Hypothesizing Music Intervention Enhances Brain Functional Connectivity Involving Dopaminergic Recruitment: Common Neuro-correlates to Abusable Drugs

Abstract

The goal of this review is to explore the clinical significance of music listening on neuroplasticity and dopaminergic activation by understanding the role of music therapy in addictive behavior treatment. fMRI data has shown that music listening intensely modifies mesolimbic structural changes responsible for reward processing (e.g., nucleus accumbens [NAc]) and may control the emotional stimuli’s effect on autonomic and physiological responses (e.g., hypothalamus). Music listening has been proven to induce the endorphinergic response blocked by naloxone, a common opioid antagonist. NAc opioid transmission is linked to the ventral tegmental area (VTA) dopamine release. There are remarkable commonalities between listening to music and the effect of drugs on mesolimbic dopaminergic activation. It has been found that musical training before the age of 7 results in changes in white-matter connectivity, protecting carriers with low dopaminergic function (DRD2A1 allele, etc.) from poor decision-making, reward dependence, and impulsivity. In this article, we briefly review a few studies on the neurochemical effects of music and propose that these findings are relevant to the positive clinical findings observed in the literature. We hypothesize that music intervention enhances brain white matter plasticity through dopaminergic recruitment and that more research is needed to explore the efficacy of these therapies.

Introduction

Systematic analysis of the role of music in the brain reward circuitry has been explored by many investigators utilizing sophisticated neuroimaging tools to dissect specific loci of music activation in the brain [1]. Our laboratory has been involved in studying the role of neurotransmitters, especially dopamine in all drug and non-drug related addictive behaviors [2]. We have subsequently published on positive outcomes of stress and deep relaxation using audio therapy (music and sound) in highly drug dependent patients attending an inpatient treatment program in North Miami Beach, Florida [3]. We have also hypothesized that the activation of the mesolimbic reward system, which causes music listening responses, can be affected by dopaminergic polymorphisms. [4] However, much more work is required to unravel the connections related to reward gene polymorphisms including those that impinge on dopaminergic function.

The neuroscience field is very familiar with the work of others using functional magnetic resonance imaging (fMRI), such as Menon and Levitin [5], who initially observed that music listening intensely modifies mesolimbic structural changes responsible for reward processing (e.g., nucleus accumbens [NAc], ventral tegmental area [VTA]) and may very well control the emotional stimuli’s effect on autonomic and physiological responses (e.g., hypothalamus, insula). There is additional work from Salimpoor et al. [6] citing the use of autonomic nervous system psychophysiological measures along with positron emission tomography (PET) scanning that identifies the neurochemical specificity of [(11)C]raclopride in pinpointing striatum endogenous dopamine release during music listening evoking peak emotional feelings. Anticipation is activated by the caudate, while peak emotional responses are activated by the nucleus accumbens. Significantly, NAc and VTA responses were positively correlated to a connection between dopamine release and NAc music response. Based on previous work from around the world, it is well established that neurogenetics plays a significant role in how we as Homo sapiens experience music and provides information as to the high value of music throughout the origins of human societies. Interestingly, even our archaic ancestors over 63,000 years ago developed musical instruments (www.pbs.org/wgbh/nova/ancient/pioneers-of-easter-island.html).

What We Have Learned from Neuroimaging

It is scientifically known and proven that the endorphinergic response impeded by naloxone, a common opioid antagonist, is induced by music listening [7]. VTA dopamine release is related to NAc opioid transmission. Furthermore, VTA dopamine release is associated with DRD2 gene polymorphisms and perhaps attention-deficit hyperactivity disorder (ADHD), where decreased dopamine (DA) release in the NAc is evident in DRD2 A1 allele carriers. This takes on even more significance in terms of reward deficiency or substance seeking/non-substance seeking behavior knowing that resting state functional connectivity is hijacked by drugs [8], food [9], and aberrant pathological internet gaming [10]. Along these lines, Alluri et al. [11] utilized two musical medleys during continuous fMRI response subject models, showing that auditory, limbic, and motor activations in the brain could be predicted. Remarkably, both the medial orbitofrontal region and anterior cingulate cortex activations, responsible for self-referential appraisal and esthetic judgments, could effectively be anticipated. Moreover, Wu et al. [12] found experimental evidence to establish rises in functional connectivity as well as increases in random network structure in the alpha2 during music perception. The networks included commonly found resting-state networks, including the default mode network, the core network, primary motor and visual network, and two lateralized parietal-frontal networks. In addition, Keller et al. [13], using fMRI with musical stimuli, examined brain responses and potential effective connectivity in relation to anhedonia. They found that anhedonia, a genetic trait, was negatively correlated with satisfaction music stimuli ratings and in regards to reward processing activation, in particular brain structures (e.g., NAc, basal forebrain, hypothalamus), the medial forebrain bundle was linked to the VTA. Brain regions, important for processing salient emotional stimuli, including anterior insula and orbitofrontal cortex were also negatively correlated with anhedonic traits.

