Project ID NS-MH2023_39


Co Supervisor 1A IoPPN/Psychosis StudiesWebsite

Co Supervisor 1B IoPPN/NeuroimagingWebsite

GABAergic mechanisms in people at clinical high risk for psychosis

Background: Abnormalities of the neurotransmitter system GABA are consistent findings in post-mortem and preclinical studies in psychosis. GABAergic abnormalities have been linked to not only psychotic symptoms but also cognitive deficits that are not treated effectively by current antipsychotics. However, linking these molecular deficits to in vivo observations in clinical populations – a critical goal to evaluate novel interventions that would target GABAergic abnormalities – has been a challenge. This project aims to address this issue through three interrelated aims:

Meta-analysis of studies combining pharmacologic exposure to GABAergic drugs with resting-state and task-based fMRI
Investigation of the acute effects of diazepam (a GABA-enhancing drug) on task-based (working memory) and resting-state fMRI in people at clinical high-risk for psychosis (CHR)
Application of a novel, multimodal analysis method informed by PET to characterise the brain’s pharmacodynamic response under diazepam (Receptor-Enriched Analysis of functional Connectivity by Targets – REACT).

The results may provide important proof-of-concept evidence to support the future development of novel interventions for psychosis.

Research methods/training: The data to be used for this independent project is being collected as part of a larger study, to be completed by early 2023. Training will be provided in the clinical and cognitive instruments used to characterise the CHR state, neuropsychopharmacology, statistical analysis (clinical, cognitive and neuroimaging data), and dissemination.

Project plan:
Year 1: Training, meta-analysis study, preliminary fMRI data analysis.
Year 2: fMRI data analysis, conference presentation, journal publications.
Years 3-3.5: Final data analysis, thesis write-up, conference presentation, journal publications.

One representative publication from each co-supervisor:

Lukow PB, Martins D, Veronese M, Vernon AC, McGuire P, Turkheimer FE, Modinos G. (2022). Cellular and molecular signatures of in vivo imaging measures of GABAergic neurotransmission in the human brain. Communications Biology; 5(1):372.

Dipasquale O, Selvaggi P, Veronese M, Gabay AS, Turkheimer F, Mehta MA. (2019). Receptor-Enriched Analysis of functional connectivity by targets (REACT): A novel, multimodal analytical approach informed by PET to study the pharmacodynamic response of the brain under MDMA. Neuroimage; 195:252-260.