Mar 04 2010

Treating Migraine with Magnetic Stimulation

Since the discovery of magnetism, using magnets and magnetic fields has been a popular subject for quacks and charlatans – starting with Anton Mesmer and his “animal magnetism.” Recently there has been a resurgence of dubious magnetic devices for arthritis, pain, injuries, and other uses.

But today I am writing about the legitimate science of using magnetic stimulation for therapeutic effects. The brain is both a biochemical organ and an electromagnetic organ. Until recently our attempts at altering the physiology and function of the brain have focused on pharmacology – mainly either increasing or decreasing the action of specific neurotransmitters. This is an effective paradigm for seizures, preventing migraines, and treating pain. It has also been the approach for treating psychiatric disorders, with clear effects for psychotic symptoms, like those caused by schizophrenia, and also anxiety, eating disorders and severe depression. The effectiveness of pharmacological treatments for some psychiatric indications, however, remains marginal and controversial, for example for mild to moderate depression.

Because the brain is also an organ that interacts with the environment, there are also several specialties dedicated to addressing psychological concerns with environmental treatments – cognitive behavioral therapy, for example.

Electrical/magnetic interventions, however, have been scant, only recently getting significant attention. The only such intervention I can think of before the last decade was electroconvulsive therapy (ECT) for depression. It was observed serendipitously that some patients with severe depression and epilepsy would have relief of their depression following a seizure. This lead to the initial crude ECT treatments, inducing whole brain seizures. Later sedatives and paralytics were added for patient safety and comfort (avoiding the “One Flew Over the Cuckoo’s Nest” scene). ECT has been further revised to only induce seizures in one hemisphere, and recently using magnetic rather than electrical stimulation. While much safer and more effective, ECT is still a very crude intervention.

There are currently two electrical-based neurological treatments that are FDA approved. The first is a vagal nerve stimulator for refractory epilepsy. This uses an implanted stimulator outside the brain to stimulate through the vagal nerve and disrupt the synchronized firing of neurons that begin a seizure. This reduces, but does not eliminate, seizures in some patients and may reduce the need for multiple medications.

The second is implanted electrodes for Parkinson’s disease. These electrodes are implanted directly in the brain, in one of the structures of the basal ganglia, and produce steady stimulation to alter the action of the basal ganglia circuitry. This can be useful in decreasing tremor and rigidity in Parkinson’s disease, and again may reduce but not eliminate symptoms and reduce the need for medication.

These two interventions are interesting, but still fairly crude. We are starting to target specific brain regions with specific frequency and intensity of stimulation, but the potential remains for far greater precision and control. For example, research is underway to develop computer chips that contain embedded neurons that will hopefully be able to release inhibitory neurotransmitters directly a the time and location of the start of a seizure.

The new treatment represents yet another approach to using electromagnetism to affect brain function – the use of transcranial magnetic stimulation (TMS). TMS today is used for research – at different frequencies TMS can either induce or inhibit the activity in a focused part of the brain, and the results can be studied to figure out what that part of the brain does.

There is already published research looking at the effects of different frequencies of TMS on the excitability of brain regions during a migraine. A migraine is, in some ways, like a seizure – it is a neurological event involving abnormal activity in certain brain circuits (the trigeminovascular reflex, for example) and also involving hyperexcitability (leading to central sensitization) of certain populations of neurons. This leads clinically to hypersensitivity to sound, light, smell, and touch – which can both trigger and exacerbate a migraine.

The new study, soon to be published in Lancet Neurology, is a placebo-controlled pilot study using the frequency of TMS that prior research suggested would decrease the excitability of neurons during a migraine. The study used a hand-held device that a migraine sufferer can place at the back of the head and activate at the beginning of a migraine. The study showed a 40% pain free result at 2 hours – which is a clinically significant result, and a greater response at 2, 24, and 48 hours beyond the placebo group.

Incidentally, this treatment may be easy to blind as the patient uses what is essentially a black box. They press the button and have no way of knowing if a real TMS is being given. I have not seen the full report yet – so I don’t know if the placebo group devices gave no magnetic field and if that can be detected by users. Alternatively, the control device could give a non-therapeutic magnetic field as an active control.

