The Cellular and Molecular Substrates of Anorexia Nervosa, Part 1

[Editor's Note: For Part 2, please click here]. Appetite regulation is made up of complex interlocking, incentive-driven motivational hormonal and neuronal circuitries . . . that can be pulled in many directions, especially where food is cheap and readily available.

The event that created the most indelible memories of my graduate experience recurred each morning as I trundled down to the lab. I always crossed paths with a well-disciplined jogger, heading in the opposite direction, running feverishly up a hill I was descending. It was very difficult not to stare at her, for she looked like someone freshly liberated from a concentration camp. Gaunt, pale, withered, bones protruding behind thin sheaths of skin, the jogger possessed a desperate, oddly determined look in her eyes. The look was unforgettable.

She grew paler and more emaciated as the months went by, and there came a time when we no longer crossed paths. I always wondered if she had moved away, got into a treatment program, or had simply died.

This month’s column-and the next (Part 2)-is all about the neural and molecular biology of anorexia nervosa, a disorder from which this jogger probably suffered. Starting with definitions and diagnostic criteria, then moving to the various neural circuits thought to be involved in its etiology, I will describe some recent findings from the 40,000-foot view of this most baffling disease. Here I discuss certain cellular interactions inside these circuits that may underlie the disease.

The field shows great promise, and some surprising recent research twists, in what turns out to be a very complex research story. Frustratingly, the field faces some real research challenges before consistently effective treatment strategies emerge and joggers like my morning friend become a thing of the past.

DEFINITIONS AND CONFOUNDERS

DSM-IV recognizes 2 types of restricting eating disorders whose most common feature is a deliberate alteration in caloric intake. As you know, bingeing/purging behavior is one type-classic bulimia nervosa-characterized mostly by the familiar intense restriction of food intake punctuated with temporary episodes of disinhibitory behavior. The other type, sometimes called restricting type anorexia nervosa, has few or no periods of disinhibition. Although many patients may freely transit between these behaviors, we focus our discussion on restricting anorexia, hereafter referred to as AN.

At first blush, researching the underlying neurobiological mechanisms behind AN might seem a fairly straightforward task. It has a fully known-even archetypal-set of symptoms. Its clinical course is well characterized. The disease has a surprisingly narrow age of onset (early puberty) and is mostly experienced by females, which easily makes AN one the most homogeneous of all psychiatric disorders. Would that investigating schizophrenia had such predictive luxury!

Scratching below the surface of the disorder reveals why research into AN has been such a challenge, however. Appetite regulation is made up of complex interlocking, incentive-driven motivational hormonal and neuronal circuitries. These circuits can be pulled in many directions, especially where the food supply is cheap and readily available to so many. From classic metabolic aberrations to more purely psycho-biological issues, there are many places where dysfunction could arise.

Given such variability, it is perhaps not surprising that AN has a bewildering, multifactorial etiology. There are sociocultural factors to consider; there are developmental factors to consider; and there are underlying genetic factors that may influence the psychosocial issues. (As we’ll see in Part 2, AN shows surprising heritability.) Even in healthy populations, the factors that determine appetite are many and include an individual’s homeostatic needs, his or her perceptions of those needs, the tendency to favor certain consumptive strategies over others, and food’s natural rewarding (and also punishing) properties.

The bottom line? No single biochemical alteration has ever been shown to be both necessary and sufficient to produce the disease. One might be tempted to say diseases.

As if this isn’t complex enough, there is a powerful chicken-and-egg issue to consider. Severe caloric restriction can cause equally severe changes in the functioning of the brain. Patients with AN usually experience profound alterations in the metabolism of specific regions in the parietal, temporal, frontal, and cingulate cortices. They tend to have reduced brain volumes. Many regress to preadolescent gonadal function. Did the changes in the brain lead to the symptoms? Did the symptoms lead to changes in the brain? Did they exaggerate a premorbid trait? Or cause the predilection to come into existence?

Navigating the distance between trait and state is a difficult feat to perform under the best of circumstances. With disorders that involve appetite regulation, researchers face many challenges on the road to identifying their underlying neurobiological substrates.

Despite these hazards, real progress has been made, and one quite attractive hypothesis has been published that has many falsifiable features. It is to this work that we turn, beginning with an embarrassingly brief summary on the neurocircuitry of appetite control.

APPETITE CONTROL

Although research on the specifics fills volumes, the functional circuitry needed to understand AN can be boiled down into 3 specific steps (Figure). We will take as an example the most studied topic (and perhaps the most delightful) . . . what happens when we bite into something sweet.

1. Initial stimulation

Chemoreceptors on the tongue detect a sweet stimulus and immediately broadcast the good news to the brain stem (via the spinal cord, medulla and, eventually, the nucleus tractus solitarii [NTS]). The NTS tosses the signal to the thalamic taste center in the middle of the brain.

2. Routing to the insula

The thalamus sends a stimulatory signal to the primary gustatory cortex, which is connected through a series of dense neural circuits to the anterior insula. That’s an important relationship. As you may know, the in-sula is involved in the process of interoception, which includes perceptions of temperature, muscle tension, itch, tickle, sensual touch, pain, perceptions of stomach pH, intestinal tension, and hunger. The insula creates an integrated perception of these disparate internal feelings, delivering to us a fairly unified appraisal of the physiological condition of our bodies. It is perhaps not surprising that when researchers looked for neurological substrates behind AN, alterations in the function of the insula were among their first targets.

