Pathophysiology Of Anorexia Nervosa Research Articles

Associations between parental rearing style and amygdala and hippocampal subfield abnormalities in drug-naive females with anorexia nervosa

BackgroundAltered volumes in the hippocampus and amygdala have been linked to anorexia nervosa (AN). This study aimed to investigate amygdala and hippocampal subfields volume abnormalities in AN patients, and their associations with parental rearing practices and clinical psychological characteristics.MethodsThis study included twenty-nine drug-naive females with AN from West China Hospital of Sichuan University, China, and fifty-nine age- and gender-matched healthy controls (HCs) recruited through advertisement. All participants underwent T1-weighted imaging. Amygdala and hippocampal subfields volume was calculated using FreeSurfer 7.0. The Core Self-Evaluation Scale (CSES) and Rosenberg Self-Esteem Scale (RSES) were used to assess the psychological characteristics of AN patients. The Egna Minnen av Barndoms Uppfostran (EMBU) was employed to evaluate parental rearing practices. Group differences in brain volumes were analyzed with covariates like age and total intracranial volume (TIV). Partial correlation analysis explored the correlations between brain region volumes and clinical psychological characteristics.ResultsAN patients exhibited lower RSES and CSES scores, and more adverse parental rearing style than healthy norms. After adjusting for covariates, AN patients showed decreased gray matter volume (GMV) in the left medial (Me) and cortical (Co) nucleus, as well as in the right hippocampal-amygdala transition area (HATA). GMV in the left Me was correlated with years of education among HCs but not among AN patients. GMV in the right HATA was positively correlated with paternal penalty and severity, as well as maternal overinterference.ConclusionThis study supports structure abnormalities in amygdala and hippocampus in AN patients and suggests that parental rearing practices may be associated with hippocampal abnormalities, potentially contributing to the pathophysiology of AN. Addressing appropriate parental rearing styles may offer a positive impact on AN.

Therapeutic ketogenic diet as treatment for anorexia nervosa.

Anorexia nervosa (AN) is a severe psychiatric disorder. However, we lack neurobiological models and interventions to explain and treat the core characteristics of food restriction, feeling fat, and body size overestimation. Research has made progress in understanding brain function involved in the pathophysiology of AN, but translating those results into biological therapies has been challenging. Studies have suggested that metabolic factors could contribute to developing and maintaining AN pathophysiology. Here, we describe a neurobiological model for why using a therapeutic ketogenic diet could address key alterations in brain function in AN and prevent the desire for weight loss and associated eating disorder-specific symptoms. This translational model is based on animal studies and human data and integrates behavioral traits, brain neural energy metabolism, and neurotransmitter function. Pilot data indicate that the intervention can dramatically reduce eating and body-related fears, although larger studies across illness stages still need to be conducted.

The Role of Central and Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker of Anorexia Nervosa Reconceptualized as a Metabo-Psychiatric Disorder.

Neurotrophic factors play pivotal roles in shaping brain development and function, with brain-derived neurotrophic factor (BDNF) emerging as a key regulator in various physiological processes. This review explores the intricate relationship between BDNF and anorexia nervosa (AN), a complex psychiatric disorder characterized by disordered eating behaviors and severe medical consequences. Beginning with an overview of BDNF's fundamental functions in neurodevelopment and synaptic plasticity, the review delves into recent clinical and preclinical evidence implicating BDNF in the pathophysiology of AN. Specifically, it examines the impact of BDNF polymorphisms, such as the Val66Met variant, on AN susceptibility, prognosis, and treatment response. Furthermore, the review discusses the interplay between BDNF and stress-related mood disorders, shedding light on the mechanisms underlying AN vulnerability to stress events. Additionally, it explores the involvement of BDNF in metabolic regulation, highlighting its potential implications for understanding the metabolic disturbances observed in AN. Through a comprehensive analysis of clinical data and animal studies, the review elucidates the nuanced role of BDNF in AN etiology and prognosis, emphasizing its potential as a diagnostic and prognostic biomarker. Finally, the review discusses limitations and future directions in BDNF research, underscoring the need for further investigations to elucidate the complex interplay between BDNF signaling and AN pathology.

Peripheral Biomarkers of Anorexia Nervosa: A Meta-Analysis.

