Lauren Breithaupt

Purpose: Anorexia nervosa (AN) is associated with significant changes in bone density and microstructure. However, the extent and nature of skeletal recovery following weight restoration is unclear. The aim of this study was to investigate these changes in bone during simulated AN in rats across short- and long-term recovery. Methods: Female Sprague Dawley rats were exposed to 50-60% food restriction for 30 days to simulate AN, followed by recovery periods of 5, 15, and 30 days. Bone parameters were assessed longitudinally using peripheral quantitative computed tomography (pQCT) and micro-computed tomography (µCT). Bodyweight and muscle strength were correlated with bone parameters. Results: AN resulted in significant reductions in total and trabecular bone density, as well as impairments in cortical and trabecular microarchitecture. Even with weight restoration, these deficits persisted and the compensatory responses were not sufficient for bone recovery. Bodyweight showed an association with total and trabecular bone density. Measures of muscle strength also correlated with total and trabecular density and were additive in multiple regression analysis prediction of total and trabecular bone density when combined with bodyweight. Conclusion: Recovery from AN-induced bone disorders is incomplete even after weight restoration and likely requires targeted interventions beyond nutritional rehabilitation. Furthermore, muscle function is an important predictor of bone health when combined with bodyweight.

Objective: To characterise the clinical and phenotypic profile of the Comprehensive Risk Evaluation for Anorexia nervosa in Twins (CREAT) cohort, identify candidate risk and illness‐related correlates of AN, and establish a foundation for forthcoming biological, neuroimaging, endocrinological, and microbiota studies. Methods: MZ twins discordant for lifetime AN (44 individuals) and control MZ twin pairs (42 individuals) were recruited. Analyses included total‐sample associations with AN, between‐group comparisons (affected, unaffected co‐twins, controls), and within‐pair analyses of discordant twins. Results: Affected twins, most of whom were weight‐restored and non‐acute, differed markedly from unaffected co‐twins and controls. Lifetime AN was associated with higher perfectionism, goal‐directed drive, neuroticism, behavioural inhibition, impulsivity, broader psychiatric symptoms, teasing history, autism symptoms, and lower quality of life. Within‐pair analyses implicated perfectionism, goal‐directed drive, and competency‐related teasing as candidate individual‐specific risk factors for AN, with evidence of additional associations with impulsivity, behavioural inhibition, neuroticism, broader psychiatric symptoms, and autism symptoms. Conclusion: Findings support a multifactorial model of AN involving individual‐specific influences and shared familial liability. Perfectionism, goal‐directed drive, and competency‐related teasing emerged as candidate individual‐specific risk factors, while the pattern of elevations, with unaffected co‐twins often falling between affected twins and healthy controls, suggests that several clinical and phenotypic features may reflect familial liability for AN.

Objective: Avoidant/restrictive food intake disorder (ARFID) is an eating disorder characterized by persistent avoidant/restrictive eating unrelated to body image. Sex differences in clinical phenotypes and neurobiology of ARFID are understudied. We hypothesized that females with ARFID would have a greater frequency of the lack of interest and fear of aversive consequences phenotypes, higher levels of anorexigenic hormones, and greater fMRI activation in brain regions associated with cognitive control during a food cue paradigm. We further hypothesized that males with ARFID would have a greater frequency of the sensory sensitivity profile, higher levels of orexigenic hormones, and greater fMRI activation in reward processing brain regions. Method: We recruited 96 children and adolescents with ARFID and sub‐threshold ARFID (49% female) from two studies on the neurobiology of ARFID and low weight eating disorders from 2016 to 2022. We analyzed ARFID clinical phenotypes; appetite‐regulating hormones, ghrelin, cholecystokinin (CCK), peptide YY (PYY), and oxytocin; and fMRI activation of cognitive control and reward‐related brain regions during a food cue paradigm using frequentist and Bayesian statistical analysis. Results: Contrary to our hypothesis, there were no sex differences in frequency of ARFID clinical phenotypes, appetite‐regulating hormone levels, or brain activation. Conclusions: This is the first study to provide empirical evidence that ARFID has a similar clinical and neurobiological presentation in males and females.

