Different learning aberrations relate to delusion-like beliefs with different contents.

The prediction error account of delusions has had success. However, its explanation of delusions with different contents has been lacking. Persecutory delusions and paranoia are the common unfounded beliefs that others have harmful intentions towards us. Other delusions include believing that one's thoughts or actions are under external control, or that events in the world have specific personal meaning. We compare learning on two different cognitive tasks, probabilistic reversal learning (PRL) and Kamin blocking, that have relationships to paranoid and non-paranoid delusion-like beliefs, respectively. We find that Clinical High-Risk status alone does not result in different behavioral results on the PRL task but that an individual's level of paranoia is associated with excessive switching behavior. During the Kamin blocking task, paranoid individuals learned inappropriately about the blocked cue. However, they also had decreased learning about the control cue, suggesting more general learning impairments. Non-paranoid delusion-like belief conviction (but not paranoia) was associated with aberrant learning about the blocked cue but intact learning about the control cue, suggesting specific impairments in learning related to cue combination. We fit task-specific computational models separately to behavioral data to explore how latent parameters vary within individuals between tasks, and how they can explain symptom-specific effects. We find that paranoia is associated with low learning rates on the PRL task as well as the blocking task. Non-paranoid delusion-like belief conviction was instead related to parameters controlling the degree and direction of similarity between cue updating during simultaneous cue presentation. These results suggest that paranoia and other delusion-like beliefs involve dissociable deficits in learning and belief updating, which - given the transdiagnostic status of paranoia - may have differential utility in predicting psychosis.

The reliability and validity of the revised Green et al. paranoid thoughts scale in individuals at clinical high-risk for psychosis.

INTRODUCTION: Paranoia is a common and impairing psychosis symptom, which exists along a severity continuum that extends into the general population. Individuals at clinical high-risk for psychosis (CHR) frequently experience paranoia and this may elevate their risk for developing full psychosis. Nonetheless, limited work has examined the efficient measurement of paranoia in CHR individuals. The present study aimed to validate an often-used self-report measure, the revised green paranoid thoughts scale (RGPTS), in this critical population. METHOD: Participants were CHR individuals (n = 103), mixed clinical controls (n = 80), and healthy controls (n = 71) who completed self-report and interview measures. Confirmatory factor analysis (CFA), psychometric indices, group differences, and relations to external measures were used to evaluate the reliability and validity of the RGPTS. RESULTS: CFA replicated a two-factor structure for the RGPTS and the associated reference and persecution scales were reliable. CHR individuals scored significantly higher on both reference and persecution, relative to both healthy (ds = 1.03, 0.86) and clinical controls (ds = 0.64, 0.73). In CHR participants, correlations between reference and persecution and external measures were smaller than expected, though showed evidence of discriminant validity (e.g., interviewer-rated paranoia, r = 0.24). When examined in the full sample, correlation magnitude was larger and follow-up analyses indicated that reference related most specifically to paranoia (ß = 0.32), whereas persecution uniquely related to poor social functioning (ß = -0.29). CONCLUSION: These results demonstrate the reliability and validity of the RGPTS, though its scales related more weakly to severity in CHR individuals. The RGPTS may be useful in future work aiming to develop symptom-specific models of emerging paranoia in CHR individuals.

Lesions causing hallucinations localize to one common brain network.

The brain regions responsible for hallucinations remain unclear. We studied 89 brain lesions causing hallucinations using a recently validated technique termed lesion network mapping. We found that hallucinations occurred following lesions to a variety of different brain regions, but these lesion locations fell within a single functionally connected brain network. This network was defined by connectivity to the cerebellar vermis, inferior cerebellum (bilateral lobule X), and the right superior temporal sulcus. Within this single hallucination network, additional connections with the lesion location dictated the sensory modality of the hallucination: lesions causing visual hallucinations were connected to the lateral geniculate nucleus in the thalamus while lesions causing auditory hallucinations were connected to the dentate nucleus in the cerebellum. Our results suggest that lesions causing hallucinations localize to a single common brain network, but additional connections within this network dictate the sensory modality, lending insight into the causal neuroanatomical substrate of hallucinations.

Paranoia, self-deception and overconfidence.

