Mindblind eyes: an absence of spontaneous theory of mind in Asperger syndrome

Adults with Asperger syndrome can understand mental states such as desires and beliefs (mentalizing) when explicitly prompted to do so, despite having impairments in social communication. We directly tested the hypothesis that such individuals nevertheless fail to mentalize spontaneously. To this end, we used an eye-tracking task that has revealed the spontaneous ability to mentalize in typically developing infants. We showed that, like infants, neurotypical adults’ (n = 17 participants) eye movements anticipated an actor’s behavior on the basis of her false belief. This was not the case for individuals with Asperger syndrome (n = 19). Thus, these individuals do not attribute mental states spontaneously, but they may be able to do so in explicit tasks through compensatory learning

The role of oxytocin in empathy to the pain of conflictual out-group members among patients with schizophrenia

Background.Oxytocin (OT) is associated with our ability to empathize and has been shown to play a major role in mediating social behaviors within the context of intergroup dynamics. Schizophrenia is associated with impaired empathy, and with a dysfunctional oxytocinergic system. The effect of OT on the empathic responses of patients with schizophrenia within the context of intergroup relationships has not been studied. The present study examined the effect of OT on the patients' empathic responses to pain experienced by in-group, conflictual out-group and neutral out-group members.Method.In a double-blind, placebo-controlled, within-subject cross-over design, the responses on the Pain Evaluation Task of 28 male patients with schizophrenia were compared to 27 healthy male controls. All participants received a single intranasal dose of 24 IU OT or placebo, 1 week apart.Results.OT induced an empathy bias in the healthy controls towards the conflictual out-group members. Although this effect was absent in the patient group, OT seems to heighten an empathic bias in the patient group towards the in-group members when rating non-painful stimuli.Conclusions.The study demonstrates that the administration of OT can result in empathic bias towards adversary out-group members in healthy controls but not in patients with schizophrenia. However, the OT-induced bias in both the patients (in the no-pain condition towards the in-group members) and the healthy controls (in the no-pain and pain conditions towards the adversary out-group) suggests that OT enhances the distinction between conflictual in-group and out-group members.</jats:sec

RNA-sequencing analysis of a multistep and hit-and-run cell and animal model of KSHV tumorigenesis reveal the roles of mutations, CpG methylation, and viral-infection footprints in oncogenesis

Human viral oncogenesis is the consequence of cell transformation mediated by virally encoded oncogenes in combination with host oncogenic alterations. Kaposi’s sarcoma (KS), caused by the Kaposi’s sarcoma-associated herpes virus (KSHV), is an AIDS-associated cancer characterized by angiogenesis and spindle-cells proliferation. KSHV-infected KS lesions are composed of latently-infected cells, as well as cells expressing lytic genes that have been implicated in the development of the KS angioproliferative phenotype. The existence of KS lesions with varying levels of KSHV-infected cells suggests also the existence of virus-independent “hit-and-run” mechanisms of sarcomagenesis, whereby viral infection irreversibly induce genetic or epigenetic oncogenic alterations in host cells. We have integrated genetic mutations, changes in expression signatures and methylation analysis to dissect genetic and epigenetic signaling pathways in an unbiased manner in the mECK36 mouse model of KSHV tumorigenesis. Pathway analysis of differential expressed genes (DEGs) showed KSHV lytic switch, DNA methylation and Epigenetic as the most regulated pathways during KSHV-dependent in vivo tumorigenesis. Methylation analysis data indicates that during the development of KSHV-infected tumors the most changes were towards hypo-methylation of tissues specific genes and oncogenic signature pathways, on the other hand during viral loss and development of KSHV-negative tumors changes are towards hyper-methylation. Mutational analysis of KSHV-infected cells and tumors revealed a set of mutations, including mutations in three inflammasome-related IFN response genes, that were absent in KSHV-infected cells but present in all KSHV-infected tumors in the same loci pointing to clonal selection “in vivo”. This result suggests that in the context of in vivo tumorigenesis both these mutations and the virus may determine tumor growth. On the other hand, clustering analysis of mutations driving KSHV-negative tumors reveal a network comprising PDGFRA D842V, Pak1 and Nucleolin mutations implicated in cell proliferation. Our results have uncovered novel specific aspects of the interplay between host oncogenic alterations and virus-induced transcriptional effects as well as the epigenetic changes induced by KSHV infection and tumorigenesis. The existence virally-induced irreversible genetic and epigenetic oncogenic alterations support the possibility for hit-and-run KSHV sarcomagenesis which is consistent with pathological and clinical findings. AUTHOR SUMMARY We performed whole genome RNA sequencing and CpG DNA methylation analysis in a mouse bone-marrow endothelial-lineage cells (mEC) transfected with the KSHVBac36 (mECK36 cells), that are able to form KSHV-infected tumors in nude mice, which were thoroughly characterized as KS-like tumors. This unique model allowed us to dissect genetic and epigenetic mechanisms of KSHV dependent and hit-and-run sarcomagenesis. We found that during KSHV in vivo lytic switch and KSHV-dependent tumorigenesis DNA methylation and Epigenetic regulation are among the most host-regulated pathways. CpG DNA methylation analysis during transformation supports the notion that loss of methylation (hypo-methylation) is the major epigenetic change during this process. Sequence analysis of KSHV-positive tumors revealed that KSHV tumorigenesis not only selects for the presence of the virus but also pre-existing host mutations that allow the KSHV oncovirus to express the oncogenic lytic program and creates a permissive environment of inflammation and viral tumorigenesis providing a selective advantage in vivo.Centro de Investigaciones Inmunológicas Básicas y Aplicada

