Psychosocial functioning in the balance between autism and psychosis: evidence from three populations.

Functional impairment is a core feature of both autism and schizophrenia spectrum disorders. While diagnostically independent, they can co-occur in the same individual at both the trait and diagnostic levels. The effect of such co-occurrence is hypothesized to worsen functional impairment. The diametric model, however, suggests that the disorders are etiologically and phenotypically diametrical, representing the extreme of a unidimensional continuum of cognition and behavior. A central prediction of this model is that functional impairment would be attenuated in individuals with mixed symptom expressions or genetic liability to both disorders. We tested this hypothesis in two clinical populations and one healthy population. In individuals with chronic schizophrenia and in individuals with first episode psychosis we evaluated the combined effect of autistic traits and positive psychotic symptoms on psychosocial functioning. In healthy carriers of alleles of copy number variants (CNVs) that confer risk for both autism and schizophrenia, we also evaluated whether variation in psychosocial functioning depended on the combined risk conferred by each CNV. Relative to individuals with biased symptom/CNV risk profiles, results show that functional impairments are attenuated in individuals with relatively equal levels of positive symptoms and autistic traits-and specifically stereotypic behaviors-, and in carriers of CNVs with relatively equal risks for either disorder. However, the pattern of effects along the "balance axis" varied across the groups, with this attenuation being generally less pronounced in individuals with high-high symptom/risk profile in the schizophrenia and CNV groups, and relatively similar for low-low and high-high individuals in the first episode psychosis group. Lower levels of functional impairments in individuals with "balanced" symptom profile or genetic risks would suggest compensation across mechanisms associated with autism and schizophrenia. CNVs that confer equal risks for both disorders may provide an entry point for investigations into such compensatory mechanisms. The co-assessment of autism and schizophrenia may contribute to personalized prognosis and stratification strategies.

Sources of Cognitive Conflict and Their Relevance to Theory-of-Mind Proficiency in Healthy Aging: A Preregistered Study.

Age-related decline in theory of mind (ToM) may be due to waning executive control, which is necessary for resolving conflict when reasoning about other individuals' mental states. We assessed how older (n = 50) and younger (n = 50) adults were affected by three theoretically relevant sources of conflict within ToM: competing self-other perspectives, competing cued locations, and outcome knowledge. We examined which best accounted for age-related difficulty with ToM. Our data show unexpected similarity between age groups when people are representing a belief incongruent with their own. Individual differences in attention and response speed best explained the degree of conflict experienced through incompatible self-other perspectives. However, older adults were disproportionately affected by managing conflict between cued locations. Age and spatial working memory were most relevant for predicting the magnitude of conflict elicited by conflicting cued locations. We suggest that previous studies may have underestimated older adults' ToM proficiency by including unnecessary conflict in ToM tasks.

Alexithymia Is a Key Mediator of the Relationship Between Magical Thinking and Empathy.

Thought action fusion (TAF), whereby internal thoughts are perceived to exert equivalent effects to external actions, is a form of magical thinking. Psychiatric disorders associated with TAF (e.g. schizophrenia; obsessive compulsive disorder) can feature atypical social cognition. We explored relationships between TAF and empathy in 273 healthy young adults. TAF was directly correlated with higher personal distress, but not perspective taking, fantasy or empathic concern. TAF moral (the belief that thinking about an action/behaviour is morally equivalent to actually performing that behaviour) was predicted by emotion contagion, alexithymia and need for closure. TAF likelihood (the belief that simply having a thought about an event makes that event more likely to occur) was predicted by personal distress, sense of agency and alexithymia. Both cognitive (TAF and negative sense of agency) and emotional (emotion contagion, alexithymia) factors contributed to personal distress. TAF, negative sense of agency and personal distress mediated the effect of emotion contagion on alexithymia. Our findings reveal complex relationships between emotional processes and TAF, shedding further light on the social cognitive profile of disorders associated with magical thinking. Furthermore, they emphasise the potential importance of alexithymia and emotion contagion as mediators or potential risk factors in the development of psychiatric symptoms linked to TAF, such as intrusive thoughts about harm to others.

Predictors of performance on the Reading the Mind in the Eyes Test.

