Multiple sclerosis is a chronic disease involving the central nervous system that is caused by a complex interplay between genetic and environmental factors.[1–4] In addition to motor involvement, other clinical manifestations significantly affect the quality of life of both the patients and their caregivers, including fatigue, pain, dysphagia, psychiatric disorders, and cognitive deficits.[5–7]
In recent years, an increasing amount of attention has been paid to cognitive impairment in MS. Cognitive impairment, in fact, is a common and debilitating symptom in people with MS, although is poorly managed by pharmacotherapy. The prevalence of cognitive dysfunction ranges from 43% to 70%, and have been reported in all stages and clinical types of MS. Patients with MS may experience cognitive dysfunction in several domains, especially in attention, visual and verbal memory, and processing speed.
The typical pattern of cognitive impairment includes reduced speed of information processing, decreased phonological and semantic speech fluency output, deficits in verbal and visual episodic memory, attention and executive dysfunctions. Otherwise, language function seems to remain relatively intact. Language impairments usually involve poor word recall and verbal fluency (phonological and semantic fluency). Cognitive deficits can often be identified through a neuropsychological assessment and subsequent cognitive rehabilitation (CR). Indeed, specific trainings have been acknowledged as promising behavioral approaches for managing MS-related cognitive impairment to improve overall cognitive abilities and quality of life (QoL). In addition, MS can have consequences on mood and patients’ behavior, leading to depression, anxious state, and a condition of excessive stress. The lifetime risk of major depression in people with MS has been estimated to be as high as 50% compared with the percentage of general population which is calculated at 10% to 15%.[12,13] In most cases, these disorders derive from: subjective reactions to the diagnosis, ability to adapt and face the disease, response to possible changes in their lifestyle and relationships with others, one's own history, personality and the environment they have lived in, and last but not least, the support of the family and caregivers. Taking into account a multimodal and ecological rehabilitation approach, which also includes the psychological problems related to MS, it could be appropriate to focus the treatment on an integrative cognitive rehabilitation (ICR). In the last decades, the potential of musical stimuli to activate “perception” and “production” areas in the human brain has been investigated with the aim to provide a series of therapeutic applications to sensory, cognitive, and motor dysfunctions due to neurological diseases. To this aim, a new integrative therapeutic approach, which was established 20 years ago in the United States, called neurologic music therapy (NMT) has provided various benefits to the conventional rehabilitative approaches on controlling mood disorders. This may help the patient to be prone to cognitive and behavioral change in therapy.
A typical NMT technique is the Associative Network Theory of Mood and Memory, which suggests that when an event or information is processed, neural connections are established together with other elements (emotional status, odors, environmental background, etc) of that event, and stored as nodes in memory. Later, this neural node can be activated by music stimuli. Furthermore, the social nature of the musical experience has been investigated by various authors. Clark suggested that music provides shared experience, promoting self-identity, healthy relationships, and quality of life, whereas Dunphy underlined the intrinsic social character of the creative arts therapies and their efficacy in reducing depression symptoms. Moreover, Särkämö et al proposed that, since many therapeutic music exercise methods offered opportunities for social learning, a neurologic music therapist should develop strategies and music-based applications that are better targeted at specific brain processes and at individual rehabilitation needs of patients. For this purpose, Music in Psychosocial Training and Counselling is another NMT technique, which uses music-based methods to help people with neurological problems to improve their psychosocial functioning (mood control; affective expression; cognitive coherence; reality orientation; and appropriate social interactions).
Considering that depression and mood disorders still remain under-diagnosed and under-treated in neurological patients and the side effects of the pharmacological treatment, music, and NMT may represent a valid support in reducing such depressive symptoms, improving mood and adherence to treatment while contributing to the functional recovery, including the cognitive one, at the same time.
In this pilot study, we sought to investigate the effects of NMT on mood, motivation, emotion status, and cognitive functions in patients with MS that are receiving CR.
2 Materials and methods
2.1 Trial design
The study was a single-blind randomized controlled trial aimed to investigate the influence of NMT on mood, motivation, emotion status, and cognitive functions in patients with MS. It was conducted in accordance with the Declaration of Helsinki and was approved by the Local Ethical Committee (study number registration 07/2017). Each patient was adequately informed about the study, and offered their collaboration and signed a written consent.
