The Cellular and Molecular Substrates of Anorexia Nervosa, Part 2
Last month, I wrote on Part One of an article from the magazine Psychiatric Times titled "The Cellular and Molecular Substrates of Anorexia Nervosa, Part One." As I promised, I am writing on Part Two now that it has appeared (the original link I found was bad, and I had to hunt down the article, so I apologize for the delay, but here it is!).
The author, John Medina, summarized the first article as follows:
A testable hypothesis was outlined: AN was described as a conflict between an un-acquired biological need to have food and an acquired negative reaction to it. Patients with AN recruit cortical executive reactions in response to appetite cues, reactions that insert a top-down “food-negative” bias into the normal drives for fuel. These executive reactions are consistently overstimulated in AN patients, leading to high anticipatory behavior and obsessive concern with future events. Derived mostly from noninvasive imaging studies, this notion of conflicting priorities (complete with a dysfunctional reward/punishment system) has surprising empirical support.
But it is hardly the complete story of AN. Besides behavioral and cellular concerns, there are also molecular interactions to consider. It is to these efforts that we turn, focusing on the “usual regulatory suspects” of dopamine and serotonin neurotransmitter biology.
Medina first begins discussing the role of malfunctions in the dopamine system in people with AN, since many anorexics report varying levels of asceticism, anhedonia (the inability to find anything pleasurable), and the difficulties in finding something consistently rewarding. This is otherwise known as the Theme of My Life. These are considered trait features because they often exist before the onset of illness and persist after recovery. Other clues pointing to the dopamine system are difficulties with visual tasks (which can often signal a malfunction in the dopamine system), lower levels of dopamine metabolites in the cerebrospinal fluid even after recovery, variances in the genes of dopamine receptors in the brain, as well as brain imaging studies.
The other major neurotransmitter being studied with respect to anorexia is serotonin. Medina included a diagram (that I've copied here) that portrays the two hypotheses related to abnormalities in the serotonin system that may contribute to anorexia. The first hypothesis is that people with AN have increased levels of serotonin in the brain, which may contribute to the common traits of harm avoidance and anxiety, as well as the general lack of effectiveness of SSRIs in treating AN. The other hypothesis has to do with an imbalance in serotonin receptors which can be altered by both hormonal changes and stress. The evidence for this has to do with the usual onset of AN during puberty/adolescence, and many times the onset coincides with a particularly stressful time in the sufferer's life.
Starvation-induced reductions in levels of extracellular 5-HT, for example, might result in reduced stimulation of postsynaptic 5-HT1a and 5-HT2a receptors, leading to behavioral alteration. The resulting dysphoria, normal in unaffected individuals, might be exaggerated in patients with AN.
There are testable questions surrounding these ideas. Forcing AN patients to eat, for example, might stimulate postsynaptic 5-HT1a and 5-HT2a receptor activity. This stimulation would lead to an elevation in dysphoric mood, transforming eating and weight gain activities into traumatic stress-inducing experiences. This might explain the no-win behaviors so common in AN patients. If the patient were allowed to continue to starve herself, anorexigenic information related to neuropeptide alterations (reduced b-endorphins, elevation in stress-related metabolism such as elevated corticotropic-releasing hormone), might exacerbate AN symptoms by driving food-restricting behaviors. Whether eating or starving, the same dysfunctional circuitry would be stimulated, all leading to the symptoms.
... Persons with AN show unique anxiety-related 5-HIAA metabolic perturbations. The weight loss in these patients results in a reduction in 5-HIAA CSF levels. But they concomitantly show dramatically elevated 5-HIAA receptor binding in specific cortical and limbic structures—something not seen in healthy controls. Food might very well be anxiogenic in these individuals.
Which, really, explains both everything and nothing. As Medina says, there is no one neurological system that is both necessary and sufficient for the development of AN. And I hate to rain on anyone's parade, but I doubt it will be just one thing or just one system or just one factor. Human behavior is way too complicated. Still, we have made enormous strides in understanding the scientific basis of anorexia, and I'm looking forward to future research.