We explored factors associated with performance on the Reading the Mind in the Eyes Test (RMET). 180 undergraduate students completed the human RMET requiring forced-choice mental state judgment; a control human Age Eyes Test (AET) requiring age judgment; a Cat Eyes Test (CET) requiring mental state judgment; and measures of executive function, empathy and psychopathology. Versions of the CET and AET were created that matched the RMET for difficulty (accuracy 71%). RMET and CET performance were strongly correlated after accounting for AET performance. Working memory, schizotypal personality and empathy predicted RMET accuracy but not CET scores. Liking dogs predicted higher accuracy on all eyes tasks, whereas liking cats predicted greater mentalizing but reduced emotional expression. Importantly, we replicated our core findings relating to accuracy and correlations between the CET and RMET in a second sample of 228 students. In conclusion, people can apply similar skills when interpreting cat and human expressions. As RMET and CET performance were found to be differentially affected by executive function and psychopathology, the use of social cognitive measures featuring non-human animals may be of particular use in future clinical research.

Re-imaging the intentional stance.

The commonly used paradigm to investigate Dennet's 'intentional stance' compares neural activation when participants compete with a human versus a computer. This paradigm confounds whether the opponent is natural or artificial and whether it is intentional or an automaton. This functional magnetic resonance imaging study is, to our knowledge, the first to investigate the intentional stance by orthogonally varying perceptions of the opponents' intentionality (responding actively or passively according to a script) and embodiment (human or a computer). The mere perception of the opponent (whether human or computer) as intentional activated the mentalizing network: the temporoparietal junction (TPJ) bilaterally, right temporal pole, anterior paracingulate cortex (aPCC) and the precuneus. Interacting with humans versus computers induced activations in a more circumscribed right lateralized subnetwork within the mentalizing network, consisting of the TPJ and the aPCC, possibly reflective of the tendency to spontaneously attribute intentionality to humans. The interaction between intentionality (active versus passive) and opponent (human versus computer) recruited the left frontal pole, possibly in response to violations of the default intentional stance towards humans and computers. Employing an orthogonal design is important to adequately capture Dennett's conception of the intentional stance as a mentalizing strategy that can apply equally well to humans and other intentional agents.

Task load modulates tDCS effects on brain network for phonological processing.

Motor participation in phonological processing can be modulated by task nature across the speech perception to speech production range. The pars opercularis of the left inferior frontal gyrus (LIFG) would be increasingly active across this range, because of changing motor demands. Here, we investigated with simultaneous tDCS and fMRI whether the task load modulation of tDCS effects translates into predictable patterns of functional connectivity. Findings were analysed under the "multi-node framework", according to which task load and the network structure underlying cognitive functions are modulators of tDCS effects. In a within-subject study, participants (N = 20) performed categorical perception, lexical decision and word naming tasks [which differentially recruit the target of stimulation (LIFG)], which were repeatedly administered in three tDCS sessions (anodal, cathodal and sham). The LIFG, left superior temporal gyrus and their right homologues formed the target network subserving phonological processing. C-tDCS inhibition and A-tDCS excitation should increase with task load. Correspondingly, the larger the task load, the larger the relevance of the target for the task and smaller the room for compensation of C-tDCS inhibition by less relevant nodes. Functional connectivity analyses were performed with partial correlations, and network compensation globally inferred by comparing the relative number of significant connections each condition induced relative to sham. Overall, simultaneous tDCS and fMRI was adequate to show that motor participation in phonological processing is modulated by task nature. Network responses induced by C-tDCS across phonological processing tasks matched predictions. A-tDCS effects were attributed to optimisation of network efficiency.

Task load modulates tDCS effects on language performance.

