Human habit neural circuitry may be perturbed in eating disorders.

Circuit-based mechanisms mediating the development and execution of habitual behaviors involve complex cortical-striatal interactions that have been investigated in animal models and more recently in humans. However, how human brain circuits implicated in habit formation may be perturbed in psychiatric disorders remains unclear. First, we identified the locations of the sensorimotor putamen and associative caudate in the human brain using probabilistic tractography from Human Connectome Project data. We found that multivariate connectivity of the sensorimotor putamen was altered in humans with binge eating disorder and bulimia nervosa and that the degree of alteration correlated with severity of disordered eating behavior. Furthermore, the extent of this circuit aberration correlated with mean diffusivity in the sensorimotor putamen and decreased basal dopamine D2/3 receptor binding potential in the striatum, consistent with previously reported microstructural changes and dopamine signaling mediating habit learning in animal models. Our findings suggest a neural circuit that links habit learning and binge eating behavior in humans, which could, in part, explain the treatment-resistant behavior common to eating disorders and other psychiatric conditions.

Metabotropic glutamate receptor 5 in bulimia nervosa.

Bulimia nervosa (BN) shares central features with substance-related and addictive disorders. The metabotropic glutamate receptor subtype 5 (mGlu5) plays an important role in addiction. Based on similarities between binge eating and substance-related and addictive disorders, we investigated mGlu5 in vivo in 15 female subjects with BN and 15 matched controls. We measured mGlu5 distribution volume ratio (DVR) with positron emission tomography (PET) using [11 C]ABP688. In BN mGlu5 DVR was higher in the anterior cingulate cortex (ACC), subgenual prefrontal cortex, and straight gyrus (p < 0.05). In BN, higher mGlu5 DVR in various brain regions, including ACC, pallidum, putamen, and caudate, positively correlated with "maturity fears" as assessed using the Eating Disorder Inventory-2 (p < 0.05). In BN and controls, smokers had globally decreased mGlu5 DVR. We present the first evidence for increased mGlu5 DVR in BN. Our findings suggest that pharmacological agents inhibiting mGlu5 might have a therapeutic potential in BN.

Early traumatic experiences impair the functioning of both components of the endogenous stress response system in adult people with eating disorders.

Childhood trauma is a non-specific risk factor for eating disorders (EDs). It has been suggested that this risk is exerted through trauma-induced long-lasting changes in the body stress response system. Therefore, we explored the activity of the hypothalamus-pituitary-adrenal axis and of the sympathetic nervous system in adult ED patients with or without a history of childhood trauma exposure. Salivary cortisol and alpha-amylase, a marker of the sympathetic nervous system activity, were measured at awakening and after 15, 30 and 60 min in 35 women with EDs. The Childhood Trauma Questionnaire (CTQ) was employed to assess exposure to childhood trauma and, according to the CTQ cut-off scores, 21 ED women were classified as maltreated (Mal) participants and 14 women as no-maltreated (noMal) ED participants. Compared to noMal ED women, Mal ED participants showed significantly decreased cortisol awakening response (between group difference: p = 0.0003) and morning salivary alpha-amylase secretion (between group difference: p = 0.02). Present results confirm that the cortisol awakening response of adult ED patients with childhood trauma exposure is lower than that of adult ED patients without childhood trauma experiences and show for the first time that also the morning secretion of salivary alpha-amylase is decreased in adult ED patients who have been exposed to early traumatic experiences. These results point for the first time to a dampening in the basal activity of both components of the endogenous stress response system in childhood maltreated adult ED women.

Cortisol levels before and after cognitive behavioural therapy in patients with eating disorders reporting childhood abuse: A follow-up study.

The etiopathogenesis of eating disorders (EDs) is complex and still not well understood. Biological, psychological and environmental factors (e.g. childhood abuse) have all been considered to be involved in the onset and the persistence of EDs. The hypothalamic-pituitary-adrenal (HPA) axis is a relevant biological factor capable of influencing the onset and the course of EDs and not many information are available about the impact of a Cognitive Behavioral Therapy (CBT) on cortisol changes in EDs. The HPA-axis functioning has been evaluated before and after CBT in a group of patients with Anorexia Nervosa (n = 34) and Bulimia Nervosa (n = 35) according to the presence/absence of a history of sexual/physical abuse. At baseline, only patients reporting childhood abuse showed lower morning cortisol levels as compared with other patients of the same diagnostic group and Healthy Controls. After CBT, a variation of cortisol levels has been found only in patients without abuse, suggesting a role of childhood adversities in the persistence of HPA-axis alterations in Eating Disorders.