5 comments:
Oh, but this fits in SO WELL with the paper Dr. Framptom posted over at ATDT! Dr. Frampton's paper, similarly supported by a broad range of empirical data, hypothesizes that it is dysfunction of the insula that causes AN.
(The insula is structure that serves as a transit station or way station for the areas of the brain primarily implicated in AN). Likewise, Dr. Framptom et al propose methods for testing thier hypothesis.
What makes these two papers dovetail so nicely is how Medina's focus is at the molecular level, while Frampton's is at the structural level. I highly recommend reading the Frampton paper even for those who aren't all that "sciency"; the explanation and first table are done in such a way as to make it highly readable.
Thanks for posting this article Carrie - and for your thoughts on it. I have yet to read the full article.
I would agree that restriction is anxiolytic in individuals with restrictive anorexia nervosa (AN) - i.e. the subtype of AN from which I have always suffered. My restricting and other 'over-regulating' behaviours were/are always triggered by anxiety and uncertainty. Those behaviours themselves are predictable and so make me feel more in control of perceived chaos in my life. I do not know how, or to what extent the brain serotonin/5-HT system is involved in my anxiety, depression and repetitive, over-regulating behaviours, but SSRIs and the older tricyclic antidepressants have never helped me. The risks outweighed any benefits. That said, my BMI was <16 at the time I took these meds.
I undertook some research 15 years ago examining the role of energy deprivation (elicited through combined increased exercise and reduced calorie intake) on the plasma ratio of free tryptophan (from which 5-HT is synthesised) to large neutral amino acids. The data demonstrated that energy deprivation increases this ratio - and therefore potentially the capacity for brain 5-HT synthesis. This might explain elevated 5-HT in starving anorexics with alteration of the structure and function of the post-synaptic receptors.
I agree this is a really complex area, albeit fascinating. On the basis that the proposed hypothesis stands, then re-feeding should reverse many symptoms. However, there are probably also other neurological pathways involved in maintaining anorexic rituals. As I have mentioned previously, I have a mild, high functioning ASD which likely contributed to both the development and maintenance of my anorexic behaviours. Given my lifelong 'penchant' for restrictive repetitive behaviours it has been easier for me to approach recovery by swapping dangerous rituals and repetitive behaviours for safer ones... This swapping helps to some extent but doesn't create the emotional 'numbness' of energy deprivation and low weight.
Irish,
I was going to blog on that paper today! And that's what is so nice about these papers (and other ones about the malfunctioning reward circuitry): they present good, testable hypotheses. Not that the testing will be easy or straightforward, but nevertheless.
Cathy,
I probably will always be rather rigid in my ways as well. What I need to do is make sure that rigidity works for me (such as eating breakfast every morning) rather than against me (only eating the same one food for breakfast every morning, when I would eat breakfast :s). I've found more freedom in accepting these parts of my personality and not trying to change them but instead trying to work with them. I've always been anxious and perfectionistic and analyzed everything way the freak too much. Although I need to tone down the volume on these (tone it way down!), total silence isn't a realistic goal.
Thanks for your feedback, as always!
Thanks Carrie :)
I really enjoy the deep analyses and philosophical discussions we have on this blog (and some other ED blogs I've recently found). Such philosophy and discussion is important, and is great 'brain fodder'. There is a need to de-construct some of the dreadful social constructions and media representations of EDs as (e.g.) 'lifestyle choices' or egocentric vanity - which EDs are sooooo not....
Hey Carrie. . .
I will have to read this again at a time when I am not so tired but. .
I was wondering how this played into the comorbidity between depression and EDs? I thought that serotonin was reduced in depression and that had also been found in EDs -- and therefore antidepressants are usually prescribed to regulate serotonin levels and increase uptake. Did I get it wrong? The study found that those with AN have increased serotonin levels?
Also, I find it interesting that dopamine is involved and many psychiatrists are now prescribing antipsychotics which are neuroleptics that act on dopamine receptors. . .
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