Identifying Medications Underlying Communication Atypicalities in Psychotic and Affective Disorders: A Pharmacovigilance Study Within the FDA Adverse Event Reporting System.

PURPOSE: Communication atypicalities are considered promising markers of a broad range of clinical conditions. However, little is known about the mechanisms and confounders underlying them. Medications might have a crucial, relatively unknown role both as potential confounders and offering an insight on the mechanisms at work. The integration of regulatory documents with disproportionality analyses provides a more comprehensive picture to account for in future investigations of communication-related markers. The aim of this study was to identify a list of drugs potentially associated with communicative atypicalities within psychotic and affective disorders. METHOD: We developed a query using the Medical Dictionary for Regulatory Activities to search for communicative atypicalities within the FDA Adverse Event Reporting System (updated June 2021). A Bonferroni-corrected disproportionality analysis (reporting odds ratio) was separately performed on spontaneous reports involving psychotic, affective, and non-neuropsychiatric disorders, to account for the confounding role of different underlying conditions. Drug-adverse event associations not already reported in the Side Effect Resource database of labeled adverse drug reactions (unexpected) were subjected to further robustness analyses to account for expected biases. RESULTS: A list of 291 expected and 91 unexpected potential confounding medications was identified, including drugs that may irritate (inhalants) or desiccate (anticholinergics) the larynx, impair speech motor control (antipsychotics), or induce nodules (acitretin) or necrosis (vascular endothelial growth factor receptor inhibitors) on vocal cords; sedatives and stimulants; neurotoxic agents (anti-infectives); and agents acting on neurotransmitter pathways (dopamine agonists). CONCLUSIONS: We provide a list of medications to account for in future studies of communication-related markers in affective and psychotic disorders. The current test case illustrates rigorous procedures for digital phenotyping, and the methodological tools implemented for large-scale disproportionality analyses can be considered a road map for investigations of communication-related markers in other clinical populations. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.23721345.

Voice Patterns as Markers of Schizophrenia: Building a Cumulative Generalizable Approach Via a Cross-Linguistic and Meta-analysis Based Investigation.

BACKGROUND AND HYPOTHESIS: Voice atypicalities are potential markers of clinical features of schizophrenia (eg, negative symptoms). A recent meta-analysis identified an acoustic profile associated with schizophrenia (reduced pitch variability and increased pauses), but also highlighted shortcomings in the field: small sample sizes, little attention to the heterogeneity of the disorder, and to generalizing findings to diverse samples and languages. STUDY DESIGN: We provide a critical cumulative approach to vocal atypicalities in schizophrenia, where we conceptually and statistically build on previous studies. We aim at identifying a cross-linguistically reliable acoustic profile of schizophrenia and assessing sources of heterogeneity (symptomatology, pharmacotherapy, clinical and social characteristics). We relied on previous meta-analysis to build and analyze a large cross-linguistic dataset of audio recordings of 231 patients with schizophrenia and 238 matched controls (>4000 recordings in Danish, German, Mandarin and Japanese). We used multilevel Bayesian modeling, contrasting meta-analytically informed and skeptical inferences. STUDY RESULTS: We found only a minimal generalizable acoustic profile of schizophrenia (reduced pitch variability), while duration atypicalities replicated only in some languages. We identified reliable associations between acoustic profile and individual differences in clinical ratings of negative symptoms, medication, age and gender. However, these associations vary across languages. CONCLUSIONS: The findings indicate that a strong cross-linguistically reliable acoustic profile of schizophrenia is unlikely. Rather, if we are to devise effective clinical applications able to target different ranges of patients, we need first to establish larger and more diverse cross-linguistic datasets, focus on individual differences, and build self-critical cumulative approaches.

Introducing tomsup: Theory of mind simulations using Python.

