schizophrenia; first episode psychosis; functional psychosis; early intervention; resting state fMRI; diffusion MRI; tractography; functional connectivity; structural connectivity; networks; biomarker; imaging; N-acetyl-cysteine; connectome; neuroprotection; gluthatione resting state fMRI
Váša František, Griffa Alessandra, Scariati Elisa, Schaer Marie, Urben Sébastien, Eliez Stephan, Hagmann Patric (2016), An affected core drives network integration deficits of the structural connectome in 22q11.2 deletion syndrome, in NeuroImage: Clinical
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Betzel Richard F., Avena-Koenigsberger Andrea, Goñi Joaquín, He Ye, de Reus Marcel A., Griffa Alessandra, Vértes Petra E., Mišic Bratislav, Thiran Jean-Philippe, Hagmann Patric, van den Heuvel Martijn, Zuo Xi-Nian, Bullmore Edward T., Sporns Olaf (2016), Generative models of the human connectome, in NeuroImage
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Griffa Alessandra, Baumann Philipp Sebastian, Ferrari Carina, Do Kim Quang, Conus Philippe, Thiran Jean-Philippe, Hagmann Patric (2015), Characterizing the connectome in schizophrenia with diffusion spectrum imagingTopology of the Schizophrenia Connectome, in Human Brain Mapping
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Mišić Bratislav, Betzel Richard F., Nematzadeh Azadeh, Goñi Joaquin, Griffa Alessandra, Hagmann Patric, Flammini Alessandro, Ahn Yong-Yeol, Sporns Olaf (2015), Cooperative and Competitive Spreading Dynamics on the Human Connectome, in Neuron
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1.1 BACKGROUNDRecent MRI techniques have been developed to study connectivity over the entire brain. Resting state functional MRI (fMRI) has been used to map functional connectivity whereas diffusion MRI allows the mapping of structural networks covering the entire brain. In combination with advanced network analysis tools, such techniques were able to characterize global connectivity patterns of the human brain, like the structural core, hubs and small-world topology and also revealed strong interdependence between functional and structural networks (1,2). Such tools are promising not only in the characterization of network topology in the normal subject but are also expected to shed light in diseases where widely distributed connection changes are expected to occur.Regional structural and functional changes have been repeatedly reported from MRI studies in psychotic disorders, in chronic schizophrenia (3,4) and more recently also in the early phase of psychosis (5-7). These modifications are likely related to changes in the local or long distance connectivity but results using dedicated network imaging technology applied to schizophrenia are very limited. Only few preliminary, though promising, results are available (8,9). The early phase of psychosis has become an important research topic in psychiatry for several reasons. (a) There is accumulating evidence that critical brain structural and functional modifications occur early in the disease process (5-7,10,11). (b) Studying patients in the early phase of psychosis is a good way to avoid confounds like chronic drug treatment and coping mechanisms. (c) Finally, early intervention might be the most efficient way to improve outcome (12,13) and therefore a better characterization of the early phase of the disease is essential.Our group has significantly contributed in showing that genetically mediated glutathione (GSH)/redox antioxidant dysregulation is a vulnerability factor contributing to the development of schizophrenia and that there is a related “high risk” GSH genetic profile (14). This redox dysregulation affects the metabolism of myelination and GABA intereurons spiking, which are both likely mechanisms contributing to the dys-connection syndrome observed in schizophrenia (15,16). Furthermore, supplementation of N-acetyl-cysteine (NAC), a GSH precursor, has been shown to moderately improve not only the clinical outcomes based on several clinical scores (17) but also improve mismatch negativity on Electro-EncephaloGraphy (EEG) (18). 1.2 AIM OF THE PROJECTThe global aim of this project is to (1) identify and characterize structural and functional network modifications occurring in the early phase of psychosis with (2) their time course and (3) assess their relation to genetic, psychopathological and neuropsychological scores. In addition to these three main goals, we will (a) see if differences in network topologies can be identified between psychosis subgroups, i.e. affective and non-affective psychosis; (b) in the setting of an ongoing clinical drug trial, we will try to quantify functional connectivity changes occurring with NAC supplementation. 1.3 METHODSThis imaging study is embedded in an ongoing clinical trial focusing on the GSH/redox dysregulation in early phase psychosis and treatment with NAC (FNS grant #320030-1224419). Currently the imaging protocol as well as the drug trial is approved by the local ethics committee and already 15 patients and 15 controls have been recruited of which 10 of each group have been scanned. To achieve these aims we will recruit 40 psychotic patients in the early phase, who will be scanned 3 times. A first study will be performed at 6 months after onset and stabilization therapy (date of enrollment into study), a second study will be performed at 1 year from onset, and a third scanning session will occur at year 2. In addition 40 age/sex matched healthy controls will be scanned once. The enrolled patients will be randomized for a 6 months treatment with NAC versus placebo supplementation.The MRI study will be performed on a high end 3T scanner with a last generation 32 channel head coil. The acquisition protocol will consist of a high resolution T1-weighted MPRAGE that will serve for segmentation and volumetric analysis, Diffusion Spectrum Imaging (DSI) for structural network mapping and resting state fMRI in order to map functional connectivity. In addition, magnetization transfer imaging will also be done. The latter is an exquisite marker for myelin and will be used to further characterize connection integrity. 1.4 EXPECTED VALUE OF THE PROPOSED PROJECTMany aspects of the disease mechanisms in schizophrenia are still unresolved. The effective structural and functional networks involvements, their temporal dynamics and relation to genetics and clinical scores are not clear. These questions are specifically addressed by studying the early phase of psychosis. The additional benefit of studying that phase of the disease is that if reliable imaging biomarkers are identified, they may pave the way to early diagnosis of schizophrenia and its differentiation from affective psychosis. In addition, we investigate whether functional connectivity mapping is a sensitive biomarker for treatment response to NAC. Beyond the specific contributions of this project to a better understanding of the disease, our conclusions will likely modify significantly our way to consider imaging in neuro-psychiatric diseases by emphasizing the importance of considering the brain as a network. If we succeed in this endeavor we will not only impact diagnostics and treatment of schizophrenia but also pave the way for new similar approaches to other neuro-psychiatric diseases.1.5 KEYWORDSSchizophrenia, first episode psychosis, functional psychosis, early intervention, neuroprotection, gluthatione, resting state fMRI, diffusion MRI, tractography, functional connectivity, structural connectivity, networks, biomarker, N-acetyl-cysteine.