Brain Imaging and Behavioural Changes Following Cued-movement Training of Finger Sequences in Healthy Older Adults

Study Overview
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Brief Summary
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The goal of this study is to examine changes in the brain, behavior, and personal experience when music is used to guide learning of finger movement sequences (compared to visual stimuli alone) in healthy older adults. The main research questions this study aims to answer are: Is auditory-based motor training associated with increased structural integrity of brain white matter tracts (connecting auditory-motor regions) compared to motor training with visual cues only? Is auditory-based motor training (as compared to visual clues only) associated with increased brain cortical thickness, and changes in brain activation while performing a task in the MRI and while at rest, in auditory and sensorimotor regions? Does auditory-based motor training lead to greater motor improvement on the trained task compared to a visually cued motor training? Does auditory-based motor training lead to greater improvement on thinking, movement, and self-reported wellbeing measures, compared to visual cues alone? In an 8-week home training, participants will be randomized into either the music-cued motor learning (Experimental Group) or visually cued only condition (Control Group), participants will complete the following measures before-and-after the training is administered at week 1 and in the end of the 8-week trial: MRI scans (structural and functional) Behavioral measures (motor, cognition) Questionnaires administered pre-and-post training (psychosocial functioning). Questionnaires administered once only (personality traits, musical background) In between measures, participants will follow an online computer-based training at home of 20 minutes per session, 3 times per week for 8 weeks, for a total of 24 sessions constituting 8 hours of training.

Detailed Description
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Rationale: Music interventions targeting motor recovery are increasingly used in clinical settings with motorically impaired patients. In recent years, research started to demonstrate the mechanism underlying motor recovery by moving to music. While neuroimaging studies began to elucidate the neural correlates of music-based movement, most of these studies have been conducted on young adults, whereas the average age at onset of movement disorders which are the target of music therapy is in the 6th decade of life. Therefore, in this study the investigators aim to elucidate the underlying mechanisms of music-based movement in healthy older adults using a motor learning, finger sequence task to a musical rhythm. The results of the study have implications for motor learning with music in the aging person and neural plasticity in old age, and may reveal the benefit of adding music-cues to motor activities for motor, cognitive, and motivational outcomes in older adults. Objective: The goal of the current study is to examine structural and functional neural correlates, as well as changes in behavioral and self-report measures of audiovisual music-based motor training compared to an identical motor training using visual cues only. The study focuses on white matter changes as the primary objective as the researchers are interested in connections between auditory and motor brain regions implicated in music-cued motor training. The research will examine brain activation, and changes in grey matter volume as secondary neuroimaging outcomes. Moreover, the study will also examine improvement on the trained task (outside of the MRI scanner), and changes on standardized measures of motor and cognitive function, as well as self-report measures of psychological wellbeing. The main hypothesis is that the music-based motor training group will show greater white matter integrity of the arcuate fasciculus and greater density of cortical thickness in motor areas in the right brain hemisphere opposite to the trained left hand, as well as greater changes in brain activation while performing the task and at rest. The music group is expected to show greater improvement on the trained task, and measures of motor and cognitive function, as well as self-report measures of wellbeing (motivational, mood, and experience). As an exploratory measure, the study will assess changes in dual-task interference before and after the training as a far-transfer measure of the training, both in motor function and the underlying brain function. Study design: In an 8-week longitudinal between-group design, participants will be randomized into two groups and will participate in pre-and-post MRI scans and behavioral measures, administered at baseline (week 1) and end of trial (week 8). The learning of an audio-visual finger movement sequence task will be compared to training on the same motor sequence with visual cues only. Participants will be assessed before and after the 8-week training on MRI and behavioral measures. Study population: A total of 50 healthy older adults (60 years and older) will be recruited for this study and randomized into two groups of 25 participants each. Inclusion criteria are being right-handed (assessed by the Edinburgh Handedness Inventory), neurologically and physically healthy adult aged 60 or older (a previous diagnosis of a neurological/psychiatric illness that is symptom-free and for which no treatment was necessary for at least 5 years may be included), other physical health conditions that are stable (no change in diagnosis or treatment in the past 2 years may be included), having age-normal cognitive function (as assessed by a score of ≥24 on the MMSE), age appropriate normal or corrected vision and hearing ability, speaking fluent Dutch, and not currently receiving musical training. Participants should have access to a computer to complete the training at home. Participants will be recruited through various channels in the Netherlands including ageing organizations, (social) media, and study recruitment websites. Sample Size: In a previous study with a longitudinal design using the same learning task in healthy young adults, the researchers found a medium size effect for changes in white matter tracts connecting auditory and motor regions (i.e., arcuate fasciculus) in the brain hemisphere opposite the trained hand. Therefore, it is estimated that the sample size needed to show a similar medium sized effect would be 22 per group, however, this number is increased to 25 healthy older participants per group to account for additional drop out at the analysis stage. Intervention: Two groups will receive a similar intervention of finger sequence movement learning following visual cues with (or without) rhythmic auditory stimulation. Participants will be trained on the task at the laboratory before baseline measures. Participants will continue training at home online on a computer and keyboard for 20 minutes per session 3 times per week for 8 weeks for a total of 24 sessions. The Music group will train the finger sequence with the aid of visual cues in synchrony with a musical rhythm, while the Control group will receive the same visual stimulation with no auditory component. Main study parameters/endpoints: The main parameter is change in white matter tracts underlying auditory-motor regions (arcuate fasciculus) in the brain hemisphere opposite the trained hand, contrasting before and after training, and between hemispheres. Secondary MRI parameters focus on cortical thickness changes in primary, premotor, and supplementary motor areas, task-related brain activation in the premotor cortex, and resting-state functional connectivity of auditory-motor regions. Motor performance on the cued motor sequence task will be assessed by measuring the accuracy of the key presses and the timing stability in synchrony with the onset of the cue. Changes in the scores of standardized motor and cognitive measures, and self-reported questionnaires on motivational and mood indices will be compared between groups and timepoints. As an exploratory outcome, the study will also assess changes in dual-task interference before and after the training both behaviorally and in terms of associated brain activity while performing the task.

