The face in the coffee beans

Howdy everyone. I realize that I've been a little lax at updating this blog- I've been launching my career as a freelance science writer, and that was a giant time suck, to say the least. But now I've gotten established and I'm looking forward to blogging regularly here about the latest ED research. To get you back in the swing of things, I'm starting off with a little brain teaser.

Do you see the face in the coffee beans?

This is one of the neuropsychological tests that researchers have used at the Institute of Psychiatry in London. People with EDs, especially anorexia, are really good at finding the face in the coffee beans. They find it easy to focus on the details and ignore the bigger picture. Essentially, they embody the phrase "can't see the forest for the trees."

These tests aren't diagnostic of anorexia, but they do indicate a detail-orientation, a tendency to lose sight of the big picture (the coffee beans) and focus in on tiny little details that ultimately reveal a face. The "Where's Waldo" books are something similar. For someone with an eating disorder, they will focus on the fact that a Hass avocado has 300 calories rather than focusing on the good fats and oils in the fruit, the buttery taste of guacamole, that California burger they had at a backyard cookout. Or even the need to eat such fats to think better and have shiny, smooth hair. No, an avocado only means 300 calories. Period.

Kara Fitzpatrick at Stanford University gives a talk about the latest eating disorder neuroscience research. It's a series of 3 videos that last slightly over 20 minutes. You can easily just listen to the talk--the visuals aren't utterly crucial.

Part One

Part Two

Part Three

I hope you enjoy!

Bone health and eating disorders

A recent study from the Journal of Bone and Mineral Research found that women with anorexia had much higher levels of fat in their bone marrow than women without AN (Ecklund et al, 2010). The study was generally publicized as "OMG! Anorexics have FAT on their bony bodies!" Which, as an interesting irony and news hook, I'll give you. But the story goes much deeper than that, which some of the news coverage touched on but really didn't delve into (they appeared to get stuck on the "WTF- could anorexics be fat?!?" part).

Eating disorders are associated with an increased risk for osteoporosis--and it ain't no joke. I've learned that the hard way, with three broken bones and several stress fractures. There are many hypotheses for this increased risk, including deficits in estrogen, high levels of cortisol, and high levels of leptin. I'm guessing each of these plays a role in the decrease in bone mass and density through either the metabolism of bone cells and/or a dramatic decrease in the formation of new bone cells during malnutrition.

This study points to a new mechanism for the dramatic bone density decrease seen in eating disorders in general and anorexia in particular. At the center of larger bones is the bone marrow, one type of which is the red bone marrow and produces new blood cells. The other type is the yellow bone marrow and contains fat cells that can be used as an energy source in cases of extreme starvation. Furthermore, the two types of bone marrow can be interchangeable--in cases of extreme blood loss, the yellow marrow can be converted to red marrow. What Ecklund et al found in this most recent study is that red marrow can be converted to yellow marrow if the body is profoundly starved, which can result in premature osteoporosis.

The study subjects with anorexia had much higher levels of yellow marrow than red marrow, and the researchers hypothesized that the body had prioritized the formation of extra fat for future energy needs at the expense of red blood cell formation (I'm wondering whether this also helps to explain the high levels of anemia seen in people with eating disorders). The innate intelligence of the body never ceases to astound me. In a starving person, fat (which is essentially energy) is much more useful than red blood cells. Without energy, the body shuts off. With fewer red blood cells, you may be more easily fatigued, but mild levels of anemia are rarely out-and-out life threatening.

It will be interesting to see if there is follow-up research done to see how weight restoration and recovery change the ratio of red and yellow marrow, and whether these changes persist for a long period of time after recovery.

Serotonin, antidepressants, and eating disorders

Earlier this week on Twitter (do you follow ED Bites on Twitter? You know you want to...), I ran across an interesting article about why some antidepressants don't work in some patients. The article was published last week in the research journal Neuron and is titled "5-HT1A Autoreceptor Levels Determine Vulnerability to Stress and Response to Antidepressants." (Clicking the link will take you to the free full-text of the article.) I'll let the opening of the article's Science Daily press release explain the research for me:

An excess of one type of serotonin receptor in the center of the brain may explain why antidepressants fail to relieve symptoms of depression for 50 percent of patients, a new study from researchers at Columbia University Medical Center shows.

...Most antidepressants -- including the popular SSRIs -- work by increasing the amount of serotonin made by cells -- called raphe neurons -- deep in the middle of the brain. Serotonin relieves symptoms of depression when it is shipped to other brain regions.

