Targeting Apathy With Music in Parkinson's Disease

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.

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.

Participants with Parkinson's Disease (PD) and apathy will be randomly assigned to one of two experimental groups: 1) A music-listening group, and 2) a podcast-listening group.

A randomization schedule will be designed by the research coordinator (MJ) and only the research coordinator will know the group allocations. If any experimental condition is shown to be harmful to any participant and it is medically crucial for a participant to know which intervention group they are in, the research coordinator will break code and disclose this information to the participant.

Participants in this arm will receive a YouTube account app to use. Prior to the start of the intervention, a research team member will guide participants in this group in constructing a playlist of music that they "find rewarding or motivating".

Participants in this arm will receive a YouTube account app to use. Prior to the start of the intervention, a research team member will guide participants in this group in choosing a podcast that they "find rewarding or motivating".

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.

This intervention involves listening to participant-selected podcasts of neutral content. YouTube Music will be used to build both personalized music and podcast interventions.

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

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

Change in univariate whole-brain analysis at rest before and after an 8-week audio-based intervention

rsfMRI - resting state functional magnetic resonance imaging; observing activity across the brain and in specific regions of interest (ROIs), including reward, auditory, and motor areas

Change in univariate whole-brain analysis during a music listening task before and after an 8-week audio-based intervention

fMRI - task-based functional magnetic resonance imaging; observing activity across the brain and in specific regions of interest (ROIs), including reward, auditory, and motor areas

Change in fMRI representational similarity analysis during a music listening task before and after an 8-week audio-based intervention

fMRI - task-based functional magnetic resonance imaging; observing correlated BOLD (blood oxygen level dependent) activity across the brain and in specific regions of interest (ROIs), including reward, auditory, and motor areas

Change in fMRI representational similarity analysis at rest before and after an 8-week audio-based intervention

rsfMRI - resting state functional magnetic resonance imaging; observing correlated BOLD (blood oxygen level dependent) activity across the brain and in specific regions of interest (ROIs), including reward, auditory, and motor areas

Short-term clinical measure of apathy before and after an 8-week audio-based intervention -Positive and Negative Affective Schedule (PANAS)

The PANAS is a self-reported 20-item scale with 2 major subscales: Positive affect score and Negative affect score. Items are scored on a scale of 1-5. Scores range from 10-50 for both the Positive and Negative Affect, with higher scores representing higher levels of Positive/Negative affect.

Short-term clinical measure of apathy after a 4-week washout period post-intervention - Positive and Negative Affective Schedule (PANAS)

The PANAS is a self-reported 20-item scale with 2 major subscales: Positive affect score and Negative affect score. Items are scored on a scale of 1-5. Scores range from 10-50 for both the Positive and Negative Affect, with higher scores representing higher levels of Positive/Negative affect.

Short-term clinical measure of apathy before and after an 8-week audio-based intervention - Visual Analogue Scale (VAS)

The VAS is a visual scale with a rating from 1-10; participants are to indicate the level of apathy and motivation felt at their current state. Higher values indicate more severe apathy.

Short-term clinical measure of apathy after a 4-week washout period post-intervention - Visual Analogue Scale (VAS)

The VAS is a visual scale with a rating from 1-10; participants are to indicate the level of apathy and motivation felt at their current state. Higher values indicate more severe apathy.

Long-term clinical measure of apathy before and after an 8-week audio-based intervention - Starkstein Apathy Scale (SAS)

The SAS is a 14-item clinical scale used to evaluate apathy in clinical populations. Higher scores indicate more severe apathy. Scores range from 0-42. Participants who score >=14 are considered as having clinical apathy.

Long-term clinical measure of apathy after a 4-week washout period post-intervention - Starkstein Apathy Scale (SAS)

The SAS is a 14-item clinical scale used to evaluate apathy in clinical populations. Higher scores indicate more severe apathy. Scores range from 0-42. Participants who score >=14 are considered as having clinical apathy.

