Reduction in presynaptic dopamine transporter may be associated with future problematic delusion.

OBJECTIVES: Psychosis, especially in delusions, greatly impairs the quality of life of patients with Parkinson's disease (PD) and their caregivers. Few objective risk indicators of the association between psychosis and clinical features has been reported. It is unclear whether the reduction in DAT binding represents the underlying mechanism of delusion or its association. There are no long-term data on the objective prognostic value of DAT binding for delusions. We investigated whether DAT binding at baseline can be a prognostic risk factor for future development of PD delusions. MATERIALS AND METHODS: We reviewed the detailed clinical chart of patients with PD without a history of psychosis who underwent [123I]FP-CIT SPECT during the disease. The endpoint was defined as when the delusions occurred during the 5 years after the examination of [123I]FP-CIT SPECT. Specific binding ratio (SBR) values were calculated. RESULTS: Sixty-one patients with PD were included in the analysis, and 11 patients had delusions within 5 years of [123I] FP-CIT SPECT. The average (p = 0.004), minimum (p = 0.004), maximum (p = 0.001), right-sided (p = 0.002), and left-sided (p = 0.003) SBRs in the striatum were significantly smaller in patients with delusions than in patients without delusions. Each difference of each SBR was significantly smaller than those without delusions after adjusting after controlling for age, gender, disease severity, timing of [123I]FP-CIT SPECT, anti-parkinsonian medications, hospitalization, administering more or newly anti-parkinsonian drugs, and receiving DBS or LCIG. CONCLUSIONS: PD delusions is still problematic, and lowering DAT binding may be helpful for predicting future delusions, regardless of the timing of [123I]FP-CIT SPECT.

Models of persecutory delusions: a mechanistic insight into the early stages of psychosis.

Identifying robust markers for predicting the onset of psychosis has been a key challenge for early detection research. Persecutory delusions are core symptoms of psychosis, and social cognition is particularly impaired in first-episode psychosis patients and individuals at risk for developing psychosis. Here, we propose new avenues for translation provided by hierarchical Bayesian models of behaviour and neuroimaging data applied in the context of social learning to target persecutory delusions. As it comprises a mechanistic model embedded in neurophysiology, the findings of this approach may shed light onto inference and neurobiological causes of transition to psychosis.

Towards a Unifying Cognitive, Neurophysiological, and Computational Neuroscience Account of Schizophrenia.

Psychotic experiences may be understood as altered information processing due to aberrant neural computations. A prominent example of such neural computations is the computation of prediction errors (PEs), which signal the difference between expected and experienced events. Among other areas showing PE coding, hippocampal-prefrontal-striatal neurocircuits play a prominent role in information processing. Dysregulation of dopaminergic signaling, often secondary to psychosocial stress, is thought to interfere with the processing of biologically important events (such as reward prediction errors) and result in the aberrant attribution of salience to irrelevant sensory stimuli and internal representations. Bayesian hierarchical predictive coding offers a promising framework for the identification of dysfunctional neurocomputational processes and the development of a mechanistic understanding of psychotic experience. According to this framework, mismatches between prior beliefs encoded at higher levels of the cortical hierarchy and lower-level (sensory) information can also be thought of as PEs, with important consequences for belief updating. Low levels of precision in the representation of prior beliefs relative to sensory data, as well as dysfunctional interactions between prior beliefs and sensory data in an ever-changing environment, have been suggested as a general mechanism underlying psychotic experiences. Translating the promise of the Bayesian hierarchical predictive coding into patient benefit will come from integrating this framework with existing knowledge of the etiology and pathophysiology of psychosis, especially regarding hippocampal-prefrontal-striatal network function and neural mechanisms of information processing and belief updating.

Associations between ZnT3, tau pathology, agitation, and delusions in dementia.

OBJECTIVE: Neuropsychiatric symptoms such as agitation and delusions occur frequently in Lewy body dementia and Alzheimer's disease and represent significant burden and unmet treatment need. The underlying aetiology remains poorly understood. METHODS: We used a multidimensional linear model to look for associations between measurements of agitation, delusions, amyloid, tau and α-synuclein pathology, and synaptic proteins (ZnT3, PSD95, synaptophysin, and ß-III-tubulin) across multiple brain regions in post-mortem tissue from a cohort of 130 Lewy body dementia and Alzheimer's disease patients and non-demented controls. RESULTS: We found both agitations and delusions to be significantly associated with increased tau pathology and decreased levels of ZnT3. ZnT3 packages Zn2+ into synaptic vesicles to be released as a long-term modulator of synaptic activity. CONCLUSIONS: Our finding adds to the evidence that zinc modulating compounds are of interest for treatment or symptomatic relief in these dementias.

