Course of avoidant/restrictive food intake disorder: Emergence of overvaluation of shape/weight.

BACKGROUND: Avoidant/restrictive food intake disorder (ARFID) is a feeding/eating disorder characterized by avoidance/restriction of food intake by volume and/or variety. The emergence of shape/weight-related eating disorder symptoms in the longitudinal course of ARFID is an important clinical phenomenon that is neither robustly documented nor well understood. We aimed to characterize the emergence of eating disorder symptoms among adults with an initial diagnosis of ARFID who ultimately developed other eating disorders. METHOD: Thirty-five participants (94% female; Mage = 23.17 ± 5.84 years) with a history of ARFID and a later, separate eating disorder completed clinical interviews (i.e., Structured Clinical Interview for DSM-5 - Research Version and Longitudinal Interval Follow-Up Evaluation) assessing the period between ARFID and the later eating disorder. Participants used calendars to aid in recall of symptoms over time. Descriptive statistics characterized the presence, order of, and time to each symptom. Paired samples t-tests compared weeks to emergence between symptoms. RESULTS: Most participants (71%) developed restricting eating disorders; the remainder (29%) developed binge-spectrum eating disorders. Cognitive symptoms (e.g., shape/weight concerns) tended to onset initially and were followed by behavioral symptoms. Shape/weight-related food avoidance presented first, objective binge eating, fasting, and excessive exercise occurred next, followed by subjective binge eating and purging. CONCLUSIONS: Diagnostic crossover from ARFID to another (typically restricting) eating disorder following the development of shape/weight concerns may represent the natural progression of a singular clinical phenomenon. Findings identify potential pathways from ARFID to the development of another eating disorder, highlighting possible clinical targets for preventing this outcome.

Prospective 2-Year Course and Predictors of Outcome in Avoidant/Restrictive Food Intake Disorder.

OBJECTIVE: To evaluate the 2-year course and outcomes of full and subthreshold avoidant/restrictive food intake disorder (ARFID) in youth aged 9 to 23 at baseline using a prospective longitudinal design to characterize the remission and persistence of ARFID, evaluate diagnostic crossover, and identify predictors of outcome. Greater severity in each ARFID profile-sensory sensitivity, fear of aversive consequences, and lack of interest-was hypothesized to predict greater likelihood of illness persistence, controlling for age, sex, body mass index percentile, ARFID treatment status, and baseline diagnosis. METHOD: Participants (N = 100; age range, 9-23 years; 49% female; 91% White) were followed over 2 years. The Pica, ARFID, and Rumination Disorder Interview was used across 3 time points (baseline, year 1, year 2) to measure the severity of each ARFID profile and evaluate illness persistence or remission, and the Eating Disorder Assessment for DSM-5 was used to evaluate diagnostic crossover. RESULTS: Across the 2-year follow-up period, half the participants persisted with their original diagnosis, and 3% of participants experienced a diagnostic shift to anorexia nervosa. Greater severity in the sensory sensitivity and lack of interest profiles was associated with higher likelihood of ARFID persistence at year 1 only; greater severity in the fear of aversive consequences profile was associated with higher likelihood of ARFID remission at year 2 only. CONCLUSION: Findings underscore the distinctiveness of ARFID from other eating disorders and emphasize its persistence over 2 years. Results also highlight the predictive validity and prognostic value of ARFID profiles (ie, sensory sensitivity, fear of aversive consequences, lack of interest).

Intranasal Oxytocin for Obesity.

BACKGROUND: Accumulating preclinical and preliminary translational evidence shows that the hypothalamic peptide oxytocin reduces food intake, increases energy expenditure, and promotes weight loss. It is currently unknown whether oxytocin administration is effective in treating human obesity. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned adults with obesity 1:1 (stratified by sex and obesity class) to receive intranasal oxytocin (24 IU) or placebo four times daily for 8 weeks. The primary end point was change in body weight (kg) from baseline to week 8. Key secondary end points included change in body composition (total fat mass [g], abdominal visceral adipose tissue [cm2], and liver fat fraction [proportion; range, 0 to 1; higher values indicate a higher proportion of fat]), and resting energy expenditure (kcal/day; adjusted for lean mass) from baseline to week 8 and caloric intake (kcal) at an experimental test meal from baseline to week 6. RESULTS: Sixty-one participants (54% women; mean age ± standard deviation, 33.6 ± 6.2 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 36.9 ± 4.9) were randomly assigned. There was no difference in body weight change from baseline to week 8 between oxytocin and placebo groups (0.20 vs. 0.26 kg; P=0.934). Oxytocin (vs. placebo) was not associated with beneficial effects on body composition or resting energy expenditure from baseline to week 8 (total fat: difference [95% confidence interval], 196.0 g [-1036 to 1428]; visceral fat: 3.1 cm2 [-11.0 to 17.2]; liver fat: -0.01 [-0.03 to 0.01]; resting energy expenditure: -64.0 kcal/day [-129.3 to 1.4]). Oxytocin compared with placebo was associated with reduced caloric intake at the test meal (-31.4 vs. 120.6 kcal; difference [95% confidence interval], -152.0 kcal [-302.3 to -1.7]). There were no serious adverse events. Incidence and severity of adverse events did not differ between groups. CONCLUSIONS: In this randomized, placebo-controlled trial in adults with obesity, intranasal oxytocin administered four times daily for 8 weeks did not reduce body weight. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT03043053.).

