Tsolaki, Magda, Vivas, Ana B., Kolassa, Iris-Tatjana
Physical as well as cognitive training interventions improve specific cognitive functions but effects barely generalize on global cognition. Combined physical and cognitive training may overcome this shortcoming as physical training may facilitate the neuroplastic potential which, in turn, may be guided by cognitive training. This study aimed at investigating the benefits of combined training on global cognition while assessing the effect of training dosage and exploring the role of several potential effect modifiers. In this multi-center study, 322 older adults with or without neurocognitive disorders (NCDs) were allocated to a computerized, game-based, combined physical and cognitive training group (n = 237) or a passive control group (n = 85). Training group participants were allocated to different training dosages ranging from 24 to 110 potential sessions. In a pre-post-test design, global cognition was assessed by averaging standardized performance in working memory, episodic memory and executive function tests. The intervention group increased in global cognition compared to the control group, p = 0.002, Cohen's d = 0.31. Exploratory analysis revealed a trend for less benefits in participants with more severe NCD, p = 0.08 (cognitively healthy: d = 0.54; mild cognitive impairment: d = 0.19; dementia: d = 0.04). In participants without dementia, we found a dose-response effect of the potential number and of the completed number of training sessions on global cognition, p = 0.008 and p = 0.04, respectively. The results indicate that combined physical and cognitive training improves global cognition in a dose-responsive manner but these benefits may be less pronounced in older adults with more severe NCD. The long-lasting impact of combined training on the incidence and trajectory of NCDs in relation to its severity should be assessed in future long-term trials.
Stigmatization Is Associated with Increased PTSD Risk and Symptom Severity After Traumatic Stress and Diminished Likelihood of Spontaneous Remission : A Study with East-African Conflict Survivors
2018-10-10, Schneider, Anna, Conrad, Daniela, Pfeiffer, Anett, Elbert, Thomas, Kolassa, Iris-Tatjana, Wilker, Sarah
Studies in conflict population have repeatedly documented that the number of traumatic event types experienced (trauma load) increases the risk to develop posttraumatic stress disorder (PTSD) in a dose-dependent manner. Misconceptions about the survivor’s experiences and actions during the war, as well as mental health symptoms frequently lead to stigmatization by their own families and the community, which might render them even more vulnerable for PTSD development and prevent successful recovery. We therefore wanted to investigate whether stigmatization affects trauma-related psychopathology beyond the well-known effect of trauma load. The study sample comprised N = 1131 survivors of the rebel war led by the Lord’s resistance Army (LRA) in Northern Uganda, including a large proportion of formerly abducted individuals and child soldiers. We investigated how the experience of stigmatization affects PTSD risk, symptom severity and the likelihood of spontaneous remission, taking trauma load into account. Further, the association of stigmatization with treatment outcome was determined in a subsample of N = 284 individuals with PTSD who received trauma-focused psychotherapy. More than one third of the total sample, and almost two-third of the therapy subsample reported experiences of stigmatization. The main reasons for stigmatization were related to an association with a terrorist rebel group (e.g. being called a rebel), followed by mental health problems/PTSD symptoms and HIV/Aids. Stigmatization was strongly associated with a higher prevalence of lifetime and current PTSD, a diminished probability of spontaneous remission and higher PTSD symptoms before and after trauma-focused psychotherapy, beyond the effect of trauma load. In sum, our results support the assumption that stigmatization aggravates trauma-related psychopathology and impede symptom improvement. In post-conflict regions, community and family interventions, which aim at reducing stigmatization and discrimination, might therefore complement individual psychotherapy in order to allow survivors to recover and reintegrate into society.
Exome sequencing of healthy phenotypic extremes links TROVE2 to emotional memory and PTSD
2017-03-27, Heck, Angela, Milnik, Annette, Vukojevic, Vanja, Petrovska, Jana, Egli, Tobias, Singer, Jochen, Escobar, Pablo, Kolassa, Iris-Tatjana, Elbert, Thomas, Papassotiropoulos, Andreas
Many mental disorders represent the extremes of the normal distribution of traits, which are related to multiple cognitive and emotional dimensions. By performing whole-exome sequencing of healthy, young subjects with extremely high versus extremely low aversive memory performance, we identified TROVE2 as a gene implicated in emotional memory in health and disease. TROVE2 encodes Ro60, a broadly expressed RNA-binding protein implicated in the regulation of inflammatory gene expression and autoimmunity. A regulatory TROVE2 variant was linked to higher emotional memory capacity and higher emotional memory-related brain activation in healthy subjects. In addition, TROVE2 was associated with traumatic memory and the frequency of post-traumatic stress disorder in genocide survivors.
Cognitive change is more positively associated with an active lifestyle than with training interventions in older adults at risk of dementia : a controlled interventional clinical trial
2016, Küster, Olivia C., Fissler, Patrick, Laptinskaya, Daria, Thurm, Franka, Scharpf, Andrea, Woll, Alexander, Kolassa, Stephan, Kramer, Arthur F., Elbert, Thomas, Kolassa, Iris-Tatjana
While observational studies show that an active lifestyle including cognitive, physical, and social activities is associated with a reduced risk of cognitive decline and dementia, experimental evidence from corresponding training interventions is more inconsistent with less pronounced effects. The aim of this study was to evaluate and compare training- and lifestyle-related changes in cognition. This is the first study investigating these associations within the same time period and sample.
