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.

Contributions of spectral frequency analyses to the study of P50 ERP amplitude and suppression in bipolar disorder with or without a history of psychosis.

OBJECTIVE: The present study investigated event-related brain potential (ERP) indices of auditory processing and sensory gating in bipolar disorder and subgroups of bipolar patients with or without a history of psychosis using the P50 dual-click procedure. Auditory-evoked activity in two discrete frequency bands also was explored to distinguish between sensory registration and selective attention deficits. METHODS: Thirty-one individuals with bipolar disorder and 28 non-psychiatric controls were compared on ERP indices of auditory processing using a dual-click procedure. In addition to conventional P50 ERP peak-picking techniques, quantitative frequency analyses were applied to the ERP data to isolate stages of information processing associated with sensory registration (20-50 Hz; gamma band) and selective attention (0-20 Hz; low-frequency band). RESULTS: Compared to the non-psychiatric control group, patients with bipolar disorder exhibited reduced S1 response magnitudes for the conventional P50 peak-picking and low-frequency response analyses. A bipolar subgroup effect suggested that the attenuated S1 magnitudes from the P50 peak-picking and low-frequency analyses were largely attributable to patients without a history of psychosis. CONCLUSIONS: The analysis of distinct frequency bands of the auditory-evoked response elicited during the dual-click procedure allowed further specification of the nature of auditory sensory processing and gating deficits in bipolar disorder with or without a history of psychosis. The observed S1 effects in the low-frequency band suggest selective attention deficits in bipolar patients, especially those patients without a history of psychosis, which may reflect a diminished capacity to selectively attend to salient stimuli as opposed to impairments of inhibitory sensory processes.

Sensorimotor gating in manic and mixed episode bipolar disorder.

OBJECTIVES: Few studies have examined acoustic startle sensorimotor gating in bipolar disorder (BPD) despite the fact that patients with BPD have exhibited inhibitory dysfunctions on a variety of early information processing tasks. The present study aimed to expand the current literature through the investigation of electromyographic (EMG) measures of acoustic startle prepulse inhibition (PPI) in manic and mixed episode BPD. METHODS: Fourteen manic and 21 mixed episode BPD patients were compared to 32 healthy controls on acoustic startle measures of PPI using a 120-ms lead interval. RESULTS: Prepulse inhibition did not significantly differ across diagnostic groups (manic, mixed, control), and the presence of psychosis in the patient sample was not significantly related to PPI levels. With respect to startle response characteristics, patients in the mixed phase of the disorder showed prolonged prepulsed startle latency and attenuated responses to both probe-alone and prepulsed probes, though no differences in startle habituation were found across diagnostic groups. CONCLUSIONS: Although PPI deficits were not observed in either BPD sub-group, attenuated probe-alone and prepulsed startle magnitudes and reduced prepulse-induced latency facilitation in the mixed episode group is consistent with evidence that the mixed phase of BPD is associated with a more severe clinical outlook than other stages of the disorder. The absence of attenuated PPI in the patient sample may be due to the low incidence of psychosis in the BPD groups, though further studies are required to systematically assess the effects of symptom factors and clinical phase on sensorimotor gating in BPD.

Neural synchronization deficits to auditory stimulation in bipolar disorder.

Patients with bipolar disorder show cognitive deficits and disorganized behavior, which may reflect a disturbance in neural synchronization. We tested whether EEG measures of auditory neural synchronization were abnormal in bipolar disorder. Nineteen symptomatic patients with bipolar disorder and 32 non-psychiatric control subjects were evaluated. Click trains (500 ms duration) presented at 20, 30, 40 and 50 Hz were used to evoke EEG synchronization. Patients with bipolar disorder showed reduced power across the frequencies of stimulation. Phase-locking across trials was also disturbed in bipolar disorder, consistent with poor phase synchronization between the stimulus and EEG. Abnormal high frequency neural synchronization may contribute to cognitive deficits in bipolar disorder.