In the January 2008 Special Topics analysis of
migraine research over the past decade, the work of
Prof. Dr. Michel Ferrari ranks at #3 by total
citations, #4 by total papers, and #3 by
His record in this analysis includes 81 papers with
3,044 cites. In addition, he has 6 papers on the list
of the top 20 papers from the past 10 years and 3
papers on the 2-year list.
According toEssential Science
Scientific, Prof. Dr. Ferrari's record includes 132 papers
cited a total of 3,659 times between January 1, 1997 and December 31,
2007—34 of these papers with a total of 1,534 cites are classified in
the field of Clinical Medicine, and 80 papers with a total of 1,940 cites
are classified in Neuroscience & Behavior.
Prof. Dr. Ferrari is Professor of Neurology at the Leiden University
Medical Center in The Netherlands. He is also Chair of the Leiden Center
for Translational Neuroscience.
In the interview below, he talks with
ScienceWatch.com correspondent Gary Taubes about his
investigations into the mechanisms of episodic brain
What do you consider the fundamental dilemma in
The main thing that interested me when I first started studying migraine,
and it still puzzles me now, is the on-off phenomena of migraine and other
paroxysmal brain disorders. They’re episodic—these are
disorders that come in attacks. For migraine, you’re completely
normal, then suddenly your brain switches off and is abnormal for one to
three days. Then it normalizes, and you’re completely fine again.
That mechanism of episodic brain disorders is my primary research topic.
Your most influential paper, which was actually not
included in this particular analysis because it was published two
months before our analysis began, is on the genetics of familial
hemiplegic migraine, published in Cell in 1996 (Ophoff RA,
et al., "Familial hemiplegic migraine and episodic ataxia
type 2 are caused by mutations in the Ca2+ channel gene CACNL1A4,"
87: 543-52, 1 November 1996). How did that research begin, and why
familial hemiplegic migraine?
That was really coincidental. I still recall the day, vividly. I saw two
different patients in my clinic with this syndrome called familial
hemiplegic migraine, which is migraine associated with half-sided
paralysis. It’s a very severe, rare subtype of migraine. And yet here
were these two different patients on the same day, presumably from two
different families, although both came from the very same region in the
Netherlands. I was struck by that. I thought that it could not be true,
that it was two different families. And it turned out that it was actually
one very, very large, extensive multi-generational family.
goal is to understand why migraine
patients get attacks."
This coincidence suddenly changed into a geneticist's delight for doing
linkage studies. And that’s exactly what we did. We started doing
linkage analysis with a new method—micro-satellites—together
with our genetics department, and particularly Rune Frants, who is a
co-author on many of our papers.
How many cases did you find?
We found 20 affected patients in this family.
And you managed to localize the gene?
No, actually. That’s a short story, but the longer story is more
interesting. We took much longer than we had hoped to find the linkage so
we were scooped by another research group working with a similar family in
Paris. They localized the gene to chromosome 19. We weren’t happy
about being scooped, but we were happy that the linkage was found. Working
from that linkage, we identified the gene two years later. So that’s
the short story and that was the first gene identified for migraine, as
reported in the 1996 Cell paper.
So what does the gene do and how does it relate to
That is the really nice longer story. We immediately knew what this gene
did. It encodes for the ion-conducting subunit of neuronal calcium
channels. So it modulated calcium influx into cells. And by doing that,
since it’s a neuronal calcium channel, it controlled and modulated
the release of neurotransmitter. That, of course, is extremely important in
The next step, which pertains immediately to your question, was the next
most important paper in that line of research. That is a Neuron
paper in 2004 (van den Maagdenberg AMJM, et al., "A CACNA1A
knock-in migraine mouse model with increased susceptibility to cortical
spreading depression," 41:701-10, 4 March 2004), which discusses the
characterization of a transgenic knock-in mouse. What we did is introduced
the human calcium channel mutation into the genome of a mouse, and
generated a knock-in mouse with this mutation. The results were very
striking: we found a whole series of mechanisms that all seemed to be
extremely important for migraine. We feel that was the first migraine mouse
Do they have the one-sided paralysis, as well?
Yes, they do, and it is, of course, quite striking. They not only show the
half-sided weakness, the paralysis, but also episodes of headache and
photophobia—super-sensitivity to light—which is also part of
Do you know why the weakness appears on only one
That’s a question we cannot answer. We did unravel the mechanism
behind the familial hemiplegic migraine, though: it’s due to a
phenomenon called cortical spreading depression. When you trigger the brain
it responds with a very brief hyper-activation, followed by a complete
cessation of neuronal function, and that then spreads along the cortex. It
recovers after around an hour. So we showed the mechanism for episodic
brain disorders. What we proved was that the migraine mouse models were
highly susceptible to cortical spreading depression. You could induce
cortical spreading depression far more easily than in the normal mouse,
which clearly explained what could happen in humans. We know already in
normal, common types of migraine, cortical spreading depression is most
likely involved. So that was a wonderful link between the mouse model and
the human situation.