Neuroendocrinology of reward in anorexia nervosa and bulimia nervosa: Beyond leptin and ghrelin.

The pathophysiology of anorexia nervosa (AN) and bulimia nervosa (BN) are still poorly understood, but psychobiological models have proposed a key role for disturbances in the neuroendocrines that signal hunger and satiety and maintain energy homeostasis. Mounting evidence suggests that many neuroendocrines involved in the regulation of homeostasis and body weight also play integral roles in food reward valuation and learning via their interactions with the mesolimbic dopamine system. Neuroimaging data have associated altered brain reward responses in this system with the dietary restriction and binge eating and purging characteristic of AN and BN. Thus, neuroendocrine dysfunction may contribute to or perpetuate eating disorder symptoms via effects on reward circuitry. This narrative review focuses on reward-related neuroendocrines that are altered in eating disorder populations, including peptide YY, insulin, stress and gonadal hormones, and orexins. We provide an overview of the animal and human literature implicating these neuroendocrines in dopaminergic reward processes and discuss their potential relevance to eating disorder symptomatology and treatment.

Neuroendocrine aspects of anorexia nervosa and bulimia nervosa.

Endocrine dysfunctions in eating disorders (anorexia nervosa, bulimia nervosa) result from disturbed regulation of hypothalamo-pituitary-gonadal, hypothalamo-pituitary-adrenal, hypothalamo-pituitary-thyroid and hypothalamo-pituitary-GH-IGF1 axes as well as of altered peripheral endocrine metabolism. Some peptides of hypothalamic origin, as well as those secreted by the adipose tissue and gastrointestinal tract including pancreatic hormones, are involved in the control of appetite and satiety. These peptides play also an important role in the mechanism of hormonal secretion. Altered activity of these biologically active substances may lead to the disturbances in the regulation of energy and hormonal homeostasis.

The Neuropeptide Hormone Oxytocin in Eating Disorders.

PURPOSE OF REVIEW: The neurohormone oxytocin (OXT) impacts food intake as well as cognitive, emotional, and social functioning-all of which are central to eating disorder (ED) pathology across the weight spectrum. Here, we review findings on endogenous OXT levels and their relationship to ED pathology, the impact of exogenous OXT on mechanisms that drive ED presentation and chronicity, and the potential role of genetic predispositions in the OXT-ED link. RECENT FINDINGS: Current findings suggest a role of the OXT system in the pathophysiology of anorexia nervosa. In individuals with bulimia nervosa, endogenous OXT levels were comparable to those of healthy controls, and exogenous OXT reduced food intake. Studies in other ED are lacking. However, genetic studies suggest a broad role of the OXT system in influencing ED pathology. Highlighting findings on why OXT represents a potential biomarker of and treatment target for ED, we advocate for a systematic research approach spanning the entire ED spectrum.

Insecure Attachment and Hypothalamus-Pituitary-Adrenal Axis Functioning in People With Eating Disorders.

OBJECTIVE: Childhood attachment experiences affect adult emotion regulation and ability to cope with stressors. Therefore, insecure attachment may influence the functioning of the hypothalamic-pituitary-adrenal (HPA) axis and a dysregulation of HPA axis has been found in insecure attached healthy individuals. The effects of attachment on HPA axis activity have never been investigated in eating disorders (EDs). Therefore, we assessed the relationships between insecure attachment and the cortisol awakening response (CAR) in adults with EDs. METHODS: Seventy-eight patients with EDs (43 with anorexia nervosa, 35 with bulimia nervosa) were recruited. They completed the Experience in Close Relationships questionnaire, which provides a rating of two insecure attachment dimensions (anxiety and avoidance) and collected saliva samples to measure the CAR. Differences in the CAR between groups with high and low attachment anxiety and between groups with high and low attachment avoidance were evaluated by repeated measures two-way analysis of variance. RESULTS: Patients with high attachment anxiety showed a reduced CAR compared with those with low attachment anxiety (F1,76 = 7.31, p = .008). The CAR did not differ between the groups with high and low attachment avoidance (F1,76 = 0.01, p = .93). Patients with high levels of insecure attachment showed a more severe eating-related psychopathology. CONCLUSIONS: Our data show, for the first time, a specific association of the anxious attachment with the HPA axis activity in EDs and suggest a possible role of attachment in the biological vulnerability to stress of adult patients with EDs.