Patients attending the Multiple Sclerosis Centre of IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina, Italy, from November 2017 to December 2018 were invited to enter the study. For the enrollment procedures, see Consort 2010 flow diagram (Fig. 1). Thirty patients affected by relapsing-remitting, primary and secondary progressive MS, were randomly assigned to either the experimental group (EG; n = 15) or the control group (CG; n = 15), in order of recruitment. For a more detailed description of the sample, see Table 1.
Inclusion criteria were: MS diagnosis according to Lublin criteria; an Expanded Disability Status Scale between 3 and 7; to love/enjoy music, either performed instrumentally or listened; absence of disabling sensory alterations (i.e., hearing and visual loss); absence of severe medical and psychiatric illness according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) and International Classification of Diseases (ICD-10).
We applied 2 different rehabilitative approaches: the CG received conventional CR (CCR), 6 times a week for 8 weeks, whereas the EG received CCR (but with a different frequency, i.e. 3 times/wk, for a total of 24 sessions) and a specific NMT 3 times/wk for 8 weeks (for a total of 24 sessions). Each single session lasted about 60 minutes. Thus, both the groups received the same amount of treatment. We used 2 NMT techniques: the Associative Mood and Memory Training (AMMT) and the Music in Psychosocial Training and Counseling (MPC) (see Table 2). AMMT involves music to induce a specific mood state that is associated with material stored in long-term memory, specifically autobiographical memories that belong to the self and one's past experiences. Through dedicated music listening or singing, the patient experiences a shift of mood, or intensification in their current mood, that activates an associative memory network, creating access to memories of information or events from the past. The primary goals of MPC include emotion identification and expression, mood control, social competence, and self-awareness. These goals are stimulated through guided music listening, musical role-playing, expressive improvisation or singing, and composition exercises.
2.4 Main outcomes measures
Each participant was evaluated by a trained neuropsychologist before (baseline: T0) and immediately after the end of the training (T1). The clinical assessors (who were different from the neuropsychologist who performed the training), and the statisticians were blinded to group allocation.
The neuropsychological battery included: the brief repeatable battery of neuropsychological test (BRB-N)[22,23] which was used to assess various cognitive abilities (attention, orientation, spatial abilities, memory, language); the multiple sclerosis quality of life-54 (MSQoL-54) a specific questionnaire for MS patient's quality of life, divided into physical and mental subitems; the Beck depression inventory (BDI) used to assess mood; the emotion awareness questionnaire (EAQ) to evaluate emotional component. EAQ is planned with a 6-factor structure defining 6 aspects of emotional functioning: differentiating emotions, verbal sharing of emotions, not-hiding emotions, bodily awareness of emotions, analyses of own emotions, attention to others’ emotions. The EAQ consists of a total of 30 items. Last, we also administered McClelland Motivational Factors, which assess subject motivation, consisting of 3 components, that is, power, competition, and affiliation; specifically, the authors recognized 3 motivators which are believed all people have: a need for achievement, a need for affiliation, and a need for power. Different characteristics will depend on the subject's dominant motivator and will act accordingly. Moreover, each experimental patient was asked to fulfil a Musical-Sound Anamnesis Form, to guide the NMT approach due to the EG.
2.5 Randomization and blinding
Patients with MS were randomized to undergo either the NMT together with conventional CR (EG) or CR alone (CG). Patients were assigned in a 1:1 ratio using a computer-generated randomization list assessed by statisticians, which was blinded to the training allocation. Patients received instructions not to tell other patients anything about what they do during NMT training techniques.
2.6 Statistical methods
Data were analyzed using IBM https://www.ibm.com/products/spss-statistics SPSS Statistics 25, considering a P < .05 as statistically significant. The descriptive statistics were analyzed and presented as a media + standard deviation (SD) for continuous variables and as frequencies (%) for categorical variables for the 2 groups (Table 1).
The Student t test for paired samples was used to compare each group between T0 (baseline) and T1 (intra-group analysis). Moreover, a double-tailed Student t test for paired samples was used to compare test score variations and discover whether in EG, a higher statistical significance was found rather than in CG (inter-group analysis). In particular, for each clinical test score we computed the differences between the 2 different evaluation times at T0 score and T1, as explained in Table 2.
