Body shape rather than facial emotion of others alters interpersonal distance in patients with anorexia nervosa.

OBJECTIVE: The study investigated interpersonal distance in patients with anorexia nervosa (AN), focussing on the role of other's facial expression and morphology, also assessing physiological and subjective responses. METHOD: Twenty-nine patients with AN and 30 controls (CTL) were exposed to virtual characters either with an angry, neutral, or happy facial expression or with an overweight, normal-weight, or underweight morphology presented either in the near or far space while we recorded electrodermal activity. Participants had to judge their preferred interpersonal distance with the characters and rated them in terms of valence and arousal. RESULTS: Unlike CTL, patients with AN exhibited heightened electrodermal activity for morphological stimuli only, when presented in the near space. They also preferred larger and smaller interpersonal distances with overweight and underweight characters respectively, although rating both negatively. Finally, and similar to CTL, they preferred larger interpersonal distance with angry than neutral or happy characters. DISCUSSION: Although patients with AN exhibited behavioural response to emotional stimuli similar to CTL, they lacked corresponding physiological response, indicating emotional blunting towards emotional social stimuli. Moreover, they showed distinct behavioural and physiological adjustments in response to body shape, confirming the specific emotional significance attached to body shape.

Trajectories and predictive factors of weight recovery in patients with anorexia nervosa completing treatment. A latent class mixed model approach.

BACKGROUND: Treatment of anorexia nervosa (AN) sometimes requires hospitalisation, which is often lengthy, with little ability to predict individual trajectory. Depicting specific profiles of treatment response and their clinical predictors could be beneficial to tailor inpatient management. The aim of this research was to identify clusters of weight recovery during inpatient treatment, and their clinical predictors. METHODS: A sample of 181 inpatients who completed a treatment programme for AN was included in a retrospective study. A latent class mixed model approach was used to identify distinct weight-gain trajectories. Clinical variables were introduced in a multinomial logistic regression model as predictors of the different classes. RESULTS: A four-class quadratic model was retained, able to correctly classify 63.7% of the cohort. It encompassed a late-rising, flattening, moderate trajectory of body mass index (BMI) increase (class 1), a late-rising, steady, high trajectory (class 2), an early-rising, flattening, high trajectory (class 3) and an early-rising, steady, high trajectory (class 4). Significant predictors of belonging to a class were baseline BMI (all classes), illness duration (class 2), and benzodiazepine prescription (class 3). CONCLUSION: Predicting different kinetics of weight recovery based on routinely collected clinical indicators could improve clinician awareness and patient engagement by enabling shared expectations of treatment response.

Risk of non-fatal self-harm and premature mortality in the three years following hospitalization in adolescents and young adults with an eating disorder: A nationwide population-based study.

INTRODUCTION: Eating disorders (ED) are associated with high rates of suicide attempts and premature mortality. However, data in large samples of adolescents and young adults are limited. This study aims to assess the risk of self-harm and premature mortality in young people hospitalized with an ED. METHODS: Individuals aged 12 to 25 years old hospitalized in 2013-2014 in France with anorexia nervosa and/or bulimia nervosa as a primary or associated diagnosis were identified from French national health records. They were compared to two control groups with no mental disorders, and with any other mental disorder than ED. The main outcomes were any hospitalization for deliberate self-harm and mortality in the 3 years following hospitalization. Logistic regression models were used. RESULTS: This study included 5, 452 patients hospitalized with an ED, 14,967 controls with no mental disorder, and 14,242 controls with a mental disorder other than an ED. During the three-year follow-up, 13.0% were hospitalized for deliberate self-harm (vs. 0.2 and 22.0%, respectively) and 0.8% died (vs. 0.03 and 0.4%). After adjustment, hospitalization with an ED was associated with more self-harm hospitalizations (hazard ratio [HR] = 46.0, 95% confidence interval [32.3-65.3]) and higher all-cause mortality (HR = 12.6 [4.3-37.3]) relative to youths without any mental disorder; less self-harm hospitalizations (HR = 0.5 [0.5-0.6]) but higher mortality (HR = 1.6 [1.0-2.4]) when compared to youths with any other mental disorder. CONCLUSION: Young patients hospitalized with an ED are at high risk of self-harm and premature mortality. It is urgent to evaluate and implement the best strategies for post-discharge care and follow-up. PUBLIC SIGNIFICANCE: We found that the risk of being hospitalized for a suicide attempt is 46 times higher and mortality 13 times higher than the general population in adolescents and young adults during the 3 years following hospitalization with an eating disorder. Eating disorders are also associated with a 1.5 higher risk of premature mortality relative to other mental disorders. This risk is particularly high in the 6 months following hospitalization. It is therefore crucial to implement careful post-discharge follow-up in patients hospitalized for eating disorders.

