Identification of a gene regulatory network associated with prion replication.

Prions consist of aggregates of abnormal conformers of the cellular prion protein (PrP(C)). They propagate by recruiting host-encoded PrP(C) although the critical interacting proteins and the reasons for the differences in susceptibility of distinct cell lines and populations are unknown. We derived a lineage of cell lines with markedly differing susceptibilities, unexplained by PrP(C) expression differences, to identify such factors. Transcriptome analysis of prion-resistant revertants, isolated from highly susceptible cells, revealed a gene expression signature associated with susceptibility and modulated by differentiation. Several of these genes encode proteins with a role in extracellular matrix (ECM) remodelling, a compartment in which disease-related PrP is deposited. Silencing nine of these genes significantly increased susceptibility. Silencing of Papss2 led to undersulphated heparan sulphate and increased PrP(C) deposition at the ECM, concomitantly with increased prion propagation. Moreover, inhibition of fibronectin 1 binding to integrin α8 by RGD peptide inhibited metalloproteinases (MMP)-2/9 whilst increasing prion propagation. In summary, we have identified a gene regulatory network associated with prion propagation at the ECM and governed by the cellular differentiation state.

Enhanced Instructed Fear Learning in Delusion-Proneness.

Psychosis is associated with distorted perceptions and deficient bottom-up learning such as classical fear conditioning. This has been interpreted as reflecting imprecise priors in low-level predictive coding systems. Paradoxically, overly strong beliefs, such as overvalued beliefs and delusions, are also present in psychosis-associated states. In line with this, research has suggested that patients with psychosis and associated phenotypes rely more on high-order priors to interpret perceptual input. In this behavioural and fMRI study we studied two types of fear learning, i.e., instructed fear learning mediated by verbal suggestions about fear contingencies and classical fear conditioning mediated by low level associative learning, in delusion proneness-a trait in healthy individuals linked to psychotic disorders. Subjects were shown four faces out of which two were coupled with an aversive stimulation (CS+) while two were not (CS-) in a fear conditioning procedure. Before the conditioning, subjects were informed about the contingencies for two of the faces of each type, while no information was given for the two other faces. We could thereby study the effect of both classical fear conditioning and instructed fear learning. Our main outcome variable was evaluative rating of the faces. Simultaneously, fMRI-measurements were performed to study underlying mechanisms. We postulated that instructed fear learning, measured with evaluative ratings, is stronger in psychosis-related phenotypes, in contrast to classical fear conditioning that has repeatedly been shown to be weaker in these groups. In line with our hypothesis, we observed significantly larger instructed fear learning on a behavioural level in delusion-prone individuals (n = 20) compared to non-delusion-prone subjects (n = 23; n = 20 in fMRI study). Instructed fear learning was associated with a bilateral activation of lateral orbitofrontal cortex that did not differ significantly between groups. However, delusion-prone subjects showed a stronger functional connectivity between right lateral orbitofrontal cortex and regions processing fear and pain. Our results suggest that psychosis-related states are associated with a strong instructed fear learning in addition to previously reported weak classical fear conditioning. Given the similarity between nocebo paradigms and instructed fear learning, our results also have an impact on understanding why nocebo effects differ between individuals.

Resistance to Extinction of Evaluative Fear Conditioning in Delusion Proneness.

Delusional beliefs consist of strong priors characterized by resistance to change even when evidence supporting another view is overwhelming. Such bias against disconfirmatory evidence (BADE) has been experimentally demonstrated in patients with psychosis as well as in delusion proneness. In this fMRI-study, we tested for similar resistance to change and associated brain processes in extinction of fear learning, involving a well-described mechanism dependent of evidence updating. A social fear conditioning paradigm was used in which four faces had either been coupled to an unconditioned aversive stimulus (CS+) or not (CS-). For two of the faces, instructions had been given about the fear contingencies (iCS+/iCS-) while for two other faces no such instructions had been given (niCS+/niCS-). Interaction analysis suggested that individuals who score high on delusion-proneness (hDP; n = 20) displayed less extinction of evaluative fear compared to those with low delusion proneness (lDP; n = 23; n = 19 in fMRI-analysis) for non-instructed faces (F = 5.469, P = .024). The resistance to extinction was supported by a difference in extinction related activity between the two groups in medial prefrontal cortex and its connectivity with amygdala, as well as in a cortical network supporting fear processing. For instructed faces no extinction was noted, but there was a larger evaluative fear (F = 5.048, P = 0.03) and an increased functional connectivity between lateral orbitofrontal cortex and fear processing regions for hDP than lDP. Our study links previous explored BADE-effects in delusion associated phenotypes to fear extinction, and suggest that effects of instructions on evaluative fear learning are more pronounced in delusion prone subjects.