3. Routing to the rest of the brain

Once the insula is stimulated, the signals become routed through an intricate series of reciprocating pathways. These pathways involve the amygdala, anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). Although complex, the route of stimulation can be divided into 2 overall cortical-striatal pathways: afferents from the cortical structures that are involved in the anterior insula and interconnected limbic structures (forming the so-called ventral neurocircuit) are directed to the ventral striatum. Cortical structures that help mediate more cognitive strategies send inputs to the dorsolateral striatum. These form a secondary dorsal neurocircuit.

These now fully aroused circuits chatter over interconnecting feedback loops that result not only in the perception of taste but also how you feel about it. The amygdala, for example, provides information about affective relevance, potentially stimulating reward systems in the brain. The ACC is involved in conflict monitoring, potentially mediating if not generating “eat” or “do not eat” commands. The OFC is involved in executive functions, and, thus, in planning future consequences and impulse control.

All these processes are stimulated by the simple act of eating a candy bar and eventually experiencing the sweet taste. As is evident here, however, such perception is not simple at all.

AN IDEA ABOUT ANOREXIA

With these background pieces of information in mind, we are ready to discuss recent behavioral and imaging data that all converge on a single idea about the neurobiology of anorexia. Some of the most interesting work has come from the finding that patients with AN have fundamentally different reactions to rewards and punishments and to the relationship between actions and outcomes than do unaffected controls.

The first set of experiments used classic “guessing game” behavioral protocols (usually involving positive and negative monetary reward exercises) while the participant’s brains were being imaged. Healthy participants generally show markedly differential activation profiles in the subgenual ACC and ventral striatum that are specific to both the positive and negative aspects of the game. These differences allow unaffected subjects to discriminate between positive and negative feedback experiences in their psychological interiors. Women who had recovered from AN did not show differential activation profiles of the subgenual ACC and ventral striatal targets in these games. They showed equivalent profiles-and in both the positive and negative aspects of the protocol. That’s not a trivial finding. It is quite possible that individuals with AN have an impaired ability to perceive the difference between positive and negative feedback information. Subsequent behavioral work using different protocols confirmed this finding. Interestingly, and for whatever reason, this impairment led to a negative bias.

The second set of experiments also used imaging in conjunction with behavioral tasks. These tasks involved measuring connections between actions and outcomes. Healthy controls showed a relatively mild activation of the caudate-dorsal striatum and the regions that project to them (the dorsolateral prefrontal cortex and parietal cortex) in such tasks. As you recall, these areas are involved in planning and foresight, impulse control, and executive functions, as well as working memory. Participants who had recovered from AN showed a greatly elevated response in the same experiments. Behaviorally, they appeared to be looking for “rules” in the tasks where there were none and were overly concerned-even obsessively concerned-with making errors. They appeared to be overdriving a broad spread of their executive functions, an insight consistent with the imaging data, as well as other behavioral experiments.

Combining these 2 sets of experiments has suggested to some researchers that a behavioral “perfect storm” is brewing in the brains of affected subjects. Anorexic patients display an absence of appropriate reward processing responses; at the same time, they possess an increased activity in the neural substrates that are concerned with the consequences of their behavior. Perhaps the latter exists in an attempt to compensate for a lack of appropriate perceptive rewards and punishment feedback loops in the former.

This has led directly to a testable hypothesis, which explains AN as a conflict between an acquired negative reaction to food and the biological need to have it. Patients with AN recruit cortical executive functions in an attempt to settle the bias, all the while carrying dysfunctional rewards and punishment systems. These modulatory circuits become consistently overstimulated, leading to high anticipatory behavior and obsessive concern with future events.

How does that work? These modulatory circuits, sometimes referred to as top-down interoceptive circuits, meet information from the ascending interoceptive circuits that provide information about the body’s physiological state. (Remember our discussion about the insula?) These 2 neuroperceptive freight trains collide at the striatum. In this model, the top-down processes win. They alter the brain’s striatal reactions in response to food, resulting in the behavioral shifts and disease course.

These ideas represent just one way to interpret an increasingly large amount of imaging data, of course. Moreover, taken by themselves, these observations remain unsatisfying; they don’t have much explanatory power about the origins of the disease.

To answer questions of origins, we have to turn to a different set of experiments-ones involving genes and molecules and the neural substrates that carry them. As the Psychiatric Times resident geneticist, that is just what we will consider in Part 2. A fairly consistent story (complete with maddeningly important confounders) is beginning to emerge, and there may be strong genetic underpinnings behind this otherwise baffling disorder.

It doesn’t make my memory of my morning running friend during graduate school any less vivid. But it may make it easier for me to understand why she looked the way she did.

PRIMARY REFERENCES BEHIND THE DATA IN THIS SERIES
Kaye WH, Fudge JL, Paulus M. New insights into symptoms and neurocircuit function of anorexia nervosa. Nat Rev Neurosci. 2009;10:573-584.

Conna F, Campbell IC, Katzman M, et al. A neurodevelopmental model for anorexia nervosa. Physiol Behav. 2003;79:13-24.

Klump K, Burt SA, McGue M, Iacono WG. Changes in genetic and environmental influences on disordered eating across adolescence: a longitudinal twin study. Arch Gen Psych. 2007;64:1409-1415.