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.

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.

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.

Computer-assisted cognitive remediation for schizophrenia: a randomized single-blind pilot study.

Cognitive impairment is a core symptom in schizophrenia that has a significant impact on psychosocial function, but shows a weak response to pharmacological treatment. Consequently, a variety of cognitive remediation strategies have been evaluated to improve cognitive function in schizophrenia. The efficacy of computer-based cognitive remediation as a stand-alone intervention on general measures of neuropsychological function remains unclear. We tested the effectiveness of biweekly training using computerized cognitive remediation programs on neuropsychological and event-related potential outcome measures. Schizophrenia patients were randomly assigned to cognitive remediation training (N=17), active control (TV-watching; N=17), or treatment-as-usual (N=10) groups for ten weeks and run in parallel. Cognitive and ERP measures revealed no differential improvement over time in the cognitive remediation group. Practice effects might explain change over time on several cognitive measures for all groups, consistent with studies indicating task-specific improvement. Computer-assisted cognitive remediation alone may not be sufficient for robust or generalized effects on cognitive and electrophysiological measures in schizophrenia patients.

Auditory steady state response in the schizophrenia, first-degree relatives, and schizotypal personality disorder.

The power and phase synchronization of the auditory steady state response (ASSR) at 40 Hz stimulation is usually reduced in schizophrenia (SZ). The sensitivity of the 40 Hz ASSR to schizophrenia spectrum phenotypes, such as schizotypal personality disorder (SPD), or to familial risk has been less well characterized. We compared the ASSR of patients with SZ, persons with schizotypal personality disorder, first degree relatives of patients with SZ, and healthy control participants. ASSRs were obtained to 20, 30, 40 and 50 Hz click trains, and assessed using measures of power (mean trial power or MTP) and phase consistency (phase locking factor or PLF). The MTP to 40 Hz stimulation was reduced in relatives, and there was a trend for MTP reduction in SZ. The 40 Hz ASSR was not reduced in SPD participants. PLF did not differ among groups. These data suggest the 40 Hz ASSR is sensitive to familial risk factors associated with schizophrenia.

Auditory steady state response in bipolar disorder: relation to clinical state, cognitive performance, medication status, and substance disorders.

OBJECTIVES: Abnormalities in auditory steady state response (ASSR) at gamma range frequencies have been found in bipolar disorder, but the relationship of these neurophysiological disturbances to clinical factors has not been well characterized. We therefore evaluated the ASSR in bipolar disorder and examined its sensitivity to clinical symptoms, cognitive function, and pharmacological treatment. METHODS: A total of 68 patients with bipolar disorder and 77 control participants were evaluated. Click trains presented at 20, 30, 40, and 50 Hz evoked ASSRs. Mean trial power (MTP) and phase locking factor (PLF) measured response magnitude and phase synchronization of the ASSR at each stimulation frequency. Clinical state, pharmacological treatment, and neuropsychological performance were assessed, and their respective relationships with ASSR measures were evaluated. RESULTS: Patients with bipolar disorder showed reduced MTP and PLF compared to control participants. Bipolar disorder patients taking psychotropic medications had decreased PLF relative to patients withdrawn from medications. Control participants performed better on neuropsychological tests than bipolar disorder patients; however, test scores did not correlate with ASSR measures. CONCLUSIONS: Deficits in the generation and maintenance of ASSR are present in bipolar disorder, implicating disturbances in auditory pathways. ASSR may be sensitive to medication status. Other clinical features, including mood state, psychotic features, cognitive performance, smoking, or history of substance use disorder, were unrelated to MTP or PLF.