The auditory steady-state response (ASSR): a translational biomarker for schizophrenia

Abstract

Electrophysiological methods have demonstrated disturbances of neural synchrony and oscillations in schizophrenia which affect a broad range of sensory and cognitive processes. These disturbances may account for a loss of neural integration and effective connectivity in the disorder. The mechanisms responsible for alterations in synchrony are not well delineated, but may reflect disturbed interactions within GABAergic and glutamatergic circuits, particularly in the gamma range. Auditory steady-state responses (ASSRs) provide a non-invasive technique used to assess neural synchrony in schizophrenia and in animal models at specific response frequencies. ASSRs are electrophysiological responses entrained to the frequency and phase of a periodic auditory stimulus generated by auditory pathway and auditory cortex activity. Patients with schizophrenia show reduced ASSR power and phase locking to gamma range stimulation. We review alterations of ASSRs in schizophrenia, schizotypal personality disorder, and first-degree relatives of patients with schizophrenia. In vitro and in vivo approaches have been used to test cellular mechanisms for this pattern of findings. This translational, cross-species approach provides support for the role of N-methyl-D-aspartate and GABAergic dysregulation in the genesis of perturbed ASSRs in schizophrenia and persons at risk.

Fig. 1

Auditory steady-state responses (ASSRs) to a 1-s, 40-Hz amplitude-modulated tone recorded at Cz in a healthy control group (HC; N = 21) and in patients with schizophrenia (SZ; N = 21). (A) The ERP in the time domain averaged across subjects, showing both a large onset response as well as the 40-Hz oscillation. In (B), the averaged wave form has been filtered between 39 and 41 Hz. (C) A power spectrum obtained by applying a Fast Fourier Transform on the ERPs in the two groups, showing the 40-Hz response in the HC group which is reduced in magnitude in the SZ group. (D) Mean power (MP) across the epoch which indicates the average change in power at a given frequency from the mean baseline power. The x-axis represents time in milliseconds, the y-axis represents frequency in Hertz, and the colors represent the magnitude of power. (E) The phase-locking factor (PLF) across trials. The x-axis indicates time in milliseconds, they-axis indicates frequency, and the colors represent phase reproducibility across trials ranging from 0 (absence of synchronization) to 1 (perfect synchronization). (For color figures, please refer to the color figures in last section of the book.)

Fig. 2

The modulation transfer function (MTF) for the ASSR recorded at Cz from healthy control (HC; N = 21) and schizophrenia (SZ; N = 21) groups. The MTFs for the each stimulus frequency are displayed. Each data point is the mean value across the entire stimulus period averaged across subjects within the group. The error bars indicate standard errors. Note the large decrement in schizophrenia for both PLF and MP between 35 and 50 Hz.

Fig. 3

Modulation transfer function of phase locking factor (PLF, left panel) and mean power (MP, right panel) to 10-s click trains in eight male rats, with frequency of stimulation on the x-axis. The peak frequency of response for hoth phase locking and mean power is at a slightly higher frequency in rats than in humans (hetween 45 and 50 Hz).