Cognitive and Emotional Processing of Music and its Effect on Pain

Transcription

1 Cognitive and Emotional Processing of Music and its Effect on Pain PhD Thesis by Eduardo Adrian Garza Villarreal, M.D. Faculty of Health Sciences Aarhus University Royal Academy of Music Aarhus/Aalborg 2011

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3 Cognitive and emotional processing of music and its effect on pain Eduardo Adrian Garza Villarreal, M.D. Ph.D. Thesis Faculty of Health Sciences Aarhus University 2011

4 Cognitive and emotional processing of music and its effect on pain The thesis is based upon the following manuscripts: I. Garza-Villarreal, E.A., Brattico E., Leino, S., Østergaard, L., Vuust, P. (2010). Distinct neural generators of the MMN and the ERAN to chord violations: A multiple source analysis study. Brain Research. Accepted. II. Garza-Villarreal, E.A., Brattico E., Vase, L., Østergaard, L., Vuust, P. (2010). Superior analgesic effects of mental arithmetic versus unfamiliar music and Sounds: The role of emotional impact and personality traits. Journal of Pain. Under Review. III. Garza-Villarreal, E.A., Brattico E., Vase, L., Østergaard, L., Vuust, P. (2010). The placebo effect of music-induced analgesia. Pain. Submitted. 2

5 Cognitive and emotional processing of music and its effect on pain Para Laura y mis padres, por su amor y apoyo. 3

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7 Cognitive and emotional processing of music and its effect on pain PREFACE The current Ph.D thesis work developed from an interest in the cognitive and emotional responses to music listening as possible mechanisms behind its well-known analgesic effects. Music is one of the passions in my life and, as such, the influence it possesses on all human cultures fascinates me. When I first learned there was an area in Neuroscience that focused on the research of music, something inside me sparked. My passion for the workings of human body and for music could actually be combined and become my field of work. It was when I embarked into the territory of the cognitive and emotional processing of music with Study 1, where I realized how different Psychology is from my background, Medicine. Understanding neural processes from a psychological perspective gave me nightmares. However after some time of reconciling psychology and medicine, it all started to make sense and music influence in cognition and emotion became my chosen path. As my understanding escalated, so did my interest in the effects of music in sensory systems beyond auditory, and thus I started to become entangled in researching the complex, and still unknown, mechanisms that give rise to analgesia with music. With my experience in cognitive and emotional processing of music, it was clear to me that the way music affects pain should be closely related to these neural processes. Therefore, I focused Study 2 specifically on the analgesic mechanisms of music by manipulating the cognitive and emotional elements of the auditory stimuli researched. I believe that it is possible to understand how music reduces pain. With this knowledge we can enhance the therapeutic uses of music, and even further understand about how cognition and emotion themselves influence pain. 5

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9 Cognitive and emotional processing of music and its effect on pain TABLE OF CONTENTS PREFACE... 5 TABLE OF CONTENTS... 7 ABBREVIATIONS INTRODUCTION AIMS BACKGROUND MUSIC Auditory processing of music Cognitive processing of music Emotional processing of music PAIN Pain processing Cognitive modulation of pain Emotional modulation of pain Placebo analgesia MUSIC AND PAIN MATERIALS AND METHODS ETHICS CHOICE OF METHODS STUDY Participants Stimuli Procedure Data acquisition and analysis STUDY Participants Stimuli Procedure Data acquisition and analysis RESULTS EXPERIMENT Event-related potentials Discrete and distributed source analysis Behavioral analysis EXPERIMENT Pain, emotion and cognition Placebo analgesia DISCUSSION COGNITIVE RESPONSES TO MUSIC AND THEIR RELATION TO EMOTIONAL PERCEPTION

