Background: Meta-analyses of studies on psychological treatment of refugees describe highly varying outcomes, and research on multi-facetted and personalized treatment of refugees with post-traumatic stress disorder (PTSD) is needed. Music therapy has been found to affect arousal regulation and emotional processing, and a pilot study on the music therapy method Trauma-focused Music and Imagery (TMI) with traumatized refugees resulted in significant changes of trauma symptoms, well-being and sleep quality. The aim of the trial is to test the efficacy of TMI compared to verbal psychotherapy. Methods: A randomized controlled study with a non-inferiority design is carried out in three locations of a regional outpatient psychiatric clinic for refugees. Seventy Arabic-, English- or Danish-speaking adult refugees (aged 18–67 years) diagnosed with PTSD are randomized to 16 sessions of either music therapy or verbal therapy (standard treatment). All participants are offered medical treatment, psychoeducation by nurses, physiotherapy or body therapy and social counseling as needed. Outcome measures are performed at baseline, post therapy and at 6 months’ follow-up. A blind assessor measures outcomes post treatment and at follow-up. Questionnaires measuring trauma symptoms (HTQ), quality of life (WHO-5), dissociative symptoms (SDQ-20, DSS-20) and adult attachment (RAAS) are applied, as well as physiological measures (salivary oxytocin, beta-endorphin and substance P) and participant evaluation of each session. Discussion: The effect of music therapy can be explained by theories on affect regulation and social engagement, and the impact of music on brain regions affected by PTSD. The study will shed light on the role of therapy for the attainment of a safe attachment style, whichrecentlyhas been showntobeimpairedintraumatized refugees.The inclusionofmusic and imagery in the treatment of traumatized refugees hopefully will inform the choice of treatment method and expand the possibilities for improving refugee health and integration. Trial registration: ClinicalTrials.gov ID number NCT03574228, registered retrospectively on 28 June 2016. Keywords: Music and imagery, Refugees, Randomized clinical trial, PTSD, Trauma, Music therapy, Non-inferiority, Oxytocin * Correspondence: firstname.lastname@example.org Department of Communication and Psychology, Aalborg University, Aalborg, Denmark Clinic for Traumatized Refugees, Køge, Region Zealand, Denmark Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Beck et al. Trials (2018) 19:301 Page 2 of 20 Background listed: (1) severe and pervasive problems in affect regula- Currently, there are more than 21 million internationally tion; (2) persistent beliefs about oneself as diminished, displaced refugees in the world, 3.5 million of them living defeated or worthless, accompanied by deep and perva- in Europe . The mental health problems and psycho- sive feelings of shame, guilt or failure related to the trau- social strain in refugees resettled in Western countries has matic event; and (3) persistent difficulties in sustaining been suggested to relate to traumatic experiences and relationships and in feeling close to others (ICD-11, draft stress while living under war, persecution and other life- version). In line with that, insecure attachment recently threatening circumstances, danger and challenges during has been shown to be common in refugees [7, 8]. Fur- flight, as well as post-migration experiences such as inse- thermore, refugees from non-Western countries show cure waiting periods during asylum and family reunion high levels of unexplained somatic symptoms that po- procedures, poverty, lack of social support, acculturation tentially can be explained by traumatization, the results difficulties and discrimination . Reviews of studies on of torture and that also might be a culturally accepted refugee health document a large variation in health status way to express psychological pain taking into consider- related to country of origin, country of resettlement and ation the stigmatization of psychiatric care . The in- the methodological quality of the studies. In a systematic creased number of refugees with severe mental health review of 20 surveys including 6743 adult refugees from problems necessitates the development of effective treat- seven countries a 9% prevalence of PTSD (99% CI 8–10%) ment modalities. was found, which is about ten times the rates in the age- matched general populations in the same countries . In Research on refugee treatment a systematic review of 29 studies including 16.010 war- Standardized short-term treatment has been shown to affected refugees, significant between-study heterogeneity be effective in the treatment of single-trauma PTSD in prevalence rates of post-traumatic stress disorder without significant comorbidity [10, 11]. However, sim- (PTSD) (4–86%), unspecified anxiety disorder (20–88%) ple PTSD is not typical in traumatized refugees, where and depression (range 2–80%) was identified, although complex trauma and comorbidity is common. The rec- prevalence estimates typically were in the range of 20% ommendation from leading trauma researchers in com- and above . All three disorders were associated with plex PTSD is a treatment based in a cross-disciplinary greater exposure to pre-migration trauma and post- setup with a phased psychotherapeutic component of a migration stress, while depression was particularly associ- duration of several years . ated with poor socio-economic status. In a study of 142 Until today the evaluation of psychological treatment newly arrived asylum seekers in Denmark 34% had symp- modalities of traumatized refugees has mostly focused toms corresponding with the PTSD diagnosis . on individual cognitive behavioral therapy (CBT) and In International Classification of Diseases (ICD-10) narrative exposure therapy (NET), with some studies in criteria for PTSD are the exposure to an exceptionally eye movement desensitization reprocessing (EMDR), threatening event of catastrophic nature and demon- combined methods/interdisciplinary treatment and strating the symptom triad (1) intrusive trauma-related group treatment. Compared to other patient groups, the imagery or nightmares, (2) avoidance of situations that evaluation of psychotherapeutic treatment of refugees reminds them of the trauma and (3) either (a) partial can be difficult, randomized controlled trials are few and amnesia of the trauma or (b) prolonged hypervigilance sample sizes are generally small. There are many pos- that causes irritability or frequent outburst of anger, con- sible explanations for this. Many refugees that have ex- centration problems, sleeping problems and/or exagger- perienced traumatic events, such as persecution, are ated startle response (F43.1, World Health Organization reluctant to trust authorities, including healthcare per- (WHO) ICD-10). In addition, PTSD influences cognitive sonal. The complexity of trauma symptoms, accultur- abilities such as memory and learning, and often causes ation difficulties and the influence of the translator upon social withdrawal, all of which affect quality of life in a the psychotherapeutic relationship also have to been profoundly negative way, making it harder for the taken into account. affected individuals to achieve successful integration and In a Cochrane review evaluating nine studies on CBT self-perseverance, including the adherence to study and and NET with torture survivors, no effect was found im- work. In the upcoming ICD-11 the diagnosis Complex mediately after treatment. However, at 6 months’ follow- PTSD will be included, a diagnosis for additional symp- up, four out of nine studies showed a medium effect on toms related to longitudinal and/or severe traumatic ex- trauma symptoms . Slobodin and de Jong  posure characterized by disturbances in emotional performed a meta-analysis of studies with quantitative regulation and relational capacities, dissociation, somatic pre-post intervention measurement of trauma symptoms, distress and alterations in belief systems . In the draft including refugees and asylum seekers. They found for the upcoming ICD-11 the following symptoms are positive effects on PTSD symptoms after treatment with Beck et al. Trials (2018) 19:301 Page 3 of 20 CBT and NET in certain refugee populations. Other inter- it is necessary to devise the treatment of refugees indi- vention studies, i.e., EMDR, psychodynamic interventions, vidually from a spectrum of possibilities. family interventions, group interventions, pharmacological treatment and combined methods/interdisciplinary treat- Physiological measures and PTSD ment, were limited by methodological considerations, Levels of stress hormones, such as cortisol have been such as lack of randomization, absence of control group widely used to measure the stress response in PTSD and small samples. Similar conclusions were found in pre- patients. However, several studies have failed to confirm vious academic literature reviews [14–17]. Palic and Elklit the expectation that cortisol is elevated in PTSD. On the  reviewed 25 refugee studies and found that the effect contrary, patients who suffer from PTSD generally have of different approaches varied from very small to medium normal levels of cortisol, and often their levels are even effect sizes. Among the reviewed studies a few demon- lower than the values of healthy participants [23, 24]. It strated very large effect sizes on PTSD symptoms after has been supposed that the HPA axis suppresses the corti- trauma-focused phased CBT with a body-oriented and sol response in PTSD (or vice versa), making this hor- culturally sensitive approach. In these approaches CBT mone difficult to use as an outcome measure in trials . was combined with guided imagery with culturally specific Oxytocin is a neuropeptide that is involved in the images such as a flowering lotus [18–20] or cognitive re- regulation of fear. It also enhances trust and prosocial structuring was combined with progressive relaxation, behavior, and it has been associated with stress reduc- affect regulation skills and guided imagery, such as im- tion, wound healing, attachment, calmness and rest . agination of a safe place . These approaches seem to It has even been suggested that oxytocin could be resemble the music therapy method applied in the present administered intranasally in the treatment of PTSD, clinical trial. especially it has been considered for early prevention, and Lambert and Alhassoon  aggregated the effect sizes as a treatment to increase social responsiveness [27, 28]. for trauma symptoms and depression in 13 randomized In a meta-review of 400 studies investigating the effect controlled trials of different psychotherapeutic interven- of music on brain chemistry, it was found that music tions for traumatized adult refugees. They found a large