GABA System in Schizophrenia and Mood Disorders: A Mini Review on Third-Generation Imaging Studies

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.

Transition of Neural Activity From the Chaotic Bipolar-Disorder State to the Periodic Healthy State Using External Feedback Signals

“…Mood disorders, including major depressive disorder, mania, and bipolar disorder (BD), exhibit high morbidity, high suicide rates, and multiple relapses during long-term treatment; effective treatments and diagnostic methods are long-standing unmet needs (reviewed in Drevets, 2000 ; Kessler et al, 2003 ; The Wellcome Trust Case Control Consortium, 2007 ; Price and Drevets, 2010 ). Accumulating neuroimaging evidence reveals the multiple and complex pathologies of mood disorders (reviewed in Baskaran et al, 2012 ; Vargas et al, 2013 ; Chiapponi et al, 2016 ; Arnone, 2019 ). Particularly, functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) have revealed region-specific enhancements and depressions in neural activity in regions such as the amygdala, hippocampus, and prefrontal cortex associated with major depressive disorder (reviewed in Baskaran et al, 2012 ; Arnone, 2019 ) and BD (Vargas et al, 2013 ).…”

In SilicoModel-driven Assessment of the Effects of Brain-derived Neurotrophic Factor Deficiency on Glutamate and Gamma-Aminobutyric Acid: Implications for Understanding Schizophrenia Pathophysiology

“…Further, these abnormalities in BDNF have shown associations with various clinical features15,21,22) of schizophrenia as well as antipsychotic treatment 23). Aberration in BDNF signaling pathways directly or circuitously influences neurotransmitters like glutamate and GABA, both of which are well understood to be altered in schizophrenia 24–26). These evidences suggest a central role for BDNF and its effector pathways in schizophrenia pathogenesis.…”

Multiscale dynamic mean field model to relate resting-state brain dynamics with local cortical excitatory-inhibitory neurotransmitter homeostasis in health and disease

“…Our group had already shown the importance of E−I balance in view of functional recovery, e.g., establishment of homeostasis over a re-organized brain network following a lesion in specific brain site (Vattikonda et al, 2016). As imbalance of inhibition and excitation is the key neuronal mechanism involved in neurological disorders (Chiapponi et al, 2016), the study on glutamate−GABA balance would play a key role in exploring mechanistic insights of neurological diseases and its deviation from normal brain function.…”