Participants

The study was carried out at the Psychological Research and Outpatient Clinic for Refugees at the University of Konstanz. Participants were refugees and asylum seekers who were referred for diagnostic examination or treatment by general practitioners, aid organizations, lawyers, or judges. Inclusion criteria were a history of organized violence or persecution and current PTSD diagnosis according to DSM-IV. Exclusion criteria were current psychosis, substance or alcohol dependence. Thirty-four participants who fulfilled inclusion criteria (see flowchart Figure 6) were randomly assigned to either a treatment (NET) group (n = 16) or a Waitlist Control (WLC) group (n = 18). Age ranged from 16-46 years in the treatment completers group and from 16-56 years in the intention to treat group. A DSM-IV affective disorder (Major Depression or dysthymia) was diagnosed in 68.8% of participants in the NET group and 94.4% of participants in the Waitlist Control group. Participants who completed therapy as well as the MEG examination at posttests and produced MEG data sets (pre and post) that could be included in the final analysis were defined as 'study completers' (SC) (see Table 2).

Figure 6 Flowchart of study participants. NET indicates Narrative Exposure Therapy, WLC indicates waitlist control condition. Full size image

Table 2 Pre-treatment demographic and clinical characteristic of study participants Full size table

Procedure

The Ethical Committee of the University of Konstanz approved the study protocol and all participants gave written informed consent. The initial assessment consisted of an extensive structured clinical interview and a MEG examination. Clinical psychologists with expertise in the examination of refugees with PTSD carried out the diagnostic interviews with the help of interpreters. MEG recordings took place one week after clinical examination to avoid any possible influence of the diagnostic interview. Participants that fulfilled the inclusion criteria were randomized into the two groups using a computer-generated list of random numbers. Treatment consisted of 12 therapy sessions on a weekly or biweekly basis. On average, treatment sessions lasted 108 (SD = 17.0) minutes. Treatment adherence was monitored by means of regular supervision. Furthermore, all testimonies written down during NET treatment by the therapists (biographical narrations usually exceeding 8000 words) were checked for indicators of vividness and consistency to ensure proper application of NET. No major deviations from treatment protocol were detected.

Posttests with the NET patients were scheduled 4 months after the end of therapy. For the participants in the WLC group, the time spans between pre- and posttests were individually matched with the NET group. Posttests included the same instruments as used in the pretest and were carried out by interviewers who were blind to treatment condition. As part of the posttest, the same MEG examination as in the initial assessment was conducted with each patient.

Clinical Assessment

The clinical assessment included a detailed structured interview regarding demographic data, traumatic experiences and psychiatric diagnoses. For the examination of traumatic life events, we used the vivo Checklist of War, Detention, and Torture Events and the Event Checklist of the Clinician Administered PTSD Scale, CAPS [46]. Standardized clinical instruments were used for the determination of DSM-IV diagnoses: The CAPS for diagnosis and quantification of PTSD, the MINI International Neuropsychiatric Interviews, M.I.N.I. [47] for comorbid DSM-IV axis one disorders, and the Hamilton Depression Scale, HDRS [48] for determining the severity of depressive symptoms.

Neuromagnetic examination

We applied magnetoencephalography to measure steady-state visual evoked field (ssVEFs) during the presentation of standardized affective pictures varying with respect to emotional content. Full details of the neuromagnetic examination procedure including stimulation, procedure, data preprocessing and analysis have been provided previously [11, 29] and are described only briefly here.

Stimuli

Seventy-five coloured pictures were chosen on the basis of their normative ratings from the International Affective Pictures System (IAPS) [49]. Of these, 25 pictures presented threat-relevant events (e.g., mutilations, assaults, weapons), 25 pleasant events (e.g., sports, erotic couples, children) and 25 neutral events (e.g., neutral faces, household objects). Amongst the unpleasant pictures, the majority of stimuli was threat-related with about one third depicting human assaults or aimed guns, another third showing mutilations or dead bodies. Scenes with soldiers or police officers were presented on three slides, and on another three, angry and sad faces were shown. Pictures were presented with a video projector on a white plastic screen attached to the ceiling of the shielded MEG chamber. In each trial, one picture was presented in a flickering mode of 10 Hz for 4 seconds with an inter-trial interval that varied randomly between 6 to 8 s.

After the initial MEG recording, subjects rated each of the 75 affective pictures for emotional valence and arousal using the Self-Assessment Manikin (SAM) scale. Two participants of the WLC group did not complete SAM ratings. Mean SAM ratings of the aversive pictures were 7.9 for the arousal and 1.4 valence category, of the pleasant pictures 3.9 for the arousal and 6.5 for the valence category and of the neutral pictures 3.3 for the arousal and 4.8 for the valence category. Arousal ratings differed between picture categories (F(2, 28) = 90.6, p < .001, ε = .80) with aversive pictures being rated as more arousing than neutral as well as pleasant (p < .001) pictures. There was no significant difference in the arousal rating between pleasant and neutral pictures.

Pictures differed with respect to patients' valence ratings (F(2, 28) = 233.03, p < .001, ε = .73). Overall, pleasant pictures were rated as most pleasant, followed by neutral and finally by aversive pictures (all comparisons p < .001). There were no statistical differences between the treatment groups with respect to their arousal or valence ratings.

