Click train elicited local gamma synchrony: differing performance and pharmacological responsivity of primary auditory and prefrontal cortices.

Auditory neural networks in the brain naturally entrain to rhythmic stimuli. Such synchronization is an accessible index of local network performance as captured by EEG. Across species, click trains delivered âˆ¼ 40 Hz show strong entrainment with primary auditory cortex (Actx) being a principal source. Imaging studies have revealed additional cortical sources, but it is unclear if they are functionally distinct. Since auditory processing evolves hierarchically, we hypothesized that local synchrony would differ between between primary and association cortices. In female SD rats (N = 12), we recorded 40 Hz click train-elicited gamma oscillations using epidural electrodes situated at two distinct sites; one above the prefrontal cortex (PFC) and another above the Actx, after dosing with saline (1 ml/kg, sc) or the NMDA antagonist, MK801 (0.025, 0.05 or 0.1 mpk), in a blocked crossover design. Post-saline, both regions showed a strong 40 Hz auditory steady state response (ASSR). The latencies for the N1 response were âˆ¼ 16 ms (Actx) and âˆ¼ 34 ms (PFC). Narrow band (38-42 Hz) gamma oscillations appeared rapidly (<40 ms from stim onset at Actx but in a more delayed fashion (∼200 ms) at PFC. MK801 augmented gamma synchrony at Actx while dose-dependently disrupting at the PFC. Event-related gamma (but not beta) coherence, an index of long-distance connectivity, was disrupted by MK801. In conclusion, local network gamma synchrony in a higher order association cortex performs differently from that of the primary auditory cortex. We discuss these findings in the context of evolving sound processing across the cortical hierarchy.

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.

Click-train evoked steady state harmonic response as a novel pharmacodynamic biomarker of cortical oscillatory synchrony.

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, recorded from a prefrontal epidural electrode. 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.

Differential Effects of Clozapine and Haloperidol on the 40 Hz Auditory Steady State Response-mediated Phase Resetting in the Prefrontal Cortex of the Female Sprague Dawley Rat.

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.