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.
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.