Fear responses to safety cues in anxious adolescents: preliminary evidence for atypical age-associated trajectories of functional neural circuits

Adolescent anxiety is common and impairing and often persists into adulthood. There is growing evidence that adult anxiety is characterized by abnormal fear responses to threat and safety cues, along with perturbations in fear-related neural circuits. Although some of this work has been extended to adolescents, with promising results, it is not yet clear whether changes in these circuits across developmental age varies between anxious and non-anxious adolescents. Here we used fMRI to examine how age modulates neural responses as adolescents are exposed to threat and safety cues. Participants were 15 anxious and 11 non-anxious adolescents (age 12-17) who completed a fear conditioning paradigm. The paradigm incorporated a threat cue comprising a neutral face which was paired with a fearful, screaming face, a safety cue comprising a different neutral face, and a control stimulus. Across the whole sample, neural activation to the threat cue (relative to the control cue) correlated positively with age in a number of regions, including the dorsal anterior cingulate and bilateral dorsolateral prefrontal cortex (PFC). However, neural activation to the safety cue (relative to the control cue) was modulated differently by age in the two groups: a more positive association between activation and age was observed in the control group compared to the anxious group in various regions including medial and dorsolateral PFC, anterior insula, and amygdala. These findings suggest that maturation of the neural substrates of fear responses to safety cues may be perturbed in anxious adolescents, potentially contributing to the emergence and maintenance of anxiety disorders in adulthood

Detecting bipolar depression from geographic location data

Objective: This work aims to identify periods of depression using geolocation movements recorded from mobile phones in a prospective community study of individuals with bipolar disorder (BD). Methods: Anonymised geographic location recordings from 22 BD participants and 14 healthy controls (HC) were collected over 3 months. Participants reported their depressive symptomatology using a weekly questionnaire (QIDS-SR16). Recorded location data were pre-processed by detecting and removing imprecise data points and features were extracted to assess the level and regularity of geographic movements of the participant. A subset of features were selected using a wrapper feature selection method and presented to (a) a linear regression model and a quadratic generalised linear model with a logistic link function for questionnaire score estimation; and (b) a quadratic discriminant analysis classifier for depression detection in BD participants based on their questionnaire responses. Results: HC participants did not report depressive symptoms and their features showed similar distributions to nondepressed BD participants. Questionnaire score estimation using geolocation-derived features from BD participants demonstrated an optimal mean absolute error rate of 3.73 while depression detection demonstrated an optimal (median±IQR) F1 score of 0.857±0.022 using 5 features (classification accuracy: 0.849±0.016; sensitivity: 0.839±0.014; specificity: 0.872±0.047). Conclusion: These results demonstrate a strong link between geographic movements and depression in bipolar disorder. Significance: To our knowledge this is the first community study of passively recorded objective markers of depression in bipolar disorder of this scale. The techniques could help individuals monitor their depression and enable healthcare providers to detect those in need of care or treatment

Verbal learning impairment in euthymic bipolar disorder: BDI v BDII

AbstractObjectivesCognitive impairment is known to occur in bipolar disorder (BD), even in euthymic patients, with largest effect sizes often seen in Verbal Learning and Memory Tasks (VLT). However, comparisons between BD Type-I and Type-II have produced inconsistent results partly due to low sample sizes.MethodsThis study compared the performance of 183 BDI with 96 BDII out-patients on an adapted version of the Rey Verbal Learning Task. Gender, age, years of education, mood scores and age at onset were all used as covariates. Current medication and a variety of illness variables were also investigated for potential effects on VLT performance.ResultsBDI patients were significantly impaired relative to BDII patients on all five VLT outcome measures after controlling for the other variables [Effect Sizes=.13–.17]. The impairments seem to be unrelated to drug treatment and largely unrelated to illness variables, although age of onset affected performance on three outcome measures and number of episodes of mood elevation affected performance on one.LimitationsThis study used historical healthy controls. Analysis of potential drug effects was limited by insufficient participants not being drug free. Cross-sectional nature of the study limited the analysis of the potential effect of illness variables.ConclusionsThis study replicates earlier findings of increased verbal learning impairment in BDI patients relative to BDII in a substantially larger sample. Such performance cannot be wholly explained by medication effects or illness variables. Thus, the cognitive impairment is likely to reflect a phenotypic difference between bipolar sub-types

