Mismatch Negativity in Response to Auditory Deviance and Risk for Future Psychosis in Youth at Clinical High Risk for Psychosis.

Importance: Although clinical criteria for identifying youth at risk for psychosis have been validated, they are not sufficiently accurate for predicting outcomes to inform major treatment decisions. The identification of biomarkers may improve outcome prediction among individuals at clinical high risk for psychosis (CHR-P). Objective: To examine whether mismatch negativity (MMN) event-related potential amplitude, which is deficient in schizophrenia, is reduced in young people with the CHR-P syndrome and associated with outcomes, accounting for effects of antipsychotic medication use. Design, Setting, and Participants: MMN data were collected as part of the multisite case-control North American Prodrome Longitudinal Study (NAPLS-2) from 8 university-based outpatient research programs. Baseline MMN data were collected from June 2009 through April 2013. Clinical outcomes were assessed throughout 24 months. Participants were individuals with the CHR-P syndrome and healthy controls with MMN data. Participants with the CHR-P syndrome who developed psychosis (ie, converters) were compared with those who did not develop psychosis (ie, nonconverters) who were followed up for 24 months. Analysis took place between December 2019 and December 2021. Main Outcomes and Measures: Electroencephalography was recorded during a passive auditory oddball paradigm. MMN elicited by duration-, pitch-, and duration + pitch double-deviant tones was measured. Results: The CHR-P group (n = 580; mean [SD] age, 19.24 [4.39] years) included 247 female individuals (42.6%) and the healthy control group (n = 241; mean age, 20.33 [4.74] years) included 114 female individuals (47.3%). In the CHR-P group, 450 (77.6%) were not taking antipsychotic medication at baseline. Baseline MMN amplitudes, irrespective of deviant type, were deficient in future CHR-P converters to psychosis (n = 77, unmedicated n = 54) compared with nonconverters (n = 238, unmedicated n = 190) in both the full sample (d = 0.27) and the unmedicated subsample (d = 0.33). In the full sample, baseline medication status interacted with group and deviant type indicating that double-deviant MMN, compared with single deviants, was reduced in unmedicated converters compared with nonconverters (d = 0.43). Further, within the unmedicated subsample, deficits in double-deviant MMN were most strongly associated with earlier conversion to psychosis (hazard ratio, 1.40 [95% CI, 1.03-1.90]; P = .03], which persisted over and above positive symptom severity. Conclusions and Relevance: This study found that MMN amplitude deficits were sensitive to future psychosis conversion among individuals at risk of CHR-P, particularly those not taking antipsychotic medication at baseline, although associations were modest. While MMN shows limited promise as a biomarker of psychosis onset on its own, it may contribute novel risk information to multivariate prediction algorithms and serve as a translational neurophysiological target for novel treatment development in a subgroup of at-risk individuals.

Reliability of mismatch negativity event-related potentials in a multisite, traveling subjects study.

OBJECTIVE: To determine the optimal methods for measuring mismatch negativity (MMN), an auditory event-related potential (ERP), and quantify sources of MMN variance in a multisite setting. METHODS: Reliability of frequency, duration, and double (frequency + duration) MMN was determined from eight traveling subjects, tested on two occasions at eight laboratory sites. Deviant-specific variance components were estimated for MMN peak amplitude and latency measures using different ERP processing methods. Generalizability (G) coefficients were calculated using two-facet (site and occasion), fully-crossed models and single-facet (occasion) models within each laboratory to assess MMN reliability. RESULTS: G-coefficients calculated from two-facet models indicated fair (0.4 < G<=0.6) duration MMN reliability at electrode Fz, but poor (G < 0.4) double and frequency MMN reliability. Single-facet G-coefficients averaged across laboratory resulted in improved reliability (G > 0.5). MMN amplitude reliability was greater than latency reliability, and reliability with mastoid referencing significantly outperformed nose-referencing. CONCLUSIONS: EEG preprocessing methods have an impact on the reliability of MMN amplitude. Within site MMN reliability can be excellent, consistent with prior single site studies. SIGNIFICANCE: With standardized data collection and ERP processing, MMN can be reliably obtained in multisite studies, providing larger samples sizeswithin rare patient groups.

