Dopaminergic basis for signalling belief updates, but not surprise, and the link to paranoia

Distinguishing between meaningful and meaningless sensory information is fundamental to forming accurate representations of the world. Dopamine is thought to play a central role in processing the meaningful information content of observations, which motivates an agent to update their beliefs about the environment. However, direct evidence for dopamine’s role in human belief updating is lacking. We addressed this question in healthy volunteers who performed a model-based functional magnetic resonance imaging (fMRI) task designed to separate the neural processing of meaningful and meaningless sensory information. We modelled participant behaviour using a normative Bayesian observer model, and used the magnitude of the model-derived belief update following an observation to quantify its meaningful information content. We also acquired positron emission tomography (PET) imaging measures of dopamine function in the same subjects. We show that the magnitude of belief updates about task structure (meaningful information), but not pure sensory surprise (meaningless information), are encoded in midbrain and ventral striatum activity. Using PET we show that the neural encoding of meaningful information is negatively related to dopamine-2/3 receptor availability in the midbrain and dexamphetamine-induced dopamine release capacity in the striatum. Trial-by-trial analysis of task performance indicated that subclinical paranoid ideation is negatively related to behavioural sensitivity to observations carrying meaningful information about the task structure. The findings provide direct evidence implicating dopamine in model-based belief updating in humans, and have implications for understating the pathophysiology of psychotic disorders where dopamine function is disrupted

Amygdala reactivity in ethnic minorities and its relationship to the social environment: an fMRI study

Background: Ethnic minority individuals have an increased risk of developing a psychotic disorder, particularly if they live in areas of ethnic segregation, or low own group ethnic density. The neurobiological mechanisms underlying this ethnic minority associated risk are unknown. We used functional MRI to investigate neural responses to faces of different ethnicity, in individuals of black ethnicity, and a control group of white British ethnicity individuals. Methods: In total 20 individuals of black ethnicity, and 22 individuals of white British ethnicity underwent a 3T MRI scan while viewing faces of black and white ethnicity. Own group ethnic density was calculated from the 2011 census. Neighbourhood segregation was quantified using the Index of Dissimilarity method. Results: At the within-group level, both groups showed greater right amygdala activation to outgroup faces. Between groups, the black ethnicity group showed greater right amygdala activation to white faces, compared to the white ethnicity group. Within the black ethnicity group, individuals living in areas of lower own group ethnic density showed greater right amygdala reactivity to white faces (r = −0.61, p = 0.01). Conclusions: This is the first time an increased amygdala response to white faces has been demonstrated in individuals of black ethnicity. In the black ethnicity group, correlations were observed between amygdala response and neighbourhood variables associated with increased psychosis risk. These results may have relevance for our understanding of the increased rates of paranoia and psychotic disorders in ethnic minority individuals

Variability in Action Selection Relates to Striatal Dopamine 2/3 Receptor Availability in Humans: A PET Neuroimaging Study Using Reinforcement Learning and Active Inference Models

Choosing actions that result in advantageous outcomes is a fundamental function of nervous systems. All computational decision-making models contain a mechanism that controls the variability of (or confidence in) action selection, but its neural implementation is unclear-especially in humans. We investigated this mechanism using two influential decision-making frameworks: active inference (AI) and reinforcement learning (RL). In AI, the precision (inverse variance) of beliefs about policies controls action selection variability-similar to decision 'noise' parameters in RL-and is thought to be encoded by striatal dopamine signaling. We tested this hypothesis by administering a 'go/no-go' task to 75 healthy participants, and measuring striatal dopamine 2/3 receptor (D2/3R) availability in a subset (n = 25) using [11C]-(+)-PHNO positron emission tomography. In behavioral model comparison, RL performed best across the whole group but AI performed best in participants performing above chance levels. Limbic striatal D2/3R availability had linear relationships with AI policy precision (P = 0.029) as well as with RL irreducible decision 'noise' (P = 0.020), and this relationship with D2/3R availability was confirmed with a 'decision stochasticity' factor that aggregated across both models (P = 0.0006). These findings are consistent with occupancy of inhibitory striatal D2/3Rs decreasing the variability of action selection in humans

