Title: Development and feasibility randomised controlled pilot study of HD-DRUM - a novel motor sequence training app for people with Huntington's disease
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Research question: Is HD-DRUM, a novel stand-alone drumming training app feasible in human Huntington’s disease (HD)? Background: HD is an uncurable inherited disease that leads to debilitating cognitive and motor impairments due to progressive degeneration of the basal ganglia (BG). There are no NHS services to help with motor and cognitive symptoms. I devised a movement and rhythm program that involves the learning of drumming patterns and trains BG functions of motor planning, sequence learning, timing, and dual-tasking12, 18 known to be affected in HD. In two small MRI pilot studies, I found drumming-related changes in BG connections and improvements in motor sequence learning and executive functioning in individuals with HD12, 18. This accords with HD mice studies showing delays in disease onset, and improvements in therapeutic effects of striatal cell implants in response to an enriched environment that is physically and mentally stimulating. Moreover, cognitive and motor training can be beneficial in people with Alzheimer’s and Parkinson’s disease, and can induce brain changes including the strengthening of neural pathways. However, the current training involves Bongo drumming that needs to be digitised so that performance and engagement can be quantitatively tracked, and the training can be scaled up. Importantly, to maximise learning effects, the training needs to be delivered in an adaptive, learner-sensitive way such that people always practice at an optimal level (~75% success rate) to avoid boredom or overchallenge. This is of particular importance in HD as apathy, depression and motivational problems are common. Aims and objectives: 1. To develop the HD-DRUM training software that addresses above problems. 2. To assess the feasibility of an RCT of three months of HD-DRUM versus standard care in terms of recruitment, retention, acceptability, and adherence in a pilot study. 3. To gain estimates of effect sizes and variability on cognitive and motor functions for a future full-scale RCT assessing the effectiveness of HD-DRUM. 4. To explore training-induced brain plasticity mechanisms. 5. To assess the feasibility of combining HD-DRUM with transplant therapy. Methods and Timeline: HD-DRUM will be developed with members of HD-Voice, the PPI group of the HD Association, and Kinneir Dufort, a digital software company (Months 0-12). Feasibility will be assessed in a two- arm randomised controlled pilot study with 50 individuals with HD (premanifest to early/moderate-manifest) (n = 25 per group) (Months 13-39). Cognitive and motor functions and brain mechanisms will be assessed before and after three months of HD-DRUM with standard-care versus standard-care only, using the most advanced ultra-high-gradient MRI system in the UK. The feasibility of combining HD-DRUM with transplant therapy will be explored in 3-5 transplant individuals (Months 13-39). Final results will be disseminated (months 40-45). Anticipated impact: If HD-DRUM was proven useful, in the future, it may help maintain and/or improve cognitive and motor function in HD without the risk of harmful side-effects. Even a small delay in disease onset due to the potential strengthening of BG connections and function would have direct benefits for the quality of life of people with HD and their families. 6.1. Problems and how they will be addressed HD leads to cognitive and motor impairments with debilitating effects on patients’ independence and quality of life and that of their families. Impairments in executive functioning, multi-tasking, and response planning occur early in the disease25 and with consequences on functional abilities such as the ability to maintain employment or looking after financial affairs. Currently there are no interventions available for targeting these cognitive difficulties; hence, there is an urgent need for interventions that help maintaining or improving them. I will address this problem by developing and testing a novel digitised movement and rhythm training (HD-DRUM) with the aim to train cognitive and motor abilities that are affected in HD. The impact of cognitive/motor training on basal ganglia (BG) networks in HD remains unknown but may provide important insights into the mechanisms of HD pathophysiology and future therapeutics. I will employ ultra-high- gradient (300mT/m) microstructural MRI techniques, only available at CUBRIC in the UK, to study the effects of HD-DRUM on BG connections. Animal studies suggest that combining transplant therapy with an enriched environment can improve graft integration and function26,27 but it remains unknown whether it is feasible to combine transplants with cognitive/motor training in humans. I will use the opportunity of an ongoing trial of HD cell therapy at Cardiff to explore whether combining this therapy with HD-DRUM is feasible. 