Periodic Reporting for period 2 - DisConn (Neural drivers of functional disconnectivity in brain disorders) Reporting period: 2020-08-01 to 2022-01-31 Summary of the context and overall objectives of the project DISCONN aims to unravel the neural basis functional dysconnectivity in brain disorders via the combination of fMRI, electrophysiology and perturbational approaches in rodents. These activities have been designed to advance our understanding of the origin and significance of brain connectopathy in several prominent brain disorders, such as such as autism or schizophrenia. We expect that the fulfilment of our research will have far reaching implications for neurophysiological interpretation of brain imaging in brain disorders, potentially improving diagnosis and stratification of patient populations, and shedding light onto the significance of brain dysconnectivity in psychiatric and brain disorders. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Most of the experimental activities we carried out during these first 18 months have been devoted to the development of the experimental platform upon which our experimental research will be carried out. We have also initiated important computational activities that will set the scene for a unified interpretational framework of our findings. From a purely experimental standpoint, we have made great progress in defining robust methods to map functional connectivity networks in the awake mouse brain, documenting the possibility of reliably mapping this phenomenon using a simple, yet robust acclimation protocol. We have also begun to assess the effect of network-level and cell-type specific manipulations of brain activity via optogenetics and chemogenetics. The resulting fMRI maps and electrophysiological recordings have revealed that silencing of cortical region results in paradoxical over-connectivity (manuscript submitted). This finding advances our understanding of the basis of neural coupling, challenging prevailing interpretations of functional and structural connectivity as being characterized by a dyadic relationship.From a computational standpoint, we were able to produce a voxel-wise description of the mouse connectome which will be very important in probing the directional hierarchy of the functional connectome. Notably, this activity was accompanied by the development of a novel framework allowing directional inferences in rsfMRI connectivity, based on the use of transfer entropy measures. The resulting platform will allow us to probe and understand the role of directional silencing on the functional hierarchy of the mouse brain as per our action plan.Most outreach activities related to this project have been carried out via my personal twitter handle (https://twitter.com/Gozzi_Ale). This choice was made to increase impact and breadth of dissemination with respect to canonical websites, which may have little or no engagement from external stakeholders and the general public. To more explicitly assess the impact of ERC funding to my research, I have added a mention to the ERC grant (and its acronym) in the description of my profile. All publications I have generated as part of this project have also been disseminated with reference to ERC funding. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Our research has already generated findings of great importance that push the boundaries of this field of research. For one, our observation that cortical silencing may lead to fMRI over-connectivity (Canella et al. submitted) has far reaching implications for the interpretation and back engineering of human neuroimaging findings in connectivity disorders. Other work carried out within the framework of the project has advanced our understanding of the neural drivers of brain-wide coupling, including the observation that recurring oscillating fMRI coactivation states govern rsfMRI dynamics, and the back translation of excitatory inhibitory imbalance into rsfMRI signature relevant from autism. We expect that the body of further research we will carry out in the reminder of our project to further integrate these investigation with crucial insight into the role of critical developmental periods and synaptic changes as sculptors of brain-wide coupling.