Clinical assessment of apathy before and after an 8-week audio-based intervention - Lille Apathy Rating Scale (LARS)

The LARS is a 33-item assessment with 9 subscales: everyday productivity, interests, taking the initiative, novelty seeking, motivation - voluntary actions, emotional responses, concern, social life, and self-awareness. There is a mix of open-ended (items scored between -2 and 2) and multiple choice items (items scored between -1 and 1). Scores range from -36 to 36. Higher scores indicate more severe apathy.

Clinical assessment of apathy after a 4-week washout period post-intervention - Lille Apathy Rating Scale (LARS)

The LARS is a 33-item assessment with 9 subscales: everyday productivity, interests, taking the initiative, novelty seeking, motivation - voluntary actions, emotional responses, concern, social life, and self-awareness. There is a mix of open-ended (items scored between -2 and 2) and multiple choice items (items scored between -1 and 1). Scores range from -36 to 36. Higher scores indicate more severe apathy.

Clinical assessment of apathy in Parkinson's Disease before and after an 8-week audio-based intervention - Movement Disorders Society Unified Parkinson's Disease Rating Scale - apathy item (MDS-UPDRS)

The MDS-UPDRS is a clinical assessment of motor and non-motor symptoms in individuals with Parkinson's Disease. It consists of four subscales. Subscales 1, 3, and 4 are administered by a trained individual with subscale 2 being self reported. Each item is rated from 0 to 4.

Clinical assessment of apathy in Parkinson's Disease after a 4-week washout period post-intervention - Movement Disorders Society Unified Parkinson's Disease Rating Scale - apathy item

The MDS-UPDRS is a clinical assessment of motor and non-motor symptoms in individuals with Parkinson's Disease. It consists of four subscales. Subscales 1, 3, and 4 are administered by a trained individual with subscale 2 being self reported. Each item is rated from 0 to 4.

Assessment of musical reward sensitivity before and after an 8-week audio-based intervention - Barcelona Musical Reward Questionnaire (BMRQ)

The BMRQ is a validated 20-item assessment of musical reward sensitivity (how responsive a participant is to the rewarding effects of music listening). It has 5 subscales: musical seeking, emotion evocation, mood regulation, social reward, and sensory-motor. Items are scored from 1-5. Higher scores indicate higher sensitivity to reward.

Assessment of musical reward sensitivity after a 4-week washout period post-intervention - Barcelona Musical Reward Questionnaire (BMRQ)

The BMRQ is a validated 20-item assessment of musical reward sensitivity (how responsive a participant is to the rewarding effects of music listening). It has 5 subscales: musical seeking, emotion evocation, mood regulation, social reward, and sensory-motor. Items are scored from 1-5. Higher scores indicate higher sensitivity to reward.

Grip force response (GFR) during a music listening fMRI task before and after an 8-week audio-based intervention

GFR is a physical effort measure; it is a validated measure of apathy in Parkinson's Disease (Zhu et al., 2021)

Grip force duration and fatigue during a music listening fMRI task before and after an 8-week audio-based intervention

Grip force duration and fatigue are physical effort measures; they are validated measures of apathy in Parkinson's Disease (Zhu et al., 2021)

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

The MoCA is a researcher-administered 30-item assessment covering 8 aspects of cognition: visuospatial/executive, naming, memory, attention, language, abstraction, delayed recall, and orientation. Scores range from 0-30. Higher scores indicate better cognition; lower scores indicate poorer cognition.

The BDI is a self reported 21-question multiple-choice self-report inventory on a scale from 0-3. Scores range from 0-63. Higher scores indicate higher levels of depression; scores over 40 are considered as extreme depression. It will be used as a screening tool to observe any overlap between apathy and depression.

Validated assessment of musical perception (contour subtest) - Montreal Battery of Evaluation of Amusia (MBEA);

The Montreal Battery of Evaluation of Amusia (MBEA) measures level of general music perception for universal musical structures. This will be used to rule out any non-effects of the music intervention due to a deficit in musical perception abilities; the contour subtest will be used to evaluate this.

The SHAPS will be used to compare with BMRQ to isolate for overall anhedonia/apathy versus music-specific apathy (Loui and Belfi, 2020). Higher scores correlate with higher apathy/less pleasure.

White matter tract - axial diffusivity; lesion analysis in white matter tracts (focus on arcuate fasciculus)

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)

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