Mismatch negativity and clinical trajectories in psychotic disorders: Five-year stability and predictive utility.

BACKGROUND: Mismatch negativity (MMN) amplitude is reduced in psychotic disorders and associated with symptoms and functioning. Due to these robust associations, it is often considered a biomarker for psychotic illness. The relationship between MMN and clinical outcomes has been examined well in early onset psychotic illness; however, its stability and predictive utility in chronic samples are not clear. METHOD: We examined the five-year stability of MMN amplitude over two timepoints in individuals with established psychotic disorders (cases; N = 132) and never-psychotic participants (NP; N = 170), as well as longitudinal associations with clinical symptoms and functioning. RESULTS: MMN amplitude exhibited good temporal stability (cases, r = 0.53; never-psychotic, r = 0.52). In cases, structural equation models revealed MMN amplitude to be a significant predictor of worsening auditory hallucinations (ß = 0.19), everyday functioning (ß = -0.13), and illness severity (ß = -0.12) at follow-up. Meanwhile, initial IQ (ß = -0.24), negative symptoms (ß = 0.23), and illness severity (ß = -0.16) were significant predictors of worsening MMN amplitude five years later. CONCLUSIONS: These results imply that MMN measures a neural deficit that is reasonably stable up to five years. Results support disordered cognition and negative symptoms as preceding reduced MMN, which then may operate as a mechanism driving reductions in everyday functioning and the worsening of auditory hallucinations in chronic psychotic disorders. This pattern may inform models of illness course, clarifying the relationships amongst biological mechanisms of predictive processing and clinical deficits in chronic psychosis and allowing us to better understand the mechanisms driving such impairments over time.

Dynamic interplay between life events and course of psychotic disorders: 10-year longitudinal study following first admission.

BACKGROUND: Life events (LEs) are a risk factor for first onset and relapse of psychotic disorders. However, the impact of LEs on specific symptoms - namely reality distortion, disorganization, negative symptoms, depression, and mania - remains unclear. Moreover, the differential effects of negative v. positive LEs are poorly understood. METHODS: The present study utilizes an epidemiologic cohort of patients (N = 428) ascertained at first-admission for psychosis and followed for a decade thereafter. Symptoms were assessed at 6-, 24-, 48-, and 120-month follow-ups. RESULTS: We examined symptom change within-person and found that negative events in the previous 6 months predicted an increase in reality distortion (ß = 0.07), disorganized (ß = 0.07), manic (ß = 0.08), and depressive symptoms (ß = 0.06), and a decrease in negative symptoms (ß = -0.08). Conversely, positive LEs predicted fewer reality distortion (ß = -0.04), disorganized (ß = -0.04), and negative (ß = -0.13) symptoms, and were unrelated to mood symptoms. A between-person approach to the same hypotheses confirmed that negative LEs predicted change in all symptoms, while positive LEs predicted change only in negative symptoms. In contrast, symptoms rarely predicted future LEs. CONCLUSIONS: These findings confirm that LEs have an effect on symptoms, and thus contribute to the burden of psychotic disorders. That LEs increase positive symptoms and decrease negative symptoms suggest at least two different mechanisms underlying the relationship between LEs and symptoms. Our findings underscore the need for increased symptom monitoring following negative LEs, as symptoms may worsen during that time.

Acquiescing to intuition in individuals prone to delusions: alterations in dual processes and cognitive control.

Anomalous beliefs exist on a continuum ranging from conventional beliefs to delusions. Recent work proposes that delusions may be formed via acquiescence, in which intuitive beliefs arise and persist despite awareness that they conflict with rationality. Cognitive control theory can similarly explain how we fail to detect that delusional beliefs conflict with rationality, and/or marshal cognitive control (analytic) resources to override them. We measured intuitive processes using a decision-making task and analytic processes using Stroop and cognitive reflection (CRT) tasks. Stronger intuition and lower CRT/Stroop scores were associated with acquiescence. Importantly, those less prone to delusions were more likely to override their intuition as their analytic strength increased; however, for more delusion-prone participants, analytic strength predicted an increased likelihood of acquiescence. Findings highlight an interactive role of intuitive and analytic processes in anomalous beliefs, including delusions, such that cognitive resources may be rallied to rationalize intuitions.

Hallucination-Proneness is Associated With a Decrease in Robust Averaging of Perceptual Evidence.

