Anorexia and Brain Imaging

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.

Brain imaging

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-HT_1A) and diminished 5-HT_2A 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-HT_1A receptor binding in anorexia, stimulation of 5-HT_1A 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.”

Asked about his research, Kaye said he and fellow researchers have conducted some fMRI imaging studies, one of which looked at taste.³

Most people who diet to an extreme will experience a strong drive to eat and a tendency to return to their previous body weight, Kaye said. In contrast, the eating patterns of individuals with anorexia are often puzzling. Although they are obsessed with food, they fear eating, particularly palatable foods, and can maintain an emaciated state.

For the fMRI study, 16 women who had recovered from restricting-type anorexia were compared with 16 control women. Researchers measured their brains’ reactions to pleasant taste (10% sucrose) and neutral taste (distilled water). Study subjects were also asked to rate their anxiety and the pleasantness of the taste stimuli. Compared with the control group, the women with remitted AN had a significantly lower neural activation of the insula, including the primary cortical taste region, and ventral and dorsal striatum to both sucrose and water. Insular neural activity correlated with pleasantness ratings for sucrose in the control group, but not in the recovered group.

The study results indicate that the “sensory hedonic aspect of food is altered in individuals with anorexia, so that they are just not getting the message they are hungry or are not driven to eat.” Such brain imaging studies, according to Kaye, will provide new insights into the pathophysiology of anorexia, which has the highest death rate of any psychiatric disorder (10%), and will ultimately facilitate development of more effective therapies.

Treatment approaches

“There are no proven pharmacological treatments for anorexia,” Kaye said. “Emerging evidence from controlled trials raises the possibility that some atypical antipsychotics may be useful for anorexia.5 It is not because people with anorexia are psychotic. Perhaps, atypicals may be helpful because of their effects on dopaminergic and serotonergic function in anorexia.” Larger controlled trials are needed to definitively prove whether atypicals are useful for treating anorexia.

There have also been a few controlled trials of fluoxetine (Prozac) for anorexia, particularly in preventing relapse after weight recovery. Kaye said, “The findings are mixed, with one but not another study, suggesting this drug might be helpful for patients with anorexia after they recover. There is little evidence that SSRIs are useful in the emaciated state.”

Kaye and his team have developed a “treatment laboratory” to test new treatments for eating disorders, such as new medications. While inpatient or residential settings can be lifesaving, in terms of reversing malnutrition and providing weight restoration, Kaye noted that the relapse rate is very high after discharge. In order to improve outcome in adolescents with anorexia, Kaye has developed a unique intensive family treatment program.

“When a child suffers from this devastating illness, all members of the family, and the relationships between them, are profoundly affected. Some of the latest research points to potentially unprecedented levels of success when families become centrally involved in the treatment process,” Kaye said. “This program teaches parents the tools necessary to understand and successfully manage their child with anorexia at home. In addition, insights from neurobiological studies are used to teach adolescents with AN how to understand the symptoms that they are having and develop more effective coping strategies. Optimally, parents, the patient, and siblings take part in the program, which may last 1 week or longer, at UCSD. Since many families cannot find anorexia experts in their local communities, the program incorporates a number of treatment components, including medical and psychiatric evaluation as well as Maudsley-based family therapy, contracting, psychoeducation, and parent coaching.”

Because anorexia is a somewhat chronic disorder, at least in terms of personality and temperament traits, Kaye said, his team is helping people understand their personality and temperament traits and develop constructive coping strategies. “Many people who have recovered from anorexia [between 50% and 70% recover] do well in life, because some of the traits that got them into trouble can be beneficial, and even highly associated with achievement. . . . These are people who are high achievers, who are very focused and detail-oriented . . . do well in professions that reward those qualities, such as medicine, research, engineering, and academia.”

References:

References

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.