6.2. Importance of proposed research for people with HD Currently, there is no cure or disease-modifying treatment for HD. While recent developments in gene therapy have generated much excitement, these have yet to be proven to lead to measurable changes in disease progression28. Furthermore, the relative strength of these future disease-modifying treatment approaches and their side effects remain unknown, and current symptomatic therapies for HD are limited with significant side effects28. This highlights the need to explore a wide range of potential therapeutic options and to consider the likelihood that combination therapies will be required. The here proposed HD-DRUM has the potential to provide a future stand-alone cognitive/motor training tool but may also be a safe and cost-effective option as combination with other therapies. While physiotherapy, exercise and language therapy services may be offered by the NHS, the greatest unmet need lies in treating cognitive symptoms, notably executive difficulties that already occur at premanifest stage and can have a significant impact on a person’s independence and quality of life. Currently there are no treatments for cognitive symptoms in HD and only very few studies into HD-specific cognitive interventions29. The proposed HD-DRUM training holds the potential to address this gap as it was conceptualised to specifically train motor and executive functions known to be impaired in HD. If HD-DRUM was shown feasible and effective, it would be possible in the future to use HD-DRUM as a remotely accessible medical tool for improving and maintaining cognitive and motor functions in HD without the risk of significant side effects. Even a small delay of disease onset would translate into direct benefits for the quality of life of patients and their families and into cost- savings for the NHS. 6.3. Support from existing evidence 1. Preclinical evidence for the benefits of environmental enrichment (EE) and myelin plasticity: Accumulating evidence from HD mice models indicates that EE, i.e., increasing physical and mental stimulation, can delay disease onset. Van Dellen et al.30-32 demonstrated that EE delayed the onset of motor deficits in R6/1 HD mice so substantially that only 14% compared to 100% of the control mice showed motor deficits at a late stage of the disease. These original findings have since been replicated in other HD rodent models33-35. Furthermore, it was shown that EE leads to better structural and functional integration of graft neurons in rodents with embryonic striatal transplants including greater spine densities, larger cell volumes, and enhanced long-term potentiation26-27. This suggests that the therapeutic efficacy of human cell transplant therapy could potentially be enhanced by combination with cognitive and motor stimulation. EE in HD mice has been associated with a number of changes including reductions in cerebro-striatal atrophy30, improved hippocampal neurogenesis36,37, synaptic plasticity38, and white matter (WM) integrity39. Indeed, WM myelin impairments may contribute to the pathophysiology of HD11,13 and may even precede neurodegeneration40-42. Myelin remodelling is important for the learning of motor skills43 and for mediating axonal sprouting and synaptogensis44-47. Thus, cognitive-motor training that can stimulate myelin plasticity has the potential to be of particular benefits in people with HD. 2. Evidence of training-induced brain plasticity: Studies into the effects of cognitive and motor training in other neurodegenerative diseases suggest moderate cognitive improvements in Mild Cognitive Impairment48, 49 and Parkinson’s disease (PD)50-52. One small pilot study assessed the effects of drum circle participation in PD and found improved quality of life and faster walking performance53. Cognitive and motor training including drumming54was also found associated with functional and structural brain changes in healthy and clinical populations8, 55-59. For instance, I showed that two months of cognitive training resulted in increased WM microstructure and cortical thickness in right-lateralised fronto-parietal executive networks5-7. 3. Pilot evidence for drumming-induced WM changes and cognitive improvements in HD HD leads to degeneration in the striatum60, 61 and its WM connections13,62, and hence impairs the information transfer within cortico-striatal-thalamic loops. Striatal atrophy and WM impairment can already be observed at premanifest stage along with cognitive deficits in executive functioning and motor speed63-66 that rely on cortico- basal ganglia loops. Characteristically, individuals with premanifest and early HD exhibit impairments in motor sequence learning67, task-switching64, attention set shifting68, multi-tasking69 and psychomotor speed70, 71. I devised a training to specifically target these executive and motor problems by teaching individuals with HD novel motor sequences as Bongo drumming patterns. The training comprises twenty-two sessions on CDs that each introduce a novel drumming pattern, starting with simple, slow patterns and gradually increasing in complexity and speed. Participants were asked to drum along on a pair of Bongo drums, initially with each hand separately and then with both hands alternating and reversing. In two small pilot studies I explored the feasibility of two months drumming training and its potential effects on cognition and WM microstructure with neuropsychological assessment and MRI scanning before and after the training. People with HD were asked to practise at home for 15 min per day, 5 times per week, for two months and to record each exercise in a diary. The first training session was supervised and thereafter the researchers remained in weekly telephone contact. In the first pilot study18 I assessed the feasibility of the training across an inclusive range of disease severities (presymptomatic to advanced). Out of 10 participants, five individuals with early to moderate HD completed the training while people with advanced