10 Cognitive and emotional processing of music and its effect on pain 6.2 INFLUENCE OF EMOTION AND COGNITION IN ANALGESIA Cognitive modulation of pain Emotional modulation of pain Placebo analgesia of music CONCLUSION PERSPECTIVES COGNITIVE MODELS OF SENSORY INPUT STRUCTURE LANGUAGE AND MUSIC PREDICTIVE CODING AND MUSIC MECHANISMS OF MUSIC ANALGESIA MUSIC COMPOSITION FOR ANALGESIA THERAPEUTIC INDICATION FOR PAIN MEDICINE FUTURE STUDIES SUMMARY ACKNOWLEDGEMENTS REFERENCES APPENDICES

11 Cognitive and emotional processing of music and its effect on pain ABBREVIATIONS AC1 ACC Am ANOVA BA BESA BPM CC DBS EEG ERAN ERP fmri HT IC IFG MMN OFC PAG PASAT PFC PPC NAcc racc RVM Primaryauditorycortex Anteriorcingulatecortex Amygdala Analysisofvariance Brodmannarea Brainelectricsourceanalysis beatsperminute Cingulatecortex Deepbrainstimulation Electroencephalogram Earlyrightanteriornegativity Eventrelatedpotential Functionalmagneticresonanceimaging Hypothalamus Insularcortex Inferiorfrontalgyrus Mismatchnegativity Orbitofrontalcortex Periacqueductalgray Pacedauditoryserialadditiontest Prefrontalcortex Posteriorparietalcortex Nucleusaccumbens Rostralanteriorcingulatecortex Rostralventromedialmedulla 9

12 Cognitive and emotional processing of music and its effect on pain SI SII SMA SPM Std STG SVC VAS VLPFC VMPF Somatosensorycortex Secondsomatosensorycortex Supplementarymotorarea Statisticalparametricmapping Standard superiortemporalgyrus Smallvolumecorrection Visualanalogscale Ventrolateralprefrontalcortex Ventralmedialprefrontalcortex 10

13 Cognitive and emotional processing of music and its effect on pain 1. INTRODUCTION The processing of the auditory elements that form music such as pitch, loudness, duration, etc., starts in the cochlea located in the inner ear, follows through the brainstem and continues in every level of the auditory pathway until the auditory stimulus reaches the auditory cortex, located in the temporal lobes, where it is first made conscious (Pickles 2008). However, this description barely scratches the surface of the complexity entailed in the processing of music. Music is processed by several regions of the brain associated with every aspect of our behavior, influencing them at the same time. These regions include the executive functions of the frontal cortex, to the impulsive and primitive emotions of the amygdala, the memories stored in the hippocampus, and even the somatosensory cortex that specializes in the processing of touch and physical pain. This wide range of neural influence by music seems to be universal as it is present in all human beings, with, however, clear cultural variants (Fritz, et al. 2009). When we listen to music, the pre-frontal cortex expects structural (syntax-analog) patterns in the music derived from long- and short-term memory (Koelsch 2005). Regardless of whether these expectations are fulfilled or violated, areas that process reward and emotions interact and are modulated by a multitude of internal and external factors related to the music (i.e. preference, personality, environment, etc) (Brattico and Jacobsen 2009). In other words, music listening involves complex cognitive and emotional processes engaging several different areas that influence behavior such as the limbic, language, motor and somatosensory systems. It is, therefore, not surprising that a complex stimulus such as music could affect the perception of one of the most complex sensations, pain. 11

