Exploring psychotherapeutic issues and agents in clinical practice
The song “Mr. Tambourine Man” was written by Bob Dylan and recorded by him for commercial release in 1965. Because of its melody and the exotic emotional imagery the words evoke, the song has been interpreted by many individuals as alluding to the effect of drugs, and that Mr. Tambourine Man is a coded reference to a drug dealer (Robertson & Fishkin, 1971). Although Dylan claims the song was not about drugs, I believe that music can be considered a drug therapy. In this month's column, I will review some of the neurobiological effects of music and studies investigating the therapeutic use of music.
Neurobiological Effects of Music
Although music might be considered noninvasive and nonpharmacological, this is not strictly true if one considers the neural processes involved in music perception and processing. Acoustic information is translated into neural activity in the cochlea and further transformed in the auditory brainstem, but then directly and indirectly engages many other brain structures (Koelsch, 2011). Much as a drug is absorbed and circulates throughout the body and brain to reach its target(s), music is absorbed by the cochlea and then transmitted throughout the central nervous system.
Music has been used therapeutically since antiquity, but study of the psychological and physiological effects underlying the putative health benefits of music are more recent (Conrad, 2010). Fancourt, Ockelford, and Belai (2014) comprehensively reviewed the literature on the chemical and biological effects of music. They identified 63 studies investigating the effect of music on various neurotransmitters, hormones, immune system components, autonomic nervous system function, and psychological responses.
The most common and consistent finding among 28 studies in their review was that music exposure reduced state and trait measures of anxiety, which was associated with decreased cortisol levels. Decreased cortisol levels were the most common endocrinological finding in 29 studies reviewed by Fancourt et al. (2014). The hypothalamic-pituitary-adrenal (HPA) axis is the body's primary stress-response system, and cortisol is the major adrenal gland glucocorticoid hormone secreted in humans. Dysregulation of the HPA axis and increased cortisol levels have been implicated in mood, psychotic, and other psychiatric disorders (Howland, 2013a).
The autonomic nervous system is composed of an interconnected and counter-regulatory balance between sympathetic and parasympathetic inputs, and this system regulates various bodily functions, including heart rate, blood pressure, and respiration. Sympathetic activation is involved in the “fight or flight” physiological response to stress, whereas parasympathetic activation has a dampening effect. Relaxing music was shown to decrease blood pressure, heart rate, and respiration rate in 16 studies (Fancourt et al., 2014).
Twelve studies evaluated changes in the neurotransmitters epinephrine and norepinephrine in response to music (Fancourt et al., 2014). Most studies found no changes in these neurotransmitters, but several studies reported decreased levels, a finding that would be consistent with a dampening effect of music on the sympathetic system (demonstrated by decreases in heart rate, blood pressure, and respiration rate as noted above). Music exposure has been shown to increase dopamine neurotransmission in animal (Sutoo & Akiyama, 2004) and human (Salimpoor, Benovoy, Larcher, Dagher, & Zatorre, 2011) studies.
Immunological responses to music have also been investigated in many studies (Fancourt et al., 2014). Variable effects are seen on the cellular immune system (i.e., leukocytes) and cytokines, although the greatest responsiveness is seen with the cytokine interleukin-6. Immunoglobulin A was the most researched antibody, with eight studies reporting an increase in its levels. These findings are pertinent to the potential effect of music on depression, as a complex relationship exists between depression and immune system function, and antidepressant drugs have immune-modulating effects (Howland, 2013b).
Functional neuroimaging and lesion studies have demonstrated that music-evoked emotions are associated with modulation of linked limbic and paralimbic brain regions, including the amygdala, hippocampus, orbitofrontal cortex, parahippocampal gyrus, temporal lobes, nucleus accumbens, hypothalamus, and insula (Chanda & Levitin, 2013; Koelsch, 2010, 2014). Some of these regions are involved in reward, motivation, and pleasure, and their activity is mediated by dopamine and endogenous opioid agents. Listening to pleasurable music was found to be associated with nucleus accumbens activation, as well as ventral tegmental area–mediated interactions between the nucleus accumbens and brain structures that regulate autonomic, emotional, and cognitive function (Chanda & Levitin, 2013).