Self-deception, paranoia, and overconfidence involve misbeliefs about the self, others, and world. They are often considered mistaken. Here we explore whether they might be adaptive, and further, whether they might be explicable in Bayesian terms. We administered a difficult perceptual judgment task with and without social influence (suggestions from a cooperating or competing partner). Crucially, the social influence was uninformative. We found that participants heeded the suggestions most under the most uncertain conditions and that they did so with high confidence, particularly if they were more paranoid. Model fitting to participant behavior revealed that their prior beliefs changed depending on whether the partner was a collaborator or competitor, however, those beliefs did not differ as a function of paranoia. Instead, paranoia, self-deception, and overconfidence were associated with participants' perceived instability of their own performance. These data are consistent with the idea that self-deception, paranoia, and overconfidence flourish under uncertainty, and have their roots in low self-esteem, rather than excessive social concern. The model suggests that spurious beliefs can have value-self-deception is irrational yet can facilitate optimal behavior. This occurs even at the expense of monetary rewards, perhaps explaining why self-deception and paranoia contribute to costly decisions which can spark financial crashes and devastating wars.

Drinking and responses to antidrinking messages among young adults: An fMRI study.

Young adults consume most of their alcohol by binge drinking, and more than one-third report binge drinking in the past month. Some will transition out of excessive drinking, while others will maintain or increase alcohol use into adulthood. Public health campaigns depicting negative consequences of drinking have shown some efficacy at reducing this behavior. However, substance use in dependent individuals is governed in part by automatic or habitual responses to drug cues rather than the consequences. This study used functional magnetic resonance imaging to measure neural responses to drinking cues and drinking cues paired with antidrinking messages among young adults who binge drink (N = 30). This study also explored responses to smoking cues and antismoking messages. Neural responses were also compared between drinking/smoking and neutral cues. Self-reported drinking and smoking were collected at baseline, postscan, and 1 month. Results indicate that activity in the ventral striatum-implicated in reward processing-was lower for drinking cues paired with antidrinking messages than drinking cues. This difference was less pronounced in young adults who reported greater baseline past month drinking quantity. Past month drinking quantity decreased from baseline to 1 month. Further, young adults who showed higher activity during antidrinking messages in the medial prefrontal cortex-implicated in processing message self-relevance- reported a greater decrease in past month drinking frequency from baseline to 1 month. Findings may help to identify young adults who are at risk for continued heavy drinking in adulthood and inform interventions aimed to reduce drinking and reward in young adults.

Modelling delusions as temporally-evolving beliefs.

Introduction: Delusions demand an explanation in terms of their neural, psychological, and sociological mechanisms. We must bridge these levels of explanation in order to understand and ultimately treat delusions. To this end, debates continue as to the number of contributing factors, how those factors interact, and their underlying computational mechanisms.Methods: One popular family of models suggests that two separate insults are necessary, a problem with perception and an independent problem with belief. In particular, new work proposes that the belief problem entails a bias against disconfirmatory evidence - yielding the characteristic fixity of delusions. Here, we evaluate that claim, as well as explanations of delusions more broadly.Results: We suggest that such a bias may not explain enough of the variance in belief updating in delusional participants, and, more fundamentally, it might rule out specific accounts of delusions, since, such a bias might prevent them from forming in the first place, under particular assumptions about cognitive architectures.Conclusion: We suggest conceptualising delusions as an evolving uncertainty driven negotiation between beliefs and evidence, in which initial formation is fuelled by unexpected uncertainty, but, once formed, the delusion engenders new expectations about uncertainty that tune down updating but also facilitate the elastic assimilation of contradictory evidence.

Factor one, familiarity and frontal cortex: a challenge to the two-factor theory of delusions.

INTRODUCTION: Two-factor theory suggests delusions require two neuropsychological impairments, one in perception (which furnishes content), and a second in belief evaluation (that augers formation and maintenance). Capgras delusion; the belief that one's loved one has been replaced by an imposter, then entails two independent processes; first a lack of skin conductance response to familiar faces so the loved one feels different. This has been demonstrated in four patients with damage to the ventromedial prefrontal cortex (vmPFC) but who do not have delusions. Thus two-factor theorists demand a second factor: a change in belief evaluation, which is associated with damage to the right dorsolateral prefrontal cortex (rDLPFC). METHODS: Literature review of foundational and related papers on the cognitive neuropsychology of delusions, perception and belief. RESULTS: The four vmPFC patients appear together in another publication, uncited by two-factor theorists, in which the full extent of their damage is documented. These four cases not only lack skin responses to familiar faces, but lack responses to salient psychological stimuli more generally, which challenges factor one. They also have damage outside vmPFC, including damage to rDLPFC, which challenges factor two. CONCLUSION: Two-factor theory is found lacking and should be reappraised.

Shamanism and psychosis: Shared mechanisms?

Individual-specific predispositions may precede the cultural evolution of shamanism and may be linked to it via principles of predictive coding. We have used these principles to identify commonalities between clinical and shaman-like non-clinical voice-hearers. The author may find this approach helpful in relating the experiences of shamans to those of their clients.