14 Cognitive and emotional processing of music and its effect on pain Music has been used as a therapy for pain since ancient times (Munro and Mount 1978). However, even to this day the mechanisms, effects, and even dosage of music for pain are not yet fully understood. Current theories suggest the analgesia secondary to music works via cognitive and emotional processes (Garza-Villarreal, et al. submitted; Mitchell, et al. 2006; Roy, et al. 2008). Cognitive processes, such as expectation of pain relief, distraction from the pain, and reappraisal, contribute to analgesia via the descending pathway of pain (Wiech, et al. 2008b). Another well-known cognitive analgesic effect is placebo analgesia. Positive emotions attached to a stimulus, as well as the mood of the individual, have also been shown to reduce pain (Chung, et al. 2007; Roy, et al. 2009; Villemure and Bushnell 2009). From all this evidence, it appears that the main mechanisms working to reduce pain during music listening are mainly derived from cognition and emotion. Therefore, it is crucial to investigate music with pharmacology-like pain designs, by studying musical stimuli as active analgesic drugs and isolate these mechanisms. This will help deduce how and to which extent cognition and emotion influence pain and whether there are other unknown mechanisms. A profound knowledge of the mechanisms responsible for the analgesic effects of any drug will effectively enhance its therapeutic use, and music is not an exception. In this thesis I will discuss the cognitive processing of music by the auditory and frontal cortices. Then, I will discuss the implications of cognitive processing and its influence for emotional processing of music, and for that of other sensory systems. Finally, the focus of the rest of this work is on the effects of music listening on pain and the cognitive and emotional mechanisms producing analgesia. 12

15 Cognitive and emotional processing of music and its effect on pain 2. AIMS To understand the neural responses of music, the cognitive and emotional mechanisms and also their influence on the analgesic effects of music, we performed two experiments with two different aims: 1) To study the cognitive and emotional processing of musical structures, we examined the event-related brain responses recorded with electroencephalography (EEG) in nonmusicians. 2) To study the influence of cognitive and emotional responses to music on pain, we induced experimental pain to investigate the effect different auditory stimuli with similar emotional characteristics, the placebo effect, and the effect of suggestion. The results of these experiments were discussed in three articles, each of which corresponded to the following hypotheses: I) Cognitive processing of music follows a hierarchical structure acquired from longterm exposure to a music culture and stored in long-term memory. Violations of culturedependent harmony rules would elicit a specific event-related brain response (early right anterior negativity or ERAN) mainly generated in the frontal cortex, whose amplitude is related to the degree of violation of the hierarchical structure and reflected by reported emotional responses. Violations of simple hierarchical structures (music scale rules) would instead elicit a brain response (mismatch negativity or MMN) mainly localized in the temporal cortex. II) Active auditory distraction (mental arithmetic) reduces pain more than environmental Sounds and Mozart Music. Passive auditory stimuli (environmental Sounds and Mozart 13

16 Cognitive and emotional processing of music and its effect on pain Music) with similar emotional characteristics have the same analgesic effect, which is also influenced by cognitive style (such as being emotional or having a tendency to focus on systematic and analytic structures). III) An important part of the analgesic effect of music is mediated by suggestion and belief (placebo analgesia), and these are influenced by happy and sad emotions attributed to the auditory stimuli. 14

17 Cognitive and emotional processing of music and its effect on pain 3. BACKGROUND 3.1 Music Auditory processing of music Music begins to be processed inside the cochlea as soon as it enters the ear. The basilar membrane encodes the elements of the music by activating the hair cells along its length. The hair cells are arranged at equal distances along the membrane to encode the sensory information. This sensory information is then transferred through the auditory nerve to the brainstem where elements like direction of the sound, pitch, timing, loudness, and consonance are unconsciously determined (Langner 1992; Scott and Johnsrude 2003). From there, music reaches the auditory cortices, both located in the temporal lobes, after roughly 13 ms. The right hemisphere is thought to be specialized for the processing of music, particularly of its spectral feature, like pitch (Maess, et al. 2001; Platel, et al. 1997; Rauschecker 1998; Trehub, et al. 1993; Zatorre 2001). However, there is clear evidence of musical processing in the left hemisphere as well (Jentschke and Koelsch 2009; Koelsch, et al. 2005; Platel, et al. 1997; Schlaug, et al. 1995b; Tervaniemi and Hugdahl 2003; Tervaniemi, et al. 2000). The auditory cortex processes all sensory aspects and elements of the music such as perceived pitch, timbre, rhythm, loudness some aspects of melody (Koelsch and Sammler 2008; Rauschecker 1998; Rauschecker 2001; Zatorre, et al. 2002). 15

