Impairments in recognition of emotional facial expressions, affective prosody, and multisensory facilitation of response time in high-functioning autism.

Introduction: Deficits in emotional perception are common in autistic people, but it remains unclear to which extent these perceptual impairments are linked to specific sensory modalities, specific emotions or multisensory facilitation. Methods: This study aimed to investigate uni- and bimodal perception of emotional cues as well as multisensory facilitation in autistic (n = 18, mean age: 36.72 years, SD: 11.36) compared to non-autistic (n = 18, mean age: 36.41 years, SD: 12.18) people using auditory, visual and audiovisual stimuli. Results: Lower identification accuracy and longer response time were revealed in high-functioning autistic people. These differences were independent of modality and emotion and showed large effect sizes (Cohen's d 0.8-1.2). Furthermore, multisensory facilitation of response time was observed in non-autistic people that was absent in autistic people, whereas no differences were found in multisensory facilitation of accuracy between the two groups. Discussion: These findings suggest that processing of auditory and visual components of audiovisual stimuli is carried out more separately in autistic individuals (with equivalent temporal demands required for processing of the respective unimodal cues), but still with similar relative improvement in accuracy, whereas earlier integrative multimodal merging of stimulus properties seems to occur in non-autistic individuals.

Neurobiological correlates and attenuated positive social intention attribution during laughter perception associated with degree of autistic traits.

Laughter plays an important role in group formation, signaling social belongingness by indicating a positive or negative social intention towards the receiver. In adults without autism, the intention of laughter can be correctly differentiated without further contextual information. In autism spectrum disorder (ASD), however, differences in the perception and interpretation of social cues represent a key characteristic of the disorder. Studies suggest that these differences are associated with hypoactivation and altered connectivity among key nodes of the social perception network. How laughter, as a multimodal nonverbal social cue, is perceived and processed neurobiologically in association with autistic traits has not been assessed previously. We investigated differences in social intention attribution, neurobiological activation, and connectivity during audiovisual laughter perception in association with the degree of autistic traits in adults [N = 31, Mage (SD) = 30.7 (10.0) years, nfemale = 14]. An attenuated tendency to attribute positive social intention to laughter was found with increasing autistic traits. Neurobiologically, autistic trait scores were associated with decreased activation in the right inferior frontal cortex during laughter perception and with attenuated connectivity between the bilateral fusiform face area with bilateral inferior and lateral frontal, superior temporal, mid-cingulate and inferior parietal cortices. Results support hypoactivity and hypoconnectivity during social cue processing with increasing ASD symptoms between socioemotional face processing nodes and higher-order multimodal processing regions related to emotion identification and attribution of social intention. Furthermore, results reflect the importance of specifically including signals of positive social intention in future studies in ASD.

Reduced humoral response to a third dose (booster) of SARS-CoV-2 mRNA vaccines by concomitant methotrexate therapy in elderly patients with rheumatoid arthritis.

BACKGROUND: Several health authorities recommend a third (booster) vaccination to protect patients with rheumatic and musculoskeletal diseases from severe COVID-19. Methotrexate has been shown to reduce the efficacy of the first and second dose of SARS-CoV-2 mRNA vaccines. So far, it remains unknown how concomitant methotrexate affects the efficacy of a COVID-19 booster vaccination. METHODS: We compared the humoral immune response to SARS-CoV-2 vaccination in 136 patients with rheumatoid arthritis (RA) treated with methotrexate and/or biological or targeted synthetic (b/tsDMARDs). IgG targeting the receptor binding domain (RBD) of SARS-CoV-2 spike protein was measured at a median of 52.5 (range 2-147) days after a third dose of the SARS-CoV-2 mRNA vaccines BNT162b2 or mRNA-1273. RESULTS: Anti-RBD IgG was significantly reduced in elderly patients receiving concomitant treatment with methotrexate as compared with elderly patients receiving monotherapy with b/tsDMARDs or methotrexate (64.8 (20.8, 600.3) binding antibody units per mL (BAU/mL) vs 1106.0 (526.3, 4965.2) BAU/mL vs 1743.8 (734.5, 6779.6) BAU/mL, median (IQR), p<0.001, Kruskal-Wallis test). In younger patients (< 64.5 years), concomitant methotrexate had no significant impact on the humoral immune response. CONCLUSIONS: Concomitant methotrexate increases the risk of an insufficient humoral immune response to SARS-CoV-2 vaccination in elderly patients with RA. Pausing methotrexate during the third vaccination period may be considered for this group of patients.