Latent profile analysis reveals overlapping ARFID and shape/weight motivations for restriction in eating disorders.

BACKGROUND: DSM-5 differentiates avoidant/restrictive food intake disorder (ARFID) from other eating disorders (EDs) by a lack of overvaluation of body weight/shape driving restrictive eating. However, clinical observations and research demonstrate ARFID and shape/weight motivations sometimes co-occur. To inform classification, we: (1) derived profiles underlying restriction motivation and examined their validity and (2) described diagnostic characterizations of individuals in each profile to explore whether findings support current diagnostic schemes. We expected, consistent with DSM-5, that profiles would comprise individuals endorsing solely ARFID or restraint (i.e. trying to eat less to control shape/weight) motivations. METHODS: We applied latent profile analysis to 202 treatment-seeking individuals (ages 10-79 years [M = 26, s.d. = 14], 76% female) with ARFID or a non-ARFID ED, using the Nine-Item ARFID Screen (Picky, Appetite, and Fear subscales) and the Eating Disorder Examination-Questionnaire Restraint subscale as indicators. RESULTS: A 5-profile solution emerged: Restraint/ARFID-Mixed (n = 24; 8% [n = 2] with ARFID diagnosis); ARFID-2 (with Picky/Appetite; n = 56; 82% ARFID); ARFID-3 (with Picky/Appetite/Fear; n = 40; 68% ARFID); Restraint (n = 45; 11% ARFID); and Non-Endorsers (n = 37; 2% ARFID). Two profiles comprised individuals endorsing solely ARFID motivations (ARFID-2, ARFID-3) and one comprising solely restraint motivations (Restraint), consistent with DSM-5. However, Restraint/ARFID-Mixed (92% non-ARFID ED diagnoses, comprising 18% of those with non-ARFID ED diagnoses in the full sample) endorsed ARFID and restraint motivations. CONCLUSIONS: The heterogeneous profiles identified suggest ARFID and restraint motivations for dietary restriction may overlap somewhat and that individuals with non-ARFID EDs can also endorse high ARFID symptoms. Future research should clarify diagnostic boundaries between ARFID and non-ARFID EDs.

Lower region-specific gray matter volume in females with atypical anorexia nervosa and anorexia nervosa.

OBJECTIVE: Few studies have focused on brain structure in atypical anorexia nervosa (atypical AN). This study investigates differences in gray matter volume (GMV) between females with anorexia nervosa (AN) and atypical AN, and healthy controls (HC). METHOD: Structural magnetic resonance imaging data were acquired for 37 AN, 23 atypical AN, and 41 HC female participants. Freesurfer was used to extract GMV, cortical thickness, and surface area for six brain lobes and associated cortical regions of interest (ROI). Primary analyses employed linear mixed-effects models to compare group differences in lobar GMV, followed by secondary analyses on ROIs within significant lobes. We also explored relationships between cortical gray matter and both body mass index (BMI) and symptom severity. RESULTS: Our primary analyses revealed significant lower GMV in frontal, temporal and parietal areas (FDR < .05) in AN and atypical AN when compared to HC. Lobar GMV comparisons were non-significant between atypical AN and AN. The parietal lobe exhibited the greatest proportion of affected cortical ROIs in both AN versus HC and atypical AN versus HC. BMI, but not symptom severity, was found to be associated with cortical GMV in the parietal, frontal, temporal, and cingulate lobes. No significant differences were observed in cortical thickness or surface area. DISCUSSION: We observed lower GMV in frontal, temporal, and parietal areas, when compared to HC, but no differences between AN and atypical AN. This indicates potentially overlapping structural phenotypes between these disorders and evidence of brain changes among those who are not below the clinical underweight threshold. PUBLIC SIGNIFICANCE: Despite individuals with atypical anorexia nervosa presenting above the clinical weight threshold, lower cortical gray matter volume was observed in partial, temporal, and frontal cortices, compared to healthy individuals. No significant differences were found in cortical gray matter volume between anorexia nervosa and atypical anorexia nervosa. This underscores the importance of continuing to assess and target weight gain in clinical care, even for those who are presenting above the low-weight clinical criteria.

Cognitive-behavioral therapy for avoidant/restrictive food intake disorder: A proof-of-concept for mechanisms of change and target engagement.