Transcranial direct current stimulation (tDCS) effects in cognition are inconsistent across studies. This study aimed to discuss why typical models might be insufficient to explain these effects, and to investigate a brain state factor, task load, with behavioral experiments on phonological processing. The motor theory of speech perception states that motor codes for articulation take part in speech perception, a view sharpened by neuroimaging findings, which show that the motor role in phonological processing is weighted by the nature of the tasks. Three groups of 20 participants, each under a different tDCS condition (anodal, cathodal, or sham), performed a categorical perception (CP), a lexical decision (LD), and a word naming (WN) task while stimulated on the pars opercularis of the left inferior frontal gyrus, a language area typically involved with the motor role. These tasks were assumed to be subserved by a network of nodes which included the target, believed to be increasingly relevant for performance from speech perception to speech production. A-tDCS facilitation and C-tDCS downregulation should directly increase with the relevance of the target for the task. Downregulation of a low relevance node could result in facilitation by compensation from other nodes. Overall, our brain stimulation findings support the neuroimaging literature in that motor participation in phonological processing depends on task nature and show that tDCS effects are modulated by task load relative to the target. Outcomes such as the improved performance following cathodal tDCS in CP and WN suggest that compensatory mechanisms may take place when the tasks involve more complex neuronal networks.

Polarity-dependent Effects of Biparietal Transcranial Direct Current Stimulation on the Interplay between Target Location and Distractor Saliency in Visual Attention.

Visual attention allows the allocation of limited neural processing resources to stimuli based on their behavioral priorities. The selection of task-relevant visual targets entails the processing of multiple competing stimuli and the suppression of distractors that may be either perceptually salient or perceptually similar to targets. The posterior parietal cortex controls the interaction between top-down (task-driven) and bottom-up (stimulus-driven) processes competing for attentional selection, as well as spatial distribution of attention. Here, we examined whether biparietal transcranial direct current stimulation (tDCS) would modulate the interaction between top-down and bottom-up processes in visual attention. Visual attention function was assessed with a visual discrimination task, in which a lateralized target was presented alone or together with a contralateral, similar or salient, distractor. The accuracy and RTs were measured before and during three stimulation sessions (sham, right anodal/left cathodal, left anodal/right cathodal). The analyses demonstrated (i) polarity-dependent effects of tDCS on the accuracy of target discrimination, but only when the target was presented with a similar distractor; (ii) the tDCS-triggered effects on the accuracy of discriminating targets, accompanied by a similar distractor, varied according to the target location; and (iii) overall detrimental effects of tDCS on RTs were observed, regardless of target location, distractor type, and polarity of the stimulation. We conclude that the observed polarity, distractor type, and target location-dependent effects of biparietal tDCS on the accuracy of target detection resulted from both a modulation of the interaction between top-down and bottom-up attentional processes and the interhemispheric competition mechanisms guiding attentional selection and spatial deployment of attention.

Autism and psychosis: Clinical implications for depression and suicide.

There is increasing recognition of the co-occurrence of autism and schizophrenia spectrum disorders. However, the clinical significance of this on outcomes such as depression and suicidal thinking has not been explored. This study examines the association of autism spectrum traits, depressive symptoms and suicidal behaviour in individuals with psychotic experiences. In two cross sectional studies, individuals from a non-help seeking university student sample and patients with first episode psychosis (FEP) service completed standardized measures of autism spectrum traits, psychotic experiences, depressive symptoms and suicidal thinking. In healthy non-help seeking students, increased autism traits and increased subclinical psychotic experiences were significantly associated with depressive symptoms; a significant interaction effect suggests their combined presence has a greater impact on depression. In FEP, high autism traits and positive symptoms were associated with increased depression, hopelessness and suicidality, however there was no significant interaction effect. In FEP a multiple mediation model revealed that the relationship between autism traits and risk for suicidality was mediated through hopelessness. Young people with subclinical psychotic experiences and all patients with FEP should be screened for autism spectrum traits, which may have significant impact on clinical outcomes. Tailored interventions for patients with high levels of autistic spectrum co-morbidities in FEP should be a priority for future research.

Through your eyes or mine? The neural correlates of mental state recognition in Huntington's disease.

