Abnormal inter-hemispheric effective connectivity from left to right auditory regions during Mismatch Negativity (MMN) tasks in psychosis.

Anomalous Mismatch Negativity (MMN) in psychosis could be a consequence of disturbed neural oscillatory activity at sensory/perceptual stages of stimulus processing. This study investigated effective connectivity within and between the auditory regions during auditory odd-ball deviance tasks. The analyses were performed on two magnetoencephalography (MEG) datasets: one on duration MMN in a cohort with various diagnoses within the psychosis spectrum and neurotypical controls, and one on duration and pitch MMN in first-episode psychosis patients and matched neurotypical controls. We applied spectral Granger causality to MEG source-reconstructed signals to compute effective connectivity within and between the left and right auditory regions. Both experiments showed that duration-deviance detection was associated with early increases of effective connectivity in the beta band followed by increases in the alpha and theta bands, with the connectivity strength linked to the laterality of the MMN amplitude. Compared to controls, people with psychosis had overall smaller effective connectivity, particularly from left to right auditory regions, in the pathway where bilateral information converges toward lateralized processing, often rightward. Blunted MMN in psychosis might reflect a deficit in inter-hemispheric communication between auditory regions, highlighting a "dysconnection" already at preattentive stages of stimulus processing as a model system of widespread pathophysiology.

MEG Microstates: An Investigation of Underlying Brain Sources and Potential Neurophysiological Processes.

Microstates are transient scalp configurations of brain activity measured by electroencephalography (EEG). The application of microstate analysis in magnetoencephalography (MEG) data remains challenging. In one MEG dataset (N = 113), we aimed to identify MEG microstates at rest, explore their brain sources, and relate them to changes in brain activity during open-eyes (ROE) or closed-eyes resting state (RCE) and an auditory Mismatch Negativity (MMN) task. In another dataset of simultaneously recorded EEG-MEG data (N = 21), we investigated the association between MEG and EEG microstates. Six MEG microstates (mMS) provided the best clustering of resting-state activity, each linked to different brain sources: mMS 1-2: left/right occipito-parietal; mMS 3: fronto-temporal; mMS 4: centro-medial; mMS 5-6: left/right fronto-parietal. Increases in occipital alpha power in RCE relative to ROE correlated with greater mMS 1-2 time coverage (τbs < 0.20, ps > .002), while the lateralization of deviance detection in MMN was associated with mMS 5-6 time coverage (τbs < 0.16, ps > .012). No temporal correlation was found between EEG and MEG microstates (ps > .05), despite some overlap in brain sources and global explained variance between mMS 2-3 and EEG microstates B-C (rs > 0.60, ps < .002). Hence, the MEG signal can be decomposed into microstates, but mMS brain activity clustering captures phenomena different from EEG microstates. Source reconstruction and task-related modulations link mMS to large-scale networks and localized activities. Thus, mMSs offer insights into brain dynamics and task-specific processes, complementing EEG microstates in studying physiological and dysfunctional brain activity.

Examining the Complex Mismatch Negativity in Early Phase Psychosis Using the Dual Rule Paradigm.

Using electroencephalography (EEG) to examine the simple mismatch negativity (MMN), a marker of auditory cortex function, has been of great interest in the exploration of biomarkers for psychotic illness. Despite many studies reporting MMN deficits in chronic schizophrenia, there are inconsistent reports of MMN reductions in the early phases of psychotic illness, suggesting the MMN elicited by traditional paradigms may not be a sensitive enough measure of vulnerability to be used as a biomarker. Recently, a more computationally complex measure of auditory cortex function (the complex mismatch negativity; cMMN) has been hypothesized to provide a more sensitive marker of illness vulnerability. The current study employed a novel dual rule paradigm, in which two pattern rules are established and violated, to examine the cMMN in 14 individuals with early phase psychosis (EPP, < 5 years illness) and 15 healthy controls (HC). Relationships between cMMN waveforms, symptom severity, and measures of functioning were explored. We found reductions of cMMN amplitudes at the site of maximal amplitude in EPP (p = .017) with large effect sizes (Hedges' g = 0.96). This study is an early step in the exploration of the cMMN as a biomarker for psychosis. Our results provide evidence that the dual rule cMMN paradigm shows promise as a method for cMMN elicitation that captures more subtle neurofunctional changes in the early stages of illness.