Objective: Cognitive‐behavioural therapy (CBT) for eating disorders (EDs) has raised concerns of appropriateness for patients in higher‐weight bodies. We evaluated acceptability (Sample 1—United States [USA]) and effectiveness (Sample 1—USA, Sample 2—United Kingdom [UK]) of CBT‐T by body mass index [BMI] category. We hypothesised that individuals with BMI ≥ 30 kg/m ² would be more likely to drop out and show smaller symptom reductions compared to participants with BMI < 30 kg/m ² . Methods: Participants with non‐underweight EDs (USA: n = 63; UK: n = 58) received CBT‐T and completed the ED‐15 to evaluate change in behaviours (objective binge eating, purging, restriction, excessive exercise) and cognitions (Eating Concern, Weight/Shape Concern, Global Score). Results: Contrary to hypotheses, CBT‐T completion did not differ by BMI category. Participants demonstrated large and significant reductions in binge eating, excessive exercise, and ED cognitions, with no significant differences by BMI (USA, UK). Although the BMI ≥ 30 kg/m ² group demonstrated significantly smaller reductions in restriction and purging (UK only), smaller reductions in the higher‐weight group were fully explained by their significantly lower pre‐treatment symptoms. Discussion: Results from this exploratory multisite study found no evidence that CBT‐T was less acceptable or effective for participants in higher‐weight bodies.

Objective: Avoidant/restrictive food intake disorder (ARFID) is characterized by limited dietary volume and/or variety due to fear of aversive consequences, lack of interest in eating, and/or sensory sensitivity. Uncontrolled studies suggest that cognitive‐behavioral therapy for ARFID (CBT‐AR) is beneficial, but neural mechanisms remain unknown. Prior work has shown hyperactivation in regions of the salience network (SN) during the presentation of food stimuli in ARFID compared to healthy controls, and the SN shows reduction from pre‐ to post‐CBT in anxiety disorders. We tested hypotheses that (1) higher pre‐treatment food‐related activation in the SN (anterior cingulate cortex [ACC], anterior insula, amygdala) would be prospectively associated with greater reductions in ARFID severity at post‐treatment, and (2) food‐related activation in the SN would decrease from pre‐ to post‐treatment. Method: In a validated functional magnetic resonance imaging (fMRI) food cue paradigm, youth with ARFID viewed images of food and non‐food in a fasted state at pre‐treatment ( N = 24) and a subset ( N = 14) also completed post‐treatment scans. Results: Pre‐treatment activation in response to food versus objects was not associated with changes in ARFID severity or remission post‐treatment. However, hyperactivation in the right ACC (MNI coordinates: 3, 53, 17; k ( E ) = 579, p (FWE _corr ) = 0.013) decreased from pre‐ to post‐treatment with a large effect size ( d = 1.1). Conclusion: These pilot findings raise the possibility that changes in SN neural activity may be candidate mechanisms through which CBT‐AR exerts its effects. Randomized controlled trials are needed to replicate and extend these results. Trial Registration: ClinicalTrials.gov identifier: NCT02963220

Objective: Avoidant/restrictive food intake disorder (ARFID) involves restrictive eating driven by sensory sensitivity, low interest in food, or fear of negative consequences of eating. ARFID affects males and females equally and presents across the weight spectrum. Leptin, an anorexigenic hormone linked to adiposity, may contribute to low hunger and early satiety in ARFID. Prior findings indicate low leptin levels in low‐weight females with ARFID; however, the role of leptin in ARFID across weight status and sex remains unknown. We hypothesized that youth with full/subthreshold ARFID, including a subgroup of low‐weight males, would exhibit lower fasting leptin levels than healthy controls (HCs). We explored cross‐sectional and longitudinal associations between leptin and clinical characteristics. Method: Participants were youth aged 10–23 years (BMI percentile M [SD] = 41.4 (33.6)) with full/subthreshold ARFID ( n = 95; 49.5% female) and HCs ( n = 28; 50.0% female). At baseline, participants completed questionnaires, a fasted blood draw, and a diagnostic interview for ARFID, readministered at 1‐ and 2year follow‐ups. Results: Leptin levels did not differ between ARFID and HC groups. Low‐weight ARFID males had significantly lower leptin than HC males ( η ² = 0.258); however, this difference was nonsignificant after adjusting for BMI percentile. Leptin showed medium‐to‐large positive associations with age, BMI, and anxiety but not appetite or ARFID severity. Baseline leptin did not predict symptom or weight changes longitudinally. Discussion: Hypoleptinemia was only evident in low‐weight ARIFD and strongly correlated with BMI percentile. However, relationships with anxiety may suggest additional roles of leptin in underlying ARFID psychopathology. Findings should be replicated in larger, more representative samples.