This is preliminary research, and larger, more rigorous follow up studies need to be done. But it is highly plausible that this kind of treatment could provide a way for migraineurs to “turn off” their migraines by inducing inhibition through TMS in the hyperexcitable neurons that trigger and propagate a migraine. Side effects should also be minimal. We should not take safety for granted, however, and of course studies will have to follow patients to make sure there are no unintended consequences (sedation, cognitive impairment, or seizures, for example).

TMS has tremendous potential, as it does not require any implantable device – the fields can be induced from the outside. And I am encouraged that they were able to design a hand-held device capable of delivering an effective TMS pulse. Frequency, duration, intensity, and location of stimulation can all be varied in order to theoretically target different symptoms and conditions. We may be seeing the beginning of a new therapeutic paradigm in neurology.

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19 responses so far

19 Responses to “Treating Migraine with Magnetic Stimulation”

  1. johncon 04 Mar 2010 at 8:27 am

    Great post. I’d just finished reading the BBC’s version of the story when yours popped up in my reader.

    Migraines are pretty scary, I used to have them with aura and other symptoms, but rarely were they very painful. I still have no idea why they stopped (I had them from about 13 to 17, so I’ve always put it down to something hormonal)

    I would love to know exactly how magnetic fields affect the brain. I do seem to remember reading about an experiment involving blindfolded people having their sense of direction compromised by a magnetic field, and the same has been observed in migrating birds.

  2. ccbowerson 04 Mar 2010 at 11:06 am

    You mention CBT in one line in this post, and it reminds me of how overlooked it is. Particularly in mild to moderate depression for which pharmacolgical interventions are of limited benefit. I don’t know why it isnt used more for all types of depression and anxiety disorders… shouldnt it be almost automatic to prescribe CBT (or other evidence based psychotherapy) if you are going to prescribe a pharmocological intervention. The numbers are staggering in terms of who gets meds, but no other help.

    I am curious about TMS… will cost be a major issue? I have no idea about the magnets/equipment involved. I imagine that in order to be strong enough to have a physiological effect in the brain then magnets would have to be fairly strong to reach the depth needed.

    As evidence builds and TMS progresses as a therapy I can imagine the scams that will follow… a ridiculous looking spinning hat lined with kitchen magnets. Or a magnetic pillow or scarf. Actually I’m pretty sure that these products already exist, but they would be able to ride the coattails of something legitimate.

  3. johncon 04 Mar 2010 at 12:04 pm

    ccbowers,

    Yes, the numbers are staggering.

    With around 18 million sufferers of depressive disorders per year (in the US) it’s just not feasible to prescribe CBT, its a very hands-on treatment and requires a high degree of skill.

    But that’s not the only reason, 18 million sufferers is a huge market for antidepressants. Pfizer sell one particular SNRI (effexor) for 1 dollar per pill at an 87% profit margin. 18million * 365 * .87 is a potential maximum of 5.7 billion dollars.

  4. ccbowerson 04 Mar 2010 at 12:25 pm

    I think that CBT can be implemented in more situations than you suggest. Some training is involved, but I’m not sure that individual skill is the most important… the process itself is the important thing, and there is evidence suggesting this. Prescribing antidepressants and psychoactive meds takes skill as well, but that doesnt stop nonspecialists from doing so.

    Pointing out the cost and dollars of pharmacological interventions further supports the idea that there is a financial incentive to treat depression most effectively.

  5. jhansenon 04 Mar 2010 at 12:39 pm

    I know it’s silly, but it reminds me of the “cortical stimulators” used in ‘Star Trek’:

    http://memory-alpha.org/en/wiki/Cortical_stimulator

  6. Watcheron 04 Mar 2010 at 2:00 pm

    TMC is a pretty cool technique. They’re doing a lot of region stimulation here at BU, especially in regards to the visual cortex. There always seems to be someone in need of test subjects for one test or another.

  7. daedalus2uon 04 Mar 2010 at 5:31 pm

    This is interesting, but I completely agree that we cannot take the issue of safety too lightly. The mechanism by which there is pain relief is unknown.

    I have heard reports of people having heart attacks where suddenly the pain disappears. What has happened is that the heart tissue has become sufficiently infarcted that it can no longer experience pain, not that the damage has stopped or been reversed.

    My understanding of migraine is that it is spreading depression, essentially ischemic preconditioning propagating across the brain. Artificially stimulating brain tissue when it does not have the metabolic capacity to support the stimulus response might be a recipe for disaster and ischemic damage, even as the pain is reduced.

