Saturday, December 18, 2010

Compulsion (with opera)

In this post I mean to review the basic neurobiology of compulsive behavior (uh oh, 90% of you just turned off your computers and started watching past episodes of "Top Chef, Just Desserts" - and how could Morgan not have won, anyway?), and also figure out why Dr. Garner's presumably serotonin deficient, hair-pulling mice began scratching and removing hair MORE on a serotonin-promoting mouse chow diet with added glucose and tryptophan.

To understand what might be happening, we have to back up and talk about obsessions and compulsions and where they exist in the brain.  For everything we are has a place in the brain (right click in new tab for a song).

Compulsions mean performing unpleasantly repetitive or seemingly unnecessary acts in order to prevent perceived negative consequences ("step on a crack, break your mother's back").  Scratching, hair pulling and twisting do fit under that definition, as people often perform the behavior to stave off anxiety.  Impulsivity is the predisposition toward rapid, thoughtless acts without regard for the eventual negative consequences (such as gambling or uncontrolled aggression), and hair-pulling (trichotillomania) and picking may also fall under this category. At first glance, compulsion and impulsivity may seem opposites, but they run in parallel neuronal tracts, and people with symptoms of one will often have symptoms of the other.

The compulsive and impulsive psychiatric diseases are among the most highly inherited diseases in psychiatry.  Obsessive compulsive disorder, ADHD, Tourette's, autism, and substance abuse disorders indisputably run in families, suggesting (more even than for other psychiatric disorders) physical brain differences between those susceptible to the disorders and those who are not.  Children with autism, for example, are likely to have tics or repetitive physical movements consistent with Tourette's or OCD, or impulsivity consistent with ADHD, or both.  Those obsessively driven to drink or gamble are also more likely to be impulsive as well.  There are all sorts of subcategories of different kinds of obsessive and impulsive behavior that exist along different neuronal tracts -  the complexity, therefore, is immense.

However, one can conceptualize the brain as doing two things for impulsive behavior and compulsions.  On one hand, the brain has tracts that promote these behaviors - these tracts generally run from the center, more "primal" parts of the brain up to the outer "civilized" cortex.  The cortex tends to work in the opposite direction, inhibiting compulsions and impulsivity.  Therefore one can become vulnerable to these behaviors via two means - either by problems that increase the "primal" signals from the center of the brain, or by problems that block the "civilizing" influence of the outer shell of the brain. 

In terms of neurotransmitters, serotonin deficiency is thought to be responsible in part for anxiety driven behaviors, obsessions, skin-picking, hair-pulling, etc.  Dopamine deficiency in the cortex is responsible for impulsivity (such as in ADHD).  However, dopamine excess is thought to be responsible for motor tics, tapping in autism, for example, and other obsessive physical acts.

But let's bring it back to Garner's mice.  They are genetically prone to hair-pulling behavior (Jaminet postulates this is due to a predominant Th1 immune/inflammation response to infection), and the hair-pulling worsened with increasing serotonin turnover in the brain, despite the "general rule" that anxiety and picking/hair-pulling behaviors are due to serotonin deficiency.

(In the mood for more opera?  If so, how about this classic?)

But not so fast.  There may not be as much of a mystery as we like to think.  In his paper, Garner brought up the fact that SSRIs (selective serotonin reuptake inhibitors), while used to treat trichotillomania, can also induce skin-picking behaviors in some.  His idea (I'm stretching, a bit) by the end of the paper was that this particular strain of mice would be a bad candidate for SSRI treatment.  He may be right, but he may be wrong, because increasing serotonin turnover in the brain via diet is not the same as administering an SSRI.

The problem with thinking we know anything about the human brain is that the brain is immensely complex.  Remember - a hundred billion neurons with 10,000 interconnections EACH who fire up to 1000 times per second.   And when we strictly limit ourselves to serotonin, we are talking 20 different flavors of receptors, each doing subtly different things.  Garner's mouse diet increased serotonin turnover overall in the brain, presumably jacking up the general serotonin signal.  Well, there are mouse models for everything, and some have shown that increasing the activation of the serotonin 2C receptor (5-HT2C receptor)  increases compulsive behavior, just like in Garner's mice.

SSRIs work a little differently than just blanket administration of serotonin in the brain.  SSRIs result in the downregulation of the post-synaptic receptors, among them 5-HT2C.  Therefore they will (in general) decrease the overall signal away from compulsion, perhaps relieving symptoms.  SSRIs will tend to favor serotonin signal to another receptor, the serotonin 2A receptor.  Activating this receptor tends to reduce anxiety and compulsions. 

(more music)

Psychiatrists use a whole host of SSRIs (prozac, paxil, zoloft, celexa, lexapro ect. ect. yawn yawn) but only one serotonin receptor activator (buspar, a 5HT2A agonist which may well be one of the most useless medicines we have in my experience).  For better or worse, and for all their limitations, SSRIs do a better job of modulating the anxiety/compulsion symptoms than straight-up administration of serotonin (via a tryptophan promoting diet or tryptophan supplements).

Again, the medicines are not my interest in this blog, but our knowledge of how they work, and the animal models, give us clues as to how our brains work, and that I find interesting.  Are our brains better off with a diet of whole foods with just enough omega 3s, not too many omega 6s, no weird industrial designer pseudofood or toxic plant proteins?  Most likely. And Garner's mice tell us that straying from the design parameters of the diet our brain likes may well cause major problems.  And that sugar and tryptophan supplementation may cause major problems, if we share genetic vulnerabilities with his mice.

