The 40-Hz auditory steady-state response: a selective biomarker for cortical NMDA function

When subjected to a phasic input, sensory cortical neurons display a remarkable ability to entrain faithfully to the driving stimuli. The entrainment to rhythmic sound stimuli is often referred to as the auditory steady-state response (ASSR) and can be captured using noninvasive techniques, such as scalp-recorded electroencephalography (EEG). An ASSR to a driving frequency of approximately 40 Hz is particularly interesting in that it shows, in relative terms, maximal power, synchrony, and synaptic activity. Moreover, the 40-Hz ASSR has been consistently found to be abnormal in schizophrenia patients across multiple studies. The nature of the reported abnormality has been less consistent; while most studies report a deficit in entrainment, several studies have reported increased signal power, particularly when there are concurrent positive symptoms, such as auditory hallucinations. However, the neuropharmacological basis for the 40-Hz ASSR, as well as its dysfunction in schizophrenia, has been unclear until recently. On the basis of several recent reports, it is argued that the 40-Hz ASSR represents a specific marker for cortical NMDA transmission. If confirmed, the 40-Hz ASSR may be a simple and easy-to-access pharmacodynamic biomarker for testing the integrity of cortical NMDA neurotransmission that is robustly translational across species.