Deficits in auditory predictive coding in individuals with the psychosis risk syndrome: Prediction of conversion to psychosis.

The mismatch negativity (MMN) event-related potential (ERP) component is increasingly viewed as a prediction error signal elicited when a deviant sound violates the prediction that a frequent "standard" sound will repeat. Support for this predictive coding framework emerged with the identification of the repetition positivity (RP), a standard stimulus ERP component that increases with standard repetition and is thought to reflect strengthening of the standard's memory trace and associated predictive code. Using electroencephalographic recordings, we examined the RP elicited by repeating standard tones presented during a traditional "constant standard" MMN paradigm in individuals with the psychosis risk syndrome (PRS; n = 579) and healthy controls (HC; n = 241). Clinical follow-up assessments identified PRS participants who converted to a psychotic disorder (n = 77) and PRS nonconverters who were followed for the entire 24-month clinical follow-up period and either remained symptomatic (n = 144) or remitted from the PRS (n = 94). In HC, RP linearly increased from early- to late-appearing standards within local trains of repeating standards (p < .0001), consistent with auditory predictive code/memory trace strengthening. Relative to HC, PRS participants showed a reduced RP across standards (p = .0056). PRS converters showed a relatively small RP deficit for early appearing standards relative to HC (p = .0.0107) and a more prominent deficit for late-appearing standards (p = .0006) relative to both HC and PRS-remitted groups. Moreover, greater RP deficits predicted shorter time to conversion in a subsample of unmedicated PRS individuals (p = .02). Thus, auditory predictive coding/memory trace deficits precede psychosis onset and predict future psychosis risk in PRS individuals. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Auditory event-related potentials and associations with sensory patterns in children with autism spectrum disorder, developmental delay, and typical development.

Atypical sensory response patterns are common in children with autism and developmental delay. Expanding on previous work, this observational electroencephalogram study assessed auditory event-related potentials and their associations with clinically evaluated sensory response patterns in children with autism spectrum disorder (n = 28), developmental delay (n = 17), and typical development (n = 39). Attention-orienting P3a responses were attenuated in autism spectrum disorder relative to both developmental delay and typical development, but early sensory N2 responses were attenuated in both autism spectrum disorder and developmental delay relative to typical development. Attenuated event-related potentials involving N2 or P3a components, or a P1 × N2 interaction, were related to more severe hyporesponsive or sensory-seeking response patterns across children with autism spectrum disorder and developmental delay. Thus, although attentional disruptions may be unique to autism spectrum disorder, sensory disruptions appear across developmental delay and are associated with atypical sensory behaviors.

Association Between P300 Responses to Auditory Oddball Stimuli and Clinical Outcomes in the Psychosis Risk Syndrome.