BACKGROUND: Cognitive-behavioral therapy for avoidant/restrictive food intake disorder (ARFID; CBT-AR) theoretically targets three prototypic motivations (sensory sensitivity, lack of interest/low appetite, fear of aversive consequences), aligned with three modularized interventions. As an exploratory investigation, we: (1) evaluated change in candidate mechanisms in relationship to change in ARFID severity, and (2) tested if assignment (vs. not) to a module resulted in larger improvements in the corresponding mechanism. METHOD: Males and females (N = 42; 10-55 years) participated in an open trial of CBT-AR. RESULTS: Decreases in scaled scores for each candidate mechanism had medium to large correlations with decreases in ARFID severity-sensory sensitivity: -0.7 decrease (r = .42, p = .01); lack of interest/low appetite: -0.3 decrease (r = .60, p < .0001); and fear of aversive consequences: -1.1 decrease (r = .33, p = .05). Linear mixed models revealed significant weekly improvements for each candidate mechanism across the full sample (ps < .0001). There were significant interactions for the sensory and fear of aversive consequences modules-for each, participants who received the corresponding module had significantly larger decreases in the candidate mechanism than those who did not receive the module. DISCUSSION: Sensory sensitivity and fear of aversive consequences improved more if the CBT-AR module was received, but lack of interest/low appetite may improve regardless of receipt of the corresponding module. Future research is needed to test target engagement in CBT-AR with adaptive treatment designs, and to identify valid and sensitive measures of candidate mechanisms. PUBLIC SIGNIFICANCE: The mechanisms through which components of CBT-AR work have yet to be elucidated. We conducted an exploratory investigation to test if assignment (vs. not) to a CBT-AR module resulted in larger improvements in the corresponding prototypic ARFID motivation that the module intended to target. Measures of the sensory sensitivity and the fear of aversive consequences motivations improved more in those who received the corresponding treatment module, whereas the lack of interest/low appetite measure improved regardless of if the corresponding module was received.

Avoidant/restrictive food intake disorder differs from anorexia nervosa in delay discounting.

BACKGROUND: Avoidant/restrictive food intake disorder (ARFID) and anorexia nervosa (AN) are the two primary restrictive eating disorders; however, they are driven by differing motives for inadequate dietary intake. Despite overlap in restrictive eating behaviors and subsequent malnutrition, it remains unknown if ARFID and AN also share commonalities in their cognitive profiles, with cognitive alterations being a key identifier of AN. Discounting the present value of future outcomes with increasing delay to their expected receipt represents a core cognitive process guiding human decision-making. A hallmark cognitive characteristic of individuals with AN (vs. healthy controls [HC]) is reduced discounting of future outcomes, resulting in reduced impulsivity and higher likelihood of favoring delayed gratification. Whether individuals with ARFID display a similar reduction in delay discounting as those with AN (vs. an opposing bias towards increased delay discounting or no bias) is important in informing transdiagnostic versus disorder-specific cognitive characteristics and optimizing future intervention strategies. METHOD: To address this research question, 104 participants (ARFID: n = 57, AN: n = 28, HC: n = 19) completed a computerized Delay Discounting Task. Groups were compared by their delay discounting parameter (ln)k. RESULTS: Individuals with ARFID displayed a larger delay discounting parameter than those with AN, indicating steeper delay discounting (M ± SD = -6.10 ± 2.00 vs. -7.26 ± 1.73, p = 0.026 [age-adjusted], Hedges' g = 0.59), with no difference from HC (p = 0.514, Hedges' g = -0.35). CONCLUSION: Our findings provide a first indication of distinct cognitive profiles among the two primary restrictive eating disorders. The present results, together with future research spanning additional cognitive domains and including larger and more diverse samples of individuals with ARFID (vs. AN), will contribute to identifying maintenance mechanisms that are unique to each disorder as well as contribute to the optimization and tailoring of treatment strategies across the spectrum of restrictive eating disorders.

Avoidant/restrictive food intake disorder (ARFID) and anorexia nervosa (AN) are both restrictive eating disorders. However, the reasons for restricting food intake differ between the two diagnoses. A key question in further understanding similarities and differences between ARFID and AN is to understand whether individuals with these disorders process information and make decisions in similar or distinct ways. When humans decide between two different outcomes (e.g., a smaller immediate or a larger delayed reward), outcomes decrease in their value the farther in the future we expect to receive them (delay discounting). Individuals with AN exhibit a reduced discounting of future outcomes, which makes them more likely to forego immediate gratification for later rewards. However, whether this holds true for individuals with ARFID too (or whether they show the opposite or no bias) is unknown. Our investigation is the first to compare delay discounting between individuals with ARFID, AN, and healthy controls (HC). Our results show that individuals with ARFID show more delay discounting than those with AN, with no difference from HC. Knowing how rewards are being chosen and decisions made (and knowing differences between diagnoses) will be helpful in further optimizing and tailoring treatments for restrictive eating disorders.