contributes to the production of peptides such as oxyto- aggregate effect size for PTSD that was independent of cin, vasopressin and dopamine that add to the creation type of outcome measure (Hedges’ g .91, p .001, 95% CI of social bonding, and endogenous opioids that contrib- [.56, 1.52]. Depression was assessed in nine studies, and ute to the maintenance of steady social relationships here the effect size was also large (Hedges’ g .63, p .001, . A number of music intervention studies have dem- 95% CI [.35, .92]. Higher number of sessions (3–12) onstrated increased peripheral oxytocin levels after post- predicted the magnitude of PTSD change significantly. operative music listening , singing lessons or impro- Translated and untranslated sessions were compared and vised singing [31–33] and choir singing . Beta- there was no visible effect of the translation process upon endorphin is also associated with the stress response and the clinical outcome of the studies. low levels have been implicated in PTSD . Beta- Because of the complex situation of traumatized refu- endorphin was lowered in healthy undergraduates after gees and the fact that the majority of refugees remain music and imagery  and in patients with coronary chronically traumatized, several of the reviews maintain, heart disease after music listening . that other measures than the level of trauma symptoms have to be recognized when evaluating the effect of spe- Research on music therapy with refugees cific therapies in this patient group. These include the For decades, music therapy as a clinical psychotherapy evaluation of long-term treatment effects, social func- model has been applied to a broad spectrum of popula- tioning, improvements in the capacity for maintaining tions in the health system . Recent Cochrane reviews meaningful relationships, and a positive experience of of music therapy treatment have demonstrated identity and meaning [13, 17]. Recently, the investigation moderate-quality evidence on reduction of depression in of attachment-based treatment strategies, and the inclu- people with dementia  improvement of walking in sion of attachment style as outcome measure has been people with stroke  and increase of social communi- recommended [7, 8]. Furthermore, treatments that could cation skills in children with autism . In a Cochrane prove effective in preventing relapse should be further review of people with schizophrenia, it was concluded investigated. These include methods that address affect that music therapy as an addition to standard care im- dysregulation and coping strategies targeted to the proved global state, mental state (including negative ongoing insecurity and uncertainty typical for the life symptoms) and social functioning . A selective re- situation of refugees [16, 17]. Personalized treatment is view of music therapy studies with PTSD patients con- currently being introduced in many psychiatric clinics. cluded that individual and group interventions seem to In line with that Slobodin and de Jong  argued that reduce core PTSD symptoms and depression and Beck et al. Trials (2018) 19:301 Page 4 of 20 increase social function, hope and resilience in both trauma symptoms . In a psychiatric group treatment adults and children . program, including patients with refugee background, A randomized controlled study including adult psychi- the outcome measures showed better outcomes of GIM atric patients with persistent PTSD, who had been unable in trauma victims than in patients without trauma his- to benefit from CBT, showed a significant decrease of all di- tory . Two pilot studies with trauma survivors dem- mensions of PTSD symptoms after group music improvisa- onstrated large effect sizes of GIM interventions. In one tion compared to a waitlist control . Studies in group study, ten women with histories of sexual/physical child- music therapy with children and adolescents showed some hood abuse who suffered from complex or single PTSD effect on PTSD symptoms after four sessions of songwriting participated in 12 sessions of trauma-focused group compared to games in nine psychiatric patients aged 9–17 GIM. All of the participants achieved significant symp- years with histories of sexual abuse . Two Australian tom relief of PTSD symptoms, dissociation, anxiety and school studies demonstrated beneficial effects of music depression . In another study, the effect of ten ses- therapy: In 31 newly arrived refugees, a decrease in hyper- sions of individual resource-oriented GIM was assessed activity, aggressive behavior, depression, anxiety and in female veterans, who had been subjected to sexual somatization were found in periods with music therapy abuse. Focus group interview analysis found that music compared to periods without music therapy . In a ran- therapy succeeded in helping the victims cope with their domized study, reduction of depression, hopelessness and PTSD symptoms, regulate their emotions, decrease anxiety after group music therapy compared to art classes arousal, express repressed emotions and connect better was demonstrated (n = 18) [47, 48]. with others. Creative processing (drawing the imagery) Jespersen and Vuust  found significant improvement provided increased creative expression and a way to con- of sleep quality in a randomized controlled trial of adult tinue processing between sessions . refugees with undiagnosed PTSD (n = 23). All participants slept on a special pillow with loudspeakers; one group lis- Pilot study tened to calming music 30 min before falling asleep, the The background for the present study is a completed other group had no music. In another sleep study, music- feasibility study in the form of a pilot project concerning guided relaxation resulted in decreased depression and treatment of traumatized refugees with PTSD in Region increased sleep quality compared to relaxation with no Zealand, Denmark . In the 1-year-long project, an music in 13 veterans . Akhtar , adapting a quasi- adaptation for trauma treatment of GIM called Trauma- experimental design, found beneficial changes in depres- focused Music and Imagery (TMI) including the central sion and anxiety in a small group of Pakistani traumatized elements music listening and imagery was applied to 16 refugees after music listening to live improvised music (in adult participants. Participants were ten men and six combination with treatment as usual). Likewise, Alanne women of different origin (Syria, Afghanistan, Iraq, Iran)  found improvements in depression and quality of life with a mean age of 40 years. All participants completed in follow-up case studies of three torture survivors. Using the 16 sessions, but weekly sessions were not always a factor analysis of 106 sessions he demonstrated improve- possible due to cancellations; therefore, length of treat- ment in the ability of the refugees to contain, process and ment was on average 26 weeks. The single group pre- contain emotions and traumatic events from before to test/post-test study showed significant positive changes after music listening . with large effect sizes (0.81–1.17) on PTSD symptoms, well-being, sleep quality and social function. Symptom Guided Imagery and Music (GIM) load measured with the Harvard Trauma Questionnaire, The Bonny method of GIM is facilitating music-evoked showed both significant change (p < 0.002) and large ef- imagery in an altered state of consciousness as an in- fect size (1.15). Three participants scored under cutoff depth psychotherapeutic method. The original method for PTSD after treatment. Patient satisfaction was mea- applies 30–45 min of listening to carefully selected sured with a 7-point smiley scale from “very dissatisfied” movements of classical Western music [53, 54]. Adapta- to “very satisfied.” The average score was 5.5 with a tions of the method to trauma survivors have been slightly higher satisfaction towards the end of treatment. promising. In a naturalistic study of 102 women suffer- According to post-treatment interviews the patients ex- ing from Complex PTSD, 50 h of GIM resulted in sig- perienced improvement as a result of treatment, and nificant improvement of PTSD symptoms, decreased they experienced music as important for coping and symptoms of dissociation and better “sense of coher- emotional regulation. Furthermore, the music influenced ence” with large effect sizes compared to PITT (im- the restoration of trust and hope, both of which are agery-based therapy without music) . In psychiatric known to be involved in the achievement of secure at- patients, GIM in group treatment conveyed restitution tachment. The music repertoire used included Arabic and increased affect regulation [56, 57] and reduced and Afghan pieces, as 25% of the participants needed Beck et al. Trials (2018) 19:301 Page 5 of 20 familiar music to work with their inner images. All par- symptoms (primary outcome) from pre to post ticipants used the music method at home for self-care, treatment and from pre-treatment to 6 months’ relaxation, affect regulation, release of pain symptoms, follow-up? and positive focusing. 2. Will music therapy (TMI) be as effective as In order to assess the positive outcome of the pilot standard treatment regarding the decrease of study in a larger study, the randomized clinical trial that dissociation and the improvement of attachment is presented here was established. style and well-being (secondary outcomes) pre to post treatment and from pre-treatment to 6 months’ Rationale for the randomized trial follow-up? The increased number of traumatized refugees and their 3. Does any variable from the patient data at baseline generally problematic situation cause pressure on the (i.e., gender, age) specifically correlate with good treatment systems in the host countries. Accordingly, ef- outcomes of music therapy on trauma symptoms fective treatment options are needed in order to help the compared to standard treatment? refugees to attain positive integration and a better qual- 4. Concerning patient satisfaction with therapy ity of life. To our knowledge, no former randomized sessions, is there a difference between music studies on music therapy with adult refugees exist, and therapy and verbal therapy, and is there any no known refugee studies include physiological mea- development in the assessment of the sessions sures. The study hereby contributes to the investigation during the therapy course? of music therapy and the GIM method as an effective 5. Will basic levels of salivary oxytocin, beta- treatment modality. Verbal psychotherapy carried out by endorphin and substance P be changed by the treat- psychologists is chosen as comparator because it is the ment, are any changes stable at follow-up, and are standard treatment modality in the field, and because there differences between the two groups? the effect of music therapy versus verbal therapy can be 6. Will the levels