146 Chapter 7 INTRODUCTION Anorexia nervosa (AN) is a challenging psychiatric disorder with the highest mortality rate of all psychiatric disorders (1, 2). AN is characterized by severe food restriction, an inability to maintain a normal body weight, and body image disturbances (DSM-5) (3). Even with the best available treatments, 21% of AN-patients will become chronic and treatment-refractory (4). Deep brain stimulation (DBS) targeted at the ventral anterior limb of the capsula interna (vALIC), part of the brain reward circuit, is being investigated as a last resort treatment option for therapy refractory AN-patients (5). A recent meta-analysis showed statistically large beneficial overall effects of DBS on weight, quality of life and symptoms of eating disorders, depression and anxiety (6). The limited research on the working mechanisms of DBS in AN focused so far on neuroimaging parameters, showing changes in the reward circuitry. However, AN and the accompanying severe weight loss is also associated with endocrine and metabolic alterations including alterations in hypothalamic-pituitary axis function (7-11). On the hypothalamic-pituitary-gonadal axis the chronic state of malnutrition in AN often results in disturbed luteinizing hormone (LH) pulsatility manifesting as hypothalamic amenorrhea. Gonadotropin releasing hormone (GnRH) levels are reduced, leading to reduced gonadotropin secretion and low androgen levels (10). The hypothalamic-pituitary-adrenal (HPA) axis is in a continuous overstimulated state with corticotrophin releasing hormone (CRH) hyperstimulation and elevated adrenocorticotropic hormone (ACTH) and cortisol levels , and the degree of hypercortisolaemia correlates inversely with BMI (9, 11). Moreover, severe malnutrition/underweight is characterized by nonthyroidal illness syndrome, with low levels of total T3, and low to normal free T4 and thyroid stimulating hormone (TSH) levels (10). In AN there is a state of acquired growth hormone (GH) resistance due to chronic nutritional deprivation, with increased GH secretion and decreased insulin-like growth factor 1 (IGF 1) (12). Alterations in adipokine and appetite-regulating hormones are also found in AN. Leptin, an anorexigenic adipokine, plays a role in satiety and thus appetite regulation. In AN, basal and pulsatile secretion of leptin is reduced in association with reduction of fat mass (10, 11). Most studies in AN found increased levels of adiponectin, but its role is unclear (13). Preclinical studies show a relationship between the noradrenergic system and binge-like behavior, some evidence suggests a noradrenergic-mediated genetic risk to develop AN (14). Clinical studies show conflicting alterations in plasma noradrenaline in patients with AN (14). Dopamine, with its direct involvement in the brain reward system, is the most studied neurotransmitter in AN. Studies show that dopamine neurotransmission is altered in AN (15), with increased dopaminergic neurotransmission.
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