Blunted cortisol response to stress in patients with eating disorders: Its association to bulimic features.

OBJECTIVE: Clinical research on cortisol response to stress in patients with eating disorders has provided controversial and even contradictory results. As this might be the consequence of the inclusion in the studies of heterogeneous clinical populations, 3 highly selected samples were studied. METHODS: Dexamethasone suppression test was performed on 15 restricting anorexia nervosa patients without history of bulimia nervosa (BN), 17 BN patients with normal weight and no history of anorexia nervosa, and 22 healthy controls. Three days later, the Trier Social Stress Test was applied, and 8 saliva samples were collected along the trial for cortisol assessment. RESULTS: When the patients were considered as a single group, a slightly blunted cortisol response to stress was observed, but when the 3 groups were considered separately, the blunted response was observed only in the BN patients. DISCUSSION: The results support the association between blunted cortisol response and bulimic features.

Molecular bases of anorexia nervosa, bulimia nervosa and binge eating disorder: shedding light on the darkness.

Eating-disorders (EDs) consequences to human health are devastating, involving social, mental, emotional, physical and life-threatening aspects, concluding on impairment and death in cases of extreme anorexia nervosa. It also implies that people suffering an ED need to find psychiatric and psychological help as soon as possible to achieve a fully physical and emotional recovery. Unfortunately, to date, there is a crucial lack of efficient clinical treatment to these disorders. In this review, we present an overview concerning the actual pharmacological and psychological treatments, the knowledge of cells, circuits, neuropeptides, neuromodulators and hormones in the human brain- and other organs- underlying these disorders, the studies in animal models and, finally, the genetic approaches devoted to face this challenge. We will also discuss the need for new perspectives, avenues and strategies to be developed in order to pave the way to novel and more efficient therapeutics.

Association between cerebral cannabinoid 1 receptor availability and body mass index in patients with food intake disorders and healthy subjects: a [(18)F]MK-9470 PET study.

Although of great public health relevance, the mechanisms underlying disordered eating behavior and body weight regulation remain insufficiently understood. Compelling preclinical evidence corroborates a critical role of the endocannabinoid system (ECS) in the central regulation of appetite and food intake. However, in vivo human evidence on ECS functioning in brain circuits involved in food intake regulation as well as its relationship with body weight is lacking, both in health and disease. Here, we measured cannabinoid 1 receptor (CB1R) availability using positron emission tomography (PET) with [(18)F]MK-9470 in 54 patients with food intake disorders (FID) covering a wide body mass index (BMI) range (anorexia nervosa, bulimia nervosa, functional dyspepsia with weight loss and obesity; BMI range=12.5-40.6 kg/m(2)) and 26 age-, gender- and average BMI-matched healthy subjects (BMI range=18.5-26.6 kg/m(2)). The association between regional CB1R availability and BMI was assessed within predefined homeostatic and reward-related regions of interest using voxel-based linear regression analyses. CB1R availability was inversely associated with BMI in homeostatic brain regions such as the hypothalamus and brainstem areas in both patients with FID and healthy subjects. However, in FID patients, CB1R availability was also negatively correlated with BMI throughout the mesolimbic reward system (midbrain, striatum, insula, amygdala and orbitofrontal cortex), which constitutes the key circuit implicated in processing appetitive motivation and hedonic value of perceived food rewards. Our results indicate that the cerebral homeostatic CB1R system is inextricably linked to BMI, with additional involvement of reward areas under conditions of disordered body weight.

Blunted Cortisol Awakening Response and Poor Self-Perceived Health in Informal Caregivers of People with Eating Disorders.

