Schizophrenia (SCZ) is a chronic mental illness, and more than half of SCZ patients have experienced auditory verbal hallucinations (AVHs) (Knapp et al., 2004; Andreasen and Flaum, 1991). Although the frequency of AVHs can be rapidly reduced in the majority of patients with antipsychotic medication (Sommer et al., 2012), approximately 30% of patients with SCZ have a chronic resistance to antipsychotics (Liu et al., 2015), known as persistent auditory verbal hallucinations (pAVHs). pAVHs are defined as hallucinations that persist for more than half year despite treatment with two different antipsychotic medications. Studies of mechanisms underlying pAVHs are needed.

Electroencephalography (EEG) technology has become the most widely used method in studying the neuron electrophysiology of SCZ. Various studies have revealed that these patients exhibit impaired neural oscillations in cognition and perception (Missonnier et al., 2020; Coffman et al., 2020; McNally et al., 2016; Uhlhaas et al., 2010), abnormal gamma oscillations (Curic et al., 2019; Kwon et al., 1999; Tsuchimoto et al., 2011; Kirihara et al., 2012). The altered γ oscillations may reflect the degree of functional impairment in SCZ (Lee et al., 2006; Uhlhaas et al., 2008). Auditory steady-state response (ASSR) has been considered the strongest indication of abnormal γ. The commonly analyzed parameters in SCZ ASSR studies include inter-trial phase synchronization and power. However, the recent meta-analysis on ASSR deficits in schizophrenia included studies with a wide range of effect sizes (Hedge's G), with an overall effect size of 0.46 (Thune et al., 2016). Moreover, the source of these symptoms remains unknown in schizophrenia. Many studies have shown that the 40 Hz ASSR originated in the auditory cortex (Korczak et al., 2012; Ross et al., 2002). The 40 Hz ASSR has the highest energy and phase synchronization compared to other frequency stimulation (Paster et al., 2002). Therefore, some studies have tried to use 40 Hz ASSR to assess auditory processing in SCZ patients (Roach et al., 2019). It has been shown that the 40Hz ASSR is lower in SCZ patients than in healthy control (HC) (Thune et al., 2016). Roach et al. (Roach et al., 2013) studied SCZ patients and HC and showed that 40 Hz ASSR energy decreased in SCZ patients, which reflects abnormal auditory cortex function. Previous studies suggested that 40 Hz ASSR decreased in SCZ patients (Tada et al., 2016; Leicht et al., 2010; Brenner et al., 2009), indicating may be a potential factor in SCZ symptom development.

Multiple studies have investigated the associations between gamma oscillations and various clinical features, but the results have been inconsistent (Gandal et al., 2012). Some studies have reported that abnormalities in gamma oscillations are associated with psychiatric symptoms such as hallucinations, thought disorders, and cognitive disturbances (Spencer et al., 2004), as well as factors like illness duration (Gallinat et al., 2004; Hall et al., 2011). Spencer et al. found a significant relationship between increased 40 Hz ASSR and more severe positive symptoms of psychosis, including hallucinations and delusions (Spencer et al., 2009; Spencer et al., 2008). However, a larger, well-powered study did not observe this association (Light et al., 2006). These findings suggest that alterations in 40 Hz ASSR may play a crucial role in the manifestation and severity of AVH.

Although, previous findings have compared the difference in 40 Hz ASSR between SCZ patients and HC. Still, few studies have directly compared the difference between in pAVHs SCZ patients and without pAVHs. Furthermore, the relationship between 40 Hz ASSR and clinical symptoms (e.g., hallucinations) remains uncertain, confirming the necessity for the further research on specific symptoms in patients with psychiatric disorders and defects in 40 Hz ASSR. Therefore, in this study, we aim to further investigate the relationship between AVH severity and ASSR measures. A better understanding of the neurological-related factors of differentiate patients with and without pAVHs and identifying reliable neurophysiological markers may lead to better strategies for treating pAVHs.

This study investigated the difference in 40 Hz ASSR between pAVHs and without pAVHs SCZ patients. Based on previous study results, we assumed that SCZ patients with pAVHs might have a lower 40 Hz ASSR than those without pAVHs. We also assumed that 40 Hz ASSR deficits might correlate to pAVHs. Moreover, impaired 40 Hz ASSR in frontal-central would be promising markers for detecting pAVHs severity in SCZ patients.