Epigenetics of traumatic stress : The association of NR3C1 methylation and posttraumatic stress disorder symptom changes in response to narrative exposure therapy
2023-01-19, Wilker, Sarah, Vukojevic, Vanja, Schneider, Anna, Pfeiffer, Anett, Inerle, Stefan, Pauly, Markus, Elbert, Thomas, Papassotiropoulos, Andreas, de Quervain, Dominique, Kolassa, Iris-Tatjana
Epigenetic processes allow plasticity in gene regulation in response to significant environmental events. Accumulating evidence suggests that effective psychotherapy is accompanied by epigenetic changes, rendering DNA methylation a potential biomarker of therapy success. Due to the central role of glucocorticoid dynamics in stress regulation and the alteration of aversive memories, glucocorticoid receptors are likely involved in the molecular processes that are required to successfully treat Posttraumatic Stress Disorder (PTSD). This study aimed to investigate the relationship between methylation at the glucocorticoid receptor gene ( NR3C1 ) and PTSD treatment success of evidence-based psychotherapy. A sample of N = 153 conflict survivors from Northern Uganda (98 females and 55 males) with PTSD were treated with Narrative Exposure Therapy (NET). Diagnostic interviews and saliva sampling took place at pretreatment and 4 and 10 months after treatment completion. We investigated potential associations between PTSD symptom development and methylation changes at 38 CpG sites spanning NR3C1 over the three times of measurement using the repeated measures correlation. After accounting for multiple comparisons, DNA methylation at CpG site cg25535999 remained negatively associated with PTSD symptoms. These results were followed up by mixed models as well as structural equation modelling. These analyses revealed that treatment responders had a significant cg25535999 methylation increase after treatment with NET. Furthermore, lower methylation at cg25535999 pretreatment predicted a higher symptom improvement. Our results suggest different epigenetic profile dynamics at NR3C1 cg25535999 in therapy responders compared to non-responders and underscore the central role of glucocorticoid signaling in trauma-focused therapy.
A combination of combat experience, early abduction and severe traumatization fuels appetitive aggression and violence among abductees of rebel war in Northern Uganda
2020-11, Rukundo-Zeller, Anja C., Conrad, Daniela, Schneider, Anna, Behnke, Alexander, Pfeiffer, Annett, Blum, Gerrit, Wilker, Sarah, Elbert, Thomas, Kolassa, Iris-Tatjana
Individuals who perpetrate violence may likely perceive violence as appealing and infliction of violence to derive pleasure is termed as appetitive aggression. Individuals who were abducted as children into an armed group often experience a higher number of traumatic event types, that is traumatic load and are usually socialized in a violence-endorsing environment. This study aims to investigate the interaction between age at initial abduction with that of traumatic load, and their influence on appetitive aggression along with perpetration of violent acts by former members of an armed rebel group of both sexes. Semi-structured interviews were conducted among a target group of formerly abducted rebel-war survivors (including participants with and without combat experience) from Northern Uganda. Participants included 596 women and 570 men with N = 1,166 (Mage = 32.58, SDage = 9.76, range: 18-80 years). We conducted robust linear regression models to investigate the influence of age at initial abduction, traumatic load, combat experience, and biological sex on appetitive aggression as well as their perpetrated violent acts. Our study shows, appetitive aggression and the number of perpetrated violent acts were specifically increased in individuals who were abducted young, experienced several traumatic events in their lifetime, and with previous combat experience. For perpetrated violence men showed increased levels whereas for appetitive aggression the association was independent of biological sex. Therefore, early abducted individuals with a higher traumatic load, who have combat experience, need to be given special intervention to prevent any further violence.
Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma : Results from two independent African cohorts
2020-01, Conrad, Daniela, Wilker, Sarah, Schneider, Anna, Karabatsiakis, Alexander, Pfeiffer, Anett, Kolassa, Stephan, Freytag, Virginie, Vukojevic, Vanja, Elbert, Thomas, Kolassa, Iris-Tatjana
The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans-membrane receptor proteins (NOTCH1-4), constitutes an evolutionarily well-conserved intercellular communication pathway (involved, e.g., in cell-cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1-4 (investigated by microarray) and genomic methylation of saliva-derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N1 = 924) and Rwanda (N2 = 371), and investigated whether NOTCH-related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (puncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (puncorrected = 0.05) in Rwandans. Yet, none of the (epi-)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (pcorrected = 0.003) and NOTCH receptor processing (pcorrected = 0.01). The environmental factor trauma load was significant in all analyses (all p < 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies.
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.
DNA methylation changes following narrative exposure therapy in a randomized controlled trial with female former child soldiers
2021-09-16, Carleial, Samuel, Nätt, Daniel, Unternaehrer, Eva, Elbert, Thomas, Robjant, Katy, Wilker, Sarah, Vukojevic, Vanja, Kolassa, Iris-Tatjana, Rukundo-Zeller, Anja C., Koebach, Anke
The aftermath of traumatization lives on in the neural and epigenetic traces creating a momentum of affliction in the psychological and social realm. Can psychotherapy reorganise these memories through changes in DNA methylation signatures? Using a randomised controlled parallel group design, we examined methylome-wide changes in saliva samples of 84 female former child soldiers from Eastern DR Congo before and six months after Narrative Exposure Therapy. Treatment predicted differentially methylated positions (DMPs) related to ALCAM, RIPOR2, AFAP1 and MOCOS. In addition, treatment associations overlapped at gene level with baseline clinical and social outcomes. Treatment related DMPs are involved in memory formation—the key agent in trauma focused treatments—and enriched for molecular pathways commonly affected by trauma related disorders. Results were partially replicated in an independent sample of 53 female former child soldiers from Northern Uganda. Our results suggest a molecular impact of psychological treatment in women with war-related childhood trauma.