Linking microcircuit dysfunction to cognitive impairment: effects of disinhibition associated with schizophrenia in a cortical working memory model.

Excitation-inhibition balance (E/I balance) is a fundamental property of cortical microcircuitry. Disruption of E/I balance in prefrontal cortex is hypothesized to underlie cognitive deficits observed in neuropsychiatric illnesses such as schizophrenia. To elucidate the link between these phenomena, we incorporated synaptic disinhibition, via N-methyl-D-aspartate receptor perturbation on interneurons, into a network model of spatial working memory (WM). At the neural level, disinhibition broadens the tuning of WM-related, stimulus-selective persistent activity patterns. The model predicts that this change at the neural level leads to 2 primary behavioral deficits: 1) increased behavioral variability that degrades the precision of stored information and 2) decreased ability to filter out distractors during WM maintenance. We specifically tested the main model prediction, broadened WM representation under disinhibition, using behavioral data from human subjects performing a spatial WM task combined with ketamine infusion, a pharmacological model of schizophrenia hypothesized to induce disinhibition. Ketamine increased errors in a pattern predicted by the model. Finally, as proof-of-principle, we demonstrate that WM deteriorations in the model can be ameliorated by compensations that restore E/I balance. Our findings identify specific ways by which cortical disinhibition affects WM, suggesting new experimental designs for probing the brain mechanisms of WM deficits in schizophrenia.

NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia.

Glutamatergic neurotransmission mediated by N-methyl-d-aspartate (NMDA) receptors is vital for the cortical computations underlying cognition and might be disrupted in severe neuropsychiatric illnesses such as schizophrenia. Studies on this topic have been limited to processes in local circuits; however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brain's global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this disruption predicted task performance and transiently evoked symptoms characteristic of schizophrenia. We offer a parsimonious hypothesis for this disruption via biophysically realistic computational modeling, namely cortical disinhibition. Together, the present findings establish links between glutamate's role in the organization of large-scale anticorrelated neural systems, cognition, and symptoms associated with schizophrenia in humans.

Ketamine-Induced Hallucinations.

BACKGROUND: Ketamine, the NMDA glutamate receptor antagonist drug, is increasingly employed as an experimental model of psychosis in healthy volunteers. At subanesthetic doses, it safely and reversibly causes delusion-like ideas, amotivation and perceptual disruptions reminiscent of the aberrant salience experiences that characterize first-episode psychosis. However, auditory verbal hallucinations, a hallmark symptom of schizophrenia, have not been reported consistently in healthy volunteers even at high doses of ketamine. SAMPLING AND METHODS: Here we present data from a set of healthy participants who received moderately dosed, placebo-controlled ketamine infusions in the reduced stimulation environment of the magnetic resonance imaging (MRI) scanner. We highlight the phenomenological experiences of 3 participants who experienced particularly vivid hallucinations. RESULTS: Participants in this series reported auditory verbal and musical hallucinations at a ketamine dose that does not induce auditory hallucination outside of the scanner. CONCLUSIONS: We interpret the observation of ketamine-induced auditory verbal hallucinations in the context of the reduced perceptual environment of the MRI scanner and offer an explanation grounded in predictive coding models of perception and psychosis - the brain fills in expected perceptual inputs, and it does so more in situations of altered perceptual input. The altered perceptual input of the MRI scanner creates a mismatch between top-down perceptual expectations and the heightened bottom-up signals induced by ketamine. Such circumstances induce aberrant percepts, including musical and auditory verbal hallucinations. We suggest that these circumstances might represent a useful experimental model of auditory verbal hallucinations and highlight the impact of ambient sensory stimuli on psychopathology.

Belief Updating, Childhood Maltreatment, and Paranoia in Schizophrenia-Spectrum Disorders.

BACKGROUND AND HYPOTHESIS: Exposure to childhood maltreatment-a risk factor for psychosis is associated with paranoia-may impact one's beliefs about the world and how beliefs are updated. We hypothesized that increased exposure to childhood maltreatment is related to volatility-related belief updating, specifically higher expectations of volatility, and that these relationships are strongest for threat-related maltreatment. Additionally, we tested whether belief updating mediates the relationship between maltreatment and paranoia. STUDY DESIGN: Belief updating was measured in 75 patients with schizophrenia-spectrum disorders and 76 nonpsychiatric controls using a 3-option probabilistic reversal learning (3PRL) task. A Hierarchical Gaussian Filter (HGF) was used to estimate computational parameters of belief updating, including prior expectations of volatility (µ03). The Childhood Trauma Questionnaire (CTQ) was used to assess cumulative maltreatment, threat, and deprivation exposure. Paranoia was measured using the Positive and Negative Syndrome Scale (PANSS) and the revised Green et al. Paranoid Thoughts Scale (R-GPTS). RESULTS: Greater exposure to childhood maltreatment is associated with higher prior expectations of volatility in the whole sample and in individuals with schizophrenia-spectrum disorders. This was specific to threat-related maltreatment, rather than deprivation, in schizophrenia-spectrum disorders. Paranoia was associated with both exposure to childhood maltreatment and volatility priors, but we did not observe a significant indirect effect of volatility priors on the relationship between maltreatment and paranoia. CONCLUSIONS: Our study suggests that individuals with schizophrenia-spectrum disorders who were exposed to threatening experiences during childhood expect their environment to be more volatile, potentially facilitating aberrant belief updating and conferring risk for paranoia.