of salivary oxytocin, beta-endorphin investigated. Due to the limited evidence and knowledge and substance P be affected by one session, and are about the efficacy of existing treatment programs on key there a difference between the groups, and between symptoms related to the complex traumatizing of refu- a session at the beginning and in the end of gees, including unsafe attachment patterns and dissoci- treatment? ation, the study attempts to add to the knowledge of the efficacy of both. Hypotheses The hypotheses of the study are that music therapy Methods (TMI) will not be less effective than verbal psychother- Aim apy according to the principle of clinical equipoise, and The aim of the study is to create increased treatment that we will see a decrease in PTSD symptoms and dis- modalities for refugees with PTSD, and to provide new sociation as well as an increase of well-being and im- knowledge about the efficacy and non-inferiority of provement of safe attachment style after both music music therapy compared to standard verbal psychother- therapy and standard treatment. Furthermore, we apy as primary psychotherapeutic methods in refugee hypothesize that patient evaluation will be equally posi- treatment. The study also seeks to point out possible tive with regard to both treatment conditions. According parameters that can aid as a help in the clinical referral to salivary hormones the hypotheses are, that music procedure and guide the choice of one or the other therapy will be no less effective than verbal therapy re- treatment modality. garding increase of basic and session levels of oxytocin Furthermore, the study aims to investigate the change and decrease of basic and session levels of beta- of symptoms on several parameters that earlier have endorphin and substance P. been tested in a pilot study as well as parameters that have not been tested before (dissociation and attach- Trial design ment). As an extension of the study, molecular data The research design is a randomized clinical trial with a (salivary oxytocin, beta-endorphin and substance P levels) parallel-group design including two intervention groups: are included as possible outcome measures. music therapy (Trauma-focused Music and Imagery (TMI)) and standard psychological treatment. We use a Research questions non-inferiority framework, where we test whether or not The following research questions are posed: music therapy is inferior to standard treatment. We in- tend to allocate 70 adult refugees diagnosed with PTSD. 1. Will music therapy (TMI) be as effective as Repeated measures take place at baseline, post therapy standard treatment regarding the decrease of TSD and at 6 months’ follow-up. A short form of the primary Beck et al. Trials (2018) 19:301 Page 6 of 20 outcome measure is also collected twice during the medium or high) for the patient, based on the actual treatment period (session 5 and 10). Session evaluation psychosocial resources and capacity for introspection, from clients is collected after each session. Saliva sam- reflection, affect regulation and empathy [64, 65]. ples are collected at baseline, post therapy and follow- The trial covers all three locations of the clinic. A list up, and also pre and post sessions 4 and 14 (see the of the places can be found in the Appendix. Four psy- Standard Protocol Items: Recommendations for Inter- chologists and four music therapists are responsible for ventional Trials (SPIRIT) flow chart; Fig. 1). All dimen- the treatment. sions of the study protocol have been described adhering to the SPIRIT Checklist (Additional file 1). We also ad- Participants here to the revised Consolidated Standards of Reporting The participants are adult refugees (age 18–67 years) ac- Trials (CONSORT) guidelines . cepted for treatment by the Clinic of Traumatized Refu- gees, i.e., by way of having a psychic trauma related to Setting war, persecution, torture, etc. Diagnoses for inclusion The study is carried out in the outpatient Trauma Clinic are: PTSD (ICD-10: F43.1 or DSM-IV-TR: 309.81), En- for Refugees under the Department of Special Functions during personality change after catastrophic experience in Psychiatry, Region Zealand, Denmark. The clinic of- (ICD-10: F62.0), or Complex PTSD/DESNOS (Disorders fers treatment in three units placed at different locations of Extreme Distress Not Otherwise Specified) (DSM-V). in the area a multidisciplinary treatment including a Comorbidity, such as depression, anxiety disorders, non- combination of medication, psychotherapeutic treat- psychotic depression, episodic psychotic symptoms ment, social counseling, health advice given by nurses, related to (Complex)PTSD, somatoform disorders or body therapy and music therapy. Translators are used as personality disorders, are accepted in the study. needed. Around 250–300 patients are referred per year, Medication for PTSD and comorbid illness as well as most from general practitioners and some from the Cen- for somatic diseases are accepted. The participants can ters of community psychiatry. Patients must have a resi- be refugees or family united with refugees from all coun- dence permit to access the clinic. The average treatment tries. Included are Arabic-, English- or Danish-speaking time is 4–6 months. When a patient is referred to the participants. These criteria are chosen to secure access clinic without a PTSD diagnosis, the physician and to self-report questionnaires in a language understood psychologist assess the patient. As part of the visitation by the participants, thereby avoiding misinterpretation and screening procedure in the clinic, the physician and of the questions. Included in the study are participants the treatment team estimate a mentalization level (small, with a medium to high mentalization level (as estimated Fig. 1 Schedule of enrollment, interventions, and assessments (Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) flow chart) Beck et al. Trials (2018) 19:301 Page 7 of 20 in the clinic after the visitation procedures). All partici- their personal data and withdraw such data from the pants receive verbal and written information in their na- project. The patient gives permission for the data to be tive language and are included after giving informed analyzed and published anonymously. The patient is consent to participate in the study. given one week to consider before giving informed con- sent. If the patient gives consent directly after the infor- Exclusion criteria mation, they sign the informed consent on the spot. If Exclusion criteria are severe psychotic disorders, defined as the patient needs time to consider their participation a psychotic disorders in the domain of F2 and F3 in ICD-10. telephone call is scheduled a week later, and a new meet- No active abuse was accepted (ICD-10 F10.24–F10.26), and ing is set up for the signing procedure. persons requiring hospitalization are not included. Patients A participant is included in the study when we have with suicidal risk at referral are not included in the study. obtained informed content. The leader of the study and the patient each have a copy of the informed consent Eligibility criteria for psychotherapists contract (see Additional file 2). Psychologists carrying out standard treatment in the study are employed as psychologist in the Clinic for Feasibility Traumatized Refugees; the music therapists have to have The pilot study leading up to the current study  had a master’s degree in music therapy and/or be a certified a high retention rate (no dropouts), the patients showed GIM therapist, and be employed in the clinic. a high degree of compliance. Filling in outcome self- report measures was feasible with the help of the trans- Recruitment lators. Recruitment took place in cooperation with the The visitation procedure of the Trauma Clinic for Refu- physician in only one clinic. In the current study, three gees includes: consultation with a physician regarding locations with 250–300 patients per year are included, diagnostics, medication and motivation for treatment, and there are 1.5–2 years to recruit 70 participants. The consultation with a nurse to obtain information about potential participants are screened for eligibility already health, consultation with a psychologist to obtain an during the clinical visitation process. We are aware that overall record of trauma history and background, coping music therapy is a new treatment option that can seem strategies and attachment style. Assessment of biopsy- difficult to understand by some patients, that the chosocial competencies and mentalization level are car- randomization process has to be explained carefully and ried out by the cross-disciplinary team at conferences. that participation in a research study can be a stress fac- tor for traumatized patients. We assume that the feasi- Procedure of obtaining informed consent bility of performing a RCT within the chosen framework Following the regulations of the regional Ethical Scien- will be reasonable. tific Committee, patients eligible to participate in the trial are invited to an information meeting with one of Interventions the music therapists or the senior staff specialist, where The refugee clinic carries out trauma treatment in a they are informed orally as well as provided with a writ- multidisciplinary clinical setting. The current study com- ten description of the study and of their rights as partici- pares only the psychotherapeutic part of treatment, but pants that is available in Arabic, Danish and English. A for ethical reasons all other services (social counseling, translator is present to translate if necessary, and the pa- body therapy, health advice) in the clinic are kept open tient is allowed to bring a companion. The meeting takes for all participants as needed, and the extent of other place in calm surroundings, and there is time set aside services will be monitored throughout the study. All par- for questions. The patient is given information about the ticipants who receive medication as part of the treat- purpose of the project, the content, pros and cons for ment in the experimental group as well as the standard participants, and their rights as a participant in a scien- treatment group are monitored continuously by the phy- tific health study. The principle of randomization is ex- sicians during the whole course of psychotherapy. Differ- plained, and both treatment options are described, so ences between groups are analyzed as possible that the participants only give informed consent when confounders related to outcome. understanding their options. The patient is given infor- mation about their right to withdraw from the study at Dose any time without missing out on options for current and A significant correlation between dose and response has future treatment. The patient is informed that they will been found for music therapy treatment