  8. kikyoon 04 Mar 2010 at 7:24 pm

    This reminds me – a friend of mine recently brought up botox as a migraine treatment. Is there anything to that? Sounds like an excuse for people to get botox treatments but then claim it’s for headaches instead of cosmetic, but from a Google search it seemed like the efficacy was speculative at best.

  9. Hyperionon 05 Mar 2010 at 12:07 am

    If a small magnet placed at the back of the skull can have such profound effects on neurological function, why do we not see even greater neurological effects during brain MRIs? After all, being placed in a torpedo tube and having a 1.5-3 Tesla field wrapped around one’s brain for 30-45 minutes really ought to have a profound effect if this study is to be believed.

    Dunno, the only thing that every happened to me during brain MRIs is that I tend to go so sleep (but I’m wierd that way, Adderall puts me to sleep too)

  10. daedalus2uon 05 Mar 2010 at 9:18 am

    Hyperion, TMS is not produced with permanant magnets, it is done with electromagnets which produce a very strong time-varying field which induces voltages inside the brain.

    The peak fields with TMS are quite strong, on the order of Tesla, the same order as the fields used in MRI, but last only a hundred microseconds or so. MRI fields are static. The MRI fields do not induce voltages inside the brain.

  11. BubbaRichon 06 Mar 2010 at 12:17 am

    @daedalus2u, I can’t imagine any way you could induce any sort of metabolic damage with magnetic stimulation. One of my lab groups was arguing about what the neuron-level effect of TMS is, but at worst for this purpose, it could open up ion channels. This would trigger the need for ATP-powered pumps to work balancing ions. I don’t know what they would do with no ATP, but I imagine they just wait for more, and the ions stay away from the normal rest state until more ATP is available. Would cellular/environment K/Na imbalances cause any tissue damage?

  12. daedalus2uon 06 Mar 2010 at 12:14 pm

    BubbaRich, You can trigger seizures with TMS. Seizures can cause metabolic stress.

    Cells require ATP to stay alive. If the ATP is depleted, the cells die. That is the mechanism for excitoxic cell death, metabolic stress due to ATP depletion which triggers apoptosis. Slow ATP depletion triggers apoptosis (when there is enough ATP remaining to go through the apoptosis subroutine), rapid depletion triggers necrosis (when there isn’t enough ATP to do apoptosis).

    There could also be problems in mitochondrial regulation that wouldn’t show up until it is too late. I talk about some of those in respect to the use of the “magic helmet” (high intensity pulsed NIR on the brain) to treat Alzheimer’s. I discuss some of the details of that in my blog post.

    http://daedalus2u.blogspot.com/2008/06/more-on-magic-light-helmet-for.html

    In the context of migraine, I think it has been pretty well established that migraine is a state of ischemic preconditioning and is either very similar or identical to spreading depression. That is a “normal” physiological state, normal in the sense that there are natural pathways that trigger the effects, they go through a regulated progression, with the key concept being that the process is under physiological regulation. Ischemic preconditioning is a stress response from deep evolutionary time, a response for cells to survive ischemia and ATP depletion. What happens when you whack that regulated process with TMS? Since the normal process is not well understood, perturbations to that normal process by non-physiological things like TMS are even less understood. I think it is unlikely that whacking brain tissue undergoing spreading depression with TMS will suddenly resolve the ischemia or ATP depletion or what ever else that triggered it in a completely benign manner.

    TMS is associated with reductions in blood flow (depending on how it is done). To me, that implies a reduction in nitric oxide levels. Normally neuronal activation is associated with increases in NO, that is what causes the vasodilatation observed in fMRI. Migraine is not associated with vasodilatation or increases in blood flow (understanding this is complicated because the main effect of ischemic preconditioning is reductions in O2 consumption, with unchanged perfusion, O2 levels would go up. If O2 levels don’t change during ischemic preconditioning, then perfusion has gone down, there are fMRI BOLD measurements indicating increases in O2 during migraine, I interpret these as being due to reduced O2 consumption, most authors interpret them as increased blood flow (the usual explanation in non-migraine)).

    Migraine all by itself may be causing neuronal damage. I suspect that might be a “feature”, to prune the brain and reduce the metabolic load. If the brain doesn’t have sufficient metabolic resources to sustain itself, excitotoxic cell death might be a safety measure to prune the excess. An evolved survival feature that may protect from a future seizure that could be lethal in the presence of predators, but which accelerated dementia a little bit. In the wild, dementia at age 60 would have essentially no consequences because few lived that long. Now it has serious consequences.