Measuring implicit associations between food and body stimuli in anorexia nervosa: a Go/No-Go Association Task.

PURPOSE: The present study aimed to explore the implicit associations between food and bodily stimuli in patients with anorexia nervosa (AN) and control subjects (HC). METHODS: A Go/No-Go Association Task was administrated to 55 participants (28 AN and 27 HC), using food stimuli (low-calorie food vs. high-calorie food) and body stimuli (underweight vs. overweight bodies). RESULTS: We evidenced an implicit association between food and body stimuli in the AN group, whereas the HC group only showed a tendency. AN and HC groups also exhibited different categorization strategies: the AN group tended to categorize stimuli as low-calorie foods and underweight bodies less than the HC group, and they tended to categorize stimuli as high-calorie foods and overweight bodies more than the HC group. CONCLUSION: The present study revealed for the first time specificities of the AN population's implicit association between food and body stimuli in terms of association strength and categorization strategy. Furthermore, the results suggest that combining implicit methodologies with other methods could contribute to a better characterization of the physiopathology of AN. LEVEL OF EVIDENCE: Level I, experimental study.

Clinical meaning of body temperatures in anorexia nervosa and bulimia nervosa.

OBJECTIVE: Bradycardia is one of the common cardiac abnormalities in patients with eating disorders. It ensues from hypometabolism, which results from reduced caloric intake and consequential weight loss. Hypothermia is another consequence of hypometabolism. While at-rest metabolism and body mass index (BMI) are typically used to assess hypometabolism and estimate potential bradycardia, we hypothesised that body temperature, which is easy to measure, could also capture the presence of this threatening cardiovascular condition. METHOD: We monitored heart rate continuously for 72 h, measured resting energy expenditure (REE) and assessed body temperature in 12 body parts for 58 patients with anorexia nervosa (AN) and 29 patients with bulimia nervosa (BN). RESULTS: Palm temperature reflects bradycardia in both AN and BN, explaining 18% of its variance (p < 0.001), capturing this aspect even more efficiently than BMI. We also observe different correlations between palm temperature, abdominal temperature, BMI, REE and levels of physical activity. CONCLUSION: Palm temperature could be used as a warning of bradycardia, a serious cardiovascular condition which can be difficult to detect in short visits with outpatients. Further studies are needed to determine how useful bradycardia and palm temperature could be to assess severity and prognosis of the disorder.

Pupil psychosensory reflex in response to own and standardised silhouettes in patients with anorexia nervosa.

OBJECTIVE: This study aimed to assess the physiological response of patients with anorexia nervosa (AN) to different types of silhouettes using pupillometry. METHODS: We measured the pupil psychosensory reflex (PSR) of 42 patients with AN and 35 healthy controls in response to standardised body silhouettes and to pictures of their own silhouettes digitally modified to represent different body mass indices (BMI). Perceptual distortion and body dissatisfaction were assessed using Anamorphic Micro Software©. Twenty-three of the recruited patients were tested up to four times during an inpatient treatment programme to assess the impact of weight gain. RESULTS: PSR correlated with the subjective rating of emotional arousal in controls but not in patients. Own silhouettes and standardised silhouettes triggered a different pupil response both in patients with AN and in controls. With pictures of their own silhouettes, pupil response to underweight stimuli differed from pupil response to normal weight or overweight stimuli in both groups. Weight gain was associated with an increase in PSR, an improvement of ideal BMI and a decrease of body dissatisfaction, but no change in perceptual distortion. CONCLUSION: Our findings support the idea that pupillometry could be a useful tool to assess the physiological state of patients with AN.

Morphing analysis of facial emotion recognition in anorexia nervosa: association with physical activity.