At the risk of sounding frivolous, how do you tell if a
mouse has a headache?
That’s an excellent question. It’s a complicated story. We are
studying that with Professor Jeff Mogil from McGill University in Montreal,
Canada. There are several lines of evidence. Part of that is not yet
published—it’s under review. What’s now in the public
domain, what we’ve presented at conferences, is that mice have a
specific grooming behavior. They start stroking their legs, tail, and body.
And they do that in a very specific way. They hardly ever stroke their
head, unless they have a headache. You can test that by inducing an
artificial headache, causing them pain, and suddenly these mice will start
stroking their heads, and not so much the rest of their bodies. When we
compare our transgenic mice with normal mice, they have a far higher rate
of head stroking. That’s one line of evidence that they actually have
What’s the significance for other episodic brain
disorders? Epilepsy, for instance?
The answer to that is complicated. In epilepsy there is hyper-excitation
and synchronization of the brain. Patients then get seizures, often with
jerking movements of the arms and legs. Still, there are a lot of
commonalities between migraine and epilepsy. First of all, both disorders
are often co-morbid; they co-occur far more frequently than you would
expect by chance. Secondly, quite a few prophylactic medications are
effective in both disorders. Not all, but a few. Thirdly, there are now a
number of genes being discovered, including our calcium channel gene, that
can cause either migraine or epilepsy or both depending on the mutation.
So there is a clinical similarity, there’s a genetic similarity, and
there’s a treatment similarity, and yet they’re different
diseases. One of my hypotheses, not proven, is that the difference is in
cortical spreading depression. Both start with hyper-excitation; in
migraine, it’s followed by depression, the cessation of neuronal
excitation; in epilepsy, it continues. After that, it’s all
speculation. But, yes, we think our findings are useful for understanding
other episodic brain disorders.
In fact, we also found that different mutation in this same gene that
causes familial hemiplegic migraine causes a completely different disease
called episodic ataxia. That’s an ever rarer disorder, where the
patients get episodes several hours long of ataxia, or loss of
coordination. They basically look like they’re drunk. It’s a
disorder of the cerebellum, the part of the brain that controls
coordination. It malfunctions for two to three hours, and it turns out this
same calcium channel gene is also responsible for that disorder.
Where do you see your research going from here?
The ultimate goal is to understand why migraine patients get attacks. Why
are they completely normal and then suddenly they have this derangement of
brain function and normalization? Our hypothesis is that these patients
have a reduced trigger threshold and that trigger threshold is defined by
There are several ways of reducing this trigger threshold. The ultimate
result is migraine patients more easily get a spreading depression, and
then, ultimate goal is to identify treatment targets to develop better
prophylactic agents that would be used by patients then on a daily basis to
prevent the migraine attacks. That’s my dream, to help develop
prophylactic migraine agents. There is an enormous demand for that. There
are no good ones available.
What kind of progress do you think you can make in, say,
the next five years?
I think it’s realistic to say that in five years we should have
several new targets for prophylactic agents. There’s already one drug
currently being tested based on this hypothesis, so that is a very
What’s the most difficult or challenging aspect of
First of all, there’s no objective test for migraine. If you deal
with cancer, for instance, or stroke or myocardial infarction, you have
objective tests; you can have a picture showing what’s wrong. You
don’t have that with migraines. You have to rely on the story that
the patient tells. And you usually don’t see the patients during the
attacks. You see them when they’re healthy and they tell you the
Secondly, it’s clear that migraine has a clinical heterogeneity. We
probably shouldn’t even speak about migraine but about migraines,
plural. There are two main kinds—with aura and without. There are
probably more. And that has implications for understanding the underlying
mechanisms and for treatments. It’s likely that different treatments
should be used for different types of migraines.
A third major complicating factor is that it’s clearly a
multifactorial disorder; there are both genetic and environmental factors
involved. In that respect, it’s very similar to asthma or
hypertension or any of the other common diseases, which are not caused by
just one or two genes, but by a combination of different genes, interacting
with non-genetic environmental factors. In this sense, it’s useful to
say that what we did was study a monogenic subtype of migraine. This is a
subtype called familial hemiplegic migraine, and its caused by one gene,
and the major step now is to go from monogenic subtypes, of which there are
several, to the multifactorial complex disorders, and that’s the big
What message would you want to give the lay public about
There are a couple of them. The first is that not every headache is a
migraine. Migraine is an enormously disabling and debilitating disorder. It
can severely affect patients and their families. It ranks in the WHO top 15
of most disabling disorders and is the most costly brain disease to
society. Having a migraine attack is among the most debilitating events for
The second is that the underlying mechanism really has nothing to do with
stress or other psychological events—it is a purely
pathophysiological process. To a scientist it’s extremely interesting
and challenging to study; the research goes from basic molecular biology to
biochemistry and pharmacology and genetics.
Michel D. Ferrari, M.D., Ph.D.
Leiden University Medical Center
Leiden, The Netherlands
Dr. Michel Ferrari's most-cited paper with 410
cites to date: