The goal of Project RELIEVE is to build the very first non-invasive effective closed-loop monitoring and intervention system for brain-related disorders. The outcomes can be used to treat or manage various psychiatric and neurological disorders. We do this by pushing the technological boundaries in two separate domains. (1) AI domain: We develop a class of mathematical and algorithmic tools for brain data based on the recently developed mathematical theories that are potentially useful for the real-time monitoring of the brain data. Such advancements have shown promise in robotics and self-driving cars and have high potential to work efficiently in highly dynamic environments where personalization and low computation power is a must. This makes such algorithms runnable using brain data such as EEG (electric activity on the head surface) on ordinary wearable devices. (2) Neurostimulation domain: We combine two characteristics of the ultrasound waves in stimulation and imaging of the nervous system to build the first smart-navigated wearable ultrasound patch. We also choose the vagus nerve as the target for neurostimulation as one of the most promising sites to interact with the nervous system with proven implications for a large spectrum of neurological and psychiatric disorders (e.g. dementia, depression, epilepsy, etc.). We call this unit 'WU-VNS' standing for non-invasive wearable ultrasound vagus nerve stimulation. In the next three years, we will use epilepsy as the first use case of the developed technologies to train and test a closed-loop system. For this, the AI monitors the brain through a patch that records EEG in addition to other physiological measures such as heart rate and motion. Upon prediction of a forthcoming anomaly (seizure in this case) by the AI unit, the neurostimulation module activates and stimulates the vagus nerve non-invasively. During this process also a so-called 'active learning' happens in which the AI learns from the reactions of the nervous system to the stimulation protocol and can fine-tune the protocol for future interventions. To achieve this, we have designed a complex phase-based development and testing plan: The first two generations (Gen. 1 and 2) are the intermediate versions of the full system and act in open loops validating each of the AI and neurostimulation subsystems. These two generations already have high potentials to independently turn into medical device products with large market needs. Ultimately, in Gen. 3 we close the loop by integrating the AI and the WU-VNS and consequently validate the efficacy and the usability of the system.

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in childhood, with more than 25,000 patients in Europe. It is due to mutations in the DMD gene that preclude the production of the protein dystrophin. In addition to the progressive muscle weakness, 50% of affected individuals have debilitating central nervous system (CNS) co-morbidities, including intellectual disability, neurodevelopmental problems encompassing autism, Attention Deficit Hyperactivity Disorder and Obsessive Compulsive Disorder. These co-morbidities are due to the deficiency of multiple dystrophin isoforms in brain whose expression is differentially affected by the site of the DMD mutation. They represent a major obstacle for patients to live a fully independent life. Current therapies do not address these co-morbidities. The postnatal restoration of one dystrophin isoform using genetic therapies in the DMD mouse model improves the neurobehavioral phenotype. This raises the exciting possibility that some of the CNS co-morbidities could improve with genetic therapies in patients. We need to address several knowledge gaps before considering clinical applications of these therapies: i. dystrophin isoforms localisation in the CNS; ii. which of the neurobehavioural features of the dystrophic mice improve after dystrophin restoration, and circuitries involved; iii. deep phenotype patients to define robust outcome measures. This project developed in partnership with advocacy groups, meets gender criteria and offers for the first time insight into how dystrophins’ affect CNS function, and on the reversibility of the DMD CNS co-morbidities, providing essential information to the field of neurodevelopmental disorders, and for other syndromes arising from dystrophin associated proteins. Our efforts to develop novel therapies that can cross the blood brain barrier could be transformative for the field of neurodegeneration and neurodevelopmental disorders.

With the growing medical possibilities, new questions arise. It is not only a matter of being able to treat, but also of considering the added value of treatment. In deciding the value of treatment, many factors have to be weighed, such as health benefit, quality of life effect and expenses. Guidelines are directive in making such treatment decisions. As such, medical guidelines have a considerable influence on the quality and effectiveness of healthcare and allow the (future) healthcare professional to be as cost-conscious as possible, especially as the role of specialists in cost conscious care is thought to have become more prominent (needs analysis by the CoCoCARE consortium). However, despite the importance of medical guidelines for cost-effective healthcare, there is little educational attention for it in regular medical training programmes. On a European level, training is dispersed in terms of content and geography. Additionally, the educational programmes that are available have limited focus on competence development, whereas guideline development and the effective implementation thereof relies heavily on a broad range of competences (CanMEDS). Therefore, teaching guideline development offers the opportunity to develop these general competences that are essential in daily practice, also when not developing guidelines. In order to fill the educational gap on guidelines and competences, this project aims to develop a state-of-the-art educational programme to be used for medical residents across Europe. The objective of the project is two-fold: 1) teaching specialists to develop and implement high quality, evidence-based guidelines and; 2) equip specialists with the competences and teach them to be more cost conscious. These objectives will be achieved by a highly integrated, international blended learning programme for medical specialists in training. The programme combines e-learning, plenary discussions and workshops, self-study and practical training from an innovative holistic approach. The content of the programme will also be comprehensive and integrated as it covers all steps that are crucial in developing medical guidelines. In order to do so it will cover the following topics: - PATIENT-CENTERED ASSESSMENT: Patient experiences are weighed. In order to do this, specialists will be taught to identify knowledge gaps and define corresponding questions. Moreover, inclusion and exclusion criteria will be defined. (>IO1)- EVIDENCE REVIEW: Participants should be taught how to properly collect, interpret, combine and evaluate evidence. (>IO2)- COST CONSCIOUS CARE. In order to be able to compare treatment options on their cost effectiveness participants should be taught to interpret changes in costs and (health) benefits of treatments. This includes estimations of long-term benefits, in terms of health outcome, health related quality of life and cost savings. (>IO3)- IMPLEMENTATION IN PRACTICE. Medical residents will learn to assess feasibility of practical implementation and will develop the skills to design an implementation strategy. (>IO4)Moreover, the CoCoCARE project will deliver an EDUCATION SUPPORT TOOLBOX (>IO5). The topics within the educational modules will have to be presented with a didactical approach that enhances learning and ensures usage of the knowledge and skills. This demands a highly integrated approach. A toolbox will offer all the needed tools, such as portals for communication among trainees and with trainers. The toolbox will also include instructions on the use of al educational materials. This will ensure the optimal learning experience and effectiveness. In CoCoCARE the described training programme and the necessary tools and materials will be developed. Moreover, they will be piloted in two subsequent rounds to enable evaluation, revision and optimisation in an iterative process. The first pilot will be run at the partner institutes (C1A1), the second also at the associate partners to enhance geographical spread, number of residents and overall impact (C1A2). In total at least 40 participants will be enrolled in the programme during this project. On the long run, much larger numbers of participants will be reached. However, not only the participants will benefit from the project. As a results of the learning process of the participants, guidelines and thus care will improve. This will have a positive effect on medical professionals as well as patients. The medical professionals will benefit from better guidelines because they will streamline and standardise the work, whereas the patients will benefit from optimal care thanks to the evidence-based reviews of treatment effectivity. Last but not least, the training programme will support medical professionals in making cost conscious decisions. In the age of ever-increasing healthcare expenses, managing healthcare costs is more important than ever.