Neurological soft signs as an external marker of neuronal dysfunction in schizophrenia: Investigation with multimodal magnetic resonance imaging

• Applicants: Professor Dr. Dusan Hirjak; Professor Dr. Klaus Maier-Hein; Professor Dr. Robert Christian Wolf
• Subject Area: Biological Psychiatry
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 319937632

At the beginning of the 20th century, many authors proposed that a considerable number of schizophrenia patients experience genuine motor abnormalities. Recent evidence suggests that the association between psychotic symptoms and motor abnormalities in schizophrenia reflects neuronal dysfunction in the cortico-cerebellar-thalamo-cortical circuit (CCTCC) as conceptualized in the model of cognitive dysmetria. If this dysfunction develops earlier than prodromal symptoms of the disorder, it might give rise to subtle motor abnormalities. In this context, subtle motor deficits have been suggested to be an external marker of underlying neuronal dysfunction that is linked with an elevated risk for developing schizophrenia. Neurological soft signs (NSS) are frequently found in psychiatric disorders of significant neurodevelopmental origin, e.g. in patients with schizophrenia, borderline and autism. Previous neuroimaging studies in patients with schizophrenia have shown that NSS are associated with abnormal cortical and subcortical structure and function. Yet, it still remains unclear whether these findings are associated with neuropathological processes underlying the disease or if they are confounded by antipsychotic treatment. Some of these issues could be addressed in individuals at clinical ultra-high risk (UHR) for developing psychosis or healthy individuals. Given that NSS are present in schizophrenia patients, UHR individuals and healthy individuals, they might suggest a neurodevelopmental signature of CCTCC dysfunction, probably as a continuum between health and disease. This project will test several important and innovative hypotheses while focusing on three study samples. So far, there has been no previous research combining this diverse set of novel neuroimaging methods with advanced data analysis techniques in the context of NSS. This project will add significantly to the previous evidence in this area by focusing on contributions of structural and functional connectivity (e.g. alterations of white matter tracts and aberrant neural activity in the CCTCC) to NSS expression in three study groups. Furthermore, we seek to combine dMRI and fMRI to examine whether regions with altered patterns of white matter connectivity correspond to areas of aberrant functional connectivity. This approach will provide substantial information on a motor phenotype within the schizophrenia spectrum in terms of behaviour, brain structure and brain function. To conclude, following a dimensional and multimodal approach we argue that there are distinct structural and functional correlates of NSS that, if precisely defined in terms of their clinical associations, have potential for use early in the stratification of patients presenting with psychotic disorders. Finally, we expect that the results from this project will provide an important data-based framework for future longitudinal studies on NSS within the schizophrenia spectrum and beyond.

• DFG Programme: Research Grants