Neurophilosophy

TRICHOTILLOMANIA (or hair pulling) is a condition characterised by excessive grooming and strong, repeated urges pull out one’s own hair. It is classified as an obsessive-compulsive disorder (OCD), and is relatively common, affecting about 2 in 100 people. Sufferers normally feel an increasing sense of tension before pulling out their scalp hair, facial hair, and even pubic hair, eyelashes or eyebrows. This provides gratification, but only briefly.

Hair pulling is usually thought of as being psychological in origin, but an intruiging new study now suggests that it occurs as a result of defects in the immune system. The study, which is published in the journal Neuron, shows that excessive grooming and hair pulling occur in mice because of reduced numbers of microglial cells, which are critical  for the brain’s immune response. It also suggests – very unexpectedly – that bone marrow transplants may be an effective treatment for trichotillomania in humans.

Shau-Kwaun Chen of the Department of Human Genetics at the University of Utah School of Medicine and his colleagues investigated mice with mutations in the Hoxb8 gene. Hox genes are well known to be involved in establishing the body plan: most organisms express numerous Hox genes, and unique combinations expressed in different regions of the two major body axes constitute a code which instructs the embryo to form each organ and body part in the correct position. 

Mice carrying Hoxb8 mutations exhibit excessive and pathological grooming, leading to hair loss. Grooming is an innate behaviour in mammals, and follows a stereotyped pattern, in which the head is groomed first, followed by the body and, finally, the genitals and tail. The Hoxb8 mutants spend twice as much time grooming as their healthy littermates. The chain of events is normal, but occurs more frequently, and each bout of grooming lasts longer, leading to hair removal and self-inflicted open sores at the grooming sites. This behaviour is very similar to that of humans with trichotillomania, so the Hoxb8 mutants serve as a useful model for the condition.

Researchers have been studying these mutants ever since they were first created in 2002, but still aren’t sure why they show excessive grooming. One hypothesis is that the behaviour is associated with reduced sensitivity to pain – the mice exhibit altered responses to noxious and thermal stimuli, which is thought to occur because of disrupted connections between neurons in the spinal cord which transmit this information up to the brain. But Hox gene mutations normally produce numerous defects, and the subtler ones often go unnoticed. And although excessive grooming involves numerous brain structures, Hoxb8 is present at very low levels in the brain, making it difficult to establish which cells express it.

Chen and his colleagues started off with an analysis of Hoxb8 expression in the brain, by generating a strain of mutant mice in which cells that express the gene also express yellow fluorescent protein as a “reporter” gene. Dissection of the animals’ brains revealed that small numbers of cells expressing yellow fluorescent protein were distributed throughout the organ, but were predominant in the cerebral cortex, striatum, olfactory bulb and brainstem. On closer inspection, the cells were identified as microglia, non-neuronal cells which constitute the main form of the brain’s immune defence. Yellow fluorescence was only seen in a subpopulation of the cells, however, which constitutes about 40% of the total number of microglia in the brain. And when the researchers looked at brain slices from Hoxb8 mutants, they saw a significant reduction of microglial cells.

mice pathological grooming.jpg

During embryonic development, one subpopulation of microglia is generated in the bone marrow, from white blood cells called monocytes, before migrating through blood vessels and into the brain soon after birth. In newborn healthy mice, the researchers observed yellow fluorescent cells in several sites, including the choroid plexus and the meninges (the membranes enveloping the brain), at which migrating microglia first gain entry into the brain. They also found that the number of fluorescent cells decreased with distance from these sites.

These findings suggest that Hoxb8 is required for specifying the subpopulation of microglial cells that is derived from the bone marrow. The researchers therefore took blood samples from their genetically engineered mice, and found that all the blood cell types – which are produced in the bone marrow – expressed yellow fluorescent protein, confirming that they also express Hoxb8. Most bone marrow cells were also positive for yellow fluorescent protein.

Next, the researchers took bone marrow cells from healthy and Hoxb8 mutant mice and transplanted into the mutants. They then monitored the animals’ grooming behaviour, as well as the regrowth of hairless patches of skin, for a period of 5 months after the transplants. Bone marrow transplants from healthy mice, but not those lacking Hoxb8, were found to abolish excessive grooming in the mutants. In this group of animals, the hairless skin patches grew back and the open wounds healed (above). By 3 months, most were fully recovered, and could not be distinguished from their healthy litter mates on the basis of either grooming behaviour or appearance.

Finally, the researchers created another strain of mutant mice, in which the Hoxb8 gene is selectively deleted from haematopoietic stem cells, which give rise to all blood cells during development and in adults. (Senior author Mario Capecchi is one of pioneers of this “conditional knock-out” technology, and was awarded the 2007 Nobel Prize for Physiology or Medicine for his contribution to developing the technique.) These animals also exhibited pathological grooming, despite lacking spinal cord defects. And another mutant strain, in which Hoxb8 was selectively deleted from spinal cord cells, was insensitive to pain but did not exhibit excessive grooming. This rules out the possibility that pathological grooming is a result of an altered pain response.

This study therefore provides strong evidence that pathological grooming in Hoxb8 mutant mice occurs because of a reduction in the number microglial cells in the brain. Behaviours such as grooming reduce the number of pathogens on the skin surface, minimizing the risk that they will enter the body and cause disease. Pathogens on the skin can be irritating, and the natural response is to try to brush them off. Microglial cells are also involved in clearing pathogens – they are the brain’s first line of defence, which are deployed to clear up damaged cells or to destroy microbes. In evolutionary terms, it might be advantageous to link behaviours with the cellular responses that perform similar functions.