The role of neurotransmitters in the development of Parkinson's disease-related psychosis.

Psychotic symptoms are common, disabling non-motor features of Parkinson's disease (PD). Despite noted heterogeneity in clinical features, natural history and therapy response, current dogma posits that psychosis generally progresses in a stereotypic manner through a cascade of events that begins with minor hallucinations and evolves to severe hallucinations and delusions. Further, the occurrence of psychotic symptoms is believed to indicate a poor prognosis. Here we propose a classification scheme that outlines the pathogenesis of psychosis as it relates to dysfunction of several neurotransmitter systems. We hypothesize that several subtypes exist, and that PD psychosis is not consistently indicative of a progressive cascade and poor prognosis. The literature was reviewed from 1990 to 2017. An overview of the features of PD psychosis is followed by a review of data indicating the existence of neurotransmitter-related subtypes of psychosis. We found that ample evidence exists to demonstrate the presence of multiple subtypes of PD psychosis, which are traced to dysfunction of the following neurotransmitter systems: dopamine, serotonin and acetylcholine. Dysfunction of each of these systems is recognizable through their clinical features and correlates, and the varied long-term prognoses. Identifying which neurotransmitter system is dysfunctional may help to develop targeted therapies. PD psychosis has various subtypes that differ in clinical features, underlying pathology and pathophysiology, treatment response and prognosis. A novel classification scheme is presented that describes the clinical subtypes with different outcomes, which could lead to the development of targeted therapies. Future research should focus on testing the viability of this classification.

Dopamine, cognitive biases and assessment of certainty: A neurocognitive model of delusions.

This paper examines the evidence that delusions can be explained within the framework of a neurocognitive model of how the brain assesses certainty. Here, 'certainty' refers to both low-level interpretations of one's environment and high-level (conscious) appraisals of one's beliefs and experiences. A model is proposed explaining how the brain systems responsible for assigning certainty might dysfunction, contributing to the cause and maintenance of delusional beliefs. It is suggested that delusions arise through a combination of perturbed striatal dopamine and aberrant salience as well as cognitive biases such as the tendency to jump to conclusions (JTC) and hypersalience of evidence-hypothesis matches. The role of emotion, stress, trauma and sociocultural factors in forming and modifying delusions is also considered. Understanding the mechanisms involved in forming and maintaining delusions has important clinical implications, as interventions that improve cognitive flexibility (e.g. cognitive remediation therapy and mindfulness training) could potentially attenuate neurocognitive processes.

Pimavanserin: First Global Approval.

Pimavanserin (Nuplazid™) is a selective and potent serotonin 2A (5-HT2A) receptor inverse agonist and antagonist developed by ACADIA Pharmaceuticals that has been approved in the US as a treatment for patients with hallucinations and delusions associated with Parkinson's disease psychosis. Up to 60 % of patients with Parkinson's disease may develop Parkinson's disease psychosis, which is associated with increased morbidity and mortality and has few treatment options. This article summarizes the milestones in the development of pimavanserin leading to this first approval for the treatment of hallucinations and delusions in patients with Parkinson's disease psychosis.

Prediction error, ketamine and psychosis: An updated model.

In 2007, we proposed an explanation of delusion formation as aberrant prediction error-driven associative learning. Further, we argued that the NMDA receptor antagonist ketamine provided a good model for this process. Subsequently, we validated the model in patients with psychosis, relating aberrant prediction error signals to delusion severity. During the ensuing period, we have developed these ideas, drawing on the simple principle that brains build a model of the world and refine it by minimising prediction errors, as well as using it to guide perceptual inferences. While previously we focused on the prediction error signal per se, an updated view takes into account its precision, as well as the precision of prior expectations. With this expanded perspective, we see several possible routes to psychotic symptoms - which may explain the heterogeneity of psychotic illness, as well as the fact that other drugs, with different pharmacological actions, can produce psychotomimetic effects. In this article, we review the basic principles of this model and highlight specific ways in which prediction errors can be perturbed, in particular considering the reliability and uncertainty of predictions. The expanded model explains hallucinations as perturbations of the uncertainty mediated balance between expectation and prediction error. Here, expectations dominate and create perceptions by suppressing or ignoring actual inputs. Negative symptoms may arise due to poor reliability of predictions in service of action. By mapping from biology to belief and perception, the account proffers new explanations of psychosis. However, challenges remain. We attempt to address some of these concerns and suggest future directions, incorporating other symptoms into the model, building towards better understanding of psychosis.

