Neural effects of deep brain stimulation on reward and loss anticipation and food viewing in anorexia nervosa: a pilot study.

BACKGROUND: Anorexia nervosa (AN) is a severe and life-threatening psychiatric disorder. Initial studies on deep brain stimulation (DBS) in severe, treatment-refractory AN have shown clinical effects. However, the working mechanisms of DBS in AN remain largely unknown. Here, we used a task-based functional MRI approach to understand the pathophysiology of AN. METHODS: We performed functional MRI on four AN patients that participated in a pilot study on the efficacy, safety, and functional effects of DBS targeted at the ventral limb of the capsula interna (vALIC). The patients and six gender-matched healthy controls (HC) were investigated at three different time points. We used an adapted version of the monetary incentive delay task to probe generic reward processing in patients and controls, and a food-specific task in patients only. RESULTS: At baseline, no significant differences for reward anticipation were found between AN and HC. Significant group (AN and HC) by time (pre- and post-DBS) interactions were found in the right precuneus, right putamen, right ventral and medial orbitofrontal cortex (mOFC). No significant interactions were found in the food viewing task, neither between the conditions high-calorie and low-calorie food images nor between the different time points. This could possibly be due to the small sample size and the lack of a control group. CONCLUSION: The results showed a difference in the response of reward-related brain areas post-DBS. This supports the hypotheses that the reward circuitry is involved in the pathogenesis of AN and that DBS affects responsivity of reward-related brain areas. Trial registration Registered in the Netherlands Trial Register ( https://www.trialregister.nl/trial/3322 ): NL3322 (NTR3469).

Anorexia Nervosa (An) is a severe eating disorder with many, sometimes life-threatening, complications. A substantial number of AN patients do not respond to the available treatment options and remain chronically ill or even die as a consequence of the AN. Because part of the causes of AN may reside in the brain, we studied the efficacy and safety of a potential new treatment option for AN, namely deep brain stimulation (DBS). DBS has proven to be an effective treatment option for movements disorders like Parkinson's Disease and other psychiatric disorders such as obsessive compulsive disorder. Our previous pilot study and other research have shown that DBS leads to improvements in weight, mood, anxiety, and eating disorder symptoms. In this substudy, we examined the effects of DBS on specific brain circuitries that are implicated in AN. We conducted brain scans (fMRI) to measure brain activity while patients performed tasks. We observed a difference in brain response when we compared scans taken before and after the DBS, which supports our thoughts on the involvement of specific parts of the brain in AN.

[Translational genetics; expectations for eating disorders and other psychiatric disorders]. / Translationele genetica: verwachtingen voor eetstoornissen en andere psychiatrische stoornissen.

BACKGROUND: Translational (genetic) research focuses on the translation of preclinical research into practice. While many genetic studies have been conducted in recent years, the results do not simply translate to the clinic.
AIM: To visualize the steps through which translational genetic research contributes to the unraveling of the biological backgrounds of psychiatric disorders, in particular of eating disorders.
METHOD: Literature review.
RESULTS: Genetic studies have unraveled a mechanism underlying the hunger and satiety system. There is hope that genome-wide studies of eating disorders will lead to identification of neural circuits in which associated genes cluster. New techniques, such as opto- and chemogenetics, provide the opportunity to define the precise role of these circuits in eating disorders.
CONCLUSION: New techniques in molecular neuroscience allow the unravelling of the complexity of how the brain works and some of those techniques (such as chemogenetics) are being further developed for application in humans. However, it will be years before we can definitively translate this into the treatment of psychiatric disorders.
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[Psychological disorders in the oral health care practice. Feeding and eating disorders]. / Serie: Psychische stoornissen in de mondzorgpraktijk. Voedings- en eetstoornissen.

Feeding and eating disorders are characterised by a persistent disturbance of eating or eating-related behaviour that results in the altered consumption or absorption of food, which significantly impairs physical health or psychosocial functioning. These disorders usually develop during childhood and are characterised by high morbidity and mortality rates. The aberrant eating habits lead to under- or overweight and the compensatory behaviours such as vomiting, laxative abuse, and rumination, can greatly impact the overall physical condition and especially the dentition and the oral cavity. Because people suffering from these conditions are often inclined to conceal these, the dentist or dental hygienist can be the first one to raise questions about possible diagnoses of eating disorders.

[Anorexia nervosa and adolescents]. / Anorexia nervosa en adolescenten.

BACKGROUND: Anorexia nervosa (AN), which is the most serious of the eating disorders, starts earlier in life and often continues into adulthood. AIM: To discuss the typical features of AN in adolescents. METHOD: We present an overview based on the literature about AN in adolescents and on analysis performed by experts. RESULTS: Youngsters with AN run considerable physical risks because their bodies are less well developed and are more easily injured. These injuries can be a lifelong handicap if the patient's body weight does not rapidly return to normal. However, if the body weight recovers satisfactory, this can point to the possibility of a full psychological recovery. The best route to recovery is to start dining again with the family, to go back to school and to participate in social activities. So far, no other types of treatment have proved to be entirely successful. CONCLUSION: Further research is needed into matters such as an ideal weight for the patient and the best ways of increasing his or her food-intake. We need to find out how best to deal with a patient's disturbed body image and how to treat any comorbid disease that often accompanies AN.

[Feeding and eating disorders in the DSM-5]. / Voedings- en eetstoornissen in de DSM-5.

