Transcutaneous Auricular Vagus Nerve Stimulation in Pediatric Patients: A Systematic Review of Clinical Treatment Protocols and Stimulation Parameters.

BACKGROUND: Noninvasive transcutaneous vagus nerve stimulation (tVNS) has promising therapeutic potential in a wide range of applications across somatic and psychiatric conditions. Compared with invasive vagus nerve stimulation, good safety and tolerability profiles also support the use of tVNS in pediatric patients. Potential neurodevelopment-specific needs, however, raise concerns regarding the age-appropriate adjustment of treatment protocols and applied stimulation parameters. OBJECTIVE: In this study, we aimed to review registered trials and published studies to synthesize existing tVNS treatment protocols and stimulation parameters applied in pediatric patients. MATERIALS AND METHODS: A systematic search of electronic data bases (PubMed, Scopus, MEDLINE, Cochrane Library, and PsycINFO) and ClinicalTrials was conducted. Information on patient and study-level characteristics (eg, clinical condition, sample size), the tVNS device (eg, brand name, manufacturer), stimulation settings (eg, pulse width, stimulation intensity), and stimulation protocol (eg, duration, dosage of stimulation) was extracted. RESULTS: We identified a total of 15 publications (four study protocols) and 15 registered trials applying tVNS in pediatric patients (<18 years of age). Most of these studies did not exclusively address pediatric patients. None of the studies elaborated on neurodevelopmental aspects or justified the applied protocol or stimulation parameters for use in pediatric patients. CONCLUSIONS: No dedicated pediatric tVNS devices exist. Neither stimulation parameters nor stimulation protocols for tVNS are properly justified in pediatric patients. Evidence on age-dependent stimulation effects of tVNS under a neurodevelopment framework is warranted. We discuss the potential implications of these findings with clinical relevance, address some of the challenges of tVNS research in pediatric populations, and point out key aspects in future device development and research in addition to clinical studies on pediatric populations.

Evidence for a modulating effect of transcutaneous auricular vagus nerve stimulation (taVNS) on salivary alpha-amylase as indirect noradrenergic marker: A pooled mega-analysis.

BACKGROUND: Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has received tremendous attention as a potential neuromodulator of cognitive and affective functions, which likely exerts its effects via activation of the locus coeruleus-noradrenaline (LC-NA) system. Reliable effects of taVNS on markers of LC-NA system activity, however, have not been demonstrated yet. METHODS: The aim of the present study was to overcome previous limitations by pooling raw data from a large sample of ten taVNS studies (371 healthy participants) that collected salivary alpha-amylase (sAA) as a potential marker of central NA release. RESULTS: While a meta-analytic approach using summary statistics did not yield any significant effects, linear mixed model analyses showed that afferent stimulation of the vagus nerve via taVNS increased sAA levels compared to sham stimulation (b = 0.16, SE = 0.05, p = 0.001). When considering potential confounders of sAA, we further replicated previous findings on the diurnal trajectory of sAA activity. CONCLUSION(S): Vagal activation via taVNS increases sAA release compared to sham stimulation, which likely substantiates the assumption that taVNS triggers NA release. Moreover, our results highlight the benefits of data pooling and data sharing in order to allow stronger conclusions in research.

Prefrontal cortex oxygenation and autonomic nervous system activity under transcutaneous auricular vagus nerve stimulation in adolescents.

INTRODUCTION: The Neurovisceral Integration Model (NIM) proposes a complex interplay of visceral and neural structures that are crucial for adaptive responses to environmental demands. The aim of the present study was to investigate this circuitry using experimental manipulation via transcutaneous auricular vagus nerve stimulation (tVNS), measures of peripheral autonomic nervous system (ANS) activity and prefrontal cortex (PFC) oxygenation, quantified using functional near-infrared spectroscopy (fNIRS). METHODS: In a sample of n = 30 adolescents (age 14-17 years), tVNS versus sham stimulation was applied each during a 15-minute stimulation phase in a within-subject-cross-randomized-design. Mean oxygenation of the PFC and functional connectivity were assessed using fNIRS. Additionally, heart rate variability (HRV), heart rate (HR), electrodermal activity (EDA), and saliva alpha-amylase (sAA) were assessed to quantify peripheral ANS activity. RESULTS: Using linear mixed-effects models, HRV increased (p < .0001) and HR (p < .0001) decreased during tVNS compared to sham. No effect on EDA or sAA was observed. PFC oxygenation increased over time under tVNS compared to sham (p = .017). The relative increase in HRV and decrease in HR was associated with increased oxygenation of the PFC (HR: p < .0001; HRV: p = .007). Exploratory analyses illustrated, that under tVNS, PFC connectivity increased compared to sham. CONCLUSION: The present study supports the NIM by showing that tVNS influences ANS activity and that relative changes in PFC oxygenation contribute to these effects. Implications of these findings and directions for further research are discussed.

