Title: Digital neuro-interventions to enhance re-learning in patients with acquired and degenerative brain diseases
Funder: Department of Health and Social Care

Abstract: Background Acquired brain injury (stroke, traumatic brain injury and tumours) and degenerative brain diseases (dementia) account for the vast majority of the cognitive impairments suffered by adults worldwide. Restorative molecular neuronal therapies have yet to deliver any meaningful improvements in cognition in these patient groups; however, there is a wealth of evidence showing that damaged brains can learn if engaged in the correct form of deliberate practice. Neuro-Interventions (practice-based treatments that target specific brain functions) can improve outcomes in adult patients with cognitive impairment, but there is currently no easy way for patients to access these treatments, which are traditionally provided during face-to-face therapy sessions. My research addresses this translational failure. I aim to produce a suite of scientifically valid, web-based therapies that improve real-world outcomes in patients with acquired or degenerative brain disease. Question to be addressed For each of the digital neuro-interventions I develop, the key question is the same: Can patients' engagement with the therapy reduce their impairment and improve their real-world outcomes? Plan of investigation (see Gantt chart) I plan to produce three digital neuro-interventions. They are all based on examples of best current practice that have themselves been validated in a number of well-controlled, phase 2 trials. The three conditions I am targeting are all high priority both for patients and the NHS in terms of reducing impairment and increasing social participation. 1) A tablet-based intervention for patients with visuospatial neglect 2) A mobile-phone based intervention for patients with dementia and problems naming the people they know 3) A tablet-based naming intervention for aphasic patients who have word-finding difficulties Developing, testing (phase 2 trial) and refining (phase 3b trial - effectiveness) each therapy Each digital therapeutic will pass through three key phases using the MRC Developing and evaluating complex interventions guidance. Phase 1. Development: All major components are shaped by iterating them between the three key stakeholders: a) the patients and their relatives; b) the scientific team; c) the software team. Phase 2. Exploratory trial: A small, well-defined sample of patients with the potential to benefit from the neuro-interventions will be recruited into the trial. The exact study design will depend on the neuro-intervention and what the team decides is the appropriate control. We will always have some form of randomization. Phase 3. Internet release of the digital neuro-intervention (a phase 3b trial): We will not control who uses it (so subjects are not randomized) but we continue to ask scientific questions that address clinical effectiveness. We do this using: a) within-subject analyses testing the differential effect of the neuro-intervention on two groups of outcome measures (those we expect to improve vs. those we don't); b) split-testing where subjects are randomized to two different versions of the neuro-intervention (we expect both to work, but one may be more effective). Developing a mechanistic understanding of how therapies affect brain structure In phase 2, longitudinal structural MRI brain imaging will be used to investigate the regional effects of neuro-intervention-driven changes on the brain. This will advance our understanding of how damaged brains instantiate environmental learning and will help stratify future patient cohorts. Potential benefits to patients and the NHS Are not limited to the UK, but are worldwide. I will deliver: 1.Three high-quality, clinically effective, digital neuro-interventions to the patients most likely to benefit from them. 2.A series of post-release trials to: i) continue optimizing the interventions; ii) calculate real-world therapeutic effect sizes to be shared with incoming users. 3.State-of-the-art structural brain imaging to identify brain areas associated with response to the digital neuro-interventions and gain insights into mechanisms underpinning benefit.

Lay abstract: Aim To produce three computer-based therapies (digital neuro-interventions) that patients with specific impairments of their thinking and memory skills can use to boost re-learning. Background The human brain is an amazing learning machine; however, it is delicate and can easily be damaged by short periods of reduced blood flow (stroke), deceleration forces (head injury) or the accumulation of damaging proteins (dementia). Importantly, many studies have shown that even in the presence of these types of injury, the remaining brain networks retain the capacity to learn. With the right type of practice-based intervention, such patients can regain lost thinking and memory skills. How much practice is needed to improve damaged thinking and memory skills? There is no single answer to this, but it is easy to forget how long it takes our brains to learn, for example, how to negotiate the environment, how to talk and how to associate spoken names with familiar faces. Patients with brain damage don't go right back to square one in terms of their cognitive abilities because they can use their retained knowledge of the world, along with their residual learning capacity, to interact with therapeutic interventions in order to improve. But this takes a lot of time and effort; time that, unfortunately, the NHS does not currently have the resources to invest in. Most therapists do not have enough face-to-face time with patients to provide practice-based therapy in high enough doses to be clinically effective. My aim is to translate proven interventions into web-based software programmes that improve thinking or memory skills; I call these digital neuro-interventions'. Patients can use these digital neuro-interventions in the community, either on their own, or with minimal assistance. This allows them to practice when, where and at what pace suits them. It also frees up time for hard-pushed therapists. I propose to develop three separate digital neuro-interventions for three common conditions that cause significant disruption to patients' real-world functioning. 1) Patients with visuospatial neglect (a syndrome where patients fail to attend to, look at or respond to stimuli on one side of their body). There are an estimated 35 million new cases of neglect world-wide per year. 2) Patients with dementia who have problems naming the people they know. People with all stages of dementia report forgetting even very familiar people's names, which they find annoying and embarrassing. 3) Aphasic patients who have word-finding difficulties. Language disorders (aphasia) are the second most common and most feared outcome by patients at risk of stroke. Aphasia is particularly socially disabling. Methods I have a strong track-record in producing digital neuro-interventions. I have two on general release for patients with acquired visual impairments (Read-Right and Eye-Search), they have been accessed by >69,000 users. I plan to follow the same successful general development and testing pipeline for all three projects: Phase 1: Development: this is a three-way partnership between patient-users, the scientific team and the software developers. Each component goes through many design cycles. The key measure is that patient-users like it and can use it. Phase 2: We will carry out a well-controlled, phase 2 trial where the software is tested against a reasonable control (either sham software or current best care') to test its clinical efficacy. We will also test for effects on real-world abilities using patient reported outcome measures. Phase 3: The software is released into the real-world, where anyone can use it. As well as the therapeutic component, the software also contains diagnostic and outcome tests so that users can judge for themselves if they are improving or not. We continue to ask scientific questions in this phase and can even pit different versions of the digital neuro-intervention against each other to continue refining its efficacy. Patient and public involvement Patients are at the heart of the development of all our digital neuro-interventions. Each component is extensively road-tested' by patients and their carers to maximise acceptability and accessibility. The interventions are often repetitive, with patients having to complete many thousands of trials to improve. To make this more engaging we use a professional software development company (SoftV) who incorporate gaming elements. Dissemination We will use all the NHS resources available to inform suitable patients about the digital neuro-interventions and will also target patients and their carers themselves, as the therapeutic range of these digital neuro-interventions is beyond the scope of the NHS alone.

Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL