Medial frontal GABA is lower in older schizophrenia: a MEGA-PRESS with macromolecule suppression study

Abstract

Gamma-butyric acid (GABA) dysfunction has been implicated in the pathophysiology of schizophrenia and its cognitive deficits. Proton magnetic resonance spectroscopy (MRS) was used to test the hypothesis that older participants with schizophrenia have lower anterior cingulate GABA levels compared to older control participants. One-hundred and forty-five participants completed this study. For detection of GABA, spectra were acquired from the medial frontal/anterior cingulate cortex using a macromolecule-suppressed MEGA-PRESS sequence. Patients were evaluated for psychopathology and all participants completed neuropsychological tests of working memory, processing speed, and functional capacity. GABA levels were significantly lower in the older participants with schizophrenia(n=31) compared to the older control(n=37) group (p=0.003) but not between the younger control(n=40) and schizophrenia (n=29) groups (p=0.994). Age strongly predicted GABA levels in the schizophrenia group accounting for 42% of the variance, but the effect of age was less in the control group accounting for 5.7% of the variance. GABA levels were specifically related to working memory but not processing speed performance, functional capacity, or positive or negative symptom severity. This is the largest MRS study of GABA in schizophrenia and the first to examine GABA without macromolecule contamination, a potentially significant issue in previous studies. GABA levels more rapidly declined with advancing age in the schizophrenia compared to the control group. Interventions targeted at halting the decline or increasing GABA levels may improve functional outcomes and quality of life as patients with schizophrenia age.

Prefrontal GABA Levels Measured With Magnetic Resonance Spectroscopy in Patients With Psychosis and Unaffected Siblings

“…While some studies (10)(11)(12) found no differences in patients with schizophrenia compared with healthy controls, others found reduced levels in the occipital (13,14) and prefrontal (15) cortices (including the dorsal anterior cingulate cortex in patients over 35 years of age [16]) and in the basal ganglia (17). In contrast, our preliminary data in a small group of patients who do not overlap with the ones presented here (18) showed elevated GABA levels in the dorsal anterior cingulate in treated patients with psychosis compared with healthy controls.…”

“…Our overall on-off medication results are consistent with those of Kelemen et al (14), who also saw no change in GABA levels after instituting antipsychotic treatment for 2 months, but power to show change was limited in this small group. Similarly, Kegeles et al (19) found no difference when they compared unmedicated to medicated patients or controls in the dorsolateral prefrontal cortex (11,16). The animal literature shows either no change (30)(31)(32)(33) or increases in GABA levels in selected areas (32)(33)(34)(35)(36) or in GAD 67 expression in the cortex (37,38) for exposures to antipsychotics ranging from 21 days to 6 months (37,38).…”

Big GABA: Edited MR spectroscopy at 24 research sites

“…MRS measurements of GABA have been associated with individual differences in hemodynamic and electrophysiological signals (Donahue et al, 2010; Hu et al, 2013; Kapogiannis et al, 2013; Muthukumaraswamy et al, 2009) and a number of measures of cognition (Fujihara et al, 2015; Shibata et al, 2017; Yoon et al, 2016) and behavior (Boy et al, 2011; Greenhouse et al, 2017; Puts et al, 2011; Silveri et al, 2013). Differential levels of GABA have been observed in a number of neuropsychiatric disorders, such as schizophrenia (Kegeles et al, 2012; Öngür et al, 2010; Rowland et al, 2016; Yoon et al, 2010) and depression (Bhagwagar et al, 2008; Hasler et al, 2007; Price et al, 2009), neurodevelopmental disorders such as autism spectrum disorder (Drenthen et al, 2016; Gaetz et al, 2014; Puts et al, 2016) and attention deficit hyperactivity disorder (Bollmann et al, 2015; Edden et al, 2012a), and neurological diseases, such as Parkinson’s disease (Emir et al, 2012), amyotrophic lateral sclerosis (Foerster et al, 2012; Foerster et al, 2013) and diabetic neuropathy (Petrou et al, 2012). …”

Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia

“…γ-Aminobutyric acid levels were assessed using an improved macromolecule suppression MRS technique. 33 Glutamate levels, including the ratio of glutamine to glutamate, were assessed with an MRS technique optimized for the detection of these metabolites. 34-36 The ratio of glutamine to glutamate is thought to reflect glutamatergic neurotransmission whereby the ratio of conversion from glutamine to glutamate may index glutamatergic function.…”