  13. Kim Barronon 06 Mar 2010 at 7:04 pm

    Regarding migrane treatment with Botox, I had heard that it was useful for people whose headaches were caused by muscle spasms. Such as a co-worker who had fallen down some stairs and landed on her head. But I don’t know if those kinds of headaches are classified as migranes.

  14. ccbowerson 07 Mar 2010 at 11:03 am

    daedalus2u-

    A lot of speculation upon speculation. Although it is natural to look for an evolutionary advantage to migraines, it could just be a pathology of the normal physiology of our nervous systems. Why does it have to have some utility or evolutionary advantage? Migraines themselves can be debilitating, and I could see it being a huge disadvantage for some, particularly in the past. Natural selection does not eliminate all things that don’t have a survival benefit. By the same reasoning, what utility do seizures have?

  15. daedalus2uon 07 Mar 2010 at 11:50 am

    Seizures are an inherent property of “active” tissue. If tissue can support the propagation of activation, then it can support an uncontrolled propagation, which in neuronal tissue is called a seizure. Normally there is exquisitely good control so there are no seizures. When that control breaks down is when seizures happen.

    Ischemic preconditioning is not speculation, that is extremely well known. Every tissue compartment exhibits it.

    If migraine is purely pathology, then why is it pretty common? Why do so many individuals have “the same” pathology? If the physiology that leads to migraine is only detrimental, then why do so many people have it? It seems to me that the idea that the migraine trait became common in the population even as migraine had only detrimental effects is much less likely than the idea that the physiology of migraine may have some protective and/or beneficial features under some circumstances.

    Migraine is not a simple trait. It is a complex trait requiring the concerted action of many different physiological sub-systems. Migraine requires the action of entire brain volumes acting together and “in sync”. That requires communication between those different tissue compartments and the propagation of the physiological state associated with migraine from one region to another.

    TMS requires a pulsed magnetic field, usuall a few kJ pulse delivered in ~100 microseconds. That is a few tens of megawatts. Pulsed equipment can deliver that and still be relatively small. For comparison, a portable Automatic External Defibrillator uses about 100 to 200 J per pulse, about 1/10 as much and over a longer time frame, maybe 10 milliseconds, about 0.01 megawatt. To a first order, a portable TMS would need to be about 10x larger in size and weight than an AED.

  16. ccbowerson 07 Mar 2010 at 8:05 pm

    “If migraine is purely pathology, then why is it pretty common? Why do so many individuals have “the same” pathology?”
    – I am not claiming that it is pure pathology, you are speculating that it is selected for. I am just stating that it may not be specifically selected for. There are many traits which are not beneficial, but are still common. The implication of your statement is that any trait must be either directly selected for, or it should be rare. Well, then name the survival benefits of the following: autism, schizophrenia, homosexuality, brown eyes, etc. Now there may be some evolutionary advantage to some of these, but just because they are common doesnt necessitate this. Even if there is some small advantage doesnt mean that this is the sole reason why it persists.

    There are many possible reasons for a trait to persist despite it not being specifically selected for, and this depends on the specific situation. In general, here are a few reasons: 1. The gene(s) involved in the trait are genetically linked to other genes that are advantageous 2. The trait involves many genes, and some of these genes are advantageous for other reasons (for example with migraines perhaps some of the genes involve may be beneficial for normal physiolgy, but contribute to migraines when other genes are present) 3. The trait is a by product of the design of normal anatomy/physiology (i.e it may be a limitation of design), etc…

    “Migraine is not a simple trait”
    – This is precisely why the argument that is explicitly selected for is harder to demonstrate. Why it is so common may be related to the fact that we all have the same basic physiology. The “in sync-ness” of migraine and seizure is a by product of the basic physiology. Perhaps we are all capable of migraines, but for some the threshold to migraine is lower. With many genes involved we get to the issue I brought up in #2 above. Some of the genes involved may be beneficial in most instances, but becomes harmful in the presence of other genes that contribute to migraines.

    No disrespect, but I just want to point out the fallacy that because a trait exists and may be even common, that it is explcitly selected for.

  17. daedalus2uon 08 Mar 2010 at 9:46 am

    I was not claiming that migraine specifically was selected for, but some aspects of the physiology that leads to migraine certainly has been selected for. Ischemic preconditioning is a fundamental part of ATP regulation. Ischemic preconditioning has been strongly selected for, so strongly that every extant organism exhibits it.

