Digital neuro-interventions to enhance re-learning in patients with acquired and degenerative brain diseases

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.