Altered threat and safety neural processing linked to persecutory delusions in schizophrenia: a two-task fMRI study.

Persecutory delusions are a clinically important symptom in schizophrenia associated with social avoidance and increased violence. Few studies have investigated the neurobiology of persecutory delusions, which is a prerequisite for developing novel treatments. The aim of this two-paradigm functional magnetic resonance imaging (fMRI) study is to characterize social "real world" and linguistic threat brain activations linked to persecutory delusions in schizophrenia (n=26) using instructed-fear/safety and emotional word paradigms. Instructed-fear/safety activations correlated to persecutory delusion severity demonstrated significant increased lateral orbitofrontal cortex and visual association cortex activations for the instructed-fear vs. safety and instructed-fear vs. baseline contrasts; decreased lateral orbitofrontal cortex and ventral occipital-temporal cortex activations were observed for the instructed-safety stimuli vs. baseline contrast. The salience network also showed divergent fear and safety cued activations correlated to persecutory delusions. Emotional word paradigm analyses showed positive correlations between persecutory delusion severity and left-lateralized linguistic and hippocampal-parahippocampal activations for the threat vs. neutral word contrast. Visual word form area activations correlated positively with persecutory delusions for both threat and neutral word vs. baseline contrasts. This study links persecutory delusions to enhanced neural processing of threatening stimuli and decreased processing of safety cues, and helps elucidate systems-level activations associated with persecutory delusions in schizophrenia.

Delusions and prediction error: re-examining the behavioural evidence for disrupted error signalling in delusion formation.

INTRODUCTION: There is now significant evidence that prediction error signalling is mediated by dopamine in the midbrain, and that dopamine dysfunction is implicated in people experiencing psychotic symptoms, including delusions. There has also been significant theorizing and experimentation concerning the remaining link in this triad, namely that deviant prediction error signalling produces or maintains psychotic symptoms. METHODS: The research supporting the link between prediction error signalling and delusional symptoms was reviewed. Numerous studies indirectly support this link, but only one set of studies claim to directly test this hypothesis by combining three crucial elements: a patient sample, a manipulation of prediction error and neuroimaging. This particular set of studies were examined in detail. RESULTS: Important methodological limitations in these studies were observed, and a reinterpretation of their data was offered. CONCLUSIONS: Methodological inconsistencies significantly weaken the claims made by these studies, but their data are consistent with current theorizing and they are instructive for future lines of inquiry in this field.

Neurobiology of delusions, memory, and insight in Alzheimer disease.

OBJECTIVE: Delusional thoughts are common among patients with Alzheimer disease (AD) and may be conceptually linked to memory deficits (cannot recall accurate information, which leads to inaccurate beliefs) and poor insight (unable to appreciate the illogic of beliefs). This study's goals were to examine the clinical associations among delusions, memory deficits, and poor insight; explore neurobiologic correlates for these symptoms; and identify shared mechanisms. METHODS: In a cross-sectional analysis, 88 outpatients with AD (mean Mini-Mental State Exam score: 19.3) were studied. Delusional thoughts were assessed with the Neuropsychiatric Inventory, level of inaccurate insight was assessed with the Neurobehavioral Rating Scale, and memory was assessed with the Mattis Dementia Rating Scale memory subscale. (18)F-fluorodeoxyglucose positron emission tomography was used to measure regional cortical metabolism. Relationships between clinical ratings and regional cortical metabolic activity (voxel-based) were assessed using SPM2. RESULTS: Patients with delusions had lower Dementia Rating Scale memory subscale scores. Neurobehavioral Rating Scale inaccurate insight scores were no different in those with and without delusions. Cortical metabolic activity was lower in the right lateral frontal cortex, orbitofrontal cortex, and bilateral temporal cortex in patients with delusions. Low cortical metabolic activity in the right lateral, inferior, and medial temporal cortex was associated with poorer memory. This region partially overlapped the region of hypometabolism associated with delusions. In contrast, low cortical metabolic activity in bilateral medial frontal cortex was associated with poor insight. CONCLUSION: Delusions in AD are associated with dysfunction in specific frontal and temporal cortical regions. Delusions are partially clinically and neurobiologically linked to memory deficits but not to poor insight.

Neural and behavioral correlates of aberrant salience in individuals at risk for psychosis.

