Advancing chemical safety assessment through an omics-based characterization of the test system-chemical interaction.

Assessing chemical safety is essential to evaluate the potential risks of chemical exposure to human health and the environment. Traditional methods relying on animal testing are being replaced by 3R (reduction, refinement, and replacement) principle-based alternatives, mainly depending on in vitro test methods and the Adverse Outcome Pathway framework. However, these approaches often focus on the properties of the compound, missing the broader chemical-biological interaction perspective. Currently, the lack of comprehensive molecular characterization of the in vitro test system results in limited real-world representation and contextualization of the toxicological effect under study. Leveraging omics data strengthens the understanding of the responses of different biological systems, emphasizing holistic chemical-biological interactions when developing in vitro methods. Here, we discuss the relevance of meticulous test system characterization on two safety assessment relevant scenarios and how omics-based, data-driven approaches can improve the future generation of alternative methods.

Longitudinal exploration of biopsychosocial profiles in individuals with anorexia nervosa.

BACKGROUND: Previous work in individuals with Anorexia Nervosa (AN) has demonstrated a range of psycho-social difficulties such as increased anxiety, depression, obsessive-compulsive symptoms, as well as difficulties in work and with interpersonal interactions. However, making inferences regarding the stability of these psycho-social difficulties from previous studies is challenging, due to lack of a control group and known frequentist statistical issues. METHODS: 134 participants, 40 healthy controls (HC) and 94 participants with AN, completed self-reported measures designed to explore eating disorder concerns, body mass index, mood symptoms, work and social functioning as well as traits associated with autism at two time points, two years apart. A principal component analysis and Bayesian mixed effects models were used to build and explore group differences in bio-psychosocial profiles at time points. RESULTS: The Bayesian models demonstrated evidence for individuals with AN having higher scores for a component representing psycho-social difficulties and lower scores for a component representing biological difficulties compared to HC, at both time points. There was no evidence of a group difference for a component representing autism. CONCLUSIONS: Our results demonstrate that persistent psycho-social difficulties are a feature in individuals with AN.

Analysis of symptom clusters amongst adults with anorexia nervosa: Key severity indicators.

This study used cluster analysis to explore clinically relevant subgroups of adult patients with anorexia nervosa (AN). Patients were clustered based on their body mass index (BMI), eating disorder symptomatology, anxiety and depression symptoms and autistic characteristics. The difference between clusters in work and social functioning, duration of illness, bingeing and purging behaviour, previous hospitalisations and number of comorbidities was also investigated. Two meaningful clusters emerged: a higher symptoms cluster with more severe eating pathology, anxiety, depression, and more autistic traits, and a second cluster with lower symptoms. BMI did not make major contributions to cluster formation. The higher symptoms cluster also reported lower self-efficacy to change, more previous hospitalisations, comorbid diagnoses, binge eating and purging behaviours and use of psychotropic medication. Our findings suggest that weight alone may not be a significant severity indicator amongst inpatients with AN, and targeted treatment of AN should consider a broader range of symptom severity indicators.

A curated gene and biological system annotation of adverse outcome pathways related to human health.

Adverse outcome pathways (AOPs) are emerging as a central framework in modern toxicology and other fields in biomedicine. They serve as an extension of pathway-based concepts by depicting biological mechanisms as causally linked sequences of key events (KEs) from a molecular initiating event (MIE) to an adverse outcome. AOPs guide the use and development of new approach methodologies (NAMs) aimed at reducing animal experimentation. While AOPs model the systemic mechanisms at various levels of biological organisation, toxicogenomics provides the means to study the molecular mechanisms of chemical exposures. Systematic integration of these two concepts would improve the application of AOP-based knowledge while also supporting the interpretation of complex omics data. Hence, we established this link through rigorous curation of molecular annotations for the KEs of human relevant AOPs. We further expanded and consolidated the annotations of the biological context of KEs. These curated annotations pave the way to embed AOPs in molecular data interpretation, facilitating the emergence of new knowledge in biomedicine.

Longitudinal Analysis of Mental Health in Autistic University Students Across an Academic Year.

BACKGROUND: Autistic people have worse mental health (MH) than non-autistic people. This proof-of-concept study explored feasibility of longitudinal research with autistic university students, focusing on their MH and coping styles across an academic year. METHODS: Twenty-two students took part at all timepoints. They completed four rounds of online MH questionnaires. RESULTS: Over 80% of students were retained. They started the year with high levels of all MH issues, which remained stable across the year. Network Change analysis showed the connections between MH and coping style changed over time. CONCLUSIONS: Autistic students are engaged participants who are likely to take part in longitudinal research. While MH levels were stable, it may be that coping styles are a useful target for intervention.

Evaluation of film stimuli for the assessment of social-emotional processing: a pilot study.

Background: Difficulties in top-down and bottom-up emotion generation have been proposed to play a key role in the progression of psychiatric disorders. The aim of the current study was to develop more ecologically valid measures of top-down interpretation biases and bottom-up evoked emotional responses. Methods: A total of 124 healthy female participants aged 18-25 took part in the study. We evaluated two sets of 18 brief film clips. The first set of film clips presented ambiguous social situations designed to examine interpretation biases. Participants provided written interpretations of each ambiguous film clip which were subjected to sentiment analysis. We compared the films in terms of the valence of participants interpretations. The second set of film clips presented neutral and emotionally provoking social scenarios designed to elicit subjective and facial emotional responses. While viewing these film clips participants mood ratings and facial affect were recorded and analysed using exploratory factor analyses. Results: Most of the 18 ambiguous film clips were interpreted in the expected manner while still retaining some ambiguity. However, participants were more attuned to the negative cues in the ambiguous film clips and three film clips were identified as unambiguous. These films clips were deemed unsuitable for assessing interpretation bias. The exploratory factor analyses of participants' mood ratings and evoked facial affect showed that the positive and negative emotionally provoking film clips formed their own factors as expected. However, there was substantial cross-loading of the neutral film clips when participants' facial expression data was analysed. Discussion: A subset of the film clips from the two tasks could be used to assess top-down interpretation biases and bottom-up evoked emotional responses. Ambiguous negatively valenced film clips should have more subtle negative cues to avoid ceiling effects and to ensure there is enough room for interpretation.

Autism and anorexia nervosa: Longitudinal prediction of eating disorder outcomes.

Background: Recently, elevated levels of autistic features and autism diagnoses have been reported among people with anorexia nervosa (AN). In clinical settings high levels of autistic features have been linked to more complex, highly comorbid illness presentation and poorer treatment outcome. This study aimed to examine whether autistic features predict AN symptom profile in long term. Methods: Altogether 118 women with lived experience of AN completed two autism assessments at time 1, the Autism Diagnostic Observation Schedule (ADOS) and the short version of the Autism Quotient (AQ10). Measures assessing AN symptom profile, including eating disorders symptoms, anxiety, depression, OCD symptoms, and Body Mass Index (BMI), were also recorded. The symptom profile measures were administered again 6 months and 2 years later. We conducted two analyses to examine the extent to which the ADOS and AQ10 scores predicted broad AN symptom profile at each three time points. Results: Overall, high levels of autistic features were consistently associated with worse psychological symptoms, but not BMI, across all time points. Both the analysis using baseline ADOS scores and self-reported AQ10 scores showed similar pattern. Conclusion: The present findings consolidate previously reported associations between autistic features and worse psychological outcome among people with AN. The findings also suggest that self-report measures may be sufficient for assessing the impact of autistic features on illness outcome among people with AN. Importantly, the study highlights the need for development and further investigation of neurodiversity accommodations in the treatment of AN.

Examining the relationship between autistic spectrum disorder characteristics and structural brain differences seen in anorexia nervosa.