Truncated isoforms of GPSM2 containing the GoLoco motif region promote CD4+ T-cell migration in SLE.

OBJECTIVE: SLE is an autoimmune disease with a complex pathogenesis. T-cell infiltration into organs contributes to inflammation and organ damage in SLE. Recently, G-protein signalling modulator 2 (GPSM2) has been shown to be implicated in T-cell migration. METHODS: We analysed the expression levels of GPSM2 and of a truncated isoform of GPSM2 containing the GoLoco motif region in CD4+ T cells from patients with SLE and from healthy individuals by western blot. In a next step, we studied the role of the truncated GPSM2 isoform using a CD4+ T-cell migration assay. RESULTS: Our experiments revealed comparable levels of GPSM2 in CD4+ T cells from patients with SLE and healthy controls. In contrast, the truncated 35 kDa isoform of GPSM2 was significantly more highly expressed in CD4+ T cells from patients with SLE as compared with healthy subjects. Antibody-mediated blockade of the 35 kDa GPSM2 isoform reduced the in vitro capacity of CD4+ T cells to migrate towards the chemokine CCL20. CONCLUSIONS: A truncated GPSM2 isoform containing the GoLoco motif region is upregulated in CD4+ T cells from patients with SLE and promotes CD4+ T-cell migration. Targeting this isoform with specific antibodies might be a promising approach to reduce CD4+ T-cell infiltration into inflamed tissues and to prevent organ damage in SLE.

Correlates of individual voice and face preferential responses during resting state.

Human nonverbal social signals are transmitted to a large extent by vocal and facial cues. The prominent importance of these cues is reflected in specialized cerebral regions which preferentially respond to these stimuli, e.g. the temporal voice area (TVA) for human voices and the fusiform face area (FFA) for human faces. But it remained up to date unknown whether there are respective specializations during resting state, i.e. in the absence of any cues, and if so, whether these representations share neural substrates across sensory modalities. In the present study, resting state functional connectivity (RSFC) as well as voice- and face-preferential activations were analysed from functional magnetic resonance imaging (fMRI) data sets of 60 healthy individuals. Data analysis comprised seed-based analyses using the TVA and FFA as regions of interest (ROIs) as well as multi voxel pattern analyses (MVPA). Using the face- and voice-preferential responses of the FFA and TVA as regressors, we identified several correlating clusters during resting state spread across frontal, temporal, parietal and occipital regions. Using these regions as seeds, characteristic and distinct network patterns were apparent with a predominantly convergent pattern for the bilateral TVAs whereas a largely divergent pattern was observed for the bilateral FFAs. One region in the anterior medial frontal cortex displayed a maximum of supramodal convergence of informative connectivity patterns reflecting voice- and face-preferential responses of both TVAs and the right FFA, pointing to shared neural resources in supramodal voice and face processing. The association of individual voice- and face-preferential neural activity with resting state connectivity patterns may support the perspective of a network function of the brain beyond an activation of specialized regions.

Th1 and Th17 cells are resistant towards T cell activation-induced downregulation of CD6.

BACKGROUND: The cell surface molecule CD6 is a modulator of T cell receptor (TCR) signaling. Recently, it has been reported that CD6 is downregulated on CD4+ T cells following T cell activation. This mechanism could limit the efficacy of anti-CD6 therapeutical antibodies. METHODS: We analyzed CD6 expression on activated and non-activated Th1 cells and Th17 cells by flow cytometry. RESULTS: Our experiments confirmed a significant downregulation of CD6 on IFNγ- and IL17-negative CD4+ T cells from healthy individuals and from patients with rheumatoid arthritis following T cell activation with anti-CD3 and anti-CD28 antibodies. In contrast, CD6 expression remained stable on activated Th17 cells and Th1 cells. CONCLUSIONS: Th1 and Th17 cells are resistant towards T cell activation-induced downregulation of CD6. These findings are relevant for the future development of CD6 targeting therapies and show that CD6 expression is differentially regulated in CD4+ T cell subsets.