Illusory generalizability of clinical prediction models.

It is widely hoped that statistical models can improve decision-making related to medical treatments. Because of the cost and scarcity of medical outcomes data, this hope is typically based on investigators observing a model's success in one or two datasets or clinical contexts. We scrutinized this optimism by examining how well a machine learning model performed across several independent clinical trials of antipsychotic medication for schizophrenia. Models predicted patient outcomes with high accuracy within the trial in which the model was developed but performed no better than chance when applied out-of-sample. Pooling data across trials to predict outcomes in the trial left out did not improve predictions. These results suggest that models predicting treatment outcomes in schizophrenia are highly context-dependent and may have limited generalizability.

Lesions to the mediodorsal thalamus, but not orbitofrontal cortex, enhance volatility beliefs linked to paranoia.

Beliefs-attitudes toward some state of the environment-guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three-choice probabilistic reversal learning task following excitotoxic lesions of the MDmc (n = 3) or OFC (n = 3) and compared performance with that of unoperated monkeys (n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose-stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia.

Assumed shared belief about conspiracy theories in social networks protects paranoid individuals against distress.

Paranoia is the belief that others intend you harm. It is related to conspiracy theories, wherein those others represent an organized faction, coordinating the harm against self and others, and violating societal norms. Current psychological studies of paranoid conspiracy theorizing focus either on the individual or their broader social network. Likewise, theories of belief formation and updating often contain individual level processes as well as broader interpersonal and organizational factors. Here we examine paranoia and conspiracy theorizing in terms of individual behavioral predictors (performance on a probabilistic reversal learning task which assays belief updating) as well as social sensing: we ask participants to report the features of their social network, including whether their friends and acquaintances share their paranoid conspiratorial beliefs. We find that people who believe paranoid conspiracy theories expect more volatility during the task. They also assume that members of their social network share their paranoid beliefs. Critically, those participants with larger social networks and greater assumed shared belief tend to harbor their conspiratorial beliefs with less emotional distress and expect less volatility in the task. This is evidence that, like political and religious beliefs, conspiracy theories may flourish under a sacred canopy of belief consensus. These data suggest that friends and acquaintances may serve as sources of credulity and moving between them may sustain conspiracy beliefs when there is detraction. This hybrid individual/social account may shed light on clinical paranoia and persecutory delusion, wherein disability is defined normatively, and social supports are fewer.

Studying Healthy Psychosislike Experiences to Improve Illness Prediction.

Importance: Distinguishing delusions and hallucinations from unusual beliefs and experiences has proven challenging. Observations: The advent of neural network and generative modeling approaches to big data offers a challenge and an opportunity; healthy individuals with unusual beliefs and experiences who are not ill may raise false alarms and serve as adversarial examples to such networks. Conclusions and Relevance: Explicitly training predictive models with adversarial examples should provide clearer focus on the features most relevant to casehood, which will empower clinical research and ultimately diagnosis and treatment.

Excessive teleological thinking is driven by aberrant associations and not by failure of reasoning.

Teleological thought - the tendency to ascribe purpose to objects and events - is useful in some cases (encouraging explanation-seeking), but harmful in others (fueling delusions and conspiracy theories). What drives excessive and maladaptive teleological thinking? In causal learning, there is a fundamental distinction between associative learning versus learning via propositional mechanisms. Here, we propose that directly contrasting the contributions of these two pathways can elucidate the roots of excess teleology. We modified a causal learning task such that we could encourage associative versus propositional mechanisms in different instances. Across three experiments (total N = 600), teleological tendencies were correlated with delusion-like ideas and uniquely explained by aberrant associative learning, but not by learning via propositional rules. Computational modeling suggested that the relationship between associative learning and teleological thinking can be explained by excessive prediction errors that imbue random events with more significance - providing a new understanding for how humans make meaning of lived events.

Relationships between cognitive biases, decision-making, and delusions.

