The effect of trauma-focused therapy on the altered T cell distribution in individuals with PTSD: evidence from a randomized controlled trial.

Posttraumatic stress disorder (PTSD) is associated with a reduced ratio of naïve cytotoxic T lymphocytes, an increased ratio of memory cytotoxic T lymphocytes, and a reduced proportion of FoxP3(+) regulatory T lymphocytes. This study investigated whether these immunological alterations are reversible through an evidence-based psychotherapeutic treatment. Therefore, 34 individuals with PTSD were randomly assigned to either a treatment condition of 12 sessions narrative exposure therapy (NET) or a waitlist control (WLC) group. PTSD symptoms were significantly reduced in the NET group, but not in the WLC group, four months post-therapy (effect size: Hedges' g = -1.61). One year after therapy, PTSD symptoms were improved even further in the NET group compared to baseline (Hedges' g = -1.96). This symptom improvement was mirrored in an increase in the originally reduced proportion of regulatory T cells (Tregs) in the NET group at the one-year follow-up, when comparing subgroups matched for baseline Treg numbers. However, no changes were found for the initially reduced proportion of CD45RA(+)CCR7(+) naïve T lymphocytes. In conclusion, NET was effective in reducing trauma-related PTSD symptoms and had a positive effect on the proportion of Tregs cells, thus demonstrating an effect of psychotherapy on an immunological level. Yet, the shift in the proportion of naïve and memory T lymphocytes in individuals with PTSD, discussed in the literature as a correlate of premature immunosenescence, was not reversible and thus might render these patients permanently more susceptible to infectious diseases.

Reduced peripheral expression of the glucocorticoid receptor α isoform in individuals with posttraumatic stress disorder: a cumulative effect of trauma burden.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a serious psychiatric condition that was found to be associated with altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis and changes in glucocorticoid (GC) responsiveness. The physiological actions of GCs are primarily mediated through GC receptors (GR) of which isoforms with different biological activities exist. This study aimed to investigate whether trauma-experience and/or PTSD are associated with altered expression of GR splice variants. METHODS: GRα and GRß mRNA expression levels were determined by real-time quantitative PCR in whole blood samples of individuals with chronic and severe forms of PTSD (n = 42) as well as in ethnically matched reference subjects (non-PTSD, n = 35). RESULTS: Individuals suffering from PTSD exhibited significantly lower expression of the predominant and functionally active GRα isoform compared to non-PTSD subjects. This effect remained significant when accounting for gender, smoking, psychotropic medication or comorbid depression. Moreover, the GRα expression level was significantly negatively correlated with the number of traumatic event types experienced, both in the whole sample and within the PTSD patient group. Expression of the less abundant and non-ligand binding GRß isoform was comparable between patient and reference groups. CONCLUSIONS: Reduced expression of the functionally active GRα isoform in peripheral blood cells of individuals with PTSD seems to be a cumulative effect of trauma burden rather than a specific feature of PTSD since non-PTSD subjects with high trauma load showed an intermediate phenotype between PTSD patients and individuals with no or few traumatic experiences.

Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with an enhanced risk for cardiovascular and other inflammatory diseases. Chronic low-level inflammation has been suggested as a potential mechanism linking these conditions. METHODS: We investigated plasma cytokine levels as well as spontaneous and lipopolysaccharide (LPS)-stimulated cytokine production by peripheral blood mononuclear cells (PBMCs) in a group of 35 severely traumatized PTSD patients compared to 25 healthy controls. RESULTS: Spontaneous production of interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α by isolated PBMCs was significantly higher in the PTSD compared to the control group and even correlated with PTSD symptom severity within the PTSD group. In contrast, circulating plasma levels of pro- and anti-inflammatory cytokines such as IL-6, IL-8, IL-10, TNF-α, or monocyte chemotactic protein (MCP)-1 were not significantly altered in PTSD patients compared to healthy controls. CONCLUSIONS: Our findings indicate that PBMCs of PTSD patients are already pre-activated in vivo, providing further evidence for low-grade inflammation in PTSD. This might possibly represent one psychobiological pathway from PTSD to poor physical health.

Victims of rape show increased cortisol responses to trauma reminders: a study in individuals with war- and torture-related PTSD.