That is one theory.  I also question whether kyurnetic and inflammation in general were escalated with Garner's mice's experimental diet.  From my comments on Dr. Jaminet's post:

Just want to add to my speculation about increasing inflammation (which I think is the more likely scenario) – tryptophan is [a] precursor for both serotonin and kyrunetic. The former helps modulate major brain circuitry communication, the latter seems to encourage excitatory communication, and in excess will be neurotoxic. Kyurnetic is elevated in cases of inflammation. SSRIs increase serotonin initially, but then after 2 weeks, the post synaptic receptors are down regulated, so the overall effect is not so much to increase serotonergic transmission, but to make what transmission there is go through more efficiently. SSRIs also seem to favor the metabolic pathway of tryptophan to serotonin rather than kyrurnetic.

It is possible that by massively increasing the tryptophan uptake into the brain in the context of the baseline inflammatory diet and a genetically vulnerable mouse population, there were increases in kyurnetic, leading to neurotoxicity and mouse psychopathology. I’m not a big fan of l tryptophan and 5 htp for that reason – I know you are not a fan due to tryptophan's role in the infectious theory of neurotoxicity. Since this scenario probably occurs in the human brain as well, it makes one wonder about our USDA diets.
  So, take your pick.  But there are many plausible methods by which increasing tryptophan can increase picking/hair-pulling behaviors, and more and more reasons to eat well from the beginning.


  1. Maybe the mice became serotonin resistant with such a high influx?

  2. That's my other theory, serotonin "burn-out" - and if it holds true for humans, it would make sense to explain some of the increase in anxiety and (carb-craving) atypical depression since the population has greatly increased the % of carbohydrate intake. However, I haven't seen evidence that serotonin resistance actually happens, or if it does, that it is a bad thing (the receptors do down-regulate with SSRIs, but that tends to happen when the meds begin to work!) (Nice Mozart!)

    The scary big picture in any case (serotonin resistance or overactivation of 5HT2C receptor or inflammation/kyrunetic massive influx) is that, again, if the vulnerability holds for humans, that diet causes the increase in symptoms which would then be partially mitigated by the administration of SSRI (again their working mechanism seems to be the down-regulation of the serotonin receptors or decreasing the conversion of tryptophan to kyurnetic), but the actual causative agent is merely being masked, and eventually the meds stop working (if you happened to get lucky and they work in the first place) as the insult keeps happening. Any decent psychiatrist uses a multi-modal approach to treat psychiatric illness - I spend much of my time talking therapy, stress-reduction, exercise (and diet). And yet often it feels like swimming againt the tide.

  3. I too am a bit compulsive (good compulsive) about opera. Here in Pittsburgh, PA we usually have four opera productions come through per year. I attended when Carmen was here last year. I had heard all the famous vocal excerpts from this opera but I had never heard this orchestral Entr’acte to Act III:

    It was very special to hear this for the first time at a live performance.

    Great examples of how animal behavior can be affected by what they eat (ingest in the case of toxoplasma gondii) can be found in several of Peter’s 2007 posts (search Memes and Fiaf at

    Thank you Dr Deans for your blog.


    Philip Thackray

  4. I recall reading in NewsWeek I think it was when I was waiting in a dentists office years back (at least 10), title was "Harvard Medical School uses dime sized lobotomies" - the story said people who underwent this treament came out compulsive about cleaning toilitries.

    Was strange, but clearly temporal lobe plays into it.

    I have a simple solution that can help people over come compulive behaviour. Just say "How would you feel if I told you you really don't have any choice in what your thoughts are" or present it as if "I'm going to show you why you don't have control" or - not appropriate for clinical setting, but "I'm going to take away from you your ability to choose"- I'd think MOST people would respond and say perhaps loudly even "No you are NOT, only I control what I think" and well ? I bet they'd have an awakening right there ! I bet Milton Erickson would like that one.

    I studied Erickson for the fun of - he's a REAL neat study. If he's alive, he's someone I'd love to meet.

  5. I was just thinking, not all compulsary behaviour is undesirable. At least at the partitiveness of organs. Take the heart. If the heart were not compulsive ? We'd die. So, clearly life requires some component of compulsive behaviour, breathing too. I suppose ones response might be, but Tim, those are autonomous - you can't stop your heart, or control your breathing, yet ? In Eastern meditation practices ? indeed we see you can control your heart rate, and indeed in yoga (I do not practice, I can't even touch my toes) breathing is the end all be all of learning to become aware in the moment I understand.

    HOWEVER, If one becomes compulsive by some clinical definition ? to where a behaviour inhibits their ability to perform tasks in life ? possibly even interfering with life ? like smoking, drinking, even masturbation (gee, I bet I hit the third one there if I follow the first two, no wonder they all go hand in hand) ? Is it neurophysiological ? is it ? I question this, because by a mere thought process I made a conscious decision to stop drinking and smoking. If I DO start ? one will lead to another and to another. I'd say there is something about pleasure center involved with compulsary behaviour but then you have massochistic behaviour in some people. Perhaps compulsive behaviour is to event phenomena what cancer is to tissue propagation. Perhaps like cancer grows with no regards for the host it kills, perhaps compulsive behaviour is rooted in a lacking - as Arhtur Koestler would say 'integrative identity'. Perhaps nationalism fragments the world, and once we accept living apart as one species ? we are bound to live compulsory until we restore homeostatis to our persona (I was tempted to tag on an 'a' there to pluralize it, but let's not open that door). In other word's - perhaps compulsory is derived from how connected or disconnected we feel we are, which might be related to Amygdala, as one of my favorite books by Karl Pribram shows this babboon who had an amagdylectomy - poor larry was #1 in the tribe? highly integrated ? Afterwards? Larry was the LOWEST in the society, totally disconnected, and I bet compolory in behaviour too - bah, hair brained theory #1 for me on this subject, but maybe someone derived something from it.