Cortical differences have been reported in Anorexia Nervosa (AN) compared with healthy controls (HC); however, it is unclear if Autism Spectrum Disorder (ASD) characteristics are related to these cortical differences. The aim of this study was to examine if structural measures were correlated to ASD traits in AN. In total 184 female participants participated in the study; 57 acutely underweight AN participants (AAN), 59 weight-restored participants (WR) and 68 HC. Participants underwent structural magnetic resonance imaging as well as completing the Autism Diagnostic Observation schedule, second edition to examine ASD characteristics. Group differences in curvature, gyrification, surface area, thickness, global grey matter and white matter were measured. Correlation and regression analysis were conducted to examine the relationship between cortical measures and ASD characteristics. Two decreased gyrification clusters in the right post central and supramarginal gyrus and decreased global grey matter were observed in the AAN group compared to HC and WR. No correlations between ASD traits and structural measures existed. Our results suggest structural differences seen in individuals with AN do not appear to be related to ASD characteristics.

The Role of Emotion Regulation in Eating Disorders: A Network Meta-Analysis Approach.

Background: Previous theoretical models and reviews have documented a strong connection between emotion dysregulation eating disorder (ED) psychopathology among the general and clinical populations. The aim of this review was to build on this previous work by conducting a network meta-analysis to explore associations between adaptive and maladaptive emotion regulation strategies and ED psychopathology trans-diagnostically across the ED spectrum to identify areas of emotion dysregulation that have the strongest association with symptomatology. Methodology: A total of 104 studies were included in the meta-analysis and correlation coefficient representing the associations between specific emotion regulation strategies and ED symptomatology were extracted. We ran a Bayesian random effects network meta-analysis and the initial network was well-connected with each emotion regulation strategy being linked to at least one other strategy. We also conducted a network meta-regression to explore whether between-study differences in body mass index (BMI), age, and whether the sample consisted of solely female participants explained any possible network inconsistency. Results: The network meta-analysis revealed that ruminations and non-acceptance of emotions were most closely associated with ED psychopathology. There was no significant network inconsistency but two comparisons approached significance and thus meta-regressions were conducted. The meta-regressions revealed a significant effect of BMI such that the associations between different emotion regulation strategies and ED symptomatology were weaker among those with low BMI. Discussion: The present findings build on previous work and highlight the role of rumination and difficulties with accepting emotions as key emotion regulation difficulties in EDs. Additionally, the finding that the associations were weaker among ED patients with low BMI may point toward a complex relationship between ED behaviors and emotion regulation. Taken together, our findings call for interventions that target emotion regulation, specifically rumination and difficulties accepting emotions, in the treatment of EDs. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021249996, PROSPERO, identifier: CRD42021249996.

Different pathways, same goals: A large-scale qualitative study of autistic and non-autistic patient-generated definitions of recovery from an eating disorder.

BACKGROUND: Definitions of recovery from an eating disorder (ED) have generally been formulated around clinical conceptualisations, rather than based on the views of patients. This paper therefore asked those with lived experience of ED for their own definitions of recovery. METHOD: Data were collected as part of an online study looking at EDs, autism and relationships. About 173 participants identified as recovered from ED and gave free-response definitions of recovery. Responses were subject to thematic analysis. RESULTS: Seven major themes were identified: Weight restoration, lack of ED behaviours, thoughts and behaviours, cognitions, emotional responses, getting on with life, and ongoing challenges. CONCLUSIONS: Many definitions of recovery given by those who have lived experience of ED echoed those used by clinicians and researchers. There were also points of divergence around the ongoing challenges of recovery. Our findings highlight the need for continuing support post-weight restoration to facilitate the successful long-term recovery for those with ED.

The neural correlates of a central coherence task in young women with anorexia nervosa.