Theory of mind (ToM) is considered crucial for understanding social-cognitive abilities and impairments. However, verbal theories of the mechanisms underlying ToM are often criticized as under-specified and mutually incompatible. This leads to measures of ToM being unreliable, to the extent that even canonical experimental tasks do not require representation of others' mental states. There have been attempts at making computational models of ToM, but these are not easily available for broad research application. In order to help meet these challenges, we here introduce the Python package tomsup: Theory of mind simulations using Python. The package provides a computational eco-system for investigating and comparing computational models of hypothesized ToM mechanisms and for using them as experimental stimuli. The package notably includes an easy-to-use implementation of the variational recursive Bayesian k-ToM model developed by (Devaine, Hollard, & Daunizeau, 2014b) and of simpler non-recursive decision models, for comparison. We provide a series of tutorials on how to: (i) simulate agents relying on the k-ToM model and on a range of simpler types of mechanisms; (ii) employ those agents to generate online experimental stimuli; (iii) analyze the data generated in such experimental setup, and (iv) specify new custom ToM and heuristic cognitive models.

Speech disturbances in schizophrenia: Assessing cross-linguistic generalizability of NLP automated measures of coherence.

INTRODUCTION: Language disorders - disorganized and incoherent speech in particular - are distinctive features of schizophrenia. Natural language processing (NLP) offers automated measures of incoherent speech as promising markers for schizophrenia. However, the scientific and clinical impact of NLP markers depends on their generalizability across contexts, samples, and languages, which we systematically assessed in the present study relying on a large, novel, cross-linguistic corpus. METHODS: We collected a Danish (DK), German (GE), and Chinese (CH) cross-linguistic dataset involving transcripts from 187 participants with schizophrenia (111DK, 25GE, 51CH) and 200 matched controls (129DK, 29GE, 42CH) performing the Animated Triangles Task. Fourteen previously published NLP coherence measures were calculated, and between-groups differences and association with symptoms were tested for cross-linguistic generalizability. RESULTS: One coherence measure, i.e. second-order coherence, robustly generalized across samples and languages. We found several language-specific effects, some of which partially replicated previous findings (lower coherence in German and Chinese patients), while others did not (higher coherence in Danish patients). We found several associations between symptoms and measures of coherence, but the effects were generally inconsistent across languages and rating scales. CONCLUSIONS: Using a cumulative approach, we have shown that NLP findings of reduced semantic coherence in schizophrenia have limited generalizability across different languages, samples, and measures. We argue that several factors such as sociodemographic and clinical heterogeneity, cross-linguistic variation, and the different NLP measures reflecting different clinical aspects may be responsible for this variability. Future studies should take this variability into account in order to develop effective clinical applications targeting different patient populations.

Vocal markers of autism: Assessing the generalizability of machine learning models.

Machine learning (ML) approaches show increasing promise in their ability to identify vocal markers of autism. Nonetheless, it is unclear to what extent such markers generalize to new speech samples collected, for example, using a different speech task or in a different language. In this paper, we systematically assess the generalizability of ML findings across a variety of contexts. We train promising published ML models of vocal markers of autism on novel cross-linguistic datasets following a rigorous pipeline to minimize overfitting, including cross-validated training and ensemble models. We test the generalizability of the models by testing them on (i) different participants from the same study, performing the same task; (ii) the same participants, performing a different (but similar) task; (iii) a different study with participants speaking a different language, performing the same type of task. While model performance is similar to previously published findings when trained and tested on data from the same study (out-of-sample performance), there is considerable variance between studies. Crucially, the models do not generalize well to different, though similar, tasks and not at all to new languages. The ML pipeline is openly shared. Generalizability of ML models of vocal markers of autism is an issue. We outline three recommendations for strategies researchers could take to be more explicit about generalizability and improve it in future studies. LAY SUMMARY: Machine learning approaches promise to be able to identify autism from voice only. These models underestimate how diverse the contexts in which we speak are, how diverse the languages used are and how diverse autistic voices are. Machine learning approaches need to be more careful in defining their limits and generalizability.

Taking others into account: combining directly experienced and indirect information in schizophrenia.