HD were lacking the motor coordination to perform the drumming. The training was well-accepted by those who completed it, and some chose to continue with drumming after study completion (see Appendix). A second pilot12 recruited fifteen people with HD at early-to-moderate disease stages who did not participate in the first pilot and thirteen age and sex-matched healthy controls. Eight individuals with HD and seven control participants completed the training and all cognitive and MRI baseline and outcome assessments. Drop-out reasons primarily concerned non-study-related issues such as MRI incompatibility or health-related issues. The most common study-related issue was not having the time to practise. Importantly in both pilots, people with HD improved their drumming performance and their executive abilities, notably multi-tasking and distractor suppression (Figure 1). This suggests that the learning of novel motor sequences may improve cognition, possibly due to the anatomical overlap of motor and cognitive cortico- striatal-thalamic loops. Furthermore, drumming was associated with changes in WM microstructure, i.e., increases in fractional anisotropy and the macromolecular proton fraction, a myelin-sensitive MRI measurement, in the corpus callosum and in BG connections (Figure 2). Anecdotally, some patients and their spouses reported improvements in hand coordination and general alertness. In summary, these two pilot studies provide encouraging, albeit preliminary observations suggesting that drumming has the potential to improve WM integrity and cognition in HD. However, to track performance and adherence reliably and to scale the training up, the current Bongo training requires digitisation. Importantly, based on participants’ feedback, the training needs to be delivered in a learner-sensitive way that avoids overchallenge/frustration or boredom.

Lay abstract: Huntington’s Disease (HD) is an inherited disease that causes cell loss in brain regions important for learning and planning movements and doing two things at once (multitasking). HD leads to a worsening of these abilities. There is no cure for HD and there are currently no NHS services that can help movement and thinking changes. Also, the current COVID-19 pandemic has highlighted the urgent need for support that can be accessed at home when clinic visits are not possible. Here, I plan to develop and test a new movement and rhythm training tool that people with HD can use at home. This involves learning drumming sequences that gradually increase in difficulty. Drumming requires key abilities of concentration, planning and making movements and multi-tasking (e.g. listening and drumming). HD affects all of these abilities as they rely on brain regions impaired by the disease. The drumming tool will train these key abilities. The training is based on many studies in HD mice showing that movement symptoms can be delayed when mice have access to an enriched environment with more for them to do and think about. Similarly, the benefits of transplant therapy, i.e., replacing damaged brain cells with healthy ones, in HD mice can be increased if they are in an enriched environment. Furthermore, movement and thinking training was shown to help people with Alzheimer’s and Parkinson’s disease and can make brain changes including the strengthening of connections. Importantly, I found that two months of drumming improved concentration and multi-tasking abilities in people with HD and strengthened their brain connections. However, these pilot findings were just in a small number of people and need to be tested in larger groups. As a next step, I need to develop a digital version of the training, where people always practise at the level that is best for them, i.e., neither too easy nor too hard. The tool would also allow to record training improvements, to see if people are training when they should be, and to make it available to everyone interested in using it. I plan to work with members of HD-Voice, a panel of people with HD, their families and carers, and will instruct Kinneir Dufort, a digital software company, to develop a new digital drumming tool (HD-DRUM). HD-Voice members have already been involved in shaping this proposal and have agreed to help develop HD-DRUM. I will then see how easy it is for people who have not yet developed movement symptoms or have only mild-moderate changes to use HD-DRUM at home for three months (15 min per day, 5 days a week). Half of them will be using HD-DRUM while continuing their standard care and the other half will receive standard care only so that I can compare the two groups. Everybody will have some movement and thinking tests and brain scans at the beginning and end of the study. These tests will let me work out the number of participants I would need for a future bigger trial for studying the effects of HD-DRUM on movement and thinking and the brain. I am also planning to look at combining HD-DRUM with transplant therapy by asking people with HD who have undergone this therapy to try out HD-DRUM. In the future, HD-DRUM may be able to provide a remotely accessible training tool to help improve movement and thinking in HD without the risk of harmful side-effects. Even a small delay in symptoms starting due to the strengthening of brain connections and function would have direct and significant benefits for the quality of life of people with HD and their families.

Research activity codes: 5.3 MEDICAL DEVICES;6.3 MEDICAL DEVICES;6.7 PHYSICAL
Health categories: NEUROLOGICAL