In summary, PRISM successfully identified quantitative biological parameters related to the diagnosis of Schizophrenia (SZ) and Alzheimer Disease (AD) as well as to social functioning and neural activity irrespective of diagnosis. A novel transdiagnostic and pathophysiological link between quantitative measures of neural integrity within the brain’s Default Mode Network (DMN) and social dysfunction was identified. Significant relationships between digital smartphone measures of objective daily social functioning as well as subjectively reported general social functioning with quantitative neuroimaging measures of DMN activity (EEG and task-fMRI) and DMN connectivity (DTI/RS-fMRI) were observed irrespective of the initial clinical diagnosis. These findings generated a novel neurobiological, quantitative, and transdiagnostic framework that requires further validation. In addition, a genome-wide association study (GWAS) on sociability in a population-based sample of over 342.000 individuals from the UK Biobank revealed 19 genome-wide significant findings. Importantly, the vast majority of the top 20 genetic hits from this GWAS are expressed in brain structures that are part of the DMN. In parallel, a preclinical rodent test battery was developed based on paradigms homologous to those assessed in the clinical study. The implemented preclinical platform can now be used to test the causality of the pathophysiological relationship between DMN integrity and social dysfunction. Finally, a novel digital tool was introduced. This provided an objective and quantitative characterisation of social dysfunction that transcended the initial diagnostic classification. A clear link between the digital measure and white matter tracts forming the structural backbone of the DMN was found. These fascinating results allowed us to open an ongoing dialogue with the European Medicine Agency (EMA) with the aim to qualify our approach as a novel digital biomarker of social dysfunction.

PRISM 2 builds on the successful implementation of PRISM outcomes, and aims to (1) determine the reproducibility of the transdiagnostic and pathophysiological relationship between DMN integrity and social dysfunction in SZ and AD and its potential to extend the findings towards Major Depressive Disorders (MDD), (2) test the causality between the quantitative variation in DMN integrity and social dysfunction, and (3) translate and communicate the project results for the benefit of key stakeholders, including patients and relatives, regulators, health care providers, the general public, scientific societies, and the pharmaceutical industry.

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PRISM group photo at the 4th General Assembly Meeting in Basel, Switzerland, in 2019.