An automatic analysis framework for FDOPA PET neuroimaging

In this study we evaluate the performance of a fully automated analytical framework for FDOPA PET neuroimaging data, and its sensitivity to demographic and experimental variables and processing parameters. An instance of XNAT imaging platform was used to store the King's College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. By re-engineering the historical Matlab-based scripts for FDOPA PET analysis, a fully automated analysis pipeline for imaging processing and data quantification was implemented in Python and integrated in XNAT. The final data repository includes 892 FDOPA PET scans organized from 23 different studies. We found good reproducibility of the data analysis by the automated pipeline (in the striatum for the Kicer: for the controls ICC = 0.71, for the psychotic patients ICC = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p < 0.001), with women showing greater dopamine synthesis capacity than men. Our automated analysis pipeline represents a valid resourse for standardised and robust quantification of dopamine synthesis capacity using FDOPA PET data. Combining information from different neuroimaging studies has allowed us to test it comprehensively and to validate its replicability and reproducibility performances on a large sample size

Simulation d'action et risque hallucinatoire à l'adolescence

Des données empiriques et théoriques suggèrent que des dysfonctions cérébrales de la discrimination soi-autre sont centrales dans le développement de symptômes psychotiques positifs. Des études récentes montrent une confusion soi-autre dans la remémoration d'actions imaginées pour des groupes à risque clinique et génétique de présenter des hallucinations auditives. Notre travail a pour but de mieux comprendre ces erreurs de mémoire de source pour actions. Pour cela, nous avons sélectionné un groupe d'adolescents contrôle (N=22), à risque clinique (N=12), et à risque génétique (N=13) pour effectuer une tâche d'imagerie par résonance magnétique fonctionnelle de simulation de l'action et d'orientation d'attention soi-autre. Nos résultats révèlent des activations cérébrales atypiques similaires pour les groupes à risque clinique et génétique dans la simulation d'action faite par autrui, impliquant des zones de prise de perspective et de mémoire épisodique. Ces données peuvent contribuer à une meilleure connaissance des mécanismes cognitifs liés aux hallucinations auditives à l'adolescence

The impact of risk factors for psychosis on the dopamine system

Risk factors are thought to dysregulate dopamine function leading to the positive psychotic symptoms of schizophrenia. The most common genetic variants affecting the DISC1 gene are associated with schizophrenia, but it is not known if they influence the dopamine system. Evidence indicates that childhood trauma sensitises the dopamine system to increase the effect of later challenges, such as amphetamine. However, it is not known if childhood trauma interacts with amphetamine on dopamine release to induce psychotic symptoms. My first hypothesis was that the DISC1 serine 704 allele (rs821616) was associated with increased dopamine synthesis using [18F]-DOPA PET. Healthy participants DISC1 serine 704 homozygotes exhibited increased striatal dopamine synthesis relative to cysteine 704 carriers, supporting the hypothesis. My second hypothesis was that the DISC1 alleles serine 704 (rs821616), leucine 607 (rs6675281) and arginine 264 (rs3738401) showed increased dopamine receptor levels, using [11C]-(+)-PHNO PET. There was no association between these polymorphisms and striatal dopamine receptor levels in healthy volunteers, refuting the hypothesis. My final hypothesis was that there was an interaction between striatal dopamine release and childhood trauma to increase dexamphetamine-induced psychotic symptoms in healthy participants, using [11C]-(+)-PHNO. Neither childhood trauma nor dopamine release in isolation were predictors of dexamphetamine-induced psychotic symptoms, but a significant interaction was observed between these two variables, supporting the hypothesis. These studies showed 1) that a genetic risk variant is associated with dopamine synthesis but that other variants affecting the gene are not associated with dopamine receptor levels; 2) that induced-psychotic symptoms depend on the interaction between childhood trauma and ventral striatal dopamine release. This is consistent with the theory that a common action of risk factors for schizophrenia is to dysregulate dopamine synthesis and release, but not receptors. Further work is needed to examine how these risk factors affect dopamine function in clinical populations.Open Acces

Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks

Recent genome-wide association studies have identified numerous loci associated with neuropsychiatric disorders. The majority of these are in non-coding regions, and are commonly assigned to the nearest gene along the genome. However, this approach neglects the three-dimensional organisation of the genome, and the fact that the genome contains arrays of extremely conserved non-coding elements termed genomic regulatory blocks (GRBs), which can be utilized to detect genes under long-range developmental regulation. Here we review a GRB-based approach to assign loci in non-coding regions to potential target genes, and apply it to reanalyse the results of one of the largest schizophrenia GWAS (SWG PGC, 2014). We further apply this approach to GWAS data from two related neuropsychiatric disorders—autism spectrum disorder and bipolar disorder—to show that it is applicable to developmental disorders in general. We find that disease-associated SNPs are overrepresented in GRBs and that the GRB model is a powerful tool for linking these SNPs to their correct target genes under long-range regulation. Our analysis identifies novel genes not previously implicated in schizophrenia and corroborates a number of predicted targets from the original study. The results are available as an online resource in which the genomic context and the strength of enhancer–promoter associations can be browsed for each schizophrenia-associated SNP

The association of psychosocial risk factors for mental health with a brain marker altered by inflammation

Psychiatric disorders associated with psychosocial risk factors, including depression and psychosis, have been shown to demonstrate increased microglia activity. Whilst preclinical studies indicate that psychosocial stress leads to increased levels of microglia in the frontal cortex, no study has yet been performed in humans. This study aimed at investigating whether psychosocial risk factors for depression and/or psychosis would be associated with alterations in a brain marker expressed by microglia, the translocator specific protein (TSPO) in humans. We used [11C]-PBR28 Positron Emission Tomography on healthy subjects exposed to childhood and adulthood psychosocial risk factors (high-risk group, N = 12) and age- and sex-matched healthy controls not exposed to childhood and adulthood psychosocial risk factors (low-risk group, N = 12). The [11C]-PBR28 volume of distribution (VT) and Distribution Volume Ratio (DVR) were measured in the total gray matter, and frontal, parietal, temporal, occipital lobes. Levels of childhood trauma, anxiety and depression were measured using respectively the Childhood Trauma Questionnaire, State-anxiety questionnaire and Beck Depression Inventory. Compared to the low-risk group, the high-risk group did not exhibit significant differences in the mean [11C]-PBR28 VT (F(1,20) = 1.619, p = 0.218) or DVR (F(1,22) = 0.952, p = 0.340) on any region. There were no significant correlations between the [11C]-PBR28 VT and DVRs in total gray matter and frontal lobe and measures of childhood trauma, anxiety and depression. Psychosocial risk factors for depression and/or psychosis are unlikely to be associated with alterations in [11C]-PBR28 binding, indicating that alterations in TSPO expression reported in these disorders is unlikely to be caused by psychosocial risk factors alone

The effect of a genetic variant at the schizophrenia associated AS3MT/BORCS7 locus on striatal dopamine function:A PET imaging study

One of the most statistically significant loci to result from large-scale GWAS of schizophrenia is 10q24.32. However, it is still unclear how this locus is involved in the pathoaetiology of schizophrenia. The hypothesis that presynaptic dopamine dysfunction underlies schizophrenia is one of the leading theories of the pathophysiology of the disorder. Supporting this, molecular imaging studies show evidence for elevated dopamine synthesis and release capacity. Thus, altered dopamine function could be a potential mechanism by which this genetic variant acts to increase the risk of schizophrenia. We therefore tested the hypothesis that the 10q24.32 region confers genetic risk for schizophrenia through an effect on striatal dopamine function. To this aim we investigated the in vivo relationship between a GWAS schizophrenia-associated SNP within this locus and dopamine synthesis capacity measured using [18F]-DOPA PET in healthy controls. 92 healthy volunteers underwent [18F]-DOPA PET scans to measure striatal dopamine synthesis capacity (indexed as Kicer) and were genotyped for the SNP rs7085104. We found a significant association between rs7085104 genotype and striatal Kicer. Our findings indicate that the mechanism mediating the 10q24.32 risk locus for schizophrenia could involve altered dopaminergic function. Future studies are needed to clarify the neurobiological pathway implicated in this association