with serious be informed if important health issues are revealed dur- mental disorders, with small effect sizes after three to ing the study, unless they do not want to receive this in- ten sessions and large effects after 16 to 51 sessions . formation, and that at anytime they can ask for sight of A review of quantitative studies of GIM concluded, that Beck et al. Trials (2018) 19:301 Page 8 of 20 at least ten sessions should be provided for clinical pop- A TMI session includes: ulations . In our pilot study, 16 sessions provided significant changes with large effect sizes on all the out- A verbal conversation used to check in and talk come measures. This number of sessions also fits with about actual issues the psychiatric clinic’s standard length of treatment. We Agreement of a focus for the music listening chose to repeat the 16 sessions as dose for both treat- Finding a music piece (patient chosen or therapist ment arms in the present study. chosen; if the therapist chooses the piece a small The patients participate in weekly sessions, lasting excerpt is played to assess the match of music with 60 min. If any cancellations occur the treatment period the patient). Music from several genres are optional: is prolonged until all 16 sessions have been received. classical, film, meditative music, or music Should the participant encounter any given events that corresponding to the patient’s cultural background would lead to further traumatizing by way of circum- Music listening; the patient is sitting on a chair or stances outside therapy, treatment can be prolonged to lying on a couch, eyes open or closed as preferred as many as 20 sessions, after consultation with the treat- A short induction; for example, mindful focus on ment team and the physician. Hence, a margin of 25% is breathing, guided relaxation or focus on an inner accepted (from 12 to 20 sessions). In both music therapy image and the comparator treatment a phase-oriented treat- Music listening (2–10 min in the beginning, up to ment according to Herman  is carried out, including 20 min in the end of therapy). The therapist can talk a stabilizing phase, a trauma-exposure phase and a re- during the music if helpful orientation phase (if possible). The development of a The therapist guides the patient back to the present safe therapeutic relationship and verbal processing are Participants are invited to draw a picture of the components in both psychological standard treatment imagery and trauma-focused GIM. Thereby, the professional Verbal communication about the drawing and the adaptation of music as a therapeutic medium, including experience with the focus on integration of the way that music influences the therapeutic relation- important imagery, acknowledgement and ship, is the independent variable in the trial. meaningfulness in the therapeutic process Homework assignment as needed (including using Trauma-focused Music and Imagery (TMI) music at home) TMI is an adaptation of GIM, a music therapy method initiated by the American music therapist Helen Bonny Treatment phases (the session numbers are indicative in the 1970s [53, 69] using music listening of selections as a patient can stay in phase 1 for the whole time or go of classical music in an altered state of consciousness as back and forth between phases): a medium for therapeutic change. During the listening experience, a non-directive verbal dialog between patient Phase 1. Stabilization phase (sessions 1–5) and therapist is carried out supporting the deepening The participants are provided with a CD containing seven and integration of the ongoing stream of imagery, emo- pieces of music for listening to at home (see Appendix 2). tions and sensations evoked by the music. GIM has The preferred piece(s) is(are) used in the first sessions. served as primary psychotherapeutic treatment in a The patient’s relationship with music is explored. Psychoe- range of clinical settings and has been modified and ducative elements are introduced (such as understanding adapted to several clinical populations . A con- of PTSD symptoms and the autonomic nervous system in tinuum of practices exists, from the full Bonny method trauma). Music accompanied breathing  is offered as (2-h sessions with challenging music and verbal dia- help to deepen the breathing (abdominal breathing) and logue) to short GIM (1-h sessions, shorter music selec- to regulate arousal. Positive inner imagery such as “the tion); music and imagery being a supportive short-form safe place” and positive memories of close relatives or that often only includes one or a few short music pieces events before the war are presented as central to increase and no verbal interaction during the music listening biopsychological resources and safety. Music as a safe part. ground and as a way to detach from pain and negative A GIM therapist holds a master’s degree in music feelings is in the focus. The therapeutic alliance develops therapy or other relevant subject followed by a mini- through shared experience with music. The music in the mum of 3 years of supervised training in the GIM stabilization phase is characterized by a high degree of method licensed by an international training institute predictability concerning the musical parameters (i.e., a (see www.music-and-imagery.eu).. The method has been stable, slow tempo, only gradual changes in volume, adapted to refugee trauma treatment by the authors rhythm, sound, register and harmony), simple dynamics Beck, Moe and Meyer . (such as ABA) and use of repetition in melody and chords. Beck et al. Trials (2018) 19:301 Page 9 of 20 The participant is asked to work with the music at home can help the patient to be reminded of their dreams, and between sessions. to keep them in focus as a beacon for their goals in life. Moreover, the imagery can serve as a way to rehearse Phase 2. Emotional containment (sessions 6–8) new kinds of behavior in a safe environment. This phase Contact with different kinds of emotions in the music is also touches on identity and existential meaning, and explored. Both positive and difficult emotions can be ex- the chosen music stimulates the patient to reflect upon perienced, while listening to music, and the ability to on these cornerstones of life. The therapy course is contain contrasting emotions, ambivalence and different brought to a closure, and the focus is on how the patient aspects of emotions are important parts of the investiga- can go on with their life. tion process. The primary focus is on giving the patients The described protocol is adapted to the specific needs an opportunity to both explore and be able to stay with of the patients. In case the patient cannot tolerate music difficult emotions with the aid of music, as well as a pos- at all as part of being hypersensitive to sound (which sibility to develop new coping skills that will allow the can happen due to insomnia, pain or re-traumatization), patients to change their emotions through their inter- there can be sessions with only verbalization and guided action with the music. If the patient is stable enough imagery without music. In case the music therapist sug- and feels safe, music with more depth and dynamics can gests that live music would be a more adequate choice be introduced. than recorded music in terms of attunement to the pa- tient, or should the patient be more able to tolerate live Phase 3. Trauma exposure and grieving (sessions 9–14) music, the music therapist can use their own voice and A process of exposure during music listening is carried musical instruments and create music on the spot to fa- out when the patient has achieved sufficient cilitate the inner experience of the patient (as there has stabilization. The narrative of traumatic events can be been examples of in the pilot study). Accordingly, pa- accompanied by, and supported by, music, or music and tients who can tolerate short GIM (longer music and imagery can be used for exploration of traumatic epi- verbal interaction during the music) are offered this sodes. Trauma imagery can also emerge during music option. listening without a fixed focus, and can be processed with the support of the therapist and the music. The Standard psychological treatment music serves as a holding structure that match the emo- Standard psychological treatment in the Clinic for Trau- tions and states of trauma processing, or the music can matized Refugees is inspired from a broad range of the- be used to regulate arousal during exposure. All sessions oretical models such as narrative therapy, cognitive are carried out with the focus on step-by-step work and therapy, social psychology and neuro-affective therapy. safety; for instance, can music pieces connected to safety EMDR is part of the treatment options in the clinic, but imagery or positive resources alternate with pieces of is not offered to participants in the trial. music accompanying trauma memory. Traumatic epi- A therapy course with verbal therapy is based on a sodes can be renegotiated during music listening, mean- phased treatment of traumatic experiences. The therapy ing that the patient finds alternative solutions in imagery course is adapted to the individual needs of the patient to a stuck situation in the past, and/or that incomplete and their symptom load. The overall goals are alleviation defense actions (fight and flight) can be carried out in of symptoms and normalization; and aiding the patient the imagination. Grieving and loss are common themes to understand that symptoms are normal reactions to that are explored in the music and imagery experiences, abnormal incidents. Another goal is to promote patients’ and can be assessed by encouraging the patient to en- reflection, making way for new insights and decrease gage in imaginary dialog with lost relatives. Anger man- conditional reflexes. Phase 1 is focused on general agement can be included as a therapeutic focus. stabilization and basic resourcing and the buildup of If a patient is overwhelmed by the music and imagery trust, making way for the formation of a therapeutic alli- experience, or suffers intruding flash-backs, the music is ance. The work is directed to strengthening the daily immediately turned down or changed. When possible, level of functioning, to learn techniques to regulate af- music from the patient’s own culture is evaluated by the fects, increase affect tolerance, and to create a common interpreter before use to ensure that the lyrics and the understanding of symptoms and discomforts. In phase 2 traditional use of the piece is appropriate for the session. a processing of traumatic memory is taking place, enab- ling the patient to break with avoidance behavior, and Phase 4. Reorientation (sessions 14–16) begin integrating the traumatic memories in the life nar- In phase 4 the patients are encouraged to develop their rative. Phase 3 includes personal integration and re- social network and engagement in activities in their habilitation. The phases are not necessarily carried out community if they are ready for it. Music and imagery in a sequence, where one phase comes to an end before Beck et al. Trials (2018) 19:301 Page 10 of 20 the next begins, but rather the phases tend to overlap to “more than once a day.” The scale shows good each other throughout the course of therapy. psychometric properties . If a patient wishes to stop treatment, the clinical team The Somatoform Dissociation Questionnaire (SDQ- find another suitable treatment modality. 