Mental Defeat and Cumulative Trauma Experiences Predict Trauma-Related Psychopathology : Evidence From a Postconflict Population in Northern Uganda
2017-11, Wilker, Sarah, Kleim, Birgit, Geiling, Angelika, Pfeiffer, Anett, Elbert, Thomas, Kolassa, Iris-Tatjana
The peritraumatic cognitive process of mental defeat, the complete loss of inner resistance, has been identified as a key predictor of PTSD. Yet, most evidence on cognitive risk factors stems from industrialized countries where survivors typically report few traumata. Research from postconflict settings indicates that individual differences decrease with accumulating traumatic experiences, as almost everybody develops PTSD at extreme levels of trauma load. Would this leave less room for the impact of cognitive processes? In a sample of 227 Ugandan rebel war survivors, we investigated whether mental defeat influences trauma-related psychopathology in regression models accounting for cumulative trauma exposure. We found strong main effects of mental defeat on lifetime PTSD risk, current PTSD severity and dissociative symptoms, but no mental defeat × trauma load interaction effects. Our results indicate that peritraumatic mental defeat is central to understand individual differences in psychological reactions after single traumatic events as well as multiple traumatization.
No Evidence That Short-Term Cognitive or Physical Training Programs or Lifestyles Are Related to Changes in White Matter Integrity in Older Adults at Risk of Dementia
2017-03-20, Fissler, Patrick, Müller, Hans-Peter, Küster, Olivia C., Laptinskaya, Daria, Thurm, Franka, Woll, Alexander, Elbert, Thomas, Kassubek, Jan, von Arnim, Christine A. F., Kolassa, Iris-Tatjana
Cognitive and physical activities can benefit cognition. However, knowledge about the neurobiological mechanisms underlying these activity-induced cognitive benefits is still limited, especially with regard to the role of white matter integrity (WMI), which is affected in cognitive aging and Alzheimer's disease. To address this knowledge gap, we investigated the immediate and long-term effects of cognitive or physical training on WMI, as well as the association between cognitive and physical lifestyles and changes in WMI over a 6-month period. Additionally, we explored whether changes in WMI underlie activity-related cognitive changes, and estimated the potential of both trainings to improve WMI by correlating training outcomes with WMI. In an observational and interventional pretest, posttest, 3-month follow-up design, we assigned 47 community-dwelling older adults at risk of dementia to 50 sessions of auditory processing and working memory training (n = 13), 50 sessions of cardiovascular, strength, coordination, balance and flexibility exercises (n = 14), or a control group (n = 20). We measured lifestyles trough self-reports, cognitive training skills through training performance, functional physical fitness through the Senior Fitness Test, and global cognition through a cognitive test battery. WMI was assessed via a composite score of diffusion tensor imaging-based fractional anisotropy (FA) of three regions of interest shown to be affected in aging and Alzheimer's disease: the genu of corpus callosum, the fornix, and the hippocampal cingulum. Effects for training interventions on FA outcomes, as well as associations between lifestyles and changes in FA outcomes were not significant. Additional analyses did show associations between cognitive lifestyle and global cognitive changes at the posttest and the 3-month follow-up (β ≥ 0.40, p ≤ 0.02) and accounting for changes in WMI did not affect these relationships. The targeted training outcomes were related to FA scores at baseline (cognitive training skills and FA composite score, rs = 0.68, p = 0.05; functional physical fitness and fornix FA, r = 0.35, p = 0.03). Overall, we found no evidence of a link between short-term physical or cognitive activities and WMI changes, despite activity-related cognitive changes in older adults at risk of dementia. However, we found positive associations between the two targeted training outcomes and WMI, hinting at a potential of long-term activities to affect WMI.
Accelerated ageing and effects of psychotherapy on DNA strand break accumulation in individuals suffering from posttraumatic stress disorders
2015, Moreno-Villanueva, Maria, Morath, Julia, Vanhooren, Valerie, Elbert, Thomas, Libert, Claude, Bürkle, Alexander, Kolassa, Iris-Tatjana
The prevalence of age-related diseases is increased in individuals with Posttraumatic Stress Disorder (PTSD). At the molecular level, N-Glycosylation is an age-dependent process, identified as a biomarker for physiological aging (GlycoAge Test). Individuals with PTSD and trauma-exposed individuals presented an upward shift in the GlycoAge Test, equivalent to an advancement of the aging process by 15 additional years.
On the other hand traumatic stress may increase carcinogenesis via increased DNA damage and impaired DNA repair mechanisms. We found higher levels of basal DNA breakage in individuals with PTSD and trauma-exposed subjects than in controls. However, single-strand break repair was unimpaired in individuals with PTSD.
In conclusion, our results suggest that cumulative exposure to traumatic stressors accelerates the process of physiological aging and show – for the first time in vivo – an association between traumatic stress and DNA breakage. Moreover, we demonstrate changes at the molecular level, i.e. the integrity of DNA, after psychotherapeutic interventions.