Cortical GABA in Subjects at Ultra-High Risk of Psychosis: Relationship to Negative Prodromal Symptoms

Abstract

BackgroundWhilst robust preclinical and postmortem evidence suggests that altered GABAergic function is central to the development of psychosis, little is known about whether it is altered in subjects at ultra-high risk of psychosis, or its relationship to prodromal symptoms.MethodsTwenty-one antipsychotic naïve ultra-high risk individuals and 20 healthy volunteers underwent proton magnetic resonance imaging at 3T. Gamma-aminobutyric acid levels were obtained from the medial prefrontal cortex using MEGA-PRESS and expressed as peak-area ratios relative to the synchronously acquired creatine signal. Gamma-aminobutyric acid levels were then related to severity of positive and negative symptoms as measured with the Community Assessment of At-Risk Mental States.ResultsWhilst we found no significant difference in gamma-aminobutyric acid levels between ultra-high risk subjects and healthy controls (P=.130), in ultra-high risk individuals, medial prefrontal cortex GABA levels were negatively correlated with the severity of negative symptoms (P=.013).ConclusionThese findings suggest that gamma-aminobutyric acidergic neurotransmission may be involved in the neurobiology of negative symptoms in the ultra-high risk state.

Baseline measures of cerebral glutamate and GABA levels in individuals at ultrahigh risk for psychosis: Implications for clinical outcome after 12 months

“…Furthermore, abnormal levels of glutamate (increased as well as decreased) have been found to be associated with the severity of attenuated psychotic symptoms [7,21,28], negative symptoms [29], and poor performance on neurocognitive tests of visuospatial attention [22] and working memory [21]. Similarly, lower levels of GABA have been associated with more severe negative symptoms [30]. We have previously-in the same cohort as investigated in this paper, comprising 122 UHR individuals and 60 healthy controls at baseline [31]-found negative correlations in the anterior cingulate cortex (ACC) in the UHR group between baseline Glx levels and CAARMS composite score and between GABA and alogia.…”

GABA levels and TSPO expression in people at clinical high risk for psychosis and healthy volunteers: a PET-MRS study

“…Second, there have been inconsistencies in the placement of 1 H-MRS voxels across GABA studies in schizophrenia, particularly in the mPFC. 8 We acknowledge that the failure of this study to detect group differences in GABA+ levels between people at CHR for psychosis and healthy volunteers may be due to the more dorsal placement of our 1 H-MRS voxel in the mPFC -consistent with Modinos and colleagues 21 -compared with a more ventral placement. 22 Third, in neurochemical brain-imaging studies, relatively small sample sizes represent a potential limitation; however, to our knowledge, this is the largest GABA 1 H-MRS study in people at CHR for psychosis.…”

“…A recent study using a smaller sample and a voxel that overlapped with ours (i.e., it was more dorsally placed in the mPFC) reported unaltered GABA levels in antipsychotic-naive people at CHR compared with healthy controls. 21 Of the 2 studies with the 1 H-MRS voxel more ventrally placed in the mPFC, 1 reported unaltered GABA levels, 20 but the other reported increased GABA levels 22 in people at CHR compared with healthy volunteers. This discrepancy could be attributable to methodological rigour, given that the MEGA-PRESS spectrum shown in the former study was of poorer quality (a very broad GABA resonance) 20 than the spectrum shown in the study that reported mPFC GABA elevations.…”

“…Wang and colleagues 20 reported unaltered GABA levels in the mPFC of antipsychotic-naive people at CHR (21 people at CHR and 23 healthy volunteers). Similarly, a recent 1 H-MRS study also failed to detect differences in GABA levels in the mPFC of antipsychotic-naive people at CHR (21 people at CHR and 20 healthy volunteers), 21 whereas another study reported increased GABA levels in the mPFC (23 people at CHR and 24 healthy volunteers). 22 Converging evidence from preclinical, genetic and peripheral studies have implicated immune-related abnormalities in the pathophysiology of schizophrenia.…”

Neurochemical effects of oxytocin in people at clinical high risk for psychosis

“…familial) high-risk groups, such as reduced N-acetylaspartate in the thalamus Tandon et al, 2013;Yoo et al, 2009), ACC (Capizzano et al, 2011;Jessen et al, 2006), and caudate (Keshavan et al, 2009)-although increases are also observed in the caudate (de la Fuente-Sandoval et al, 2011). Increased Glx has been reported in the thalamus and caudate, as well as increased (de la or decreased (Menschikov et al, 2016) medial prefrontal GABA-although differences are not always found (Modinos et al, 2018b;Wang et al, 2016). Finally, other studies have reported increased choline in the ACC (Tandon et al, 2013), prefrontal cortex (Wood et al, 2003) and hippocampus (Capizzano et al, 2011) in populations at risk for psychosis.…”