Sensory networks naturally entrain to rhythmic stimuli like a click train delivered at a particular frequency. Such synchronization is integral to information processing, can be measured by electroencephalography (EEG), and is an accessible index of neural network function. Click trains evoke neural entrainment not only at the driving frequency (F), referred to as the auditory steady-state response (ASSR), but also at its higher multiples called the steady-state harmonic response (SSHR). Since harmonics play an important and non-redundant role in acoustic information processing, we hypothesized that SSHR may differ from ASSR in presentation and pharmacological sensitivity. In female SD rats, a 2 s-long train stimulus was used to evoke ASSR at 20 Hz and its SSHR at 40, 60, and 80 Hz. Narrow band evoked responses were evident at all frequencies; signal power was strongest at 20 Hz while phase synchrony was strongest at 80 Hz. SSHR at 40 Hz took the longest time (~180 ms from stimulus onset) to establish synchrony. The NMDA antagonist MK801 (0.025-0.1 mg/kg) did not consistently affect 20 Hz ASSR phase synchrony but robustly and dose-dependently attenuated synchrony of all SSHR. Evoked power was attenuated by MK801 at 20 Hz ASSR and 40 Hz SSHR only. Thus, presentation, as well as pharmacological sensitivity, distinguished SSHR from ASSR, making them non-redundant markers of cortical network function. SSHR is a novel and promising translational biomarker of cortical oscillatory dynamics that may have important applications in CNS drug development and personalized medicine.

Background Neural synchrony at gamma frequency (~40 Hz) is important for information processing and is disrupted in schizophrenia. From a drug development perspective, molecules that can improve local gamma synchrony are promising candidates for therapeutic development. Hypothesis Given their differentiated clinical profile, clozapine, and haloperidol may have distinct effects on local gamma synchrony engendered by 40 Hz click trains, the so-called auditory steady-state response (ASSR). Study Design Clozapine and haloperidol at doses known to mimic clinically relevant D2 receptor occupancy were evaluated using the ASSR in separate cohorts of female SD rats. Results Clozapine (2.5–10 mg/kg, sc) robustly increased intertrial phase coherence (ITC), across all doses. Evoked response increased but less consistently. Background gamma activity, unrelated to the stimulus, showed a reduction at all doses. Closer scrutiny of the data indicated that clozapine accelerated gamma phase resetting. Thus, clozapine augmented auditory information processing in the gamma frequency range by reducing the background gamma, accelerating the gamma phase resetting and improving phase precision and signal power. Modest improvements in ITC were seen with Haloperidol (0.08 and 0.24 mg/kg, sc) without accelerating phase resetting. Evoked power was unaffected while background gamma was reduced at high doses only, which also caused catalepsy. Conclusions Using click-train evoked gamma synchrony as an index of local neural network function, we provide a plausible neurophysiological basis for the superior and differentiated profile of clozapine. These observations may provide a neurophysiological template for identifying new drug candidates with a therapeutic potential for treatment-resistant schizophrenia.