Cortical and subcortical neuroanatomical signatures of schizotypy in 3004 individuals assessed in a worldwide ENIGMA study.

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = -0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, pspin = 0.006), BD (rho = -0.672, pspin = 0.009), and MDD (rho = -0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

Dopamine Modulates Adaptive Prediction Error Coding in the Human Midbrain and Striatum.

Learning to optimally predict rewards requires agents to account for fluctuations in reward value. Recent work suggests that individuals can efficiently learn about variable rewards through adaptation of the learning rate, and coding of prediction errors relative to reward variability. Such adaptive coding has been linked to midbrain dopamine neurons in nonhuman primates, and evidence in support for a similar role of the dopaminergic system in humans is emerging from fMRI data. Here, we sought to investigate the effect of dopaminergic perturbations on adaptive prediction error coding in humans, using a between-subject, placebo-controlled pharmacological fMRI study with a dopaminergic agonist (bromocriptine) and antagonist (sulpiride). Participants performed a previously validated task in which they predicted the magnitude of upcoming rewards drawn from distributions with varying SDs. After each prediction, participants received a reward, yielding trial-by-trial prediction errors. Under placebo, we replicated previous observations of adaptive coding in the midbrain and ventral striatum. Treatment with sulpiride attenuated adaptive coding in both midbrain and ventral striatum, and was associated with a decrease in performance, whereas bromocriptine did not have a significant impact. Although we observed no differential effect of SD on performance between the groups, computational modeling suggested decreased behavioral adaptation in the sulpiride group. These results suggest that normal dopaminergic function is critical for adaptive prediction error coding, a key property of the brain thought to facilitate efficient learning in variable environments. Crucially, these results also offer potential insights for understanding the impact of disrupted dopamine function in mental illness.SIGNIFICANCE STATEMENT To choose optimally, we have to learn what to expect. Humans dampen learning when there is a great deal of variability in reward outcome, and two brain regions that are modulated by the brain chemical dopamine are sensitive to reward variability. Here, we aimed to directly relate dopamine to learning about variable rewards, and the neural encoding of associated teaching signals. We perturbed dopamine in healthy individuals using dopaminergic medication and asked them to predict variable rewards while we made brain scans. Dopamine perturbations impaired learning and the neural encoding of reward variability, thus establishing a direct link between dopamine and adaptation to reward variability. These results aid our understanding of clinical conditions associated with dopaminergic dysfunction, such as psychosis.

Scaling prediction errors to reward variability benefits error-driven learning in humans.

Effective error-driven learning requires individuals to adapt learning to environmental reward variability. The adaptive mechanism may involve decays in learning rate across subsequent trials, as shown previously, and rescaling of reward prediction errors. The present study investigated the influence of prediction error scaling and, in particular, the consequences for learning performance. Participants explicitly predicted reward magnitudes that were drawn from different probability distributions with specific standard deviations. By fitting the data with reinforcement learning models, we found scaling of prediction errors, in addition to the learning rate decay shown previously. Importantly, the prediction error scaling was closely related to learning performance, defined as accuracy in predicting the mean of reward distributions, across individual participants. In addition, participants who scaled prediction errors relative to standard deviation also presented with more similar performance for different standard deviations, indicating that increases in standard deviation did not substantially decrease "adapters'" accuracy in predicting the means of reward distributions. However, exaggerated scaling beyond the standard deviation resulted in impaired performance. Thus efficient adaptation makes learning more robust to changing variability.

Cortical thickness in individuals with non-clinical and clinical psychotic symptoms.