MEG Recording and Data Processing

MEG was recorded continuously and digitized at a rate of 678.17 Hz using a 148-channel whole head magnetometer (MAGNES™ 2500 WH, 4D Neuroimage, San Diego, USA) and an online band-pass filter of 0.1 - 200 Hz. Cardiac and eye artifacts were recorded with a SynAmps amplifier (Neuroscan™) and corrected offline using procedures included in the MEG acquisition software package (Whole Head system software, version 1.2.5; 4D Neuroimaging) as well as algorithms implemented in BESA™ software. In order to determine the position of the head in the MEG-dewar for source localization, individual head shapes and reference points were digitized before the recording session. Offline, MEG data were visually inspected and corrected for movement, cardiac, and eye artifacts as well as for global noise. MEG data were digitally band-pass filtered between 1 Hz and 25 Hz (slopes: 6 and 24 dB/octave, respectively). Finally, trials were baseline-adjusted (500 ms baseline) and averaged over picture category (pleasant, neutral and aversive). For each category average, a moving window averaging procedure was applied [31, 50]. To avoid contamination of results with the event related early activity, the initial 400 ms of the picture presentation interval were excluded. A 400 ms window containing four cycles of the 10 Hz flickering stimuli was shifted in steps of 100 ms (one cycle) across the epoch, and the magnetic field data within the shifting windows in the time domain were further averaged. As a result, we obtained for each category, subject, and MEG channel a 400 ms segment of four 10 Hz cycles reflecting an average across 32 sliding windows. Figure 7 shows the four cycles of the 10 Hz steady state response of the 148 MEG channels for one representative participant. These four cycles were submitted to fast Fourier transform (FFT) technique and the extracted real and imaginary parts of the 10 Hz Fourier coefficients were used for source localization.

Figure 7 Four cycles of the 10 Hz steady state response of the 148 MEG channels for one representative participant. Full size image

Using the Matlab-based software EMEGS©[51], the distribution of likely generators of the neuromagnetic activity was estimated by calculating L2 minimum norm solutions based on a spherical one shell (6 cm radius) head model with 197 evenly distributed dipolar sources [52].

Treatment

Clinical psychologists of the University of Konstanz with expertise in PTSD and NET carried out the treatment according to the manual [53], with the help of a translator if necessary. During the therapy sessions, the patient, assisted by the therapist, constructs a detailed chronological account of his or her own biography. Particular attention is given to traumatic experiences (often events linked to violence and war situations). The autobiography is recorded by the therapist in written form and is corrected and elaborated on each subsequent reading. The therapist writes down the biography and reads it aloud at the beginning of each following session for completion and correction. The aim of the therapy is the reorganization of the generally fragmented report of traumatic experiences into a coherent narrative. During the confrontation with the aversive life events, the therapist asks for current and past emotional, physiological, cognitive, and behavioral reactions, and probes for respective observations. While narrating, the patient is encouraged to relive these emotions. The exposure to the traumatic experience is not terminated during the session until the related fear reaction, presented and reported by the patient, shows a significant diminution. During the last session, the participant receives the written report of the biography [23]. In order to meet the needs of patients with insecure asylum status, the last two sessions were kept flexible to allow patients and therapists to discuss issues related to the current situation.

Statistical Analysis of Demographic and Clinical Data

Baseline characteristics of the groups were compared to examine the effects of randomization using the Mann-Whitney U test for continuous variables and the Chi-Square test for dichotomous variables. As this study focuses on brain changes through psychotherapy rather than examining the clinical efficacy of the treatment, we restricted all analyses to the sample of study completers. Changes in clinical symptoms were evaluated using repeated-measures ANOVA with Treatment Condition (NET and WLC) as between-factor and Time (pretest and posttest) as within-factor. Greenhouse-Geisser's correction of the degrees of freedom was used where appropriate. The associated epsilon and adjusted p-values are reported. Statistically significant interactions were investigated further by using Tukey's HSD test for post-hoc evaluation of unequal sample sizes. Moreover, clinical significance was estimated by calculating within-treatment effect sizes (Cohen's d) for PTSD (CAPS score) and depressive symptoms (HAM-D score).

Analysis of MEG Data

For MEG data analysis, brain maps consisting of the minimum norm estimates (MNE) source strengths at 197 dipoles represented the cortical activity induced by the stimulation. The dependent variable in the analysis relates to the cortical activity induced by threatening stimuli. To control for different levels of overall stimulus-driven activity, we subtracted each subject's average activity related to neutral pictures from the average activity in response to threatening pictures ('aversive minus neutral' difference). For simplicity reasons, we refer to the resulting contrast maps as Threat effects. As an indicator of the changes induced by the NET group and WLC group, we calculated the differences of the Threat effects between pre- and post test for each group. These contrast maps were defined as Time effects. Finally, the Time × Treatment interaction was determined as the contrast map that resulted from the group difference (NET minus WLC) within the Time effects.

The statistical analysis of the MEG data was carried out with permutation statistics rather than t-tests or ANOVAs for several reasons. First of all, due to the small sample size and the skewed distribution of the MEG data the prerequisites of parametric statistics were not fulfilled. In contrast, the permutation test does not require any a priori assumptions about the distribution of data, as it generates a representative subset of a sufficiently large number of permutations of the data to represent the data distribution [54, 55]. Secondly, the permutation test avoids the danger of alpha inflation in the comparison of brain maps without the necessity to pre-define regions of interest. The appropriateness of this procedure for analyzing visual-evoked steady-state responses has been demonstrated in previous studies [11, 29, 32].

Permutation tests were calculated as follows. For each pair-wise comparison, we determined cut-off values for significant differences of the maps at single dipole locations based on 1000 draws. For each draw, the individuals' condition contrast maps were randomly exchanged between groups (NET vs. WLC) and between time points (pre vs. post) to generate data for a random composition with respect to group and time. The maximum as well as the minimum differences at all dipole locations obtained from each draw entered the distributions of 1000 maximum and minimum difference values. The upper and the lower critical values were determined as the 25th lowest and highest values in this distribution (p < .05). Values indicating a significant difference (smaller than the lower and higher than the upper critical values) were plotted onto the MNI brain. For illustrative purposes only, we calculated t-tests for each pair-wise comparison.