A two-week course of transcutaneous vagal nerve stimulation improves global sleep: Findings from a randomised trial in community-dwelling adults.

Short sleep duration and poor sleep quality are common in the general population. This study tested if a 2-week course of daily transcutaneous vagal nerve stimulation (tVNS) improves sleep in community-dwelling adults. Participants were n = 68 men and women aged 18-75 years randomised into four groups: early and sham tVNS and late and sham tVNS. Early groups underwent daily 4 h stimulation between Day 0 and 13, while late groups underwent daily 4 h stimulation between Day 14 and 28. tVNS was performed with transcutaneous electrical nerve stimulation (TENS) on the left tragus, and sham tVNS (control conditions) was applied on the left earlobe. Sleep was measured with the Pittsburgh Sleep Quality Index. Analysis of prespecified contrasts (C), based on linear mixed modelling, revealed that for tVNS there were significant improvements in global sleep scores over time between Day 0 and Day 13 in the early stimulation phase (C = -1.90; 95% CI = -2.87 to -0.94), and between Day 14 and Day 28 in the late phase (C = -0.87; 95% CI = -1.41 to -0.32). No such differences were found under sham tVNS (applied early or late). However, global sleep scores showed no significant improvement under tVNS when compared against control groups during both the early (χ2 = 0.83, p = 0.36), or late stimulation phase (χ2 = 0.24, p = 0.63). We showed that two weeks of tVNS improves global sleep scores, but the change in sleep was not significantly different to control groups. Further studies are warranted to test the utility of tVNS in alleviating sleep complains in community-dwelling adults.

Smartphone based music intervention in the treatment of episodic migraine headaches - A pilot trial.

OBJECTIVES: Migraine headaches are a prevalent and burdening disorder for the public worldwide. Both traditional preventive drugs and behavioral-based interventions have been used as treatment in the prevention of migraine attacks. However, benefits of alternative interventions in patients with primary headache disorders have not yet been fully explored. The present investigation sought to examine the impact of a patient controlled music intervention (MUSIC CARE) on episodic migraine headache. DESIGN: A sample of 20 episodic migraine patients (17 females, mean age of 42 years) was included in the pilot trial. Patients completed a pre-treatment assessment on headache severity, associated psychopathological distress (anxiety and depression) and functional impairment, and provided reports on their medication intake. During the 3-months intervention period, patients required 1-2 music sessions (based on the "U" sequence) per day with a minimum of 15 per month. RESULTS: Following the intervention, patients reported a significant reduction in the frequency of migraine attacks (MDiff = -2.8, p = .01). Ten patients reported a 50% reduction in the frequency of migraine attacks. Additionally, there was a significant reduction in medication intake (MDiff = -2.85, p = .02), the duration of migraine attacks (MDiff = -5.45, p = .002), anxiety (MDiff = -1.65 (2.88), p = .02) and depression (MDiff = -2.45 (3.5), p = .002). CONCLUSION: These data provide evidence that music intervention may significantly prevent migraine attacks. Moreover, this method is easily accessible and administered. Future well-controlled clinical trials are necessary to further explore the efficiency of the intervention.

Does transcutaneous auricular vagus nerve stimulation affect vagally mediated heart rate variability? A living and interactive Bayesian meta-analysis.

Non-invasive brain stimulation techniques, such as transcutaneous auricular vagus nerve stimulation (taVNS), have considerable potential for clinical use. Beneficial effects of taVNS have been demonstrated on symptoms in patients with mental or neurological disorders as well as transdiagnostic dimensions, including mood and motivation. However, since taVNS research is still an emerging field, the underlying neurophysiological processes are not yet fully understood, and the replicability of findings on biomarkers of taVNS effects has been questioned. The objective of this analysis was to synthesize the current evidence concerning the effects of taVNS on vagally mediated heart rate variability (vmHRV), a candidate biomarker that has, so far, received most attention in the field. We performed a living Bayesian random effects meta-analysis. To keep the synthesis of evidence transparent and up to date as new studies are being published, we developed a Shiny web app that regularly incorporates new results and enables users to modify study selection criteria to evaluate the robustness of the inference across potential confounds. Our analysis focuses on 16 single-blind studies comparing taVNS versus sham in healthy participants. The meta-analysis provides strong evidence for the null hypothesis (g = 0.014, CIshortest = [-0.103, 0.132], BF01 = 24.678), indicating that acute taVNS does not alter vmHRV compared to sham. To conclude, there is no support for the hypothesis that vmHRV is a robust biomarker for acute taVNS. By increasing transparency and timeliness, the concept of living meta-analyses can lead to transformational benefits in emerging fields such as non-invasive brain stimulation.