Symptoms that are linked to psychosis are also experienced by individuals who are not in need of care. In the present study, cortical thickness was investigated in these individuals. Fifty individuals with non-clinical auditory verbal hallucinations (most of them also experienced other non-clinical psychotic symptoms), 50 patients with a psychotic disorder and auditory verbal hallucinations, and 50 healthy control subjects underwent structural magnetic resonance imaging. Data were analysed using FreeSurfer. Cortical thickness in the pars orbitalis, paracentral lobule, fusiform gyrus and inferior temporal gyrus was lowest in patients, intermediate in the non-clinical hallucinating group, and highest in control subjects. The patients also showed thinning in widespread additional areas compared to the two other groups, whereas both hallucinating groups showed similar levels of thinning in the insula. Ranking the levels of cortical thickness per brain region across groups revealed that for 88% of brain regions, cortical thickness was lowest in patients, intermediate in the non-clinical hallucinating group, and highest in controls. These findings show that individuals with non-clinical psychotic symptoms show a similar but less pronounced pattern of cortical thinning as patients with a psychotic disorder, which is suggestive of a similar, but milder underlying pathophysiology in this group compared to the psychosis group.

Network analysis of auditory hallucinations in nonpsychotic individuals.

BACKGROUND: Auditory verbal hallucinations (AVH) are a cardinal feature of schizophrenia and can severely disrupt behavior and decrease quality of life. Identification of areas with high functional connectivity (so-called hub regions) that are associated with the predisposition to hallucinate may provide potential targets for neuromodulation in the treatment of AVH. METHODS: Resting-state fMRI scans during which no hallucinations had occurred were acquired from 29 nonpsychotic individuals with AVH and 29 matched controls. These nonpsychotic individuals with AVH provide the opportunity to study AVH without several confounds associated with schizophrenia, such as antipsychotic medication use and other symptoms related to the illness. Hub regions were identified by assessing weighted connectivity strength and betweenness centrality across groups using a permutation analysis. RESULTS: Nonpsychotic individuals with AVH exhibited increased functioning as hub regions in the temporal cortices and the posterior cingulate/precuneus, which is an important area in the default mode network (DMN), compared to the nonhallucinating controls. In addition, the right inferior temporal gyrus, left paracentral lobule and right amygdala were less important as a hub region in the AVH group. CONCLUSIONS: These results suggest that the predisposition to hallucinate may be related to aberrant functioning of the DMN and the auditory cortices.

Towards a scalable approach to assess speech organization across the psychosis-spectrum -online assessment in conjunction with automated transcription and extraction of speech measures.

Automatically extracted measures of speech constitute a promising marker of psychosis as disorganized speech is associated with psychotic symptoms and predictive of psychosis-onset. The potential of speech markers is, however, hampered by (i) lengthy assessments in laboratory settings and (ii) manual transcriptions. We investigated whether a short, scalable data collection (online) and processing (automated transcription) procedure would provide data of sufficient quality to extract previously validated speech measures. To evaluate the fit of our approach for purpose, we assessed speech in relation to psychotic-like experiences in the general population. Participants completed an 8-minute-long speech task online. Sample 1 included measures of psychometric schizotypy and delusional ideation (N = 446). Sample 2 included a low and high psychometric schizotypy group (N = 144). Recordings were transcribed both automatically and manually, and connectivity, semantic, and syntactic speech measures were extracted for both types of transcripts. 73%/86% participants in sample 1/2 completed the experiment. Nineteen out of 25 speech measures were strongly (r > 0.7) and significantly correlated between automated and manual transcripts in both samples. Amongst the 14 connectivity measures, 11 showed a significant relationship with delusional ideation. For the semantic and syntactic measures, On Topic score and the Frequency of personal pronouns were negatively correlated with both schizotypy and delusional ideation. Combined with demographic information, the speech markers could explain 11-14% of the variation of delusional ideation and schizotypy in Sample 1 and could discriminate between high-low schizotypy with high accuracy (0.72-0.70, AUC = 0.78-0.79) in Sample 2. The moderate to high retention rate, strong correlation of speech measures across manual and automated transcripts and sensitivity to psychotic-like experiences provides initial evidence that online collected speech in combination with automatic transcription is a feasible approach to increase accessibility and scalability of speech-based assessment of psychosis.

Aberrations in the arcuate fasciculus are associated with auditory verbal hallucinations in psychotic and in non-psychotic individuals.