Huntington's disease (HD) can impair social cognition. This study investigated whether patients with HD exhibit neural differences to healthy controls when they are considering mental and physical states relating to the static expressions of human eyes. Thirty-two patients with HD and 28 age-matched controls were scanned with fMRI during two versions of the Reading the Mind in the Eyes Task: The standard version requiring mental state judgments, and a comparison version requiring judgments about age. HD was associated with behavioral deficits on only the mental state eyes task. Contrasting the two versions of the eyes task (mental state > age judgment) revealed hypoactivation within left middle frontal gyrus and supramarginal gyrus in HD. Subgroup analyses comparing premanifest HD patients to age-matched controls revealed reduced activity in right supramarginal gyrus and increased activity in anterior cingulate during mental state recognition in these patients, while manifest HD was associated with hypoactivity in left insula and left supramarginal gyrus. When controlling for the effects of healthy aging, manifest patients exhibited declining activation within areas including right temporal pole. Our findings provide compelling evidence for a selective impairment of internal emotional status when patients with HD appraise facial features in order to make social judgements. Differential activity in temporal and anterior cingulate cortices may suggest that poor emotion regulation and emotional egocentricity underlie impaired mental state recognition in premanifest patients, while more extensive mental state recognition impairments in manifest disease reflect dysfunction in neural substrates underlying executive functions, and the experience and interpretation of emotion.

The 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) reduces palatable food consumption and BOLD fMRI responses to food images in healthy female volunteers.

RATIONALE: Brain 5-HT2C receptors form part of a neural network that controls eating behaviour. 5-HT2C receptor agonists decrease food intake by activating proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus, but recent research in rodents has suggested that 5-HT2C receptor agonists may also act via dopaminergic circuitry to reduce the rewarding value of food and other reinforcers. No mechanistic studies on the effects of 5-HT2C agonists on food intake in humans have been conducted to date. OBJECTIVES: The present study examined the effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) on food consumption, eating microstructure and blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) responses to food pictures in healthy female volunteers. METHODS: In a double-blind, placebo-controlled, crossover design, participants were randomized immediately after screening to receive oral mCPP (30mg) in a single morning dose, or placebo, in a counterbalanced order. Test foods were served from a Universal Eating Monitor (UEM) that measured eating rate and fMRI BOLD signals to the sight of food and non-food images were recorded. RESULTS: mCPP decreased rated appetite and intake of a palatable snack eaten in the absence of hunger but had no significant effect on the consumption of a pasta lunch (although pasta eating rate was reduced). mCPP also decreased BOLD fMRI responses to the sight of food pictures in areas of reward-associated circuitry. A post hoc analysis identified individual variability in the response to mCPP (exploratory responder-non-responder analysis). Some participants did not reduce their cookie intake after treatment with mCPP and this lack of response was associated with enhanced ratings of cookie pleasantness and enhanced baseline BOLD responses to food images in key reward and appetite circuitry. CONCLUSIONS: These results suggest that 5-HT2C receptor activation in humans inhibits food reward-related responding and that further investigation of stratification of responding to mCPP and other 5-HT2C receptor agonists is warranted.

Right Lateral Cerebellum Represents Linguistic Predictability.

Mounting evidence indicates that posterolateral portions of the cerebellum (right Crus I/II) contribute to language processing, but the nature of this role remains unclear. Based on a well-supported theory of cerebellar motor function, which ascribes to the cerebellum a role in short-term prediction through internal modeling, we hypothesize that right cerebellar Crus I/II supports prediction of upcoming sentence content. We tested this hypothesis using event-related fMRI in male and female human subjects by manipulating the predictability of written sentences. Our design controlled for motor planning and execution, as well as for linguistic features and working memory load; it also allowed separation of the prediction interval from the presentation of the final sentence item. In addition, three further fMRI tasks captured semantic, phonological, and orthographic processing to shed light on the nature of the information processed. As hypothesized, activity in right posterolateral cerebellum correlated with the predictability of the upcoming target word. This cerebellar region also responded to prediction error during the outcome of the trial. Further, this region was engaged in phonological, but not semantic or orthographic, processing. This is the first imaging study to demonstrate a right cerebellar contribution in language comprehension independently from motor, cognitive, and linguistic confounds. These results complement our work using other methodologies showing cerebellar engagement in linguistic prediction and suggest that internal modeling of phonological representations aids language production and comprehension.SIGNIFICANCE STATEMENT The cerebellum is traditionally seen as a motor structure that allows for smooth movement by predicting upcoming signals. However, the cerebellum is also consistently implicated in nonmotor functions such as language and working memory. Using fMRI, we identify a cerebellar area that is active when words are predicted and when these predictions are violated. This area is active in a separate task that requires phonological processing, but not in tasks that require semantic or visuospatial processing. Our results support the idea of prediction as a unifying cerebellar function in motor and nonmotor domains. We provide new insights by linking the cerebellar role in prediction to its role in verbal working memory, suggesting that these predictions involve phonological processing.