Importance: In most patients, a prodromal period precedes the onset of schizophrenia. Although clinical criteria for identifying the psychosis risk syndrome (PRS) show promising predictive validity, assessment of neurophysiologic abnormalities in at-risk individuals may improve clinical prediction and clarify the pathogenesis of schizophrenia. Objective: To determine whether P300 event-related potential amplitude, which is deficient in schizophrenia, is reduced in the PRS and associated with clinical outcomes. Design, Setting, and Participants: Auditory P300 data were collected as part of the multisite, case-control North American Prodrome Longitudinal Study (NAPLS-2) at 8 university-based outpatient programs. Participants included 552 individuals meeting PRS criteria and 236 healthy controls with P300 data. Auditory P300 data of participants at risk who converted to psychosis (n = 73) were compared with those of nonconverters who were followed up for 24 months and continued to be symptomatic (n = 135) or remitted from the PRS (n = 90). Data were collected from May 27, 2009, to September 17, 2014, and were analyzed from December 3, 2015, to May 1, 2019. Main Outcomes and Measures: Baseline electroencephalography was recorded during an auditory oddball task. Two P300 subcomponents were measured: P3b, elicited by infrequent target stimuli, and P3a, elicited by infrequent nontarget novel stimuli. Results: This study included 788 participants. The PRS group (n = 552) included 236 females (42.8%) (mean [SD] age, 19.21 [4.38] years), and the healthy control group (n = 236) included 111 females (47.0%) (mean [SD] age, 20.44 [4.73] years). Target P3b and novelty P3a amplitudes were reduced in at-risk individuals vs healthy controls (d = 0.37). Target P3b, but not novelty P3a, was significantly reduced in psychosis converters vs nonconverters (d = 0.26), and smaller target P3b amplitude was associated with a shorter time to psychosis onset in at-risk individuals (hazard ratio, 1.45; 95% CI, 1.04-2.00; P = .03). Participants with the PRS who remitted had baseline target P3b amplitudes that were similar to those of healthy controls and greater than those of converters (d = 0.51) and at-risk individuals who remained symptomatic (d = 0.41). Conclusions and Relevance: In this study, deficits in P300 amplitude appeared to precede psychosis onset. Target P3b amplitudes, in particular, may be sensitive to clinical outcomes in the PRS, including both conversion to psychosis and clinical remission. Auditory target P3b amplitude shows promise as a putative prognostic biomarker of clinical outcome in the PRS.

Neural Mechanisms of Qigong Sensory Training Massage for Children With Autism Spectrum Disorder: A Feasibility Study.

OBJECTIVES: Despite the enormous prevalence of autism spectrum disorder (ASD), its global impact has yet to be realized. Millions of families worldwide need effective treatments to help them get through everyday challenges like eating, sleeping, digestion, and social interaction. Qigong Sensory Training (QST) is a nonverbal, parent-delivered intervention recently shown to be effective at reducing these everyday challenges in children with ASD. This study tested the feasibility of a protocol for investigating QST's neural mechanism. METHODS: During a single visit, 20 children, 4- to 7-year-old, with ASD viewed images of emotional faces before and after receiving QST or watching a video (controls). Heart rate variability was recorded throughout the visit, and power in the high frequency band (0.15-0.4 Hz) was calculated to estimate parasympathetic tone in 5-s nonoverlapping windows. Cerebral oximetry of prefrontal cortex was recorded during rest and while viewing emotional faces. RESULTS: 95% completion rate and 7.6% missing data met a priori standards confirming protocol feasibility for future studies. Preliminary data suggest: (1) during the intervention, parasympathetic tone increased more in children receiving massage (M = 2.9, SD = 0.3) versus controls (M = 2.5, SD = 0.5); (2) while viewing emotional faces post-intervention, parasympathetic tone was more affected (reduced) in the massage group (p = 0.036); and (3) prefrontal cortex response to emotional faces was greater after massage compared to controls. These results did not reach statistical significance in this small study powered to test feasibility. DISCUSSION/CONCLUSION: This study demonstrates solid protocol feasibility. If replicated in a larger sample, these findings would provide important clues to the neural mechanism of action underlying QST's efficacy for improving sensory, social, and communication difficulties in children with autism.

Prenatal Nicotine Exposure Disrupts Infant Neural Markers of Orienting.

