Auditory Oddball Responses Across the Schizophrenia-Bipolar Spectrum and Their Relationship to Cognitive and Clinical Features.

OBJECTIVE: Neural activations during auditory oddball tasks may be endophenotypes for psychosis and bipolar disorder. The authors investigated oddball neural deviations that discriminate multiple diagnostic groups across the schizophrenia-bipolar spectrum (schizophrenia, schizoaffective disorder, psychotic bipolar disorder, and nonpsychotic bipolar disorder) and clarified their relationship to clinical and cognitive features. METHODS: Auditory oddball responses to standard and target tones from 64 sensor EEG recordings were compared across patients with psychosis (total N=597; schizophrenia, N=225; schizoaffective disorder, N=201; bipolar disorder with psychosis, N=171), patients with bipolar disorder without psychosis (N=66), and healthy comparison subjects (N=415) from the second iteration of the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP2) study. EEG activity was analyzed in voltage and in the time-frequency domain (low, beta, and gamma bands). Event-related potentials (ERPs) were compared with those from an independent sample collected during the first iteration of B-SNIP (B-SNIP1; healthy subjects, N=211; psychosis group, N=526) to establish the repeatability of complex oddball ERPs across multiple psychosis syndromes (r values >0.94 between B-SNIP1 and B-SNIP2). RESULTS: Twenty-six EEG features differentiated the groups; they were used in discriminant and correlational analyses. EEG variables from the N100, P300, and low-frequency ranges separated the groups along a diagnostic continuum from healthy to bipolar disorder with psychosis/bipolar disorder without psychosis to schizoaffective disorder/schizophrenia and were strongly related to general cognitive function (r=0.91). P50 responses to standard trials and early beta/gamma frequency responses separated the bipolar disorder without psychosis group from the bipolar disorder with psychosis group. P200, N200, and late beta/gamma frequency responses separated the two bipolar disorder groups from the other groups. CONCLUSIONS: Neural deviations during auditory processing are related to psychosis history and bipolar disorder. There is a powerful transdiagnostic relationship between severity of these neural deviations and general cognitive performance. These results have implications for understanding the neurobiology of clinical syndromes across the schizophrenia-bipolar spectrum that may have an impact on future biomarker research.

Schizophrenia Exhibits Bi-directional Brain-Wide Alterations in Cortico-Striato-Cerebellar Circuits.

Distributed neural dysconnectivity is considered a hallmark feature of schizophrenia (SCZ), yet a tension exists between studies pinpointing focal disruptions versus those implicating brain-wide disturbances. The cerebellum and the striatum communicate reciprocally with the thalamus and cortex through monosynaptic and polysynaptic connections, forming cortico-striatal-thalamic-cerebellar (CSTC) functional pathways that may be sensitive to brain-wide dysconnectivity in SCZ. It remains unknown if the same pattern of alterations persists across CSTC systems, or if specific alterations exist along key functional elements of these networks. We characterized connectivity along major functional CSTC subdivisions using resting-state functional magnetic resonance imaging in 159 chronic patients and 162 matched controls. Associative CSTC subdivisions revealed consistent brain-wide bi-directional alterations in patients, marked by hyper-connectivity with sensory-motor cortices and hypo-connectivity with association cortex. Focusing on the cerebellar and striatal components, we validate the effects using data-driven k-means clustering of voxel-wise dysconnectivity and support vector machine classifiers. We replicate these results in an independent sample of 202 controls and 145 patients, additionally demonstrating that these neural effects relate to cognitive performance across subjects. Taken together, these results from complementary approaches implicate a consistent motif of brain-wide alterations in CSTC systems in SCZ, calling into question accounts of exclusively focal functional disturbances.

Early and late auditory information processing show opposing deviations in aniridia.

Aniridia is a congenital disorder, predominantly caused by heterozygous mutations of the PAX6 gene. While ocular defects have been extensively characterized in this population, brain-related anatomical and functional abnormalities are emerging as a prominent feature of the disorder. Individuals with aniridia frequently exhibit auditory processing deficits despite normal audiograms. While previous studies have reported hypoplasia of the anterior commissure and corpus callosum in some of these individuals, the neurophysiological basis of these impairments remains unexplored. This study provides direct assessment of neural activity related to auditory processing in aniridia. Participants were presented with tones designed to elicit an auditory steady-state response (ASSR) at 22 Hz, 40 Hz, and 84 Hz, and infrequent broadband target tones to maintain attention during electroencephalography (EEG) recording. Persons with aniridia showed increased early cortical responses (P50 AEP) in response to all tones, and increased high-frequency oscillatory entrainment (84 Hz ASSR). In contrast, this group showed a decreased cortical integration response (P300 AEP to target tones) and reduced neural entrainment to cortical beta-band stimuli (22 Hz ASSR). Collectively, our results suggest that subcortical and early cortical auditory processing is augmented in aniridia, while functional cortical integration of auditory information is deficient in this population.

Alterations in intrinsic fronto-thalamo-parietal connectivity are associated with cognitive control deficits in psychotic disorders.

Despite a growing number of reports about alterations in intrinsic/resting brain activity observed in patients with psychotic disorders, their relevance to well-established cognitive control deficits in this patient group is not well understood. Totally 88 clinically stabilized patients with a psychotic disorder and 50 healthy controls participated in a resting-state magnetic resonance imaging study (rs-MRI) and performed an antisaccade task in the laboratory to assess voluntary inhibitory control ability. Deficits on this task are a well-established biomarker across psychotic disorders as we found in the present patient sample. First, regional cerebral function was evaluated by measuring the amplitude of low frequency fluctuations (ALFF) in rs-MRI BOLD signals. We found reduced ALFF in patients in regions known to be relevant to antisaccade task performance including bilateral frontal eye fields (FEF), supplementary eye fields (SEF) and thalamus. Second, areas with ALFF alterations were used as seed areas in whole-brain functional connectivity (FC) analysis. Altered FC was observed in a fronto-thalamo-parietal network that was associated with inhibition error rate in patients but not in controls. In contrast, faster time to generate a correct antisaccade was associated with FC in FEF and SEF in controls but this effect was not seen in patients. These findings establish a behavioral relevance of resting-state fMRI findings in psychotic disorders, and extend previous reports of alterations in fronto-thalamo-parietal network activation during antisaccade performance seen in task-based fMRI studies.

Frequency-specific disruptions of neuronal oscillations reveal aberrant auditory processing in schizophrenia.

Individuals with schizophrenia exhibit abnormalities in evoked brain responses in oddball paradigms. These could result from (a) insufficient salience-related cortical signaling (P300), (b) insufficient suppression of irrelevant aspects of the auditory environment, or (c) excessive neural noise. We tested whether disruption of ongoing auditory steady-state responses at predetermined frequencies informed which of these issues contribute to auditory stimulus relevance processing abnormalities in schizophrenia. Magnetoencephalography data were collected for 15 schizophrenia and 15 healthy subjects during an auditory oddball paradigm (25% targets; 1-s interstimulus interval). Auditory stimuli (pure tones: 1 kHz standards, 2 kHz targets) were administered during four continuous background (auditory steady-state) stimulation conditions: (1) no stimulation, (2) 24 Hz, (3) 40 Hz, and (4) 88 Hz. The modulation of the auditory steady-state response (aSSR) and the evoked responses to the transient stimuli were quantified and compared across groups. In comparison to healthy participants, the schizophrenia group showed greater disruption of the ongoing aSSR by targets regardless of steady-state frequency, and reduced amplitude of both M100 and M300 event-related field components. During the no-stimulation condition, schizophrenia patients showed accentuation of left hemisphere 40 Hz response to both standard and target stimuli, indicating an effort to enhance local stimulus processing. Together, these findings suggest abnormalities in auditory stimulus relevance processing in schizophrenia patients stem from insufficient amplification of salient stimuli.

Identification of Distinct Psychosis Biotypes Using Brain-Based Biomarkers.

OBJECTIVE: Clinical phenomenology remains the primary means for classifying psychoses despite considerable evidence that this method incompletely captures biologically meaningful differentiations. Rather than relying on clinical diagnoses as the gold standard, this project drew on neurobiological heterogeneity among psychosis cases to delineate subgroups independent of their phenomenological manifestations. METHOD: A large biomarker panel (neuropsychological, stop signal, saccadic control, and auditory stimulation paradigms) characterizing diverse aspects of brain function was collected on individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis (N=711), their first-degree relatives (N=883), and demographically comparable healthy subjects (N=278). Biomarker variance across paradigms was exploited to create nine integrated variables that were used to capture neurobiological variance among the psychosis cases. Data on external validating measures (social functioning, structural magnetic resonance imaging, family biomarkers, and clinical information) were collected. RESULTS: Multivariate taxometric analyses identified three neurobiologically distinct psychosis biotypes that did not respect clinical diagnosis boundaries. The same analysis procedure using clinical DSM diagnoses as the criteria was best described by a single severity continuum (schizophrenia worse than schizoaffective disorder worse than bipolar psychosis); this was not the case for biotypes. The external validating measures supported the distinctiveness of these subgroups compared with clinical diagnosis, highlighting a possible advantage of neurobiological versus clinical categorization schemes for differentiating psychotic disorders. CONCLUSIONS: These data illustrate how multiple pathways may lead to clinically similar psychosis manifestations, and they provide explanations for the marked heterogeneity observed across laboratories on the same biomarker variables when DSM diagnoses are used as the gold standard.

Stimulus train duration but not attention moderates γ-band entrainment abnormalities in schizophrenia.

Electroencephalographic (EEG) studies of auditory steady-state responses (aSSRs) non-invasively probe gamma-band (40-Hz) oscillatory capacity in sensory cortex with high signal-to-noise ratio. Consistent reports of reduced 40-Hz aSSRs in persons with schizophrenia (SZ) indicate its potential as an efficient biomarker for the disease, but studies have been limited to passive or indirect listening contexts with stereotypically short (500ms) stimulus trains. An inability to modulate sensorineural processing in accord with behavioral goals or within the sensory environmental context may represent a fundamental deficit in SZ, but whether and how this deficit relates to reduced aSSRs is unknown. We systematically varied stimulus duration and attentional contexts to further mature the 40-Hz aSSR as biomarker for future translational or mechanistic studies. Eighteen SZ and 18 healthy subjects (H) were presented binaural pure-tones with or without sinusoidal amplitude modulation at 40-Hz. Stimulus duration (500-ms or 1500-ms) and attention (via a button press task) were varied across 4 separate blocks. Evoked potentials recorded with dense-array EEGs were analyzed in the time-frequency domain. SZ displayed reduced 40-Hz aSSRs to typical stimulation parameters, replicating previous findings. In H, aSSRs were reduced when stimuli were presented in longer trains and were slightly enhanced by attention. Only the former modulation was impaired in SZ and correlated with sensory discrimination performance. Thus, gamma-band aSSRs are modulated by both attentional and stimulus duration contexts, but only modulations related to physical stimulus properties are abnormal in SZ, supporting its status as a biomarker of psychotic perceptual disturbance involving non-attentional sensori-cortical circuits.

Event-related potential and time-frequency endophenotypes for schizophrenia and psychotic bipolar disorder.

BACKGROUND: The investigators compared event-related potential (ERP) amplitudes and event-related oscillations across a broad frequency range during an auditory oddball task using a comprehensive analysis approach to describe shared and unique neural auditory processing characteristics among healthy subjects (HP), schizophrenia probands (SZ) and their first-degree relatives, and bipolar disorder I with psychosis probands (BDP) and their first-degree relatives. METHODS: This Bipolar-Schizophrenia Network on Intermediate Phenotypes sample consisted of clinically stable SZ (n = 229) and BDP (n = 188), HP (n = 284), first-degree relatives of schizophrenia probands (n = 264), and first-degree relatives of bipolar disorder I with psychosis probands (n = 239). They were administered an auditory oddball task in the electroencephalography environment. Principal components analysis derived data-driven frequency bands evoked power. Spatial principal components analysis reduced ERP and frequency data to component waveforms for each subject. Clusters of time bins with significant group differences on response magnitude were assessed for proband/relative differences from HP and familiality. RESULTS: Nine variables survived a linear discriminant analysis between HP, SZ, and BDP. Of those, two showed evidence (deficit in relatives and familiality) as genetic risk markers more specific to SZ (N1, P3b), one was specific to BDP (P2) and one for psychosis in general (N2). CONCLUSIONS: This study supports for both shared and unique deficits in early sensory and late cognitive processing across psychotic diagnostic groups. Additional ERP and time-frequency component alterations (frontal N2/P2, late high, early, mid, and low frequency) may provide insight into deficits in underlying neural architecture and potential protective/compensatory mechanisms in unaffected relatives.

Family history of psychosis moderates early auditory cortical response abnormalities in non-psychotic bipolar disorder.

OBJECTIVES: Bipolar I disorder is a disabling illness affecting 1% of people worldwide. Family and twin studies suggest that psychotic bipolar disorder (BDP) represents a homogeneous subgroup with an etiology distinct from non-psychotic bipolar disorder (BDNP) and partially shared with schizophrenia. Studies of auditory electrophysiology [e.g., paired-stimulus and oddball measured with electroencephalography (EEG)] consistently report deviations in psychotic groups (schizophrenia, BDP), yet such studies comparing BDP and BDNP are sparse and, in some cases, conflicting. Auditory EEG responses are significantly reduced in unaffected relatives of psychosis patients, suggesting that they may relate to both psychosis liability and expression. METHODS: While 64-sensor EEGs were recorded, age- and gender-matched samples of 70 BDP, 35 BDNP {20 with a family history of psychosis [BDNP(+)]}, and 70 psychiatrically healthy subjects were presented with typical auditory paired-stimuli and auditory oddball paradigms. RESULTS: Oddball P3b reductions were present and indistinguishable across all patient groups. P2s to paired stimuli were abnormal only in BDP and BDNP(+). Conversely, N1 reductions to stimuli in both paradigms and P3a reductions were present in both BDP and BDNP(-) groups but were absent in BDNP(+). CONCLUSIONS: Although nearly all auditory neural response components studied were abnormal in BDP, BDNP abnormalities at early- and mid-latencies were moderated by family psychosis history. The relationship between psychosis expression, heritable psychosis risk, and neurophysiology within bipolar disorder, therefore, may be complex. Consideration of such clinical disease heterogeneity may be important for future investigations of the pathophysiology of major psychiatric disturbance.

Neural activations during auditory oddball processing discriminating schizophrenia and psychotic bipolar disorder.

BACKGROUND: Reduced amplitude of the P300 event-related potential in auditory oddball tasks may characterize schizophrenia (SZ) but is also reported in bipolar disorder. Similarity of auditory processing abnormalities between these diagnoses is uncertain, given the frequent combination of both psychotic and nonpsychotic patients in bipolar samples; abnormalities may be restricted to psychosis. In addition, typically only latency and amplitude of brain responses at selected sensors and singular time points are used to characterize neural responses. Comprehensive quantification of brain activations involving both spatiotemporal and time-frequency analyses could better identify unique auditory oddball responses among patients with different psychotic disorders. METHODS: Sixty SZ, 60 bipolar I with psychosis (BPP), and 60 healthy subjects (H) were compared on neural responses during an auditory oddball task using multisensor electroencephalography. Principal components analysis was used to reduce multisensor data before evaluating group differences on voltage and frequency of neural responses over time. RESULTS: Linear discriminant analysis revealed five variables that best differentiated groups: 1) late beta activity to standard stimuli; 2) late beta/gamma activity to targets discriminated BPP from other groups; 3) midlatency theta/alpha activity to standards; 4) target-related voltage at the late N2 response discriminated both psychosis groups from H; and 5) target-related voltage during early N2 discriminated BPP from H. CONCLUSIONS: Although the P300 significantly differentiated psychotic groups from H, it did not uniquely discriminate groups beyond the above variables. No variable uniquely discriminated SZ, perhaps indicating utility of this task for studying psychosis-associated neurophysiology generally and BPP specifically.

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.

Spatiotemporal and frequency domain analysis of auditory paired stimuli processing in schizophrenia and bipolar disorder with psychosis.

Individuals with schizophrenia (SZ) or bipolar disorder with psychosis (BPP) may share neurophysiological abnormalities as measured in auditory paired-stimuli paradigms with electroencephalography (EEG). Such investigations have been limited, however, by quantifying only event-related potential peaks and/or broad frequency bands at limited scalp locations without considering possible mediating factors (e.g., baseline differences). Results from 64-sensor EEG collected in 180 age- and gender-matched participants reveal (i) accentuated prestimulus gamma oscillations and (ii) reduced P2 amplitudes and theta/alpha oscillations to S1 among participants with both SZ and BPP. Conversely, (iii) N1s in those with SZ to S1 were reduced compared to healthy volunteers and those with BPP, whereas (iv) beta range oscillations 200-300 ms following S2 were accentuated in those with BPP but not those with SZ. Results reveal a pattern of both unique and shared neurophysiological phenotypes occurring within major psychotic diagnoses.

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.

Event-related potential abnormalities in schizophrenia: a failure to "gate in" salient information?

Sensory gating refers to the central nervous system's ability to filter sensory inputs, and can be measured by comparing the suppression of event-related brain potential (ERP) amplitudes in a paired auditory stimulus procedure. Poor gating scores in schizophrenia may be caused by abnormal responses to the first (S1), the second (S2) or both of the paired stimuli. However, since S1 and S2 responses may index separate psychological phenomenon, corresponding to the ability to "gate in" and "gate out" sensory stimuli respectively, the precise mechanism affected in schizophrenia remains unclear. To examine the extent to which saliency processing abnormalities may contribute to S1 response deficits, standard and rare (15% probability) paired stimuli were presented to 21 participants with schizophrenia and 22 healthy controls. P50 and N100 ERP amplitude as well as low, beta and gamma frequency power were measured to examine the time course and relative contributions of oscillatory activity affecting auditory processing in schizophrenia. In this study, schizophrenia patients exhibited less evoked beta 1 power (12-20 Hz) in response to salient stimuli at S1, and lower N100 amplitude in response to all S1 stimuli. No group differences were found in the low, beta 2 (20-30 Hz), or gamma frequency ranges. These findings suggest aberrant sensory processing during stages of stimulus evaluation and saliency detection 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.

Ear of stimulation determines schizophrenia-normal brain activity differences in an auditory paired-stimuli paradigm.

Schizophrenia patients have abnormalities of auditory information processing, theoretically associated with dysfunction of neuronal excitation. Auditory paired-stimuli (S1-S2) paradigms are used to evaluate the nature of these abnormalities. It is unknown whether patients' abnormalities during S1-S2 paradigms are attributable to specific hemispheric differences in cortical processing. The present studies used whole head magnetoencephalography and monaural or binaural versions of the paired-stimuli paradigm to evaluate auditory processing among 38 schizophrenia and 38 normal subjects. The strengths of auditory-evoked brain responses over time were quantified using distributed source reconstructions with L2 minimum norm constraint and realistic head models. For left ear stimuli, schizophrenia and normal groups did not differ on either left or right hemisphere activity over auditory cortex. For right ear and binaural stimuli, schizophrenia patients had less activity over left auditory cortex from 80 to 120 ms post-stimulus but did not differ from normal on activity over right auditory cortex. Additionally, in response to monaural stimulation, schizophrenia patients had significantly less activity than normal over right temporal parietal junction from 60 to 120 ms post-stimulus. These data are consistent with four propositions about schizophrenia: (i). right auditory cortex is functioning normally; (ii). processing of simple auditory stimuli is abnormal in left auditory cortex, probably specifically in supra-granular layers; (iii). auditory localization abilities are deficient; and (iv). auditory cortex abnormalities are not a function of deficient hemispheric communication because they are evident early in processing as long as stimuli are delivered directly to left hemisphere.