Multiple measures of decision-making under uncertainty (e.g. jumping to conclusions (JTC), bias against disconfirmatory evidence (BADE), win-switch behavior, random exploration) have been associated with delusional thinking in independent studies. Yet, it is unknown whether these variables explain shared or unique variance in delusional thinking, and whether these relationships are specific to paranoia or delusional ideation more broadly. Additionally, the underlying computational mechanisms require further investigation. To investigate these questions, task and self-report data were collected in 88 individuals (46 healthy controls, 42 schizophrenia-spectrum) and included measures of cognitive biases and behavior on probabilistic reversal learning and explore/exploit tasks. Of those, only win-switch rate significantly differed between groups. In regression, reversal learning performance, random exploration, and poor evidence integration during BADE showed significant, independent associations with paranoia. Only self-reported JTC was associated with delusional ideation, controlling for paranoia. Computational parameters increased the proportion of variance explained in paranoia. Overall, decision-making influenced by strong volatility and variability is specifically associated with paranoia, whereas self-reported hasty decision-making is specifically associated with other themes of delusional ideation. These aspects of decision-making under uncertainty may therefore represent distinct cognitive processes that, together, have the potential to worsen delusional thinking across the psychosis spectrum.

Phenomenological and Cognitive Features Associated With Auditory Hallucinations in Clinical and Nonclinical Voice Hearers.

BACKGROUND AND HYPOTHESES: Auditory verbal hallucinations (AVH) are central features of schizophrenia (SZ). However, AVH also occur in a small percentage of the general population who do not have a need for care, termed nonclinical voice hearers (NCVH). We sought to determine the degree to which the experience of AVH was similar in NCVH and in people with schizophrenia (PSZ) and evaluate the degree to which NCVH shared other features of SZ such as delusional beliefs, cognitive impairment, and negative symptoms. STUDY DESIGN: We recruited 76 people with a DSM-V diagnosis of SZ/schizoaffective disorder (PSZ; 49 with current AVH, 27 without), 48 NCVH, and 51 healthy controls. Participants received a broad battery of clinician-administered and self-report symptom assessments and a focused cognitive assessment. STUDY RESULTS: The AVH of NCVH and PSZ shared very similar sensory features. NCVH experienced less distress, had greater control over their AVH, and, unlike PSZ, rarely heard 2 voices speaking to each other. NCVH demonstrated a wide range of deeply held unusual beliefs, but reported less paranoia, and fewer first-rank symptoms such as passivity and alterations in self-experience. NCVH showed no evidence of cognitive deficits or negative symptoms. CONCLUSIONS: The AVH in NCVH and PSZ demonstrate important similarities as well as clear differences. Specific features, rather than the presence, of AVH appear to determine the need for care. NCVH do not share the cognitive and motivational deficits seen in PSZ. These results suggest that AVH and unusual beliefs can be separated from the broader phenotype of SZ.

A pilot randomized controlled trial of ketamine in Borderline Personality Disorder.

This study is the first randomized controlled trial to test the effects of ketamine in Borderline Personality Disorder (BPD). BPD remains undertreated in the community and no medication has FDA approval for this indication. People with BPD experience chronic mood disturbances with depressed mood, suicidal ideation, and severe social difficulties. In this double-blind, randomized controlled pilot study, we tested the effects of one infusion of ketamine (0.5 mg/kg, n = 10) or the psychoactive comparator drug midazolam (0.04 mg/kg, n = 12) in adults with BPD. Infusions were well tolerated in both groups. Dissociative symptoms during infusion were more intense with ketamine than midazolam (t(12.3) = 3.61, p = 0.01), but they resolved by 40 min after infusion in both groups. Post-infusion adverse events were at the expected low levels in both groups. For our primary outcome measure of suicidal ideation and our secondary outcome measure of depression, we found numerical reduction but not significant group or group x timepoint difference (p > 0.05). For our secondary outcome measures of anxiety and BPD symptoms, we did not observe group or group x timepoint differences. There was a group x timepoint effect for socio-occupational functioning (F(1,20.12) = 5.16, p = 0.03, at Day 14, ketamine group showed more improvement than midazolam group). An exploratory analysis revealed that improvement in socio-occupational functioning was correlated with improvement in depression in the ketamine group (r(8) = 0.65, p = 0.04) but not midazolam group (r(9) = 0.41, p = 0.216). This pilot study provides the first randomized controlled evidence of the effects of antidepressant-dosed ketamine in people with BPD. Our results provide reason for optimism that antidepressant-dosed ketamine will be well-tolerated in larger studies and may provide clinical benefit for mood symptoms and related impairments in people with BPD.