Long-latency auditory evoked response amplitudes at first episode of psychosis predict six-month recovery in positive symptom severity.

Predicting treatment response would facilitate individualized medical treatment in first-episode psychosis (FEP). We examined relationships between auditory-evoked M100 and longitudinal change in positive symptoms in FEP. M100 was measured from source-resolved magnetoencephalography and symptoms were assessed at initial contact and six months later. M100 at baseline significantly predicted symptom change. Larger M100 at baseline predicted symptom improvement, as did shorter untreated psychosis. Shorter untreated psychosis also correlated with larger M100, and M100 mediated the effect of untreated psychosis on treatment response. Thus, M100 may provide a proximal and objective index of untreated psychosis and a viable route to individualized medicine.

Predicted Brain Age in First-Episode Psychosis: Association with Inexpressivity.

Accelerated brain aging is a possible mechanism of pathology in schizophrenia. Advances in MRI-based brain development algorithms allow for the calculation of predicted brain age (PBA) for individuals. Here, we assessed PBA in 70 first-episode schizophrenia-spectrum individuals (FESz) and 76 matched healthy neurotypical comparison individuals (HC) to determine if FESz showed advanced aging proximal to psychosis onset and whether PBA was associated with neurocognitive, social functioning, or symptom severity measures. PBA was calculated with BrainAgeR (v2.1) from T1-weighted MR scans. There were no differences in the PBAs between groups. After controlling for actual age, a "younger" PBA was associated with higher vocabulary scores among all individuals, while an "older" PBA was associated with more severe negative symptom "Inexpressivity" component scores among FESz. Female participants in both groups had an elevated PBA relative to male participants. These results suggest that a relatively younger brain age is associated with a better semantic memory performance. There is no evidence for accelerated aging in FESz with a late adolescent/early adult onset. Despite a normative PBA, FESz with a greater residual PBA showed impairments in a cluster of negative symptoms, which may indicate some underlying age-related pathology proximal to psychosis onset. Although a period of accelerated aging cannot be ruled out with disease course, it does not occur at the time of the first episode.

Development of Biomarkers Potentially Sensitive to Early Psychosis Using Mismatch Negativity (MMN) to Complex Pattern Deviations.

Infrequent stimulus deviations from repetitive sequences elicit mismatch negativity (MMN) even passively, making MMN practical for clinical applications. Auditory MMN is typically elicited by a change in one (or more) physical stimulus parameters (eg, pitch, duration). This lower-order simple MMN (sMMN) is impaired in long-term schizophrenia. However, sMMN contains activity from release from stimulus adaptation, clouding its face validity as purely deviance-related. More importantly, it is unreliably reduced in samples of first-episode psychosis, limiting its utility as a biomarker. Complex pattern-deviant MMN (cMMN) tasks, which elicit early and late responses, are based on higher-order abstractions and better isolate deviance detection. Their abstract nature may increase the sensitivity to processing deficits in early psychosis. However, both the early and late cMMNs are small, limiting separation between healthy and psychotic samples. In 29 healthy individuals, we tested a new dual-rule cMMN paradigm to assess additivity of deviance. Sounds alternated lateralization between left and right, and low and high pitches, creating a left-low, right-high alternating pattern. Deviants were a repeated left-low, violating lateralization and pitch patterns. Early and late cMMNs on the dual-rule task were significantly larger than those on the one-rule extra tone cMMN task (P < .05). Further, the dual-rule early cMMN was not significantly smaller than pitch or duration sMMNs (P > .48, .28, respectively). These results demonstrate additivity for cMMN pattern-violating rules. This increase in cMMN amplitude should increase group difference effect size, making it a prime candidate for a biomarker of disease presence at first psychotic episode, and perhaps even prior to the emergence of psychosis.

Intensity-dependent modulation of the early auditory gamma-band response in first-episode schizophrenia and its association with disease symptoms.