Introduction: Prenatal nicotine exposure (PNE) from maternal cigarette smoking is linked to developmental deficits, including impaired auditory processing, language, generalized intelligence, attention, and sleep. Fetal brain undergoes massive growth, organization, and connectivity during gestation, making it particularly vulnerable to neurotoxic insult. Nicotine binds to nicotinic acetylcholine receptors, which are extensively involved in growth, connectivity, and function of developing neural circuitry and neurotransmitter systems. Thus, PNE may have long-term impact on neurobehavioral development. The purpose of this study was to compare the auditory K-complex, an event-related potential reflective of auditory gating, sleep preservation and memory consolidation during sleep, in infants with and without PNE and to relate these neural correlates to neurobehavioral development. Methods: We compared brain responses to an auditory paired-click paradigm in 3- to 5-month-old infants during Stage 2 sleep, when the K-complex is best observed. We measured component amplitude and delta activity during the K-complex. Results: Infants with PNE demonstrated significantly smaller amplitude of the N550 component and reduced delta-band power within elicited K-complexes compared to nonexposed infants and also were less likely to orient with a head turn to a novel auditory stimulus (bell ring) when awake. Conclusions: PNE may impair auditory sensory gating, which may contribute to disrupted sleep and to reduced auditory discrimination and learning, attention re-orienting, and/or arousal during wakefulness reported in other studies. Implications: Links between PNE and reduced K-complex amplitude and delta power may represent altered cholinergic and GABAergic synaptic programming and possibly reflect early neural bases for PNE-linked disruptions in sleep quality and auditory processing. These may pose significant disadvantage for language acquisition, attention, and social interaction necessary for academic and social success.

Association of Thalamic Dysconnectivity and Conversion to Psychosis in Youth and Young Adults at Elevated Clinical Risk.

IMPORTANCE: Severe neuropsychiatric conditions, such as schizophrenia, affect distributed neural computations. One candidate system profoundly altered in chronic schizophrenia involves the thalamocortical networks. It is widely acknowledged that schizophrenia is a neurodevelopmental disorder that likely affects the brain before onset of clinical symptoms. However, no investigation has tested whether thalamocortical connectivity is altered in individuals at risk for psychosis or whether this pattern is more severe in individuals who later develop full-blown illness. OBJECTIVES: To determine whether baseline thalamocortical connectivity differs between individuals at clinical high risk for psychosis and healthy controls, whether this pattern is more severe in those who later convert to full-blown illness, and whether magnitude of thalamocortical dysconnectivity is associated with baseline prodromal symptom severity. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, 2-year follow-up, case-control study, we examined 397 participants aged 12-35 years of age (243 individuals at clinical high risk of psychosis, of whom 21 converted to full-blown illness, and 154 healthy controls). The baseline scan dates were January 15, 2010, to April 30, 2012. MAIN OUTCOMES AND MEASURES: Whole-brain thalamic functional connectivity maps were generated using individuals' anatomically defined thalamic seeds, measured using resting-state functional connectivity magnetic resonance imaging. RESULTS: Using baseline magnetic resonance images, we identified thalamocortical dysconnectivity in the 243 individuals at clinical high risk for psychosis, which was particularly pronounced in the 21 participants who converted to full-blown illness. The pattern involved widespread hypoconnectivity between the thalamus and prefrontal and cerebellar areas, which was more prominent in those who converted to full-blown illness (t(173) = 3.77, P < .001, Hedge g = 0.88). Conversely, there was marked thalamic hyperconnectivity with sensory motor areas, again most pronounced in those who converted to full-blown illness (t(173) = 2.85, P < .001, Hedge g = 0.66). Both patterns were significantly correlated with concurrent prodromal symptom severity (r = 0.27, P < 3.6 × 10(-8), Spearman ρ = 0.27, P < 4.75 × 10(-5), 2-tailed). CONCLUSIONS AND RELEVANCE: Thalamic dysconnectivity, resembling that seen in schizophrenia, was evident in individuals at clinical high risk for psychosis and more prominently in those who later converted to psychosis. Dysconnectivity correlated with symptom severity, supporting the idea that thalamic connectivity may have prognostic implications for risk of conversion to full-blown illness.

Dysregulation of working memory and default-mode networks in schizophrenia using independent component analysis, an fBIRN and MCIC study.

