Migraines

                 “I’ve had a strange day.”

                “Oh?”

                “I spilled formaldehyde on my desk today and now I smell it everywhere.  I can’t wash my hands enough.  It’s not like I spilled it on myself, just on the bench top, but the smell!  I feel like it’s on everything!”

                “Weird.”

                “Oh, that’s not all.  My salad tasted like everything was coated in sugar.  And those crackers at Happy Hour?  Peanut butter-flavored.”

                “Okay.  The crackers were not made with peanuts and I’m assuming you didn’t dip your lettuce in sugar.  What’s wrong with you?”

                Soon after, I came down with a terrible headache associated with sensitivity to light and smells.  The pain was originally diffuse but then localized to a throbbing area over my right eye.  It took a few doses of Excedrin coupled with a dark room, sleep and lots of positive thinking from myself before the pain receded.  Unfortunately, the nausea took a few more days to go away.  The residual pain roamed to the left side of my head and back to my right side before throbbing again twenty fours later.  One last dose of Excedrin extinguished it.

                Migraine is a complex brain disorder – it is not simply “a bad headache.”  The International Headache Society has criteria that define migraines with and without aura, cluster headaches and tension headaches.  You can read the definitions here, but the most common characteristics of a migraine headache are pain on one side of the head that pulsates or throbs, inhibition of daily activities, sensitivity to light or sound and nausea or vomiting.  

                What is even more interesting is that migraine headaches are not the only kind: abdominal migraines are experienced by nearly 2% of all children.  The severe pain typically occurs in the abdomen near the belly button and is associated with nausea, cramping and vomiting.  Interestingly, many of these patients go on to suffer from migraine headaches as an adult.  

                The underlying molecular mechanisms that lead to a migraine are not well understood.  In my research for this post, I found many migraine research papers in journals that focus on neuroscience and several ideas that neurons (brain cells) hold the keys to understanding what triggers migraines.  Some recent studies have made use of functional magnetic resonance imaging (fMRI, or as my favorite podcasters call it: the wonder machine).  These types of studies can identify areas of the brain that become activated prior to or during migraine headaches.  Since the symptoms combine pain, light, sound, and smell stimuli, the overwhelming conclusions must be that patients suffer from occasional disturbances of their central nervous system’s ability to process sensory information.  fMRI results have highlighted the brain stem, as well as other brain structures, as potential key players.

                Anyone who suffers from migraines will talk about their triggers, which are environmental situations that commonly lead to a migraine attack.  For me, triggers are dehydration and alcohol; for others, it might be caffeine or strong smells.  They are variable and personal.  In addition, migraines tend run in families.  This fact implies that something in our genes also plays a role.  To this end, researchers are hunting through the genomes of migraine sufferers and comparing their results with non-migraine patients to identify any common differences.

                How is this accomplished?  I will give you an example!

                A paper was published recently that was a combined effort between scientists in Australia, Tasmania, Germany and the United States that focused on identifying SNPs or single nucleotide polymorphisms on the X chromosome of migraine sufferers in an isolated population.  Let’s break down what that means.

SNPs: As was covered in the Central Dogma post, DNA leads to RNA, which leads to protein.  Our DNA is actually a blueprint for building all the proteins our cells need to survive.  The As, Gs, Ts and Cs encode for the amino acids necessary to build a functional protein.  The proteins then carry out all sorts of biological processes.  

Genes are more than that, though.  When an RNA molecule is transcribed from DNA gene, it has the information necessary to make a particular protein but it also has extra bases added to the end (called the 5’ untranslated region or 5’-UTR).  In addition, the RNA molecule has regions that must be cut out and spliced back together before the ribosome can properly read it.  The sequence of bases within the gene is important not only for making a functional protein, but also for ensuring proper processing of a new RNA molecule.

Sometimes, for whatever reason, a base in the DNA becomes something else.  For example, perhaps at one particular point, where most people have a G, you have a T.  It might affect what amino acid is placed in the protein or it might affect processing of the RNA molecule.  It also might affect nothing; considering you are alive and well, the change must not lead to catastrophic consequences on cellular behavior.  These changes at one particular base within a DNA molecule are called single (just one) nucleotide (base) polymorphisms (differences).

X chromosome: Human cells have 23 chromosomes with two of them being the sex chromosomes, X and Y.  A male has an X and an Y while a female has two Xs.  Females are more likely to suffer from migraines as opposed to men so when looking for SNPs these scientists chose to focus on the X chromosome.

Isolated Population: As described above, migraine is a combination of environmental factors (triggers) and genetics (since migraines run in families).  Teasing out the relative contribution of each on a person’s likelihood of developing migraines is difficult.  Part of what keeps a population healthy is genetic variability.  Scientists might be able to identify SNPs in migraine patients across the world, but those people probably each have their own very diverse set of SNPs that might counteract, exacerbate or have no effect on migraines.  The best way to identify DNA base changes that might play a role in migraines is to look at a population where most people have exactly the same genes.  

While difficult to achieve in this day and age, populations like this still exist!  The scientists in this paper went to Norfolk Island, an off shoot of Pitcairn Island, in the Pacific Ocean.  The inhabitants are all descendants of the Bounty mutineers and their Tahitian women (I love the story of the Bounty’s mutiny!!  READ IT!).  The population has also been incredibly isolated since that time and those living there share a significant proportion of their genes.

                And so, the scientists sequenced the X chromosome of many migraine and non-migraine patients on the island to identify nucleotide differences between the two groups.  A particular area of the X chromosome was identified as having a few SNPs.  One protein at this locus in particular, hephaestin, is known to be expressed in several areas of the brain and has been shown in mice to be necessary for iron homeostasis in the central nervous system.  Ah – we come full circle!

REFERENCES             

Abdominal Migraines: http://www.webmd.com/migraines-headaches/abdominal-migraines-children-adults

IHS Headache Standards: http://www.medicine.ox.ac.uk/bandolier/booth/migraine/IHScrit.html

Migraine Info: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001728/

 

Russo et al. “The pain in migraine beyond the pain of migraine.” (2012) Neurol. Sci. 33 (Suppl 1), pgs S103 – 106.

Maher et al. “X Chromosome Associated Scan of the Norfolk Island Genetic Isolate Provides Evidence for a Novel Migraine Susceptibility Locus at Xq12.” (2012) PLos One, 7(5), e37903