Common Features of Brain Connectivity

In the addiction medicine scientific literature, it has been shown that chronic cocaine use reduces brain white matter [14], which dynamically changes during withdrawal from the drug. Lim et al. [15] found using diffusion tensor imaging (DTI) analysis that cocaine users had lower fractional anisotropy (FA) than controls, specifically in inferior frontal white matter. FA is a measure used in DTI to indicate areas of fiber density, axonal diameter, as well as white matter myelination. Our ability to measure the cognitive components of complex decision-making across species has greatly facilitated our understanding of its neurobiological mechanisms. Vulnerability could be indexed by reversal learning, particularly for disorders categorized by impulsive behaviors, including tendencies for substance abuse and also compulsiveness associated with dependence [16]. Dopamine in the striatum is known to be important for reversal learning. van der Schaaf et al. [17] suggested two interconnected mechanisms that are postulated for neuroadaptations in addiction, often associated with poor reversal learning; the dysregulation of frontocorticostriatal circuitry as well as the changes in poor dopamine (D2 receptor) of this specific circuitry. By using a fiber-based approach, they show that dopaminergic drug effects on striatal BOLD signal varied as a function of FA in a pathway connecting the OFC with the amygdala. There are many studies showing the role of music therapy as an adjunct to addiction therapy as espoused by Ross et al. [18]. In an attempt to understanding the mechanisms by which listening to music affects neurological processes, we are struck by the work of Steele et al. [19], who found that early trained musicians had greater connectivity in the posterior mid-body/isthmus of the corpus callosum and that the beginning age of training and sensorimotor synchronization performance is linked to FA in this area. They proposed that training before the age of 7 years results in changes in the white-matter connectivity that could protect carriers with low circuitry as well as reduced dopamine function (DRD2 A1 allele, etc.) from poor decision-making, reward dependence, and impulsivity.

Luhar et al. [20] reported that compared to non-smoking non-alcoholics, alcoholics who smoke had volumetric abnormalities in pre- and para-central frontal cortical areas and rostral middle frontal white matter, the amygdala, parahippocampal and temporal pole regions, the pallidum, the lateral ventricle, and the ventral diencephalic region. They also found that the comorbid group performed worse than non-smoking non-alcoholics on tests of executive functioning and on visually based memory tests. This would suggest that these impairments could be attenuated by chronic music therapy for smoking alcoholics and warrants further testing. On another note, psychiatrists in London, England are embracing hip-hop therapy for schizophrenics such as the popular tune “Happy” (http://www.theguardian.com/society/2014/oct/11/hip-hop-rap-therapy-mental-health-psychiatrists-pharrell-happy).

In addition, other work reveals very specific changes following musical training. More et al. [21] reviewed the current literature and revealed that modifications in cross-hemispheric networks can be induced by musical training, evident with substantial distinctions in several corpus callosum regions of musicians when compared with non-musicians. Neuroplasticity in musicians have been found by a number of investigators [22–24]. Specifically, Imfeld et al. [22] evaluated fiber tractography and subsequent voxelwise analysis, region of interest (ROI) analysis, and detailed slicewise analysis of diffusion parameters in the corticospinal tract (CST) on 26 professional musicians and a control group of 13 participants. They found that training-induced changes in diffusion characteristics of the axonal membrane lead to increased radial diffusivity as reflected in decreased fractional anisotropy (FA) values. Han et al. [23] found that voxel-based analysis of the DT-MRI data showed that pianists had higher FA (indicating higher white matter integrity [WMI]) in the right posterior limb of the internal capsule. The sMRI and DT-MRI results indicate that both the gray matter density (GMD) and WMI of pianists may exhibit movement-related increases during adolescence or even early adulthood compared with non-musicians. Schmithorst and Wilke [24] found that musicians, compared to controls, displayed significantly greater FA in the genu of the corpus callosum, while significantly less FA was found in the corona radiata and the internal capsule bilaterally.

Neurogenetics of Musical Aptitude

While there is paucity with regard to the neurogenetics of music and how it plays out in the addiction field, there have been some clues. Firstly, it is important to realize that composing and interpreting music by singing, playing an instrument, or dancing are very complex, but creative functions based on still unknown reward circuitry of the human brain [25]. Certainly, the ability to think creatively has been considered to be based on genetics [26]. In terms of gifted children, Winner [27] proposed that the well-known child prodigy phenomenon in the music field supports genetic differences in musical creativity at an early age. Winner [27] correctly espoused that environmental factors (e.g., parental guidance), practice, or random occurrences are not sufficient to describe the remarkable creative accomplishments of great artists at very young ages such as Mozart, Yehudi Menuhin, or Jacqueline du Pré, and jazz artists like Kevin Lovejoy, Ephraim Owens, and Stanley Clark.