PURPOSE: Anorexia Nervosa (AN) has been linked to emotion processing inefficiencies, social cognition difficulties and emotion dysregulation, but data on Facial Emotion Recognition (FER) are heterogenous and inconclusive. This study aims to explore FER in patients with AN using a dynamic and ecological evaluation, and its relationship with Physical Activity (PA), an important aspect of AN that could impact emotional processing. METHODS: Sixty-six participants (33 patients with AN and 33 healthy controls) performed a morphed facial emotional recognition task and 49 of them wore an accelerometer during seven days to assess PA. Axis-I disorders and depressive symptoms have been assessed. RESULTS: No difference was found regarding time to recognize facial emotions. However, patients with AN correctly recognize emotions more frequently than controls. This was specific to disgust, although there was also a tendency for sadness. Among patients, higher depressive scores are associated with a faster and more accurate recognition of disgust, while a higher level of PA is associated to decreased accuracy in recognizing sadness. CONCLUSION: Patients with AN are capable of recognizing facial emotions as accurately as controls, but could have a higher sensitivity in recognizing negative emotions, especially disgust and sadness. PA has opposite effects and, thus, could be considered as an emotional regulation strategy against negative affect. LEVEL OF EVIDENCE II: Controlled trial without randomization.

Physical exercise-related endophenotypes in anorexia nervosa.

BACKGROUND: The persistence of physical exercise in anorexia nervosa (AN) despite underweight and its maintaining factors are poorly understood. The aim of this study was to explore the attitudes toward physical exercise and its effects on emotions, cognitive functioning, and body image perception in patients with AN, and to search for exercise-related endophenotypes of the pathology. METHODS: Physical exercise dependence, quantity, and dysregulation were assessed by the Exercise Dependence Scale (EDS), the Godin Leisure Time Exercise Questionnaire (GLTEQ) and a standardized effort test in 88 patients with AN, 30 unaffected relatives and 89 healthy controls. Changes in positive and negative affect, cognitive rigidity, and body image distortion were measured before and after the effort test in the three groups. RESULTS: Patients with AN had higher scores on the EDS and the GLTEQ and used more effort in the standardized effort test. These three measures of physical exercise correlated with negative emotions at baseline. After the effort test, patients with AN had marked emotional improvement, a moderate increase in body image distortion and a small increase in cognitive rigidity compared to HC. Unaffected relatives also had a significant postexercise increase of positive emotion. DISCUSSION: The mood-related drive for physical exercise has the characteristics of an endophenotype of the disorder. Excessive and driven physical exercise may be state-associated features of AN, driven by the positive effect on emotional wellbeing.

Increased cognitive flexibility mediates the improvement of eating disorders symptoms, depressive symptoms and level of daily life functioning in patients with anorexia nervosa treated in specialised centres.

OBJECTIVE: Poor cognitive flexibility has been highlighted in patients with anorexia nervosa (AN), contributing to the development and maintenance of symptoms. The aim of the present study is to investigate how enhanced cognitive flexibility is involved in treatment outcomes in patients with AN. METHOD: One hundred thirty female out-patients treated for AN have been assessed at baseline and after 4 months of treatment. Path analyses were used to investigate the mediating role of cognitive flexibility, measured through the Brixton test, on a wide range of outcomes: body mass index, eating disorder symptoms, daily life functioning, anxiety, depression, emotions, self-rated silhouette. RESULTS: Cognitive flexibility was improved during treatment, and enhanced cognitive flexibility explains a significant part of level of the improvement in daily life functioning (26%), reduction of eating disorder symptoms (18%) and reduction of depressive symptoms (17%). Others outcomes were also improved, but these improvements were not mediated by cognitive flexibility. CONCLUSIONS: Results suggest that enhancing cognitive flexibility could help reduce rigid cognitive and behavioural patterns involved in AN, thus improving everyday functioning and clinical severity. Further studies combining different types of cognitive flexibility evaluation as well as neuroimaging may be necessary to better establish which of its aspects are involved in patients' improvement.

Mindfulness-based cognitive therapy efficacy in reducing physiological response to emotional stimuli in patients with bipolar I disorder and the intermediate role of cognitive reactivity.