Caring for offspring diagnosed with eating disorders (EDs) entails being under high chronic stress, with negative consequences for health. However, most previous research has only evaluated self-report measures of health, biological markers being poorly studied. In this regard, the evaluation of the cortisol awakening response (CAR) could add significant information about the biological basis of health disturbances in this population. The main aim of the present study was to compare CAR and self-reported health between informal caregivers (ICs) of people with EDs and non-caregivers. Furthermore, we explored the effect of the nature of the diagnosis, comparing ICs of people with anorexia and bulimia nervosa. ICs had a blunted CAR, and more anxiety and insomnia, and social dysfunction, together with poorer perceived general health than non-caregivers. ICs of people with anorexia nervosa had higher levels of morning cortisol and burden, and more social dysfunction and severe depression than those of people with bulimia nervosa. Our results demonstrate marked health problems in ICs of people with EDs, especially when the care recipient has anorexia nervosa. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.

Repetitive Transcranial Magnetic Stimulation Changes Cerebral Oxygenation on the Left Dorsolateral Prefrontal Cortex in Bulimia Nervosa: A Near-Infrared Spectroscopy Pilot Study.

Previous studies showed that food craving in eating disorders can be weakened with high-frequency repetitive transcranial magnetic stimulation (rTMS) on the left dorsolateral prefrontal cortex (DLPFC). The aims of this study were to assess cerebral oxygenation change induced with rTMS and to assess the short-term impact of rTMS on food craving and other bulimic symptoms in patients with bulimia nervosa (BN). Eight women diagnosed with BN according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria participated in this study. We measured haemoglobin concentration changes in the DLPFC with near-infrared spectroscopy during cognitive tasks measuring self-regulatory control in response to food photo stimuli, both at baseline and after a single session of rTMS. Subjective ratings for food cravings demonstrated significant reduction. A significant decrease in cerebral oxygenation of the left DLPFC was also observed after a single session of rTMS. Measurement with NIRS after rTMS intervention may be applicable for discussing the mechanisms underlying rTMS modulation in patients with BN.

Parotid salivary parameters in bulimic patients - a controlled clinical trial.

OBJECTIVES: The aim of this study was to determine whether patients with purging-type bulimia and/or non-bulimic patients, treated with serotonin reuptake inhibitor SI-5-HT (fluoxetine), have dental erosion and changes in selected buffer components of parotid saliva (bicarbonates, phosphates, urea), compared with the healthy population. METHODS: A controlled clinical trial was designed for three, age-matched, female groups of 94 patients: 1) bulimic patients treated with fluoxetine 40 mg/day (n = 25), 2) non-bulimic patients diagnosed with bipolar affective disorder, treated with fluoxetine 20mg/day (n = 25), and 3) healthy controls (n = 44). Parotid saliva was collected from the subjects by means of Lashley cup at rest and stimulated chemically with a 3% citric acid solution. In clinical examination the dental erosion was determined as non-carious tooth substance loss using the Tooth Wear Index (TWI). The concentrations of inorganic phosphates, bicarbonate, urea and pH in saliva were measured. RESULTS: In the bulimic subjects higher TWI (24%) and lower levels of pH, bicarbonates and phosphates compared with controls were observed. There were no significant differences in urea concentration. CONCLUSIONS: Erosive-abrasive tooth surface loss seems to be a significant diagnostic tool of bulimia nervosa. The presence of pathological changes in teeth structure indicates the loss of protective properties of saliva, which is proved by pH value and concentration of buffer ions. It is advisable to monitor salivary parameters, such as salivary flow rate, pH and the concentration of buffer ions in long-term treatment with SI-5-HT drugs in case of patients with purging-type bulimia. There is also a need for regular dental check-ups of the oral cavity tissues.

Childhood trauma and cortisol awakening response in symptomatic patients with anorexia nervosa and bulimia nervosa.