OBJECTIVE: Heightened detail-processing and low levels of central coherence are common in individuals with anorexia nervosa (AN) and predict poorer prognosis. However, it is unclear whether these processing styles predate the disorder or, rather, emerge during later stages of AN. The current study aimed to address this question by investigating central coherence, and the neural correlates of central coherence, in a sample of young women with AN with shorter duration of illness than previous studies recruiting adult samples. METHODS: We recruited 186 participants, including: 73 young women with AN, 45 young women weight-recovered from AN, and 68 age-matched controls. Participants completed the Embedded Figures Task during an fMRI scan. RESULTS: There were no significant differences between the participant groups in performance accuracy or reaction time. There were no other between-groups differences in neural response to the Embedded Figures Task. CONCLUSIONS: These findings contrast with evidence from older adults demonstrating differences in the neural underpinning of central coherence amongst participants with AN versus control participants. The current study adds to an increasing literature base demonstrating the resilience of neuropsychological traits and associated brain systems in the early stages of AN.

Exploring neuropsychological and socio-emotional task performance in anorexia nervosa: A cluster analytic approach.

OBJECTIVE: The aim of this study was to characterise heterogeneity in neuropsychological and socio-emotional task performance in young women with anorexia nervosa (AN) using hierarchical cluster analysis. Further, we aimed to test whether cognitive profiles were associated with differences in clinical variables (body mass index, illness duration and age at diagnosis), psychopathology (eating disorder, autistic symptoms, anxiety and depression) and functional impairment. METHOD: Set-shifting, central coherence and theory of mind abilities were measured in 118 women with acute or remitted AN. A hierarchical cluster analysis using Ward's method with a Euclidean distance measure was performed with the neuropsychological and socio-emotional variables. Differences between clusters were assessed using ANOVAs. RESULTS: Four clusters emerged, with significant differences in neuropsychological and socio-emotional task performance. There were no significant differences between clusters in clinical variables, psychopathology or functional impairment, however, these analyses lacked power due to small cluster sizes. CONCLUSIONS: Our results demonstrate significant heterogeneity in cognitive profiles in AN, supporting a more personalised approach to treatment. Studies in larger samples are required to establish whether these variables map onto clinically significant differences in aetiology, clinical presentation, comorbidity patterns and/or treatment responses.

Critical incidents in anorexia nervosa: perspectives of those with a lived experience.

BACKGROUND: Although social-emotional difficulties are believed play a key role in anorexia nervosa (AN), there is uncertainty regarding what these difficulties might look like. Previous research has largely focused on a "disease model" of social-emotional processing in AN with little attention paid to positive emotions and experiences. Therefore, the aim of the present study was to obtain a fuller picture of critical life events as identified by those with lived AN experience. METHODS: Thirty-four participants aged 16-48 with current or past AN completed an online survey describing self-defined positive and difficult critical events. Thematic analysis was used to assess patterns in participants narrative responses. RESULTS: Two major themes were identified in the descriptions of positive critical events: Moments of celebration and Unexpected positive outcomes. These major themes revealed increased external focus and some corrective experiences that challenged the participants pre-existing expectations leading to new positive outcomes. Difficult events clustered into life events that were identified as Eating disorder (ED) related and Non-ED related and included the dimensions of relational conflict and feeling unsupported. DISCUSSION: The findings suggest that although negative emotionality was identified in the accounts of those with lived experience of AN capacity for "big-picture" thinking with and explicit focus on others was also identified. Moreover, an openness to corrective experiences that worked to challenge negative expectations was evident for some participants. Together these findings have scope as targets for further clinical research and treatment interventions.

The emotional face of anorexia nervosa: The neural correlates of emotional processing.

Social-emotional processing difficulties have been reported in Anorexia Nervosa (AN), yet the neural correlates remain unclear. Previous neuroimaging work is sparse and has not used functional connectivity paradigms to more fully explore the neural correlates of emotional difficulties. Fifty-seven acutely unwell AN (AAN) women, 60 weight-recovered AN (WR) women and 69 healthy control (HC) women categorised the gender of a series of emotional faces while undergoing Functional Magnetic Resonance Imaging. The mean age of the AAN group was 19.40 (2.83), WR 18.37 (3.59) and HC 19.37 (3.36). A whole brain and psychophysical interaction connectivity approach was used. Parameter estimates from significant clusters were extracted and correlated with clinical symptoms. Whilst no group level differences in whole brain activation were demonstrated, significant group level functional connectivity differences emerged. WR participants showed increased connectivity between the bilateral occipital face area and the cingulate, precentral gyri, superior, middle, medial and inferior frontal gyri compared to AAN and HC when viewing happy valenced faces. Eating disorder symptoms and parameter estimates were positively correlated. Our findings characterise the neural basis of social-emotional processing in a large sample of individuals with AN.