The "aberrant salience" model proposes that psychotic symptoms first emerge when chaotic brain dopamine transmission leads to the attribution of significance to stimuli that would normally be considered irrelevant. This is thought to occur during the prodromal phase of psychotic disorders, but this prediction has not been tested previously. In the present study, we tested this model in 18 healthy volunteers and 18 unmedicated individuals at ultra-high risk of psychosis. Subjects performed the Salience Attribution Test, which provides behavioral measures of adaptive and aberrant motivational salience, during functional magnetic resonance imaging to assess neural responses to relevant and irrelevant stimulus features. On a separate occasion, the same subjects were also studied with [(18)F]fluorodopa positron emission tomography to measure dopamine synthesis capacity. Individuals at ultra-high risk of psychosis were more likely to attribute motivational salience to irrelevant stimulus features (t(26.7) = 2.8, P = .008), and this bias was related to the severity of their delusion-like symptoms (r = .62, P = .008). Ventral striatal responses to irrelevant stimulus features were also correlated with delusion-like symptoms in the ultra-high risk group (r = .59, P = .017). Striatal dopamine synthesis capacity correlated negatively with hippocampal responses to irrelevant stimulus features in ultra-high risk individuals, but this relationship was positive in controls. These data are consistent with the hypothesis that aberrant salience processing underlies psychotic symptoms and involves functional alterations in the striatum, hippocampus, and the subcortical dopamine system.

Neurobiological correlates of delusion: beyond the salience attribution hypothesis.

Dopamine dysfunction is a mainstay of theories aimed to explain the neurobiological correlates of schizophrenia symptoms, particularly positive symptoms such as delusions and passivity phenomena. Based on studies revealing dopamine dysfunction in addiction research, it has been suggested that phasic or chaotic firing of dopaminergic neurons projecting to the (ventral) striatum attribute salience to otherwise irrelevant stimuli and thus contribute to delusional mood and delusion formation. Indeed, several neuroimaging studies revealed that neuronal encoding of usually irrelevant versus relevant stimuli is blunted in unmedicated schizophrenia patients, suggesting that some stimuli that are irrelevant for healthy controls acquire increased salience for psychotic patients. However, salience attribution per se may not suffice to explain anxieties and feelings of threat that often accompany paranoid ideation. Here, we suggest that beyond ventral striatal dysfunction, dopaminergic dysregulation in limbic areas such as the amygdala in interaction with prefrontal and temporal cortex may contribute to the formation of delusions and negative symptoms. Neuroleptic medication, on the other hand, appears to interfere with anticipation of reward in the ventral striatum and can thus contribute to secondary negative symptoms such as apathy and avolition.

The relationship among neuregulin 1-stimulated phosphorylation of AKT, psychosis proneness, and habituation of arousal in nonclinical individuals.

BACKGROUND: Previous studies reported an association between weak habituation of skin conductance orienting response and psychosis proneness. The aim of this study was to investigate the relationship among neuregulin 1 (NRG1)-stimulated AKT phosphorylation (a putative marker of psychosis), orienting response habituation, delusional ideas, anxiety, and depression in nonclinical individuals. METHODS: One hundred twenty individuals participated in the skin conductance measurements. Weak and strong habituators were compared on measures of NRG1-stimulated AKT phosphorylation in B lymphoblasts, delusional ideas, anxiety, and depression. The predictors of delusional ideas were determined by multiple regression analysis. RESULTS: Weak habituators displayed higher levels of delusional ideas/anxiety and a lower ratio of phosphorylated AKT as compared with strong habituators. There were 3 significant predictors of delusional ideas: decreased habituation, NRG1-induced AKT phosphorylation, and anxiety. Age, gender, education, IQ, and depression did not predict delusional ideas. CONCLUSIONS: These results suggest that decreased habituation of arousal, NRG1-induced AKT phosphorylation, and anxiety are related to delusional ideation in the general population.

Increased striatal dopamine (D2/D3) receptor availability and delusions in Alzheimer disease.