Music may also affect gene expression. Kanduri et al. (2015) compared the gene transcription response (measured in peripheral blood cells) in musically experienced and inexperienced individuals listening to classical music separately with that of controls without music exposure. Up-regulated and down-regulated expression of various genes was observed in musically experienced individuals compared to controls, but this was not seen in the musically inexperienced individuals. The musically experienced individuals had substantial periods of music education/training or had relatively higher musical aptitude scores. Hence, musical abilities that either are innate or acquired through training/education (Herholz & Zatorre, 2012) may influence gene transcription in response to music. Some of the genes influenced by music in the Kanduri et al. (2015) study are related to dopamine secretion and signaling, the glucocorticoid receptor, and cognitive function (e.g., long-term potentiation, memory).
Music Therapy for Treating Depression
A 2008 Cochrane review of music therapy for depression evaluated the findings from five randomized controlled trials (RCTs), and four of these studies reported greater reductions in depression symptoms compared to usual care conditions (Maratos, Gold, Wang, & Crawford, 2008). More recently, Chan, Wong, and Thayala (2011) conducted a systematic review of studies evaluating music listening for the treatment of depression. Of the 17 included studies, 11 studies (nine of which were RCTs) indicated evidence of improvement in depression scores due to music listening. An 8-week RCT study not included in this review (Castillo-Perez, Gomez-Perez, Velasco, Perez-Campos, & Mayoral, 2010) found that the music therapy group had significantly less depression symptoms at end-point than psychotherapy patients. These studies do not necessarily evaluate depression specifically as a diagnosis or disorder (i.e., major depression per current criteria). Many of the studies have evaluated symptoms of depression in mixed patient populations or have focused on less severe, non-chronic forms of depression, which are nevertheless associated with significant morbidity and functional impairment (Howland et al., 2008).
The mechanism of action of music on reducing depressive symptoms has not been clearly established, but attenuation of HPA axis activity (as evidenced by decreases in cortisol) may be a contributing factor (Fancourt et al., 2014). Antidepressant medications and other psychotropic drugs are known to reduce HPA activity. Antidepressant drugs also increase expression of brain-derived neurotrophic factor (BDNF), and music exposure increases BDNF brain concentrations in animals (Angelucci, Ricci, Padua, Sabino, & Tonali, 2007; Li et al., 2010).
Music Therapy for Treatment of Behavioral and Psychological Symptoms of Dementia
Music therapy has been investigated for the treatment of behavioral and psychological symptoms of dementia (BPSD). A review of 20 studies (including nine RCTs and one controlled clinical trial) found a moderate effect of music therapy on anxiety and small effects on depression and behavior problems (Ueda, Suzukamo, Sato, & Izumi, 2013). In studies of longer duration, music therapy had a larger effect on anxiety. Compared to the findings from previous meta-analyses of antipsychotic drugs for BPSD, music therapy has a smaller effect than antipsychotic drugs, but is devoid of the adverse effects seen with antipsychotic drugs in this population. In addition, compared to the findings from meta-analyses of other nonpharmacological interventions, music therapy appears to be more effective for BPSD. Use of music therapy may therefore be considered similar to antidepressant medications, which have demonstrated benefits for BPSD and are safer than antipsychotic drugs in older adults with dementia (Howland, 2008).