OBJECTIVES: This study aims to investigate the impact of Mindfulness-Based Cognitive Therapy (MBCT) for bipolar disorders on emotional responses by using skin conductance recording, and to investigate a mediating or predictive effect of cognitive reactivity. METHODS: Sixty-seven patients with bipolar disorder were assessed at baseline, pre-MBCT and post-MBCT. After answering inventories regarding depression and dysfunctional attitudes, they were instructed to focus on emotional pictures from the International Affective Pictures System while electrodermal recording. RESULTS: For a subgroup of patients having a significant change of the electrodermal response, MBCT reduced dysfunctional attitudes and the amplitude of the physiological response to negative stimuli. Findings also show that lower dysfunctional attitudes at baseline predicted a larger reduction of physiological reactivity. CONCLUSIONS: MBCT could decrease patient's reactivity to negative stimuli by decreasing its physiological component, which is coherent with its aim to facilitate disengaging from affective stimuli. Further studies are needed to better understand the mechanisms involved and how this could translate in reducing the risk of relapse.

Lower leptin level at discharge in acute anorexia nervosa is associated with early weight-loss.

OBJECTIVE: Predictive values of acute phase metabolic abnormalities of anorexia nervosa (AN) have seldom been studied. As early postrestoration weight loss is associated with poor outcome, discharge biologic parameters were assessed to detect an association with 2-month follow-up weight loss as a proxy to poor outcome. METHOD: Fasting plasma levels of leptin, acyl-ghrelin, obestatin, PYY, oxytocin and BDNF were measured in 26 inpatients, at inclusion, at discharge and 2 months later. A body mass index less than 18 2-month postdischarge was considered a poor outcome. RESULTS: Nineteen patients (73%) had a fair outcome and seven (27%) had a poor one with a mean loss of 0.69 versus 4.54 kg, respectively. Only discharge leptin levels were significantly higher in fair versus poor outcome patients (14.1 vs. 7.0 ng/ml, p = 0.006). The logistic regression model using discharge leptin, acyl-ghrelin, obestatin, oxytocin, PYY and BDNF levels as predictors of outcome disclosed a nearly significant effect of leptin (p < 0.10). Receiver operating characteristic analysis showed 11.9 ng/ml was the best value of threshold. Neither clinical variables differed according to outcome. CONCLUSION: Leptin level may be a biomarker of early weight relapse after acute inpatient treatment of AN. Its clinical usefulness in monitoring care in AN should further be determined.

Does physical activity associated with chronic food restriction alleviate anxiety like behaviour, in female mice?

Anorexia nervosa (AN) is an eating disorder characterized by excessive weight loss, persistent food restriction and inappropriate physical activity relative to declining energy balance. The comorbidity with depression and/or anxiety disorders might contribute to the "chronicization" of the disease. We aimed here to question first the link between physical activity and anxiety from a clinical investigation of AN patients (n = 206). Then, using a rodent model mimicking numerous physiological and metabolic alterations commonly seen in AN patients, we examined whether 1) chronic food restriction increased anxiety-like behaviour and 2) physical activity plays a role in regulating anxiety levels. To this end, we exposed young female mice to a chronic food restriction (FR, n = 8) paradigm combined or not with access to a running wheel (FRW, n = 8) for two weeks. The mice were compared to a group of mice fed ad libitum without (AL, n = 6) or with running wheel access (ALW, n = 8). We explored anxiety-like behaviour of all mice in the following tests: hyponeophagia, marble burying, elevated plus maze, open field, and the light and dark box. On the last day, we used a restraint test of 30 min duration and measured their stress reactivity by assaying plasma corticosterone. In the open field and the elevated plus-maze, we found that FRW mice behaved similarly to AL and ALW mice whereas FR mice did not express anxiety-like behaviour. The FRW mice displayed the lowest latency to reach the food in the hyponeophagia test. Regarding stress reactivity, FRW mice exhibited corticosterone reactivity after acute stress that was similar to the control mice, while FR mice did not fully return to basal corticosterone at one hour after the restraint stress. Taken together, these data demonstrate a differential reactivity to acute stress in FR conditions and a beneficial effect of running wheel activity in ALW and FRW conditions. Moreover, we report the absence of a typical anxiety-like behaviour associated with the food restriction (FR and FRW groups). We conclude that this model (FR and FRW mice) did not express typical anxiety-like behaviour, but that physical activity linked to food restriction improved coping strategies in an anxiogenic context.

De novo deleterious variants that may alter the dopaminergic reward pathway are associated with anorexia nervosa.

PURPOSE: Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. Up to now, four genome-wide association studies of AN have been conducted to date and identified only few significant loci. However, both previous studies focused on common variation and on rare exonic variants. Currently, de novo variants are one of the most significant risk factors for neurodevelopmental disorders and psychiatric disorders. METHODS: We analyzed by whole exome sequencing a cohort of nine female AN individuals and their parents (mother and father), and focused our analysis on de novo variants. RESULTS: Here, we found seven de novo missense variants in potential genes in nine studied AN patients. Four of these genes (CSMD1, CREB3, PTPRD and GAB1) belong to a same signaling pathway involving neuron differentiation and dopamine pathway. CONCLUSIONS: This study provides a list of interesting genes such as CSDM1 and CREB3 that are candidates to be involved in the etiology of anorexia nervosa. LEVEL OF EVIDENCE: basic research.

Exome sequencing in a familial form of anorexia nervosa supports multigenic etiology.

Anorexia nervosa (AN) is a severe debilitating eating disorder. To date, only very few genes that predispose to AN have been identified. An alternative to association studies is to characterize ultra-rare variants in familial forms of AN. Here, we have implemented this approach to identify pathways that contribute to the development of AN through the analysis of a family with three members suffering from AN by exome analysis. We identified three ultra-rare deleterious variants in three genes (DRD4, CCKAR, NMS), already connected to the reward pathway, that co-segregate with AN, suggesting that this pathway might be playing a predisposing role in AN at least in familial forms.

The value of plasma cell-free DNA levels as biomarker in patients with eating disorders: A preliminary study.

OBJECTIVE: Circulating cell-free DNA (cfDNA) holds promise as a rapid and convenient biomarker for identifying individuals with eating disorders. To investigate this hypothesis, we measured plasma cfDNA in patients with different eating disorders. METHODS: In this study, 110 participants (98 patients with eating disorders divided into 30 patients with bulimia nervosa, 33 patients with anorexia nervosa (AN) Restricting subtype, 35 patients with AN Binge-eating/purging subtype and 12 controls) were enrolled. We measured both cell-free nuclear DNA (cf-nDNA) and cell-free mitochondrial DNA (cf-mtDNA) from plasma using two specific droplet digital PCR assays each, referring to two amplicon sizes. RESULTS: Levels of plasma cf-nDNA and cf-mtDNA showed no significant differences between control participants and those with eating disorders. However, we observed a higher proportion of long cf-nDNA fragments in patients with eating disorders, suggesting its potential as a biomarker for eating disorders. CONCLUSION: This is the first study of cfDNA in patients with eating disorders. Our findings highlight the potential for qualitative exploration of cfDNA, although not of quantitative interest. Full characterization of cfDNA may serve as a valuable biomarker for eating disorders and provide some insights into the hidden mechanisms underlying the chronic development of these conditions. Future studies are needed to confirm or refute this hypothesis.

The capacity of cognitive tests to detect generalized anxiety disorder (GAD): A pilot study.

Cognitive impairment remains understudied in generalized anxiety disorder (GAD), despite the high prevalence and substantial burden associated with this disorder. We aimed to assess cognitive impairment in patients with GAD and evaluate the ability of cognitive tests to detect this disorder. Because of its high rate of comorbidity, we also examined how other anxiety disorders and current major depressive episodes affected our results. We tested 263 consecutive general practice outpatients. We used the GAD-7 and the Mini International Neuropsychiatric Interview (MINI) to detect anxiety and mood disorders. We assessed cognitive performance with the Stroop test, a facial emotion recognition test, and the trail-making test (TMT). Compared to patients without GAD, patients with GAD were significantly slower to complete the TMT(B-A) and faster to recognize emotions, especially negative ones such as disgust and anger. When controlling for other anxiety disorders and current major depressive episode, GAD retained a significant effect on the TMT(B-A), but not on the emotion recognition test. The TMT(B-A) could detect GAD with good accuracy (area under the curve (AUC) = 0.83, maximal Youden's index = 0.56), which was by no means comparable to the GAD-7 (AUC = 0.97, Youden's index = 0.81). While it is not efficient enough to replace the GAD-7 as a diagnostic tool, the capacity of the TMT(B-A) to detect GAD emphasizes the importance of cognitive flexibility impairment in GAD.