OBJECTIVE: Exposure to trauma during childhood is a risk factor for eating disorders (EDs) in adulthood. The biological mechanisms underlying such increased risk seem to involve the endogenous stress response system (i.e., the hypothalamic-pituitary-adrenal [HPA] axis), which undergoes trauma-induced functional changes that may persist later in life. In the present study, we examined the effects of childhood trauma experiences on HPA-axis activity, comparing saliva cortisol awakening response (CAR) in adult patients with anorexia nervosa (AN) or bulimia nervosa (BN) with CAR in adult healthy controls. METHOD: Twenty-three patients with symptomatic AN, 21 patients with symptomatic BN, and 29 healthy women collected saliva samples at awakening and again after 15, 30, and 60 min. Participants also completed the Childhood Trauma Questionnaire and eating-related psychopathological rating scales. RESULTS: According to the Childhood Trauma Questionnaire, 13 individuals with AN and 12 individuals with BN, but none of the healthy women, reported childhood maltreatment. Compared with the control group, the non-maltreated AN patient group exhibited an enhanced CAR, whereas the group of non-maltreated BN patients showed a normal CAR. Moreover, both AN and BN patient groups with childhood maltreatment exhibited statistically significant blunting of CAR compared with non-maltreated groups. DISCUSSION: The present findings add to the evidence supporting the concept that there is a dysregulation of HPA-axis activity in symptomatic patients with EDs and suggest that childhood trauma exposure may contribute to such dysregulation.

Testing the efficacy of pure versus guided mirror exposure in women with bulimia nervosa: A combination of neuroendocrine and psychological indices.

BACKGROUND AND OBJECTIVES: Body exposure improves body image problems in women with eating disorders. However it has almost always been combined with other interventions. Thus, the efficacy of body exposure alone (i.e., pure exposure) remains largely unclear. We aimed to compare the efficacy of two body exposure techniques through psychological and neuroendocrine indices recorded within and between successive sessions. METHOD: Twenty-nine women with high body dissatisfaction and diagnosis of bulimia nervosa were randomly assigned to one of two treatment groups: Pure Exposure (n = 14) or Guided Exposure (n = 15). Participants received 6 exposure sessions. After each session, changes in thoughts (positive/negative) and body satisfaction were assessed. Also, we assessed the body discomfort experienced by participants within and between sessions. Finally, the changes in salivary cortisol levels within and between the initial and final treatment sessions were measured. RESULTS: Both groups showed a reduction in negative thoughts and a progressive increase in positive thoughts throughout the treatment. However, the increase in body satisfaction and the reduction in subjective discomfort within the sessions were greater in the pure exposure group. The cortisol levels during the initial and final treatment sessions decreased in both groups. LIMITATIONS: Methodological limitations are reported. CONCLUSIONS: These results suggest that pure and guided exposures are effective interventions for improving thoughts and neuroendocrine responses, although pure exposure increased more body satisfaction feelings in bulimic women. Subjective discomfort also showed different patterns of change within and along sessions for each treatment. Reasons for these results are discussed.

Highly increased risk of type 2 diabetes in patients with binge eating disorder and bulimia nervosa.

OBJECTIVE: We aimed to examine the prevalence and incidence of type 2 diabetes (T2D) in a large patient cohort treated for binge eating disorder (BED), bulimia nervosa (BN), and anorexia nervosa. METHOD: Patients (N = 2,342) treated at the Eating Disorder Unit of Helsinki University Central Hospital over the period up to 16 years were compared with matched general population controls (N = 9,368) in three stages: before entering to the treatment for an eating disorder, after the entrance until the end of the study period, and combined any time before, during, and after the treatment. The study population was linked with the oral TSD medication data of 17 years from The Medical Reimbursement Register. Data were analyzed using conditional and Poisson regression models. RESULTS: Before entering to the treatment for eating disorders, the risk of T2D was substantially increased in patients compared with controls (OR 6.6, 95% CI 4.0-10.7). At the end of the study period, the lifetime prevalence of T2D was 5.2% among patients, 1.7% among controls (OR 3.4, 95% CI 2.6-4.4), and in male patients, it was significantly higher compared with females. Of those treated for BED, every third had T2D by the end of the study period (OR 12.9, 95% CI 7.4-22.5), whereas the same was true for 4.4% of those with BN (OR 2.4, 95% CI 1.7-3.5). DISCUSSION: Our findings provide strong support for the association between T2D and clinically significant binge eating. Disturbed glucose metabolism may contribute to the onset and maintenance of BED and BN.

Blunted neuroendocrine stress reactivity in young women with eating disorders.