Official Title
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Neural Correlates of Multisensory Stimulation in Healthy Older Adults

Conditions
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Aging, Music, Motor Activity, Magnetic Resonance Imaging, Neuronal Plasticity

Intervention / Treatment
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* Behavioral: Music-cued audiovisual motor training
* Behavioral: Visually-cued motor training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Right-handed (assessed by the Edinburgh Handedness Inventory), Neurologically and physically healthy adults (a previous diagnosis of a neurological/psychiatric illness that is symptom-free and for which no treatment was necessary for at least 5 years may be included), other physical health conditions that are stable (no change in diagnosis or medication in the past 2 years may be included) aged 60 or older, Age-normal cognitive function (as assessed by a score of ≥24 on the MMSE), Age appropriate normal or corrected vision and hearing ability, Speaking fluent Dutch, Not currently receiving musical training. Participants should have access to a computer and internet to complete the training at home. Exclusion Criteria: MRI contraindications (e.g., having ferromagnetic metals, such as implants, or claustrophobia) Starting or currently engaged in hand training, including musical training, and for example knitting, type-writing, or other hobbies (musical activities such as dancing or singing that do not involve the hand). Changes in medications that may affect fMRI measures. Not being able to follow the training at the laboratory or at home, or not completing the practice at home despite alerts and reminders.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized into either the audiovisual condition (Experimental Group) or visual cues only condition (Control Group). A randomization list stratified by gender will be generated before commencing data collection.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Music-Cued Audiovisual Motor Training<br>Participants will be instructed on the task which they will perform at home online using a keyboard. The training involved auditory-cued audiovisual finger movement sequence learning task. Participants will complete an online computer-based training of 20 minutes at home 3 times per week for the duration of 8 weeks, and a total of 24 sessions, the duration and number of sessions. | Behavioral: Music-cued audiovisual motor training<br>* In addition to visual cues, music stimuli guide finger sequence movement both rhythmically (temporal component) and sonically (pitch-finger alignment).<br>* Other names: rhythmic auditory stimulation;|
| Active Comparator: Visually-Cued Motor Training<br>Participants will be instructed on the task which they will perform at home online using a keyboard. The training involved visual cues for finger-movement sequence learning task. Participants will complete an online computer-based training of 20 minutes at home 3 times per week for the duration of 8 weeks, and a total of 24 sessions, the duration and number of sessions | Behavioral: Visually-cued motor training<br>* Visual cues guide finger sequence movement by indicating which finger to move in alignment with the position and of the visual cue.<br>* Other names: Control Group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to week 8 in white matter diffusivity of the arcuate fasciculus | Change to white matter diffusivity (baseline to post training; within and between hemispheres contralateral to the trained vs. untrained hand) will be assessed by comparing fractional anisotropy (FA) radial diffusivity (RD), and mean diffusivity (MD) of the left and right arcuate fasciculus between groups across the two timepoints, pre-and post-training in the hemisphere contralateral to the trained hand, and between the hemispheres. | Baseline and week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor performance on the cued motor sequence task across three time points (pre-post measurement visits, and mid-trial online) based on the timing stability and synchrony with the onset of the cue. | Motor performance on the cued motor sequence task across three time points (pre-post measurement visits of the 8 week training, and mid-trial at week 4 online) based on the timing stability in synchrony with the onset of the cue. The number of correctly performed motor sequences and movement will be averaged. | Baseline, week 4, and week 8 | 
| Change from baseline in the scores of Grooved Pegboard Task at week 8 | Change from baseline to week 8 in scores of the Grooved Pegboard Task (measured in time in seconds) for both the dominant and non-dominant hand. A total of 240 seconds is the maximum allowed (minimum of 0), where a higher score indicates worse outcome. | Baseline and week 8 | 
| Change from baseline in the scores of Box and Blocks Test at week 8 | Change from baseline to week 8 in scores of the Box and Block test (measured in number of blocks transferred in one minute, rule breaks are deducted) for both the dominant and non-dominant hand. A score of 150 is the maximum (minimum of 0), where a higher score indicates a better outcome. | Baseline and week 8 | 
| Change from baseline in the scores of Digit Span Forward at week 8 | Change from baseline to week 8 in scores of the Digit Span task (number of correctly recalled digits in a sequence is recorded), a maximum score of 2-9, with a higher score meaning a better outcome. | Baseline and week 8 | 
