Assessing Trial-to-Trial Variability in Auditory ERPs in Autism and Schizophrenia.

Sensory abnormalities are characteristic of autism and schizophrenia. In autism, greater trial-to-trial variability (TTV) in sensory neural responses suggest that the system is more unstable. However, these findings have only been identified in the amplitude and not in the timing of neural responses, and have not been fully explored in schizophrenia. TTV in event-related potential amplitudes and inter-trial coherence (ITC) were assessed in the auditory mismatch negativity (MMN) in autism, schizophrenia, and controls. MMN was largest in autism and smallest in schizophrenia, and TTV was greater in autism and schizophrenia compared to controls. There were no differences in ITC. Greater TTV appears to be characteristic of both autism and schizophrenia, implicating several neural mechanisms that could underlie sensory instability.

Reduced late mismatch negativity and auditory sustained potential to rule-based patterns in schizophrenia.

Complex rule-based auditory processing is abnormal in individuals with long-term schizophrenia (SZ), as demonstrated by reduced mismatch negativity (MMN) to deviants in rule-based patterns and reduced auditory sustained potential (ASP) that appears when grouping tones together. Together, this suggests deficits later in the auditory processing hierarchy in Sz. Here, MMN and ASP were elicited by deviations from a complex zig-zag pitch pattern that cannot be predicted by simple linear rules. Twenty-seven SZ and 26 matched healthy controls (HC) participated. Frequent groups of patterns contained eight tones that zig-zagged in a two-up one-down pitch-based paradigm. There were two deviant patterns: the final tone was either higher in pitch than expected (creating a jump in pitch) or was repeated. Simple MMN to pitch-deviants among repetitive tones was measured for comparison. Sz exhibited a smaller pitch MMN compared to HC as expected. HC produced a late MMN in response to the repeat and jump-deviant and a larger ASP to the standard group of tones, all of which were significantly blunted in SZ. In Sz, the amplitude of the late complex MMN was related to neuropsychological functioning, whereas ASP was not. ASP and late MMN did not significantly correlate in HC or in Sz, suggesting that they are not dependent on one another and may originate within distinct processing streams. Together, this suggests multiple deficits later in the auditory sensory-perceptual hierarchy in Sz, with impairments evident in both segmentation and deviance detection abilities.

Complex mismatch negativity to tone pair deviants in long-term schizophrenia and in the first-episode schizophrenia spectrum.

Mismatch negativity (MMN) is an event-related potential to stimulus change. MMN to infrequent deviant tones that differs in a simple physical parameter from repetitive standard tones is reduced in patients with long-term schizophrenia (Sz; d=~1). However, this simple MMN is not uniformly reduced at the first-episode of schizophrenia-spectrum psychosis (FESz; d<0.1 for pitch; <0.4 for duration). Deviant stimuli that violate pattern rules also evoke MMN. This complex MMN is evoked by deviations in the relation of sounds to each other. The simplest pattern involves tone pairs. Although the pitch of first tone in the pair varies, the second tone's pitch always follows a rule (e.g., always 3 semitones higher). We measured complex MMN to deviant tone pairs that descended in pitch among standard tone pairs that ascended in pitch, never before examined in Sz or in FESz. Experiment 1 showed significant reductions in complex MMN in 20 Sz compared to 22 matched controls. Experiment 2 replicated smaller complex MMN in a shorter protocol in 24 Sz compared to 21 matched controls, but showed no significant complex MMN reduction in 21 FESz compared to 21 matched controls. Although reduced in Sz, indicating deficits in generation of a simple acoustic pattern rule, the tone pair complex MMN was within normal limits in FESz. This suggests that more complex perceptual pattern analysis processes are, at least partially, still intact at the first break. Future work will determine at what point of pattern complexity subtle auditory perception pathophysiology will be revealed in FESz.

Reduced auditory segmentation potentials in first-episode schizophrenia.

Auditory scene analysis (ASA) dysfunction is likely an important component of the symptomatology of schizophrenia. Auditory object segmentation, the grouping of sequential acoustic elements into temporally-distinct auditory objects, can be assessed with electroencephalography through measurement of the auditory segmentation potential (ASP). Further, N2 responses to the initial and final elements of auditory objects are enhanced relative to medial elements, which may indicate auditory object edge detection (initiation and termination). Both ASP and N2 modulation are impaired in long-term schizophrenia. To determine whether these deficits are present early in disease course, we compared ASP and N2 modulation between individuals at their first episode of psychosis within the schizophrenia spectrum (FE, N=20) and matched healthy controls (N=24). The ASP was reduced by >40% in FE; however, N2 modulation was not statistically different from HC. This suggests that auditory segmentation (ASP) deficits exist at this early stage of schizophrenia, but auditory edge detection (N2 modulation) is relatively intact. In a subset of subjects for whom structural MRIs were available (N=14 per group), ASP sources were localized to midcingulate cortex (MCC) and temporal auditory cortex. Neurophysiological activity in FE was reduced in MCC, an area linked to aberrant perceptual organization, negative symptoms, and cognitive dysfunction in schizophrenia, but not temporal auditory cortex. This study supports the validity of the ASP for measurement of auditory object segmentation and suggests that the ASP may be useful as an early index of schizophrenia-related MCC dysfunction. Further, ASP deficits may serve as a viable biomarker of disease presence.

