1. MRC Challenge Grant Defining the disturbance in cortical glutamate and GABA function in psychosis, its origins and consequences A Collaboration between Manchester, Nottingham and Cardiff Universities using Advanced Neuroimaging

2. Outline of Programme Aims Through an experimental study in human volunteers and subjects with schizophrenia: – Understand the role of glutamate and GABA neurotransmission in Scz: 1 H and 13 C MRS; – Relate this to neuro-inflammation and reactive oxygen: TSPO-PET, 1 H MRS of glutathione; – Relate disturbances in neurotransmitters to perturbation of long range network oscillations in Scz: MEG;

3. Priorities Problem – Identify need – Show its importance – Show how the plan will address this need Novelty / Risk – At the core of the proposal should be a new approach Collaborators

4. The Proposal Clear statement of purpose upfront with the benefits Enough background to demonstrate importance of the problem and our understanding of it, not just to show off our erudition and knowledge Inclusion of highly relevant preliminary data with figures Very clear experimental plan (with tables) with outcomes identified for each stage

5. The Process A lot of work went into the outline Extensive discussions with co-applicants in all 3 centres Attempted realistic estimates of costs Designed the full study, including subject numbers and groups at each of the centres Effectively, we wrote the Outline like a full application, but without sign off of costs – Included preliminary data – Emphasized the importance of all 3 centres and how their expertize was complementary

6. From Outline to Full Application Relatively limited criticism, but important points raised: – Feasibility and evidence for measuring glutamate and glutamine separately by MRS – Clearer hypothesis and better linkage between Glut/GABA and network oscillations – Unclear whether a treatment is to be proposed based on the outcomes of the study Panel recognized the application as important Complemented the strength of the team Discussion with the MRC Exp Med contact was very helpful in interpreting the Panel’s comments

7. Full Application The leads at each centre were fully engaged in working up the full application – Regular T/Cs – Drafts circulated by e-mail Research Admin involved throughout application drafting to ensure good costing models We dropped one set of experiments (on animals) from the Outline, otherwise the experiments remained the same

8. Response to Referees Referees liked: – Innovation (4/5) – High impact (5/5) – Scientific case / team / environment (5/5) Concerns about – Sensitivity of 13C and specificity of 1H – Validation across centres – Effect sizes and power

9. Applicant’s Story