"I know that you know that I know": neural substrates associated with social cognition deficits in DM1 patients

Myotonic dystrophy type-1 (DM1) is a genetic multi-systemic disorder involving several organs including the brain. Despite the heterogeneity of this condition, some patients with non-congenital DM1 can present with minimal cognitive impairment on formal testing but with severe difficulties in daily-living activities including social interactions. One explanation for this paradoxical mismatch can be found in patients' dysfunctional social cognition, which can be assessed in the framework of the Theory of Mind (ToM). We hypothesize here that specific disease driven abnormalities in DM1 brains may result in ToM impairments. We recruited 20 DM1 patients who underwent the "Reading the Mind in the Eyes" and the ToM-story tests. These patients, together with 18 healthy controls, also underwent resting-state functional MRI. A composite Theory of Mind score was computed for all recruited patients and correlated with their brain functional connectivity. This analysis provided the patients' "Theory of Mind-network", which was compared, for its topological properties, with that of healthy controls. We found that DM1 patients showed deficits in both tests assessing ToM. These deficits were associated with specific patterns of abnormal connectivity between the left inferior temporal and fronto-cerebellar nodes in DM1 brains. The results confirm the previous suggestions of ToM dysfunctions in patients with DM1 and support the hypothesis that difficulties in social interactions and personal relationships are a direct consequence of brain abnormalities, and not a reaction symptom. This is relevant not only for a better pathophysiological comprehension of DM1, but also for non-pharmacological interventions to improve clinical aspects and impact on patients' success in life

Simple mindreading abilities predict complex theory of mind: developmental delay in autism spectrum disorders

Theory of Mind (ToM) is impaired in individuals with Autism Spectrum Disorders (ASD). The aims of this study were to: i) examine the developmental trajectories of ToM abilities in two different mentalizing tasks in children with ASD compared to TD children; and ii) to assess if a ToM simple test known as Eyes-test could predict performance on the more advanced ToM task, i.e. Comic Strip test. Based on a sample of 37 children with ASD and 55 TD children, our results revealed slower development at varying rates in all ToM measures in children with ASD, with delayed onset compared to TD children. These results could stimulate new treatments for social abilities, which would lessen the social deficit in ASD

Host epigenetic modifications by oncogenic viruses

Epigenetic alterations represent an important step in the initiation and progression of most human cancers, but it is difficult to differentiate the early cancer causing alterations from later consequences. Oncogenic viruses can induce transformation via expression of only a small number of viral genes. Therefore, the mechanisms by which oncogenic viruses cause cancer may provide clues as to which epigenetic alterations are critical in early carcinogenesis

Interdependent Utilities: How Social Ranking Affects Choice Behavior

Organization in hierarchical dominance structures is prevalent in animal societies, so a strong preference for higher positions in social ranking is likely to be an important motivation of human social and economic behavior. This preference is also likely to influence the way in which we evaluate our outcome and the outcome of others, and finally the way we choose. In our experiment participants choose among lotteries with different levels of risk, and can observe the choice that others have made. Results show that the relative weight of gains and losses is the opposite in the private and social domain. For private outcomes, experience and anticipation of losses loom larger than gains, whereas in the social domain, gains loom larger than losses, as indexed by subjective emotional evaluations and physiological responses. We propose a theoretical model (interdependent utilities), predicting the implication of this effect for choice behavior. The relatively larger weight assigned to social gains strongly affects choices, inducing complementary behavior: faced with a weaker competitor, participants adopt a more risky and dominant behavior

Prefrontal Cortex Glutamate Correlates with Mental Perspective-Taking

Background: Dysfunctions in theory of mind and empathic abilities have been suggested as core symptoms in major psychiatric disorders including schizophrenia and autism. Since self monitoring, perspective taking and empathy have been linked to prefrontal (PFC) and anterior cingulate cortex (ACC) function, neurotransmitter variations in these areas may account for normal and pathological variations of these functions. Converging evidence indicates an essential role of glutamatergic neurotransmission in psychiatric diseases with pronounced deficits in empathy. However, the role of the glutamate system for different dimensions of empathy has not been investigated so far. Methodology/Principal Findings: Absolute concentrations of cerebral glutamate in the ACC, left dorsolateral PFC and left hippocampus were determined by 3-tesla proton magnetic resonance spectroscopy (1H-MRS) in 17 healthy individuals. Three dimensions of empathy were estimated by a self-rating questionnaire, the Interpersonal Reactivity Index (IRI). Linear regression analysis showed that dorsolateral PFC glutamate concentration was predicted by IRI factor ‘‘perspective taking’’ (T = 22.710, p = 0.018; adjusted alpha-level of 0.017, Bonferroni) but not by ‘‘empathic concern’ ’ or ‘‘personal distress’’. No significant relationship between IRI subscores and the glutamate levels in the ACC or left hippocampus was detected. Conclusions/Significance: This is the first study to investigate the role of the glutamate system for dimensions of theory of mind and empathy. Results are in line with recent concepts that executive top-down control of behavior is mediated b