Recovery of auditory evoked response attentional gain modulation following the first psychotic episode indexes improvements in symptom severity.

Attentional control of auditory N100/M100 gain is reduced in individuals with first-episode psychosis (FEP). Persistent problems with executive modulation of auditory sensory activity may impact multiple aspects of psychosis. As a follow-up to our prior work reporting deficits in attentional M100 gain modulation in auditory cortex, we examined changes in M100 gain modulation longitudinally, and further examined relationships between auditory M100 and symptoms of psychosis. We compared auditory M100 in auditory sensory cortex between 21 FEP and 29 matched healthy participants and between timepoints separated by 220 ± 100 days. Magnetoencephalography data were recorded while participants alternately attended or ignored tones in an auditory oddball task. M100 was measured as the average of 80-140 ms post-stimulus in source-localized evoked responses within bilateral auditory cortex. Symptoms were assessed using the PANSS and PSYRATS. M100 amplitudes, attentional modulation of M100 amplitudes, and symptom severity all improved in FEP over time. Further, improvement in M100 modulation correlated with improvements in negative symptoms (PANSS) as well as physical, cognitive, and emotional components of hallucinations (PSYRATS). Conversely, improvements in the overall size of the M100, rather than the difference between active and passive M100 amplitudes, were related to worsening of positive symptoms (PANSS) and physical components of hallucinations. Results indicate a link between symptoms (particularly auditory hallucinations) and auditory cortex neurophysiology in FEP, where auditory attention and auditory sensation have opposed relationships to symptom change. These findings may inform current models of psychosis etiology and could provide nonpharmaceutical avenues for early intervention.

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.

Attentional M100 gain modulation localizes to auditory sensory cortex and is deficient in first-episode psychosis.

Selective attention is impaired in first-episode psychosis (FEP). Selective attention effects can be detected during auditory tasks as increased sensory activity. We previously reported electroencephalography scalp-measured N100 enhancement is reduced in FEP. Here, we localized magnetoencephalography (MEG) M100 source activity within the auditory cortex, making novel use of the Human Connectome Project multimodal parcellation (HCP-MMP) to identify precise auditory cortical areas involved in attention modulation and its impairment in FEP. MEG was recorded from 27 FEP and 31 matched healthy controls (HC) while individuals either ignored frequent standard and rare oddball tones while watching a silent movie or attended tones by pressing a button to oddballs. Because M100 arises mainly in the auditory cortices, MEG activity during the M100 interval was projected to the auditory sensory cortices defined by the HCP-MMP (A1, lateral belt, and parabelt parcels). FEP had less auditory sensory cortex M100 activity in both conditions. In addition, there was a significant interaction between group and attention. HC enhanced source activity with attention, but FEP did not. These results demonstrate deficits in both sensory processing and attentional modulation of the M100 in FEP. Novel use of the HCP-MMP revealed the precise cortical areas underlying attention modulation of auditory sensory activity in healthy individuals and impairments in FEP. The sensory reduction and attention modulation impairment indicate local and systems-level pathophysiology proximal to disease onset that may be critical for etiology. Further, M100 and N100 enhancement may serve as outcome variables for targeted intervention to improve attention in early psychosis.

Intensity and inter-stimulus-interval effects on human middle- and long-latency auditory evoked potentials in an unpredictable auditory context.

It is not known how Auditory-Evoked Responses (AERs) comprising Middle Latency Responses (MLRs) and Long Latency Responses (LLRs) are modulated by stimulus intensity and inter-stimulus interval (ISI) in an unpredictable auditory context. Further, intensity and ISI effects on MLR and LLR have never been assessed simultaneously in the same humans. To address this important question, thirty participants passively listened to a random sequence of auditory clicks of three possible intensities (65, 75, and 85 dB) at five possible ISI ranges (0.25 to 0.5 s, 0.5 to 1 s, 1 to 2 s, 2 to 4 s, 4 to 8 s) over four to seven one-hour sessions while EEG was recorded. P0, Na, Pa, Nb, and Pb MLR peaks and N1 and P2 LLR peaks were measured. MLRs P0 (p = .005), Pa (p = .021), and Pb (p = <.001) were modulated by intensity, while only MLR Pb (p = <.001) was modulated by ISI. LLR N1 and P2 were modulated by both intensity and ISI (all p values < .001). Intensity and ISI interacted at Pb, N1, and P2 (all p values < .001), with greater intensity effects at longer ISIs and greater ISI effects at louder intensities. Together, these results provide a comprehensive picture of intensity and ISI effects on AER across the entire thalamocortical auditory pathway, while controlling for stimulus predictability. Moreover, they highlight P0 as the earliest MLR response sensitive to stimulus intensity and Pb (~50 ms) as the earliest cortical response coding for ISIs above 250 ms and showing an interdependence between intensity and ISI effects.