The pathophysiology of auditory verbal hallucinations (AVH) is still unclear. Cognitive as well as electrophysiological studies indicate that a defect in sensory feedback (corollary discharge) may contribute to the experience of AVH. This could result from disruption of the arcuate fasciculus, the major tract connecting frontal and temporo-parietal language areas. Previous diffusion tensor imaging studies indeed demonstrated abnormalities of this tract in schizophrenia patients with AVH. It is, however, difficult to disentangle specific associations with AVH in this patient group as many other factors, such as other positive and negative symptoms, medication or halted education could likewise have affected tract integrity. We therefore investigated AVH in relative isolation and studied a group of non-psychotic individuals with AVH as well as patients with AVH and non-hallucinating matched controls. We compared tract integrity of the arcuate fasiculus and of three other control tracts, between 35 non-psychotic individuals with AVH, 35 schizophrenia patients with AVH, and 36 controls using diffusion tensor imaging and magnetization transfer imaging. Both groups with AVH showed an increase in magnetization transfer ratio (MTR) in the arcuate fasciculus, but not in the other control tracts. In addition, a general decrease in fractional anisotropy (FA) for almost all bundles was observed in the patient group, but not in the non-psychotic individuals with AVH. As increased MTR in the arcuate fasciculus was present in both hallucinating groups, a specific association with AVH seems plausible. Decreases in FA, on the other hand, seem to be related to other disease processes of schizophrenia.

Automated analysis of speech as a marker of sub-clinical psychotic experiences.

Automated speech analysis techniques, when combined with artificial intelligence and machine learning, show potential in capturing and predicting a wide range of psychosis symptoms, garnering attention from researchers. These techniques hold promise in predicting the transition to clinical psychosis from at-risk states, as well as relapse or treatment response in individuals with clinical-level psychosis. However, challenges in scientific validation hinder the translation of these techniques into practical applications. Although sub-clinical research could aid to tackle most of these challenges, there have been only few studies conducted in speech and psychosis research in non-clinical populations. This work aims to facilitate this work by summarizing automated speech analytical concepts and the intersection of this field with psychosis research. We review psychosis continuum and sub-clinical psychotic experiences, and the benefits of researching them. Then, we discuss the connection between speech and psychotic symptoms. Thirdly, we overview current and state-of-the art approaches to the automated analysis of speech both in terms of language use (text-based analysis) and vocal features (audio-based analysis). Then, we review techniques applied in subclinical population and findings in these samples. Finally, we discuss research challenges in the field, recommend future research endeavors and outline how research in subclinical populations can tackle the listed challenges.

The Placebo Effect in Psychosis: Why It Matters and How to Measure It.

Psychosis is characterized by unusual percepts and beliefs in the form of hallucinations and delusions. Antipsychotic medication, the primary treatment for psychosis, is often ineffective and accompanied by severe side effects, but research has not identified an effective alternative in several decades. One reason that clinical trials fail is that patients with psychosis tend to show a significant therapeutic response to inert control treatments, known as the placebo effect, which makes it difficult to distinguish drug effects from placebo effects. Conversely, in clinical practice, a strong placebo effect may be useful because it could enhance the overall treatment response. Identifying factors that predict large placebo effects could improve the future outlook of psychosis treatment. Biomarkers of the placebo effect have already been suggested in pain and depression, but not in psychosis. Quantifying markers of the placebo effect would have the potential to predict placebo effects in psychosis clinical trials. Furthermore, the placebo effect and psychosis may represent a shared neurocognitive mechanism in which prior beliefs are weighted against new sensory information to make inferences about reality. Examining this overlap could reveal new insights into the mechanisms underlying psychosis and indicate novel treatment targets. We provide a narrative review of the importance of the placebo effect in psychosis and propose a novel method to assess it.

Belief updating in psychosis, depression and anxiety disorders: A systematic review across computational modelling approaches.