Sailing in rough waters: Examining volatility of fMRI noise.

BACKGROUND: The assumption that functional magnetic resonance imaging (fMRI) noise has constant volatility has recently been challenged by studies examining heteroscedasticity arising from head motion and physiological noise. The present study builds on this work using latest methods from the field of financial mathematics to model fMRI noise volatility. METHODS: Multi-echo phantom and human fMRI scans were used and realised volatility was estimated. The Hurst parameter H ∈ (0,1), which governs the roughness/irregularity of realised volatility time series, was estimated. Calibration of H was performed pathwise, using well-established neural network calibration tools. RESULTS: In all experiments the volatility calibrated to values within the rough case, H < 0.5, and on average fMRI noise was very rough with 0.03 < H < 0.05. Some edge effects were also observed, whereby H was larger near the edges of the phantoms. DISCUSSION: The findings suggest that fMRI volatility is not only non-constant, but also substantially more irregular than a standard Brownian motion. Thus, further research is needed to examine the impact such pronounced oscillations in the volatility of fMRI noise have on data analyses.

Corrigendum: Neural Correlates of Theory of Mind Are Preserved in Young Women With Anorexia Nervosa.

[This corrects the article DOI: 10.3389/fpsyg.2020.568073.].

Neural Correlates of Theory of Mind Are Preserved in Young Women With Anorexia Nervosa.

People with anorexia nervosa (AN) commonly exhibit social difficulties, which may be related to problems with understanding the perspectives of others, commonly known as Theory of Mind (ToM) processing. However, there is a dearth of literature investigating the neural basis of these differences in ToM and at what age they emerge. This study aimed to test for differences in the neural correlates of ToM processes in young women with AN, and young women weight-restored (WR) from AN, as compared to healthy control participants (HC). Based on previous findings in AN, we hypothesized that young women with current or prior AN, as compared to HCs, would exhibit a reduced neural response in the medial prefrontal cortex (mPFC), the inferior frontal gyrus, and the temporo-parietal junction (TPJ) whilst completing a ToM task. We recruited 73 young women with AN, 45 WR young women, and 70 young women without a history of AN to take part in the current study. Whilst undergoing a functional magnetic resonance imaging (fMRI) scan, participants completed the Frith-Happé task, which is a commonly used measure of ToM with demonstrated reliability and validity in adult populations. In this task, participants viewed the movements of triangles, which depicted either action movements, simple interactions, or complex social interactions. Viewing trials with more complex social interactions in the Frith-Happé task was associated with increased brain activation in regions including the right TPJ, the bilateral mPFC, the cerebellum, and the dorsolateral prefrontal cortex. There were no group differences in neural activation in response to the ToM contrast. Overall, these results suggest that the neural basis of spontaneous mentalizing is preserved in most young women with AN.

Exposure to food in anorexia nervosa and brain correlates of food-related anxiety: findings from a pilot study.

BACKGROUND: Although the primary target of treatment for anorexia nervosa (AN) is weight gain, established psychological interventions focus on maintaining factors of AN, and do not specifically address eating behaviours. We have previously reported results of a case series investigating in-vivo food exposure in AN, demonstrating the feasibility and acceptability of this treatment together with evidence of significant clinical change (Cardi, Leppanen, Mataix-Cols, Campbell, & Treasure, 2019). The current study examined the neural circuitry of food-related anxiety. METHODS: We examined neural reactivity (fMRI) to food images pre- and post-food exposure therapy (n=16), and compared it to a group of healthy control participants (HC n=21) who were scanned on two occasions. RESULTS: Prior to treatment, the AN group (compared to HC) showed less reactivity in the anterior cingulate cortex (ACC). Following exposure treatment, patients (compared to HC), show increased activity in the dorsolateral prefrontal cortex, decreased activity in the superior parietal lobe and no differences in the ACC. The level of activation of the insula (pre-treatment) predicted the degree of post-treatment reduction in self-reported food anxiety in AN. Changes in food-related anxiety were also associated with changes in neural activation in a cluster located in the middle temporal gyrus/lateral parietal cortex. LIMITATIONS: The primary limitations of this work are the small sample size and lack of patient comparison group. CONCLUSIONS: Exposure to food in AN may be associated with changes in neural circuitries implicated in emotion regulation and attentional processes. However, these findings need replication in larger and controlled studies.