Reduced impact of nonverbal cues during integration of verbal and nonverbal emotional information in adults with high-functioning autism.

Background: When receiving mismatching nonverbal and verbal signals, most people tend to base their judgment regarding the current emotional state of others primarily on nonverbal information. However, individuals with high-functioning autism (HFA) have been described as having difficulties interpreting nonverbal signals. Recognizing emotional states correctly is highly important for successful social interaction. Alterations in perception of nonverbal emotional cues presumably contribute to misunderstanding and impairments in social interactions. Methods: To evaluate autism-specific differences in the relative impact of nonverbal and verbal cues, 18 adults with HFA (14 male and four female subjects, mean age 36.7 years (SD 11.4) and 18 age, gender and IQ-matched typically developed controls [14 m/4 f, mean age 36.4 years (SD 12.2)] rated the emotional state of speakers in video sequences with partly mismatching emotional signals. Standardized linear regression coefficients were calculated as a measure of the reliance on the nonverbal and verbal components of the videos for each participant. Regression coefficients were then compared between groups to test the hypothesis that autistic adults base their social evaluations less strongly on nonverbal information. Further exploratory analyses were performed for differences in valence ratings and response times. Results: Compared to the typically developed control group, nonverbal cue reliance was reduced in adults with high-functioning autism [t(23.14) = -2.44, p = 0.01 (one-sided)]. Furthermore, the exploratory analyses showed a tendency to avoid extreme answers in the HFA group, observable via less positive as well as less negative valence ratings in response to emotional expressions of increasingly strong valence. In addition, response time was generally longer in HFA compared to the control group [F (1, 33) = 10.65, p = 0.004]. Conclusion: These findings suggest reduced impact of nonverbal cues and longer processing times in the analysis of multimodal emotional information, which may be associated with a subjectively lower relevance of this information and/or more processing difficulties for people with HFA. The less extreme answering tendency may indicate a lower sensitivity for nonverbal valence expression in HFA or result from a tendency to avoid incorrect answers when confronted with greater uncertainty in interpreting emotional states.

The Neural Correlates of Face-Voice-Integration in Social Anxiety Disorder.

Faces and voices are very important sources of threat in social anxiety disorder (SAD), a common psychiatric disorder where core elements are fears of social exclusion and negative evaluation. Previous research in social anxiety evidenced increased cerebral responses to negative facial or vocal expressions and also generally increased hemodynamic responses to voices and faces. But it is unclear if also the cerebral process of face-voice-integration is altered in SAD. Applying functional magnetic resonance imaging, we investigated the correlates of the audiovisual integration of dynamic faces and voices in SAD as compared to healthy individuals. In the bilateral midsections of the superior temporal sulcus (STS) increased integration effects in SAD were observed driven by greater activation increases during audiovisual stimulation as compared to auditory stimulation. This effect was accompanied by increased functional connectivity with the visual association cortex and a more anterior position of the individual integration maxima along the STS in SAD. These findings demonstrate that the audiovisual integration of facial and vocal cues in SAD is not only systematically altered with regard to intensity and connectivity but also the individual location of the integration areas within the STS. These combined findings offer a novel perspective on the neuronal representation of social signal processing in individuals suffering from SAD.

Tuned to voices and faces: Cerebral responses linked to social anxiety.

