Neurobiology of hyperactivity and reward:Agreeable restlessness in Anorexia Nervosa

Restricted food intake is associated with increased physical activity, very likely an evolutionary advantage, initially both functional and rewarding. The hyperactivity of patients with Anorexia Nervosa, however, is a main problem for recovery. This seemingly paradoxical reward of hyperactivity in Anorexia Nervosa is one of the main aspects in our framework for the neurobiological changes that may underlie the development of the disorder. Here, we focus on the neurobiological basis of hyperactivity and reward in both animals and humans suggesting that the mesolimbic dopamine and hypothalamic orexin neurons play central roles. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009. (C) 2010 Elsevier Inc. All rights reserved

Initial low-dose oral levothyroxine in a child with Down syndrome, myxedema, and cardiogenic shock.

Myxedema is extremely rare in children, and guidelines are lacking. We treated a 12-year-old girl with myxedema and cardiogenic shock with initial low dose (0.3-2.5 μg/kg body weight/day) of oral levothyroxine and intensive care. Oral administration may safely revert children's myxedema in a dosage resembling that for hypothyroidism

Food availability, physical activity and body weight : Role of dopamine, neuropeptide Y and orexin

During the last decades our knowledge about neuroendocrine control of energy balance has increased tremendously. Numerous neuropeptides and hormones with pronounced effects on feeding and body weight have been identified and put into schemes as anorexic or orexigenic signals. So far this has not rendered new insights into how to explain or treat human pathology such as obesity or anorexia nervosa. Although different in many aspects, obese patients and patients suffering from anorexia nervosa share the feature of abnormal body weight. In this thesis I try to elucidate the role of NPY, orexin and dopamine all three known to have pronounced effects on ingestive behavior and body weight under different experimental conditions, with emphasis on availability of food and physical activity. The aim is to get a better understanding of human body weight pathology such as anorexia nervosa and obesity. If food supply is restricted to only 1 hour each day, rats that have access to running wheels run excessively and lose control over body weight, which rapidly falls. This provides a model of activity based anorexia. In this model NPY mRNA is up regulated in the arcuate nucleus. We show that treatment with NPY increases the fall in body weight by increasing wheel running and decreasing food intake in this model. While appetitive ingestive behavior is complex, with a wide representation in the central nervous system, consummatory ingestive behavior is stereotyped and involves mainly the brainstem. The intra oral intake test separates the consummatory phase of ingestive behavior. We use this test to characterize the effects of NPY on ingestive behavior and compare the effect of NPY to the known effects of CCK on ingestive behavior and on c-fos pattern in the brainstem. While CCK decreases both appetitive and consummatory ingestive behavior NPY decreases the consummatory phase (an effect additive to that of CCK), and increases the appetitive phase. Both peptides activate neurons in the nucleus of the solitary tract, also indicating similar effects on consummatory ingestive behavior, but there is no evidence that they interact at this level. To evaluate the role of dopamine D1 and D5 receptors on two major readouts of energy expenditure, namely physical activity and core temperature, two full dopamine D1 receptor family agonists, the isochroman A 68930 and the benzazepine SKF 82958 were compared. The compounds differ in several behavioral aspects and in the pattern of immediately early gene expression they induce. Quantitative receptor autoradiography shows that A 68930 is more potent than SKF 82958 at displacing the selective dopamine D1 antagonist [3H]SCH 23390. This difference agrees with the difference observed in cAMP formation in cells transfected with the D1 receptor. In contrast, SKF 82958 is more potent than A 68930 in cells transfected with the D5 receptor. We suggest that the balance between signaling via dopamine D1 and D5 receptors determines the functional effects of agonists at D1/D5 receptors. The increased activity seen in activity based anorexia predominantly occurs during the normally sedentary light phase of a 24 h light-darkness cycle. Treatment with the D1 antagonist SCH 23390 prevented the development of this running pattern and also prevented the c-fos and orexin induction in the lateral hypothalamus typically seen in activity based anorexia. Quantitative receptor autoradiography shows [3H]SCH 23390 binding in the lateral hypothalamus and we propose that the D1 antagonist, by acting in in this brain structure, alters orexin signaling and thereby reduces light phase running. The experiments in this thesis show that the effects of NPY, dopamine and orexin are highly dependent upon environmental factors. Labeling them as anorexic or orexigenic is therefore in most cases an over-simplification. Developing new treatment strategies for diseases like obesity and anorexia nervosa will require a deeper knowledge about how the environment, and especially the availability of food and need for physical activity, influences ingestive behavior, energy expenditure and body weight

Neurobiology of hyperactivity and reward: Agreeable restlessness in Anorexia Nervosa

Restricted food intake is associated with increased physical activity, very likely an evolutionary advantage, initially both functional and rewarding. The hyperactivity of patients with Anorexia Nervosa, however, is a main problem for recovery. This seemingly paradoxical reward of hyperactivity in Anorexia Nervosa is one of the main aspects in our framework for the neurobiological changes that may underlie the development of the disorder. Here, we focus on the neurobiological basis of hyperactivity and reward in both animals and humans suggesting that the mesolimbic dopamine and hypothalamic orexin neurons play central roles.