Aberrant attentional modulation of the auditory steady state response (ASSR) is related to auditory hallucination severity in the first-episode schizophrenia-spectrum.

The 40-Hz auditory steady state response (ASSR) is reduced early in schizophrenia, with differences evident even at the first episode of schizophrenia-spectrum psychosis (FESz). Although robust, there is high variability in effect size across studies, possibly due to differences in experimental control of attention and heterogeneity of symptom profiles across studies, both of which may affect the ASSR. We investigated the relationships among ASSR deficits, attention-mediated sensory gain, and auditory hallucinations in 25 FESz (15 male; 23.3 ± 4.5 years) and 32 matched healthy comparison subjects (HC, 22 male; 24.7 ± 5.8 years). ASSR was measured to 40-Hz click trains at three intensities (75, 80, and 85 dB) while participants attended or ignored stimuli. ASSR evoked power and inter-trial phase coherence (ITPC) were measured using the Morlet wavelet transform. FESz did not show overall ASSR power reduction (p > 0.1), but power was significantly increased with attention in HC (p < 0.01), but not in FESz (p > 0.1). Likewise, FESz did not evince overall ASSR ITPC reduction (p > 0.1), and ITPC was significantly increased with attention in HC (p < 0.01), but not in FESz (p > 0.09). Attention-related change in ASSR correlated with auditory hallucination severity for power (r = -0.49, p < 0.05) and ITPC (r = -0.58, p < 0.01). FESz with auditory hallucinations may have pathologically increased basal excitability of auditory cortex and consequent reduced ability to further increase auditory cortex sensory gain with focused attention. These findings indicate hallucination-related pathophysiology early in schizophrenia and may guide novel intervention strategies aimed to modulate basal activity levels.

Deficits in attentional modulation of auditory N100 in first-episode schizophrenia.

Reductions of the auditory N100 are present in schizophrenia, even at the first episode (FESz). Because most studies examine auditory N100 on active target detection oddball tasks, it remains unclear if the abnormality in FESz results from sensory deficits or impaired enhancement of N100 by selective attention, or both. N100 was recorded from 21 FESz and 22 matched healthy controls (HC) on a single-tone task and a two-tone oddball task. Overall, N100 was smaller in FESz (p = .036). Attention enhanced N100 amplitude (p < .001), but this differed between groups, with FESz impaired in N100 modulation (group x attention, p = .012). The oddball task showed greater N100 enhancement than the single-tone task (p < .001) in both groups. Group differences in N100 enhancement in the oddball task were large (Cohen's d = 0.85). Exploratory correlations showed that better N100 enhancement on the oddball task in FESz was associated with better MATRICS Overall Composite scores (cognitive tasks highly sensitive to psychosis), lower PANNS Negative factor and SANS scores, and better interpersonal (social) and role functioning in the last year. N100 during ignore conditions showed no significant difference between groups, albeit smaller in FESz, with small to medium effect sizes. Although sensory deficits in N100 are likely present, they are compounded by a failure to enhance N100 with attention. The failure of N100 enhancement by attentional gain control in FESz suggests functional dysconnection between cognitive control areas and the sensory cortex. N100 amplitude on active attention tasks may be a useful outcome biomarker for targeted enhancement of the cognitive control system.

Deficit Effect Sizes and Correlations of Auditory Event-Related Potentials at First Hospitalization in the Schizophrenia Spectrum.

The N1, P2, and P3 event-related potentials (ERPs) are impaired in first-episode schizophrenia (FESz). Reduced pitch-deviant mismatch negativity (MMN) is present in chronic schizophrenia but not FESz. We examined effect sizes of, and correlations between, N1, P2, P3, and MMN in 106 FESz and 114 matched psychiatrically well controls to determine which ERPs maximally differentiated groups, and whether late sensory/perceptual deficits (N1, P2) affected preattentive memory (MMN) and conscious attention (P3). Furthermore, we compared hallucinators and nonhallucinators within FESz. Participants completed 1 of 3 oddball tasks, silently counting target tones among standard tones. Sixty-seven FESz and 72 matched participants also completed pitch-deviant MMN testing. Measures were z-scored from task appropriate controls before merging samples. Mean z-scores for N1, P2, and P3 were significantly abnormal in FESz, while pitch-deviant MMN was not. N1 showed the largest deficit (z = 0.53), and only N1 was smaller in hallucinators (n = 71) than nonhallucinators (n = 27). Among all participants, early sensory processing (N1, P2) correlated with later cognitive processing (P3), and P2 and P3 also correlated with automatic preattentive memory (pitch-deviant MMN). In well individuals, N1 was associated with MMN. These data are consistent with bottom-up sensory/perceptual processes affecting more cognitive processes. However, N1 and MMN were not associated in FESz, suggesting different auditory cortex physiology underlie these ERPs, which is differentially affected in FESz. Larger P2 and P3 with greater estimated premorbid intellect in patients indicate a possible neuroprotective effect of intellect in FESz.