Assessing biomarkers of remission in female patients with anorexia nervosa (REMANO): a protocol for a prospective cohort study with a nested case-control study using clinical, neurocognitive, biological, genetic, epigenetic and neuroimaging markers in a French specialised inpatient unit.

BACKGROUND: Anorexia nervosa (AN) is a severe psychiatric disorder associated with frequent relapses and variability in treatment responses. Previous literature suggested that such variability is influenced by premorbid vulnerabilities such as abnormalities of the reward system. Several factors may indicate these vulnerabilities, such as neurocognitive markers (tendency to favour delayed reward, poor cognitive flexibility, abnormal decision process), genetic and epigenetic markers, biological and hormonal markers, and physiological markers.The present study will aim to identify markers that can predict body mass index (BMI) stability 6 months after discharge. The secondary aim of this study will be focused on characterising the biological, genetic, epigenetic and neurocognitive markers of remission in AN. METHODS AND ANALYSIS: One hundred and twenty-five (n=125) female adult inpatients diagnosed with AN will be recruited and evaluated at three different times: at the beginning of hospitalisation, when discharged and 6 months later. Depending on the BMI at the third visit, patients will be split into two groups: stable remission (BMI≥18.5 kg/m²) or unstable remission (BMI<18.5 kg/m²). One hundred (n=100) volunteers will be included as healthy controls.Each visit will consist in self-reported inventories (measuring depression, anxiety, suicidal thoughts and feelings, eating disorders symptoms, exercise addiction and the presence of comorbidities), neurocognitive tasks (Delay Discounting Task, Trail-Making Test, Brixton Test and Slip-of-action Task), the collection of blood samples, the repeated collection of blood samples around a standard meal and MRI scans at rest and while resolving a delay discounting task.Analyses will mainly consist in comparing patients stabilised 6 months later and patients who relapsed during these 6 months. ETHICS AND DISSEMINATION: Investigators will ask all participants to give written informed consent prior to participation, and all data will be recorded anonymously. The study will be conducted according to ethics recommendations from the Helsinki declaration (World Medical Association, 2013). It was registered on clinicaltrials.gov on 25 August 2020 as 'Remission Factors in Anorexia Nervosa (REMANO)', with the identifier NCT04560517 (for more details, see https://clinicaltrials.gov/ct2/show/record/NCT04560517). The present article is based on the latest protocol version from 29 November 2019. The sponsor, Institut National de la Santé Et de la Recherche Médicale (INSERM, https://www.inserm.fr/), is an academic institution responsible for the monitoring of the study, with an audit planned on a yearly basis.The results will be published after final analysis in the form of scientific articles in peer-reviewed journals and may be presented at national and international conferences. TRIAL REGISTRATION NUMBER: clinicaltrials.govNCT04560517.

The human VGLUT3-pT8I mutation elicits uneven striatal DA signaling, food or drug maladaptive consumption in male mice.

Cholinergic striatal interneurons (ChIs) express the vesicular glutamate transporter 3 (VGLUT3) which allows them to regulate the striatal network with glutamate and acetylcholine (ACh). In addition, VGLUT3-dependent glutamate increases ACh vesicular stores through vesicular synergy. A missense polymorphism, VGLUT3-p.T8I, was identified in patients with substance use disorders (SUDs) and eating disorders (EDs). A mouse line was generated to understand the neurochemical and behavioral impact of the p.T8I variant. In VGLUT3T8I/T8I male mice, glutamate signaling was unchanged but vesicular synergy and ACh release were blunted. Mutant male mice exhibited a reduced DA release in the dorsomedial striatum but not in the dorsolateral striatum, facilitating habit formation and exacerbating maladaptive use of drug or food. Increasing ACh tone with donepezil reversed the self-starvation phenotype observed in VGLUT3T8I/T8I male mice. Our study suggests that unbalanced dopaminergic transmission in the dorsal striatum could be a common mechanism between SUDs and EDs.