| Change from baseline in the scores of Digit Span Backwards at week 8 | Change from baseline to week 8 in scores of the Digit Span task (number of correctly recalled digits in a sequence is recorded) with a score ranging from 2-8 and a higher score indicating better outcome. | Baseline and week 8 | 
| Change from baseline in the scores of Trail Making Test at week 8 | Change from baseline to week 8 in scores of the Trail Making Test (measured in time over 5 trials). The final score is trial 4 (letter-switching) (score range: 0-240) minus the average of trials 1,2, 3, and 5 (Visual scanning, number sequencing, letter sequencing, and motor speed, respectively). The minimum possible score is 0 and the maximum is 240, where a higher score indicates a worse outcome. | Baseline and week 8 | 
| Change from baseline in the scores of Stroop Color Word Interference Test at week 8 | Change from baseline to week 8 in scores of the Stroop Color Word Interference Test (the combined time during the two congruent trials is subtracted from the time during the non-congruent trial), the lowest possible score is 0 and the maximum is 180, where a higher score indicates a worse outcome. | Baseline and week 8 | 
| Change from baseline in the scores of Verbal Fluency Test at week 8 | Change from baseline to week 8 in scores of the Verbal Fluency Test (total number of correct responses across trials excluding repeats, and deducting errors for phonemic and categorical subtests are recorded), where a higher score indicates better performance, a minimum of 0 and a maximum of 480. | Baseline and week 8 | 
| Change from baseline in the scores of Rey Auditory Verbal-Learning Test at week 8 | Change from baseline to week 8 in scores of the Rey Auditory Verbal-Learning Test, the number of correct responses is recorded for both immediate, interference and delayed recall trials, the final score is the highest achieved number on the learning trails (0 - 15) minus the delayed recall score (0 - 15), where a higher score indicates a worse outcome. The maximum score is 15 and the lowest is -15. | Baseline and week 8 | 
| Change from baseline in scores of Quality of Life measure at week 8 | Change from baseline to week 8 in scores of the EuroQol- 5 (Dimensions: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression) range from 1-5 where a higher number is a worse outcome, and a visual analogue scale from 0-100 where a higher number is a better outcome. | Baseline and week 8 | 
| Change from baseline in scores of mood measure at week 8 | Change from baseline to week 8 in scores of the Depression Anxiety Stress Scale, where Depression symptoms related items: 3, 5, 10, 13, 16, 17, 21 (range from 0-21) Anxiety disorder-related items: 2, 4, 7, 9, 15, 19, 20 (range from 0-21) Stress-related items: 1, 6, 8, 11, 12, 14, 18 (range from 0-21), where a higher score indicates a worse outcome for all domains. | Baseline and week 8 | 
| Change in cortical thickness in motor areas from baseline at week 8 | Change from baseline in cortical thickness of the primary, premotor, and supplementary motor areas contralateral to the trained hand before and after training will be compared between the musical group and the control group focusing on regions of interest in sensorimotor areas. Cortical thickness is measured using an initial surface generated for each hemisphere by tiling the outside of the white matter mass for that hemisphere. This initial surface is then refined to follow the intensity gradients between the white and gray matter (this is referred to as the white surface). The white surface is then nudged to follow the intensity gradients between the gray matter and cerebrospinal fluid (this is the pial surface). The white and pial surfaces are overlaid on the original T1-weighed image, and the distance between the white and the pial surfaces is measured to determine the thickness at each location of cortex. | Baseline and week 8 | 
| Change form baseline in task-based functional magnetic resonance imaging (fMRI) activation in the premotor cortex at week 8 | Change from baseline in task-based functional MRI activation (Blood Oxygen Level Dependent; BOLD) in the premotor cortex, examining the contrast (Cued Tapping vs Rest) at week 8. | Baseline and week 8 | 
| Change from baseline in resting state fMRI connectivity in the auditory and sensorimotor networks at week 8 | Change from baseline in resting state connectivity will focus on nodes of auditory network and sensorimotor network strength in functional MRI activation at week 8 | Baseline and week 8 | 
| Motor performance on the cued motor sequence task across three time points (pre-post measurement visits, and mid-trial online) based on accuracy of the key presses | Motor performance on the cued motor sequence task across three time points (pre-post measurement visits of the 8-week training, and mid-trial at week 4 online) based on accuracy of the key presses. The number of correctly performed motor sequences and movement will be averaged for trained and untrained sequences. | Baseline, week 4, and week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diffusion Tensor Imaging, auditory, multisensory, stimulation, auditory cued, music based, music therapy training, rhythmic auditory stimulation, Diffusion Magnetic Resonance Imaging, motor learning, movement training