The pathogenesis of anorexia nervosa (AN) has been hypothesized to involve several biological systems. However, reliable biomarkers for AN have yet to be established. This study was aimed to identify statistically significant and clinically meaningful peripheral biomarkers associated with AN. A systematic literature search was conducted to identify studies published in English from inception until 30 June 2022. We conducted two-level random-effects meta-analyses to examine the difference between AN and comparison groups across 52 distinct biomarkers and found that acylated ghrelin, adrenocorticotropic hormone (ACTH), carboxy-terminal collagen crosslinks (CTX), cholesterol, cortisol, des-acyl ghrelin, ghrelin, growth hormone (GH), obestatin, and soluble leptin receptor levels were significantly higher in cases of AN compared with those in non-AN controls. Conversely, C-reactive protein (CRP), CD3 positive, CD8, creatinine, estradiol, follicle-stimulating hormone (FSH), free thyroxine, free triiodothyronine, glucose, insulin, insulin-like growth factor 1 (IGF-1), leptin, luteinizing hormone, lymphocyte, and prolactin levels were significantly lower in AN compared with those in non-AN controls. Our findings indicate that peripheral biomarkers may be linked to the pathophysiology of AN, such as processes of adaptation to starvation. Scientific investigation into peripheral biomarkers may ultimately yield breakthroughs in personalized clinical care for AN.

Pro-inflammatory cytokine alterations in recent onset anorexia nervosa adolescent female patients before and after 6 months of integrated therapy: A case-control study.

Anorexia nervosa (AN) is a complex disorder affecting mainly, but not only, teenagers. Researchers agree that AN is deeply associated with a pro-inflammatory state following an impaired immune system, resulting from altered levels of cytokines such as IL-1β and TNF-α, also impacted by the frequent depressive states. Thus, this case-control study aimed to evaluate the relationship between patients suffering from AN undergoing specialized eating disorder treatment for AN and pro-inflammatory cytokines. To reach our purpose, we assessed eating-related psychopathology and depressive symptoms and measured serum concentration of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α before and after 6 months of integrated therapy (which included psychopharmacotherapy, psychotherapy, and nutritional treatment), to define whether selected pro-inflammatory cytokines could be considered a pathophysiological marker of the disorder. A sample of 16 young female patients with early diagnosis of AN, and without any previous treatment, and 22 healthy controls matched by age, sex, and socioeconomic status were enrolled. After 6 months of integrated therapy, a significant decrease of all selected pro-inflammatory cytokines was detected. In addition, an improvement in the anxiety-depressant aspects was also noted. In conclusion, the results obtained suggest that pro-inflammatory cytokines are indeed related to the pathophysiology of AN. However, further investigations, involving larger samples of patients with distinct subtypes of AN, are essential to confirm the current findings.

Gastrointestinal Microbiota & Symptoms of Depression and Anxiety in Anorexia Nervosa-A Re-Analysis of the MICROBIAN Longitudinal Study.

The microbiota-gut-brain axis may play a role in the pathophysiology of anorexia nervosa (AN). Here, the relationship between the gastrointestinal microbiota and symptoms of depression, anxiety, and eating disorder pathology in patients with AN before (n = 55) and after weight restoration (n = 44) was investigated by reanalyzing the data of the MICROBIAN study. The gastrointestinal microbiota was analyzed using 16S rRNA amplicon sequencing. Symptoms of anxiety disorder, depression, and the severity of the eating disorder were measured by validated questionnaires. All analyses were adjusted for the body mass index (BMI). Several significant findings between psychological parameters and the gastrointestinal microbiota were not evident after controlling for the BMI. No differences in alpha and beta diversity between groups of higher and lower symptom severity levels for depression and anxiety were found. Positive associations between species of Blautia and Ruminococcus and depression symptoms, and between the phylum Firmicutes and anxiety symptoms were observed after rehabilitation, respectively. A positive correlation was found between propionate and acetate levels and the reduction of depression severity during inpatient treatment. Accounting for the weight status when analyzing the relationship between psychological parameters and the gastrointestinal microbiota in patients with underweight is important since the BMI may be the driver for many observed changes.

Reduced dorsal fronto-striatal connectivity at rest in anorexia nervosa.

