Electrophysiological evidence for abnormal glutamate-GABA association following psychosis onset

Abstract

Previous studies have shown glutamatergic dysfunction and γ-aminobutyric acid (GABA)-ergic dysfunction in schizophrenia. Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) dysfunction and GABA-ergic dysfunction interact with each other and lead to alterations in excitatory/inhibitory balance. The NMDAR and GABAergic-interneuron functions may be indexed by mismatch negativity (MMN) and auditory steady-state gamma-band response (ASSR), respectively. However, no previous studies have tested the hypothesis of an abnormal association between MMN and gamma-band ASSR in the same patients to identify the in vivo evidence of NMDAR-GABA association during the early stages of psychosis. Participants were individuals with recent-onset schizophrenia (ROSZ; N = 21), ultra-high risk (UHR; N = 27), and healthy controls (HCs; N = 24). The MMN amplitude was significantly impaired in ROSZ (p = 0.001, d = 1.20) and UHR (p = 0.003, d = 1.01) compared with HCs. The intertrial phase coherence (ITC) index of gamma-band ASSR was significantly reduced in ROSZ compared with HCs (p < 0.001, d = –1.27) and UHR (p = 0.032, d = –0.75). The event-related spectral perturbation (ERSP) index of gamma-band ASSR was significantly smaller in ROSZ compared with HCs (p < 0.001, d = −1.21). The MMN amplitude was significantly correlated with the ITC in ROSZ (r = −0.69, p < 0.001). These findings provide the first in vivo evidence that an abnormal association of the electrophysiological indices of NMDAR and GABA dysfunctions may be present in recent-onset schizophrenia.

Unique contributions of sensory discrimination and gamma synchronization deficits to cognitive, clinical, and psychosocial functional impairments in schizophrenia

“…The MMN is a negative-going peak reflecting the differences between scalp-level ERP responses to deviant vs. standard stimuli measured across a 135-205-ms time window and thought to reflect an automatic deviance detection process. Several studies have reported large effect sizes for MMN differences between schizophrenia patients and controls using electroencephalography (EEG;Hermens et al, 2010;Javitt et al, 1995;Koshiyama et al, 2017Koshiyama et al, , 2018bKoshiyama et al, , 2018cLight and Braff, 2005;Rasser et al, 2011;Salisbury et al, 2017;Wynn et al, 2010) or magnetoencephalography (Braeutigam et al, 2018;Yamasue et al, 2004), and these findings have been confirmed by several meta-analyses (Erickson et al, 2016;Umbricht and Krljes, 2005); These impairments are among the most consistently replicated findings in schizophrenia research (Keshavan et al, 2008;Näätänen et al, 2019). Many studies have also identified important associations between MMN and cognition (Koshiyama et al, 2018c;Rissling et al, 2014;Toyomaki et al, 2008;Wynn et al, 2010), negative symptoms and functional outcomes (Koshiyama et al, 2018c;Light and Braff, 2005;Rissling et al, 2014) in schizophrenia patients.…”

“…Standard (p = 0.90, 50-ms duration) and Deviant (p = 0.10, 100ms duration) tones were presented in pseudorandom order with a minimum of 6 Standard stimuli presented between each Deviant stimulus. The MMN amplitude at the Fz was measured using the mean voltage from 135 to 205 ms post stimuli in accordance with previous studies (Koshiyama et al, 2017(Koshiyama et al, , 2018b(Koshiyama et al, , 2018c). During the MMN and ASSR sessions, participants watched a silent cartoon video.…”

“…The gamma-band ASSR is also a robust biomarker that is increasingly studied in neuropsychiatric disorders (Tada et al, 2019a;Uhlhaas and Singer, 2010). Previous studies have found selectively reduced power and synchronization in response to 40-Hz auditory stimulation in schizophrenia patients using EEG (Brenner et al, 2003;Hamm et al, 2015;Hirano et al, 2015;Kirihara et al, 2012;Koshiyama et al, 2018aKoshiyama et al, , 2018bKoshiyama et al, , 2019Kwon et al, 1999;Light et al, 2006;Spencer et al, 2008;Tada et al, 2016) and MEG (Edgar et al, 2014;Teale et al, 2008;Tsuchimoto et al, 2011;Vierling-Claassen et al, 2008;Wilson et al, 2008). A recent meta-analysis confirmed that the 40-Hz ASSR is a robust index of gamma synchronization deficits in schizophrenia patients (Thuné et al, 2016).…”

“…We performed timefrequency analyses with a short-term Fourier transformation (STFT) and then calculated event-related spectral perturbation (ERSP) as an index of ASSR. We calculated the mean ERSP by averaging the data over stimulation time (0-500 ms) and stimulation frequency (40 Hz: 35-45 Hz) in accordance with previous studies (Koshiyama et al, 2018a(Koshiyama et al, , 2018b(Koshiyama et al, , 2019).…”

40 Hz Auditory Steady-State Responses Predict Transition to Psychosis in Clinical-High-Risk Participants: A MEG Study

“…Currently, there is robust evidence that both amplitude and phase of 40-Hz-ASSR is impaired in schizophrenia (12,13). There is mixed evidence, however, for the presence of 40-Hz-ASSRs deficits in both clinical high risk for psychosis (CHR-P) individuals (14,15) and patients with first-episode psychosis (FEP) (16).…”