But too many serotonin receptors of the 1A type on the raphe neurons sets up a negative feedback loop that reduces the production of serotonin, Dr. Hen and his colleagues discovered. "The more antidepressants try to increase serotonin production, the less serotonin the neurons actually produce, and behavior in mice does not change," Dr. Hen says.

Seeing as anti-depressant therapy hasn't shown much promise in the treatment of anorexia nervosa (although it does appear to help treat co-morbid conditions like depression and anxiety), this research could help with the development of new treatments for AN. It also seemed like a good a time as any to discuss the links between serotonin levels and eating disorders. In a 2005 review article, titled "Serotonin alterations in anorexia and bulimia nervosa," Walter Kaye wrote that people with either anorexia and/or bulimia showed alterations of brain functioning in specific neural areas:

Importantly, such disturbances are present when subjects are ill and persist after recovery, suggesting that these may be traits that are independent of the state of the illness. Emerging data point to a dysregulation of serotonin pathways in cortical and limbic structures that may be related to anxiety, behavioral inhibition, and body image distortions...Alterations of these circuits may affect mood and impulse control as well as the motivating and hedonic aspects of feeding behavior. Such imaging studies may offer insights into new pharmacology and psychotherapy approaches.

The serotonin/anorexia connection has been researched over the years (searching PubMed for "serotonin anorexia" gives you over 700 results), and the most recent thinking goes something like this. People with anorexia are generally thought to have unusually high levels of serotonin in their brains, and high levels of brain serotonin have been linked to anxiety and obsessionality. An old BBC article titled "Genetic clues to eating disorders" has a quote from Janet Treasure that explains some of the link:

People with high levels of serotonin are prone to anxiety. Dr Janet Treasure, director of the eating disorders unit at the Maudsley, believes this could be behind anorexic patients' ability to suppress appetite. She said: "In anorexia nervosa the drive to eat can be inhibited, but we know that in normal people who are starved they will kill each other and do all sorts of morally repugnant things, and eat all sorts of foodstuffs that you wouldn't normally touch.

"Yet that doesn't happen in anorexia nervosa, so there's some aspect of the appetite system that isn't working."

The unit looked at the biology of stress mechanisms, in particular the fight or flight response. This is where the body prepares itself for action when confronted by a stressful situation. Heart rate and blood pressure rise and two of what are usually humans' highest priorities, eating and reproducing, are put on hold. It is possible that anorexic people are chronically in an acute state of stress reaction - they are constantly in a fight or flight state of mind.

And by restricting food intake, people with anorexia can lower the amount of serotonin their bodies can make (serotonin is ultimately derived from the essential amino acid tryptophan). This actually makes people with anorexia feel better. However, the brain begins to sense the decreased serotonin production and tries to maintain homeostasis by increasing the number of serotonin receptors. Thus the brain is back at Square One, as it is producing less serotonin but is using the decreased amount much more efficiently. So restricting doesn't feel as good, and the (obvious!) solution is to eat even less. And thus that negative cycle is born and the anorexic becomes trapped by their own brain chemistry.

Refeeding would then increase the amount of serotonin in the brain before the brain has a chance to decrease the number of serotonin receptors. This could be the neurological equivalent of All Hell Breaking Loose and could very well explain why refeeding is so distressing, although I don't think there has been any formal research done on the subject.

In bulimia, the serotonin problem is reversed. People with BN appear to have much lower than average levels of serotonin in the brain, which may be temporarily increased by binge eating.* Purging increases levels of vasopressin, which can have a euphoric and sedating effect, thus making the binge/purge cycle addictive much in the same way that starvation becomes addictive in AN. The chronic low levels of serotonin in BN also explain why SSRIs can be effective at reducing the urges to binge and purge.

Of course, plenty of people cross over from anorexia to bulimia, and I haven't the slightest idea of how serotonin might affect that crossover. So many brain systems are thrown out of whack during an ED that I don't know an exact answer will ever be found.

*The story is, as usual, a little more complicated than this, but the basic idea is the same.

Reward and punishment in anorexia nervosa

A recent review article titled "Theoretical perspective on anorexia nervosa: The conflict of reward," has to be one of the most fascinating scientific reads I've had for a long time (and my Facebook friends can confirm that I read a lot!). The gist of the paper is that many of the behaviors of AN, such as food restriction and excessive exercise, are initially rewarding, they eventually become punishing. An overlap in the neural circuits that process reward and punishment enables these two factors to become all knotted up, or "contaminated."