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.

Decomposing P300 into correlates of genetic risk and current symptoms in schizophrenia: An inter-trial variability analysis.

BACKGROUND: The P300 event-related potential (ERP) component, which reflects cognitive processing, is a candidate biomarker for schizophrenia. However, the role of P300 in the pathophysiology of schizophrenia remains unclear because averaged P300 amplitudes reflect both genetic predisposition and current clinical status. Thus, we sought to identify which aspects of P300 are associated with genetic risk versus symptomatic status via an inter-trial variability analysis. METHODS: Auditory P300, clinical symptoms, and neurocognitive function assessments were obtained from forty-five patients with schizophrenia, thirty-two subjects at genetic high risk (GHR), thirty-two subjects at clinical high risk (CHR), and fifty-two healthy control (HC) participants. Both conventional averaging and inter-trial variability analyses were conducted for P300, and results were compared across groups using analysis of variance (ANOVA). Pearson's correlation was utilized to determine associations among inter-trial variability for P300, current symptoms and neurocognitive status. RESULTS: Average P300 amplitude was reduced in the GHR, CHR, and schizophrenia groups compared with that in the HC group. P300 inter-trial variability was elevated in the CHR and schizophrenia groups but relatively normal in the GHR and HC groups. Furthermore, P300 inter-trial variability was significantly related to negative symptom severity and neurocognitive performance results in schizophrenia patients. CONCLUSIONS: These results suggest that P300 amplitude is an endophenotype for schizophrenia and that greater inter-trial variability of P300 is associated with more severe negative and cognitive symptoms in schizophrenia patients.

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 Complex Auditory Pattern Analysis in Schizophrenia Reflected in an Absent Missing Stimulus Mismatch Negativity.

The simple mismatch negativity (MMN) to tones deviating physically (in pitch, loudness, duration, etc.) from repeated standard tones is robustly reduced in schizophrenia. Although generally interpreted to reflect memory or cognitive processes, simple MMN likely contains some activity from non-adapted sensory cells, clouding what process is affected in schizophrenia. Research in healthy participants has demonstrated that MMN can be elicited by deviations from abstract auditory patterns and complex rules that do not cause sensory adaptation. Whether persons with schizophrenia show abnormalities in the complex MMN is unknown. Fourteen schizophrenia participants and 16 matched healthy underwent EEG recording while listening to 400 groups of 6 tones 330 ms apart, separated by 800 ms. Occasional deviant groups were missing the 4th or 6th tone (50 groups each). Healthy participants generated a robust response to a missing but expected tone. The schizophrenia group was significantly impaired in activating the missing stimulus MMN, generating no significant activity at all. Schizophrenia affects the ability of "primitive sensory intelligence" and pre-attentive perceptual mechanisms to form implicit groups in the auditory environment. Importantly, this deficit must relate to abnormalities in abstract complex pattern analysis rather than sensory problems in the disorder. The results indicate a deficit in parsing of the complex auditory scene which likely impacts negatively on successful social navigation in schizophrenia. Knowledge of the location and circuit architecture underlying the true novelty-related MMN and its pathophysiology in schizophrenia will help target future interventions.

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.

Finding the missing-stimulus mismatch negativity (MMN) in early psychosis: altered MMN to violations of an auditory gestalt.