A total of 30 patients underwent randomization, and 15 were assigned to each group (see Fig. 1). No harms or unintended effects were found in both groups.
Firstly, at baseline T0, no significant differences between EG and CG were found concerning age, sex instruction, and disability states as shown in Table 1. The between group comparison of the test score variations from baseline (T0) to the end of the treatment (T1) highlighted improvements in various sub-scales of the cognitive evaluation battery (BRB-N) in the EG, as compared with CG (Table 3). In particular, in the EG a significant improvement was found concerning selective reminding test long term storage (P < .000), long term retrieval (P = .007), and delayed recall of the 10/36 spatial recall test (P = .001). Regarding the quality of life test results, the EG showed a more significant improvement in mental sub-test (P < .000) than the CG (P = .928). Moreover, in the EG, we observed a significant improvement in mood, as shown by the BDI test scores (P < .000), as compared with the CG (P = .278). Both groups revealed significant improvements in patients’ emotional status, mood, and expressing emotions, as shown by the final scores in the EAQ (Table 3). However, in the EG, the scores obtained were statistically higher concerning verbal sharing of emotions (P < .000), not hiding emotions (P < .000), attending to others emotions (P < .000), and the analysis of own emotions (P < .000). Finally, only in the EG a significant improvement in motivational factors was observed, with the highest significance level in affiliation component (P < .000), compared with competition and power components final scores P = .002 and P = .008 respectively (see Table 3).
Our pilot study supported NMT as a possible effective additional method to improve mood, motivation, emotional status (awareness and expression), and cognitive functions in patients with MS. There is growing evidence suggesting how music may help to elicit images from memory, based on associative memory network operations, helping to retrieve mood/emotional quality of a particular life situation in the imaging process. MS patients have been observed to recall individual words or song lyrics better when presented in sung than spoken format. According to VanArsdall et al, animate stimuli are better remembered than matched inanimate stimuli in free recall because the encoding and retrieval of information are not a passive adaptation but active paths of discrimination: “Increasing the encoding of memories generally improves retrieval performance (…) because it increases the percentage that the distinguishing features of encoding will come into play.” These findings are in agreement with our data, as music stimulus helped the retrieval of information acting like an additional external cue, which triggers environmental, interior, physical, emotional, and even very personalized neural pathways. In fact, we found significant cognitive improvements in attention control and long-term memory storage, as well as retrieval of verbal inputs and delayed recall of visual-spatial information.
Emotional and behavioral disturbances with a polymorphic symptomatology are often connected to neurological disorders such as MS.[31,32] In line with Galińska, our results showed that music may help to organize therapeutic experiences according to the affective and motivational values for the individual, and could lead to re-thinking personal problems, changing perception of others, learning new coping skills, processing significant life experiences, dealing with fears and setting new goals.
In this regard, increasing evidence highlighted the triggering of “eco-mirror neurons” during the execution of music-related movements (playing instruments, singing, clapping hands, stamping feet) or even during the imagination of a song or a melody. Indeed, it has been proposed that another important aspect of music is the ability to evoke and alter emotional reactions promoting motivation.
Recently, Hodgens and Hodgens and Sebard described affective-mood responses to music and concluded that: music evokes emotional reactions, including emotional peak experiences, music can alter a listener's mood, emotional and mood responses to music are accompanied by physiological changes, and existing mood, musical preference, cultural expectations, and arousal needs also play a role in determining affective responses. This is probably due to the ability of music to stimulate the production of dopamine, through activation of the tegmental ventral area. This neurotransmitter exerts different effects in various regions and pathways throughout the brain. In fact, in the mesolimbic pathway, dopamine is believed to be involved in motivation and addiction due to the feelings of reward and pleasure associated with its release, while, in the mesocortical pathway, dopamine is linked to emotional and motivational activities. Music can stimulate each neural pathway by linking the neurotransmitter to the musical input. This may be partly the reason why EG had, during NMT, a highest need for affiliation, with a consequent improvement in their behaviour. Indeed, within a short space of time from the beginning of NMT treatment, patients themselves referred that they enjoyed and wanted to belong to that “musical” group, because they felt better personal acceptance and affiliated to the rest of the group (these results that are confirmed by MSQOL, EAQ, and BDI outcomes measures). Finally, they preferred collaboration to competition, as shown by the MC Lelland Motivational Factors final scores (higher especially in Affiliation sub-scale).