Anorexia nervosa (AN) is a serious psychiatric illness that remains difficult to treat. Elucidating the neural mechanisms of AN is necessary to identify novel treatment targets and improve outcomes. A growing body of literature points to a role for dorsal fronto-striatal circuitry in the pathophysiology of AN, with increasing evidence of abnormal task-based fMRI activation within this network among patients with AN. Whether these abnormalities are present at rest and reflect fundamental differences in brain organization is unclear. The current study combined resting-state fMRI data from patients with AN (n = 89) and healthy controls (HC; n = 92) across four studies, removing site effects using ComBat harmonization. First, the a priori hypothesis that dorsal fronto-striatal connectivity strength - specifically between the anterior caudate and dlPFC - differed between patients and HC was tested using seed-based functional connectivity analysis with small-volume correction. To assess specificity of effects, exploratory analyses examined anterior caudate whole-brain connectivity, amplitude of low-frequency fluctuations (ALFF), and node centrality. Compared to HC, patients showed significantly reduced right, but not left, anterior caudate-dlPFC connectivity (p = 0.002) in small-volume corrected analyses. Whole-brain analyses also identified reduced connectivity between the right anterior caudate and left superior frontal and middle frontal gyri (p = 0.028) and increased connectivity between the right anterior caudate and right occipital cortex (p = 0.038). No group differences were found in analyses of anterior caudate ALFF and node centrality. Decreased coupling of dorsal fronto-striatal regions indicates that circuit-based abnormalities persist at rest and suggests this network may be a potential treatment target.

Short-chain fatty acids in plasma and feces: An optimized and validated LC-QqQ-MS method applied to study anorexia nervosa

Short-chain fatty acids (SCFAs) are organic saturated monocarboxylic acids with fewer than six carbon atoms. Their recently described relevance in health and disease has brought to the table the need for a convenient method for their analysis. The current research presents an optimized and validated LC-QqQ-MS method for the absolute quantification of SCFAs in plasma and feces. This method has proven to be accurate and precise in a wide range of concentrations (0.2 – 200 µM). It has been applied to more than 500 samples showing good precision, reproducibility, and linearity results. The method was applied to study samples from anorexia nervosa (AN) patients and matched healthy controls (HC). The results showed significant differences in the concentration of plasmatic and fecal SCFAs between both groups whose implications in AN are yet to be determined. Nonetheless, these findings denote important alterations in the SCFAs homeostasis in AN which can be linked to the metabolic alterations and the intestinal dysbiosis already characterized in the disease. More research is still required to identify the function of these metabolites in the pathophysiology of AN, but the present work provides a reliable methodology and valuable information to continue delving into the potential role of the microbiota as a therapeutic target via the gut-brain axis.

Challenges and priorities for researching the gut microbiota in individuals living with anorexia nervosa.

The gut microbiota is implicated in several symptoms and biological pathways relevant to anorexia nervosa (AN). Investigations into the role of the gut microbiota in AN are growing, with a specific interest in the changes that occur in response to treatment. Findings suggest that microbial species may be associated with some of the symptoms common in AN, such as depression and gastrointestinal disturbances (GID). Therefore, researchers believe the gut microbiota may have therapeutic relevance. Whilst research in this field is rapidly expanding, the unique considerations relevant to conducting gut microbiota research in individuals with AN must be addressed. We provide an overview of the published literature investigating the relationship between the gut microbiota and symptoms and behaviors present in AN, discuss important challenges in gut microbiota research, and offer recommendations for addressing these. We conclude by summarizing research design priorities for the field to move forward. Several ways exist to reduce participant burden and accommodate challenges when researching the gut microbiota in individuals with AN. Recommendations from this article are foreseen to encourage scientific rigor and thoughtful protocol planning for microbiota research in AN, including ways to reduce participant burden. Employing such methods will contribute to a better understanding of the role of the gut microbiota in AN pathophysiology and treatment. The field of gut microbiota research is rapidly expanding, including the role of the gut microbiota in anorexia nervosa. Thoughtful planning of future research will ensure appropriate data collection for meaningful interpretation while providing a positive experience for the participant. We present current challenges, recommendations for research design and priorities to facilitate the advancement of research in this field.

Gut-Associated Lymphatic Tissue in Food-Restricted Rats: Influence of Refeeding and Probiotic Supplementation.