An abnormality in inference, resulting in distorted internal models of the world, has been argued to be a common mechanism underlying the heterogeneous psychopathology in schizophrenia. However, findings have been mixed as to wherein the abnormality lies and have typically failed to find convincing relations to symptoms. The limited and inconsistent findings may have been due to methodological limitations of the experimental design, such as conflating other factors (e.g. comprehension) with the inferential process of interest, and a failure to adequately assess and model the key aspects of the inferential process. Here, we investigated probabilistic inference based on multiple sources of information using a new digital version of the beads task, framed in a social context. Thirty-five patients with schizophrenia or schizoaffective disorder with a wide range of symptoms and 40 matched healthy control subjects performed the task, where they guessed the colour of the next marble drawn from a jar based on a sample from the jar as well as the choices and the expressed confidence of four people, each with their own independent sample (which was hidden from participant view). We relied on theoretically motivated computational models to assess which model best captured the inferential process and investigated whether it could serve as a mechanistic model for both psychotic and negative symptoms. We found that 'circular inference' best described the inference process, where patients over-weighed and overcounted direct experience and under-weighed information from others. Crucially, overcounting of direct experience was uniquely associated with most psychotic and negative symptoms. In addition, patients with worse social cognitive function had more difficulties using others' confidence to inform their choices. This difficulty was related to worse real-world functioning. The findings could not be easily ascribed to differences in working memory, executive function, intelligence or antipsychotic medication. These results suggest hallucinations, delusions and negative symptoms could stem from a common underlying abnormality in inference, where directly experienced information is assigned an unreasonable weight and taken into account multiple times. By this, even unreliable first-hand experiences may gain disproportionate significance. The effect could lead to false perceptions (hallucinations), false beliefs (delusions) and deviant social behaviour (e.g. loss of interest in others, bizarre and inappropriate behaviour). This may be particularly problematic for patients with social cognitive deficits, as they may fail to make use of corrective information from others, ultimately leading to worse social functioning.

Psychological adjustment in care providers following restraint of psychiatric patients.

Mental healthcare providers face many difficult interactions with patients that can be emotionally demanding and have adverse effects on their well-being. Recent theoretical models suggest that the interpretation of stressful episodes may be more important for psychological adjustment than the nature of the episodes. This study examined whether care providers' interpretations of mechanical restraint episodes were related to their adjustment. We asked 80 mental healthcare providers to recall mechanical restraint episodes and to rate them on centrality to identity and positive and negative influence on self-understanding. They also completed scales measuring current symptoms of post-traumatic stress, depression, life satisfaction, and well-being. The results showed that care providers who interpreted mechanical restraint episodes as having a central negative influence on their identity experienced more symptoms of post-traumatic stress. Care providers who gave higher ratings of positive self-change following episodes reported more well-being. Our findings suggest, that considering care providers' subjective interpretations of episodes and not merely the objective facts surrounding them is critical if we wish to mitigate the negative emotional impact of episodes.

Cross-cultural comparison of theory of mind deficits in patients with schizophrenia from China and Denmark: different aspects of ToM show different results.

Introduction: Theory of mind (ToM) has been established as one of the most investigated and pronounced social cognitive deficits in schizophrenia. Yet, knowledge on whether measures of ToM can be used and compared across cultures is sparse. In this study, we used two simple, non-verbal ToM tests in patients with schizophrenia and non-clinical controls from China and Denmark to investigate whether culture has an impact on ToM performance.Methods: Sixty-six patients with schizophrenia (35 Chinese) and 67 matched non-clinical controls (38 Chinese) from China and Denmark were tested with Brünés Picture Sequencing Task and Animated Triangles Task. We compared three models for each outcome variable in order to investigate which model best fitted the data: the first model included group (controls, patients) as a predictor variable, the second included group and nationality (Chinese, Danish), and the third included both predictors and their interaction.Results: On most ToM subtests, culture seemed to play a role. Only performance on Brüne's 1st order ToM were best described as similar in both countries. The second model had the best fit for most of the subtests indicating that the difference between patients and controls in China and Denmark, respectively, is similar.Conclusions: Caution to cultural differences should be taken when comparing ToM in Asian and Western patients with schizophrenia as well as healthy individuals.

