Pharmacological dissociation between transient auditory evoked response and the 40 Hz auditory steady state response

Brief, discrete sounds such as tone pips or clicks evoke transient, time-locked EEG changes known as evoked responses, revealed through averaging across trials. Steady-state potentials arise from averaging responses to trains of tones or clicks delivered at a specific frequency. Prior modeling and empirical work have suggested that the 40 Hz auditory steady-state response (ASSR) reflects the summation of back-to-back discrete evoked responses. An alternative view proposes that the ASSR represents frequency-specific endogenous entrainment of the oscillating field potential of the brain. Supporting this, only frequencies near the natural resonance of cortical regions reliably entrain oscillations, that emerge gradually over hundreds of milliseconds and often persist beyond stimulus offset. In this study, we used a pharmacological approach to directly compare tone-evoked responses and the 40 Hz ASSR, hypothesizing that if the ASSR simply reflects repeated evoked responses, drug effects should be similar across the two measures. We tested two compounds, MK-801 and clozapine, which are known to modulate the 40 Hz response in opposite directions. While both drugs produced robust effects, these were largely uncorrelated across measures. Our findings suggest that tone-evoked responses and the 40 Hz ASSR engage distinct and partially non-overlapping cortical networks. We further speculate that transient responses such as tone-evoked N1 are primarily driven by rapid feedforward transmission, whereas 40 Hz oscillations emerge from recurrent network activity that builds up gradually. Their established cross-species translational utility and strong but uncorrelated pharmacological responsiveness establish the two measures as largely independent pharmacodynamic biomarkers for drug development.