Impact of TNF-α Inhibitors on Body Weight and BMI: A Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this systematic review and meta-analysis of longitudinal studies was to ascertain to effects of TNF-α inhibitor therapy on body weight and BMI. METHODS: Three databases (PubMed, OVID, and EMBASE) were systematically searched from inception to August 2018. We identified prospective, retrospective, and randomized controlled studies in adults with immune-mediated inflammatory diseases treated with TNF-α inhibitors based on pre-specified inclusion criteria. A random-effects model was used to estimate standardised mean change (SMCC). RESULTS: Twenty-six longitudinal studies with a total of 1,245 participants were included in the meta-analysis. We found evidence for a small increase in body weight (SMCC = 0.24, p = .0006, 95% CI [0.10, 0.37]) and in BMI (SMCC = 0.26, p < .0001, 95% CI [0.13, 0.39]). On average, patients gained 0.90kg (SD = 5.13) under infliximab, 2.34kg (D = 5.65) under etanercept and 2.27kg (SD = 4.69) during treatment with adalimumab within the duration of the respective studies (4-104 weeks). CONCLUSION: Our results yield further support the for the view that TNF-α inhibitors increase body weight and BMI as a potential side effect. Modulating cytokine signaling could be a future therapeutic mechanism to treat disorders associated with weight changes such as anorexia nervosa.

A pilot study investigating the influence of oxytocin on attentional bias to food images in women with bulimia nervosa or binge eating disorder.

BACKGROUND: Previous research has found that exogenous oxytocin administration has the potential to modulate attentional biases in women with anorexia nervosa. Recent work has indicated that attentional biases to food may reinforce the recurrent binge eating behaviour characterising bulimia nervosa and binge eating disorder. To date, however, no study has yet investigated the effect of oxytocin on attentional biases to palatable food in women with bulimia nervosa and binge eating disorder. METHODS: The present study employed a single-session cross-over design to test the hypothesis that a divided dose of 64 IU of intranasal oxytocin, administered as one intranasal dose of 40 IU of oxytocin followed by a top-up of 24 IU of oxytocin 80 minutes later, vs placebo administration administered in the same dosing schedule would reduce attentional biases towards food images in a dot probe task. We hypothesised that oxytocin administration would reduce vigilance towards food to a greater degree in women with bulimia nervosa or binge eating disorder vs healthy comparison women. Twenty-five women with bulimia nervosa or binge eating disorder and 27 comparison women without history of an eating disorder were recruited to take part in the study. RESULTS: In contrast to our hypothesis, there was no main effect of diagnosis on attentional bias to food (fixed effect = 5.70, P = 0.363), nor a significant interaction between diagnosis and drug condition (fixed effect =-14.80, P = 0.645). There was a main effect of drug condition, such that oxytocin increased vigilance towards food vs neutral images in the dot probe task (fixed effect = 10.42, P = 0.044). A correlation analysis revealed that this effect was moderated by attentional bias in the placebo condition, such that greater avoidance of food stimuli in the placebo condition was associated with a greater increase in vigilance induced by oxytocin. CONCLUSIONS: The findings of the present study add to a mixed body of literature investigating the therapeutic effects of oxytocin in women. Future research would benefit from dose-response studies investigating the optimal dose of oxytocin for modulating the attentional processing of palatable food in populations with eating disorders.