18 Cognitive and emotional processing of music and its effect on pain Figure 1: (adapted from Purves, D. et al. (eds.) Neuroscience (3 rd edition, 2004)) Simplification of the auditory pathway, from the cochlea to the auditory cortex. It is anatomically and functionally divided in primary and non-primary auditory cortex. The primary auditory cortex (AC1) is located in Heschl s gyrus and it is tonotopically organized. It is thought to be specialized for the processing of pitch and loudness. The non-primary auditory cortex is loosely located surrounding AC1 in the planum temporal and planum polare. Its function is less known, and it is thought to process broadband sounds (bandwidth), sound motion and location, and integration of other elements of the sounds (Hall, et al. 2003). 16

19 Cognitive and emotional processing of music and its effect on pain Cognitive processing of music The auditory and frontal cortices are able to extract regularities and form hierarchical structures from the music (Koelsch, et al. 2001; Koelsch, et al. 2006; Näätänen 1995). Some regularities may consist of repetitions of one or more features contained in the sounds or in rules of succession of particular sound features (Paavilainen, et al. 2007). Other kinds of regularities are hierarchically organized, meaning that events within those regularities have different weights and roles according to previous knowledge, e.g., music harmony (Koelsch and Sammler 2008). Some theories state that harmony processing is analog to syntax processing in language, as both processes occur in the frontal cortex in a region called Broca s area (although harmony processing occurs more frequently in the right hemisphere). These areas keep us attentive to the music and make us expect a coherent musical structure derived from repeated exposure and long-term memory. Any resolution or violation of these expectations influences other brain regions. Violations in successive sounds elicit a specific event-related potential (ERP), detected on electroencephalography (EEG) called the mismatch negativity (MMN), which originates in the auditory cortex and inferior frontal cortex, whereas violations of harmonic structure elicit the early right anterior negativity (ERAN), which is thought to be located in Broca s area and its right homologue (Maess, et al. 2001). 17

20 Cognitive and emotional processing of music and its effect on pain Figure 2: (adapted from Tramo (2001) Representation of the areas of the brain that might be involved in music perception and performance, and their suggested function in the network. Music processing also involves pre-motor and motor areas, as it is not strange to tap to a beat or even dance to music (Koelsch 2006; Schlaug, et al. 1995a; Zatorre, et al. 2007). It also involves memory areas like the hippocampus and the dorsal medial prefrontal cortex, as familiar and even unfamiliar music can evoke strong memories and nostalgia (Barrett, et al. 2010; Janata 2009; Miranda and Ullman 2007; Quoniam, et al. 2003). 18

21 Cognitive and emotional processing of music and its effect on pain Emotional processing of music Music is a strong inducer of emotions (Barrett, et al. 2010; Blood, et al. 1999; Fritz, et al. 2009), and the consequent emotional reactions involve endogenous opioids (Benedetti and Amanzio 1997; Goldstein 1980; Rhudy and Meagher 2001). These reactions correlate with activity in paralimbic brain regions, changes in serotonin levels, increased levels of growth hormone and decreased levels of IL-6 and epinephrine (Blood, et al. 1999; Conrad, et al. 2007; Evers and Suhr 2000). During unpleasant music listening, serotonin levels increase and there is activity in the parahippocampal gyrus and precuneus regions (regions related to memory), whereas pleasant music activates brain regions implicated in reward and emotion, such as the ventral striatum, midbrain, amygdala (Am), the orbitofrontal cortex (OFC), and ventral medial prefrontal cortex (VMPF) (Blood and Zatorre 2001; Green, et al. 2008; Koelsch, et al. 2008; Menon and Levitin 2005). In general, the processing of music involves an extensive active neural network connected to almost every cortical and sub-cortical structure in the brain. Several studies have shown that pleasant and unpleasant music modulates emotion and mood (Roy, et al. 2009; Vrana, et al. 1988; Walker, et al. 1997). Clinical studies with music have also shown that it is successful at reducing anxiety and pain in patients (Allred, et al. 2010; Conrad, et al. 2007; Klassen, et al. 2008; Nilsson 2008; Shabanloei, et al. 2010). One recent study by Juslin and Västfjäll (2008) proposes that there are many mechanisms of how music evokes emotions: brain stem reflexes, evaluate conditioning, emotional contagion, visual imagery, episodic memory, and musical expectancy. In conjunction, all of these mechanisms could explain the variation and wide extent of the musical experience, and could possibly explain the mechanisms behind the analgesic effect of music. 19