High unacylated ghrelin levels support the concept of anorexia in infants with prader-willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with different nutritional phases from suckling deficit with failure to thrive to early onset of obesity. Hyperghrelinemia has been described in PWS long before the development of obesity. Ghrelin is found in both acylated (AG) and unacylated (UAG) forms in the circulation. In contrast to AG, UAG has been shown to inhibit food intake and to be elevated in anorexia nervosa. The present project is aiming to determine the underlying mechanisms driving the different nutritional phases in PWS. METHODS: Measurement of at least 4 h-fasting plasma acylated and unacylated ghrelin in 37 infants with a genetic diagnosis of PWS aged from 1 month to 4 years and in 100 age-matched controls without endocrine disorder recruited prior to minor surgery. One blood sampling was analysed for each patient/control and clinical data were recorded. Eleven PWS infants underwent repetitive blood samples at 3 or 6-month intervals during routine visits. RESULTS: In infants with PWS, AG is not elevated (p = 0.45), UAG is significantly higher (p = 0.0044; confidence interval 1.06;1.33) resulting in a low AG/UAG ratio (p = 0.0056; confidence interval 0.76;0.95) compared to controls. CONCLUSION: Unlike children and adults with PWS that have high AG and AG/UAG ratio, infants with PWS have elevated UAG that supports the concept of anorexia in the early phases of the disease. The change in AG/UAG ratio possibly drives the switch from failure to thrive to obesity. CLINICAL TRIAL REGISTRATION: NCT02529085

Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation

Prader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on chromosome 15q11.2-q13. It is characterized by poor feeding and hypotonia in infancy, intellectual disability, behavioral abnormalities, dysmorphic features, short stature, obesity, and hypogonadism. PWS is not a known cancer predisposition syndrome, but previous investigations regarding the prevalence of cancer in these patients suggest an increased risk of developing specific cancer types such as myeloid leukemia and testicular cancer. We present the results from a Swedish national population-based cohort study of 360 individuals with PWS and 18,000 matched comparisons. The overall frequency of cancer was not increased in our PWS cohort, but we found a high frequency of pediatric cancers. We also performed whole-genome sequencing of blood- and tumor-derived DNAs from a unilateral dysgerminoma in a 13-year-old girl with PWS who also developed bilateral ovarian sex cord tumors with annular tubules. In germline analysis, there were no additional findings apart from the 15q11.2-q13 deletion of the paternal allele, while a pathogenic activating KIT mutation was identified in the tumor. Additionally, methylation-specific multiplex ligation-dependent probe amplification revealed reduced methylation at the PWS locus in the dysgerminoma but not in the blood. In conclusion, our register-based study suggests an increased risk of cancer at a young age, especially testicular and ovarian tumors. We found no evidence of a general increase in cancer risk in patients with PWS. However, given our limited observational time, further studies with longer follow-up times are needed to clarify the lifetime cancer risk in PWS. We have also described the second case of locus-specific loss-of-imprinting in a germ cell tumor in PWS, suggesting a possible mechanism of carcinogenesis

Additional file 1: Figure S1. of High unacylated ghrelin levels support the concept of anorexia in infants with prader-willi syndrome

Nonlinear regression (± SEM) of acylated (AG) (A), unacylated (UAG) ghrelin (B) levels and AG/UAG ratio (C) according to age in both groups. Black line: control; Red line: PWS infants. For Supplementary Figure1, we used nonlinear regressions by B-splines to draw the curves. Because the curves are compatible with linear regressions, we did not use nonlinear regressions for the statistical analysis. (DOCX 86 kb

Study protocol of comprehensive risk evaluation for anorexia nervosa in twins (CREAT) : a study of discordant monozygotic twins with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a severe disorder, for which genetic evidence suggests psychiatric as well as metabolic origins. AN has high somatic and psychiatric comorbidities, broad impact on quality of life, and elevated mortality. Risk factor studies of AN have focused on differences between acutely ill and recovered individuals. Such comparisons often yield ambiguous conclusions, as alterations could reflect different effects depending on the comparison. Whereas differences found in acutely ill patients could reflect state effects that are due to acute starvation or acute disease-specific factors, they could also reflect underlying traits. Observations in recovered individuals could reflect either an underlying trait or a "scar" due to lasting effects of sustained undernutrition and illness. The co-twin control design (i.e., monozygotic [MZ] twins who are discordant for AN and MZ concordant control twin pairs) affords at least partial disambiguation of these effects. METHODS: Comprehensive Risk Evaluation for Anorexia nervosa in Twins (CREAT) will be the largest and most comprehensive investigation of twins who are discordant for AN to date. CREAT utilizes a co-twin control design that includes endocrinological, neurocognitive, neuroimaging, genomic, and multi-omic approaches coupled with an experimental component that explores the impact of an overnight fast on most measured parameters. DISCUSSION: The multimodal longitudinal twin assessment of the CREAT study will help to disambiguate state, trait, and "scar" effects, and thereby enable a deeper understanding of the contribution of genetics, epigenetics, cognitive functions, brain structure and function, metabolism, endocrinology, microbiology, and immunology to the etiology and maintenance of AN