BACKGROUND AND HYPOTHESIS: Hallucinations are characterized by disturbances in perceptual decision-making about environmental stimuli. When integrating across multiple stimuli to form a perceptual decision, typical observers engage in "robust averaging" by down-weighting extreme perceptual evidence, akin to a statistician excluding outlying data. Furthermore, observers adapt to contexts with more unreliable evidence by increasing this down-weighting strategy. Here, we test the hypothesis that hallucination-prone individuals (n = 38 high vs n = 91 low) would show a decrease in this robust averaging and diminished sensitivity to changes in evidence variance. STUDY DESIGN: We used a multielement perceptual averaging task to elicit dichotomous judgments about the "average color" (red/blue) of an array of stimuli in trials with varied strength (mean) and reliability (variance) of decision-relevant perceptual evidence. We fitted computational models to task behavior, with a focus on a log-posterior-ratio (LPR) model which integrates evidence as a function of the log odds of each perceptual option and produces a robust averaging effect. STUDY RESULTS: Hallucination-prone individuals demonstrated less robust averaging, seeming to weigh inlying and outlying extreme or untrustworthy evidence more equally. Furthermore, the model that integrated evidence as a function of the LPR of the two perceptual options and produced robust averaging showed poorer fit for the group prone to hallucinations. Finally, the weighting strategy in hallucination-prone individuals remained insensitive to evidence variance. CONCLUSIONS: Our findings provide empirical support for theoretical proposals regarding evidence integration aberrations in psychosis and alterations in the perceptual systems that track statistical regularities in environmental stimuli.

Abnormal neurophysiological sensitivity to rewards in depression is moderated by sex and age in middle adulthood.

A candidate pathophysiological process in major depressive disorder is diminished neural reactivity to reward delivery, which is theorized to give rise to anhedonia. Reduced amplitude in the reward positivity (RewP), which captures initial reward evaluation, has been linked to current symptoms of depression among child, adolescent, and young adult samples. However, the developmental trajectory of this association is incomplete, with relatively few studies in middle and older adulthood. Further, emerging evidence in the literature also suggests that this association may be linked to female sex-specific processes, but no studies to date have directly contrasted the effect of sex on the depression-RewP association. The current study sought to address these gaps by testing how sex and age may moderate the depression-RewP association within a mature adult community sample. Symptoms of depression were evaluated using a survey and a clinical interview, and the RewP was elicited using a simple guessing task. There was a three-way interaction between depression symptom severity, age, and sex in predicting RewP amplitude. This was driven by younger (late 30's to early 40's) female-sexed people such that for this group, elevated symptoms of depression were associated with blunting of the RewP. This association tapered around age 50. This effect was specific to clinician-rated rather than self-reported depressive symptom severity. This pattern of effects suggests that among female-sexed people, developmental processes continue to shape the association between reward responsiveness and depression throughout middle adulthood.

Pleasant and unpleasant odor identification ability is associated with distinct dimensions of negative symptoms transdiagnostically in psychotic disorders.

Negative symptoms are among the greatest sources of functional impairment for individuals with schizophrenia, yet their mechanisms remain poorly understood. Olfactory impairment is associated with negative symptoms. The processing of pleasant olfactory stimuli is subserved by reward-related neural circuitry while unpleasant olfactory processing is subserved by emotion-related neural circuitry, suggesting that these two odor dimensions may offer a window into differential mechanisms of negative symptoms. We examined whether pleasant and unpleasant odor identification bears differential relationships with avolition and inexpressivity dimensions of negative symptoms, whether these relationships are transdiagnostic, and whether pleasant and unpleasant odor processing also relate differently to other domains of functioning in a sample of individuals diagnosed with schizophrenia (N = 54), other psychotic disorders (N = 65), and never-psychotic adults (N = 160). Hierarchical regressions showed that pleasant odor identification was uniquely associated with avolition, while unpleasant odor identification was uniquely associated with inexpressivity. These relationships were largely transdiagnostic across groups. Additionally, pleasant and unpleasant odor identification displayed signs of specificity with other functional and cognitive measures. These results align with past work suggesting dissociable pathomechanisms of negative symptoms and provide a potential avenue for future work using valence-specific olfactory dysfunction as a semi-objective and low-cost marker for understanding and predicting the severity of specific negative symptom profiles.

Conspiratorial Thinking During COVID-19: The Roles of Paranoia, Delusion-Proneness, and Intolerance of Uncertainty.

The COVID-19 global pandemic has left many feeling a sense of profound uncertainty about their world, safety, and livelihood. Sources espousing misinformation and conspiracy theories frequently offer information that can help make sense of this uncertainty. Individuals high in intolerance of uncertainty (IU) may be particularly impacted by the impoverished epistemic environment and may thus be more drawn to conspiratorial thinking (CT). In the present work, we show across 2 studies (N = 519) that COVID-19-specific CT is associated with higher levels of IU as well as delusion-proneness, and paranoia. Furthermore, delusion-proneness and paranoia explained the relationship between IU and CT and emerged as independent partial correlates of CT even when controlling for other facets of schizotypy. In contrast, anxiety did not explain the relationship between IU and CT. Overall, our findings highlight the importance of individual differences in IU, delusion-proneness and paranoia in the development of CT in the context of the acute uncertainty of a global crisis, in which conspiracy theories are more prevalent and salient. Informational intervention designs may benefit from leveraging the body of work demonstrating the efficacy of targeting IU to incite meaningful changes in thinking.