OBJECTIVE: Dysfunction within corticostriatal dopaminergic neurocircuitry has been implicated in neuropsychiatric symptoms associated with Alzheimer disease (AD). This study aimed to test the hypothesis that the symptom domains delusions and apathy would be associated with striatal dopamine (D2) receptor function in AD. METHODS: In vivo dopamine (D2/D3) receptor availability was determined with [(11)C]raclopride (RAC) PET in 23 patients with mild and moderate probable AD. Behavioral symptoms were measured using the Neuropsychiatric Inventory and the Apathy Inventory. Imaging data were analyzed using a region-of-interest approach. The potential confounding effects of age, sex, and disease stage were explored using a linear mixed model. Correlational and independent samples comparisons were used to examine the relationship between behavioral and binding potential (BP(ND)) measures. RESULTS: Mean [(11)C]RAC BP(ND) was higher in patients with delusions (n = 7; 5 men) than in patients without delusions (n = 16; 6 men) (p = 0.006). When women were excluded from the analysis, [(11)C]RAC BP(ND) was higher in men with delusions than in men without delusions (p = 0.05). Apathy measures showed no association with [(11)C]RAC BP(ND). CONCLUSIONS: Striatal dopamine (D2/D3) receptor availability is increased in Alzheimer disease patients with delusions, to an extent comparable to that observed in drug-naive patients with schizophrenia. Whether this represents up-regulation of dopamine (D2) or possibly dopamine (D3) receptors and how this relates to responsivity of the striatal dopaminergic system merit further exploration.

[Some questions about the essence of delusions in the light of recent neurobiological findings]. / Kilka pytan o nature urojen w swietle wspólczesnych neurobiologicznych koncepcji psychozy.

Formation of delusions in the phase of acute psychosis is based on two subsequent processes. The first one is dopamine hyperactivity in mesolimbic neural pathways, the second one is a cognitive process of up-down attribution of meanings of this subjectively perceived state of mind by the higher levels of brain. After the successful antipsychotic treatment, the subjectivity of patients changes. When the state of acute psychosis resolves patients must re-interpret this new emerging subjective experience. These interpretations are often incorrect and bizarre. In most cases they are regarded as delusions (sometimes "chronic delusions"). The question asked in the presented paper is whether they are truly delusions. The essence of delusion must include in the same time an active neurobiological basis of delusion (hyperdopaminergic state) and its cognitive level. It's not clear what is the proper term for the phenomenon when only incorrect or bizarre cognitive convictions are present after successful treatment of psychosis, but without dopaminergic hyperactivity.

Right prefrontal hypometabolism predicts delusions in dementia with Lewy bodies.

Delusions (DEL) are frequent in dementia with Lewy bodies (DLB); however, the neural equivalent is poorly understood. The present study therefore aimed to identify the cerebral metabolic pattern of glucose of a DLB group suffering from DEL (DLB+DEL) as compared to a non-delusional group (DLB-DEL) and a control group (NL); and to determine the predictive value of the regional metabolic deficit for DEL symptomatology in comparison to other clinical variables significantly associated with DEL. Voxel-wise comparisons were conducted between the patient and control groups in SPM2. The most significant regional metabolic deficit of the DLB+DEL group was used a predictor for DEL symptomatology in a logistic regression analysis along with other variables significantly associated with DEL, such as visual hallucinations (VH), and overall cognitive impairment. A significant relative hypometabolism of the right prefrontal cortex was found in the DLB+DEL group, which predicted DEL symptomatology in the regression analysis. VH and overall cognitive dysfunction were no significant predictors. These results underline the significance of right prefrontal damage for DEL in DLB.

Parasitosis, dopaminergic modulation and metabolic disturbances in schizophrenia: evolution of a hypothesis.

Recent meta-analyses have provided a comprehensive overview of studies investigating Toxoplasma gondii antibodies in schizophrenic patients, thus attempting to clarify the potential role these infections might play in causing schizophrenia. Issues for further research have been suggested. Associations and theories that may enrich the current level of knowledge with regard to this significant subject deserve attention. Anti-parasitic agents as well as antipsychotics are effective in treating parasitosis. Both classes of drugs have been shown to exert dopaminergic activity. Parasites and human organisms have a long history of mutual contact. The effect of parasitosis on the host and the host's response to infection are undoubtedly the product of a long evolutionary process. The neurochemical background of delusions of parasitosis is potentially similar to ancient evolutionary traces of altered neurotransmission and neuropeptide gene expression caused by parasites; these include fungal and viral infections. This is very unique in medicine if a class of drugs is effective in the treatment of an illness but also cures the delusion of the same disorder as well. Furthermore, metabolic disturbances such as hyperglycemia and insulin resistance were reported several decades before the antipsychotic era. Toxoplasmosis may also be linked to insulin resistance. Schizophrenia research can benefit from understanding this evolutionary link. New chemical entities that are liable to alter neurochemical changes related to the brain's perception of the risk of predation secondary to parasites may result in new approaches for the treatment of psychosis. These findings suggest that further research is needed to clarify this evolutionary link between parasite infection and delusions of parasitosis. We believe this model may well open up new avenues of research in the discovery of drugs to counteract schizophrenia.