Project

Discipline

tractography; resting state fMRI; structural connectivity; at risk mental state; diffusion MRI; functional connectivity; staging; biomarker; networks; first episode psychosis; schizophrenia; imaging; connectome

Lead
The progression of schizophrenia is studied with MR connectomics with the aim of improving our understanding of the disease mechanisms and eventually identify biomarkers disease severity and progression.
Lay summary
La schizophrénie est une maladie caractérisée par des modifications biochimiques, fonctionnelles et structurelles du cerveau. Des altérations régionales on été démontrées par IRM de multiples fois que ce soit pour la schizophrénie chronique ou dans les phases précoces de la maladie. Le concept de stade est fréquemment utilisé en médecine et a été récemment introduit dans le domaine de la psychiatrie. Pour la schizophrénie cette manière de caracterisér la maladie gagne en acceptance car les découvertes neurobiologiques suggère une tell progression et qu’il est de plus en plus reconnu que une intervention précoce minimize le risque de développer une maladie sévèrement handicapante.  L’objectif général de ce projet est de caractériser le syndrome de déconnection le long du développement de la schizophrénie avec la Connectomique par IRM. Ce projet s’inscrit dans la continuité des nos subsides précédents (#320030_130090 imagerie de la psychose) et du pôle de recherche lausannois sur la schizophrénie (#320030-122419, NCCR-synapsy #125759). Sur la base de notre expertise multidisciplinaire nous espérons pouvoir produire des investigation révélant de nouvelles information sur la pathophysiologie de la progression de la schizophrénie en reliant le syndrome de déconnection avec l’avancement de la maladie et le pronostic. De plus nous espérons pouvoir identifier des biomarqueurs de progression et de sévérité de la maladie et ainsi avoir un réel impact sur la prise en charge des patients.

Direct link to Lay Summary

Last update: 13.02.2015

Natural persons

Number	Title	Start	Funding scheme

1. SUMMARY1.1 BACKGROUNDSchizophrenia is a disease of widespread biochemical, functional and structural brain alterations that leads to positive and negative symptoms, cognitive impairment and to important alterations of global functional level. Regional structural and functional changes have been repeatedly reported from MRI studies in psychotic disorders, in chronic schizophrenia and more recently also in the early phase of psychosis and even in the presymptomatic stage in at risk subjects. A promising step ahead has been taken in the approach to investigate the schizophrenia dysconnectivity syndrome with the emergence of MR connectomics, field in which the applicants have been pioneers. Cumulating evidence suggests some degree of global disconnectivity with decreased integration capacity in chronic schizophrenia. Previous research from our group supports this theory and contributed to better define which areas of the brain are involved in this phenomenon. However neither the evolution of this dysconnectivity syndrome over the development of psychosis, from at risk mental state to full-blown chronic schizophrenia nor the imaging biomarkers of stage transition have been studied. MR connectomics has until now been relying on semi-quantitative measures of structural connectivity, like the number of streamlines connecting 2 areas or the average diffusivity along a connection. This matter of fact limits our capacity to infer pathophysiology and potentially limits our sensitivity to the disease since our measures are based on a mixture of several biological compartments and phenomena. Long-standing efforts have been made in order to create a plausible biophysical model of water diffusion in the brain. Limitation factors are multiple from hardware to computational cost and limitation to local voxel-wise modelling. Nevertheless once these limitations have been overcome the perspective of measuring quantitatively the human connectome with MRI may become reality providing us with quantitative measures of biological parameters relevant to brain connectivity. Work in this field is on going and our group is at the forefront of these developments. The concept of staging is common in many fields of medicine but has only recently been applied to psychiatric disorders. For schizophrenia the staging concept is gaining acceptance as prodromal phases of psychosis become better characterized, as neurobiologic discoveries, including, imaging, support the progressiveness of the disease and as the awareness that early intervention is the most promising therapeutic approach to avoid or to minimize the risk of developing a debilitating disease. In this framework the ability to identify network alterations that progress with the disease severity is important for staging theory. Even more the stratification of patients in a given stage into progressors and non-progressors is a key challenge since it may help focussing intensive therapy to patients at high risk to progress. 1.2 AIM OF THE PROJECTThe general aim of the project is to characterize quantitatively the structural disconnection syndrome of schizophrenia as a function of disease progression. Identify connectomic biomarkers of disease progression. Specific aims are:•Express the already identified chronic schizophrenia (CSCHZ) structural dysconnectivity pattern with quantitative connectomics measures to increase sensitivity and gain specificity in disease mechanism.•Quantify the above-mentioned biomarkers (dysconnectivity pattern) in first episode of psychosis (FEP, stage II) and in at risk mental state subjects (ARMS, stage I).•Identify additional dysconnectivity patterns specific to individual stages.•Compare FEP patients with and without progression to chronic schizophrenia at 2 and 5 years from imaging time point to explore their connectivity differences and develop a stratification biomarker distinguishing progressors from non-progressors.•Compare ARMS individuals with and without progression to a FEP at 2 years of imaging to explore their connectivity differences and develop a stratification biomarker distinguishing progressors from non-progressors.•Study the relation between the integrity of specific cognitive networks and patients executive function and symptomatology scores1.3 METHODSCohort:•Control subjects (CTRL) : 100 (already 74 scanned)•At risk mental state subjects (ARMS), stage I: 60 (recruitment not started)•First episode of psychosis patients (FEP), stage II: 70 (already 51 scanned)•Chronic schizophrenia patients (CSCHZ), stage III and IV: 40 (already 25 scanned)Investigations:•Clinical and neuropsychological battery, long term follow up•MRI: T1w high resolution, Diffusion Spectrum Imaging, resting state fMRIAnalysis:•MRI: network measures of global and local integration and segregation of structural networks used to test hypothesis mentioned in 1.2.1.4 EXPECTED VALUE OF THE PROPOSED PROJECTThis project proposal is in full continuation with our previous grant #320030_130090 dedicated to the imaging of psychosis and integrates itself to the broad Lausanne effort on schizophrenia research (grant 320030-122419, NCCR-synapsy #125759). We want to build on i. our previous patient recruitment and expand our cohort in terms of sample number but also in terms of disease stage by recruiting presymptomatic subjects; ii. our previous analysis experience on the later stage of psychosis to explore the not well characterized early stages of psychosis; iii. our tractography technology development experience to bring the latest quantitative biophysically realistic methods to clinical research.Based on this multidisciplinary expertise we expect to provide the research community with impactful investigations revealing new insight in the pathophysiology of progression of psychosis linking brain dys-connectivity with disease advancement and finally clinical outcome. Even more we hope to be able identify stratification biomarkers of disease progression, which would have a significant impact on care.