Predicting Long-Term Outcomes in First-Admission Psychosis: Does the Hierarchical Taxonomy of Psychopathology Aid DSM in Prognostication?

The Hierarchical Taxonomy of Psychopathology (HiTOP) is an empirical, dimensional model of psychological symptoms and functioning. Its goals are to augment the use and address the limitations of traditional diagnoses, such as arbitrary thresholds of severity, within-disorder heterogeneity, and low reliability. HiTOP has made inroads to addressing these problems, but its prognostic validity is uncertain. The present study sought to test the prediction of long-term outcomes in psychotic disorders was improved when the HiTOP dimensional approach was considered along with traditional (ie, DSM) diagnoses. We analyzed data from the Suffolk County Mental Health Project (N = 316), an epidemiologic study of a first-admission psychosis cohort followed for 20 years. We compared 5 diagnostic groups (schizophrenia/schizoaffective, bipolar disorder with psychosis, major depressive disorder with psychosis, substance-induced psychosis, and other psychoses) and 5 dimensions derived from the HiTOP thought disorder spectrum (reality distortion, disorganization, inexpressivity, avolition, and functional impairment). Both nosologies predicted a significant amount of variance in most outcomes. However, except for cognitive functioning, HiTOP showed consistently greater predictive power across outcomes-it explained 1.7-fold more variance than diagnoses in psychiatric and physical health outcomes, 2.1-fold more variance in community functioning, and 3.4-fold more variance in neural responses. Even when controlling for diagnosis, HiTOP dimensions incrementally predicted almost all outcomes. These findings support a shift away from the exclusive use of categorical diagnoses and toward the incorporation of HiTOP dimensions for better prognostication and linkage with neurobiology.

Mismatch negativity amplitude in first-degree relatives of individuals with psychotic disorders: Links with cognition and schizotypy.

Mismatch negativity (MMN) amplitude is reliably reduced in psychotic disorders. While several studies have examined this effect in first-degree relatives of individuals with schizophrenia, few have sought to quantify deficits in relatives of individuals with other psychotic disorders. While some conclude that, compared to healthy subjects, first-degree relatives of schizophrenia show reduced MMN, others contradict this finding. Furthermore, though MMN is often shown to be associated with cognitive impairments and clinical symptoms in psychotic disorders, to our knowledge no studies have sought to fully examine these relationships in studies of first-degree relatives. The present study sought to clarify the extent of MMN amplitude reductions in a large sample of siblings of individuals with diverse psychotic disorders (n = 67), compared to probands with psychosis (n = 221) and never psychotic comparison subjects (n = 251). We further examined associations of MMN amplitude with cognition and schizotypal symptoms across these groups. We found that MMN amplitude was intact in siblings compared to probands. MMN amplitude was associated with cognition and schizotypal symptoms dimensionally across levels of familial risk. The present results imply that MMN reductions do not reflect genetic risk for psychotic disorders per se, and instead emerge as a result of, or in conjunction with, clinical features associated with psychosis. Such findings carry important implications for the utility of MMN amplitude as an indicator of inherited risk, and suggest that this component may be best conceptualized as an endophenotype for clinical symptoms and cognitive impairments, rather than risk for psychosis per se.

Associations of mismatch negativity with psychotic symptoms and functioning transdiagnostically across psychotic disorders.