Deficits in volumetric bone mineral density, bone microarchitecture, and estimated bone strength in women with atypical anorexia nervosa compared to healthy controls.

OBJECTIVE: Anorexia nervosa is associated with low bone mineral density (BMD) and deficits in bone microarchitecture and strength. Low BMD is common in atypical anorexia nervosa, in which criteria for anorexia nervosa are met except for low weight. We investigated whether women with atypical anorexia nervosa have deficits in bone microarchitecture and estimated strength at the peripheral skeleton. METHOD: Measures of BMD and microarchitecture were obtained in 28 women with atypical anorexia nervosa and 27 controls, aged 21-46 years. RESULTS: Mean tibial volumetric BMD, cortical thickness, and failure load were lower, and radial trabecular number and separation impaired, in atypical anorexia nervosa versus controls (p < .05). Adjusting for weight, deficits in tibial cortical bone variables persisted (p < .05). Women with atypical anorexia nervosa and amenorrhea had lower volumetric BMD and deficits in microarchitecture and failure load versus those with eumenorrhea and controls. Those with a history of overweight/obesity or fracture had deficits in bone microarchitecture versus controls. Tibial deficits were particularly marked. Less lean mass and longer disease duration were associated with deficits in high-resolution peripheral quantitative computed tomography (HR-pQCT) variables in atypical anorexia nervosa. DISCUSSION: Women with atypical anorexia nervosa have lower volumetric BMD and deficits in bone microarchitecture and strength at the peripheral skeleton versus controls, independent of weight, and particularly at the tibia. Women with atypical anorexia nervosa and amenorrhea, less lean mass, longer disease duration, history of overweight/obesity, or fracture history may be at higher risk. This is salient as deficits in HR-pQCT variables are associated with increased fracture risk. PUBLIC SIGNIFICANCE: Atypical anorexia nervosa is a psychiatric disorder in which psychological criteria for anorexia nervosa are met despite weight being in the normal range. We demonstrate that despite weight in the normal range, women with atypical anorexia nervosa have impaired bone density, structure, and strength compared to healthy controls. Whether this translates to an increased risk of incident fracture in this population requires further investigation.

Anticipatory and consummatory pleasure in avoidant/restrictive food intake disorder.

BACKGROUND: Recent research suggests that individuals with eating disorders (EDs) report elevated anhedonia, or loss of pleasure. Although individuals with avoidant/restrictive food intake disorder (ARFID) often express that they do not look forward to eating, it is unclear whether they experience lower pleasure than those without EDs. Thus, identifying whether individuals with ARFID experience anhedonia may yield important insights that inform clinical conceptualization and treatment. METHODS: A sample of 71 participants ages 10-23 with full and subthreshold ARFID and 33 healthy controls (HCs) completed the Pica, ARFID, and Rumination Disorder Interview, a diagnostic interview to assess ARFID profile severity (lack of interest in food, sensory sensitivity, fear of aversive consequences) and the Temporal Experience of Pleasure Scale (TEPS), a self-report measure of consummatory and anticipatory pleasure. Statistical analyses were performed using the full TEPS and also the TEPS with food-related items removed. RESULTS: The ARFID group reported significantly lower anticipatory and consummatory pleasure compared to HCs, but these differences were no longer significant after controlling for depression, nor after removing food items from the TEPS. Within the ARFID sample, greater ARFID severity was associated with lower anticipatory pleasure across analyses, and greater endorsement of the lack of interest in food profile was related to lower anticipatory pleasure. ARFID severity was also associated with lower consummatory pleasure using the full TEPS, but this relationship was no longer significant with food items removed. CONCLUSIONS: These results provide initial evidence for lower pleasure before potentially pleasurable events in individuals with more severe ARFID, particularly those with the lack of interest phenotype. Our findings also suggest that depression is likely to contribute low pleasure in this population. Future research should seek to further characterize how dimensions of pleasure relate to the maintenance and treatment of ARFID symptoms.

Individuals with eating disorders often report elevated anhedonia, or an inability to experience pleasure. Past research on pleasure in eating disorders has focused primarily on individuals with anorexia nervosa and bulimia nervosa, and it is unclear whether people with other eating disorders also experience lower pleasure than healthy individuals. In the current study, we measured anticipatory pleasure (looking forward to something enjoyable) and consummatory pleasure (enjoying a pleasant stimulus) in a sample with avoidant/restrictive food intake disorder (ARFID) and healthy controls. We also repeated our analyses after removing food-related items from the scale assessing pleasure. The ARFID group scored lower on both dimensions of pleasure than controls, but this difference was primarily due to greater depression symptoms and the presence of food-related items in the pleasure questionnaire. Within the ARFID sample, individuals with more severe ARFID reported less anticipatory pleasure, even after removing questions about enjoyment of food. Lower anticipatory pleasure was especially characteristic of the lack of interest in eating phenotype of ARFID. These results suggest that ARFID severity, lack of interest in eating, and depression contribute to low pleasure in this population.

