Effects of Memantine on the Auditory Steady-State and Harmonic Responses to 40 Hz Stimulation Across Species

BACKGROUND: Click trains elicit an auditory steady-state response (ASSR) at the driving frequency (1F) and its integer multiple frequencies (2F, 3F, etc.) called harmonics; we call this harmonic response the steady-state harmonic response (SSHR). We describe the 40 Hz ASSR (1F) and 80 Hz SSHR (2F) in humans and rats and their sensitivity to the uncompetitive NMDA antagonist memantine. METHODS: In humans (healthy control participants, n = 25; patients with schizophrenia, n = 28), electroencephalography was recorded after placebo or 20 mg memantine in a within -participant crossover design. ASSR used 1 ms, 85 -dB clicks presented in 250 40/s 500 -ms trains. In freely moving rats (n = 9), electroencephalography was acquired after memantine (0, 0.3, 1, 3 mg/kg) in a within -participant crossover design; 65 -dB click trains used 5 -mV monophasic, 1 -ms square waves (40/s). RESULTS: Across species, ASSR at 1F generated greater evoked power (EP) than the 2F SSHR. 1F > 2F intertrial coherence (ITC) was also detected in humans, but the opposite relationship (ITC: 2F > 1F) was seen in rats. EP and ITC at 1F were deficient in patients and were enhanced by memantine across species. EP and ITC at 2F were deficient in patients. Measures at 2F were generally insensitive to memantine across species, although in humans the ITC harmonic ratio (1F:2F) was modestly enhanced by memantine, and in rats, both the EP and ITC harmonic ratios were significantly enhanced by memantine. CONCLUSIONS: ASSR and SSHR are robust, nonredundant electroencephalography signals that are suitable for cross -species analyses that reveal potentially meaningful differences across species, diagnoses, and drugs.