Abstract
Third-generation neuroimaging research has been enriched by advances in magnetic resonance spectroscopy (MRS) measuring the concentration of important neurotrasmitters, such as the inhibitory amino acid GABA. Here, we performed a systematic mini-review on brain MRS studies measuring GABA concentration in patients affected by schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We wondered whether multimodal investigations could overcome intrinsic technical limits of MRS giving a broader view of mental disorders pathogenesis. In SZ, unimodal studies gave mixed results, as increased, decreased, or unaltered GABA levels were reported depending on region, disease phase, and treatment. Conversely, multimodal results showed reduced level of glutamate, but not of GABA, in patients mirrored by in vitro biochemical findings revealing hippocampal reduction in glutamate signaling in SZ, and no deficits in GABA synthesis. Moreover, a mouse model confirmed the unique pathological characteristic of glutamate function in SZ. Unimodal studies in BD revealed again, inconsistent results, while no multimodal investigations including MRS on GABA exist. In MDD, unimodal studies could not differentiate patients from controls nor characterize high-risk subjects and remitted patients. However, a multimodal study combining functional magnetic resonance imaging and MRS revealed that cingulate cortex activity is related to glutamate, N-acetylaspartate levels and anhedonia in patients, and to GABA concentration in healthy subjects, improving the distinction between MDD and physiology. Overall, our results show that unimodal studies do not indicate GABA as a biomarker for the psychiatric disorders considered. Conversely, multimodal studies can widen the understanding of the link between psychopathology, genetics, neuroanatomy, and functional–biochemical brain activity in mental disorders. Although scarce, multimodal approaches seem promising for moving from GABA MRS unimodal-descriptive to causal level, and for integrating GABA results into a more comprehensive interpretation of mental disorder pathophysiology.
Highlights
An imbalance between excitation and inhibition in brain neuronal transmission has been hypothesized as one of the molecular mechanisms responsible for psychiatric disorders (1–5)
Inclusion criteria for studies selection were (1) English language, (2) articles published in peer-reviewed journals after 2000, (3) original research article, (4a) inclusion of patients diagnosed with the specific neuropsychiatric disorder of interest according to ICD or DSM criteria or (4b) inclusion of high risk (HR) subjects, (5) inclusion of at least 10 patients, (6) comparison between patients and healthy controls (HC), (7) performance of magnetic resonance spectroscopy (MRS) using a magnetic field of at least 3 T
We reviewed the body of evidence on gamma-aminobutyric acid (GABA) concentration, as measured by MRS in localized brain regions of SZ, bipolar disorder (BD), and major depressive disorder (MDD) patients, highlighting results obtained by multimodal methods and multiple experimental techniques
Summary
An imbalance between excitation and inhibition in brain neuronal transmission has been hypothesized as one of the molecular mechanisms responsible for psychiatric disorders (1–5). In this context, multimodal studies coupling the continuous technical progresses in neuroimaging to methods for measuring neurotramsitter concentrations may represent a turning point for in vivo evidence of postmortem (6–8) and animal model (9–12) results. Theories on its dysfunction in schizophrenia (SZ) assume that alterations in the neural circuitry involving GABA have a role in the mechanisms of the disorder and associated cognitive deficits (19–21). The role of GABA dysfunction in different psychiatric disorders such as bipolar disorder (BD), or major depressive disorder (MDD) is established (3, 22, 23)
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