Clinical utility and genetics of neuronal intra-individual variability in severe mental illness: A Norwegian-German collaboration

Mental disorders are among the largest contributors to years lived with disability and schizophrenia (SZ) and bipolar disorder (BD) are among the most debilitating mental disorders. Despite immense recent research efforts, severe mental illness remains practically unchanged with respect to both prevalence and disability, and the etiology and pathophysiology remain elusive. A critical aim of translational neuroscience is to identify sensitive phenotypes, with the goal of increasing discriminant and predictive validity of clinical diagnosis. The beneficial role of variability in complex systems has provided a novel window into the enigmatic neuronal antecedents of human mind and behavior. In particular, the brain, representing the most complex human system, is inherently variable, from the molecular and cellular levels to the level of behavioral output. Indeed, whereas the brain in the adaptive and healthy individual is characterized by homeostasis between variability and stability, disorders perturbing brain biology shift the degree of variability at one or several levels. This proposal targets neuronal intra-individual variability (IIV) as a novel intermediate phenotype, its cognitive correlates and genetic underpinnings, with the long-term imperative of improving clinical diagnostics, predictions, treatment, and patient care. By approaching imaging data with a focus on neuronal IIV, the current proposal leverages the huge amounts of imaging, cognitive and genetic data available through NORMENT and collaborating partners, potentially revealing novel mechanisms that have eluded discovery by conventional approaches. The proposal promotes a recently formed collaboration between young research leaders in psychiatry and neuroimaging and their respective institutions, namely the Lifespan Neural Dynamics Group within the Max Planck UCL Centre for Computational Psychiatry (Dr. Doug Garrett) and the NORMENT Multimodal Imaging Group (Dr. Lars T. Westlye).