Social withdrawal and neurocognitive correlates in schizophrenia

Poor neurocognitive performance has been associated with poor functional outcome in schizophrenia (SCZ) in past studies. Nonetheless, the likely association between neurocognition and social withdrawal has never been investigated. The aim of our study was to investigate in a large and heterogeneous sample of SCZ patient cross-sectional associations between neurocognitive domains and social withdrawal. The sample included 761 SCZ patients who completed the baseline visit in the CATIE study. Neurocognition was assessed by a comprehensive battery of tests resulting in five domain scores and a composite score. Social withdrawal was measured by a specific item of the Heinrichs-Carpenter Quality of Life Scale. Social withdrawal was associated with a lower score in the neurocognitive composite score and in 'Verbal memory,' 'Processing speed' and 'Working memory' scores. 'Verbal memory' score showed the strongest association with social withdrawal. Eight percent of the total variance of social withdrawal was explained by these three cognitive domains and additional clinical and sociodemographic factors (education years, PANSS positive symptoms score, and employment). Our results confirmed the wide heterogeneity and specificity of the correlation between neurocognitive domains and indicators of functional outcome in SCZ, underlining the role of certain neurocognitive abilities in social withdrawal

Working definitions, subjective and objective assessments and experimental paradigms in a study exploring social withdrawal in schizophrenia and Alzheimer's disease

Social withdrawal is one of the first and common signs of early social dysfunction in a number of important neuropsychiatric disorders, likely because of the enormous amount and complexity of brain processes required to initiate and maintain social relationships (Adolphs, 2009). The Psychiatric Ratings using Intermediate Stratified Markers (PRISM) project focusses on the shared and unique neurobiological basis of social withdrawal in schizophrenia, Alzheimer and depression. In this paper, we discuss the working definition of social withdrawal for this study and the selection of objective and subjective rating scales to assess social withdrawal chosen or adapted for this project. We also discuss the MRI and EEG paradigms selected to study the systems and neural circuitry thought to underlie social functioning and more particularly to be involved in social withdrawal in humans, such as the social perception and the social affiliation networks. A number of behavioral paradigms were selected to assess complementary aspects of social cognition. Also, a digital phenotyping method (a smartphone application) was chosen to obtain real-life data.This work was supported by the European Union Horizon 2020 Innovative Medicines Initiative 2 Joint Undertaking grant 115916 for the project ‘Psychiatric ratings using intermediate stratified markers

Oxytocin Modulates the Cognitive Appraisal of the Own and Others Close Intimate Relationships

Close and intimate relationships are important promoters of health. Oxytocin and its association with social cognition have been investigated in a large number of studies, especially highlighting the neuropeptide's involvement in attachment behavior and intimate relationships. However, mixed findings on exogenous oxytocin application have led to the focus on moderators and mediators, suggesting that the effects are depended on specific factors - namely context and salience. The objective of the current study was to assess the effect of intranasal oxytocin on social appraisal of own and others' close intimate relationship characteristics. Different characteristics of relationships, including trust or closeness, between romantic couples (unknown and own) were assessed using the Couple Appraisal Task. In a randomized controlled double-blind cross-over within subject design, = 71 healthy men and women were investigated after receiving first intranasal oxytocin and 2 weeks later placebo, or vice versa. We found an oxytocin-induced increase in the positive appraisal of one's own overall relationship characteristics but not in the evaluation of the relationship of others. The present study - one of the first of its kind administrating oxytocin in a repeated measures cross-over design - adds further evidence to the mediating role of oxytocin in social cognition, specifically with regard to romantic relationship characteristics

Digital behavioural signatures reveal trans-diagnostic clusters of schizophrenia and Alzheimer's disease patients

The current neuropsychiatric nosological categories underlie pragmatic treatment choice, regulation and clinical research but does not encompass biological rationale. However, subgroups of patients suffering from schizophrenia or Alzheimer's disease have more in common than the neuropsychiatric nature of their condition, such as the expression of social dysfunction. The PRISM project presents here initial quantitative biological insights allowing the first steps toward a novel trans-diagnostic classification of psychiatric and neurological symptomatology intended to reinvigorate drug discovery in this area. In this study, we applied spectral clustering on digital behavioural endpoints derived from passive smartphone monitoring data in a subgroup of Schizophrenia and Alzheimer's disease patients, as well as age matched healthy controls, as part of the PRISM clinical study. This analysis provided an objective social functioning characterization with three differential clusters that transcended initial diagnostic classification and was shown to be linked to quantitative neurobiological parameters assessed. This emerging quantitative framework will both offer new ways to classify individuals in biologically homogenous clusters irrespective of their initial diagnosis, and also offer insights into the pathophysiological mechanisms underlying these clusters.</p

Effect of disease related biases on the subjective assessment of social functioning in Alzheimer's disease and schizophrenia patients