Voice patterns in schizophrenia: A systematic review and Bayesian meta-analysis.

Voice atypicalities have been a characteristic feature of schizophrenia since its first definitions. They are often associated with core negative symptoms such as flat affect and alogia, and with the social impairments seen in the disorder. This suggests that voice atypicalities may represent a marker of clinical features and social functioning in schizophrenia. We systematically reviewed and meta-analyzed the evidence for distinctive acoustic patterns in schizophrenia, as well as their relation to clinical features. We identified 46 articles, including 55 studies with a total of 1254 patients with schizophrenia and 699 healthy controls. Summary effect sizes (Hedges'g and Pearson's r) estimates were calculated using multilevel Bayesian modeling. We identified weak atypicalities in pitch variability (g = -0.55) related to flat affect, and stronger atypicalities in proportion of spoken time, speech rate, and pauses (g's between -0.75 and -1.89) related to alogia and flat affect. However, the effects were mostly modest (with the important exception of pause duration) compared to perceptual and clinical judgments, and characterized by large heterogeneity between studies. Moderator analyses revealed that tasks with a more demanding cognitive and social component showed larger effects both in contrasting patients and controls and in assessing symptomatology. In conclusion, studies of acoustic patterns are a promising but, yet unsystematic avenue for establishing markers of schizophrenia. We outline recommendations towards more cumulative, open, and theory-driven research.

Socially Learned Attitude Change is not reduced in Medicated Patients with Schizophrenia.

Schizophrenia is often associated with distinctive or odd social behaviours. Previous work suggests this could be due to a general reduction in conformity; however, this work only assessed the tendency to publicly agree with others, which may involve a number of different mechanisms. In this study, we specifically investigated whether patients display a reduced tendency to adopt other people's opinions (socially learned attitude change). We administered a computerized conformity task, assumed to rely on reinforcement learning circuits, to 32 patients with schizophrenia or schizo-affective disorder and 39 matched controls. Each participant rated 153 faces for trustworthiness. After each rating, they were immediately shown the opinion of a group. After approximately 1 hour, participants were unexpectedly asked to rate all the faces again. We compared the degree of attitude change towards group opinion in patients and controls. Patients presented equal or more social influence on attitudes than controls. This effect may have been medication induced, as increased conformity was seen with higher antipsychotic dose. The results suggest that there is not a general decline in conformity in medicated patients with schizophrenia and that previous findings of reduced conformity are likely related to mechanisms other than reinforcement based social influence on attitudes.

Hyper- and Hypomentalizing in Patients with First-Episode Schizophrenia: fMRI and Behavioral Studies.

BACKGROUND: Historically, research investigating neural correlates of mentalizing deficits in schizophrenia has focused on patients who have been ill for several years with lengthy exposure to medication. Little is known about the neural and behavioral presentations of theory-of-mind deficits in schizophrenia, shortly after the first episode of psychosis. METHODS: We investigated social cognition in 17 recently diagnosed first-episode schizophrenia (FES) patients with little or no exposure to antipsychotic medication and 1:1 matched healthy controls. We recorded behavioral and neural responses to the Animated Triangles Task (ATT), which is a nonverbal validated mentalizing task that measures the ascription of intentionality to the movements of objects. RESULTS: FES patients under-interpreted social cues and over-interpreted nonsocial cues. These effects were influenced by current intelligence (IQ). Control group and FES neural responses replicated earlier findings in healthy adults. However, a region of anterior medial prefrontal cortex (amPFC) of FES patients showed a different response pattern to that of controls. Unlike healthy controls, patients increased activity in this social cognition region while studying "random" movements of shapes, as compared to the study of movements normally interpreted as "intentional". CONCLUSIONS: Mentalizing deficits in FES consists of hypo- and hypermentalizing. The neural pattern of FES patients is consistent with deficits in the ability to switch off mentalizing processes in potentially social contexts, instead increasing them when intentionality is not forthcoming. Overall, results demonstrate complexities of theory of mind deficits in schizophrenia that should be considered when offering social cognitive training programs.