4.1 Study limitations
The main limitation of the study is the small sample size that limits the generalization of our results. Larger sample studies, using specific structural and functional examinations (such as EEG, and fMRI) in addition to neuropsychological evaluation, should be fostered to confirm these findings. Moreover, a more structured and homogeneous intervention is needed to guarantee better results.
NMT uses primarily the potential of musical stimuli to activate perception and production areas in the human brain, providing a series of additional therapeutic applications to sensory, cognitive, and motor dysfunctions resulting from neurological disease. When applied to neurological disorders, such as MS, NMT may promote functional recovery, collaborate in neurorehabilitation programs, and improve social and psychological outcomes including socialization, motivation, mood, and depression.
Conceptualization: Federica Impellizzeri, Margherita Russo, Rocco Salvatore Calabrò.
Data curation: Federica Impellizzeri, Simona Leonardi, Dèsiréè Latella, Marilena Foti Cuzzola, Rosaria De Luca.
Formal analysis: Federica Impellizzeri.
Investigation: Simona Leonardi, Dèsiréè Latella, Maria Grazia Maggio, Marilena Foti Cuzzola, Rosaria De Luca, Rocco Salvatore Calabrò.
Methodology: Federica Impellizzeri, Dèsiréè Latella, Maria Grazia Maggio, Marilena Foti Cuzzola, Margherita Russo, Rosaria De Luca, Rocco Salvatore Calabrò.
Project administration: Edoardo Sessa, Placido Bramanti.
Supervision: Marilena Foti Cuzzola, Margherita Russo, Placido Bramanti, Rocco Salvatore Calabrò.
Validation: Edoardo Sessa, Placido Bramanti.
Visualization: Simona Leonardi, Maria Grazia Maggio, Edoardo Sessa.
Writing – original draft: Federica Impellizzeri, Marilena Foti Cuzzola.
Writing – review & editing: Margherita Russo, Rocco Salvatore Calabrò.
. Steri M, Orrù V, Idda ML, et al. Overexpression of the cytokine BAFF and autoimmunity risk. N Engl J Med 2017;376:1615–26.
. Cocco E, Meloni A, Murru MR, et al. Vitamin D responsive elements within the HLA-DRB1 promoter region in Sardinian multiple sclerosis associated alleles. PLoS One 2012;7:e41678.
. Cocco E, Murru R, Costa G, et al. Interaction between HLA-DRB1-DQB1 haplotypes in Sardinian multiple sclerosis population. PLoS One 2013;8:e59790.
. Thompson AJ, Baranzini SE, Geurts J, et al. Multiple sclerosis. Lancet 2018;391:1622–36.
. Lorefice L, Fenu G, Frau J, et al. The impact of visible and invisible symptoms on employment status, work and social functioning in multiple sclerosis. Work 2018;60:263–70.
. Toosy A, Ciccarelli O, Thompson A. Symptomatic treatment and management of multiple sclerosis. Handb Clin Neurol 2014;122:513–62.
. Solaro C, Trabucco E, Signori A, et al. Depressive symptoms correlate with disability and disease course in multiple sclerosis patients: an Italian multi-center study using the Beck depression inventory. PLoS One 2016;11:e0160261.
. Sumowski J, Benedict R, Enzinger C, et al. Cognition inmultiple sclerosis: state of the field and priorities for the future. Neurology 2018;90:278–88.
. Langdon D. Cognition in multiple sclerosis. Curr Opin Neurol 2011;24:244–9.
. Prakash R, Snook E, Lewis J, et al. Cognitive impairments in relapsing-remitting multiple sclerosis: a meta-analysis. Mult Scler 2008;14:1250–61.
. Lezak M, Howieson D, Bigler E, et al. Neuropsychological Assessment. 5th ed.New York: Oxford University Press; 2012.
. Siegert R, Abernethy D. Depression in multiple sclerosis: a review. J Neurol Neurosurg Psychiatry 2005;76:469–75.