Deficits in working memory (WM) are a consistent neurocognitive marker for schizophrenia. Previous studies have suggested that WM is the product of coordinated activity in distributed functionally connected brain regions. Independent component analysis (ICA) is a data-driven approach that can identify temporally coherent networks that underlie fMRI activity. We applied ICA to an fMRI dataset for 115 patients with chronic schizophrenia and 130 healthy controls by performing the Sternberg Item Recognition Paradigm. Here, we describe the first results using ICA to identify differences in the function of WM networks in schizophrenia compared to controls. ICA revealed six networks that showed significant differences between patients with schizophrenia and healthy controls. Four of these networks were negatively task-correlated and showed deactivation across the posterior cingulate, precuneus, medial prefrontal cortex, anterior cingulate, inferior parietal lobules, and parahippocampus. These networks comprise brain regions known as the default-mode network (DMN), a well-characterized set of regions shown to be active during internal modes of cognition and implicated in schizophrenia. Two networks were positively task-correlated, with one network engaging WM regions such as bilateral DLPFC and inferior parietal lobules while the other network engaged primarily the cerebellum. Our results suggest that DLPFC dysfunction in schizophrenia might be lateralized to the left and intrinsically tied to other regions such as the inferior parietal lobule and cingulate gyrus. Furthermore, we found that DMN dysfunction in schizophrenia exists across multiple subnetworks of the DMN and that these subnetworks are individually relevant to the pathophysiology of schizophrenia. In summary, this large multisite study identified multiple temporally coherent networks, which are aberrant in schizophrenia versus healthy controls and suggests that both task-correlated and task-anticorrelated networks may serve as potential biomarkers.

Neural correlates of impaired cognitive-behavioral flexibility in anorexia nervosa.

OBJECTIVE: Impaired cognitive-behavioral flexibility is regarded as a trait marker in anorexia nervosa patients. The authors sought to investigate the neural correlates of this deficit in executive functioning in anorexia nervosa. METHOD: Fifteen women with anorexia nervosa and 15 age-matched healthy comparison women underwent event-related functional MRI while performing a target-detection task. The task distinguished between shifts in behavioral response and shifts in cognitive set. It involved infrequent target and non-target distractor stimuli embedded in a sequence of prepotent standard stimuli. RESULTS: Relative to comparison subjects, anorexia nervosa patients showed a significantly higher error rate in behavioral response shifting, independent of whether those runs also involved cognitive set shifting. During behavioral response shifting, patients showed reduced activation in the left and right thalamus, ventral striatum, anterior cingulate cortex, sensorimotor brain regions, and cerebellum that differed significantly from the comparison group but showed dominant activation in frontal and parietal brain regions. These differential activations in patients and comparison subjects were specific to shifts in behavioral response: except for thalamic activation, they were not observed in response to non-target distractor trials that required no alteration in behavioral response. CONCLUSION: Impaired behavioral response shifting in anorexia nervosa seems to be associated with hypoactivation in the ventral anterior cingulate-striato-thalamic loop that is involved in motivation-related behavior. In contrast, anorexia nervosa patients showed predominant activation of frontoparietal networks that is indicative of effortful and supervisory cognitive control during task performance.

Neural correlates of automatic and controlled auditory processing in schizophrenia.

Individuals with schizophrenia demonstrate impairments in selective attention and sensory processing. The authors assessed differences in brain function between 26 participants with schizophrenia and 17 comparison subjects engaged in automatic (unattended) and controlled (attended) auditory information processing using event-related functional MRI. Lower regional neural activation during automatic auditory processing in the schizophrenia group was not confined to just the temporal lobe, but also extended to prefrontal regions. Controlled auditory processing was associated with a distributed frontotemporal and subcortical dysfunction. Differences in activation between these two modes of auditory information processing were more pronounced in the comparison group than in the patient group.

Graded visual attention modulates brain responses evoked by task-irrelevant auditory pitch changes.