Bone Density, Geometry, Structure and Strength Estimates in Adolescent and Young Adult Women with Atypical Anorexia Nervosa versus Typical Anorexia Nervosa and Normal-Weight Healthy Controls.

Our objective was to characterize bone outcomes in adolescent and young adult women with atypical anorexia nervosa (AAN) compared to typical AN and normal-weight healthy controls (HC) based on DSM-5 criteria. Four hundred thirty-two participants (141 AN, 131 AAN and 160 HC), ages 12-21 years, underwent dual-energy X-ray absorptiometry for areal BMD, and a subset had high-resolution peripheral quantitative CT assessment of the distal radius and tibia for volumetric BMD (vBMD), bone geometry and microarchitecture, and microfinite element analysis for estimated strength. The groups did not differ for age, pubertal stage, menarcheal age or physical activity. BMI and bone outcomes overall were intermediate in AAN compared with AN and HC. This applied to spine, total hip and femoral neck BMD measures and many distal tibial measures. However, the mean whole-body less head BMD Z-score did not differ between AAN and AN, and it was lower in both vs. HC. Similarly, many distal radius measures did not differ between AAN vs. AN or HC but were lower in AN than HC. Lower BMI, lean mass and bone age, older menarcheal age and longer illness duration correlated with greater impairment of bone outcomes. These data indicate that individuals with AAN overall have bone outcomes that are intermediate between AN and HC.

Identification of State Markers in Anorexia Nervosa: Replication and Extension of Inflammation Associated Biomarkers Using Multiplex Profiling in Anorexia Nervosa and Atypical Anorexia Nervosa.

Proteomics provides an opportunity for detection and monitoring of anorexia nervosa (AN) and its related variant, atypical-AN (atyp-AN). However, research to date has been limited by the small number of proteins explored, exclusive focus on adults with AN, and lack of replication across studies. This study performed Olink Proseek Multiplex profiling of 92 proteins involved in inflammation among females with AN and atyp-AN (N = 64), all < 90% of expected body weight, and age-matched healthy controls (HC; N=44). After correction for multiple testing, nine proteins differed significantly in the AN/atyp-AN group relative to HC group ( lower levels: CXCL1, HGF, IL-18R1, TNFSF14, TRANCE; higher levels: CCL23, Flt3L, LIF-R, MMP-1). The expression levels of three proteins ( lower IL-18R1, TRANCE; higher LIF-R) were uniquely disrupted in females with AN. No unique expression levels emerged for atyp-AN. Across the whole sample, twenty-one proteins correlated positively with BMI (ADA, AXIN1, CD5, CD244, CD40, CD6, CXCL1, FGF-21, HGF, IL-10RB, IL-12B, IL18, IL-18R1, IL6, LAP TGF-beta-1, SIRT2, STAMBP, TNFRSF9, TNFSF14, TRAIL, TRANCE) and six (CCL11, CCL23, FGF-19, IL8, LIF-R, OPG) were negatively correlated with BMI. Overall, our results replicate the prior study demonstrating a dysregulated inflammatory status in AN, and extend these results to atyp-AN (AN/atyp-AN all < 90% of expected body weight). Of the 27 proteins correlated with BMI, 18 were replicated from a prior study using similar methods, highlighting the promise of inflammatory protein expression levels as biomarkers of disease monitoring. Additional studies of individuals across the entire weight spectrum are needed to understand the role of inflammation in atyp-AN.

Oxytocin response to food intake in avoidant/restrictive food intake disorder.

OBJECTIVE: To investigate the response of anorexigenic oxytocin to food intake among adolescents and young adults with avoidant/restrictive food intake disorder (ARFID), a restrictive eating disorder characterized by lack of interest in food or eating, sensory sensitivity to food, and/or fear of aversive consequences of eating, compared with healthy controls (HC). DESIGN: Cross-sectional. METHODS: A total of 109 participants (54 with ARFID spectrum and 55 HC) were instructed to eat a ∼400-kcal standardized mixed meal. We sampled serum oxytocin at fasting and at 30-, 60-, and 120-min postmeal. We tested the hypothesis that ARFID would show higher mean oxytocin levels across time points compared with HC using a mixed model ANOVA. We then used multivariate regression analysis to identify the impact of clinical characteristics (sex, age, and body mass index [BMI] percentile) on oxytocin levels in individuals with ARFID. RESULTS: Participants with ARFID exhibited greater mean oxytocin levels at all time points compared with HC, and these differences remained significant even after controlling for sex and BMI percentile (P = .004). Clinical variables (sex, age, and BMI percentile) did not show any impact on fasting and postprandial oxytocin levels among individuals with ARFID. CONCLUSIONS: Consistently high oxytocin levels might be involved in low appetite and sensory aversions to food, contributing to food avoidance in individuals with ARFID.

