The auditory steady-state response (ASSR): a translational biomarker for schizophrenia

Electrophysiological methods have demonstrated disturbances of neural synchrony and oscillations in schizophrenia which affect a broad range of sensory and cognitive processes. These disturbances may account for a loss of neural integration and effective connectivity in the disorder. The mechanisms responsible for alterations in synchrony are not well delineated, but may reflect disturbed interactions within GABAergic and glutamatergic circuits, particularly in the gamma range. Auditory steady-state responses (ASSRs) provide a non-invasive technique used to assess neural synchrony in schizophrenia and in animal models at specific response frequencies. ASSRs are electrophysiological responses entrained to the frequency and phase of a periodic auditory stimulus generated by auditory pathway and auditory cortex activity. Patients with schizophrenia show reduced ASSR power and phase locking to gamma range stimulation. We review alterations of ASSRs in schizophrenia, schizotypal personality disorder, and first-degree relatives of patients with schizophrenia. In vitro and in vivo approaches have been used to test cellular mechanisms for this pattern of findings. This translational, cross-species approach provides support for the role of N-methyl-D-aspartate and GABAergic dysregulation in the genesis of perturbed ASSRs in schizophrenia and persons at risk

Phencyclidine Disrupts the Auditory Steady State Response in Rats

The Auditory Steady-State Response (ASSR) in the electroencephalogram (EEG) is usually reduced in schizophrenia (SZ), particularly to 40 Hz stimulation. The gamma frequency ASSR deficit has been attributed to N-methyl-D-aspartate receptor (NMDAR) hypofunction. We tested whether the NMDAR antagonist, phencyclidine (PCP), produced similar ASSR deficits in rats. EEG was recorded from awake rats via intracranial electrodes overlaying the auditory cortex and at the vertex of the skull. ASSRs to click trains were recorded at 10, 20, 30, 40, 50, and 55 Hz and measured by ASSR Mean Power (MP) and Phase Locking Factor (PLF). In Experiment 1, the effect of different subcutaneous doses of PCP (1.0, 2.5 and 4.0 mg/kg) on the ASSR in 12 rats was assessed. In Experiment 2, ASSRs were compared in PCP treated rats and control rats at baseline, after acute injection (5 mg/kg), following two weeks of subchronic, continuous administration (5 mg/kg/day), and one week after drug cessation. Acute administration of PCP increased PLF and MP at frequencies of stimulation below 50 Hz, and decreased responses at higher frequencies at the auditory cortex site. Acute administration had a less pronounced effect at the vertex site, with a reduction of either PLF or MP observed at frequencies above 20 Hz. Acute effects increased in magnitude with higher doses of PCP. Consistent effects were not observed after subchronic PCP administration. These data indicate that acute administration of PCP, a NMDAR antagonist, produces an increase in ASSR synchrony and power at low frequencies of stimulation and a reduction of high frequency (> 40 Hz) ASSR activity in rats. Subchronic, continuous administration of PCP, on the other hand, has little impact on ASSRs. Thus, while ASSRs are highly sensitive to NMDAR antagonists, their translational utility as a cross-species biomarker for NMDAR hypofunction in SZ and other disorders may be dependent on dose and schedule

Acute Phencyclidine Alters Neural Oscillations Evoked by Tones in the Auditory Cortex of Rats

BACKGROUND/AIMS: The onset response to a single tone as measured by electroencephalography (EEG) is diminished in power and synchrony in schizophrenia. Because neural synchrony, particularly at gamma frequencies (30-80 Hz), is hypothesized to be supported by the N-methyl-D-aspartate receptor (NMDAr) system, we tested whether phencyclidine (PCP), an NMDAr antagonist, produced similar deficits to tone stimuli in rats. METHODS: Experiment 1 tested the effect of a PCP dose (1.0, 2.5, and 4.5 mg/kg) on response to single tones on intracranial EEG recorded over the auditory cortex in rats. Experiment 2 evaluated the effect of PCP after acute administration of saline or PCP (5 mg/kg), after continuous subchronic administration of saline or PCP (5 mg/kg/day), and after a week of drug cessation. In both experiments, a time-frequency analysis quantified mean power (MP) and phase locking factor (PLF) between 1 and 80 Hz. Event-related potentials (ERPs) were also measured to tones, and EEG spectral power in the absence of auditory stimuli. RESULTS: Acute PCP increased PLF and MP between 10 and 30 Hz, while decreasing MP and PLF between approximately 50 and 70 Hz. Acute PCP produced a dose-dependent broad-band increase in EEG power that extended into gamma range frequencies. There were no consistent effects of subchronic administration on gamma range activity. Acute PCP increased ERP amplitudes for the P16 and N70 components. CONCLUSIONS: Findings suggest that acute PCP-induced NMDAr hypofunction has differential effects on neural power and synchrony which vary with dose, time course of administration and EEG frequency. EEG synchrony and power appear to be sensitive translational biomarkers for disrupted NMDAr function, which may contribute to the pathophysiology of schizophrenia and other neuropsychiatric disorders

Experiment 1: Phase locking factor and mean power as a function of PCP dose at the vertex electrode site.

<p>Note: The † in the measure column indicates a significant main effect of PCP dose (p < .05). The asterisk (*) with bold mean and SD values indicates a significant difference relative to baseline, with asterisks indicating *p≤.05, **p≤.01, ***p≤.001. Phase locking factor (PLF) is scaled from 0 to 1, and mean power (MP) is scaled in microvolts².</p><p>Experiment 1: Phase locking factor and mean power as a function of PCP dose at the vertex electrode site.</p

Experiment 2: Phase locking factor and mean power at baseline, acute treatment, after subchronic treatment, and after washout for the saline and PCP groups at the vertex electrode site.

<p>Note: The † in the measure column indicates an effect of time (p < .05) for a specific measure and frequency. The asterisk (*) with bold mean and SD values indicates a significant difference relative to baseline, with asterisks indicating *p≤.05, **p≤.01, ***p≤.001. Phase locking factor (PLF) is scaled from 0 to 1, and mean power (MP) is scaled in microvolts².</p><p>Experiment 2: Phase locking factor and mean power at baseline, acute treatment, after subchronic treatment, and after washout for the saline and PCP groups at the vertex electrode site.</p

Experiment 1, Dose Response Study.

<p>Graphs showing the mean PLF and MP values at each acute dose of PCP as a function of frequency of stimulation at the auditory cortex electrode. Asterisks indicate differences from baseline values (* p≤.05, # p≤.01). PCP caused a dose-dependent increase of PLF at low frequencies of stimulation (10, 20, 30 and 40 Hz), and suppressed PLF at high frequencies (50 and 55 Hz.)</p

Experiment 2, Acute vs. Subchronic PCP Administration.

<p>Graphs showing the mean PLF values for each condition (baseline, acute injections, subchronic administration, washout) as a function of frequency of stimulation at the auditory cortex site. Asterisks indicate differences from baseline values (*p ≤. 05, #p ≤ .01).</p

Experiment 1 Design: Effects of acute PCP dose on ASSRs.

<p>All rats received saline injection prior to baseline ASSR recordings. After one week, rats received injections of 1.0, 2.5, and 4.0 mg/kg at one week intervals with the order of the three doses randomized among rats. One week after the final PCP injection, washout ASSRs were recorded after a saline injection.</p