The author, Charlotte Keating, begins her argument with the concept of anhedonia, or an inability to experience pleasure, which is central to both major depression and a clinical feature of AN. Moreover, excessive exercisers tend to report greater levels of anhedonia, perhaps because exercise is being misused as a mood elevator. Initially, exercise and food restriction are very rewarding, which may be partly why people with AN become entrenched in these behaviors in the first place. Not eating feels better. Exercising feels better. Continued food restriction and excessive exercise only reinforces the reward, leading to the expectation that not eating and over-exercising will make the person with AN feel better.

The problem, says Keating, is that food restriction and excessive exercise are ultimately rather punishing behaviors. So how can punishing behaviors simultaneously be rewarding? The answer appears to lay in the anterior cingulate cortex, which (among many other things) is involved in the processing of reward, punishment, conflict, empathy, and other rational cognitive behaviors. In people with AN, the ACC doesn't process reward the same way; whether ultimately derived from dopamine circuits, reward is blunted in people with AN.

Writes Keating:

"...it may be that hypoactivity in ACC (which reflects the bulk of literature investigating this region in AN) reflects an impaired ability to adjust maladaptive behaviors which may also lead to illness maintenance."

Thus reward-punishment contamination means that the AN sufferer has a greatly reduced capacity for motivation to change, and to regulate his/her pathological behaviors. Furthermore, a low motivation for change only increases the neural "blurring" between reward and punishment.

The ultimate goal is not only to improve motivation to change by decreasing the blurring between reward and punishment in AN sufferers, but also to target "the mechanisms that may be responsible for bringing about behavior modification."

(cross posted at ED Bites)

High cholesterol in anorexia nervosa

One of the (many) paradoxes of anorexia is that the excessive weight loss that accompanies the disorder often results in high cholesterol levels. This seems to go against what many doctors and researchers say about cholesterol: decreasing food and fat intake as well as increasing exercise should decrease cholesterol levels, not raise them.

It turns out that this high cholesterol (formally known as hypercholesterolemia) also happens to starving people, and is a well-known side effect of malnutrition. The question that remains, then, is why? Why this paradoxical effect?

Let me back up a bit and explain what cholesterol is and what it does. Cholesterol "is a lipidic, waxy alcohol found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes where it is required to establish proper membrane permeability and fluidity." Cholesterol is hydrophobic, meaning it doesn't dissolve in water or blood, so it is transported in the body by lipoproteins. Your total cholesterol count is a combination of triglycerides, low-density lipoproteins (LDLs, aka "bad" cholesterol) and high-density lipoproteins (HDLs, aka "good" cholesterol). Both LDLs and HDLs transport fats along with cholesterol. The lipid hypothesis holds that there is a causal link between high intake of saturated fats, hypercholesterolemia, and heart disease, promulgated by none other than Ancel Keys, he of the Minnesota Starvation Study.

So. What does this all mean?

Besides just having unusually high levels of total cholesterol, patients with anorexia were found to have unusually high levels of an enzyme called cholesterylester transfer protein (CETP), which swaps cholesterol and fat molecules between the different lipoproteins. The researchers speculated that low levels of thyroid hormones and low breakdown of existing cholesterol contributed to high cholesterol levels, and that "CETP activity increases cholesterol turnover as an adaptation to its low intake." The highest levels were seen amongst AN patients who also binged and purged. In severely malnourished AN patients, however, cholesterol levels and CETP activities drop dramatically.

Other studies have suggested that starvation results in the increased synthesis of lipoproteins. It could also be that these lipoproteins are transporting fats in the body, which the body is relying on as fuel due to insufficient food intake. If the body is going to rely on fat as fuel, it needs some way to mobilize those fat molecules and get them to a location where they can be broken down effectively. This could perhaps explain the abnormal rise in cholesterol levels. As body fat is essentially depleted in the severely malnourished AN patients, the body may rely more and more on breaking down organ and muscle tissue, thus decreasing the need for abundant lipoproteins.

Regardless of the reasons for hypercholesterolemia during anorexia, it is NOT an indication that the sufferer needs a low-fat or low-cholesterol diet. With sufficient foot (and fat!) intake, cholesterol levels typically right themselves rather rapidly.

(cross-posted at ED Bites)

Starving in the Midst of Plenty

One of the characteristics of anorexia, says researcher and clinician Daniel LeGrange, is not just starvation; rather, he says, it is starvation in the midst of plenty. While one theory is that anorexia may have evolved as an adaptation to allow humans to better withstand famine, most modern cases of anorexia occur where food is abundant. In that sense, perhaps anorexia can be understood as self-administered starvation.

