Neurofunctional Correlates of Excitation/Inhibition Imbalance Across the Psychosis Spectrum

Glutamatergic and GABAergic dysfunction, and the resulting excitation/inhibition (E/I) imbalance, is implicated in the pathophysiology of schizophrenia and psychotic disorders more broadly(De Rosa et al., 2022; Howes et al., 2024; Howes & Shatalina, 2022; Knight et al., 2022; Modinos et al., 2015). In healthy volunteers, multimodal 1H-MRS-fMRI studies have shown a negative association between GABA levels and local brain activation (e.g. in the occipital cortex and anterior cingulate cortex, ACC), and a positive association between glutamate levels and activation in distal regions (Egerton et al., 2017; Kiemes et al., 2021; Merritt et al., 2016). The 2023 systematic review by Zahid, Onwordi, Hedges, Wall, Modinos, Murray and Egerton evaluated whether these relationships between neurometabolite levels and fMRI-measured brain activity (both resting-state and task-related) are disrupted in psychosis, identifying 17 multimodal case-control studies (594 patients, 538 healthy volunteers) that combined in vivo 1H-MRS with fMRI in the same participants. Since the original search, additional studies combining 1H-MRS and fMRI (resting-state and task-based) have been published, both within the schizophrenia-spectrum/psychosis population originally studied and, more broadly, across other diagnostic categories characterised by glutamatergic/GABAergic dysfunction (e.g. clinical high risk for psychosis, first-episode psychosis, schizoaffective disorder, bipolar disorder with psychotic features, substance-induced psychosis). An updated and extended review is therefore warranted to (a) capture newly published multimodal evidence within the original psychosis-focused scope, and (b) evaluate whether the same E/I-neurofunctional relationships generalise across a broader transdiagnostic psychosis spectrum.