Effects of acute transcutaneous vagus nerve stimulation on emotion recognition in adolescent depression.

BACKGROUND: Transcutaneous vagus nerve stimulation (tVNS) is a promising therapeutic option for major depressive disorder (MDD) in adults. Alternative third-line treatments for MDD in adolescents are scarce. Here we aimed to assess the effects of acute tVNS on emotion recognition in adolescents with MDD. METHODS: Adolescents (14-17 years) with MDD (n = 33) and non-depressed controls (n = 30) received tVNS or sham-stimulation in a cross-sectional, case-control, within-subject cross-randomized controlled trial, while performing different tasks assessing emotion recognition. Correct responses, response times, and errors of omission and commission on three different computerized emotion recognition tasks were assessed as main outcomes. Simultaneous recordings of electrocardiography and electro dermal activity, as well as sampling of saliva for the determination of α-amylase, were used to quantify the effects on autonomic nervous system function. RESULTS: tVNS had no effect on the recognition of gradually or static expressed emotions but altered response inhibition on the emotional Go/NoGo-task. Specifically, tVNS increased the likelihood of omitting a response toward sad target-stimuli in adolescents with MDD, while decreasing errors (independent of the target emotion) in controls. Effects of acute tVNS on autonomic nervous system function were found in non-depressed controls only. CONCLUSIONS: Acute tVNS alters the recognition of briefly presented facial expressions of negative valence in adolescents with MDD while generally increasing emotion recognition in controls. tVNS seems to specifically alter early visual processing of stimuli of negative emotional valence in MDD. These findings suggest a potential therapeutic benefit of tVNS in adolescent MDD that requires further evaluation within clinical trials.

[Indicated Stress Prevention for Adolescents in the Group Setting - A manual based on Acceptance- and Commitment-Therapy]. / Indizierte Stressprävention bei Jugendlichen im Gruppensetting ­ Manual für einen Akzeptanz- und Commitment-Therapie-basierten Ansatz.

Indicated Stress Prevention for Adolescents in the Group Setting - A manual based on Acceptance- and Commitment-Therapy Stress in adolescence has become a topic of interest in recent years. Long-term exposure to stress can play a significant role in the development and maintenance of mental disorders. Previous studies have shown that especially the more severely stressed adolescents benefit from targeted interventions. However, evidence-based treatment concepts targeting this group are scarce. In this article we introduce the first German-language treatment manual for indicated stress prevention, addressing adolescents based on Acceptance and Commitment Therapy (ACT). ACT is part of the third wave of behavioral therapies, designed for treatment across disorders, which makes it suitable for the treatment of chronic stress symptoms. Previous studies show good efficacy of the ACT-approach in the treatment of adult stress and first promising successes in treatment of adolescents in non-German-speaking countries. The focus of our training lies in practical exercises based on ACT which are conveyed by the use of metaphors, art therapy techniques, role plays and group discussions. The concept is complemented by psychoeducation on stress, mindfulness exercises and training in problem solving. Worksheets and tasks for the week facilitate the transfer into everyday life. Alongside the presentation of the treatment manual, first experiences in the implementation of the program are discussed.

A case series on the potential effect of omega-3-fatty acid supplementation on 24-h heart rate variability and its circadian variation in children with attention deficit (hyperactivity) disorder.

Attention deficit disorder with and without hyperactivity (ADHD) in children is associated with decreased 24-h heart rate variability (HRV). Previous research has shown that supplementation of omega-3-fatty acid increases HRV. Here, we aimed to investigate whether the supplementation of omega-3-fatty acids would increase 24-h HRV in an uncontrolled case series of children with ADHD. HRV was recorded in 18 children and adolescents (age 13.35 ± 2.8 years) before and after omega-3 supplementation. Preliminary results indicate that omega-3 supplementation in children with AD(H)D may reduce mean heart rate and increase its variability. Future studies would do well to implement randomized, placebo-controlled designs with greater methodological rigor.