Alterations in belief updating are proposed to underpin symptoms of psychiatric illness, including psychosis, depression, and anxiety. Key parameters underlying belief updating can be captured using computational modelling techniques, aiding the identification of unique and shared deficits, and improving diagnosis and treatment. We systematically reviewed research that applied computational modelling to probabilistic tasks measuring belief updating in stable and volatile (changing) environments, across clinical and subclinical psychosis (n = 17), anxiety (n = 9), depression (n = 9) and transdiagnostic samples (n = 9). Depression disorders related to abnormal belief updating in response to the valence of rewards, evidenced in both stable and volatile environments. Whereas psychosis and anxiety disorders were associated with difficulties adapting to changing contingencies specifically, indicating an inflexibility and/or insensitivity to environmental volatility. Higher-order learning models revealed additional difficulties in the estimation of overall environmental volatility across psychosis disorders, showing increased updating to irrelevant information. These findings stress the importance of investigating belief updating in transdiagnostic samples, using homogeneous experimental and computational modelling approaches.

Online speech assessment of the psychotic spectrum: Exploring the relationship between overlapping acoustic markers of schizotypy, depression and anxiety.

BACKGROUND: Remote assessment of acoustic alterations in speech holds promise to increase scalability and validity in research across the psychosis spectrum. A feasible first step in establishing a procedure for online assessments is to assess acoustic alterations in psychometric schizotypy. However, to date, the complex relationship between alterations in speech related to schizotypy and those related to comorbid conditions such as symptoms of depression and anxiety has not been investigated. This study tested whether (1) depression, generalized anxiety and high psychometric schizotypy have similar voice characteristics, (2) which acoustic markers of online collected speech are the strongest predictors of psychometric schizotypy, (3) whether including generalized anxiety and depression symptoms in the model can improve the prediction of schizotypy. METHODS: We collected cross-sectional, online-recorded speech data from 441 participants, assessing demographics, symptoms of depression, generalized anxiety and psychometric schizotypy. RESULTS: Speech samples collected online could predict psychometric schizotypy, depression, and anxiety symptoms with weak to moderate predictive power, and with moderate and good predictive power when basic demographic variables were added to the models. Most influential features of these models largely overlapped. The predictive power of speech marker-based models of schizotypy significantly improved after including symptom scores of depression and generalized anxiety in the models (from R2 = 0.296 to R2 = 0. 436). CONCLUSIONS: Acoustic features of online collected speech are predictive of psychometric schizotypy as well as generalized anxiety and depression symptoms. The acoustic characteristics of schizotypy, depression and anxiety symptoms significantly overlap. Speech models that are designed to predict schizotypy or symptoms of the schizophrenia spectrum might therefore benefit from controlling for symptoms of depression and anxiety.

Semantic Speech Networks Linked to Formal Thought Disorder in Early Psychosis.

BACKGROUND AND HYPOTHESIS: Mapping a patient's speech as a network has proved to be a useful way of understanding formal thought disorder in psychosis. However, to date, graph theory tools have not explicitly modelled the semantic content of speech, which is altered in psychosis. STUDY DESIGN: We developed an algorithm, "netts," to map the semantic content of speech as a network, then applied netts to construct semantic speech networks for a general population sample (N = 436), and a clinical sample comprising patients with first episode psychosis (FEP), people at clinical high risk of psychosis (CHR-P), and healthy controls (total N = 53). STUDY RESULTS: Semantic speech networks from the general population were more connected than size-matched randomized networks, with fewer and larger connected components, reflecting the nonrandom nature of speech. Networks from FEP patients were smaller than from healthy participants, for a picture description task but not a story recall task. For the former task, FEP networks were also more fragmented than those from controls; showing more connected components, which tended to include fewer nodes on average. CHR-P networks showed fragmentation values in-between FEP patients and controls. A clustering analysis suggested that semantic speech networks captured novel signals not already described by existing NLP measures. Network features were also related to negative symptom scores and scores on the Thought and Language Index, although these relationships did not survive correcting for multiple comparisons. CONCLUSIONS: Overall, these data suggest that semantic networks can enable deeper phenotyping of formal thought disorder in psychosis. Whilst here we focus on network fragmentation, the semantic speech networks created by Netts also contain other, rich information which could be extracted to shed further light on formal thought disorder. We are releasing Netts as an open Python package alongside this manuscript.