Anorexia nervosa (AN) is a severe and often chronic eating disorder that leads to alterations in the gut microbiome, which is known to influence several processes, such as appetite and body weight regulation, metabolism, gut permeability, inflammation, and gut-brain interactions. Using a translational activity-based anorexia (ABA) rat model, this study examined the effect of chronic food starvation, as well as multistrain probiotic supplementation and refeeding, on the structure of the gut and gut-associated lymphatic tissue (GALT). Our results indicated that ABA had an atrophic influence on intestinal morphology and increased the formation of GALT in the small bowel and colon. Higher formation of GALT in ABA rats appeared to be reversible upon application of a multistrain probiotic mixture and refeeding of the starved animals. This is the first time that increased GALT was found following starvation in the ABA model. Our results underscore a potential role of gut inflammatory alterations in the underlying pathophysiology of AN. Increased GALT could be linked to the gut microbiome, as probiotics were able to reverse this finding. These results emphasize the role of the microbiome-gut-brain axis in the pathomechanisms of AN and point to probiotics as potentially beneficial addendum in the treatment of AN.

Anaplastic Lymphoma Kinase Receptor: Possible Involvement in Anorexia Nervosa

The pathophysiology of Anorexia Nervosa (AN) has not been fully elucidated. Anaplastic lymphoma kinase (ALK) receptor is a protein-tyrosine kinase mainly known as a key oncogenic driver. Recently, a genetic deletion of ALK in mice has been found to increase energy expenditure and confers resistance to obesity in these animals, suggesting its role in the regulation of thinness. Here, we investigated the expression of ALK and the downstream intracellular pathways in female rats subjected to the activity-based anorexia (ABA) model, which reproduces important features of human AN. In the hypothalamic lysates of ABA rats, we found a reduction in ALK receptor expression, a downregulation of Akt phosphorylation, and no change in the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) phosphorylation. After the recovery from body weight loss, ALK receptor expression returned to the control baseline values, while it was again suppressed during a second cycle of ABA induction. Overall, this evidence suggests a possible involvement of the ALK receptor in the pathophysiology of AN, that may be implicated in its stabilization, resistance, and/or its exacerbation.

Volume and complexity of the thalamus in Anorexia Nervosa: An exploratory evaluation.

Recent neuroscientific findings have highlighted the role of the thalamus in several cognitive functions, ranging from perception to cognitive flexibility, memory, and body representation. Since some of these functions may be involved in the pathophysiology of Anorexia Nervosa (AN), this study aims at exploring thalamic structure in different phases of the disorder. The sample included 38 patients with acute AN, 20 patients who fully recovered from AN (recAN), and 38 healthy controls (HC), all female. All participants underwent high-resolution MRI. The volumes of the whole thalamus and 25 thalamic nuclei were extracted using an automated segmentation algorithm, and thalamic fractal dimension was estimated using the calcFD toolbox. Patients with acute AN, compared to HC, displayed reduced thalamic volume and complexity both at the whole level and at the level of specific nuclei. In patients recAN, instead, alterations were observed only at the level of the right laterodorsal and central lateral nuclei. In the acute phase of the disorder patients with AN present a widespread reduction in thalamic volume and complexity. However, these alterations seem to normalise almost completely following weight restoration, thus suggesting the involvement of malnutrition-related mechanisms.

Food Restriction in Mice Induces Food-Anticipatory Activity and Circadian-Rhythm-Related Activity Changes.

Anorexia nervosa (AN) is characterized by emaciation, hyperactivity, and amenorrhea. To what extent AN-related symptoms are due to food restriction or neuronal dysfunction is currently unknown. Thus, we investigated the relevance of food restriction on AN-related symptoms. Disrupted circadian rhythms are hypothesized to contribute to the pathophysiology of AN. Starvation was induced by restricting food access in early adolescent or adolescent mice to 40% of their baseline food intake until a 20% weight reduction was reached (acute starvation). To mimic chronic starvation, the reduced weight was maintained for a further 2 weeks. Locomotor activity was analyzed using running wheel sensors. The circadian-rhythm-related activity was measured using the tracking system Goblotrop. Amenorrhea was determined by histological examination of vaginal smears. All cohorts showed an increase in locomotor activity up to 4 h before food presentation (food-anticipatory activity, FAA). While amenorrhea was present in all groups except in early adolescent acutely starved mice, hyperactivity was exclusively found in chronically starved groups. Adolescent chronically starved mice showed a decrease in circadian-rhythm-related activity at night. Chronic starvation most closely mimics AN-related behavioral changes. It appears that the FAA is a direct consequence of starvation. The circadian activity changes might underlie the pathophysiology of AN.

