This study is the first to show a relationship between in-vivo brain gamma-amino butyric acid (GABA) levels and auditory inhibitory electrophysiological measures in schizophrenia. Results revealed a strong association between GABA levels and gating of the theta-alpha and beta activities in schizophrenia.
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"Interestingly, these findings of impaired MNA and its association with negative symptoms and social cognition deficits, aligns equitably with the aberrant frontoparietal networks underlying socio-emotional functioning described in patients with deficit schizophrenia (Rowland et al., 2013). Impairments in this frontoparietal network in deficit schizophrenia have been described using regional cerebral blood flow studies (Lahti et al., 2001), neuropathological studies in postmortem brains (Kirkpatrick et al., 1999, 2003) and diffusion tensor imaging studies of white-matter tract (superior and inferior longitudinal fasciculi) abnormalities (Voineskos et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: Dysfunctional mirror neuron activity (MNA) has been posited to underlie diverse symptoms of schizophrenia (e.g., ego-boundary disturbances, negative symptoms, social cognition impairments and catatonic symptoms). In this paper, we systematically review studies that have empirically compared putative MNA in schizophrenia patients and healthy subjects using different neurophysiological probes. Majority of the studies (n = 9) reported reduced MNA in patients. Two each reported either increased MNA or mixed (both increased and decreased) results, while only one study reported normal findings. Reduced MNA was associated with greater negative symptoms and theory of mind deficits. The neurophysiological technique, task paradigms used, specific brain regions studied and laterality did not influence these findings. Further, we propose an overarching model to understand the heterogeneous symptom dimensions of schizophrenia, in which an inherent mirror system deficit underlying persistent negative symptoms, social cognition impairments and self-monitoring deficits triggers a pathological metaplastic reorganization of this system resulting in aberrant excessive MNA and the phasic catatonic symptoms, affective instability and hallucinations. Despite being preliminary in nature, evidence of abnormal MNA in schizophrenia reported necessitates more detailed investigation. Future research directions of using this model within the Research Domain Criteria framework of the National Institute of Mental Health are discussed.
Full-text · Article · Nov 2014 · Schizophrenia Research
"The AIS is innervated by a specialized subtype of GABAergic interneuron, the chandelier cell, which is thought to be one of the interneuron types that are dysfunctional in the SCZ cerebral cortex as evidenced by molecular alterations both on the pre-and postsynaptic site of the AIS (Woo et al., 1998; Pierri et al., 1999; Volk et al., 2002). Importantly, these postmortem studies, together with related work in preclinical model systems, paved the way for clinical trials and novel treatment approaches aimed at alleviating GABAergic deficits at the AIS and other key nodes of the cortical inhibitory system (Lewis et al., 2008; Geffen et al., 2012; Radhu et al., 2012; Stan and Lewis, 2012; Lett et al., 2014; Rowland et al., 2013; Rudolph and Mohler, 2014). For example to test the concept that reduced GABA signaling from chandelier cells to pyramidal neurons contributes to working memory dysfunction via parvalbumin-positive GABA neurons, a benzodiazepine-like compound, MK-0777, a selective agonist of GABA A α-2 and α-3 subunits, was tested in clinical trials. "
[Show abstract][Hide abstract] ABSTRACT: Expression of GAD1 GABA synthesis enzyme is highly regulated by neuronal activity and reaches mature levels in the prefrontal cortex not before adolescence. A significant portion of cases diagnosed with schizophrenia show deficits in GAD1 RNA and protein levels in multiple areas of adult cerebral cortex, possibly reflecting molecular or cellular defects in subtypes of GABAergic interneurons essential for network synchronization and cognition. Here, we review 20 years of progress towards a better understanding of disease-related regulation of GAD1 gene expression. For example, deficits in cortical GAD1 RNA in some cases of schizophrenia are associated with changes in the epigenetic architecture of the promoter, affecting DNA methylation patterns and nucleosomal histone modifications. These localized chromatin defects at the 5′ end of GAD1 are superimposed by disordered locus-specific chromosomal conformations, including weakening of long-range promoter-enhancer loopings and physical disconnection of GAD1 core promoter sequences from cis-regulatory elements positioned 50 kilobases further upstream. Studies on the 3-dimensional architecture of the GAD1 locus in neurons, including developmentally regulated higher order chromatin compromised by the disease process, together with exploration of locus-specific epigenetic interventions in animal models, could pave the way for future treatments of psychosis and schizophrenia.
Full-text · Article · Oct 2014 · Schizophrenia Research
"Similarly, GABA function has been connected to cognitive performance through a clinical trial ( Lewis et al., 2008 ) and an MRS study ( Yoon et al., 2010 ). Although in-vivo GABA levels of patients with schizophrenia have been showed to associate with oscillatory measures of paired-click paradigm ( Rowland et al., 2013 a), no studies relating GABA levels to gamma oscillations during a working memory task, or comparing all three domains within the same participants, have been performed in schizophrenia. These comparisons are the subject of the current study: We hypothesize that there are relationships across working memory performance, gamma neural oscillations, and DLPFC GABA levels that indicate a key role for GABA in subserving cognitive functions. "
[Show abstract][Hide abstract] ABSTRACT: A relationship between working memory impairment, disordered neuronal oscillations, and abnormal prefrontal GABA function has been hypothesized in schizophrenia; however, in vivo GABA measurements and gamma band neural synchrony have not yet been compared in schizophrenia. This case-control pilot study (N = 24) compared baseline and working memory task-induced neuronal oscillations acquired with high-density electroencephalograms (EEGs) to GABA levels measured in vivo with magnetic resonance spectroscopy. Working memory performance, baseline GABA level in the left dorsolateral prefrontal cortex (DLPFC), and measures of gamma oscillations from EEGs at baseline and during a working memory task were obtained. A major limitation of this study is a relatively small sample size for several analyses due to the integration of diverse methodologies and participant compliance. Working memory performance was significantly lower for patients than for controls. During the working memory task, patients (n = 7) had significantly lower amplitudes in gamma oscillations than controls (n = 9). However, both at rest and across working memory stages, there were significant correlations between gamma oscillation amplitude and left DLPFC GABA level. Peak gamma frequency during the encoding stage of the working memory task (n = 16) significantly correlated with GABA level and working memory performance. Despite gamma band amplitude deficits in patients across working memory stages, both baseline and working memory-induced gamma oscillations showed strong dependence on baseline GABA levels in patients and controls. These findings suggest a critical role for GABA function in gamma band oscillations, even under conditions of system and cognitive impairments as seen in schizophrenia.
Full-text · Article · Mar 2014 · Clinical neuroimaging