This month's issue of Psychiatric Times contains the first of a two-part series on examining The Cellular and Molecular Substrates of Anorexia Nervosa. Although it's not a simple read (the author assumes some basic neuroscience knowledge, but it's nothing super-prohibitive), John Medina does a wonderful job of explaining some very complicated research results.

Research into the whats, wheres, hows, and whys of anorexia is a rather complicated matter. Compared to other brain diseases, Medina says, AN should be pretty straightforward. After all, age of onset and other characteristics of sufferers are almost stereotypical. Yet some of the research has been hampered by difficulties in discerning underlying neurologcal differences, those that are due to current malnutrition, and those that may be a neural "scar" from previous malnutrition. As well, appetite regulation is a very complex and convoluted process. There are signals for hunger, satiety, disgust, pleasure, to find food, to share food, to eat food, to digest food...you get the idea.

Moreso, says Medina,

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?

After discussing appetite signaling and regulation (be sure to click on the figure!), he then discusses two fascinating studies on reward regulation in people with AN.

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...Women who had recovered from 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...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.

Indeed, the conflict between reward and punishment has been proposed as a hypothesis by researcher Charlotte Keating in a paper titled "Theoretical Perspective on Anorexia Nervosa: The Conflict of Reward," that I blogged about here.

Medina says that in next month's Psychiatric Times, he'll discuss the genetics and neurobiology of the origins of anorexia. I'll keep you posted!