Voices and faces are the most common sources of threat in social anxiety (SA) where the fear of negative evaluation and social exclusion is the central element. SA itself is spectrally distributed among the general population and its clinical manifestation, termed social anxiety disorder, is one of the most common anxiety disorders. While heightened cerebral responses to angry or contemptuous facial or vocal expressions are well documented, it remains unclear if the brain of socially anxious individuals is generally more sensitive to voices and faces. Using functional magnetic resonance imaging, we investigated how SA affects the cerebral processing of voices and faces as compared to various other stimulus types in a study population with greatly varying SA (N = 50, 26 female). While cerebral voice-sensitivity correlated positively with SA in the left temporal voice area (TVA) and the left amygdala, an association of face-sensitivity and SA was observed in the right fusiform face area (FFA) and the face processing area of the right posterior superior temporal sulcus (pSTSFA). These results demonstrate that the increase of cerebral responses associated with social anxiety is not limited to facial or vocal expressions of social threat but that the respective sensory and emotion processing structures are also generally tuned to voices and faces.

Cerebral resting state markers of biased perception in social anxiety.

Social anxiety (SA) comprises a multitude of persistent fears around the central element of dreaded negative evaluation and exclusion. This very common anxiety is spectrally distributed among the general population and associated with social perception biases deemed causal in its maintenance. Here, we investigated cerebral resting state markers linking SA and biased social perception. To this end, resting state functional connectivity (RSFC) was assessed as the neurobiological marker in a study population with greatly varying SA using fMRI in the first step of the experiment. One month later the impact of unattended laughter-exemplifying social threat-on a face rating task was evaluated as a measure of biased social perception. Applying a dimensional approach, SA-related cognitive biases tied to the valence, dominance and arousal of the threat signal and their underlying RSFC patterns among central nodes of the cerebral emotion, voice and face processing networks were identified. In particular, the connectivity patterns between the amygdalae and the right temporal voice area met all criteria for a cerebral mediation of the association between SA and the laughter valence-related interpretation bias. Thus, beyond this identification of non-state-dependent cerebral markers of biased perception in SA, this study highlights both a starting point and targets for future research on the causal relationships between cerebral connectivity patterns, SA and biased perception, potentially via neurofeedback methods.

Fear of Being Laughed at in Borderline Personality Disorder.

Building on the assumption of a possible link between biases in social information processing frequently associated with borderline personality disorder (BPD) and the occurrence of gelotophobia (i.e., a fear of being laughed at), the present study aimed at evaluating the prevalence rate of gelotophobia among BPD patients. Using the Geloph<15> , a questionnaire that allows a standardized assessment of the presence and severity of gelotophobia symptoms, rates of gelotophobia were assessed in a group of 30 female BPD patients and compared to data gathered in clinical and non-clinical reference groups. Results indicate a high prevalence of gelotophobia among BPD patients with 87% of BPD patients meeting the Geloph<15> criterion for being classified as gelotophobic. Compared to other clinical and non-clinical reference groups, the rate of gelotophobia among BPD patients appears to be remarkably high, far exceeding the numbers reported for other groups in the literature to date, with 30% of BPD patients reaching extreme levels, 37% pronounced levels, and 20% slight levels of gelotophobia.

Neurobiological correlates of emotional intelligence in voice and face perception networks.

Facial expressions and voice modulations are among the most important communicational signals to convey emotional information. The ability to correctly interpret this information is highly relevant for successful social interaction and represents an integral component of emotional competencies that have been conceptualized under the term emotional intelligence. Here, we investigated the relationship of emotional intelligence as measured with the Salovey-Caruso-Emotional-Intelligence-Test (MSCEIT) with cerebral voice and face processing using functional and structural magnetic resonance imaging. MSCEIT scores were positively correlated with increased voice-sensitivity and gray matter volume of the insula accompanied by voice-sensitivity enhanced connectivity between the insula and the temporal voice area, indicating generally increased salience of voices. Conversely, in the face processing system, higher MSCEIT scores were associated with decreased face-sensitivity and gray matter volume of the fusiform face area. Taken together, these findings point to an alteration in the balance of cerebral voice and face processing systems in the form of an attenuated face-vs-voice bias as one potential factor underpinning emotional intelligence.

Prefrontal mediation of emotion regulation in social anxiety disorder during laughter perception.

