60.4 Multimodal Evidence of GABAergic Circuit Dysfunction in People at Clinical High Risk of Psychosis

Background: Preclinical and neuropathological research in psychosis suggest that prefrontal and hippocampal GABAergic deficits in fast-spiking, parvalbumin-positive interneurons play a central role in the development of the elevations in striatal dopamine function typically observed in psychosis. This multimodal study aimed to examine in vivo prefrontal GABAergic levels in antipsychotic naive subjects at clinical high risk for psychosis (CHR) and their association with hippocampal resting-state perfusion and severity of prodromal symptomatology. Methods: We assessed GABA concentrations at 3T in the dorsomedial prefrontal cortex (dmPFC) using magnetic resonance spectroscopy, and resting-state perfusion with arterial spin labeling (ASL), in 20 CHR subjects and 21 age-matched healthy males. All spectra were analyzed using LCModel, and ASL images were preprocessed with SPM. Between-group differences in dmPFC GABA concentrations were examined with a 2-sample t -test in SPSS. Within the CHR group, we investigated associations between resting-state perfusion and GABA levels using multiple regression in SPM. Correlations between GABA levels and severity of prodromal symptoms were examined within the CHR group using Pearson’s correlation in SPSS. Results: Individuals at CHR for psychosis showed an 11% reduction in dmPFC GABA levels compared with controls ( P = .032), together with decreased NAA (9%, P = .012) and GSH concentrations (16%, trend level P = .060). Within the CHR group, GABA levels were positively correlated with hippocampal resting-state perfusion ( P = .013 FWE). Finally, there was a significant negative correlation between GABA levels and severity of overall prodromal, negative and anxiety symptoms. Conclusion: Our study is the first to report that abnormal GABA levels in CHR individuals are associated with alterations in hippocampal perfusion. These changes support animal and postmortem findings suggesting that GABAergic circuit dysregulation reflects an increased vulnerability to psychosis and may predate the first episode of frank psychosis. These UHR subjects are currently being followed-up to assess whether altered GABA levels are related to clinical and functional outcomes.