Transcranial direct current stimulation can enhance working memory in Huntington's disease.

Transcranial direct current stimulation (tDCS) combined with a cognitive task can enhance targeted aspects of cognitive functioning in clinical populations. The movement disorder Huntington's disease (HD) is associated with progressive cognitive impairment. Deficits in working memory (WM) can be apparent early in the disease and impact functional capacity. We investigated whether tDCS combined with cognitive training could improve WM in patients with HD, and if baseline clinical or cognitive measures may predict efficacy. Twenty participants with HD completed this crossover trial, undergoing 1.5mA anodal tDCS over left dorsolateral prefrontal cortex and sham stimulation on separate visits. Participants and assessor were blinded to condition order, which was randomised across participants. All participants completed baseline clinical and cognitive assessments. Pre- and post-stimulation tasks included digit reordering, computerised n-back tests and a Stroop task. During 15min of tDCS/sham stimulation, participants practiced 1- and 2-back WM tasks. Participants exhibited an increase in WM span on the digit re-ordering span task from pre- to post-stimulation after tDCS, but not after sham stimulation. Gains in WM were positively related to motor symptom ratings and negatively associated with verbal fluency scores. Patients with more severe motor symptoms showed greatest improvement, suggesting that motor symptom ratings may help identify patients who are most likely to benefit from tDCS. CONCLUSIONS: Dorsolateral prefrontal tDCS appears well tolerated in HD and enhances WM span compared to sham stimulation. Our findings strongly encourage further investigation of the extent to which tDCS combined with cognitive training could enhance everyday function in HD. ClinicalTrials.gov; NCT02216474 Brain stimulation in Movement Disorders; https://clinicaltrials.gov/ct2/show/NCT02216474.

Autism Tendencies and Psychosis Proneness Interactively Modulate Saliency Cost.

Atypical responses to salient information are a candidate endophenotype for both autism and psychosis spectrum disorders. The present study investigated the costs and benefits of such atypicalities for saliency-based selection in a large cohort of neurotypical adults in whom both autism and psychosis expressions were assessed. Two experiments found that autism tendencies and psychosis proneness interactively modulated the cost incurred in the presence of a task-irrelevant salient distractor. Specifically, expressions of autism and psychosis had opposing effects on responses to salient information such that the benefits associated with high expressions for autism offset costs associated with high expressions for psychosis. The opposing influences observed on saliency cost may be driven by distinct attentional mechanisms that are differentially affected by expressions for autism and psychosis.

Autism and psychosis expressions diametrically modulate the right temporoparietal junction.

The mentalizing network is atypically activated in autism and schizophrenia spectrum disorders. While these disorders are considered diagnostically independent, expressions of both can co-occur in the same individual. We examined the concurrent effect of autism traits and psychosis proneness on the activity of the mentalizing network in 24 neurotypical adults while performing a social competitive game. Activations were observed in the paracingulate cortex and the right temporoparietal junction (rTPJ). Autism traits and psychosis proneness did not modulate activity within the paracingulate or the dorsal component of the rTPJ. However, diametric modulations of autism traits and psychosis proneness were observed in the posterior (rvpTPJ) and anterior (rvaTPJ) subdivisions of the ventral rTPJ, which respectively constitute core regions within the mentalizing and attention-reorienting networks. Within the rvpTPJ, increasing autism tendencies decreased activity, and increasing psychosis proneness increased activity. This effect was reversed within the rvaTPJ. We suggest that this results from an interaction between regions responsible for higher level social cognitive processing (rvpTPJ) and regions responsible for domain-general attentional processes (rvaTPJ). The observed diametric modulation of autism tendencies and psychosis proneness of neuronal activity within the mentalizing network highlights the importance of assessing both autism and psychosis expressions within the individual.