Mismatch negativity (MMN) amplitude has been widely shown to be diminished in schizophrenia and, more recently, in other psychotic disorders. Although there is considerable evidence linking MMN reduction to cognitive and functional deficits in schizophrenia, there is little evidence of associations with specific psychotic symptoms. Further, it is unclear if MMN reductions relate to specific symptoms, cognitive, and functional deficits transdiagnostically across different psychotic disorders. The present study examines MMN amplitude in a large cohort of cases diagnosed with psychotic disorders including schizophrenia and schizoaffective disorder (N = 116); bipolar disorder and major depressive disorder (N = 75); and other psychotic disorders (N = 25), as well as individuals with no psychotic disorder diagnoses (N = 248). Furthermore, we examined the association of MMN with symptoms, cognitive functioning, and real-world functioning to determine whether these relationships differ by diagnosis. Results showed that MMN amplitude was reduced in cases overall compared to never-psychotic individuals, with no differences between psychotic disorders. Furthermore, there were transdiagnostic associations of reduced duration MMN (MMN-D) with worse auditory hallucinations (r = .14) and disorganization (r = .14), frequency MMN (MMN-F) with real-word functioning (r = .20) and episodic memory (r = -.22), and both components with executive functioning (MMN-D: r = -.17; MMN-F: r = -.15). Our findings relating MMN reductions with cognitive and real-world functioning replicate earlier research in schizophrenia and extend these relationships to other psychotic disorders. Furthermore, our correlations with MMN-D are consistent with computational modeling research and theoretical proposals that view MMN reduction, cognitive dysfunction, and psychotic symptoms as reflecting underlying predictive coding deficits. However, differences in relationships with MMN-F suggest that additional work is warranted on this topic. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Effects of conflict and strategic processing on neural responses to errors in schizophrenia.

The error-related negativity (ERN) and error-positivity (Pe) are commonly linked to error-detection and strategic processing. Studies have documented the influence of conflict probability on ERN amplitude. However, the influence of conflict probability on ERN/Pe in schizophrenia, where such components are reduced, is unknown. A modified flanker paradigm was used to examine how the probability of conflict modulates ERN and Pe amplitudes in patients with schizophrenia (n = 33) and healthy controls (n = 25). Increased ERN was observed in response to errors on low probability, incongruent trials. No such differences were observed in Pe. While ERN and Pe showed significantly reduced amplitudes in patients relative to controls, patients showed normal condition-dependent ERN and reaction-time modulation. This suggests that while the neural mechanisms generating the ERN and Pe are compromised in schizophrenia, those modulating task performance strategy and neurophysiological responses to errors based on conflict probability are intact.

Should I Stay or Should I Go? FMRI Study of Response Inhibition in Early Illness Schizophrenia and Risk for Psychosis.

Response inhibition (RI) is a component of the cognitive control systems that support optimal cognition. Cognitive control deficits are well-described in schizophrenia, but are not well characterized in individuals at clinical high risk (CHR) for developing psychosis. Functional magnetic resonance imaging during Go/NoGo task performance was collected from 30 CHR youth, 23 early illness schizophrenia patients (ESZ), and 72 healthy adolescents and young adults (HC). Voxelwise main effects of group were examined (P < .005 height threshold, family-wise error-corrected cluster threshold, P < .05) for correct NoGo-Go contrast values and task-based functional connectivity. CHR and ESZ groups had slower and more variable reaction times (RT) on Go trials compared to HCs. Significant main effects of group in bilateral dorsal anterior cingulate (dACC) and right inferior frontal cortex stemmed from CHR and ESZ groups showing significantly less NoGo-Go activation, relative to HCs. Faster responding HCs had less functional coupling between dACC and medial prefrontal cortex, a default mode network (DMN) region during NoGo vs Go trials. This functional connectivity-performance relationship was not present in ESZ or CHR groups. The pattern of findings suggests CHR and ESZ groups were deficient in developing strong and consistent prepotent responding, based on their slow and variable motor responses and decreased engagement of dACC and right inferior frontal regions implicated in inhibitory control. Furthermore, only the control group showed a functional connectivity relationship consistent with greater response prepotency requiring more decoupling of inhibitory control regions from DMN regions during RI.

The temporal dynamics of reversal learning: P3 amplitude predicts valence-specific behavioral adjustment.

Adapting behavior to dynamic stimulus-reward contingences is a core feature of reversal learning and a capacity thought to be critical to socio-emotional behavior. Impairment in reversal learning has been linked to multiple psychiatric outcomes, including depression, Parkinson's disorder, and substance abuse. A recent influential study introduced an innovative laboratory reversal-learning paradigm capable of disentangling the roles of feedback valence and expectancy. Here, we sought to use this paradigm in order to examine the time-course of reward and punishment learning using event-related potentials among a large, representative sample (N=101). Three distinct phases of processing were examined: initial feedback evaluation (reward positivity, or RewP), allocation of attention (P3), and sustained processing (late positive potential, or LPP). Results indicate a differential pattern of valence and expectancy across these processing stages: the RewP was uniquely related to valence (i.e., positive vs. negative feedback), the P3 was uniquely associated with expectancy (i.e., unexpected vs. expected feedback), and the LPP was sensitive to both valence and expectancy (i.e., main effects of each, but no interaction). The link between ERP amplitudes and behavioral performance was strongest for the P3, and this association was valence-specific. Overall, these findings highlight the potential utility of the P3 as a neural marker for feedback processing in reversal-based learning and establish a foundation for future research in clinical populations.