Recent multiple brain imaging studies of patients with restricting-type anorexia nervosa (AN) reveal neurocircuit dysregulation and may help clarify the disorder’s confounding symptoms.
In a review article, Walter Kaye, MD, director of the Eating Disorders Program at the University of California, San Diego (UCSD), and his coauthors1 said that insights into the ventral (limbic) and dorsal (cognitive) neural circuit dysfunction, perhaps related to altered serotonin and dopamine (DA) metabolism, may help explain why individuals with anorexia often report that dieting reduces their anxiety while eating increases it and why they worry about long-term consequences but seem impervious to immediate gratification and unable to live in the moment.
Many women diet in this culture, but relatively few (0.5%) have anorexia, Kaye told Psychiatric Times. “Why is that? Well, you pretty much have to have a certain temperament and personality in childhood to be vulnerable for . . . an eating disorder,” said Kaye. “Not everyone who develops anorexia has all these traits in childhood, but most have one or more of them,” he said. “These traits include harm avoidance, anxiety, behavioral inhibition, difficulty with set shifting [easily moving from one mental set to another], a tendency to focus on details rather than the big picture, and perfectionism.” Even after recovery, these personality and temperament traits persist, pointing to underlying neurobiological factors.
Another clue is the relatively stereotypic course of anorexia. That is, anorexia tends to occur in females with onset during adolescence when some combination of puberty, brain development, stress and/or sociocultural factors comes into play, provoking the onset of anorexic symptoms. Anorexia is marked by body image distortions and the fear of being fat and results in a downward spiral of weight loss that is difficult to reverse.
Once an individual becomes anorexic, starvation and malnutrition affect every system of the body, including the brain. Such changes include neurochemical imbalances, which may, in turn, exaggerate the preexisting traits and accelerate the disease process. Individuals with anorexia, for example, have a reduced brain volume and a regression to prepubertal gonadal function, Kaye said. Yet, these disturbances tend to normalize after weight restoration, which suggests that they are state-related alterations.
In their article, Kaye and colleagues distinguish between state-related and trait-related abnormalities, and then review how new brain imaging technologies are helping identify the brain pathways involved in AN.
Studies using positron emission tomography (PET) brain imaging and related technologies have assessed serotonin and DA neurotransmitter systems in individuals with anorexia and in those who have recovered, while studies using functional MRI (fMRI) have illuminated altered activity in interconnected brain regions of these individuals.
Imaging studies suggest that individuals with anorexia have an imbalance between circuits in the brain that regulate reward and emotion (ventral) and circuits that are associated with consequences and planning ahead (dorsal).2 Brain-imaging studies also show that individuals with anorexia have alterations in those parts of the brain (eg, anterior insula) involved with interoceptive self-awareness that may be implicated in disturbed bodily sensations.3 In addition, altered function of other related regions may contribute to altered sensing of the rewarding aspects of pleasurable foods. Individuals with anorexia may literally not recognize when they are hungry.
The neurotransmitters serotonin and DA are primary targets of study, according to Kaye. “Simply put, the serotonin system tends to be inhibitory while the dopamine system is associated with signals about reward.”
Kaye said that evidence from imaging studies suggests that disturbances in the serotonergic system might contribute to vulnerability for restricted eating and behavioral inhibition as well as a bias toward anxiety, particularly excessive concern with consequences. Meanwhile, DA dysfunction, particularly in striatal circuits, may contribute to altered reward, decision making, stereotypic motor movements, and decreased food ingestion.
Evidence that the dopamine system is involved includes reduced cerebrospinal fluid levels of DA metabolites both in ill individuals and in those who have recovered from anorexia, functional DA D2 receptor gene (DRD2) polymorphisms in individuals with anorexia, and impaired visual discrimination learning. A PET study found that subjects who recovered from AN had increased D2/D3 receptor binding in the ventral striatum, a region that modulates responses to reward stimuli.4 This finding could indicate increased D2/D3 receptor densities, decreased extracellular DA, or both in individuals who recovered from anorexia.
With regard to serotonin, brain imaging studies consistently show that when compared with healthy subjects, individuals with or those who have recovered from eating disorders have an imbalance between enhanced 5-hydroxytryptamine (serotonin) receptor 1A (5-HT1A) and diminished 5-HT2A receptor binding potential.1 “Eating carbohydrates is thought to increase extracellular serotonin levels, which, in turn, may drive anxiety and harm avoidance in AN. . . . Because these symptoms are correlated with 5-HT1A receptor binding in anorexia, stimulation of 5-HT1A receptors offers a potential explanation for feeding-related dysphoric mood in AN. When individuals with AN starve, extracellular serotonin concentrations might diminish, resulting in a brief respite from dysphoric mood.”
1. Kaye WH, Fudge JL, Paulus M. New insights into symptoms and neurocircuit function of anorexia nervosa. Nat Rev Neurosci. 2009;10:573-584.
2. Wagner A, Aizenstein H, Venkatraman VK, et al. Altered reward processing in women recovered from anorexia nervosa. Am J Psychiatry. 2007;164:1842-1849.
3. Wagner A, Aizenstein H, Mazurkewicz L, et al. Altered insula response to taste stimuli in individuals recovered from restricting-type anorexia nervosa. Neuropsychopharmacology. 2008;33:513-523.
4. Frank GK, Bailer UF, Henry SE, et al. Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11c]raclopride. Biol Psychiatry. 2005;58:908-912.
5. Bissada H, Tasca GA, Barber AM, Bradwejn J. Olanzapine in the treatment of low body weight and obsessive thinking in women with anorexia nervosa: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2008;165:1281-1288.