Low bone mineral density is found in low weight female youth with avoidant/restrictive food intake disorder and associated with higher PYY levels.

BACKGROUND: Avoidant/restrictive food intake disorder (ARFID) is a restrictive eating disorder commonly associated with medical complications of undernutrition and low weight. In adolescence, a critical time for bone accrual, the impact of ARFID on bone health is uncertain. We aimed to study bone health in low-weight females with ARFID, as well as the association between peptide YY (PYY), an anorexigenic hormone with a role in regulation of bone metabolism, and bone mineral density (BMD) in these individuals. We hypothesized that BMD would be lower in low-weight females with ARFID than healthy controls (HC), and that PYY levels would be negatively associated with BMD. METHODS: We performed a cross-sectional study in 14 adolescent low-weight females with ARFID and 20 HC 10-23 years old. We assessed BMD (total body, total body less head and lumbar spine) using dual x-ray absorptiometry (DXA) and assessed fasting total PYY concentration in blood. RESULTS: Total body BMD Z-scores were significantly lower in ARFID than in HC (- 1.41 ± 0.28 vs. - 0.50 ± 0.25, p = 0.021). Mean PYY levels trended higher in ARFID vs. HC (98.18 ± 13.55 pg/ml vs. 71.40 ± 5.61 pg/ml, p = 0.055). In multivariate analysis within the ARFID group, PYY was negatively associated with lumbar BMD adjusted for age (ß = -0.481, p = 0.032). CONCLUSION: Our findings suggest that female adolescents with low-weight ARFID may have lower BMD than healthy controls and that higher PYY levels may be associated with lower BMD at some, but not all, sites in ARFID. Further research with larger samples will be important to investigate whether high PYY drives bone loss in ARFID.

Avoidant/restrictive food Intake disorder (ARFID) is a condition characterized by lack of interest in eating/food, sensory sensitivity and/or fear of aversive consequences of eating. It is associated with low weight and undernutrition, which can lead to medical complications. Specifically, low weight in patients with ARFID raises concerns of impaired bone health. In this study, we compared bone mineral density (BMD), a measure of bone health, in 14 low-weight females with ARFID and 20 healthy females 10­23 years old. We also examined the association between BMD and peptide YY (PYY), a hormone that induces satiety and inhibits bone formation. A strong negative association between bone health and PYY was previously reported in females with anorexia nervosa. Thus, we hypothesized a similar association in low weight females with ARFID. We found that BMD may be lower in low-weight females with ARFID than in healthy females and that higher PYY levels are associated with lower BMD at some but not all sites. We concluded that bone health may be a concern in low-weight females with ARFID. This finding is important as low BMD raises concerns for increased fracture risk, which in turn could have a detrimental effect on quality of life.

Depressive and anxiety symptoms, and neural correlates of reward and punishment anticipation in female athletes with amenorrhea.

Objective: Studies in estrogen deficiency states such as primary ovarian insufficiency and Turner syndrome suggest that estrogen status may be an important modulator of mood and emotions. In this study we compared depressive and anxiety symptoms between adolescent and young adult female oligo-amenorrheic athletes (AA) and eumenorrheic females (EM), and explored structural, and functional changes in related brain areas during reward processing, a behavioral construct that is altered in depression and anxiety. Methods: We included (i) 24 AA participating in ≥4 hours/week of aerobic exercise or running ≥20 miles/week for ≥6 months in the preceding year, with lack of menstrual cycles for ≥3 months within at least 6 preceding months of oligo-amenorrhea, OR in premenarchal girls, absence of menses at >15 years), and (ii) 27 EM aged 14-25 years. Participants completed the Beck Depression Inventory-II (BDI-II), State and Trait Anxiety Inventory (STAI), and Mood and Anxiety Symptoms Questionnaire (MASQ). Structural MRI and brain activation during a functional MRI (fMRI) task that probes reward and punishment processing was examined in a subset of 10 AA and 23 EM. Results: Median (IQR) age and BMI of AA and EM groups were 20.6 (19.0-22.6) vs. 20.6 (19.2-23.7) years, p=0.6 and v 20.3 (18.8-21.5) vs. 21.9 (19.6-23.5) kg/m2, p=0.005, respectively. While groups did not differ for BDI-II scores, AA had higher anhedonic depression MASQ scores (p=0.04), and STAI (p=0.03) scores vs. EM. In the fMRI subset, AA had higher caudate volumes vs. EM [F(1, 29)=9.930, p=0.004]. Lower activation observed in the right caudate during reward anticipation in AA compared with EM (p=0.036) suggests blunted reward processing in the striatum in estrogen deficient states. Conclusion: Athletes with amenorrhea had higher depressive and anxiety symptomatology compared to eumenorrheic young women. Exploratory analyses demonstrated increased caudate volumes and decreased caudate activation during reward processing in athletes with amenorrhea suggesting that estrogen may play a role in reward processing.