20) [78, 79] is a supplementary scale for the evaluation of somatic dissociation, but going a little more in depth. Assessment of treatment fidelity The 20 questions ask about dissociative symptoms that Both music therapists and psychologists receive clinical are evaluated on a 5-point Likert scale, ranging from supervision from experienced supervisors. All clinicians “does not at all fit with me” to “fits extremely well with report on each session in a special field in the data col- me.” If an item is acknowledged as fitting for the person, lection system directly after the session. In this way there is an additional question to whether a physician treatment fidelity can be monitored throughout the has provided a physical diagnosis that explains the study, and violations can be reported. Additionally, the symptom or not. The scale has good psychometric prop- music therapists complete notes of music pieces and in- erties and has been found to correlate with self-reported ductions accompanying the music listening, and the ab- traumatization [78, 80]. sence of music listening in a treatment can be noticed. The WHO Well-being-5 (WHO-5) is a short form that allows information of general health and absence of dis- Outcome measures tress to appear . The scale consists of five questions The primary outcome measure is the therapist- measuring quality of life and well-being (joy, energy, administered Harvard Trauma Questionnaire (HTQ) healthy rest, motivation and meaningful activities). , demonstrating an acceptable reliability in different At the end of each session a session evaluation is car- languages, including Arabic [72, 73]. The first 16 items ried out. Music therapy patients are asked to what de- of part IV are used, describing to which degree the par- gree they have used the music method since their last ticipants felt disturbed by trauma symptoms correspond- session. All patients are asked to rate to what extent they ing with the PTSD diagnosis in DSM-IV. The scale has feel understood and heard by the therapist (0–10) and three subscales: avoidance, hypervigilance and intrusion. how helpful they find the session (0–10) to be. They are Eight of the HTQ questions are included in the scale also asked to name the most important themes of the PTSD-8 , which is administered at the beginning of session, and what they think they will remember/tell sessions 5 and 10 (of 16 sessions) to monitor the effect their spouse when returning home. The music therapists on trauma symptoms during treatment. are collecting data about the use of music, intervention and themes of the session. Secondary outcomes The secondary outcomes assess changes in attachment Translation of scales and dissociation, both factors have been associated with All scales are available in Danish, English and Arabic. PTSD and Complex PTSD, playing a role for the thera- The author SM performed a translation of SDQ-20, peutic alliance, relational capacities and ongoing develop- DSS-20 and RAAS into Arabic together with an expert ment of integrative capacity in the patient. The Revised group of experienced Arabic-Danish translators, and the Adult Attachment Scale (RAAS)  is a revision of the author BB performed a translation of SDQ-20 from original Adult Attachment Scale evaluating the experience Swedish to Danish with the help of a Swedish health- of emotional closeness or distance with 18 questions informed translator living in Denmark. The translations which are answered on a Likert scale with 5 points ran- were back-translated and checked for misspellings and ging from “right for me” to “not at all right for me.” The misinterpretations following the guidelines for transla- questionnaire indicates whether a person has a predomin- tion of research questionnaires (Process of translation antly safe, defensive/anxious or dependent attachment and adaptation of instruments, WHO, n.d.). style. Safe attachment measured with RAAS correlates negatively with the PTSD diagnosis . Two dissociation scales are included in the study. Explorative outcome measure: assessment of levels of The Dissociative Symptoms Scale (DSS)  evaluates neuropeptides moderate to severe levels of depersonalization, de- As mentioned in the background section several stud- realization, gaps in awareness or memory, and dis- ies have assessed oxytocin in connection with PTSD sociative re-experiencing. The DSS is applied with the patients, but only after a single intervention. In the permission from the developers. The 20 questions are present study, we chose to assess the change in in answered in relation to the amount of time that the neuropeptide concentrations following a single inter- person experiences each symptom on a 5-point Likert vention and the possible changes in basic levels of scale ranging from “not at all,”“once or twice a day” the neuropeptides oxytocin, beta-endorphin and Beck et al. Trials (2018) 19:301 Page 11 of 20 substance P after treatment. This remains an explora- age, gender, country of origin, native language, tory part of the trial. education, civil state, number of children at home, The collection of saliva is ethically less invasive than whether the patient has been sexually or physically blood sample collection, it is self-administered and it abused during their childhood, imprisonment takes less than a minute to collect a sample. (number of weeks), exposure to torture, number of weeks on flight, number of weeks in refugee Collection and analysis of saliva samples camps and/or asylum centers. The patient fills out The collection of saliva samples is carried out by the self-report questionnaires and a saliva sample is therapists in the project. A description of the collection collected. The scoring of the primary questionnaire procedure is available for all therapists. 1–2 ml of saliva HTQ is done by a psychologist or trained music are collected from the patients in a tube (Disposable therapist, as it requires specialist knowledge and plastic tube, Thermo Scientific Nunc 345,608, 14 ml) or training, and is based on an interview with the a small petri bowl (Thermo Scientific Nunc IVF ICSI patient. The secondary questionnaires are filled out Dish). The patients are given the possibility to be alone in the presence of one of the researchers or with in the room while collecting saliva. The therapist fills the presence of a translator trained in assisting the out a label with patient ID, time and date and data time scoring of the questionnaires point. The female patients are asked whether they are 5. The patient is randomized to treatment with music menstruating, and this is noted on the label, as it could therapy or standard treatment influence the hormone levels. The samples are stored 6. Treatment is carried out according to the immediately in a freezer at − 18–20 °C. The samples are descriptions under “Interventions” transported to the Translational Unit, Neuropsychiatry 7. Patient data are recorded in all sessions (session Unit (TNU), Aarhus University in a flamingo box with evaluation), session data regarding use of music and cool freeze bricks (Farusa emballage, foam refrigerant themes for the therapy are collected by the music bricks) at a temperature of − 70 °C. At TNU they are therapists with the help of translators stored at − 80 °C until further handling. When all sam- 8. Data collection (PTSD-8) is carried out in sessions ples have been collected, the levels of oxytocin, beta- 6 and 11 and saliva samples are collected in sessions endorphin and substance P will be analyzed using a 3 and 14 (see “Outcome measures” and the flow Luminex and a Milliplex kit (Human Neuropeptide chart in Fig. 1) Magnetic Bead Panel; Neuroscience Multiplex Assay 9. After the last session, a post-treatment data collection (HNPMAG-35 K)). session is scheduled, where all questionnaires are filled out, HTQ is scored by an external psychologist Procedures (and translator) who is not a part of the treatment team and who is blinded to the patient’streatment 1. After assessment by the visitation team and at the group. Three questions regarding the patient’sown team conference, eligible patients are invited to evaluation of their current life situation are posed by participate in the study by one of the three music the music therapist/researcher. In order to leave out therapists/researchers confounders of diurnal variation, the time of the 2. The patient is informed orally and in writing about meeting is scheduled so that the collection of the study saliva can occur at the same hour as the baseline 3. If the patient accepts participation, informed sample was collected. Any need for additional consent is signed by patient and therapist. If treatment is assessed by the clinical team. If participation is rejected the patient is offered other additional psychotherapeutic treatment is needed, the treatment in the clinic participant is excluded from follow-up measurement. 