Enhanced Automatic Action Imitation and Intact Imitation-Inhibition in Schizophrenia.

Imitation plays a key role in social learning and in facilitating social interactions and likely constitutes a basic building block of social cognition that supports higher-level social abilities. Recent findings suggest that patients with schizophrenia have imitation impairments that could contribute to the social impairments associated with the disorder. However, extant studies have specifically assessed voluntary imitation or automatic imitation of emotional stimuli without controlling for potential confounders. The imitation impairments seen might therefore be secondary to other cognitive, motoric, or emotional deficits associated with the disorder. To overcome this issue, we used an automatic imitation paradigm with nonemotional stimuli to assess automatic imitation and the top-down modulation of imitation where participants were required to lift one of 2 fingers according to a number shown on the screen while observing the same or the other finger movement. In addition, we used a control task with a visual cue in place of a moving finger, to isolate the effect of observing finger movement from other visual cueing effects. Data from 33 patients (31 medicated) and 40 matched healthy controls were analyzed. Patients displayed enhanced imitation and intact top-down modulation of imitation. The enhanced imitation seen in patients may have been medication induced as larger effects were seen in patients receiving higher antipsychotic doses. In sum, we did not find an imitation impairment in schizophrenia. The results suggest that previous findings of impaired imitation in schizophrenia might have been due to other cognitive, motoric, and/or emotional deficits.

Independent Neural Computation of Value from Other People's Confidence.

Expectation of reward can be shaped by the observation of actions and expressions of other people in one's environment. A person's apparent confidence in the likely reward of an action, for instance, makes qualities of their evidence, not observed directly, socially accessible. This strategy is computationally distinguished from associative learning methods that rely on direct observation, by its use of inference from indirect evidence. In twenty-three healthy human subjects, we isolated effects of first-hand experience, other people's choices, and the mediating effect of their confidence, on decision-making and neural correlates of value within ventromedial prefrontal cortex (vmPFC). Value derived from first-hand experience and other people's choices (regardless of confidence) were indiscriminately represented across vmPFC. However, value computed from agent choices weighted by their associated confidence was represented with specificity for ventromedial area 10. This pattern corresponds to shifts of connectivity and overlapping cognitive processes along a posterior-anterior vmPFC axis. Task behavior and self-reported self-reliance for decision-making in other social contexts correlated. The tendency to conform in other social contexts corresponded to increased activation in cortical regions previously shown to respond to social conflict in proportion to subsequent conformity (Campbell-Meiklejohn et al., 2010). The tendency to self-monitor predicted a selectively enhanced response to accordance with others in the right temporoparietal junction (rTPJ). The findings anatomically decompose vmPFC value representations according to computational requirements and provide biological insight into the social transmission of preference and reassurance gained from the confidence of others. SIGNIFICANCE STATEMENT: Decades of research have provided evidence that the ventromedial prefrontal cortex (vmPFC) signals the satisfaction we expect from imminent actions. However, we have a surprisingly modest understanding of the organization of value across this substantial and varied region. This study finds that using cues of the reliability of other peoples' knowledge to enhance expectation of personal success generates value correlates that are anatomically distinct from those concurrently computed from direct, personal experience. This suggests that representation of decision values in vmPFC is suborganized according to the underlying computation, consistent with what we know about the anatomical heterogeneity of the region. These results also provide insight into the observational learning process by which someone else's confidence can sway and reassure our choices.

Serotoninergic effects on judgments and social learning of trustworthiness.