Background: Avoidant/restrictive food intake disorder (ARFID) leads to faltering growth and psychosocial impairment. Three phenotypes can co-occur: fear of aversive consequences of eating ( ARFID-fear phenotype), sensory sensitivity, and lack of interest in eating/food. We hypothesized that youth with ARFID, especially ARFID-fear phenotype, would show hyperactivation of fear-related regions in response to ARFID-specific fear images, compared to healthy controls (HC), and activation of these regions would positively correlate with ARFID fear severity. Methods: Youth (N=103: 76 ARFID, including 20 ARFID-fear phenotype; 27 HC) underwent functional MRI scanning while viewing ARFID-specific fear (e.g. vomiting, choking) versus neutral images. We compared blood-oxygen-level-dependent (BOLD) response in fear-related region of interests (ROI; e.g. amygdala, hippocampus, insula) between ARFID and ARFID-fear phenotype versus HC. We evaluated the association between brain response and ARFID fear severity in ARFID-fear phenotype. Results: Across individuals, there was a robust bilateral amygdala response to ARFID-specific fear versus neutral images. Compared to HC, ARFID-fear phenotype showed a greater insula response to ARFID-specific fear versus neutral images (p=0.049). There were no other group differences and no significant relationships between BOLD response and ARFID fear severity in ARFID-fear phenotype. Conclusions: ARFID-specific fear images elicit amygdala responses across individuals, with greater activation in the insula only in ARFID-fear phenotype versus HC. These findings validate the ARFID-specific fear paradigm and highlight the intriguing possibility that, in the ARFID-fear phenotype, universally feared experiences such as choking and vomiting serve as the unconditioned stimulus in developing ARFID and may partially be mediated by the insular cortex.

Objective: Restrictive eating disorders (EDs), including anorexia nervosa (AN) and atypical AN (Atyp‐AN), are often associated with cognitive rigidity that can impede treatment. The dorsolateral prefrontal cortex (dlPFC) plays a central role in cognitive control, but it remains unclear whether its activation during cognitive flexibility will differ across restrictive ED presentations. Method: Eighty‐seven females with restrictive EDs (aged 14–35) (AN: n = 31; atyp‐AN with history of AN [hx‐AN]: n = 33; atyp‐AN without history of AN [Atyp‐AN]: n = 23) completed a task‐switching paradigm during functional magnetic resonance imaging. We examined dlPFC activation during sustained (task‐switching vs. completing a single task) and transient control (switching between task rules vs. repeating the same rule), testing for group differences and symptom associations. Results: The AN group showed a greater difference in left dlPFC activation during task switching vs. the single task compared to the hx‐AN and Atyp‐AN groups, driven by reduced activation during the single task condition. All groups showed similar increases in dlPFC activation during task switching and no differences in task performance. Across all participants, higher dlPFC activation during task switching vs. single task was associated with greater restraint symptoms. Discussion: These novel findings identified shared versus unique neural features of sustained and transient control across restrictive ED groups. Heightened dlPFC activation during transient control associated with restraint may represent a transdiagnostic feature shared across restrictive EDs. Alternatively, reduced dlPFC activation during the low‐demand, single‐task condition in those with typical, but not atypical AN, may reflect a difference in sustained control, with implications for tailoring interventions to distinct restrictive ED presentations.

Anorexia nervosa (AN) is a psychiatric disorder characterized by severe caloric restriction, leading to health complications. In addition to fat loss, AN also results in profound skeletal muscle loss, yet molecular pathways underlying these musculoskeletal complications or how long-lasting these musculoskeletal consequences may be are currently unknown. The purpose of this study was to investigate the effects of AN and subsequent weight recovery on muscle strength, size, and moderators of protein turnover in a rat model of AN. Female Sprague Dawley rats (n=11/group, 8 weeks of age) underwent 30 days of simulated AN (50-60% food restriction) followed by varying recovery periods. Muscle mass, strength, and protein synthesis/degradation pathways were assessed. AN led to substantial reductions in muscle mass and strength. While muscle mass recovered within 30 days, muscle strength remained depressed in rats with a prior history of AN, suggesting alterations to muscle quality. Moreover, moderators of protein synthesis (Igf1, Redd1, Deptor) remained altered following 30 days of AN and subsequent recovery. These findings suggest muscle impairments in AN may be longer-lasting than previously thought and may contribute to increased health complications and reduced quality of life in those with a history of AN.