Intestinal permeability and appetite regulating peptides-reactive immunoglobulins in severely malnourished women with anorexia nervosa

In the last decades, the role of microbiota-gut-brain axis has emerged in the regulation of eating behavior and in the pathophysiology of anorexia nervosa (AN) that remains poorly understood. Particularly, a gut-derived dysregulation of immune response has been proposed leading to immunoglobulins directed against appetite-regulating peptides. However, intestinal permeability in patients with anorexia nervosa has been poorly documented. In the present prospective case-control study, we thus compared intestinal permeability, appetite-regulating peptides and their reactive immunoglobulins measured in severely malnourished women with AN (n=17; 28 [21-35] y; 14.9 [14.1-15.2] kg/m2) to healthy volunteers (HV, n=34; 26 [23-35] y; 22.3 [20.6-23.6] kg/m2). Patients with AN exhibited an increased urinary lactulose/mannitol ratio, both in 0-5h (0.033 [0.013-0.116]) and 5-24h samples (0.115 [0.029-0.582]), when compared to HV (0.02 [0.008-0.045], p=0.0074 and 0.083 [0.019-0.290], p=0.0174, respectively), suggesting an increased intestinal permeability. Urinary excretion of sucralose and plasma zonulin were not different. The levels of plasma total ghrelin and desacyl-ghrelin were increased in patients with AN compared to HV, whereas plasma leptin concentration was decreased. In addition, αMSH remained unchanged compared to HV. Finally, we did not observe any modification of the levels of total or free αMSH, leptin or ghrelin-reactive immunoglobulin G and M, as well as for their affinity properties. Only, a weak decrease of the dissociation constant (kd) for acyl-ghrelin-reactive IgG was observed in patients with AN (p=0.0411). In conclusion, severely malnourished patients with AN show a higher intestinal permeability than HV without evidence of an effect on appetite regulating peptides-reactive immunoglobulins.

No effects of acute tryptophan depletion on anxiety or mood in weight-recovered female patients with anorexia nervosa

BackgroundPrevious studies have suggested that individuals recovered from anorexia nervosa (AN) are characterized by increased serotonergic (5-HT) activity that might be related to elevated levels of anxiety. Assuming these traits to be also present in individuals at risk for AN, it was further hypothesized that restricting food intake might be a means to temporarily alleviate dysphoric affective states by reducing central nervous availability of tryptophan (TRP), the sole precursor of 5-HT. One study that supported this hypothesis found anxiolytic effects in individuals with a history of AN during an experimentally induced short-term depletion of TRP supply to the brain.MethodsIn this placebo-controlled, double-blind cross-over study, 22 patients weight-recovered from AN (recAN) and 25 healthy control participants (HC) completed questionnaires assessing anxiety and momentary mood during acute tryptophan depletion (ATD), a dietary intervention that lowers central 5-HT synthesis.ResultsThe ATD procedure effectively reduced the ratio of TRP to competing for large neutral amino acids in the peripheral blood, indicating decreased TRP supply to the brain. Effects of ATD on anxiety and mood did not differ between recAN and HC. Bayesian null hypothesis testing confirmed these initial results.DiscussionOur results do not support the hypothesis that short-term depletion of TRP and its impact on the brain 5-HT reduces anxiety or improves mood in AN. As the evidence for the role of 5-HT dysfunction on affective processes in patients with AN is limited, further studies are needed to assess its relevance in the pathophysiology of AN.

A D2 to D1 shift in dopaminergic inputs to midbrain 5-HT neurons causes anorexia in mice.

Midbrain dopamine (DA) and serotonin (5-HT) neurons regulate motivated behaviors, including feeding, but less is known about how these circuits may interact. In this study, we found that DA neurons in the mouse ventral tegmental area bidirectionally regulate the activity of 5-HT neurons in the dorsal raphe nucleus (DRN), with weaker stimulation causing DRD2-dependent inhibition and overeating, while stronger stimulation causing DRD1-dependent activation and anorexia. Furthermore, in the activity-based anorexia (ABA) paradigm, which is a mouse model mimicking some clinical features of human anorexia nervosa (AN), we observed a DRD2 to DRD1 shift of DA neurotransmission on 5-HTDRN neurons, which causes constant activation of these neurons and contributes to AN-like behaviors. Finally, we found that systemic administration of a DRD1 antagonist can prevent anorexia and weight loss in ABA. Our results revealed regulation of feeding behavior by stimulation strength-dependent interactions between DA and 5-HT neurons, which may contribute to the pathophysiology of AN.