Music-based interventions to reduce internalizing symptoms in children and adolescents: A meta-analysis.

BACKGROUND: Existing systematic reviews provide evidence that music therapy is an effective intervention in the treatment of children and adolescents with psychopathology. The objective of the present review was to systematically review and quantify the effects of music-based interventions in reducing internalizing symptoms (i.e., depression and anxiety) in children and adolescents using a meta-analytical approach. METHODS: Databases and journals were systematically screened for studies eligible for inclusion in meta-analysis on the effects of music-based interventions in reducing internalizing symptoms. A random-effect meta-analysis using standardized mean differences (SMD) was conducted. RESULTS: Five studies were included. Analysis of data from (randomized) controlled trials, yielded a significant main effect (Hedge's g = -0.73; 95%CI [-1.42;-0.04], Z = 2.08, p = 0.04, k = 5), indicating a greater reduction of internalizing symptoms in youth receiving music-based interventions (n = 100) compared to different control group interventions (n = 95). LIMITATIONS: The existing evidence is limited to studies of low power and methodological quality. Included studies were highly heterogeneous with respect to the nature of the intervention, the measurements applied, the samples studied, and the study design. CONCLUSIONS: Findings indicate that music-based interventions may be efficient in reducing the severity of internalizing symptoms in children and adolescents. While these results are encouraging with respect to the application of music-based intervention, rigorous research is necessary to replicate existing findings and provide a broader base of evidence. More research adopting well controlled study designs of high methodological quality is needed.

[Effects of Monochord Music on Heart Rate Variability and Self-Reports of Relaxation in Healthy Adults].

BACKGROUND: Music-based interventions are considered an effective and low-cost treatment option for stress-related symptoms. The present study aimed to examine the trajectories of the psychophysiological response in apparently healthy participants during a music-based relaxation intervention compared to a verbal relaxation exercise. MATERIAL AND METHODS: 70 participants were assigned to either receptive live music (experimental group) or a prerecorded verbal relaxation exercise (control group). Self-ratings of relaxation were assessed before and after each intervention on visual analogue scales and the Relaxation Inventory (RI). The heart rate variability (HRV) was continuously recorded throughout the sessions. Statistical analysis focused on HRV parameters indicative of parasympathetic cardiovascular outflow. RESULTS: We found significant quadratic main effects for time on the mean R-R interval (heart rate), the high-frequency power of HRV (indicative of parasympathetic activity), and the self-ratings of relaxation in both groups. A significant group × time interaction was observed for the cognitive tension subscale of the RI. CONCLUSIONS: Participants in both groups showed psychophysiological changes indicative of greater relaxation over the course of the interventions. However, differences between groups were only marginal. Music might be effective in relieving stress and promoting relaxation by altering the autonomic nervous system function. Future studies need to explore the long-term outcomes of such interventions.

A randomized-controlled trial of heart rate variability biofeedback for psychotic symptoms.

Arousal and the way it is coped with are relevant to the emergence of psychotic symptoms. Heart rate variability (HRV) stems from autonomic responses to environmental demands such as stress and is an index of physiological arousal, adaptability, and homeostatic reflexes forming autonomic balance. A randomized-controlled between-subjects trial that compared HRV-biofeedback (BF) to an active relaxation and to a waiting control condition was conducted in a sample with attenuated subclinical psychotic symptoms (N = 84). A 20-min intervention was preceded and followed by repeated assessments of stress responses. Change scores of the post-stress periods were analyzed using ANOVAs for HRV, subjective stress, perceived control, and state paranoia. As expected, BF participants showed greater improvements in perceived control than waiting controls (p = 0.006). However, no group differences occurred in HRV, paranoid symptoms or subjective stress. In exploratory analyses in a subset of participants who were breathing per protocol, the expected effects were found for total HRV and state paranoia. Thus, this trial of HRV-BF for people with attenuated psychotic symptoms indicates that the intervention may hold potential if conducted per protocol. To reach this, longer training might be inevitable. Future studies are needed to further elucidate efficacy and applicability of HRV-BF in clinical samples.

Smartphone-based Music Listening to Reduce Pain and Anxiety Before Coronarography: A Focus on Sex Differences.