Neural activation of regions involved in food reward and cognitive control in young females with anorexia nervosa and atypical anorexia nervosa versus healthy controls.

Anorexia nervosa (AN) and atypical AN (AtypAN) are complex neurobiological illnesses that typically onset in adolescence with an often treatment-refractory and chronic illness trajectory. Aberrant eating behaviors in this population have been linked to abnormalities in food reward and cognitive control, but prior studies have not examined respective contributions of clinical characteristics and metabolic state. Research is needed to identify specific disruptions and inform novel intervention targets to improve outcomes. Fifty-nine females with AN (n = 34) or AtypAN (n = 25), ages 10-22 years, all ≤90% expected body weight, and 34 age-matched healthy controls (HC) completed a well-established neuroimaging food cue paradigm fasting and after a standardized meal, and we used ANCOVA models to investigate main and interaction effects of Group and Appetitive State on blood oxygenation level-dependent (BOLD) activation for the contrast of exposure to high-calorie food images minus objects. We found main effects of Group with greater BOLD activation in the dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (DLPFC), hippocampus, caudate, and putamen for AN/AtypAN versus HC groups, and in the three-group model including AN, AtypAN, and HC (sub-)groups, where differences were primarily driven by greater activation in the AtypAN subgroup versus HC group. We found a main effect of Appetitive State with increased premeal BOLD activation in the hypothalamus, amygdala, nucleus accumbens, and caudate for models that included AN/AtypAN and HC groups, and in BOLD activation in the nucleus accumbens for the model that included AN, AtypAN, and HC (sub-)groups. There were no interaction effects of Group with Appetitive State for any of the models. Our findings demonstrate robust feeding-state independent group effects reflecting greater neural activation of specific regions typically associated with reward and cognitive control processing across AN and AtypAN relative to healthy individuals in this food cue paradigm. Differential activation of specific brain regions in response to the passive viewing of high-calorie food images may underlie restrictive eating behavior in this clinical population.

Lower Ghrelin Levels Are Associated With Higher Anxiety Symptoms in Adolescents and Young Adults With Avoidant/Restrictive Food Intake Disorder.

Objective: Avoidant/restrictive food intake disorder (ARFID) is associated with increased risk for anxiety, which may adversely affect prognosis. The appetite-stimulating hormone, ghrelin, increases in response to stress, and exogenous ghrelin decreases anxiety-like behaviors in animal models. The aim of this study was to evaluate the relationship between ghrelin levels and measures of anxiety in youth with ARFID. We hypothesized that lower ghrelin levels would be associated with increased anxiety symptoms.Methods: We studied a cross-sectional sample of 80 subjects with full and subthreshold ARFID diagnosed by DSM-5 criteria, aged 10-23 years (female, n = 39; male, n = 41). Subjects were enrolled in a study of the neurobiology of avoidant/restrictive eating conducted from August 2016 to January 2021. We assessed fasting ghrelin levels and anxiety symptoms (State-Trait Anxiety Inventory [STAI] and STAI for Children [STAI-C] measuring general trait anxiety; Beck Anxiety Inventory [BAI] and BAI for youth [BAI-Y] assessing cognitive, emotional, and somatic symptoms of anxiety; and Liebowitz Social Anxiety Scale [LSAS] assessing symptoms of social anxiety).Results: Consistent with our hypothesis, ghrelin levels were inversely associated with anxiety symptoms as assessed by STAI/STAI-C T scores (r = -0.28, P = .012), BAI/BAI-Y T scores (r = -0.28, P = .010), and LSAS scores (r = -0.3, P = .027), all with medium effect sizes. Findings held in the full threshold ARFID group when adjusting for body mass index z scores (STAI/STAI-C T scores, ß = -0.27, P = .024; BAI/BAI-Y T scores, ß = -0.26, P = .034; LSAS, ß = -0.34, P = .024).Conclusions: These findings demonstrate that lower levels of ghrelin are associated with more severe anxiety symptoms in youth with ARFID and raise the question of whether ghrelin pathways could be targeted in the treatment of ARFID.

Atypical anorexia nervosa diagnosis should exclude those with lifetime anorexia nervosa: Commentary on Walsh, Hagan, and Lockwood (2022).