Impairment in Mismatch Negativity but not Repetition Suppression in Schizophrenia.

Schizophrenia is characterized by impaired auditory-evoked potentials (AEPs), mismatch negativity (MMN), and sensory gating of AEPs to repeated stimuli (repetition suppression, RS). In the predictive modeling framework, MMN and RS reflect encoding of prediction error and model sharpening, respectively. We compared P50, N100, P200 RS, and pitch and duration MMN in 26 participants diagnosed with schizophrenia (SZ) and 26 matched healthy controls (HC), and assessed relationships between MMN, RS, and SZ diagnosis. RS was measured by comparing responses to individual tones presented as 5-tone groups (1 kHz, 75 dB, 50 ms, 5 ms rise/fall times, 330 ms SOA), separated by a 750 ms inter-trial interval. For MMN, the same tones were presented, with occasional pitch (1.2 kHz, 10%) or duration deviants (100 ms, 10%) interspersed. Pitch and duration MMN were reduced in SZ (p < 0.01). There were no group differences in P50 RS, N100 RS, or P200 RS (p's > 0.1). Importantly, although pitch and duration MMN both correlated with RS of AEPs within the MMN time range (p's < 0.01), SZ diagnosis predicted MMN over and above RS (p < 0.05) and shared little variance with RS in prediction of MMN amplitude (tolerance > 0.93). We suggest that reduced MMN in SZ is related to deficits in encoding prediction error but not repetition suppression.

Mismatch Negativity in First-Episode Schizophrenia: A Meta-Analysis.

Mismatch negativity (MMN) to deviant stimuli is robustly smaller in individuals with chronic schizophrenia compared with healthy controls (Cohen's d > 1.0 or more), leading to the possibility of MMN being used as a biomarker for schizophrenia. However, there is some debate in the literature as to whether MMN is reliably reduced in first-episode schizophrenia patients. For the biomarker to be used as a predictive marker for schizophrenia, it should be reduced in the majority of cases known to have the disease, particularly at disease onset. We conducted a meta-analysis on the fourteen studies that measured MMN to pitch or duration deviants in healthy controls and patients within 12 months of their first episode of schizophrenia. The overall effect size showed no MMN reduction in first-episode patients to pitch-deviants (Cohen's d < 0.04), and a small-to-medium reduction to duration-deviants (Cohen's d = 0.47). Together, this indicates that pitch-deviant MMN is not a candidate biomarker for schizophrenia prediction, while duration-deviant MMN may hold some promise, albeit nearly a third as large an effect as in chronic schizophrenia. Potential causes for discrepancies between studies are discussed.

Abnormal auditory pattern perception in schizophrenia.

Mismatch negativity (MMN) in response to deviation from physical sound parameters (e.g., pitch, duration) is reduced in individuals with long-term schizophrenia (Sz), suggesting deficits in deviance detection. However, MMN can appear at several time intervals as part of deviance detection. Understanding which part of the processing stream is abnormal in Sz is crucial for understanding MMN pathophysiology. We measured MMN to complex pattern deviants, which have been shown to produce multiple MMNs in healthy controls (HC). Both simple and complex MMNs were recorded from 27 Sz and 27 matched HC. For simple MMN, pitch- and duration-deviants were presented among frequent standard tones. For complex MMN, patterns of five single tones were repeatedly presented, with the occasional deviant group of tones containing an extra sixth tone. Sz showed smaller pitch MMN (p=0.009, ~110ms) and duration MMN (p=0.030, ~170ms) than healthy controls. For complex MMN, there were two deviance-related negativities. The first (~150ms) was not significantly different between HC and SZ. The second was significantly reduced in Sz (p=0.011, ~400ms). The topography of the late complex MMN was consistent with generators in anterior temporal cortex. Worse late MMN in Sz was associated with increased emotional withdrawal, poor attention, lack of spontaneity/conversation, and increased preoccupation. Late MMN blunting in schizophrenia suggests a deficit in later stages of deviance processing. Correlations with negative symptoms measures are preliminary, but suggest that abnormal complex auditory perceptual processes may compound higher-order cognitive and social deficits in the disorder.

Event-related potentials demonstrate deficits in acoustic segmentation in schizophrenia.

Segmentation of the acoustic environment into discrete percepts is an important facet of auditory scene analysis (ASA). Segmentation of auditory stimuli into perceptually meaningful and localizable groups is central to ASA in everyday situations; for example, separation of discrete words from continuous sentences when processing language. This is particularly relevant to schizophrenia, where deficits in perceptual organization have been linked to symptoms and cognitive dysfunction. Here we examined event-related potentials in response to grouped tones to elucidate schizophrenia-related differences in acoustic segmentation. We report for the first time in healthy subjects a sustained potential that begins with group initiation and ends with the last tone of the group. These potentials were reduced in schizophrenia, with the greatest differences in responses to first and final tones. Importantly, reductions in sustained potentials in schizophrenia patients were associated with greater negative symptoms and deficits in IQ, working memory, learning, and social cognition. These results suggest deficits in auditory pattern segmentation in schizophrenia may compound deficits in many higher-order facets of the disorder.