RATIONALE: Certain disorders, such as depression and anxiety, to which serotonin dysfunction is historically associated, are also associated with lower assessments of other people's trustworthiness. Serotonergic changes are known to alter cognitive responses to threatening stimuli. This effect may manifest socially as reduced apparent trustworthiness of others. Trustworthiness judgments can emerge from either direct observation or references provided by third parties. OBJECTIVE: We assessed whether explicit judgments of trustworthiness and social influences on those judgments are altered by changes within serotonergic systems. METHODS: We implemented a double-blind between-subject design where 20 healthy female volunteers received a single dose of the selective serotonin reuptake inhibitor (SSRI) citalopram (2 × 20 mg), while 20 control subjects (matched on age, intelligence, and years of education) received a placebo. Subjects performed a face-rating task assessing how trustworthy they found 153 unfamiliar others (targets). After each rating, the subjects were told how other subjects, on average, rated the same target. The subjects then performed 30 min of distractor tasks before, unexpectedly, being asked to rate all 153 faces again, in a random order. RESULTS: Compared to subjects receiving a placebo, subjects receiving citalopram rated targets as less trustworthy. They also conformed more to opinions of others, when others rated targets to be even less trustworthy than subjects had initially indicated. The two effects were independent of negative effects of citalopram on subjective state. CONCLUSIONS: This is evidence that serotonin systems can mediate explicit assessment and social learning of the trustworthiness of others.

In for a penny, in for a pound: methylphenidate reduces the inhibitory effect of high stakes on persistent risky choice.

Methylphenidate (MPH) is a stimulant that increases extracellular levels of dopamine and noradrenaline. It can diminish risky decision-making tendencies in certain clinical populations. MPH is also used, without license, by healthy adults, but the impact on their decision-making is not well established. Previous work has found that dopamine receptor activity of healthy adults can modulate the influence of stake magnitude on decisions to persistently gamble after incurring a loss. In this study, we tested for modulation of this effect by MPH in 40 healthy human adults. In a double-blind experiment, 20 subjects received 20 mg of MPH, while 20 matched controls received a placebo. All were provided with 30 rounds of opportunities to accept an incurred loss from their assets or opt for a "double-or-nothing" gamble that would either avoid or double it. Rounds began with a variable loss that would double with every failed gamble until it was accepted, recovered, or reached a specified maximum. Probability of recovery on any gamble was low and ambiguous. Subjects receiving placebo gambled less as the magnitude of the stake was raised and as the magnitude of accumulated loss escalated over the course of the task. In contrast, subjects treated with MPH gambled at a consistent rate, well above chance, across all stakes and trials. Trait reward responsiveness also reduced the impact of high stakes. The findings suggest that elevated catecholamine activity by MPH can disrupt inhibitory influences on persistent risky choice in healthy adults.

Modulation of social influence by methylphenidate.

The ability to infer value from the reactions of other people is a common and essential ability with a poorly understood neurobiology. Commonly, social learning matches one's values and behavior to what is perceived as normal for one's social group. This is known as conformity. Conformity of value correlates with neural activity shared by cognitions that depend on optimum catecholamine levels, but catecholamine involvement in conformity has not been tested empirically. Methylphenidate (MPH) is an indirect dopamine and noradrenalin agonist, commonly used for the treatment of attention-deficit hyperactivity disorder for which it reduces undesirable behavior as evaluated by peers and authority figures, indicative of increased conformity. We hypothesized that MPH might increase conformity of value. In all, 38 healthy adult females received either a single oral 20 mg dose of MPH or placebo (PL). Each subject rated 153 faces for trustworthiness followed immediately by the face's mean rating from a group of peers. After 30 min and a 2-back continuous-performance working-memory task, subjects were unexpectedly asked to rate all the faces again. Both the groups tended to change their ratings towards the social norm. The MPH group exhibited twice the conformity effect of the PL group following moderate social conflict, but this did not occur following large conflicts. This suggests that MPH might enhance signals that would otherwise be too weak to evoke conformity. MPH did not affect 2-back performance. We provide a new working hypothesis of a neurocognitive mechanism by which MPH reduces socially disruptive behavior. We also provide novel evidence of catecholamine mediation of social learning [corrected].