Alcohol addiction ranks among the primary global causes of preventable death and disabilities in human population, but treatment options are very limited. Rational strategies for design and development of novel, evidence based therapies for alcohol addiction are still missing. Within this project, we will utilize a translational approach based on clinical studies and animal experiments to fill this gap. We will provide a novel discovery strategy based on systems biology concepts that uses mathematical and network theoretical models to identify brain sites and functional networks that can be targeted specifically by therapeutic interventions. To build predictive models of the ‘relapse-prone’ state of brain networks we will use magnetic resonance imaging and neurochemical data from patients and laboratory animals. The mathematical models will be rigorously tested through experimental procedures aimed to guide network dynamics towards increased resilience. We expect to identify hubs that promote ‘relapse-proneness’ and to predict how aberrant network states could be normalized. Proof of concept experiments in animal will need to demonstrate this possibility by showing directed remodeling of functional brain networks by targeted interventions prescribed by the theoretical framework. Thus, our translational goal will be achieved by a theoretical and experimental framework for making predictions based on fMRI and mathematical modeling, which is verified in animals, and which can be transferred to humans. To achieve this goal we have assembled an interdisciplinary consortium (eight European countries) of world-class expertise in all complementary skills required for the project. If successful this project will positively impact on the development of new therapies for a disorder with largely unmet clinical needs, and thus help to address a serious and widespread health problem in our societies.

Chronic pain is a major health problem typically associated with mental disorders such as depression or anxiety and is still difficult to treat despite enormous efforts in the biomedical community. This project proposes a radical shift from the symptomatic focus on chronic pain and predefined diagnostic categories to a mechanistic analysis and treatment of psychobiological factors that shape the transition to chronic pain and its associated mental diorders in a transdiagnostic approach. The proposal aims to identify transdiagnostic mechanisms of the development of chronic pain across three major diagnostic subtypes of pain (primary musculoskeletal pain, neuropathic pain, primary headache) that are usually analyzed and treated in isolation and conducts a proof of principle study of mechanism-based modular digital and virtual reality-based interventions. Work package (WP) 1 will use meta-analyses to determine common and specific transdiagnostic mechanisms of chronicity across these three diverse pain disorders, WP 2 will analyze longitudinal data from existing databases on pain development, using machine learning and knowledge graph approaches. WP 3 will develop an assessment battery for core psychobiological mechanisms and identify predictors of chronicity as well as comorbidity with mental disorder across diagnostic groups using advanced unsupervised learning algorithms. WP 4 will devise easy to apply real life digital and virtual reality interventions that target core psychobiological processes. WP 5 will contain a proof of principle study that contrasts standard cognitive-behavioral pain management with the mechanism-based intervention modules. They will be applied in a digital format and contain virtual reality-based interventions. Statistical analyses will include linear mixed models, an n=1 design as well as a microrandomized trial. We believe that this transdiagnostic mechanistic approach will make a major contribution to the prevention of chronic pain.

The TrePsy project aims to integrate the Maj Institute of Pharmacology of the Polish Academy of Sciences (IP PAS) with leading European brain research centres in development of novel treatments of psychiatric disorders, strengthen research excellence at the IP PAS, and empower it to become leader in other Horizon Europe projects. To this end we will create a unique advanced research curriculum for students and early-career scientists, who will lead future neuropharmacological research, and form a cluster of institutions of excellence in the fields of Neuropsychopharmacology. The project will provide students, and PhD programme participants at the Maj Institute of Pharmacology of the Polish Academy of Sciences (IP PAS), as well as partner Institutes, with lectures and training in emerging topics and research methodologies. These activities will be organised through four advanced schools, each including lectures and hands-o training in advanced research methods, and additionally a “University Specialist” course that will be developed by the consortium. The training activities will be complemented with participation in regional science outreach events, with presentations focused on brain research, the importance of Neuropsychopharmacology-driven research. Furthermore, as an exploratory research project, we selected the study of neuronal and molecular mechanisms involved in the actions of cannabidiol. Each of the partners will contribute their unique research competence including transgenic mice and rats, a ‘multiome’ approach to gene regulation analysis with RNA-Seq and ATAC-Seq, advanced methods of imaging and controlling neuronal activity in behaving animals, and multimodal neuroimaging methodology. The planned research activities emphasize mutual benefits for all consortium partners, nevertheless, interactions with the three leading European research centres will have the greatest impact on research excellence at the IP PAS.