Abstract
GABAergic and glutamatergic dysfunction in the dorsolateral prefrontal cortex (DLPFC) are thought to be the core pathophysiological mechanisms of schizophrenia. Recently, we have established a method to index these functions from the DLPFC using the paired transcranial magnetic stimulation (TMS) paradigms of short interval intracortical inhibition (SICI) and facilitation (ICF) combined with electroencephalography (EEG). In this study, we aimed to evaluate neurophysiological indicators related to GABAA and glutamate receptor-mediated functions respectively from the DLPFC in patients with schizophrenia using these paradigms, compared to healthy controls. Given that these activities contribute to cognitive functions, the relationship between the TMS-evoked potential (TEP) modulations by SICI/ICF and cognitive/clinical measures were explored. Compared to controls, patients showed reduced inhibition in P60 (t22 = −4.961, p < 0.0001) by SICI and reduced facilitation in P60 (t22 = 5.174, p < 0.0001) and N100 (t22 = 3.273, p = 0.003) by ICF. In patients, the modulation of P60 by SICI was correlated with the longest span of the Letter-Number Span Test (r = −0.775, p = 0.003), while the modulation of N100 by ICF was correlated with the total score of the Positive and Negative. Syndrome Scale (r = 0.817, p = 0.002). These findings may represent the pathophysiology, which may be associated with prefrontal GABAA and glutamatergic dysfunctions, in the expression of symptoms of schizophrenia.
Highlights
Schizophrenia is a chronic and devastating mental disorder, which is a leading cause of years of life lost to disability[1]
The present study demonstrated modulatory effects of Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) paradigms on TMS-evoked potential (TEP) components from the dorsolateral prefrontal cortex (DLPFC) in patients with schizophrenia compared to healthy controls
In patients with schizophrenia, the degree of the modulatory effect on P60 by SICI was significantly correlated with working memory performance as assessed by longest span of the Letter-Number Span Test and the extent of modulation on N100 by ICF was significantly correlated with the severity of the symptoms of schizophrenia as evaluated with the total score of the Positive and Negative Symptom Scale (PANSS)
Summary
Schizophrenia is a chronic and devastating mental disorder, which is a leading cause of years of life lost to disability[1]. A reduction of SICI in motor cortex, which is thought to be associated with GABAA receptor-mediated inhibition, has been a replicated finding[5]. Intracortical facilitation (ICF) in motor cortex appears to be unaltered in patients with schizophrenia[16,17], despite genetic and pharmacological studies suggesting potential deficits of glutamate-mediated excitatory neurotransmission through the N-methyl-D-aspartic acid (NMDA) receptor in schizophrenia[18]. Postmortem studies have demonstrated decreased transcription levels and enzyme activity for glutamate carboxy peptidase in the dorsolateral prefrontal cortex (DLPFC) in patients with schizophrenia, which in turn results in reduced NMDA receptor-mediated signaling[19]. It can be possible to more directly investigate the relationship between working memory performance and neurophysiological property associated with GABAA receptor-mediated function in the DLPFC described below, which has not been determined yet
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