Social anxiety disorder (SAD) is characterized by negatively biased perception of social cues and deficits in emotion regulation. While negatively biased perception is thought to maintain social anxiety, emotion regulation represents an ability necessary to overcome both biased perception and social anxiety. Here, we used laughter as a social threat in a functional magnetic resonance imaging (fMRI) study to identify cerebral mediators linking SAD with attention and interpretation biases and their modification through cognitive emotion regulation in the form of reappraisal. We found that reappraisal abolished the negative laughter interpretation bias in SAD and that this process was directly mediated through activation patterns of the left dorsolateral prefrontal cortex (DLPFC) serving as a cerebral pivot between biased social perception and its normalization through reappraisal. Connectivity analyses revealed reduced prefrontal control over threat-processing sensory cortices (here: the temporal voice area) during cognitive emotion regulation in SAD. Our results indicate a central role for the left DLPFC in SAD which might represent a valuable target for future research on interventions either aiming to directly modulate cognitive emotion regulation in SAD or to evaluate its potential as physiological marker for psychotherapeutic interventions relying on emotion regulation.

Perception of Verbal and Nonverbal Emotional Signals in Women With Borderline Personality Disorder: Evidence of a Negative Bias and an Increased Reliance on Nonverbal Cues.

Studies conducted in patients diagnosed with borderline personality disorder (BPD) have documented a variety of anomalies concerning patients' abilities to interpret emotional signals. Attempting to clarify the bases of these anomalies, the current literature draws attention to a possible role of dysfunctional expectations, such as the expectation of social rejection. Dysfunctional expectations, however, may not only bias social interpretations, but may also focus attention on social cues most important in conveying emotional messages, such as nonverbal signals. To explore these assumptions, 30 female BPD patients were tasked to judge the valence of emotional states conveyed by combinations of verbal and nonverbal emotional cues. Compared to controls, BPD patients exhibited a negative bias in their interpretations and relied more on available nonverbal cues. Shifts in the relative importance of nonverbal cues appeared to be rooted mainly in a reduced reliance on positive verbal cues presumably deemed less credible by BPD patients.

Effects of cue modality and emotional category on recognition of nonverbal emotional signals in schizophrenia.

BACKGROUND: Impaired interpretation of nonverbal emotional cues in patients with schizophrenia has been reported in several studies and a clinical relevance of these deficits for social functioning has been assumed. However, it is unclear to what extent the impairments depend on specific emotions or specific channels of nonverbal communication. METHODS: Here, the effect of cue modality and emotional categories on accuracy of emotion recognition was evaluated in 21 patients with schizophrenia and compared to a healthy control group (n = 21). To this end, dynamic stimuli comprising speakers of both genders in three different sensory modalities (auditory, visual and audiovisual) and five emotional categories (happy, alluring, neutral, angry and disgusted) were used. RESULTS: Patients with schizophrenia were found to be impaired in emotion recognition in comparison to the control group across all stimuli. Considering specific emotions more severe deficits were revealed in the recognition of alluring stimuli and less severe deficits in the recognition of disgusted stimuli as compared to all other emotions. Regarding cue modality the extent of the impairment in emotional recognition did not significantly differ between auditory and visual cues across all emotional categories. However, patients with schizophrenia showed significantly more severe disturbances for vocal as compared to facial cues when sexual interest is expressed (alluring stimuli), whereas more severe disturbances for facial as compared to vocal cues were observed when happiness or anger is expressed. CONCLUSION: Our results confirmed that perceptual impairments can be observed for vocal as well as facial cues conveying various social and emotional connotations. The observed differences in severity of impairments with most severe deficits for alluring expressions might be related to specific difficulties in recognizing the complex social emotional information of interpersonal intentions as compared to "basic" emotional states. Therefore, future studies evaluating perception of nonverbal cues should consider a broader range of social and emotional signals beyond basic emotions including attitudes and interpersonal intentions. Identifying specific domains of social perception particularly prone for misunderstandings in patients with schizophrenia might allow for a refinement of interventions aiming at improving social functioning.

Integration of verbal and nonverbal emotional signals in patients with schizophrenia: Decreased nonverbal dominance.