The Pathophysiology of Anorexia Nervosa in Hypothalamic Endocrine Function and Bone Metabolism.

Anorexia nervosa (AN) is a persistent psychiatric disorder that is marked by abnormal reduced weight and amenorrhea, which may be primary or secondary. AN affects multiple endocrine axes such as gonadal, thyroid, and adrenal axis, growth hormone, and insulin-like growth factor-1, adipokines such as leptin, gut peptides like ghrelin, peptide YY, and amylin. As a result of these changes bone mineral density is reduced, which increases the risk of bone fracture in patients. In this review, we focus on substantial endocrine alterations in AN with a particular emphasis on the severe bone loss associated with this condition and current bone therapies. The disorder primarily affects girls and women, who are the focus of this review. Although the majority of AN-related endocrinopathies improve over time, long-term consequences such as short stature, osteoporosis, and infertility may occur. To avoid serious consequences, nutrition therapy in these patients requires a full understanding of bone complications, and new therapeutic options for treatment should be researched.

Intestinal permeability and appetite regulating peptides-reactive immunoglobulins in severely malnourished women with anorexia nervosa

Rationale: The role of microbiota-gut-brain axis has emerged in the regulation of eating behavior and in the pathophysiology of anorexia nervosa (AN). Particularly, a gut-derived dysregulation of immune response has been proposed leading to immunoglobulins (Ig) directed against appetite-regulating peptides but intestinal permeability has been poorly documented. We thus aimed to evaluate intestinal permeability, appetite-regulating peptides and their reactive Ig in severely malnourished women with AN.

Unveiling Metabolic Phenotype Alterations in Anorexia Nervosa through Metabolomics

Anorexia nervosa (AN) is a mental disorder characterized by an intense fear of weight gain that affects mainly young women. It courses with a negative body image leading to altered eating behaviors that have devastating physical, metabolic, and psychological consequences for the patients. Although its origin is postulated to be multifactorial, the etiology of AN remains unknown, and this increases the likelihood of chronification and relapsing. Thus, expanding the available knowledge on the pathophysiology of AN is of enormous interest. Metabolomics is proposed as a powerful tool for the elucidation of disease mechanisms and to provide new insights into the diagnosis, treatment, and prognosis of AN. A review of the literature related to studies of AN patients by employing metabolomic strategies to characterize the main alterations associated with the metabolic phenotype of AN during the last 10 years is described. The most common metabolic alterations are derived from chronic starvation, including amino acid, lipid, and carbohydrate disturbances. Nonetheless, recent findings have shifted the attention to gut-microbiota metabolites as possible factors contributing to AN development, progression, and maintenance. We have identified the areas of ongoing research in AN and propose further perspectives to improve our knowledge and understanding of this disease.

Structural brain changes in severe and enduring anorexia nervosa: A multimodal magnetic resonance imaging study of gray matter volume, cortical thickness, and white matter integrity

Whole-brain T1-weighted imaging and diffusion tensor imaging was performed in 35 adult women with anorexia nervosa (AN) and 35 healthy controls. We conducted voxel-based group comparisons for gray matter volume (GMV), cortical thickness (CT), and fractional anisotropy (FA) values, using age and total intracranial volume as nuisance covariates. We then conducted the same group comparisons for these three measures, but this time also controlled for the following global pathological measures: total GMV, mean CT across the whole brain, and mean FA across the entire white matter skeleton. Compared with the healthy controls, AN patients had lower GMV and CT in widespread cortical regions, and smaller FA values in widespread white matter regions. After controlling for global parameters, almost all of the differences between the two groups disappeared, except for higher CT in the medial orbital gyrus and parietal operculum in the AN group. Structural brain changes in AN are likely to be composed of both global and region-specific changes. The former changes are likely to have a dominant impact, while the latter changes might in part explain the disease-specific pathophysiology of AN.