BACKGROUND: Gamma-band activity has been the focus of considerable research in schizophrenia. Discrepancies exist regarding the integrity of the early auditory gamma-band response (EAGBR), a stimulus-evoked oscillation, and its relationship to symptoms in early disease. Variability in task design may play a role. This study examined sensitivity of the EAGBR to stimulus intensity and its relation to symptoms and functional impairments in the first-episode schizophrenia spectrum (FESz). METHOD: Magnetoencephalography was recorded from 35 FESz and 40 matched healthy controls (HC) during presentation of 3 tone intensities (75 dB, 80 dB, 85 dB). MRIs were collected to localize auditory cortex activity. Wavelet-transformed single trial epochs and trial averages were used to assess EAGBR intertrial phase coherence (ITPC) and evoked power, respectively. Symptoms were assessed using the Positive and Negative Syndrome Scale. RESULTS: Groups did not differ in overall EAGBR power or ITPC. While HC exhibited EAGBR enhancement to increasing intensity, FESz exhibited reduced power to the 80 dB tone and, relative to HC, increased power to the 75 dB tone. Larger power and ITPC were correlated with more severe negative, thought disorganization, and resistance symptoms. Stronger ITPC was associated with impaired social functioning. DISCUSSION: EAGBR showed no overall deficit at disease onset. Rather, FESz exhibited a differential response across tone intensity relative to HC, emphasizing the importance of stimulus characteristics in EAGBR studies. Associations between larger EAGBR and more severe symptoms suggest aberrant synchronization driving overinclusive perceptual binding that may relate to deficits in executive inhibition of initial sensory activity.

Using brain structural neuroimaging measures to predict psychosis onset for individuals at clinical high-risk.

Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.

A whole-brain neuromark resting-state fMRI analysis of first-episode and early psychosis: Evidence of aberrant cortical-subcortical-cerebellar functional circuitry.

Psychosis (including symptoms of delusions, hallucinations, and disorganized conduct/speech) is a main feature of schizophrenia and is frequently present in other major psychiatric illnesses. Studies in individuals with first-episode (FEP) and early psychosis (EP) have the potential to interpret aberrant connectivity associated with psychosis during a period with minimal influence from medication and other confounds. The current study uses a data-driven whole-brain approach to examine patterns of aberrant functional network connectivity (FNC) in a multi-site dataset comprising resting-state functional magnetic resonance images (rs-fMRI) from 117 individuals with FEP or EP and 130 individuals without a psychiatric disorder, as controls. Accounting for age, sex, race, head motion, and multiple imaging sites, differences in FNC were identified between psychosis and control participants in cortical (namely the inferior frontal gyrus, superior medial frontal gyrus, postcentral gyrus, supplementary motor area, posterior cingulate cortex, and superior and middle temporal gyri), subcortical (the caudate, thalamus, subthalamus, and hippocampus), and cerebellar regions. The prominent pattern of reduced cerebellar connectivity in psychosis is especially noteworthy, as most studies focus on cortical and subcortical regions, neglecting the cerebellum. The dysconnectivity reported here may indicate disruptions in cortical-subcortical-cerebellar circuitry involved in rudimentary cognitive functions which may serve as reliable correlates of psychosis.

Is source-resolved magnetoencephalographic mismatch negativity a viable biomarker for early psychosis?

Mismatch negativity (MMN) is an auditory event-related response reflecting the pre-attentive detection of novel stimuli and is a biomarker of cortical dysfunction in schizophrenia (SZ). MMN to pitch (pMMN) and to duration (dMMN) deviant stimuli are impaired in chronic SZ, but it is less clear if MMN is reduced in first-episode SZ, with inconsistent findings in scalp-level EEG studies. Here, we investigated the neural generators of pMMN and dMMN with MEG recordings in 26 first-episode schizophrenia spectrum (FEsz) and 26 matched healthy controls (C). We projected MEG inverse solutions into precise functionally meaningful auditory cortex areas. MEG-derived MMN sources were in bilateral primary auditory cortex (A1) and belt areas. In A1, pMMN FEsz reduction showed a trend towards statistical significance (F(1,50) = 3.31; p = .07), and dMMN was reduced in FEsz (F(1,50) = 4.11; p = .04). Hypothesis-driven comparisons at each hemisphere revealed dMMN reduction in FEsz occurred in the left (t(56) = 2.23; p = .03; d = .61) but not right (t(56) = 1.02; p = .31; d = .28) hemisphere, with a moderate effect size. The added precision of MEG source solution with high-resolution MRI and parcellation of A1 may be requisite to detect the emerging pathophysiology and indicates a critical role for left hemisphere pathology at psychosis onset. However, the moderate effect size in left A1, albeit larger than reported in scalp MMN meta-analyses, casts doubt on the clinical utility of MMN for differential diagnosis, as a majority of patients will overlap with the healthy individual's distribution.