Cannabinoids, reward processing, and psychosis.

BACKGROUND: Evidence suggests that an overlap exists between the neurobiology of psychotic disorders and the effects of cannabinoids on neurocognitive and neurochemical substrates involved in reward processing. AIMS: We investigate whether the psychotomimetic effects of delta-9-tetrahydrocannabinol (THC) and the antipsychotic potential of cannabidiol (CBD) are underpinned by their effects on the reward system and dopamine. METHODS: This narrative review focuses on the overlap between altered dopamine signalling and reward processing induced by cannabinoids, pre-clinically and in humans. A systematic search was conducted of acute cannabinoid drug-challenge studies using neuroimaging in healthy subjects and those with psychosis RESULTS: There is evidence of increased striatal presynaptic dopamine synthesis and release in psychosis, as well as abnormal engagement of the striatum during reward processing. Although, acute THC challenges have elicited a modest effect on striatal dopamine, cannabis users generally indicate impaired presynaptic dopaminergic function. Functional MRI studies have identified that a single dose of THC may modulate regions involved in reward and salience processing such as the striatum, midbrain, insular, and anterior cingulate, with some effects correlating with the severity of THC-induced psychotic symptoms. CBD may modulate brain regions involved in reward/salience processing in an opposite direction to that of THC. CONCLUSIONS: There is evidence to suggest modulation of reward processing and its neural substrates by THC and CBD. Whether such effects underlie the psychotomimetic/antipsychotic effects of these cannabinoids remains unclear. Future research should address these unanswered questions to understand the relationship between endocannabinoid dysfunction, reward processing abnormalities, and psychosis.

Characterizing cerebral metabolite profiles in anorexia and bulimia nervosa and their associations with habitual behavior.

Anorexia nervosa (AN) and bulimia nervosa (BN) are associated with altered brain structure and function, as well as increased habitual behavior. This neurobehavioral profile may implicate neurochemical changes in the pathogenesis of these illnesses. Altered glutamate, myo-inositol and N-acetyl aspartate (NAA) concentrations are reported in restrictive AN, yet whether these extend to binge-eating disorders, or relate to habitual traits in affected individuals, remains unknown. We therefore used single-voxel proton magnetic resonance spectroscopy to measure glutamate, myo-inositol, and NAA in the right inferior lateral prefrontal cortex and the right occipital cortex of 85 women [n = 22 AN (binge-eating/purging subtype; AN-BP), n = 33 BN, n = 30 controls]. To index habitual behavior, participants performed an instrumental learning task and completed the Creature of Habit Scale. Women with AN-BP, but not BN, had reduced myo-inositol and NAA concentrations relative to controls in both regions. Although patient groups had intact instrumental learning task performance, both groups reported increased routine behaviors compared to controls, and automaticity was related to reduced prefrontal glutamate and NAA participants with AN-BP. Our findings extend previous reports of reduced myo-inositol and NAA levels in restrictive AN to AN-BP, which may reflect disrupted axonal-glial signaling. Although we found inconsistent support for increased habitual behavior in AN-BP and BN, we identified preliminary associations between prefrontal metabolites and automaticity in AN-BP. These results provide further evidence of unique neurobiological profiles across binge-eating disorders.

Subcortical volume reduction and cortical thinning 3 months after switching to clozapine in treatment resistant schizophrenia.