Music Therapy for Stroke Recovery
Stroke is associated with motor, cognitive, and emotional changes (especially depression). Curiously, selective serotonin reuptake inhibitor antidepressant agents have been shown to improve motor recovery, cognitive function, and prevent depression in non-depressed stroke patients (Adams & Robinson, 2012; Mead et al., 2013). The beneficial neurological effects of antidepressant medications may be related to their neurotrophic and neuroprotective effects (Howland, 2016). Särkämö et al. (2008) conducted a RCT comparing a music intervention, language intervention, and a control condition in patients early in their recovery from a stroke. Music listening was found to significantly enhance cognitive recovery and prevent depression compared to the language and control groups. Music-supported training has also been shown to improve motor recovery in stroke patients in several studies (Särkämö, Altenmüller, Rodríguez-Fornells, & Peretz, 2016; Thaut, McIntosh, & Rice, 1997). The neurobiological mechanisms mediating the benefits of music may include enhanced expression of neurotrophic factors, such as BDNF (Angelucci et al., 2007; Li et al., 2010).
Music Therapy for Pain Relief
A 2006 Cochrane review of music for pain relief in adults and children evaluated findings from 51 RCTs (Cepeda, Carr, Lau, & Alvarez, 2006). Listening to music reduced pain intensity levels and reduced opioid analgesia requirements. Although the magnitude of benefit was small when the outcomes from all studies combined underwent meta-analysis, there was significant heterogeneity among individual studies. RCTs have also demonstrated that music interventions are effective in reducing pain in palliative care and cancer patients (Gutgsell et al., 2013).
Hole, Hirsch, Ball, and Meads (2015) conducted a systematic review of 73 RCTs of adult patients undergoing surgical procedures, in which any form of music initiated before, during, or after surgery was compared with standard care or other non-drug interventions. Music reduced postoperative pain, anxiety, and analgesia use, and increased patient satisfaction. Music was effective even when patients were under general anesthesia.
How music exerts its beneficial effect on pain has not been clearly elucidated, but different mechanisms may be involved (Bernatzky, Presch, Anderson, & Panksepp, 2011; Hauck, Metzner, Rohlffs, Lorenz, & Engel, 2013). Beta-endorphin is an endogenous opioid peptide neurotransmitter released from midbrain structures that binds to mu-opioid receptors (Chanda & Levitin, 2013). In a study investigating music and imagery on plasma beta-endorphin levels in healthy individuals, McKinney, Tims, Kumar, and Kumar (1997) found that music imagery lowered the peripheral levels compared to a control condition. Stefano, Zhu, Cadet, Salamon, and Manitione (2004) determined that mu-opioid receptor expression was increased in peripheral blood mononuclear cells in individuals listening to music compared to control individuals. In a preliminary double-blind placebo-controlled experiment, the opioid receptor antagonist drug naloxone attenuated the emotionally arousing “thrills” elicited by music in three of 10 individuals (Goldstein, 1980).
Music Therapy for Treating Schizophrenia
A 2011 Cochrane review of music therapy for schizophrenia analyzed findings from eight RCTs using music therapy alone or as an add-on therapy to usual care compared to usual care alone or no treatment (Mossler, Chen, Heldal, & Gold, 2011). Music therapy was found to improve patients' global state, negative symptoms, general mental state, depression, anxiety, social function, and certain aspects of cognitive function. In studies of patients with schizophrenia, there is evidence of increased HPA axis activity and elevated cortisol levels (Howland, 2013a). Antipsychotic drugs also typically decrease cortisol levels. The therapeutic benefit of music in schizophrenia may include anti-stress effects as evidenced by its ability to reduce cortisol levels (Fancourt et al., 2014).
Music exposure has measurable neurobiological effects that appear to be linked to systems regulating reward, motivation, and pleasure; stress and arousal; and immunity. Music may also influence health positively through effects on social affiliation, which are mediated by underlying neurochemical processes (Chanda & Levitin, 2013). Controlled clinical studies have demonstrated significant benefits with the use of music for the treatment of depression and anxiety, pain relief, stroke recovery, schizophrenia, and BPSD, although the magnitude of benefit is variable. Music therapy interventions can be easily implemented in the context of nursing care (Wakim, Smith, & Guinn, 2010). Because music is not likely to be associated with significant adverse effects, it should be considered as a potentially viable treatment for many patients in many different clinical settings.
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