Targeting Apathy With Music in Parkinson's Disease

Official title

The Role of a Personalized Music Intervention Towards Alleviating Apathy in Parkinson's Disease

Overview

Parkinson's Disease (PD) is often accompanied by non-motor symptoms that make treatment more difficult. One such symptom is apathy (lack of motivation and emotion). There are no treatments for apathy in PD, and this remains a major unmet need in PD patients. One possible way to target apathy in PD patients is listening to music, which has been shown to help improve apathy in older adults. Little work has explored the mechanism in which music targets apathy. Thus, the goal of this study is to understand how music listening can impact the brain towards decreasing apathy in PD patients.

Detailed description

Apathy is a common neuropsychiatric disturbance that manifests in approximately a quarter of patients in early stages of Parkinson's Disease (PD) and becomes more prevalent over disease progression and cognitive decline. Apathy in PD has been categorized as a distinct behavioural syndrome which can be differentiated from depression and anxiety, and is independently associated with lower functioning in daily life, decreased treatment response, and worse quality of life compared with PD patients without apathy. Characterized by a dysfunction in motivation, or lack of self-initiated goal-directed actions, apathy in PD has been hypothesized to stem from dysfunction in goal-directed reward-seeking networks that rely on dopaminergic transmission in the mesocorticolimbic and frontostriatal pathways, which includes the striatum (includes the nucleus accumbens, or NAc), prefrontal cortex (PFC), hippocampus, and amygdala. Pharmacological trials have attempted to target apathy through the neurotransmitter systems with limited success and sometimes adverse effects. The treatment of apathy remains a major unmet need in PD; thus, it is crucial to develop therapeutic interventions targeting apathy in PD and better understand the underlying mechanisms that may lead to apathy.

Evidence of the positive effects of music-based interventions (MBIs) in both healthy aging and clinical geriatric populations has been examined extensively across the literature. The positive effects of MBIs on alleviating apathy and increasing motivation have been reported in studies focusing on several clinical populations, such as dementia, autism spectrum disorder, and patients undergoing cardiac rehabilitation. A major gap in the MBI clinical trials literature is the lack of attention on the underlying mechanisms in which music can carry out its effects, especially regarding reward pathways. Dysfunction in the reward pathways, which involve the striatum, limbic system, and prefrontal cortices, underlie many disorders, symptoms, and syndromes, and elucidating the role of this underlying network with music is important towards understanding how music can mediate reward deficiencies, such as apathy. Understanding how music works to improve brain functioning is a key gap in understanding how to best inform the development of new therapies and interventions.

Recent work in functional, neurochemical, and pharmacological studies have helped elucidate the role of music in activating reward pathways. Namely, the nucleus accumbens (NAc) has been shown to be involved with processing peak emotionally arousing musical experiences, such as the "chills", and subjective valuations from music. Dopamine transmission in the ventral and dorsal striatum is implicated in regulating this process determined through positron emission tomography (PET) imaging. This work has established the role that the NAc and striatum, and dopaminergic transmission play in processing reward from music and its effects on aspects of cognition, such as motivation, learning, and memory. Thus, the effects of music may be able to mediate the underlying reward system that is compromised in PD patients.

More recently, connectivity between reward and auditory circuits, which include the superior temporal gyrus (STG), superior temporal sulcus (STS) and Heschl's gyrus (HG), have been implicated in musical reward processing and evaluation. No studies to date have observed the immediate and long-term effects of rewarding music on the implicated auditory-reward circuitry and action-oriented behaviour. Thus, this study aims to examine the immediate and longitudinal effects of participant-evaluated rewarding music on clinical apathy measures, connectivity in the auditory-reward networks, and effortful activity in PD patients with and without apathy.

Interventions

• Other Music listening
  This intervention involves listening to participant-selected music that they have evaluated as rewarding/motivating. YouTube Music will be used to build both personalized music and podcast interventions.
• Other Podcast listening
  This intervention involves listening to participant-selected podcasts of neutral content. YouTube Music will be used to build both personalized music and podcast interventions.

Primary outcome measures

• Change in seed-based functional connectivity between auditory, reward, and motor areas (implicated in musical reward processing) during a music-listening task, before and after an 8-week audio-based intervention [Time frame: 8 weeks]
• Change in seed-based functional connectivity between auditory, reward, and motor areas (implicated in musical reward processing) at rest, before and after an 8-week audio-based intervention [Time frame: 8 weeks]
• Change in univariate whole-brain analysis at rest before and after an 8-week audio-based intervention [Time frame: 8 weeks]
• Change in univariate whole-brain analysis during a music listening task before and after an 8-week audio-based intervention [Time frame: 8 weeks]
• Change in fMRI representational similarity analysis during a music listening task before and after an 8-week audio-based intervention [Time frame: 8 weeks]
• Change in fMRI representational similarity analysis at rest before and after an 8-week audio-based intervention [Time frame: 8 weeks]
• Short-term clinical measure of apathy before and after an 8-week audio-based intervention -Positive and Negative Affective Schedule (PANAS) [Time frame: 8 weeks]
• Short-term clinical measure of apathy after a 4-week washout period post-intervention - Positive and Negative Affective Schedule (PANAS) [Time frame: 4 weeks]
• Short-term clinical measure of apathy before and after an 8-week audio-based intervention - Visual Analogue Scale (VAS) [Time frame: 8 weeks]
• Short-term clinical measure of apathy after a 4-week washout period post-intervention - Visual Analogue Scale (VAS) [Time frame: 4 weeks]