Studies investigating cortisol responses to trauma-related stressors in patients with posttraumatic stress disorder (PTSD) have yielded inconsistent results, demonstrating that cortisol responses were enhanced or unaffected when confronted with trauma reminders. This study investigated the effect of the type of trauma experienced on both salivary and plasma cortisol responses during confrontation with trauma-related material. Participants were 30 survivors of war and torture, with and without rape among the traumatic events experienced. Participants of both groups (raped vs. non-raped) fulfilled DSM-IV criteria of PTSD. Plasma and salivary cortisol levels were measured at three time points during a standardized clinical interview: once before and twice after assessing individual traumatic experiences. Results show that groups did not differ in basal plasma and salivary cortisol levels. However, differential salivary cortisol responses were observed in PTSD patients who had been raped compared to those who had not been raped (p<.05) but had experienced an equal number of traumatic events and showed equally high PTSD symptom severity. Whereas salivary cortisol levels decreased in the course of the interview for the group with no past experience of rape (p<.05), those PTSD patients who had been raped showed a significant cortisol increase when reminded of their traumatic events (p<.001). This effect was not found in plasma cortisol. Our results indicate that the type of traumatic stress experienced contributes to cortisol responses during the confrontation with trauma-related material. We hypothesize, that the nearness of the perpetrator during the traumatic event might shape later psychophysiological responding to trauma reminders.

Narrative exposure therapy for PTSD increases top-down processing of aversive stimuli--evidence from a randomized controlled treatment trial.

BACKGROUND: Little is known about the neurobiological foundations of psychotherapy for Posttraumatic Stress Disorder (PTSD). Prior studies have shown that PTSD is associated with altered processing of threatening and aversive stimuli. It remains unclear whether this functional abnormality can be changed by psychotherapy. This is the first randomized controlled treatment trial that examines whether narrative exposure therapy (NET) causes changes in affective stimulus processing in patients with chronic PTSD. METHODS: 34 refugees with PTSD were randomly assigned to a NET group or to a waitlist control (WLC) group. At pre-test and at four-months follow-up, the diagnostics included the assessment of clinical variables and measurements of neuromagnetic oscillatory brain activity (steady-state visual evoked fields, ssVEF) resulting from exposure to aversive pictures compared to neutral pictures. RESULTS: PTSD as well as depressive symptom severity scores declined in the NET group, whereas symptoms persisted in the WLC group. Only in the NET group, parietal and occipital activity towards threatening pictures increased significantly after therapy. CONCLUSIONS: Our results indicate that NET causes an increase of activity associated with cortical top-down regulation of attention towards aversive pictures. The increase of attention allocation to potential threat cues might allow treated patients to re-appraise the actual danger of the current situation and, thereby, reducing PTSD symptoms. REGISTRATION OF THE CLINICAL TRIAL: Number: NCT00563888Name: "Change of Neural Network Indicators Through Narrative Treatment of PTSD in Torture Victims" ULR: http://www.clinicaltrials.gov/ct2/show/NCT00563888.

Early processing of threat cues in posttraumatic stress disorder-evidence for a cortical vigilance-avoidance reaction.

BACKGROUND: The present study investigated the influence of posttraumatic stress disorder (PTSD) on early visual processing of affective stimuli in survivors of war and torture. METHODS: Trauma-exposed refugees with (n = 36) and without (n = 21) PTSD as well as unexposed control subjects (n = 16) participated in a magnetoencephalography study with pictures that varied in emotional content. RESULTS: We found evidence for a biphasic cortical response in patients with PTSD in comparison with the two control groups. In response to aversive (relative to neutral or positive) pictures, PTSD patients showed elevated cortical activity over right prefrontal areas as early as 130-160 msec after stimulus onset followed by a decrease of the affect-related response in the parieto-occipital cortex at 206-256 msec. CONCLUSIONS: The increased early activity in the right prefrontal cortex most likely represents an enhanced alarm response or the fear network toward aversive stimuli in PTSD, whereas the subsequent decreased activation in right parieto-occipital areas in response to aversive pictures seems to reflect the tendency to disengage from emotional content. This finding is consistent with the hypothesis of a vigilance-avoidance reaction pattern to threat in anxiety disorders and helps to reconcile contradicting results of over- and under-responsiveness in the sensory processing of threatening stimuli in PTSD.

Is freezing an adaptive reaction to threat? Evidence from heart rate reactivity to emotional pictures in victims of war and torture.

The influence of past traumatic experiences on the defense cascade in response to affective pictures was examined in survivors of war and torture. Trauma-exposed refugees with and without Posttraumatic Stress Disorder (PTSD) as well as healthy individuals viewed 75 pictures that varied in emotional content. Heart rate (HR) was recorded during the flickering stimulation of affective pictures in the context of a steady-state experiment. Whereas healthy controls showed the typical orienting response to aversive stimuli, PTSD patients reacted with an almost immediate increase in HR toward unpleasant pictures. Trauma-exposed participants without PTSD showed an indiscriminate orienting response regardless of picture category. The present findings argue for a faster flight/fight response to threatening cues in PTSD. In contrast, trauma-exposed controls seem to exhibit a state of permanent alertness toward a wide range of stimuli.