Dopamine D1 receptor availability is not associated with delusional ideation measures of psychosis proneness.

The dopamine D1 receptor (D1R) is thought to play a role in psychosis and schizophrenia, however positron emission tomography studies comparing patients and controls have been inconsistent. To circumvent some of the limitations of clinical studies, such as antipsychotic exposure, an alternative approach is to examine subclinical psychotic symptoms within the general population, i.e. psychosis proneness traits. In this study, we investigated whether D1R availability is associated with delusional ideation in healthy controls, in four experiments, using [11C]SCH23390 PET (n = 76) and psychometric questionnaires (n = 217). We performed exploratory analyses, direct self-replication, and confirmatory analyses using Bayesian statistical modelling. Collectively, we found strong evidence that there is little to no linear association between delusional ideation and D1R. If hypothesised changes in D1R in drug-naive psychosis patients can be confirmed, our results suggest that they may either occur at disease onset, or that they are associated with specific aspects of psychosis other than delusional ideation.

Delusion-proneness displays comorbidity with traits of autistic-spectrum disorders and ADHD.

There is an increasing body of evidence suggesting a significant comorbidity between psychotic disorders such as schizophrenia and attention-deficit/hyperactivity disorder (ADHD) or autism-spectrum disorders (ASD). Recently, research on psychosis-proneness in otherwise healthy individuals has been a promising way to better understand the mechanisms underlying psychosis. As both ADHD and ASD symptoms show a normal distribution in the general population, such trait comorbidity may confound studies on psychosis-proneness. Thus, understanding the extent to which psychosis-proneness relates to ADHD and ASD symptoms in healthy subjects is crucial for studies focusing on at-risk or psychosis-prone populations. In the present paper we tested the robustness of overlap between psychosis-proneness and ADHD/ASD symptoms, by studying correlations between the scores of three commonly-used questionnaires assessing delusion-proneness (Peters' Delusion Inventory), ADHD tendencies (Adult ADHD Self-Report Scale) and ASD tendencies (Autism Quotient), on a large sample of healthy individuals (n = 925) using raw scores, prototypical questions and a factor analysis. The results showed consistently positive correlations between psychosis-proneness and ADHD-, as well as ASD-symptoms. While the effect was weak for ASD, it was moderate for ADHD. The findings support the idea that when investigating psychosis-proneness it is crucial to also take ADHD- and ASD-tendencies into account, in order to conclude that the reported results in a given study are specific to psychosis-proneness. The observed trait correlations also suggest a common pathway in the underlying information processing of these states.

When Passive Feels Active--Delusion-Proneness Alters Self-Recognition in the Moving Rubber Hand Illusion.

Psychotic patients have problems with bodily self-recognition such as the experience of self-produced actions (sense of agency) and the perception of the body as their own (sense of ownership). While it has been shown that such impairments in psychotic patients can be explained by hypersalient processing of external sensory input it has also been suggested that they lack normal efference copy in voluntary action. However, it is not known how problems with motor predictions like efference copy contribute to impaired sense of agency and ownership in psychosis or psychosis-related states. We used a rubber hand illusion based on finger movements and measured sense of agency and ownership to compute a bodily self-recognition score in delusion-proneness (indexed by Peters' Delusion Inventory - PDI). A group of healthy subjects (n=71) experienced active movements (involving motor predictions) or passive movements (lacking motor predictions). We observed a highly significant correlation between delusion-proneness and self-recognition in the passive conditions, while no such effect was observed in the active conditions. This was seen for both ownership and agency scores. The result suggests that delusion-proneness is associated with hypersalient external input in passive conditions, resulting in an abnormal experience of the illusion. We hypothesize that this effect is not present in the active condition because deficient motor predictions counteract hypersalience in psychosis proneness.