Functional and structural connectivity correlates of semantic verbal fluency deficits in first-episode psychosis.

INTRODUCTION: Semantic verbal fluency (SVF) impairments are debilitating and present early in the course of psychotic illness. Deficits within frontal, parietal, and temporal brain regions contribute to this deficit, as long-range communication across this functionally integrated network is critical to SVF. This study sought to isolate disruptions in functional and structural connectivity contributing to SVF deficits during first-episode psychosis in the schizophrenia spectrum (FESz). METHODS: Thirty-three FESz and 34 matched healthy controls (HC) completed the Animal Naming Task to assess SVF. Magnetoencephalography was recorded during an analogous covert SVF task, and phase-locking value (PLV) used to measure functional connectivity between inferior frontal and temporoparietal structures bilaterally. Diffusion imaging was collected to measure fractional anisotropy (FA) of the arcuate fasciculus, the major tract connecting frontal and temporoparietal language areas. RESULTS: SVF scores were lower among FESz compared to HC. While PLV and FA did not differ between groups overall, FESz exhibited an absence of the left-lateralized nature of both measures observed in HC. Among FESz, larger right-hemisphere PLV was associated with worse SVF performance (ρ = -0.51) and longer DUP (ρ = -0.50). DISCUSSION: In addition to worse SVF, FESz exhibited diminished leftward asymmetry of structural and functional connectivity in fronto-temporoparietal SVF network. The relationship between theta-band hyperconnectivity and poorer performance suggests a disorganized executive network and may reflect dysfunction of frontal cognitive control centers. These findings illustrate an aberrant pattern across the distributed SVF network at disease onset and merit further investigation into development of asymmetrical hemispheric connectivity and its failure among high-risk populations.

White matter tracts differentially associated with auditory hallucinations in first-episode psychosis: A correlational tractography diffusion spectrum imaging study.

Auditory hallucinations (AH) are a debilitating symptom in psychosis, impacting cognition and real world functioning. Recent thought conceptualizes AH as a consequence of long-range brain communication dysfunction, or circuitopathy, within the auditory sensory/perceptual, language, and cognitive control systems. Recently we showed in first-episode psychosis (FEP) that, despite overall intact white matter integrity in the cortical-cortical and cortical-subcortical language tracts and the callosal tracts connecting auditory cortices, the severity of AH correlated inversely with white matter integrity. However, that hypothesis-driven isolation of specific tracts likely missed important white matter concomitants of AH. In this report, we used a whole-brain data-driven dimensional approach using correlational tractography to associate AH severity with white matter integrity in a sample of 175 individuals. Diffusion Spectrum Imaging (DSI) was used to image diffusion distribution. Quantitative Anisotropy (QA) in three tracts was greater with increased AH severity (FDR < 0.001) and QA in three tracts was lower with increased AH severity (FDR < 0.01). White matter tracts showing associations between QA and AH were generally associated with frontal-parietal-temporal connectivity (tracts with known relevance for cognitive control and the language system), in the cingulum bundle, and in prefrontal inter-hemispheric connectivity. The results of this whole brain data-driven analysis suggest that subtle white matter alterations connecting frontal, parietal, and temporal lobes in the service of sensory-perceptual, language/semantic, and cognitive control processes impact the expression of auditory hallucination in FEP. Disentangling the distributed neural circuits involved in AH should help to develop novel interventions, such as non-invasive brain stimulation.

Longitudinal Investigation of Auditory Dynamic Range Deficits in Early Psychosis and its Relationship to Negative Symptoms.