4. Baseline measurement is carried out by the music All participants who have completed the protocol are therapists/researchers. Information about health invited to a 6-month follow-up session, where according to height, weight, exercise, use of alcohol, questionnaires and saliva samples are collected, with smoking habits, symptoms and medication is an external psychologist assisting in scoring HTQ, collected during the visitation procedures in the and a trained translator, who is blinded to the clinic, and transferred to the dataset by the affiliation, assisting in scoring the remaining researchers. All data collection is carried out on questionnaires laptops with a data collection environment called Xpsy (see below in the “Data management” section). Adherence to treatment is monitored through the Demographic data and information relevant for the evaluation of sessions, and in case of dropout partici- trauma history are collected and scored regarding pants are asked about their reasons for stopping Beck et al. Trials (2018) 19:301 Page 12 of 20 treatment, if possible. A research log including dropout numbers in the Xpsy environment. Access will also be information is kept by the researcher team. Additional granted to the statistical consultant who works in the sessions in the clinic during participation (such as body same organization (Region Zealand). A signed data therapy or social counseling) and change of medication agreement contract is made between the Regional Zea- are followed in the patient journal and scored in the data land and Aarhus University for exchanging information collection environment. on the saliva data. Data management Translators All data related to the study are stored with highest Arabic translators are included for Arabic-speaking par- possible level of security. Questionnaire data, session ticipants as needed. The translator is physically present evaluation and demographic data (including health during translation. The translators are trained in the and trauma history data) are typed into a database management of questionnaires and the Xpsy environ- with the program Xpsy, which is a quality assurance ment for data collection. Translators assist the comple- system for psychiatric clinics developed by PsyMeta tion of questionnaires for Arabic-speaking participants. Gmbh by Franz Fischer, Shafisheim in Switzerland All translators are asked about their educational back- (https://www.xpsy.eu/). It is administered by the co- ground and experience of translation, so that only trans- researcher and data manager (second author SM). All lators with adequate education and experience with the questionnaires are set up in electronic versions in psychotherapy are used. All translators used in music the program in three languages, and are stored in the therapy treatment are instructed in translating during in- database as soon as they are typed in. The program duction and music listening, and they receive a self- ensures that all data can be typed by the participants experience of music and imagery to educate them in the and/or translators without missing any questions, the special use of the voice during music and imagery with data time point for the single participant is clearly in- participants. dicated and the dates of entering the system can be monitored. All patients have their own login based on ID number. Researchers have a common code to ac- Statistical methods cess the participant’s actual session or questionnaire Statistical analysis will be carried out in the statistical session, and typing in of demographic data. environment R  in cooperation with the statistical department in the research unit of Region Zealand Data confidentiality and PFI Region Zealand (Production, Research and The project is approved by the Danish data management Innovation Unit). Data will be treated according to authorities “Datatilsynet” under the protocol number the intention-to-treat principle. Analysis of all data REV-50-2014. Data are stored until the completion of will take place after the conclusion of data collection. analysis and are then deleted. Saliva samples are stored Following the initial screening of the data significance until 2027 in case of the need to go back and do add- tests concerning differences between standard treat- itional analyses. In that case all participants will be asked ment and music therapy will be carried out in order for additional consent. to assess the non-inferiority of music therapy. Signifi- The research data typed into the Xpsy database are cance and variance for the primary outcome measure stored on a secured server that is placed in a locked cabi- will be calculated with analysis of covariance net. Confidential data regarding patients, such as list of (ANCOVA), including data from five measuring patients in the study, reasons for decline of participation points. Secondary questionnaire outcome data will for eligible patients and list of completed saliva samples also be calculated with ANCOVA, using three data are stored at a protected website for clinicians at the points. Correlations between trauma symptoms, at- Clinic of Traumatized Refugees. Any other data, such as tachment, dissociation and demographic parameters informed consent contracts, clinical notes, patients’ draw- are investigated. A regression analysis will be applied ings, are stored in locked cabinets. Patient data related to to look for predictors of improvement of trauma treatment, other than research data, are stored in the symptoms (HTQ) and change of attachment style, as patient database OPUS, Region Zealand, or after 25. well as predictors for improvement connected to November 2017 in the application “Sundhedsplatformen.” treatment (music therapy or standard treatment). Saliva samples are stored in research freezers placed in Analysis of hormones will be split up in an ANCOVA locked local facilities. testing variance between groups and with time (base- For the data analysis, the members of the Steering line to follow-up), and simple significance tests of Group and the group of three music therapist/re- change after single sessions (between the third and searchers will have access to data, stored under ID 14th session and between the interventions). Session Beck et al. Trials (2018) 19:301 Page 13 of 20 satisfaction data will be treated with descriptive researcher logs on to the randomization website and statistical methods. types patient ID number, gender and location. Informa- tion of the treatment group is provided immediately on Power calculation the website and is also sent by email to the researcher. In order to estimate the level of power we reviewed ran- The status of the patient is typed into the Xpsy database, domized and non-randomized trials where refugees suf- and the patient is referred to either music therapy or fering from PTSD were treated with stabilization and standard treatment at the location. trauma exposure strategies with cognitive and narrative elements corresponding to the standard treatment in Blinding our study, and where the Harvard Trauma Question- There is no blinding connected to the randomization of naire was used to measure changes in trauma symptoms intervention. Questionnaire data are blinded to all clini- (the primary outcome in the current study). The varia- cians who are performing the treatment and data collec- tions in the studies were considerable, and we chose to tion in the project, so that none of the clinicians or only look at studies that had a number of sessions that researchers have access to completed questionnaire data were similar to the current study, and where the mean from their own patients or any other participant in the baseline value of HTQ were around 3.3, a value that we trial. This ensures that the clinical processes are not in- found to correspond to our population in the pilot study fluenced by the outcome results data. [18, 62, 83–86]. Non-significant differences between 0.1 External psychologists are called in to assist the scor- and 0.5 was found in HTQ from pre to post treatment. ing of HTQ post treatment and follow-up, they are Based on our clinical experience and data from these blinded to the treatment of the participant. Data remain studies, we estimate a clinical insignificant difference of concealed until the entire trial is completed. 0.3 as the maximal difference between music therapy and standard treatment to confirm the non-inferiority Potential harms hypothesis. A mean standard deviation of 0.48 on post- Potential harms of the trial can occur as harms of the inter- scores of HTQ was calculated from the studies referred ventions as well as harms of the research procedures. Music above. therapy is a relatively new treatment modality for refugees, The power calculation was based on a significance and the art of choosing music for the right phase of treat- level of 0.05, power 0.08, d = 0.3 and SD = 0.48. The cal- ment is still being developed. According to the pilot study, culation was carried out with software from Epi-info 7 the treatment method is not harmful when used with care (http://wwwn.cdc.gov/epiinfo/) in cooperation with and ongoing attunement to the needs of the patient, but Department for Statistics, Psychiatric Research Unit, the music therapists must pay attention to avoid adverse re- Region Zealand and PFI. actions in case of hypersensitivity to sound, restimulation The result indicates a minimum of 64 participants of trauma by using too loud or dynamic pieces of music, or (32 in each group). restimulation of trauma in former musicians or persons Adherence to music therapy has been found to be good who have been tortured with sound or music. Music listen- in psychiatric patients with a low dropout rate (11.5%) ing that triggers trauma memory has been found to happen . In three former randomized clinical studies on psy- frequently and, therefore, the music therapists have to be chological treatment of refugees with large samples low specifically trained when working with this clinical group. dropout rates (7–10%) were demonstrated at follow-up Trauma exposure with music is very effective, but it re- [21, 83, 88]. quires that both the patient and the therapist can work to- We have, therefore, chosen to include a dropout rate gether to keep arousal at a manageable level. The patient is of 10% and thus end up with n = 70 (35 in each group). given control over music choice and volume, and is edu- cated to give feedback before, during and after music listen- Randomization ing, as well as how to use music safely at home. Randomization is carried out with the help of the It is well-known, that the exposure phase of trauma randomization software Sealed Envelope (https://seale- treatment both in music therapy and standard treatment denvelope.com/). Stratification is applied regarding geog- will stir up traumatic memories which can worsen the raphy (three different locations) and gender (male/ symptoms for a period. The patients are informed about female). Within the strata, random permuted blocks of this and supported to cope with the symptoms. The even length (blocks of four or six participants) are used. therapists can go back to stabilization work whenever When a participant has given informed consent and needed to facilitate a safe therapeutic course of treat- completed baseline measures with one of the three ment. Some of the patients express a need for longer music therapists who takes care of the research proce- treatment periods, that collides with the six months’ dures (one in each location), the music therapist/ follow-up period without treatment. The therapists Beck et al. Trials (2018) 19:301 Page 14 of 20 normally have the same amount of time for each patient Dissemination as planned for in the study, and the closure of therapy is Both positive and negative results of the trial will be re- planned for with care. However, some patients happen ported in the relevant scientific journals and at inter- to be re-traumatized by external events, and in such national conferences. A summary of the results will also cases the treatment team of the clinic can estimate be published in the healthcare system and to the public. whether they can receive additional treatment and be ex- A conference day for refugee