Imaging cortical activity following affective stimulation with a high temporal and spatial resolution.

BACKGROUND: The affective and motivational relevance of a stimulus has a distinct impact on cortical processing, particularly in sensory areas. However, the spatial and temporal dynamics of this affective modulation of brain activities remains unclear. The purpose of the present study was the development of a paradigm to investigate the affective modulation of cortical networks with a high temporal and spatial resolution. We assessed cortical activity with MEG using a visual steady-state paradigm with affective pictures. A combination of a complex demodulation procedure with a minimum norm estimation was applied to assess the temporal variation of the topography of cortical activity. RESULTS: Statistical permutation analyses of the results of the complex demodulation procedure revealed increased steady-state visual evoked field amplitudes over occipital areas following presentation of affective pictures compared to neutral pictures. This differentiation shifted in the time course from occipital regions to parietal and temporal regions. CONCLUSION: It can be shown that stimulation with affective pictures leads to an enhanced activity in occipital region as compared to neutral pictures. However, the focus of differentiation is not stable over time but shifts into temporal and parietal regions within four seconds of stimulation. Thus, it can be crucial to carefully choose regions of interests and time intervals when analyzing the affective modulation of cortical activity.

Substantial reduction of naïve and regulatory T cells following traumatic stress.

Posttraumatic stress disorder (PTSD) is associated with an enhanced susceptibility to various somatic diseases. However, the exact mechanisms linking traumatic stress to subsequent physical health problems have remained unclear. This study investigated peripheral T lymphocyte differentiation subsets in 19 individuals with war and torture related PTSD compared to 27 non-PTSD controls (n=14 trauma-exposed controls; n=13 non-exposed controls). Peripheral T cell subpopulations were classified by their characteristic expression of the lineage markers CD45RA and CCR7 into: naïve (CD45RA(+) CCR7(+)), central memory (T(CM): CD45RA(-) CCR7(+)) and effector memory (T(EM): CD45RA(-) CCR7(-) and T(EMRA): CD45RA(-) CCR7(-)) cells. Furthermore, we analyzed regulatory T cells (CD4(+)CD25(+)FoxP3(+)) and ex vivo proliferation responses of peripheral blood mononuclear cells after stimulation with anti-CD3 monoclonal antibody. Results show that the proportion of naïve CD8(+) T lymphocytes was reduced by 32% (p=0.01), whereas the proportions of CD3(+) central (p=0.02) and effector (p=0.01) memory T lymphocytes were significantly enhanced (+22% and +34%, respectively) in PTSD patients compared to non-PTSD individuals. To a smaller extent, this effect was also observed in trauma-exposed non-PTSD individuals, indicating a cumulative effect of traumatic stress on T cell distribution. Moreover, PTSD patients displayed a 48% reduction in the proportion of regulatory T cells (p<0.001). Functionally, these alterations were accompanied by a significantly enhanced (+34%) ex vivo proliferation of anti-CD3 stimulated T cells (p=0.05). The profoundly altered composition of the peripheral T cell compartment might cause a state of compromised immune responsiveness, which may explain why PTSD patients show an increased susceptibility to infections, and inflammatory and autoimmune diseases.

Pattern of cortical activation during processing of aversive stimuli in traumatized survivors of war and torture.

Posttraumatic stress disorder (PTSD) has been associated with an altered processing of threat-related stimuli. In particular, an attentional bias towards threat cues has been consistently found in behavioral studies. However, it is unclear whether increased attention towards threat cues translates into preferential processing as neurophysiological studies have yielded inconsistent findings. The aim of the present study was to investigate the neocortical activity related to the processing of aversive stimuli in patients with PTSD. 36 survivors of war and torture with PTSD, 21 Trauma Controls and 20 Unexposed Subjects participated in a visual evoked magnetic field study using flickering pictures of varying affective valence as stimulus material. Minimum norm source localization was carried out to estimate the distribution of sources of the evoked neuromagnetic activity in the brain. Statistical permutation analyses revealed reduced steady-state visual evoked field amplitudes over occipital areas in response to aversive pictures for PTSD patients and for Trauma Controls in comparison to unexposed subjects. Furthermore, PTSD patients showed a hyperactivation of the superior parietal cortex selectively in response to aversive stimuli, which was related to dissociative symptoms as well as to torture severity. The results indicate a different pattern of cortical activation driven by aversive stimuli depending on the experience of multiple traumatic events and PTSD. Whereas, a decreased visual processing of aversive stimuli seems to be associated with trauma exposure in general, the superior parietal activity might represent a specific process linked to the diagnosis of PTSD.