Augmented gamma band auditory steady-state responses: support for NMDA hypofunction in schizophrenia.

Individuals with schizophrenia (SZ) have deviations in auditory perception perhaps attributable to altered neural oscillatory response properties in thalamo-cortical and/or local cortico-cortical circuits. Previous EEG studies of auditory steady-state responses (aSSRs; a measure of sustained neuronal entrainment to repetitive stimulation) in SZ have indicated attenuated gamma range (≈40 Hz) neural entrainment. Stimuli in most such studies have been relatively brief (500-1000 ms) trains of 1 ms clicks or amplitude modulated pure tones (1000 Hz) with short, fixed interstimulus intervals (200-1000 ms). The current study used extended (1500 ms), more aurally dense broadband stimuli (500-4000 Hz noise; previously demonstrated to elicit larger aSSRs) with longer, variable interstimulus intervals (2700-3300 ms). Dense array EEG (256 sensor) was collected while 17 SZ and 16 healthy subjects passively listed to stimuli modulated at 15 different frequencies spanning beta and gamma ranges (16-44 Hz in 2 Hz steps). Results indicate that SZ have augmented aSSRs that were most extreme in the gamma range. Results also constructively replicate previous findings of attenuated low frequency auditory evoked responses (2-8 Hz) in SZ. These findings (i) highlight differential characteristics of low versus high frequency and induced versus entrained oscillatory auditory responses in both SZ and healthy stimulus processing, (ii) provide support for an NMDA-receptor hypofunction-based pharmacological model of SZ, and (iii) report a novel pattern of aSSR abnormalities suggesting that gamma band neural entrainment deviations among SZ may be more complex than previously supposed, including possibly being substantially influenced by physical stimulus properties.

Abnormalities of neuronal oscillations and temporal integration to low- and high-frequency auditory stimulation in schizophrenia.

BACKGROUND: Electroencephalography and magnetoencephalography studies indicate among schizophrenia patients (SZ) abnormal, often reduced, entrained steady-state (aSSR) and transient (N100/M100) neural responses to auditory stimuli. We complement this literature by focusing analyses on auditory cortices, assessing a wide range of stimulation frequencies with long driving periods and evaluating relationships between aSSR and M100 reductions in SZ. METHODS: Seventeen SZ and 17 healthy subjects (H) participated. Stimuli were 1500 msec binaural broadband noise sequences modulated at 5, 20, 40, 80, or 160 Hz. Magnetoencephalography data were collected and co-registered with structural magnetic resonance images. The aSSRs and M100s projected into brain space were analyzed as a function of hemisphere, stimulus density, and time. RESULTS: For aSSR, SZ displayed weaker entrainment bilaterally at low (5-Hz) and high (80-Hz) modulation frequencies. To 40-Hz stimuli, SZ showed weaker entrainment only in right auditory cortex. For M100, while responses for H increased linearly with stimulus density, this effect was weaker or absent in SZ. A principal components analysis of SZ deficits identified low (5-Hz entrainment and M100) and high (40- to 80-Hz entrainment) frequency components. Discriminant analysis indicated that the low-frequency component uniquely differentiated SZ from H. The high-frequency component correlated with negative symptoms among SZ. CONCLUSIONS: The SZ auditory cortices were unable to 1) generate healthy levels of theta and high gamma band (80-Hz) entrainment (aSSR), and 2) augment transient responses (M100s) to rapidly presented auditory information (an index of temporal integration). Only the latter was most apparent in left hemisphere and may reflect a prominent neurophysiological deficit in schizophrenia.

Hemispheric differences in auditory oddball responses during monaural versus binaural stimulation.

Hemispheric lateralization of early event-related potentials (ERPs; e.g. N1) is largely based on anatomy of the afferent pathway; lateralization of later auditory ERPs (P2/N2, P250, P3b) is less clear. Using 257-channel EEG, the present study examined hemispheric laterality of auditory ERPs by comparing binaural and monaural versions of an auditory oddball task. N1 showed a contralateral bias over auditory cortex in both hemispheres as a function of ear of stimulation, although right hemisphere sources were activated regardless of which ear received input. Beginning around N1 and continuing through the time of P3b, right hemisphere temporal-parietal and frontal areas were more activated than their left hemisphere counterparts for stimulus evaluation/comparison and target detection. P250 and P3b component amplitudes, topographies, and source estimations were significantly influenced by ear of stimulation, with right hemisphere activity being stronger. This was particularly true for anterior temporal and inferior frontal sources which were more strongly associated with the later, more cognitive components (P250, P3b). Results are consistent with theories of a right hemisphere network that is prominently involved in sustained attention, stimulus evaluation, target detection, and working memory/context updating.

Stimulus sequence affects schizophrenia-normal differences in event processing during an auditory oddball task.

Schizophrenia patients have difficulty distinguishing relevant from irrelevant auditory information. Auditory oddball paradigms are commonly used to investigate the processing of stimulus relevance. The present study used dense-array EEG and distributed source reconstructions to examine schizophrenia-normal differences in the processing of targets and standards as a function of the temporal sequence of stimuli. Brain responses were evaluated separately for early and late standards (standards 1-3 and 4-6 following a target, respectively) and early and late targets (those following 2-3 standards and 4-6 standards, respectively). The latencies of peaks (N1, P2, P3) in the event-related potential (ERP) waveforms did not differ between schizophrenia and normal subjects. However, schizophrenia-normal differences in neural activity, derived from minimum norm estimation, occurred at specific times during stimulus processing as a function of stimulus sequence. Schizophrenia patients displayed smaller activity than normals in early ERPs (left hemispheric N1, right frontal P2) to late targets, and they produced P3-like responses to late standards. Furthermore, during the P2/N2 time interval, opposite patterns of brain activity were elicited in schizophrenia and normal subjects in response to standards, indicating different neural responses to the same stimulus events. These results suggest attention allocation to task-irrelevant stimuli in schizophrenia, consequent upon insufficient representation of stimulus significance and context. Thus, schizophrenia compromises the ability to properly use context to solve even simple cognitive problems.

Rate of stimulation affects schizophrenia-normal differences on the N1 auditory-evoked potential.

The present study examined how increasing the rate of steady-state stimulation affects schizophrenia-normal differences on the N1 auditory-evoked potential, an index of auditory integration. Dense-array EEG was recorded while schizophrenia and normal subjects heard 1 kHz tones amplitude modulated at 10, 20, 40, or 80 Hz. Spectral power across frequency and time was calculated. The typically lower N1 amplitude in schizophrenia, observed at the 10 Hz burst rate, increased to nearly equal that of normal individuals at 20 Hz. Unlike normal subjects, schizophrenia subjects' power at N1 failed to increase at the 40 and 80 Hz burst rates. These results suggest steady-state stimuli, up to a point, provide the extra information needed for schizophrenia patients to more efficiently integrate auditory information.