NTRK2 methylation is related to reduced PTSD risk in two African cohorts of trauma survivors
2020-09-01, Vukojevic, Vanja, Coynel, David, Ghaffari, Navid R., Freytag, Virginie, Elbert, Thomas, Kolassa, Iris-Tatjana, Wilker, Sarah, McGaugh, James L., Papassotiropoulos, Andreas, de Quervain, Dominique J.-F.
Extensive pharmacologic, genetic, and epigenetic research has linked the glucocorticoid receptor (GR) to memory processes, and to risk and symptoms of posttraumatic stress disorder (PTSD). In the present study we investigated the epigenetic pattern of 12 genes involved in the regulation of GR signaling in two African populations of heavily traumatized individuals: Survivors of the rebel war in northern Uganda (n = 463) and survivors of the Rwandan genocide (n = 350). The strongest link between regional methylation and PTSD risk and symptoms was observed for NTRK2, which encodes the transmembrane receptor tropomyosin-related kinase B, binds the brain-derived neurotrophic factor, and has been shown to play an important role in memory formation. NTRK2 methylation was not related to trauma load, suggesting that methylation differences preexisted the trauma. Because NTRK2 methylation differences were predominantly associated with memory-related PTSD symptoms, and because they seem to precede traumatic events, we next investigated the relationship between NTRK2 methylation and memory in a sample of nontraumatized individuals (n = 568). We found that NTRK2 methylation was negatively associated with recognition memory performance. Furthermore, fMRI analyses revealed NTRK2 methylation-dependent differences in brain network activity related to recognition memory. The present study demonstrates that NTRK2 is epigenetically linked to memory functions in nontraumatized subjects and to PTSD risk and symptoms in traumatized populations.
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 cumulative exposure to traumatic stressors predict treatment outcome of community-implemented exposure-based therapy for PTSD?
2020-12-31, Schneider, Anna, Pfeiffer, Anett, Conrad, Daniela, Elbert, Thomas, Kolassa, Iris-Tatjana, Wilker, Sarah
Background: Posttraumatic Stress Disorder (PTSD) is associated with high levels of functional impairments such as difficulties in academic or occupational performance and in social relationships. With an increasing number of traumatic event types experienced (trauma load), PTSD risk increases in a dose-dependent manner. Accordingly, high rates of PTSD can impair the reconstruction process in post-conflict societies. In order to meet these high needs for mental health services in societies with little access to professional care, task shifting approaches and community-based interventions have been suggested. Narrative Exposure Therapy (NET) has been developed as a short and pragmatic exposure-based PTSD treatment that can be easily trained to lay personnel. Yet, it remains unclear whether NET can be effectively provided by trained lay counsellors even at high levels of trauma load.
Objective: To investigate whether trauma load influences the treatment effectiveness of NET provided by trained and supervised local lay counsellors.
Method: Linear mixed models were calculated to investigate the influence of trauma load on treatment effectiveness in a sample of N = 323 rebel war survivors from Northern Uganda with PTSD.
Results: We found a strong reduction of PTSD symptoms following NET, which was not influenced by trauma load. However, individuals with higher levels of trauma load reported higher PTSD symptoms before therapy as well as 4 and 10 months following treatment completion compared to individuals with lower trauma load.
Conclusions: Treatment with NET by lay counsellors is effective independent of trauma load. However, individuals with higher trauma load have a higher probability to show residual symptoms, which might require additional time, sessions or treatment modules.
Global EEG coherence as a marker for cognition in older adults at risk for dementia
2020-04, Laptinskaya, Daria, Fissler, Patrick, Küster, Olivia Caroline, Wischniowski, Jakob, Thurm, Franka, Elbert, Thomas, von Arnim, Christine A. F., Kolassa, Iris-Tatjana
Quantitative electroencephalography (EEG) provides useful information about neurophysiological health of the aging brain. Current studies investigating EEG coherence and power for specific brain areas and frequency bands have yielded inconsistent results. This study assessed EEG coherence and power indices at rest measured over the whole skull and for a wide frequency range as global EEG markers for cognition in a sample at risk for dementia. Since global markers are more reliable and less error‐prone than region‐ and frequency‐specific indices they might help to overcome previous inconsistencies. Global EEG coherence (1–30 Hz) and an EEG slowing score were assessed. The EEG slowing score was calculated by low‐frequency power (1–8 Hz) divided by high‐frequency power (9–30 Hz). In addition, the prognostic value of the two EEG indices for cognition and cognitive decline was assessed in a 5‐year follow‐up pilot study. Baseline global coherence correlated positively with cognition at baseline, but not with cognitive decline or with cognition at the 5‐year follow‐up. The EEG slowing ratio showed no significant association, neither with cognition at baseline or follow‐up, nor with cognitive decline over a period of 5 years. The results indicate that the resting state global EEG coherence might be a useful and easy to assess electrophysiological correlate for neurocognitive health in older adults at risk for dementia. Because of the small statistical power for the follow‐up analyses, the prognostic value of global coherence could not be determined in the present study. Future studies should assess its prognostic value with larger sample sizes.
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.