In day-to-day social interaction, emotions are usually expressed by verbal (e.g. spoken words) and nonverbal signals (e.g. facial expressions, prosody). In case of conflicting signals nonverbal signals are perceived as being the more reliable source of information. Deficits in interpreting nonverbal signals - as described for patients with schizophrenic disorders - might interfere with the ability to integrate verbal and nonverbal social cues into a meaningful whole. The aim of this study was to examine how schizophrenic disorders influence the integration of verbal and nonverbal signals. For this purpose short video sequences were presented to 21 patients with schizophrenia and 21 healthy controls. Each sequence showed an actor speaking a short sentence with independently varying emotional connotations at the verbal and the nonverbal level. The participants rated the valence of the speaker's emotional state on a four-point scale (from very negative to very positive). The relative impact of nonverbal cues as compared to verbal cues on these ratings was evaluated. Both groups base their decisions primarily on nonverbal information. However, this effect is significantly less prominent in the patient group. Patients tend to base their decisions less on nonverbal signals and more on verbal information than healthy controls.

Reduced functional connectivity to the frontal cortex during processing of social cues in autism spectrum disorder.

People diagnosed with autism spectrum disorder (ASD) characteristically present with severe difficulties in interpreting every-day social signals. Currently it is assumed that these difficulties might have neurobiological correlates in alterations in activation as well as in connectivity in and between regions of the social perception network suggested to govern the processing of social cues. In this study, we conducted functional magnetic resonance imaging (fMRI)-based activation and connectivity analyses focusing on face-, voice-, and audiovisual-processing brain regions as the most important subareas of the social perception network. Results revealed alterations in connectivity among regions involved in the processing of social stimuli in ASD subjects compared to typically developed (TD) controls-specifically, a reduced connectivity between the left temporal voice area (TVA) and the superior and medial frontal gyrus. Alterations in connectivity, moreover, were correlated with the severity of autistic traits: correlation analysis indicated that the connectivity between the left TVA and the limbic lobe, anterior cingulate and the medial frontal gyrus as well as between the right TVA and the frontal lobe, anterior cingulate, limbic lobe and the caudate decreased with increasing symptom severity. As these frontal regions are understood to play an important role in interpreting and mentalizing social signals, the observed underconnectivity might be construed as playing a role in social impairments in ASD.

Laughter perception in social anxiety.

BACKGROUND: Laughter is a powerful signal of social acceptance or rejection while the fear of being embarrassed and humiliated is central in social anxiety (SA). This type of anxiety is associated with cognitive biases indicating increased sensitivity to social threat as well as with deficits in emotion regulation. Both are thought to be implicated in the maintenance of social anxiety. METHOD: Using laughter as a novel stimulus, we investigated cognitive biases and their modulation through emotion regulation and cue ambiguity in individuals with varying degrees of SA (N = 60). RESULTS: A combination of a negative laughter interpretation bias and an attention bias away from joyful/social inclusive laughter in SA was observed. Both biases were not attributable to effects of general anxiety and were closely correlated with the concept of gelotophobia, the fear of being laughed at. DISCUSSION: Thus, our study demonstrates altered laughter perception in SA. Furthermore, it highlights the usefulness of laughter as a highly prevalent social signal for future research on the interrelations of interpretation and attention biases in SA and their modulation through emotion regulation.

Cerebral processing of prosodic emotional signals: evaluation of a network model using rTMS.

A great number of functional imaging studies contributed to developing a cerebral network model illustrating the processing of prosody in the brain. According to this model, the processing of prosodic emotional signals is divided into three main steps, each related to different brain areas. The present study sought to evaluate parts of the aforementioned model by using low-frequency repetitive transcranial magnetic stimulation (rTMS) over two important brain regions identified by the model: the superior temporal cortex (Experiment 1) and the inferior frontal cortex (Experiment 2). The aim of both experiments was to reduce cortical activity in the respective brain areas and evaluate whether these reductions lead to measurable behavioral effects during prosody processing. However, results obtained in this study revealed no rTMS effects on the acquired behavioral data. Possible explanations for these findings are discussed in the paper.