The mechanism by which a microglial deficiency leads to pathological grooming is as yet unknown, but the researchers offer an hypothesis. Microglia are known to be closely associated with synapses in the brain, and to regulate signalling between nerve cells by releasing chemical messengers called cytokines. Chen and his colleagues note that they observed microglia in many of the brain regions linked to OCD. A reduction in their numbers is, therefore, likely to disrupt activity in the neural circuits involved in pathological grooming. Regardless of the underlying mechanism, the surprise finding that bone marrow transplants abolish compulsive grooming behaviour in the Hoxb8 mutant mice has obvious implications for the treatment of obsessive-compulsive disorders in humans.

Related:


Chen, S., et al. (2010). Hematopoietic Origin of Pathological Grooming in Hoxb8 Mutant Mice. Cell 141: 775-785 DOI: [PDF].

Huey, E.D., et al. (2008). A psychological and neuroanatomical model of obsessive-compulsive disorder. J. Neuropsychiatry Clin. Neurosci. 20: 390-40. [PDF]

Comments

  1. #1 Chris Phoenix
    June 7, 2010

    Might this be related in any way to feather-plucking in birds?

  2. #2 Kevin
    June 8, 2010

    With mouse study reults in hand, wouldn’t the next logical step be to cut to the chase, and assess the microglial cell levels of trich patients? Another thought: there have been about 50,000 bone marrow transplants done in the US so far. Based on the 2% estimate, that should translate to 1,000 cases of BMTs that have already been performed on people suffering from trichotillomania… has there been any effort to assess whether the BMTs have had an impact on trich in these patients?

  3. #3 SL
    June 8, 2010

    Could it also be related to nail-biting and skin picking, both grooming habits done to excess? Another question is, are these behaviors related to trying to clear the skin of perceived excess hair or nail or scabs, or are they repetitive behaviors to reduce tension in and of themselves (e.g. gum chewing can reduce stress but has nothing to do with grooming).

  4. #4 anon
    June 8, 2010

    So now I know I’m mutant and my super-power is hair plucking :)

    This is a really embarrassing condition, it’s very frustrating not being able to keep my hands away from my beard (which I grew so I could keep my eyebrows). I assume my own case is a mild one as I’m able to maintain normal social and professional activities, but still it really sucks

    BMT seems a bit rash, but if it works…

  5. #5 Kilukkam
    June 9, 2010

    “Microglial cells are also involved in clearing pathogens – they are the brain’s first line of defence, which are deployed to clear up damaged cells or to destroy microbes.In evolutionary terms, it might be advantageous to link behaviours with the cellular responses that perform similar functions.”

    I wonder if there is some kind of common code connecting the pathogen-clearing actions inside and outside? Such a finding would be really interesting, as it would imply that cellular “actions” and physical actions are related in a micro-macro fashion.

  6. #6 ferkan
    June 10, 2010

    This article is a bit credulous.

    Firstly Trichotillomania is not normally classed as part of OCD. It has been suggested that it is part of an Obsessive–compulsive spectrum. However, this spectrum is not universally accepted to exist as a valid concept. Trichotillomania is more normally classified as an impulse control disorder.

    Secondly, OCD is a disorder that generally responds very well to psychological treatment and has a well characterised cognitive model (please see: Salkovskis, P. M. (1999). Understanding and treating obsessive-compulsive disorder. Behaviour Research and Therapy, 37, s29-s52.) Thus, although more research is always useful, the need to reduce everything to a simple biological substrate is simplistic and unhelpful. That the whole article makes no comment to psychological mechanisms is problematic.

    Next and perhaps most relevant. There is little evidence to suggest that the mouse model described here has anything to do with trichotillomania, let alone typical OCD. Just because a behaviour has a similar form does not mean it has a similar aetiology or function. There may well be some overlap with trichotillomania, but that remains to be proven.

    It’s undeniably interesting work, but the implications are overplayed.

    At the very least, could we have a question mark on the title: Hair pulling is a neuroimmunological condition?

  7. #7 janedoe
    October 3, 2010

    SEA SPA SKIN CARE BLACK MUD BODY WRAP FROM THE DEAD SEA

    I don’t work for this company or have any knowledge of the company. I purchased this yesterday and applied it to my head area and after I washed the mask off it calmed the area 90% and the pulse deep with in the brain that hurts is now barable no pain. It’s the first day but for the first time in 25 years my brain is at peace what a difference. I used the salt scrub in the orange jar after so it could be the mixture of the two. I can still feel the salt seeping into the pours deep inside and it actually feels great!
    what are you researchers working on? Perhaps I can suggest some areas no one yet has mentioned. simple x ray,or brain EKG,or brain mapping machines,acupuncture,massage,boyox the area,numbing injection to calm the pulse that increases if we don’t pull the area.Doctors are clueless try teaching them about it so we don’t regret bringing it up. I mean the looks on their face really makes us look crazy.

  8. #8 BRIDGET
    October 3, 2010

    When I die one day,I want to donate my brain to trichotillamina research to help find a cure for every person that deserves to live a healthy normal life. How can I go about this?