Background • Music Care is a smartphone-based application providing a musical intervention for the management of pain and anxiety in a clinical setting. Coronarography is a medical procedure frequently associated with examination anxiety. Objectives • The study intended to perform an initial evaluation of the application for use with patients undergoing a coronarography. Design • The research team performed an uncontrolled, observational study. Setting • The study took place at Nouméa General Hospital in Nouméa, New Caledonia, France. Participants • Participants were 35 patients, 17 women and 18 men, who were undergoing a coronarography between November 2010 and April 2011 at the Nouméa General Hospital. Intervention • Participants listened to a standardized musical sequence of adjustable length by choosing a preferred style of music (eg, classic rock or folk music) from a variety of choices that the research team had chosen to include in the application. Outcome Measures • Before and after listening to the music, all participants were asked to rate their anxiety and pain on an 11-item, visual analogue scale and to complete a questionnaire on their satisfaction with use of the application. Results • The paired sample t test revealed a significant reduction in participants' anxiety (t33 = 4.12, P < .0001) after they had listened to the music. No significant reduction in self-reported pain occurred; however, only a few participants reported pain associated with the procedure. No significant sex differences existed. Women and men both showed reduced anxiety after listening to music as well as reported a high level of satisfaction in using the Music Care application. Conclusions • The smartphone-based Music Care application is an easy-to-use tool to reduce anxiety in patients undergoing coronarography. Future large-scale, controlled trials are necessary to compare its effectiveness with other interventions. Both women and men can benefit from the use of the application.

Short-term effects of espresso coffee on heart rate variability and blood pressure in habitual and non-habitual coffee consumers--a randomized crossover study.

OBJECTIVE: Coffee is one of the most widely consumed beverages worldwide. Aim of this study was to investigate short-term effects of espresso coffee on heart rate variability (HRV), a marker of vagal activity, in healthy habitual and non-habitual coffee consumers. METHODS: Seventy-seven healthy subjects (38 habitual and 39 non-habitual coffee consumers, 74% women, mean age 26.97 ± 6.88 years) took part in three laboratory sessions in a randomized order. In condition 1, subjects consumed espresso; in condition 2, subjects consumed decaffeinated espresso; and in condition 3, subjects consumed warm water. HRV and blood pressure were assessed at rest before and after ingestion of the respective beverage. RESULTS: HRV was significantly increased after consumption of caffeinated espresso, decaffeinated espresso, or water, indicating increased vagal activity in the course of the experiments. In the habitual coffee consumers, the increase in vagally mediated HRV was significantly lower after consumption of decaffeinated espresso compared to caffeinated espresso. Increases of systolic blood pressure were only found in the non-habitual consumers. CONCLUSION: We found no evidence for specific short-term effects of caffeinated espresso on vagal activity in healthy subjects. Instead, consumption of decaffeinated espresso inhibited vagal activity in habitual consumers. This may be explained by an attempt of the organism to establish a sympathovagal equilibrium comparable to that after caffeine consumption. In the absence of caffeine-induced sympathetic activation, this may have been achieved by relative vagal withdrawal.

Music for insomnia in adults.