BACKGROUND AND HYPOTHESIS: Despite accounting for significant disease morbidity in schizophrenia, the neuropathological basis of negative symptoms remains poorly understood and options for treatment limited. Our recent study identified robust associations between diminished auditory cortex (AC) dynamic range and social functioning impairments and negative symptoms in first episode psychosis (FESz). The current investigation examined the progression of these relationships 4-8 months from baseline testing. STUDY DESIGN: Twenty-six FESz and 38 healthy controls (HC) were tested at baseline and follow-up. Magnetoencephalography (MEG) was recorded during binaural presentation of tones (75, 80, and 85 dB). Assessments included the MATRICS cognitive consensus battery (MCCB) and Global Functioning: Role and Social scales (GFR/GFS) and the Positive and Negative Syndrome Scale. STUDY RESULTS: Overall, FESz exhibited a blunted response to increasing tone intensity relative to HC. While this deficit did not change over time at the group level, recovery of right hemisphere AC dynamic range (85-75 dB response) among FESz individuals was associated with reductions in negative symptoms (ρ = -0.50). Diminished dynamic range was also associated with impaired GFS (ρ = 0.65), GFR (ρ = 0.51), and MCCB (ρ = 0.49) at baseline and increased negative symptoms at baseline (ρ = -0.53) and follow-up (ρ = -0.51). CONCLUSION: Despite persistent dynamic range impairment in FESz as a group, individual recovery of this AC response property was associated with significant reduction in negative symptoms. Identification of a functional neural deficit that tracts progression of negative symptoms during a critical period for disease modification is essential to the management of these devastating and historically treatment refractory symptoms.

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.

Functional connectivity and gray matter deficits within the auditory attention circuit in first-episode psychosis.

Background: Selective attention deficits in first episode of psychosis (FEP) can be indexed by impaired attentional modulation of auditory M100. It is unknown if the pathophysiology underlying this deficit is restricted to auditory cortex or involves a distributed attention network. We examined the auditory attention network in FEP. Methods: MEG was recorded from 27 FEP and 31 matched healthy controls (HC) while alternately ignoring or attending tones. A whole-brain analysis of MEG source activity during auditory M100 identified non-auditory areas with increased activity. Time-frequency activity and phase-amplitude coupling were examined in auditory cortex to identify the attentional executive carrier frequency. Attention networks were defined by phase-locking at the carrier frequency. Spectral and gray matter deficits in the identified circuits were examined in FEP. Results: Attention-related activity was identified in prefrontal and parietal regions, markedly in precuneus. Theta power and phase coupling to gamma amplitude increased with attention in left primary auditory cortex. Two unilateral attention networks were identified with precuneus seeds in HC. Network synchrony was impaired in FEP. Gray matter thickness was reduced within the left hemisphere network in FEP but did not correlate with synchrony. Conclusion: Several extra-auditory attention areas with attention-related activity were identified. Theta was the carrier frequency for attentional modulation in auditory cortex. Left and right hemisphere attention networks were identified, with bilateral functional deficits and left hemisphere structural deficits, though FEP showed intact auditory cortex theta phase-gamma amplitude coupling. These novel findings indicate attention-related circuitopathy early in psychosis potentially amenable to future non-invasive interventions.

Diminished Auditory Cortex Dynamic Range and its Clinical Correlates in First Episode Psychosis.

BACKGROUND AND HYPOTHESIS: There is growing appreciation for the contribution of sensory disruptions to disease morbidity in psychosis. The present study examined auditory cortex (AC) dynamic range: the scaling of neurophysiological responses to stimulus intensity, among individuals with a schizophrenia spectrum illness (FESz) and its relationship to clinical outcomes at disease onset. STUDY DESIGN: Magnetoencephalography (MEG) was recorded from 35 FESz and 40 healthy controls (HC) during binaural presentation of tones at three intensities (75 dB, 80 dB, and 85 dB). MRIs were obtained to enhance cortical localization of MEG sensor-level activity. All participants completed the MATRICS cognitive battery (MCCB) and Global Functioning: Role and Social scales (GFR/GFS). Patients were administered the Positive and Negative Syndrome Scale (PANSS). STUDY RESULTS: FESz exhibited reduced AC response relative to HC. Enhancement of AC activity to tones of increasing intensity was blunted in FESz relative to HC. Reduced dynamic range (85-75 dB AC response) was associated with lower GFS (r = .58) and GFR (r = .45) scores, worse MCCB performance (r = .45), and increased PANSS Negative symptom subscale scores (r = -.55) among FESz, relationships not observed with AC responses to individual tones. CONCLUSION: Beyond an impaired AC response to pure tones, FESz exhibit reduced dynamic range relative to HC. This impairment was correlated with markers of disease morbidity including poorer community functioning as well as cognitive and negative symptoms. The relationship with impaired social functioning may reflect the role of AC dynamic range in decoding the emotional content of language and highlights its importance to future therapeutic sensory remediation protocols.

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.

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.

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.