22 Cognitive and emotional processing of music and its effect on pain In paper I, our aim was to finally dissociate the ERAN from the MMN to further understand the cognitive processing of musical structure and the relation between the elicited eventrelated potentials and emotional perception. 3.2 Pain Pain processing Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage according to the International Association for the Study of Pain (IASP). It is a subjective experience created by a neural representation, influenced by psychological factors. The pathways that process pain are twofold: ascending and descending (Bingel and Tracey 2008; Jensen 1997; Kong, et al. 2006). The ascending pathway originates from the peripheral nerve endings, ascends through the spinal cord and the brainstem, and ends at different brain regions usually referred to as the pain matrix, which includes the cingulated cortex (CC), somatosensory cortex (SI), thalamus and insular cortex (IC). However, this concept oversimplifies the extent of the sensory, cognitive and affective regions normally involved in pain perception depending on the type of pain, its intensity and unpleasantness, such as the posterior parietal cortex (PPC), hypothalamus (HT), supplementary motor area (SMA), prefrontal cortex (PFC) and Am (Kong, et al. 2006; Porro, et al. 1998; Price 2000). Two dimensions of pain are studied: pain intensity and pain unpleasantness. 20

23 Cognitive and emotional processing of music and its effect on pain Figure 3: (adapted from Bingel and Tracey (2006)) fmri BOLD activity in response to thermal painful stimuli overlaid on a structural MRI to visualize the pain matrix. Pain intensity can be described as the physical or sensory dimension of pain. Perception of the intensity of pain can be divided into sensory encoding and cognitive evaluation. Sensory encoding is thought to be processed by the SI, secondary somatosensory cortex (SII), anterior cingulate cortex (ACC), thalamus, and IC (Coghill, et al. 1999; Derbyshire, et al. 1997; Kong, et al. 2006; Porro, et al. 1998). Pain unpleasantness is described as the emotional or affective dimension of pain, and the main neural regions related are the ACC, IC, and Am (Price 2000; Schon, et al. 2008) Cognitive modulation of pain The descending pain pathway is connected to the ascending sensory pathway, and it modulates and controls pain perception through various neurotransmitters including endogenous opioids (Bingel and Tracey 2008; Jensen 1997; Jensen and Sindrup 2002). These 21

24 Cognitive and emotional processing of music and its effect on pain modulatory pathways descend mainly from the prefrontal cortex, cingulated cortex, amygdala, and hypothalamus, to converge in an area in the midbrain called the periacqueductal gray (PAG), that controls pain transmission neurons through a relay in the rostral ventromedial medulla (RVM) (Bingel and Tracey 2008; Fields 2000; Wiech, et al. 2008b). Therefore, at least anatomically, there seems to be a relationship between cognition and pain. Figure4:(adapted from Bingel and Tracey (2006)) Schematic of the ascending and descending pathways of pain, showing cortical structures and pain modulation in the brainstem. 22