BACKGROUND: In the DSM-5, feeding disorders and eating disorders have been integrated into one single category. AIM: To review the rationale for changes in the criteria for feeding and eating disorders in DSM-5. METHOD: The revised criteria were drafted and formulated by a DSM-5 workgroup. Next, professionals were given the opportunity to react to the proposed revisions by participating in several discussion rounds. RESULTS: The criteria for anorexia nervosa have been reworded and the amenorrhea criterion has been removed. The threshold for the diagnosis of bulimia nervosa has been lowered so that once-a-week binge eating and complementary behaviours are now sufficient for a patient to be diagnosed as having bulimia nervosa. Subtyping of bulimia nervosa has been removed. There are hardly any changes in the criteria for pica and rumination disorder. Two new official feeding and eating disorders have been introduced into DSM-5: avoidant/restrictive food intake disorder and binge eating disorder. CONCLUSION: The definition of and the criteria for feeding and eating disorders given in DSM-5 are an improvement on those used in dsm-iv and should help to reduce the eating disorders not otherwise specified (EDNOS).

Association study in eating disorders: TPH2 associates with anorexia nervosa and self-induced vomiting.

Twin studies suggest that genetic factors play a substantial role in anorexia nervosa (AN) and self-induced vomiting (SV), a key symptom that is shared among different types of eating disorders (EDs). We investigated the association of 25 single nucleotide polymorphisms (SNPs), capturing 71-91% of the common variance in candidate genes, stathmin (STMN1), serotonin receptor 1D (HTR1D), tryptophan hydroxylase 2 (TPH2) and brain-derived neurotrophic factor (BDNF), with AN and EDs characterized by regular SV. The first allele frequencies of all the SNPs were compared between a Dutch case group (182 AN, 149 EDs characterized by SV) and 607 controls. Associations rendering P-values < 0.05 from this initial study were then tested for replication in a meta-analysis with two additional independent ED case-control samples, together providing 887 AN cases, 306 cases with an ED characterized by SV and 1914 controls. A significant effect for the minor C-allele of tryptophan hydroxylase 2 rs1473473 was observed for both AN [odds ratio (OR) = 1.30, 95% CI 1.08-1.57, P < 0.003] and EDs characterized by SV (OR = 1.52, 95% CI 1.28-2.04, P < 0.006). In the combined case group, a dominant effect was observed for rs1473473 (OR = 1.38, 95% CI 1.16-1.64, P < 0.0003). The meta-analysis revealed that the tryptophan hydroxylase 2 polymorphism rs1473473 was associated with a higher risk for AN, EDs characterized by SV and for the combined group.

Leptin's effect on hyperactivity: potential downstream effector mechanisms.

Up to 80% of patients with Anorexia Nervosa (AN) demonstrate hyperactivity. Hyperactivity counteracts weight gain during treatment and is associated with poor outcome of the disease. We hypothesized that hyperactivity in AN patients has a neurobiological basis and used an animal model-based translational approach to gain insight in mechanisms underlying this hyperactivity. Previously we and others showed that leptin treatment attenuates hyperactivity in the rat activity-based anorexia (ABA) model. The mechanisms involved in this process are, however, unknown. Here we describe potential downstream effector mechanisms involved in the attenuation of hyperactivity by leptin treatment in ABA rats.

The impact of hyperactivity and leptin on recovery from anorexia nervosa.

In anorexia nervosa (AN), hyperactivity is observed in about 80% of patients and has been associated with low leptin levels in the acute stage of AN and in anorexia animal models. To further understand the importance of this correlation in AN, we investigated the relationship between hypoleptinaemia and hyperactivity in AN patients longitudinally and assessed their predictive value for recovery. Body weight, activity levels, and serum leptin levels were assessed in adolescents and adult AN patient groups at the start and during treatment, up to a year. In the adolescent group, initial leptin and activity levels were correlated. This negative correlation changes over time into a positive correlation with physiological recovery. Treatment outcome in both groups could be predicted by initial BMI and leptin levels but not by activity levels. No major relationship of activity with the course of recovery was detected, suggesting that in contrast to the acute stage of the disease, leptin and activity levels during the recovery process are dissociated.

Association between an agouti-related protein gene polymorphism and anorexia nervosa.

Anorexia nervosa (AN) is a life threatening disorder affecting mostly adolescent women. It is a dramatic psychiatric syndrome accompanied by severe weight loss, hyperactivity and neuroendocrine changes (reviewed in Refs 1 and 2). Several studies have shown a strong genetic component in AN (reviewed in Ref 3). Recent advances in unraveling the mechanisms of weight control point to a crucial role of the melanocortin-4 receptor (MC4-r) system in regulating body weight. The orexigenic neuropeptide agouti-related protein (AGRP), a MC4-r antagonist, plays a crucial role in maintaining body weight, by inducing food intake. The sequence of the coding region of the human AGRP gene (AGRP) was determined and the AGRP of 100 patients with AN was screened for variations. Three single nucleotide polymorphisms (SNPs) were identified and screened in a further 45 patients and 244 controls. Two alleles were in complete linkage disequilibrium and were significantly enriched in anorectic patients (11%; P = 0.015) compared to controls (4.5%). These data indicate that variations of AGRP are associated with susceptibility for AN. This is possibly caused by defective suppression of the MC4-r by the variant AGRP, leading to a decreased feeding signal, increasing the risk of developing AN. These results implicate that antagonism of the MC4-r might be considered as pharmacotherapy for patients with AN.