Which is where a recent study on cocaine addiction comes in.

A recent study from the University of California, San Francisco found that self-administered cocaine had different effects on dopamine receptors than a passive infusion of the drug.

Says a press release:

...cocaine-associated changes were due to an associative process and not just to the pharmacological effects of the drug. "We suggest that neuroadaptations induced specifically by drug self-administration may form a powerful 'memory' that can be activated by drug-associated cues," explains coauthor Dr. Billy T. Chen.

How self-administration of a drug but not a natural reward can elicit enduring changes within the brain remains a mystery. "Future studies are required to identify the exact mechanisms through which drugs of abuse alter neural circuitry that is normally accessed by naturally reinforcing events but is usurped by cocaine to persistently cement these synaptic adaptations, perhaps ultimately leading to pathological drug-seeking behavior," concludes Dr. Bonci.

While anorexia is not cocaine addiction, the illness does involve differences in dopamine levels and receptors in the brain. Perhaps part of what cements anorexia (besides the starvation itself) is the self-seeking behavior. The "benefits" of starvation to the sufferer are reinforced each time he or she skips a meal, binges, purges, and overexercises.

From an evolutionary standpoint, the survival of the human species means that people will need to begin eating after a famine has passed. The ability to withstand starvation may have descended from this. But anorexia nervosa may cement itself into a life-threatening illness when a person begins to starve while food is abundant.

Unearthing anorexia's genetic roots

While eating disorders remain complex, multifaceted brain diseases, research is uncovering the importance of genetics in causing these diseases. Some families have long known that eating disorders, like other illnesses such as depression, bipolar disorder, and anxiety disorders, run in families.

The question that has remained is how: how are risks for these illnesses inherited? And what are these risks, anyway? Despite all of the talk, there will almost certainly be no "anorexia gene" or "bulimia gene" uncovered. Issues likely involve differences in appetite regulation (especially the hormones leptin and ghrelin), and altered levels of the neurotransmitters serotonin and dopamine, which regulate mood.

Abnormal levels of serotonin have also been found in those with obsessive-compulsive disorder, an anxiety disorder that is several times more common in those with anorexia nervosa.* The close links between OCD and AN have prompted some researchers and clinicians to question whether anorexia should be classified as an obsessive-compulsive spectrum disorder. This spectrum includes Tourette's syndrome, tic disorders, compulsive skin picking, trichotillomania (compulsive hair pulling), and body dysmorphic disorder. All of which are, not surprisingly, more common in people with anorexia than in the general population.** This confirms and strengthens the contribution of serotonin to anorexia.

Now, researchers have made links between anorexia and what appears to be the illness' mirror image: 'bigorexia,' or muscle dysmorphia. Those who suffer from muscle dysmorphia, almost exclusively men, believe themselves to be small and unfit. Their response (again, the eerie mirror image of anorexia) is to bulk up through weight lifting, special diets, and occasionally injectible steroids.

The initial commonality between anorexia and bigorexia are the obvious body image distortions. But the similarities may go deeper than that. Finnish researchers studied five pairs of twins, which included at least one male with anorexia nervosa in each twin pair. A story on Reuter's Health revealed that the researchers found "a 'striking familial liability' for traits related to the eating disorder, including major depression, muscle dysmorphic disorder (which is sometimes called 'bigorexia), and obsessive compulsive disorder. The findings suggest that all of the symptoms have similar genetic roots, the researchers point out."

Just as telling, eight out of the ten twins had suffered from a mood disorder during their lifetime. And body dysmorphic disorder (especially muscle dysmophia) was common in the twins without AN.

The abstract of the study says this: In males, overweight commonly predated AN, and symptoms of body dysmorphic disorder, particularly of muscle dysmorphia, were common among the anorexia-discordant co-twins. Affective and anxiety disorders were present in both the probands and their co-twins. CONCLUSION: We found a strong familial clustering of AN, affective and anxiety disorders, and symptoms of muscle dysmorphia among men in the general population. In men, muscle dysmorphia may represent an alternative phenotype of AN.

While a study involving five pairs of twins is by no means conclusive, the link to muscle dysmorphia and mood disorders implicates a serotonin dysfunction as a contributing factor to anorexia and the body image disturbances that so often accompany it.

*And the reverse is also true: those with OCD are more likely to have AN or BN. Although this study out of Spain provides evidence that eating disorders and OCD might not be related.
**Sadly, research on bulimia, EDNOS, and binge eating disorder is limited at best.

(Cross-posted on ED Bites)