. Arnett P, Barwick F, Beeney J. Depression in multiple sclerosis: review and theoretical proposal. J Int Neuropsychol Soc 2008;14:691–724.
. Thaut M. Music therapy, affect modification, and therapeutic change: towards an integrative model. Music Therapy Perspectives 1989;7:55–62.
. Maratos A, Gold C, Wang X, et al. Music therapy for depression. Cochrane Database Syst Rev 2008. CD004517.
. Clark I, Tamplin J, Baker F. Community-Dwelling people living with Dementia and their family caregivers experience enhanced relationships and feelings of wee-being following therapeutic group singing: a qualitative thematic analysis. Front Psychol 2018;9:1332.
. Dunphy K, Baker FA, Dumaresq E, et al. Creative arts interventions to address depression in older adults: a systematic review of outcomes, processes, and mechanisms. Front Psychol 2019;9:2655.
. Särkämö T, Altenmüller E, Rodríguez-Fornells A, et al. Editorial: music, brain, and rehabilitation: emerging therapeutic applications and potential neural mechanisms. Front Hum Neurosci 2016;10:103.
. Pucak M, Carroll K, Kerr D, et al. Neuropsychiatric manifestations of depression in multiple sclerosis: neuroinflammatory, neuroendocrine, and neurotrophic mechanisms in the pathogenesis of immune-mediated depression. Dialogues Clin Neurosci 2007;9:125–39.
. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Washington, DC; 2013.
. Genova, Switzerland, World Health Organization W. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. 1992.
. Bever CT Jr, Grattan L, Panitch HS, et al. The brief repeatable battery of neuropsychological tests for multiple sclerosis: a preliminary serial study. Mult Scler 1995;1:165–9.
. Boringa JB, Lazeron RH, Reuling IE, et al. The brief repeatable battery of neuropsychological tests: normative values allow application in multiple sclerosis clinical practice. Mult Scler 2001;7:263–7.
. Solari A, Filippini G, Mendozzi L, et al. Validation of Italian multiple sclerosis quality of life 54 questionnaire. J Neurol Neurosurg Psychiatry 1999;67:158–62.
. Beck A, Steer R, Brown G. Manual for the Beck Depression Inventory – II. San Antonio, TX: Psychological Corporation; 1996.
. Camodeca M, Rieffe C. Validation of the Italian Emotion Awareness Questionnaire for children and adolescents. Eur J Dev Psychol 2013;10:402–9.
. McClelland D. Human Motivation. New York, NY, US: Cambridge University Press; 1987.
. Ferreri L, Bigand E, Perrey S, et al. Less effort, better results: how does music act on prefrontal cortex in older adults during verbal encoding? An fNIRS study. Front Hum Neurosci 2014;8:301.
. Särkämö T, Sihvonen AJ. Golden oldies and silver brains: deficits, preservation, learning, and rehabilitation effects of music in ageing-related neurological disorders. Cortex 2018;109:104–23.
. VanArsdall J, Nairne J, Pandeirada J, et al. A categorical recall strategy does not explain animacy effects in episodic memory. Q J Exp Psychol (Hove) 2017;70:761–71.
. Skokou M, Soubasi E, Gourzis P. Depression in multiple sclerosis: a review of assessment and treatment approaches in adult and pediatric populations. ISRN Neurol 2012;2012:427102.
. Koch M, Patten S, Berzins S, et al. Depression in multiple sclerosis: a long-term longitudinal study. Mult Scler 2014;21:76–82.
. Galińska E. Music therapy in neurological rehabilitation settings. Psychiatr Pol 2015;49:835–46.
. Houd J, Rajmohanc R, Fanga D, et al. Mirror neuron activation of musicians and non-musicians in response to motion captured piano performances. Brain Cogn 2017;115:47–55.
. Hodgens D. Psychophysiological Measures Handbook of Music and Emotion. Oxford: Oxford University Press; 2010.
. Hodgens D, Sebald D. Music in the Human Experience: An Introduction to Music Psychology. New York: Routledge; 2011.
. Blum K, Simpatico T, Febo M, et al. Hypothesizing music intervention enhances brain functional connectivity involving dopaminergic recruitment: common neuro-correlates to abusable drugs. Mol Neurobiol 2017;54:3753–8.