The mismatch negativity (MMN) is an EEG-derived event-related potential (ERP) elicited by any violation of a predicted auditory 'rule', regardless of whether one is attending to the stimuli, and is thought to reflect updating of the stimulus context. Chronic schizophrenia patients exhibit robust MMN deficits, while MMN reduction in first-episode and early phase psychosis is significantly less consistent. Traditional two-tone "oddball" MMN measures of sensory information processing may be considered too simple for use in early phase psychosis in which pathology has not progressed fully, and a paradigm that probes higher order processes may be more appropriate for elucidating auditory change detection deficits. This study investigated whether MMN deficits could be detected in early phase psychosis (EP) patients using an abstract 'missing stimulus' pattern paradigm (Salisbury, 2012). The stimuli were 400 groups of six tones (1000Hz, 50ms duration, 330ms stimulus onset asynchrony), which was presented with an inter-trial interval of 750ms. Occasionally a group contained a deviant, meaning that it was missing either the 4th or 6th tone (50 trials each). EEG recordings of 13 EP patients (≤5year duration of illness) and 15 healthy controls (HC) were collected. Patients and controls did not significantly differ on age or years of education. Analyses of MMN amplitudes elicited by missing stimuli revealed amplitude reductions in EP patients, suggesting that these deficits are present very early in the progression of the illness. While there were no correlations between MMN measures and measures such as duration of illness, medication dosage or age, MMN amplitude reductions were correlated with positive symptomatology (i.e. auditory hallucinations). These findings suggest that MMNs elicited by the 'missing stimulus' paradigm are impaired in psychosis patients early in the progression of illness and that previously reported MMN-indexed deficits related to auditory hallucinations in chronic patients may also be present in EP patients. As such, this paradigm may have promise in identifying early processing deficits in this population.

Early auditory gamma band response abnormalities in first hospitalized schizophrenia.

BACKGROUND: Abnormalities in coherent cortical circuit functioning, reflected in gamma band activity (to approximately 40 Hz), may be a core deficit in schizophrenia. The early auditory gamma band response (EAGBR) is a neurophysiologically simple probe of circuit functioning in primary auditory cortex. We examined the EAGBR in first hospitalized schizophrenia to assess whether it was reduced at first hospitalization. METHOD: Wavelet evoked power and intertrial phase locking of the EAGBR at Fz to standard tones during an oddball target detection task were examined in 28 first hospitalized schizophrenia patients (10 female) and 44 control subjects (17 female). RESULTS: At first hospitalization EAGBR trial-to-trial phase locking and evoked power were significantly reduced in patients. Although reduced overall in patients, greater total symptoms were significantly associated with greater gamma phase locking and power. Additionally, greater EAGBR power was marginally associated with greater positive factor scores, hallucinations, and thinking disturbance. CONCLUSIONS: Abnormalities of gamma band functioning in local auditory sensory circuits are present in schizophrenia at first hospitalization further evidence that basic sensory processes are impaired in schizophrenia. It remains to be determined whether the EAGBR becomes permanently impaired with disease progression, and if its reduction is specific to schizophrenia.

Patterns of deficits in brain function in bipolar disorder and schizophrenia: a cluster analytic study.

Historically, bipolar disorder and schizophrenia have been considered distinct disorders with different etiologies. Growing evidence suggests that overlapping genetic influences contribute to risk for these disorders and that each disease is genetically heterogeneous. Using cluster analytic methods, we empirically identified homogeneous subgroups of patients, their relatives, and controls based on distinct neurophysiologic profiles. Seven phenotypes were collected from two independent cohorts at two institutions. K-means clustering was used to identify neurophysiologic profiles. In the analysis of all participants, three distinct profiles emerged: "globally impaired", "sensory processing", and "high cognitive". In a secondary analysis, restricted to patients only, we observed a similar clustering into three profiles. The neurophysiological profiles of the Schizophrenia (SZ) and Bipolar Disorder (BPD) patients did not support the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic distinction between these two disorders. Smokers in the globally impaired group smoked significantly more cigarettes than those in the sensory processing or high cognitive groups. Our results suggest that empirical analyses of neurophysiological phenotypes can identify potentially biologically relevant homogenous subgroups independent of diagnostic boundaries. We hypothesize that each neurophysiology subgroup may share similar genotypic profiles, which may increase statistical power to detect genetic risk factors.

Finding the missing stimulus mismatch negativity (MMN): emitted MMN to violations of an auditory gestalt.

Deviations from repetitive auditory stimuli evoke a mismatch negativity (MMN). Counterintuitively, omissions of repetitive stimuli do not. Violations of patterns reflecting complex rules also evoke MMN. To detect a MMN to missing stimuli, we developed an auditory gestalt task using one stimulus. Groups of six pips (50 ms duration, 330 ms stimulus onset asynchrony [SOA], 400 trials), were presented with an intertrial interval (ITI) of 750 ms while subjects (n=16) watched a silent video. Occasional deviant groups had missing 4th or 6th tones (50 trials each). Missing stimuli evoked a MMN (p<.05). The missing 4th (-0.8 µV, p<.01) and the missing 6th stimuli (-1.1 µV, p<.05) were more negative than standard 6th stimuli (0.3 µV). MMN can be elicited by a missing stimulus at long SOAs by violation of a gestalt grouping rule. Patterned stimuli appear more sensitive to omissions and ITI than homogenous streams.