Previous studies suggested that auditory change-specific neural responses are attention-independent and reflect central auditory processing. The automaticity of the brain's response to infrequent changes in pitch within a series of auditory tone pips was examined in parallel functional magnetic resonance imaging (fMRI) and event-related potential (ERP) studies. Subjects performed a continuous perceptual-motor visual tracking task at two levels of difficulty while simultaneously hearing a series of task-irrelevant standard tone pips and infrequent pitch-deviant tones. fMRI results revealed that the unattended pitch-deviant tones strongly activated superior temporal and frontal cortical regions. These activations were significantly modulated by the tracking difficulty of the primary task. ERP results revealed that the amplitude of the scalp-negative component evoked by deviant tones (MMN) was attenuated during the more difficult tracking task. Our results demonstrate that the brain's response to task-irrelevant sensory changes is strongly influenced by intermodal attentional demands.

Functional magnetic resonance imaging measure of automatic and controlled auditory processing.

Activity within fronto-striato-temporal regions during processing of unattended auditory deviant tones and an auditory target detection task was investigated using event-related functional magnetic resonance imaging. Activation within the middle frontal gyrus, inferior frontal gyrus, anterior cingulate gyrus, superior temporal gyrus, thalamus, and basal ganglia were analyzed for differences in activity patterns between the two stimulus conditions. Unattended deviant tones elicited robust activation in the superior temporal gyrus; by contrast, attended tones evoked stronger superior temporal gyrus activation and greater frontal and striatal activation. The results suggest that attention enhances neural activation evoked by auditory pitch deviance in auditory brain regions, possibly through top-down control from the dorsolateral prefrontal cortex involved in goal-directed selection and response generation.

Hemodynamic correlates of stimulus repetition in the visual and auditory cortices: an fMRI study.

We examined the effects of stimulus repetition upon the evoked hemodynamic response (HDR) in auditory and visual cortices measured by magnetic resonance imaging in two experiments. Experiment 1 focused on the effects of the interval duration between two identical stimuli on HDR. Pure auditory tones (1000 Hz) of 100-ms duration were presented singly or in pairs with intrapair intervals (IPIs: onset-to-onset) of 1, 4, and 6 s. In Experiment 2, using a within-subject design, we aimed to compare the HDR refractory period in both sensory cortices as well as the HDRs to auditory and visual stimuli. Identical auditory tone as described above and visual stimuli of 500-ms high-contrast checkerboard patterns were presented singly or in identical pairs with an IPI of 1 s. Images were acquired at 1.5 T using a gradient-echo echo-planar imaging sequence sensitive to blood oxygenation level-dependent (BOLD) contrast. Experiment 1 revealed that the HDR evoked by an auditory stimulus is followed by a refractory period of 4-6 s in the auditory cortex, as indicated by smaller HDR amplitudes to the second of each pair of stimuli. Furthermore, peak latency was dependent upon IPI, with longer latencies observed for shorter IPIs. Experiment 2 revealed that the HDR evoked in both sensory cortices by paired stimulus presentations is suppressed and delayed similarly by the refractory effects imposed by the preceding stimulus, suggesting similar refractory properties of the HDR at this specific IPI. We also provide evidence for additional neural resource allocation in response to repeated stimuli.

NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development.

There is an urgent need to improve the pharmacotherapy of schizophrenia despite the introduction of important new medications. New treatment insights may come from appreciating the therapeutic implications of model psychoses. In particular, basic and clinical studies have employed the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, as a probe of NMDA receptor contributions to cognition and behavior. These studies illustrate a translational neuroscience approach for probing mechanistic hypotheses related to the neurobiology and treatment of schizophrenia and other disorders. Two particular pathophysiologic themes associated with schizophrenia, the disturbance of cortical connectivity and the disinhibition of glutamatergic activity may be modeled by the administration of NMDA receptor antagonists. The purpose of this review is to consider the possibility that agents that attenuate these two components of NMDA receptor antagonist response may play complementary roles in the treatment of schizophrenia.