Background: Questionnaires are the current hallmark for quantifying social functioning in human clinical research. In this study, we compared self- and proxy-rated (caregiver and researcher) assessments of social functioning in Schizophrenia (SZ) and Alzheimer's disease (AD) patients and evaluated if the discrepancy between the two assessments is mediated by disease-related factors such as symptom severity. Methods: We selected five items from the WHO Disability Assessment Schedule 2.0 (WHODAS) to assess social functioning in 53 AD and 61 SZ patients. Caregiver- and researcher-rated assessments of social functioning were used to calculate the discrepancies between self-rated and proxy-rated assessments. Furthermore, we used the number of communication events via smartphones to compare the questionnaire outcomes with an objective measure of social behaviour. Results: WHODAS results revealed that both AD (p &lt; 0.001) and SZ (p &lt; 0.004) patients significantly overestimate their social functioning relative to the assessment of their caregivers and/or researchers. This overestimation is mediated by the severity of cognitive impairments (MMSE; p = 0.019) in AD, and negative symptoms (PANSS; p = 0.028) in SZ. Subsequently, we showed that the proxy scores correlated more strongly with the smartphone communication events of the patient when compared to the patient-rated questionnaire scores (self; p = 0.076, caregiver; p &lt; 0.001, researcher-rated; p = 0.046). Conclusion: Here we show that the observed overestimation of WHODAS social functioning scores in AD and SZ patients is partly driven by disease-related biases such as cognitive impairments and negative symptoms, respectively. Therefore, we postulate the development and implementation of objective measures of social functioning that may be less susceptible to such biases.The PRISM project (www.prism-project.eu) leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the authors’ views neither IMI JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein. Dr. Arango has also received funding support by the Spanish Ministry of Science and Innovation. Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), co-financed by ERDF Funds from the European Commission, “A way of making Europe”, CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds. Fundación Familia Alonso and Fundación Alicia Koplowit

Cross-disorder and disorder-specific deficits in social functioning among schizophrenia and Alzheimer's disease patients

BACKGROUND: Social functioning is often impaired in schizophrenia (SZ) and Alzheimer's disease (AD). However, commonalities and differences in social dysfunction among these patient groups remain elusive.MATERIALS AND METHODS: Using data from the PRISM study, behavioral (all subscales and total score of the Social Functioning Scale) and affective (perceived social disability and loneliness) indicators of social functioning were measured in patients with SZ (N = 56), probable AD (N = 50) and age-matched healthy controls groups (HC, N = 29 and N = 28). We examined to what extent social functioning differed between disease and age-matched HC groups, as well as between patient groups. Furthermore, we examined how severity of disease and mood were correlated with social functioning, irrespective of diagnosis.RESULTS: As compared to HC, both behavioral and affective social functioning seemed impaired in SZ patients (Cohen's d's 0.81-1.69), whereas AD patients mainly showed impaired behavioral social function (Cohen's d's 0.65-1.14). While behavioral indices of social functioning were similar across patient groups, SZ patients reported more perceived social disability than AD patients (Cohen's d's 0.65). Across patient groups, positive mood, lower depression and anxiety levels were strong determinants of better social functioning (p's &lt;0.001), even more so than severity of disease.CONCLUSIONS: AD and SZ patients both exhibit poor social functioning in comparison to age- and sex matched HC participants. Social dysfunction in SZ patients may be more severe than in AD patients, though this may be due to underreporting by AD patients. Across patients, social functioning appeared as more influenced by mood states than by severity of disease.</p

Relationships between social withdrawal and facial emotion recognition in neuropsychiatric disorders

Background: Emotion recognition constitutes a pivotal process of social cognition. It involves decoding social cues (e.g., facial expressions) to maximise social adjustment. Current theoretical models posit the relationship between social withdrawal factors (social disengagement, lack of social interactions and loneliness) and emotion decoding. Objective: To investigate the role of social withdrawal in patients with schizophrenia (SZ) or probable Alzheimer's disease (AD), neuropsychiatric conditions associated with social dysfunction. Methods: A sample of 156 participants was recruited: schizophrenia patients (SZ; n = 53), Alzheimer's disease patients (AD; n = 46), and two age-matched control groups (SZc, n = 29; ADc, n = 28). All participants provided self-report measures of loneliness and social functioning, and completed a facial emotion detection task. Results: Neuropsychiatric patients (both groups) showed poorer performance in detecting both positive and negative emotions compared with their healthy counterparts (p < .01). Social withdrawal was associated with higher accuracy in negative emotion detection, across all groups. Additionally, neuropsychiatric patients with higher social withdrawal showed lower positive emotion misclassification. Conclusions: Our findings help to detail the similarities and differences in social function and facial emotion recognition in two disorders rarely studied in parallel, AD and SZ. Transdiagnostic patterns in these results suggest that social withdrawal is associated with heightened sensitivity to negative emotion expressions, potentially reflecting hypervigilance to social threat. Across the neuropsychiatric groups specifically, this hypervigilance associated with social withdrawal extended to positive emotion expressions, an emotional-cognitive bias that may impact social functioning in people with severe mental illness