Secondary outcome measures (2)

• Clinical assessment for Quality of Life before and after an 8-week audio-based intervention - Quality of Life Scale (QOLS); observing if the intervention improves QoL measures [Time frame: 8 weeks]
• White and grey matter distribution [Time frame: 8 weeks]

Eligibility criteria

Inclusion criteria

\- Clinical diagnosis of Parkinson's Disease following MDS Parkinson's disease criteria

Exclusion criteria

• Participants with atypical Parkinsonism (eg. Progressive supranuclear palsy, multiple system atrophy, drug induced, etc.)
• Epilepsy
• Other neurological disease/complications (eg. myopathy, stroke, brain lesion, MS)
• Significant cognitive impairment (MoCa <21)
• Moderate depression (Beck's Depression Inventory >20)
• Severe/multiple head trauma(s)
• Participants with metal/medical implants, including any of the following: artificial heart valve, brain aneurysm clip, electrical stimulators, ear or eye implant, implanted drug infusion pump, coil, catheter, or filter in any blood vessel, orthopedic hardware such as artificial joint, plate, and/or screws, other metallic prostheses, shrapnel, bullets, or other metal fragments, surgery or tattoos, including tattooed eyeliner, in the last six weeks, cardiac pacemaker, wires or defibrillator, or ferromagnetic aneurysm clip)
• Participants who have gone through specific injuries/brain surgery (eg. an injury where a piece of metal lodged in the eye or orbit)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Supportive care

Study locations

Canada · 1 center

• Djavad Mowafghian Centre for Brain Health — Vancouver

Publications

• Pagonabarraga J, Kulisevsky J. Apathy in Parkinson's Disease. Int Rev Neurobiol. 2017;133:657-678. doi: 10.1016/bs.irn.2017.05.025. Epub 2017 Jul 10. PMID 28802937
• Pagonabarraga J, Kulisevsky J, Strafella AP, Krack P. Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol. 2015 May;14(5):518-31. doi: 10.1016/S1474-4422(15)00019-8. Epub 2015 Apr 12. PMID 25895932
• Aarsland D, Bronnick K, Alves G, Tysnes OB, Pedersen KF, Ehrt U, Larsen JP. The spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson's disease. J Neurol Neurosurg Psychiatry. 2009 Aug;80(8):928-30. doi: 10.1136/jnnp.2008.166959. PMID 19608786
• Barone P, Antonini A, Colosimo C, Marconi R, Morgante L, Avarello TP, Bottacchi E, Cannas A, Ceravolo G, Ceravolo R, Cicarelli G, Gaglio RM, Giglia RM, Iemolo F, Manfredi M, Meco G, Nicoletti A, Pederzoli M, Petrone A, Pisani A, Pontieri FE, Quatrale R, Ramat S, Scala R, Volpe G, Zappulla S, Bentivoglio AR, Stocchi F, Trianni G, Dotto PD; PRIAMO study group. The PRIAMO study: A multicenter assessm PMID 19514014
• Golebiowski D, van der Bom IMJ, Kwon CS, Miller AD, Petrosky K, Bradbury AM, Maitland S, Kuhn AL, Bishop N, Curran E, Silva N, GuhaSarkar D, Westmoreland SV, Martin DR, Gounis MJ, Asaad WF, Sena-Esteves M. Direct Intracranial Injection of AAVrh8 Encoding Monkey beta-N-Acetylhexosaminidase Causes Neurotoxicity in the Primate Brain. Hum Gene Ther. 2017 Jun;28(6):510-522. doi: 10.1089/hum.2016.109. E PMID 28132521
• Marin RS. Apathy: Concept, Syndrome, Neural Mechanisms, and Treatment. Semin Clin Neuropsychiatry. 1996 Oct;1(4):304-314. doi: 10.1053/SCNP00100304. PMID 10320433
• Schmidt L, d'Arc BF, Lafargue G, Galanaud D, Czernecki V, Grabli D, Schupbach M, Hartmann A, Levy R, Dubois B, Pessiglione M. Disconnecting force from money: effects of basal ganglia damage on incentive motivation. Brain. 2008 May;131(Pt 5):1303-10. doi: 10.1093/brain/awn045. Epub 2008 Mar 15. PMID 18344560
• Chatterjee A, Fahn S. Methylphenidate treats apathy in Parkinson's disease. J Neuropsychiatry Clin Neurosci. 2002 Fall;14(4):461-2. doi: 10.1176/jnp.14.4.461. No abstract available. PMID 12426416

Identifiers

NCT: NCT05505019 · H22-00905

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