25 Cognitive and emotional processing of music and its effect on pain Cognitive modulation of pain is ruled by three mechanisms: attention, expectation and reappraisal (Wiech, et al. 2008b). First, the direction of attention affects the perceived intensity and unpleasantness of painful stimuli (i.e. attending the pain increases it) (Brooks, et al. 2002; Miron, et al. 1989; Mitchell, et al. 2006; Tracey, et al. 2002). Functional Magnetic Resonance Imaging (fmri) studies show that when we expect pain or pain relief, the brain areas related to pain itself increase or decrease activation respectively (Bingel and Tracey 2008; decharms, et al. 2005; Ploghaus, et al. 1999; Wager, et al. 2004). If we anticipate pain, the noxious stimulus is felt more strongly than it really is and several brain areas related to pain are activated (Ploghaus, et al. 1999), whereas if we expect analgesia, the pain will be reduced (Christopher, et al. 2008). The belief of an individual that she or he is in control (coping resources are believed to be sufficient) of the painful situation gives rise to reappraisal (reevaluating the meaning of the painful situation) Reappraisal has been correlated with activation of the ventrolateral prefrontal cortex (VLPFC), an area related to cognitive evaluation of pain that interacts with the amygdala (Blair 2004; decharms, et al. 2005; Goldin, et al. 2008; Kringelbach and Rolls 2003). The best example of cognitive modulation of pain is placebo analgesia, which we will discuss more ahead Emotional modulation of pain Studies on the relationship between emotion and pain have shown that there is a clear affective modulation of pain at spinal and supraspinal levels (Meagher, et al. 2001; Rhudy, et al. 2007; Rhudy, et al. 2005; Rhudy, et al. 2006; Rhudy, et al. 2008; Williams and Rhudy 2009a; Williams and Rhudy 2009b). Emotional stress, anxiety, and negative affect decrease the pain threshold i.e. pain is felt with less stimulation, whereas positive affect increases the 23

26 Cognitive and emotional processing of music and its effect on pain pain threshold. According to the evidence, pleasant stimuli reduce pain, whereas unpleasant stimuli increase pain perception (Berna, et al. 2010; de Tommaso, et al. 2008; Rhudy, et al. 2008; Wiech and Tracey 2009). In imaging studies, empathy toward pain and social exclusion (social pain) activate brain areas related to pain (Cheng, et al. 2010; Singer, et al. 2004). Also, with verbal suggestions and environmental cues, it is possible to create pain in an individual without physical stimulation (Bayer, et al. 1991). There also seems to be a difference in pain perception related to gender (Fillingim, et al. 2009; Rhudy and Williams 2005). In general, emotional people may, in theory, be more affected by emotional stimuli during pain (Ploner, et al. 2010; Salovey and Birnbaum 1989; Taenzer, et al. 1986; Wakabayashi, et al. 2007) Placebo analgesia The best example of cognitive modulation of pain is placebo analgesia. Placebo analgesia refers to pain relief by means of the placebo effect (Benedetti and Amanzio 1997; Wager, et al. 2007). The placebo effect is a treatment effect caused not by the physical properties of the treatment, but by the meaning ascribed to it. The person expects pain relief from a certain treatment due to verbal suggestion and/or previous exposure, and as a result the person could experience an analgesic effect as strong as morphine by ingesting a placebo substance (i.e. a sugar pill ) (Benedetti and Amanzio 1997; Petrovic, et al. 2005). As the person assumes the placebo will somehow reduce the pain, she or he expects pain relief (expectation) and feels in control of the pain (reappraisal) (Wiech, et al. 2008a; Wiech, et al. 2008b). Recent studies show that during placebo analgesia there is increased activity in the PFC, OFC, PAG, and the lower pons, areas in which cognitive modulation of analgesia takes place, whereas activity decreases in the thalamus, IC, and ACC, areas related to pain unpleasantness (Petrovic, et al. 24

27 Cognitive and emotional processing of music and its effect on pain 2005; Wager, et al. 2004). According to some theories, placebo treatment affects the cognitive interpretation of pain, and rostral anterior cingulate cortex (racc) activation triggers endogenous opioid release in the brainstem, in other words, a top-down pain regulation (Bingel and Tracey 2008; Petrovic, et al. 2002). Figure5:(adaptedfromWiechetal.(2008))Possibleneuralpathwaysforcognitivemodulationofpain.I includedareaswhichmayberelatedtoemotionalmodulationsuchasofc,nucleusaccumbensandam. 25