The neurobiological effects of clozapine are under characterised. We examined the effects clozapine treatment on subcortical volume and cortical thickness and investigated whether macrostructural changes were linked to alterations in glutamate or N-acetylaspartate (NAA). Data were acquired in 24 patients with treatment-resistant schizophrenia before and 12 weeks after switching to clozapine. During clozapine treatment we observed reductions in caudate and putamen volume, lateral ventricle enlargement (P < 0.001), and reductions in thickness of the left inferior temporal cortex, left caudal middle frontal cortex, and the right temporal pole. Reductions in right caudate volume were associated with local reductions in NAA (P = 0.002). None of the morphometric changes were associated with changes in glutamate levels. These results indicate that clozapine treatment is associated with subcortical volume loss and cortical thinning and that at least some of these effects are linked to changes in neuronal or metabolic integrity.

Decreased language lateralization is characteristic of psychosis, not auditory hallucinations.

Decreased language lateralization is a well-replicated finding in psychotic patients. It is currently unclear, however, whether this abnormality is related to a particular symptom of psychosis or to psychosis in general. It has been argued that decreased language lateralization may be related to auditory verbal hallucinations. To elucidate this, these hallucinations should be studied in isolation. Thirty-five patients with a psychotic disorder, 35 non-psychotic subjects with relatively isolated auditory verbal hallucinations and 35 healthy control subjects participated in this study. All subjects were scanned on a 3T magnetic resonance imaging scanner, while covertly performing a paced verbal fluency task. In order to measure performance on the task, one additional task block was presented during which subjects had to generate words overtly. In addition to calculating language lateralization indices, group-wise brain activation during verbal fluency was compared between the three groups. Task performance was nearly maximal for all groups and did not differ significantly between the groups. Compared with the healthy control subjects and non-psychotic subjects with auditory verbal hallucinations, language lateralization was significantly reduced for the patient group. In addition, the patients displayed significantly greater activity in the right precentral gyrus and left insula when compared with the healthy control subjects and the non-psychotic subjects with auditory verbal hallucinations. Furthermore, the patients showed greater activity in the right superior parietal lobule when compared with the healthy control subjects. Lateralization indices did not differ significantly between the non-psychotic subjects with auditory verbal hallucinations and the healthy control subjects. Moreover, there were no significant differences in brain activation during verbal fluency between the two non-psychotic groups. As language lateralization was not significantly reduced in the non-psychotic individuals with auditory verbal hallucinations, a direct relationship between auditory verbal hallucinations and decreased language lateralization can not be established at present.

Treatment of Alice in Wonderland syndrome and verbal auditory hallucinations using repetitive transcranial magnetic stimulation: a case report with fMRI findings.

BACKGROUND: Alice in Wonderland syndrome (AIWS) is a rare cluster of CNS symptoms characterized by visual distortions (i.e. metamorphopsias), body image distortions, time distortions, and déjà experiences. Verbal auditory hallucinations (VAHs) are the most prevalent type of hallucination in adults with or without a history of psychiatric illness. Here, we report the case of a woman with AIWS, long-lasting VAHs, and various additional perceptual and mood symptoms. METHODS: Semi-structured interviews were used to assess symptoms, and functional MRI (fMRI) was employed to localize cerebral activity during self-reported VAHs. Treatment consisted of repetitive transcranial magnetic stimulation (rTMS) at a frequency of 1 Hz at T3P3, overlying Brodmann's area 40. RESULTS: Activation during VAHs was observed bilaterally in the basal ganglia, the primary auditory cortex, the association auditory cortex, the temporal poles, and the anterior cingulated gyrus. The left and right inferior frontal gyri (Broca's area and its contralateral homologue) were involved, along with the dorsolateral prefrontal cortex. Interestingly, synchronized activation was observed in the primary visual cortex (areas V1 and V2), and the bilateral dorsal visual cortex. The higher visual association cortex also showed significant, but less prominent, activation. During the second week of rTMS treatment, not only the VAHs, but also the other sensory deceptions/distortions and mood symptoms showed complete remission. The patient remained free of any symptoms during a 4-month follow-up phase. After 8 months, when many of the original symptoms had returned, a second treatment phase with rTMS was again followed by complete remission. CONCLUSIONS: This case indicates that VAHs and metamorphopsias in AIWS are associated with synchronized activation in both auditory and visual cortices. It also indicates that local rTMS treatment may have global therapeutic effects, suggesting an effect on multiple brain regions in a distributed network. Although a placebo effect cannot be ruled out, this case warrants further investigation of the effects of rTMS treatment in AIWS.