clinics in the country and cluded from follow-up measures in the study. neighboring countries is planned for. A poster with a Regarding the potential harms of working with the re- summary of the results will be placed in the refugee search questionnaires, the trauma symptoms question- clinics and translated into Arabic. naire and the dissociation scales sometimes can be challenging for the patients as they are reminded about Discussion traumatic incidents. The number of self-report question- Music therapy and mechanisms of change naires utilized has been kept at a reasonable number, but Brain research on the perception of music indicates that in case the patients experience fatigue or confusion, music positively affects brain chemistry associated with breaks are introduced, or the scoring is extended to two stress, immune defense, reward and attachment systems different days. Even though the sampling of saliva is , and that music strongly affects and changes activity non-invasive and quick, some patients experience nausea in brain areas connected to emotion regulation and so- or disgust, or they are reminded of traumatic experi- cial response such as the limbic and paralimbic struc- ences. Patients who are not able to give saliva are tures . PTSD is connected to stress-related loss of respected, and the procedure is cancelled. Any negative hippocampal mass  and hypervigilance related to an reaction is processed by the therapist/researcher. increased amygdala-hippocampus connectivity . The plan for monitoring and acting on any incidents Brain studies have shown how music can enhance the of harm or unintended reactions is embedded in the connection between prefrontal areas and amygdala/ clinical emergency report system. The clinicians monitor hippocampus and thereby calm down hypervigilance and adverse patient reactions, report them in the journal sys- enhance reflectivity and cognitive processing of emo- tem, and also immediately report to the leading phys- tions . Furthermore, music listening has been shown ician, who has clinical responsibility. Patients can to reduce stress and enhance emotional responses, such telephone the clinic at any time during opening hours to as joy, peacefulness and calmness . A recent func- receive support and have additional appointments. Inci- tional magnetic resonance imaging (fMRI) study com- dents will also be discussed on the weekly clinical team pared guided imagery, music alone, GIM and a control meeting and by the team of music therapist researchers group in participants recalling personal episodic memory at monthly meetings. with negative-emotion. The study indicated that GIM was most effective in the processing of traumatic memories affecting cortical and subcortical structures and func- Auditing tions . Music can intervene in the avoidance re- All clinicians of the trial (psychologists and music thera- sponse seen in many PTSD patients: “Superficial pists) have meetings at the beginning of the trial to be amygdala, nucleus accumbens and mediodorsal thalamus informed about procedures and to resolve questions and constitute a network that modulates approach- problems related to the trial conduct. The group of withdrawal behavior in response to socio-affective cues music therapist researchers meets once a month to co- such as music.” . ordinate and monitor the trial. The Steering Committee In order to understand possible mechanisms of music of the study meets every four months to oversee the de- therapy in the treatment of refugees with PTSD, the the- velopment of the study. Both groups include investiga- ory of neuroception [95, 96] might explain how music tors as well as clinicians, but the researchers have no can decrease hypervigilance. Trauma disrupts basic access to data before the end of data collection. autonomic regulation, where exaggerated sympathetic responses known as fight and flight, and parasympa- thetic responses known as freeze and feign death/total Protocol amendment submission occur. Based on studies of heart rate vari- The protocol cannot be changed without corresponding ability, Porges argued that the mammal parasympathetic with the Regional Scientific Committee. Any changes to branch is divided into a dorsal branch associated with the protocol have to be approved by the Regional Scien- immobility responses and a ventral part associated with tific Committee, following the regulations for protocol “social engagement.” He showed how facial muscles, amendment applications. Protocol amendment is also ears, eyes, heart and stomach functions are connected, reported to ClinicalTrials.com. and that face-to-face interaction and communication Beck et al. Trials (2018) 19:301 Page 15 of 20 can calm the nervous system down and act as a brake and follow-up times are concealed to the allocation (and on the heart rate. During stress the ears accomodate for the patients are not asked about it). Imbalances between very high and very deep sound frequencies and during treatment groups are prevented by the use of stratifica- deactivation of stress the middle frequency area, such as tion (gender and location). the human speaking voice, is augmented in the auditory As music therapists carry out the information meet- system . Hence, calm music and speaking combined ings and measurement, the participants might be more with a thorough attunement to the patient might acti- motivated for music therapy than standard treatment vate the social engagement system, lead to down- (comparator), and be more likely to drop out from regulation of arousal, and enable the patient to unfreeze standard treatment. This could possibly influence the re- and experience aliveness and energy. sults in favor of music therapy. Adherence to the treat- The use of music in trauma treatment serves as a way ment is secured, as none of the participants can cross to build up inner resources in the patient necessary for over to the other group. If a patient drops out from working through the trauma story, such as positive music therapy and is offered standard treatment, they memories, a feeling of strength, a safe place, or the aes- are excluded from follow-up. If participants are offered thetic experience of music. Exposure is part of many other types of treatment in the clinic parallel to the trauma therapies and includes the narration of the assigned treatment, this will be monitored and an ana- trauma story, the re-imagination being part of this retell- lysis of any group differences will be carried out. ing. When the narration of trauma episodes is accom- Protocol fidelity is assured by data collection of the ther- panied by music, the music serves both as a holding and apist notes for all sessions, by team supervision and fre- structuring framework that keeps the patient from frag- quent meetings between music therapists and psychologists menting. It also helps the stimulation of imagery so that and in the group of music therapy researchers. The use of the recalling of trauma memory can change from being Xpsy for data collection ensures that no participant data stuck in repetitive flashback. With the music as a sup- are analyzed in the wrong group. port, processing of trauma fragments can take place at an implicit level of body sensation and imagery forma- Limitations and complexities tion, a symbolization process where the memory is A number of factors adds to the complexity of the trial transformed into a metaphor [98, 99]. The ability to and possibly influence the outcome in different ways. symbolize an experience allows it to be installed as According to the treatment recommendations for com- memory that can be placed in the past instead of occur- plex PTSD mentioned in the academic literature review, ring as a recurrent flashback experienced as real time. adequate length of treatment is in the range from 1 to 2 When working with imagination to music, it also seems years, compared to our timeframe of 4 to 6 months. that the memory of a traumatic episode sometimes be- Very few of in the target population have simple forms gins to transform and the patient imagines a new solu- of PTSD, where short-term standard treatments have tion; for example, of escape, control or victory, that been proven effective. As studies have shown, complex allows for the completion of fight and flight actions that forms of PTSD and compromised attachment are preva- were impossible to carry out at the time of the trauma, lent in the population. However, the trial is conducted which, according to Peter Levine, is at the core of the within the premises of Psychiatry in Region Zealand, trauma-healing process [100, 101]. where the countrywide recommendations are followed. Those recommendations are currently updated. This Risk of bias means that we cannot expect large effect sizes. In a psychotherapy trial such as this, it is often not pos- Ongoing stressors in participants’ worlds include sible to blind the intervention of the participants, and news and video footage of current bombings of there can be an influence of their knowledge of being in people in their home town or where their friends or the intervention or the control group. However, in this family live, confusion about the explicit and implicit trial we investigate two types of treatment in a single rules and norms in their host society, exhaustion clinic with equal dose (16 sessions) and equal weight as from having to follow language training and work- primary trauma treatment modalities. According to con- placepracticewithongoing PTSD symptoms as well cealment of allocation, the randomization procedure is as raising children on a minimal budget, and last but generated by computer software at Sealed Envelope, and not least the alienation of witnessing a hostile tone none of the researchers have any influence over the pro- towards them from governments as well as citizens in cedure. Baseline tests are carried out before the public news. Such elements make it very difficult randomization, so that the allocation does not influence to construct a social and psychological space suitable the measurement. Psychologists carrying out data collec- for healing past trauma. Overall, this contributes to a tion concerning the primary outcome measure at post lesser effect size, but the load is spread unevenly and Beck et al. Trials (2018) 19:301 Page 16 of 20 the aim should be to record the most important of thepatient to createanarrativeof thelifestorythat these circumstances in each case. helps them to be able to make meaning and live on Translators are used with participants, who find it after trauma; it is by the way not the same as NET). beneficial. In a translated session, the verbal informa- In reviews of psychological treatment with refugees, tion passedislittlelessthan halfofthatofa session the two treatments with highest effect sizes are cul- without, as everything has to be said twice and quite turallysensitive