28 Cognitive and emotional processing of music and its effect on pain 3.3 Music and pain A considerable number of studies support the notion that music reduces pain intensity and unpleasantness and increases pain tolerance. (Huang, et al. 2010; Klassen, et al. 2008; McCaffrey and Freeman 2003; Mitchell and MacDonald 2006; Mitchell, et al. 2006; Mitchell, et al. 2007; Nilsson 2008; Podder 2007; Roy, et al. 2008). Listening to music has been shown to increase the expression of mu opiate receptors, the place where opioids bind to produce analgesia (Stefano, et al. 2004). A meta-analysis that included several pain studies involving music as a therapy showed that there was a positive analgesic effect secondary to music listening in 59% of those studies (Nilsson 2008). Another recent study showed that music reduces pain by 18%, comparable to the analgesic effect of ibuprofen (Roy, et al. 2008). Furthermore, listening to music reduces the dosage of sedatives and analgesic medication in institutionalized patients, and benefits their overall well-being (Allred, et al. 2010; Browning 2000; Huang, et al. 2010; Klassen, et al. 2008; Laopaiboon, et al. 2009; Mitchell, et al. 2007; Nichols and Humenick 2000; Nilsson 2008; Podder 2007; Spiby, et al. 2003). The main mechanisms behind the analgesic effect of music are believed to be cognitive (Kreutz, et al. 2008; Mitchell, et al. 2006; Wiech, et al. 2008b) and emotional (Koelsch, et al. 2008; Roy, et al. 2009; Roy, et al. 2008). Nevertheless, most studies about music and pain have not fully controlled for confounders such as distractibility of the auditory stimulus, emotional elements, familiarity with the music, and the personality of the participants. Furthermore, the potential placebo analgesia of music has not been taken into consideration as possibly one of the main underlying analgesic mechanisms. 26

29 Cognitive and emotional processing of music and its effect on pain In paper II, we investigated the analgesic effects of music, attempting to control for as many confounders as possible. We compared a distraction task to passive music listening to control for distractibility. We investigated environmental Sounds and Mozart Music characterized by similar valence, arousal and liking. We explored the individual variation in analgesic effects of primary tasks due to gender, and cognitive styles. In paper III, we investigated the placebo effect of music by the use of a placebo stimulus (Sounds) and an active stimulus (Music). We investigated the influence of suggestion and emotion on the placebo effect of music-induced analgesia. 27

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31 Cognitive and emotional processing of music and its effect on pain 4. MATERIALS AND METHODS 4.1 Ethics All studies described in this dissertation followed the instructions, rules, and restrictions determined by The Danish National Committee on Biomedical Research Ethics. Ethical agreement was received from The Health Committee for Region Mid-Jutland in Denmark. The experiments were in accordance with the Declaration of Helsinki and the recommendations from the American Pain Society, the World Medical Association, the World Health Organization and the Council for International Organizations of Medical Sciences, the American College of Physicians, and the American Psychological Association. The ethics of research involving normal human volunteers or patients have been clarified by several international and national organizations. The following principles taken from the American Pain Society were followed in our experiments: 1. All planned clinical studies should be reviewed by an independent committee on human research prior to implementation. The committee, which should include scientists, healthcare practitioners, and lay persons, should evaluate the risks inherent in the research and the extent to which the significance of the potential results justifies the risks involved, even if minimal. The committee also should ensure that potential subjects have the opportunity to provide informed consent prior to participation. 2. Informed consent implies that potential subjects are fully apprised of the goals, procedures, and risks of the study. Potential subjects must be able to decline, and those who consent must be able to withdraw prior to completion, without any risk of penalty. 29