BACKGROUND: Insomnia is a common sleep disorder in modern society. It causes reduced quality of life and is associated with impairments in physical and mental health. Listening to music is widely used as a sleep aid, but it remains unclear if it can actually improve insomnia in adults. OBJECTIVES: To assess the effects of listening to music on insomnia in adults and to assess the influence of specific variables that may moderate the effect. SEARCH METHODS: We searched CENTRAL, PubMed, Embase, nine other databases and two trials registers in May 2015. In addition, we handsearched specific music therapy journals, reference lists of included studies, and contacted authors of published studies to identify additional studies eligible for inclusion, including any unpublished or ongoing trials. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials that compared the effects of listening to music with no treatment or treatment-as-usual on sleep improvement in adults with insomnia. DATA COLLECTION AND ANALYSIS: Two authors independently screened abstracts, selected studies, assessed risk of bias, and extracted data from all studies eligible for inclusion. Data on pre-defined outcome measures were subjected to meta-analyses when consistently reported by at least two studies. We undertook meta-analyses using both fixed-effect and random-effects models. Heterogeneity across included studies was assessed using the I² statistic. MAIN RESULTS: We included six studies comprising a total of 314 participants. The studies examined the effect of listening to pre-recorded music daily, for 25 to 60 minutes, for a period of three days to five weeks.Based on the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) approach, we judged the evidence from five studies that measured the effect of music listening on sleep quality to be of moderate quality. We judged the evidence from one study that examined other aspects of sleep (see below) to be of low quality. We downgraded the quality of the evidence mainly because of limitations in design or being the only published study. As regards risk of bias, most studies were at high risk of bias on at least one domain: one study was at high risk of selection bias and one was judged to be at unclear risk; six studies were at high risk of performance bias; three studies were at high risk of detection bias; one study was at high risk of attrition bias and was study was judged to be at unclear risk; two studies were judged to be at unclear risk of reporting bias; and four studies were at high risk of other bias.Five studies (N = 264) reporting on sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) were included in the meta-analysis. The results of a random-effects meta-analysis revealed an effect in favour of music listening (mean difference (MD) -2.80; 95% confidence interval (CI) -3.42 to -2.17; Z = 8.77, P < 0.00001; moderate-quality evidence). The size of the effect indicates an increase in sleep quality of the size of about one standard deviation in favour of the intervention compared to no treatment or treatment-as-usual.Only one study (N = 50; low-quality evidence) reported data on sleep onset latency, total sleep time, sleep interruption, and sleep efficiency. However, It found no evidence to suggest that the intervention benefited these outcomes. None of the included studies reported any adverse events. AUTHORS' CONCLUSIONS: The findings of this review provide evidence that music may be effective for improving subjective sleep quality in adults with insomnia symptoms. The intervention is safe and easy to administer. More research is needed to establish the effect of listening to music on other aspects of sleep as well as the daytime consequences of insomnia.

Music therapy to promote psychological and physiological relaxation in palliative care patients: protocol of a randomized controlled trial.

BACKGROUND: Music therapy is one of the most frequently used complementary therapies in different palliative care settings. Despite its long tradition and high acceptance by other health-care professionals, evidence on the effectiveness of music therapy interventions for terminally ill patients is rare. Recent reviews and health-care reports consistently point out the need of music therapists to provide an evidence-based rationale for their clinical treatments in this field. Therefore, the present study evaluates the psychological and physiological response of palliative care patients to a standardized music therapy relaxation intervention in a randomized controlled trial. METHODS/DESIGN: A sample of 84 participants from a palliative care unit in Heidelberg is randomized to either two sessions of music therapy or two sessions of a verbal relaxation exercise, each lasting 30 minutes. The music therapy sessions consist of live played monochord music and a vocal improvisation, the control group uses a prerecorded excerpt from the mindfulness-based stress reduction program containing no musical elements. Outcome measures include self-report data on subjective relaxation, well-being, pain intensity, and quality of life, as well as continuous recording of heart rate variability and blood volume pulse as indicators of autonomous nervous system functioning. DISCUSSION: To our knowledge, this study is the first clinical trial in Europe and one of very few randomized controlled trials worldwide to systematically examine the effects of music therapy in palliative care. TRIAL REGISTRATION: German Clinical Trials Register - DRKS00006137.

Specific music therapy techniques in the treatment of primary headache disorders in adolescents: a randomized attention-placebo-controlled trial.

UNLABELLED: Migraine and tension-type headache have a high prevalence in children and adolescents. In addition to common pharmacologic and nonpharmacologic interventions, music therapy has been shown to be efficient in the prophylaxis of pediatric migraine. This study aimed to assess the efficacy of specific music therapy techniques in the treatment of adolescents with primary headache (tension-type headache and migraine). A prospective, randomized, attention-placebo-controlled parallel group trial was conducted. Following an 8-week baseline, patients were randomized to either music therapy (n = 40) or a rhythm pedagogic program (n = 38) designed as an "attention placebo" over 6 sessions within 8 weeks. Reduction of both headache frequency and intensity after treatment (8-week postline) as well as 6 months after treatment were taken as the efficacy variables. Treatments were delivered in equal dose and frequency by the same group of therapists. Data analysis of subjects completing the protocol showed that neither treatment was superior to the other at any point of measurement (posttreatment and follow-up). Intention-to-treat analysis revealed no impact of drop-out on these results. Both groups showed a moderate mean reduction of headache frequency posttreatment of about 20%, but only small numbers of responders (50% frequency reduction). Follow-up data showed no significant deteriorations or improvements. PERSPECTIVE: This article presents a randomized placebo-controlled trial on music therapy in the treatment of adolescents with frequent primary headache. Music therapy is not superior to an attention placebo within this study. These results draw attention to the need of providing adequate controls within therapeutic trials in the treatment of pain.