Temporo-parietal dysfunction in Tourette syndrome: Insights from an fMRI study of Theory of Mind.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by tics, repetitive movements and vocalizations which are prompted by a sensory-cognitive premonitory urge. Complex tics include environmentally dependent social behaviors such as echoing of other people's speech and actions. Recent studies have suggested that adults with TS can show differences to controls in Theory of Mind (ToM): reasoning about mental states (e.g. beliefs, emotions). In this study, twenty-five adults with uncomplicated TS (no co-morbid disorders, moderate tic severity), and twenty-five healthy age and gender matched controls were scanned with fMRI during an established ToM task. Neural activity was contrasted across ToM trials involving reasoning about false-belief, and matched trials requiring judgments about physical states rather than mental states. Contrasting task conditions uncovered differential fMRI activation in TS during ToM involving the right temporo-parietal junction (TPJ), right amygdala and posterior cingulate. Further analysis revealed that activity within the right TPJ as localised by this task covaried with the severity of symptoms including echophenomena, impulse control problems and premonitory urges in TS. Amygdala activation was also linked to premonitory urges, while activity in the left TPJ during ToM was linked to ratings of non-obscene socially inappropriate symptoms. These findings indicate that patients with TS exhibit atypical functional activation within key neural substrates involved in ToM. More generally, our data could highlight an important role for TPJ dysfunction in driving compulsive behaviors.

Resting state morphology predicts the effect of theta burst stimulation in false belief reasoning.

When required to represent a perspective that conflicts with one's own, functional magnetic resonance imaging (fMRI) suggests that the right ventrolateral prefrontal cortex (rvlPFC) supports the inhibition of that conflicting self-perspective. The present task dissociated inhibition of self-perspective from other executive control processes by contrasting belief reasoning-a cognitive state where the presence of conflicting perspectives was manipulated-with a conative desire state wherein no systematic conflict existed. Linear modeling was used to examine the effect of continuous theta burst stimulation (cTBS) to rvlPFC on participants' reaction times in belief and desire reasoning. It was anticipated that cTBS applied to rvlPFC would affect belief but not desire reasoning, by modulating activity in the Ventral Attention System (VAS). We further anticipated that this effect would be mediated by functional connectivity within this network, which was identified using resting state fMRI and an unbiased model-free approach. Simple reaction-time analysis failed to detect an effect of cTBS. However, by additionally modeling individual measures from within the stimulated network, the hypothesized effect of cTBS to belief (but, importantly, not desire) reasoning was demonstrated. Structural morphology within the stimulated region, rvlPFC, and right temporoparietal junction were demonstrated to underlie this effect. These data provide evidence that inconsistencies found with cTBS can be mediated by the composition of the functional network that is being stimulated. We suggest that the common claim that this network constitutes the VAS explains the effect of cTBS to this network on false belief reasoning. Hum Brain Mapp 37:3502-3514, 2016. © 2016 Wiley Periodicals, Inc.

Perspective-taking abilities in the balance between autism tendencies and psychosis proneness.

Difficulties with the ability to appreciate the perspective of others (mentalizing) is central to both autism and schizophrenia spectrum disorders. While the disorders are diagnostically independent, they can co-occur in the same individual. The effect of such co-morbidity is hypothesized to worsen mentalizing abilities. The recent influential 'diametric brain theory', however, suggests that the disorders are etiologically and phenotypically diametrical, predicting opposing effects on one's mentalizing abilities. To test these contrasting hypotheses, we evaluated the effect of psychosis and autism tendencies on the perspective-taking (PT) abilities of 201 neurotypical adults, on the assumption that autism tendencies and psychosis proneness are heritable dimensions of normal variation. We show that while both autism tendencies and psychosis proneness induce PT errors, their interaction reduced these errors. Our study is, to our knowledge, the first to observe that co-occurring autistic and psychotic traits can exert opposing influences on performance, producing a normalizing effect possibly by way of their diametrical effects on socio-cognitive abilities. This advances the notion that some individuals may, to some extent, be buffered against developing either illness or present fewer symptoms owing to a balanced expression of autistic and psychosis liability.