Atypical anorexia nervosa (AN) is not well-defined. Walsh, Hagan, and Lockwood (2022) review the data on atypical AN published in the last decade demonstrating overwhelming clinical similarities between atypical AN and AN. As written, atypical AN includes at least three clinical presentations that may not have the same underlying illness, and in turn, may have different prognoses and treatment needs: (1) higher-weight AN; (2) prodromal AN; and (3) partial remission from AN. While useful for the first two presentations, we suggest that the atypical AN diagnosis is not appropriate for those in partial remission from AN. Extant data document symptom fluctuation is part of illness course in AN rather than crossover to a distinct disorder. Further, lifetime AN carries the greatest risk for relapse to low-weight, premature death, and medical morbidities. Finally, emerging data support unique biobehavioral mechanisms in AN suggesting its combination with atypical AN is premature. Therefore, at this time, we recommend that the atypical AN diagnosis be reserved for those without lifetime AN. We encourage research to test and validate operational definitions of atypical AN and partial remission from AN, and further suggest documentation of lifetime AN across the eating disorders given its prognostic value.

Association Between Ghrelin and Body Weight Trajectory in Individuals With Anorexia Nervosa.

Importance: Individuals with anorexia nervosa maintain extremely low body weights despite elevations in the circulating orexigenic hormone ghrelin. Whether circulating levels of endogenous ghrelin are associated with weight gain in anorexia nervosa is unknown. Objective: To examine the association between baseline ghrelin and future weight change in individuals with anorexia nervosa. Design, Setting, and Participants: This prospective cohort study was conducted between April 1, 2014, and March 31, 2020, in the US. Girls and women aged 10 to 22 years were recruited from the greater Boston area from community and area treatment centers, enrolled, and followed up for 18 months. Statistical analyses were performed between January and August 2022. Exposures: Presence or absence of anorexia nervosa and elevations in endogenous ghrelin. Main Outcomes and Measures: Changes in age- and sex-standardized body mass index percentiles from baseline to 9- and 18-month follow-up were the main outcomes of interest. Results: A total of 68 girls and young women (11 [16%] Asian, 4 [6%] Hispanic or Latina, 51 [75%] White [non-Hispanic or Latina], and 2 [3%] other race or ethnicity), including 35 with anorexia nervosa and 33 healthy controls of similar Tanner stage, were included in this study. Anorexia nervosa and healthy control groups were not statistically different by race and ethnicity, Tanner stage, number completing follow-up visits, and the duration between baseline and follow-up visits. At baseline, individuals with anorexia nervosa were slightly older (median [IQR], 20.1 [18.5-21.0] vs 18.7 [14.7-19.4] years; P = .005), had lower body mass index percentiles (median [IQR], 2.4 [0.3-4.7] vs 52.9 [40.4-68.3]; P < .001), and had elevated circulating ghrelin area under the curve composite index (median [IQR], 1389.4 [1082.5-1646.4] vs 958.5 [743.0-1234.5] pg/mL; P = .003) compared with healthy individuals. In linear mixed-effects regression analyses, baseline ghrelin was associated with prospective weight gain after adjusting for diagnosis, age, race, and duration of follow-up (odds ratio, 2.35; 95% CI, 1.43-3.73; P = .004). Conclusions and Relevance: In this cohort study, endogenous ghrelin was associated with longitudinal weight gain in individuals with anorexia nervosa. Further studies are warranted to confirm this result and examine its potential clinical utility in treatment development.

History of trying exclusion diets and association with avoidant/restrictive food intake disorder in neurogastroenterology patients: A retrospective chart review.

BACKGROUND: Exclusion diets for gastrointestinal symptom management have been hypothesized to be a risk factor for avoidant/restrictive food intake disorder (ARFID; a non-body image-based eating disorder). In a retrospective study of pediatric and adult neurogastroenterology patients, we aimed to (1) identify the prevalence and characteristics of an exclusion diet history and (2) evaluate if an exclusion diet history was concurrently associated with the presence of ARFID symptoms. METHODS: We conducted a chart review of 539 consecutive referrals (ages 6-90, 69% female) to adult (n = 410; January-December 2016) and pediatric (n = 129; January 2016-December 2018) neurogastroenterology clinics. Masked coders (n = 4) retrospectively applied DSM-5 criteria for ARFID and a separate coder assessed documentation of exclusion diet history. We excluded patients with no documentation of diet in the chart (n = 35) or who were not orally fed (n = 9). RESULTS: Of 495 patients included, 194 (39%) had an exclusion diet history, and 118 (24%) had symptoms of ARFID. Of reported diets, dairy-free was the most frequent (45%), followed by gluten-free (36%). Where documented, exclusion diets were self-initiated by patients/parents in 66% of cases, and recommended by gastroenterology providers in 30%. Exclusion diet history was significantly associated with the presence of ARFID symptoms (OR = 3.12[95% CI 1.92-5.14], p < 0.001). CONCLUSIONS: History of following an exclusion diet was common and was most often patient-initiated among pediatric and adult neurogastroenterology patients. As patients with self-reported exclusion diet history were over three times as likely to have ARFID symptoms, providers should be cognizant of this potential association when considering dietary interventions.