Creativity is a biological activity that requires decreased levels of cortical activation, relatively higher right than left-hemisphere activation and decreased levels of frontal-lobe activation [28]. Bengtsson et al. [29] found that a pianist’s cortical regions—right dorsolateral prefrontal cortex, pre-supplementary motor area, rostral part of the dorsal premotor cortex, and the left posterior portion of the superior temporal gyrus—were triggered during improvisation. Limb and Braun [30] reported that prefrontal activity accompanied by widespread activation of neocortical sensory-motor areas was demonstrated in fMRI experiments of improvising professional jazz pianists. These studies taken together provide evidence that improvising jazz requires distributed neural pattern to provide a cognitive context that enables the emergence of spontaneous creative activity.

Certainly, most agree that music perception and musical aptitude are cognitive functions of the human brain. While there are many genes involved in cognitive function in both animals and humans, arginine vasopressin (AVP) is a hormone that plays a significant role in regulating higher cognitive activities, such as memory and learning [31]. Wassink et al. [32] suggested that the AVP receptor 1A that is coded by the AVPR receptor 1A gene, affects the AVP hormone in neural circuits of the brain. Moreover, AVP has been observed to affect many social, emotional, and behavioral traits, especially pair bonding and aggression in males [33], parenting [34], sibling relationships [35], love [36], and altruism [37].

While the dopaminergic and serotoninergic systems and related genes have been observed to affect cognitive and motor functions in human and animal studies, little is known about the relationship of polymorphisms of these genes and musical aptitude [38, 39]. It is known that the human serotonin transporter (SLC6A4; 5-HTT) is expressed in the brain, particularly in areas involved with emotions in the cortex and limbic systems. The role of the SLC6A4 polymorphism 5-HTTLPR has been linked to reward-seeking behaviors [39] by influencing the release of dopamine at the VTA. Interestingly, the SLC6A4 with the arginine vasopressin receptor gene (AVPR1A) polymorphisms has been shown to associate with artistic creativity in professional dancers [40] and with short-term musical memory [41]. Furthermore, tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), regulates the quantitative amount of serotonin in the synaptic cleft [42]. In fact, the tryptophan hydroxylase gene 1 (TPH1) polymorphism A779C A-allele is associated with figural and numeric creativities [26]. Moreover, TPH1 A779C has been associated with addiction, specifically nicotine dependence [43].

Catechol-O-methyltransferase (COMT) inactivates dopamine in the synaptic cleft, and the Val158Met polymorphism of the COMT gene has shown up to a 40 % increased COMT activity than those who have the Met allele [44]. Those who are carriers of the Met allele may have a cognitive advantage [45, 46]. Val158Met polymorphism has been associated with basal cognitive processes. While the Met carriers have a better memory and cognition [47], the Val carriers have emotional difficulties and addiction liability [48]. In fact, when a number of gene polymorphisms including the arginine vasopressin receptor 1A (AVPR1A), serotonin transporter (SLC6A4), catecol-O-methyltranferase (COMT), dopamine receptor D2 (DRD2), and tyrosine hydroxylase 1 (TPH1) were tested in a Finnish population of musicians and amateurs, it was found for the very first time that creative music behaviors have a substantial genetic element in these Finnish multigenerational families [49].

While there may be many genes involved in a musical performance, it is interesting that Kanduri et al. [50] showed that following a 2-h concert performed by professional musicians, their upregulated genes affected dopaminergic neurotransmission, motor actions, neuronal plasticity, and neurocognitive activities such as learning and memory. Specifically, candidate genes including SNCA, FOS, and DUSP1 were identified, which are known to be involved in song perception and production in songbirds. Thus, showing evolutionary need for musical events in both animals and humans alike provides the never-ending importance of music in societies now and then.

Conclusion

A PubMed search using the terms “Music Therapy and Addiction” resulted in only 16 published articles [4–16–15]. Based on this brief medical hypothesis and the advent of neuroimaging and genetic tools, we are beginning to understand the potential of music therapy in the treatment and potential prevention of RDS. In fact, Parkinson and Wheatley [51] correctly pointed out the importance of why white matter microstructure predicts emotional empathy. They found that empathic concern was positively correlated with FA in tracts providing communicative pathways within the limbic system. These effects may have relevance in terms of enhancing functional connectivity, especially during resting state, following drug abuse and obesity [52].

Finally and importantly, we know that long–term exposure to listening to music, especially by trained musicians results in neural adaptations dependent on the period of interaction, the initial age, the role of attention, the extent of motor practice, and the musical genre played [53]. This notation may be relevant for exposure to pleasurable music in addicts to assist in the recovery process. We encourage more neuroimaging and genetic studies including the role of epigenetics to assess the effect of listening to music in not only professional musicians, but also ordinary non-musicians, especially addicts [54]. In the future, genetic and epigenetic testing for specific polymorphic and DNA methylation of reward genes like the DRD2, DAT1, and COMT, may help provide further evidence of the importance of music and even music therapy. The reason being this modality may play a significant role in reducing relapse to RDS behaviors [55].