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  • Schizophrenia is also characterized by abnormalities in


    Schizophrenia is also characterized by abnormalities in the cortical circuitry underlying gamma oscillations elicited by a variety of stimuli and tasks (Uhlhaas et al., 2010). Especially, individuals with schizophrenia exhibit deficits in the auditory steady state response (ASSR) induced by gamma frequency (>30-Hz) stimulation. In healthy individuals, the ASSR contains resonant frequencies around 40-Hz and 80-Hz, with a larger power at 40-Hz (Sivarao, 2015). The power of the ASSR is enhanced at these frequencies. At the cellular level, the generation and maintenance of gamma oscillations critically depend on networks of fast-spiking parvalbumin-expressing gamma aminobutyric adenosine receptor (GABA)-ergic interneurons (Owen et al., 2016). In addition, N-methyl-d-aspartate receptor (NMDAR) signaling in parvalbumin-expressing GABAergic interneurons is critical for the regulation of spontaneous (non-stimulus locked) and evoked gamma oscillations (Carlen et al., 2012). ASSR deficits in individuals with chronic schizophrenia have been correlated with reduced evoked gamma responses (Tsuchimoto et al., 2011) and increased spontaneous gamma activities (Hirano et al., 2015) during auditory stimulation, indicating that neural circuitry abnormalities in schizophrenia patients may be associated with an imbalance between excitatory glutamate and inhibitory GABA neurotransmission. Thus, it is important to investigate both evoked gamma responses and spontaneous gamma activities during auditory stimulation in this population. Although most ASSR studies have used electroencephalography (EEG) and megnetoencephalography (MEG), hemodynamic signals have been found to strongly correlate with synchronized gamma oscillations (Niessing et al., 2005). Niessing et al. reported that hemodynamic responses were significantly and positively correlated with neuronal synchronization in the gamma range (52–90Hz) in the visual cortex of cats. More recently, specific gamma-BOLD correlations have been reported in humans during a cognitive visual attention task (Scheeringa et al., 2011). Other reports (Logothetis et al., 2001, 2010; Kayser et al., 2004; Goense and Logothetis, 2008; Murayama et al., 2010; Scholvinck et al., 2010) have consistently demonstrated the significant involvement of gamma oscillations in neurovascular coupling. In addition, Kann et al. (2011) reported that gamma band neural oscillations were particularly associated with higher mitochondrial oxidative metabolism, which is characterized by higher oxygen consumption and mitochondrial gene expression, indicating significant associations between gamma oscillations and BOLD signals. Therefore, we consider functional MRI (fMRI) to be suitable for evaluating evoked gamma and spontaneous gamma oscillations during periodic click stimuli by blood oxygenation level dependent (BOLD) signals (Fig. 1 shows the relationships between fMRI signals and electrophysiological responses for ASSR).
    Materials & Methods
    Discussion As noted in the introduction section, fMRI can be used to detect both evoked and spontaneous gamma activities during auditory stimulation, and increased spontaneous gamma responses have previously been reported in patients with schizophrenia (Hirano et al., 2015). The present results indicate that schizophrenia patients in the acute state exhibit an overall increase in neural activation in the left auditory cortex during 80-Hz auditory stimulation. Considering the potential association between abnormal spontaneous gamma activities and increased glutamate levels, our data might reflect glutamate toxicity in the left auditory cortex in the acute state of schizophrenia, which may then trigger progressive changes in the left transverse temporal gyrus and left planum temporale. Accumulating EEG and MEG evidence indicates that patients with schizophrenia show reduced gamma band ASSR in the chronic state (e.g., Kwon et al., 1999; Carlen et al., 2012; O\'Donnell et al., 2013) and during the first episode (e.g., Tada et al., 2014). In the present study, however, we found significantly increased ASSR-BOLD signals in response to 80-Hz but not 40-Hz stimuli. Rivolta et al. (2015) reported that resting-state spontaneous neural oscillations in the gamma frequencies were increased by ketamine. NMDAR antagonists increase pyramidal cell activity and extracellular glutamate levels (Homayoun and Moghaddam, 2007), and blocking the NMDAR with ketamine can cause schizophrenia-like symptoms, including cognitive dysfunction, in healthy subjects (Krystal et al., 1994; Fletcher and Honey, 2006). Recently, high gamma (>60-Hz) band oscillations have become an increasingly frequent subject of interest. For example, Uhlhaas et al. (2011) reported that high gamma band activities may be a fundamental aspect of temporal coding in cortical networks. Although the ASSR-BOLD may not independently reflect cognitive processes, this may be the case for the 80-Hz ASSR, as basic neural circuits that predominantly oscillate at high gamma frequencies might be more strongly implicated in cognitive processes. In another resting-state EEG study, Mitra et al. (2015) reported that patients with schizophrenia at the untreated acute stage showed significantly higher spontaneous activities in high gamma (70 to 100-Hz) band, but not low gamma band. Given the question of why we only found hyperactivation for the 80-Hz stimuli, it is possible that increased spontaneous gamma activities are more apparent for 80-Hz compared with 40-Hz stimuli in the AESZ group. Alternatively, there may be a strong association between BOLD signals and high gamma band electrophysiological activities. The 80-Hz stimulation may be a resonant frequency for ASSR-BOLD responses in the AESZ group, resulting in hyperactivation for the 80-Hz stimuli only.