The influence of novelty detection on the 40-Hz auditory steady-state response in schizophrenia: A novel hypothesis from meta-analysis

The 40-Hz auditory steady-state response (ASSR) is influenced not only by parameters such as attention, stimulus type, and analysis level but also by stimulus duration and inter-stimulus interval (ISI). In this meta-analysis, we examined these parameters in 33 studies that investigated 40-Hz ASSRs in patients with schizophrenia. The average Hedges' g random effect sizes were − 0.47 and − 0.43 for spectral power and phase-locking, respectively. We also found differences in ASSR measures based on stimulus duration and ISI. In particular, ISI was shown to significantly influence differences in the 40-Hz ASSR between healthy controls and patients with schizophrenia. We proposed a novel hypothesis focusing on the role of novelty detection, dependent on stimulus duration and ISI, as a critical factor in determining these differences. Specifically, longer stimulus durations and shorter ISIs under random presentation, or shorter stimulus durations and longer ISIs under repetitive presentation, decrease the 40-Hz ASSR in healthy controls. Patients with schizophrenia show minimal changes in response to stimulus duration and ISI, thus reducing the difference between controls and patients. This hypothesis can consistently explain most of the studies that have failed to show a reduction in 40-Hz ASSR in patients with schizophrenia. Increased novelty-related activity, reflected as an increase in auditory evoked potential components at stimulus onset, such as the N1, could suppress the 40-Hz ASSR, potentially reducing the peak measures of spectral power and phase-locking. To establish the 40-Hz ASSR as a truly valuable biomarker for schizophrenia, further systematic research using paradigms with various stimulus durations and ISIs is needed.