CBT and NET, buttheyhavebeen often there is necessary conversation about the mean- conducted almost exclusively by the same two groups ing of a single sentence. Consequently, the doses of of researchers, and have been criticized for having therapy for participants with translators are not com- low-qualityevidence. Studies of other types of parable to those without translators. There are often intervention, including multimodal therapy, reach an limits to the conversation with the translator, who average medium-large effect size, and this is also what might be a young and relatively inexperienced person we will expect from the outcomes of the present with a limited vocabulary on matters relating to psy- study. A recent review by Tribe et al. concluded that chotherapy and trauma in either one of the languages refugee research should include more “real-world” used. Many of the Arabic-speaking participants do multidisciplinary interventions that better model clin- not have Arabic as their mother tongue. There is no ical practice, which we agree upon from our clinical officially approved education for translators, the clinic experience . is notfreetochoosethe best availabletranslators, Several of the outcome measures were not used in our but is bound by an exclusivity contract with one pilot study, so we do not have previous experience with vendor. Most of the translators are bi-lingual persons the use of the questionnaires in the present context. Fur- without any formal training as translator or any thermore, the translations of the scales that we performed higher education in either language. The translator for the study has not been validated. According to the brings their own presence into the therapy room and physiological outcome measurement, one limitations is the therapeutic dyad effectively becomes a triad. The that the existing knowledge is limited, and no reference official goal of the translator is not to be personally levels are established, making the results provisional and present, but in a psychotherapy session, where the implicit exploratory. To our knowledge no previous studies of sub- is just as important as the explicit, this becomes impos- stance P in relation to treatment have been carried out. sible, and the best implicitly present translator is the one who can join the atmosphere that develops in the session Implications and not stick to a rigid pretence of not being there. It We expect that the trial will demonstrate that music follows that translation alone is a complex phenomenon therapy can be a feasible and effective intervention for that influences outcome more for some clients and not at the treatment of refugees, and that we will know more all for those who do not use translators. Furthermore, it about which subgroups of patients will have special perhaps influences music therapy and standard treatment benefit of music therapy. We also hope that the trial will differently. provide arguments for extended use of music therapists The use of the interdisciplinary team during the in the treatment of refugees with severe trauma. If corre- course of treatment according to individual needs means lations between physiological and self-report measures that some participants receive more treatment than can be found this will support the strength of the trial, others, especially so for participants needing physiother- and make way for new knowledge about trauma and bio- apy or body therapy (psychomotorical therapy). This is markers. As the intervention group is asked to use music usually prescribed for patients having specific and dis- at home as a tool for affect and arousal regulation, in- turbing physical symptoms. Also, advice from a social creased knowledge about music as a health resource for worker helps clarify issues with authorities and other traumatized refugees will be provided. The study on the professionals. The amount of extra treatment and coun- use of music therapy hopefully will add new possibilities seling is monitored and recorded in each case. for the treatment of this vulnerable population, and Another limitation is the broadness of standard thereby be helpful for the increase of refugee health and treatment; as the psychologists in the clinic work with integration in the society. an integrative approach, it is not possible in this study to compare music therapy with a standardized or manualized psychological treatment. As described Trial status in the intervention section, the main perspectives The current protocol version has number 04, and is adapted in the clinic are a flexible adaptation of CBT dated 30 March 2016. Recruitment began on 9 May to severely traumatized patients from diverse cultures 2016. We estimate that recruitment will be completed and narrative therapy (which is focused on helping by 1 March 2018. Beck et al. Trials (2018) 19:301 Page 17 of 20 Appendix 1 Availability of data and materials The datasets generated during the current study are available from the Locations of the three units of the clinic: corresponding author on reasonable request after termination of data collection. 1. Clinic for Traumatized Refugees, Glæisersvej 50, Coordinating teams 4600 Køge Psychiatric Research Unit, Region Zealand, Denmark supports the design, 2. Clinic for Traumatized Refugees, Fælledvej 6, 1., management and statistical analysis of the trial (last author TM has a senior 4200 Slagelse researcher part-time position, third author ES is a leader of the research unit). Aalborg University supports the publication (first author BB has a research pos- 3. Clinic for Traumatized Refugees, Færgegaardsvej ition at the Department of Communication and Psychology, Music Therapy). 15, 4760 Vordingborg Translational Neuropsychiatry Unit, University of Aarhus carries out the saliva analysis and contributes in the interpretation and publication of results. The Steering Group oversees the coordination of clinical and research issues Appendix 2 related to the project: project leader Torben Moe; representing Aalborg University Bolette Beck; leader of the Psychiatric Research Unit Erik Simonsen; Music on the CD for home listening/assessment scientific consultant Ulf Søgaard; physician Torben Cordtz; and leaders of the 1. Satie, E. (1990). Trois Gymnopédies nr. 1 (Klara Department for Specialized Functions Sussie Bratbjerg Israelson and Thomas Körmendi, piano). On: Piano Works (Selection) (CD), Christian Tellier. The Steering Group is responsible for the conduct of the trial and for stopping the trial in case of harms or adversities. Label: Naxos Data Management Team: Steen Meyer and Franz Fischer. 2. Enya (1988). Watermark. On: Watermark (CD). Label: WEA Authors’ contributions 3. Pärt, A. (1994) Spiegel im Spiegel (Tasmin Little, TM serves as administrative project leader, conceived of the study, contributed to the development of the design and protocol, participated as violin; Martin Roscoe, piano). On: Fratres (CD). Label: a clinician and helped to draft the manuscript. BB conceived of the study, EMI Classics contributed to the development of the design and protocol, is responsible 4. Richter, M. (2015). Dream 13 (minus even). On: for the biomarker section, participated as a clinician and translated and adapted the protocol to the SPIRIT guidelines. SM conceived of the study, Sleep, (CD). Label: Deutsche Grammofon contributed to the development of the design and protocol, participated as 5. Deva Premal (2002). Om Namoh Bhagavate. On: a clinician and is responsible for data management. US participated in the Embrace (CD). Label: White Swan design of the study and co-edition of the protocol. ES participated in the design of the study, and supervises the ongoing trial. TO had the clinical 6. Norge, K. (2013). Homage to Life (opus 11, No.1). responsibility for the trial as leading physician and guided the recruitment in On: Fiesta (CD). Label: Digidi the first 2 years, TT took over the clinical responsibility for the trial during 7. Tekbilek, OF. (1994). Moment of Doubt.On: the last phase, and contributed with language revision to the protocol. GL advised the power calculation and plan for statistical analysis. All authors Whirling (CD). Label: Celestial Harmonies contributed to the manuscript concerning the study protocol and reviewed the manuscript. All authors read and approved the final manuscript. Additional files Ethics approval and consent to participate The study was approved by the Regional Ethical Scientific Committee Additional file 1: Standard Protocol Items: Recommendations for in Region Zealand on 26 March 2016; case number 51976, SJ-529. Interventional Trials (SPIRIT) 2013 Checklist: recommended items to Additional applications have been approved on 15 June 2017 address in a clinical trial protocol and related documents*. (DOCX 45 kb) (3294704) and 20 December 2017 (3470641). Informed consent will be obtained from all participants in the study. Additional file 2: Informed consent (English version). (DOCX 167 kb) Competing interests Abbreviations The authors declare that they have no competing interests. ANCOVA: Analysis of covariance; CBT: Cognitive behavioral therapy; C- PTSD: Complex post-traumatic stress disorder; DSM-IV: Diagnostic and Statistic Publisher’sNote manual of Mental Disorders, version 4; DSS: Dissociation Symptoms Scale; Springer Nature remains neutral with regard to jurisdictional claims in EMDR: Eye movement desensitization and reprocessing; HTQ: Harvard published maps and institutional affiliations. Trauma Questionnaire; ICD-10: International Classification of Diseases; NET: Narrative exposure therapy; PTSD: Post-traumatic stress disorder; Author details RAAS: Revised Adult Attachment Scale; SDQ: Somatoform Dissociation Department of Communication and Psychology, Aalborg University, Questionnaire; TMI: Trauma-focused Music and Imagery; WHO: World Health Aalborg, Denmark. Clinic for Traumatized Refugees, Køge, Region Zealand, Organization Denmark. Department of Specialized Functions, Psychiatry, Køge, Region Zealand, Denmark. Institute for Clinical Medicine, SUND, Copenhagen Acknowledgements 5 University, København, Denmark. Research Unit in Psychiatry, Slagelse, Betina Elfving from Translational Neuropsychiatry Unit, University of Aarhus 6 Region Zealand, Denmark. PFI (Production, Research, Innovation), Sorø, advised the analysis of saliva samples and reviewed the protocol. Region Zealand, Denmark. We thank all the participants who, in spite of their poor psychological states, gave consent to participate in the study. Received: 17 January 2018 Accepted: 3 May 2018 Funding The study has been funded by the Obel Family Foundation, grant no. 27688. References Contact information: Director Søren Bøier Nielsen, Aalborg, DK. Phone: + 1. Refugees UNHC for. UNHCR Global Trends 2015. UNHCR. http://www.unhcr. 4598127300, email: email@example.com. 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