OBJECTIVE: Stress is known to influence risk and progression of eating disorders (EDs). However, studies investigating physiological and psychological stress responses under laboratory conditions in patients with Anorexia nervosa or Bulimia nervosa are scarce and often produce conflicting findings. We therefore aimed to compare the neuroendocrine and affective stress response in ED inpatients and healthy controls. METHODS: Twenty-eight female inpatients with Anorexia or Bulimia nervosa and 26 healthy women were exposed to the Trier Social Stress Test (TSST). Salivary cortisol and alpha-amylase (sAA) levels were assessed before as well as repeatedly after stress exposure, while heart rate and heart rate variability were determined before and during the TSST. Negative affective state was assessed at baseline and post-TSST. RESULTS: Compared to healthy controls, ED patients showed blunted cortisol stress responses combined with overall attenuated sAA levels. The latter was reflected in generally enhanced parasympathetic activity indicated by lower heart rate and stronger high-frequency heart rate variability throughout the TSST. Although patients reported more negative affect overall, they did not differ in their affective stress response. CONCLUSIONS: In summary, patients suffering from eating disorders show a blunted HPA axis reactivity to stress exposure and a generally reduced sympathetic/exaggerated parasympathetic nervous system activity. This combination may contribute to elevated health risks seen in eating disorder patients, such as enhanced inflammatory activity, and thus provide insight into the underlying stress-related mechanisms.

Behavioral responses to catecholamine depletion in unmedicated, remitted subjects with bulimia nervosa and healthy subjects.

BACKGROUND: Bulimia nervosa (BN) has been associated with dysregulation of the central catecholaminergic system. An instructive way to investigate the relationship between catecholaminergic function and psychiatric disorder has involved behavioral responses to experimental catecholamine depletion (CD). The purpose of this study was to examine a possible catecholaminergic dysfunction in the pathogenesis of bulimia nervosa. METHODS: CD was achieved by oral administration of alpha-methyl-para-tyrosine (AMPT) in 18 remitted female subjects with BN (rBN) and 31 healthy female control subjects. The study design consisted of a randomized, double blind, placebo-controlled crossover, single-site experimental trial. The main outcome measures were bulimic symptoms assessed by the Eating Disorder Examination-Questionnaire. Measures were assessed before and 26, 30, 54, 78, 102 hours after the first AMPT or placebo administration. RESULTS: In the experimental environment (controlled environment with a low level of food cues) rBN subjects had a greater increase in eating disorder symptoms during CD compared with healthy control subjects (condition × diagnosis interaction, p < .05). In the experimental environment, rBN subjects experienced fewer bulimic symptoms than in the natural environment (uncontrolled environment concerning food cues) 36 hours after the first AMPT intake (environment × diagnosis interaction, p < .05). Serum prolactin levels increased significantly, and to a comparable degree across groups, after AMPT administration. CONCLUSIONS: This study suggests that rBN is associated with vulnerability for developing eating disorder symptoms in response to reduced catecholamine neurotransmission after CD. The findings support the notion of catecholaminergic dysfunction as a possible trait abnormality in BN.

The effects of serotonin1A receptor on female mice body weight and food intake are associated with the differential expression of hypothalamic neuropeptides and the GABAA receptor.

Both common eating disorders anorexia nervosa and bulimia nervosa are characteristically diseases of women. To characterize the role of the 5-HT1A receptor (5-HT1A-R) in these eating disorders in females, we investigated the effect of saline or 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) treatment on feeding behavior and body weight in adult WT female mice and in adult 5-HT1A-R knockout (KO) female mice. Our results showed that KO female mice have lower food intake and body weight than WT female mice. Administration of 8-OH-DPAT decreased food intake but not body weight in WT female mice. Furthermore, qRT-PCR was employed to analyze the expression levels of neuropeptides, γ-aminobutyric acid A receptor subunit ß (GABAA ß subunits) and glutamic acid decarboxylase in the hypothalamic area. The results showed the difference in food intake between WT and KO mice was accompanied by differential expression of POMC, CART and GABAA ß2, and the difference in body weight between WT and KO mice was associated with significantly different expression levels of CART and GABAA ß2. As such, our data provide new insight into the role of 5-HT1A-R in both feeding behavior and the associated expression of neuropeptides and the GABAA receptor.