Dopamine, Prediction Error and Beyond.

A large body of work has linked dopaminergic signaling to learning and reward processing. It stresses the role of dopamine in reward prediction error signaling, a key neural signal that allows us to learn from past experiences, and that facilitates optimal choice behavior. Latterly, it has become clear that dopamine does not merely code prediction error size but also signals the difference between the expected value of rewards, and the value of rewards actually received, which is obtained through the integration of reward attributes such as the type, amount, probability and delay. More recent work has posited a role of dopamine in learning beyond rewards. These theories suggest that dopamine codes absolute or unsigned prediction errors, playing a key role in how the brain models associative regularities within its environment, while incorporating critical information about the reliability of those regularities. Work is emerging supporting this perspective and, it has inspired theoretical models of how certain forms of mental pathology may emerge in relation to dopamine function. Such pathology is frequently related to disturbed inferences leading to altered internal models of the environment. Thus, it is critical to understand the role of dopamine in error-related learning and inference.

Lower speech connectedness linked to incidence of psychosis in people at clinical high risk.

BACKGROUND: Formal thought disorder is a cardinal feature of psychotic disorders, and is also evident in subtle forms before psychosis onset in individuals at clinical high-risk for psychosis (CHR-P). Assessing speech output or assessing expressive language with speech as the medium at this stage may be particularly useful in predicting later transition to psychosis. METHOD: Speech samples were acquired through administration of the Thought and Language Index (TLI) in 24 CHR-P participants, 16 people with first-episode psychosis (FEP) and 13 healthy controls. The CHR-P individuals were then followed clinically for a mean of 7 years (s.d. = 1.5) to determine if they transitioned to psychosis. Non-semantic speech graph analysis was used to assess the connectedness of transcribed speech in all groups. RESULTS: Speech was significantly more disconnected in the FEP group than in both healthy controls (p < .01) and the CHR-P group (p < .05). Results remained significant when IQ was included as a covariate. Significant correlations were found between speech connectedness measures and scores on the TLI, a manual assessment of formal thought disorder. In the CHR-P group, lower scores on two measures of speech connectedness were associated with subsequent transition to psychosis (8 transitions, 16 non-transitions; p < .05). CONCLUSION: These findings support the utility and validity of speech graph analysis methods in characterizing speech connectedness in the early phases of psychosis. This approach has the potential to be developed into an automated, objective and time-efficient way of stratifying individuals at CHR-P according to level of psychosis risk.

Natural Language Processing markers in first episode psychosis and people at clinical high-risk.

Recent work has suggested that disorganised speech might be a powerful predictor of later psychotic illness in clinical high risk subjects. To that end, several automated measures to quantify disorganisation of transcribed speech have been proposed. However, it remains unclear which measures are most strongly associated with psychosis, how different measures are related to each other and what the best strategies are to collect speech data from participants. Here, we assessed whether twelve automated Natural Language Processing markers could differentiate transcribed speech excerpts from subjects at clinical high risk for psychosis, first episode psychosis patients and healthy control subjects (total N = 54). In-line with previous work, several measures showed significant differences between groups, including semantic coherence, speech graph connectivity and a measure of whether speech was on-topic, the latter of which outperformed the related measure of tangentiality. Most NLP measures examined were only weakly related to each other, suggesting they provide complementary information. Finally, we compared the ability of transcribed speech generated using different tasks to differentiate the groups. Speech generated from picture descriptions of the Thematic Apperception Test and a story re-telling task outperformed free speech, suggesting that choice of speech generation method may be an important consideration. Overall, quantitative speech markers represent a promising direction for future clinical applications.