    I go into great detail on my blog how the ability to support an autism phenotype might have been selected for.

    Bonding to other humans in love relationships; same gender and opposite gender; certainly has advantages and certainly has been selected for. Those advantages depend on individual circumstances and humans exhibit a continuum of behaviors. Complex traits with complex genetics that exhibit a continuum of behaviors in the phenotype have been selected for. Specific points on the phenotype continuum might not be advantageous (depending on the circumstances), but the ability of a genotype to produce a phenotype with a continuum of behaviors certainly must have been selected for.

    Brown eyes do exhibit greater resistance to glare and probably reduced UV damage. There does seem to be a reduced incidence of cataracts in people with dark eyes. Brown eyes are more common in regions with greater sunlight.

    The point I am trying to make is not that migraine has some advantages and that stopping migraines will cause problems. I don’t think that is the case. What I am trying to say is that migraine is a complex process, a process which is not fully understood. A treatment that interrupts that process via non-physiological methods and stops pain symptoms may cause harm disproportionate to the harm of the normal progression. It might be treating the symptoms vs. treating the underlying pathology.

    This is a cartoonish example, but if an individual has a broken leg and is in a lot of pain, treating the pain with opiates doesn’t fix the problem, the leg is still broken.

    If the pain from light sensitivity during migraine is a “feature”, blocking that pain might cause adverse effects. For example, if pain is triggered because there is a disruption of automatic regulation of neuronal activity in the visual cortex, matching metabolic capacity to neuronal activation, reducing stimulation until the automatic regulation is restored might be a mechanism by which the pain is adaptive. If the pain is blocked and the automatic regulation not restored, cells may become overloaded and forced into excitotoxic apoptosis (which is painless).

    Right now, the mechanism by which TMS has effects is not known. Without knowing the mechanism and without having a lot of experience that the practice does not have adverse effects, whether there are adverse effects is unknown. There might be no adverse effects, but until it is looked at pretty carefully that is unknown.

  18. johncon 08 Mar 2010 at 10:55 am

    @daedalus2u

    As we’re a work in progress, not a finished product, it could be that migraine is a side effect of another feature which is selected for, in the same way that sickle cell anemia is a side effect of higher resistance to malaria.

    The question is whether it has individual benefits and shouldn’t be treated, or whether it’s only a benefit when seen in the context of the entire gene pool, in which case treating individuals is still a good idea.

  19. daedalus2uon 08 Mar 2010 at 6:36 pm

    johnc, you are not understanding the point I am trying to make. I am not suggesting that migraine should not be treated, but any proposed treatment needs to be tested to ensure that it doesn’t have side effects that are worse than not treating it.

    Even if there is a treatment that has adverse effects, people may decide that the adverse effects are worth the pain relief. But to make that evaluation the side effects need to be known. So far side effects for TMS are unknown, and the mechanism(s) by which TMS works are unknown too.

    Conventional treatments for migraine have been around a long time and have a known side effect profile. New therapies do have new therapeutic potentials, but they also have new side effect potentials.

    An analogy might be something like anaphylaxis. When you have a very strong immune system stimulation, like bacteria in the blood stream, you have a very strong immune system response, sometimes anaphylaxis which can be lethal. Preventing lethal anaphylaxis is important, but having an intact immune system is important too. High dose immunosuppressive drugs might be prophylactic for anaphylaxis, but too much suppression makes you hyper-susceptible to infections.

    A lot of physiology is regulated by feedback mechanisms, where one stimulus generates an adverse effect and that adverse effect stimulates an even larger protective effect. There is some thought that this is how anti-carcinogens in food work, the compound causes metabolic or oxidative stress, and then protective mechanisms hyper-respond and overcompensate for the stress. That is how exercise works, your muscle is unable to do the task that you call it to do, so your body makes the muscle bigger. If you stopped the overload signal from the muscle so overexertion didn’t hurt, would physiology make the muscle bigger? It might not.

    If migraine is ischemic preconditioning, and one of the effects of a migraine is to cause vascular remodeling that increases blood supply to the ischemic tissue, then if the migraine is interrupted before the signal to generate vascular remodeling is generated, a signal might not be generated and vascular remodeling would not happen. That might (note the speculation) have adverse effects. That is not to say that migraine should not be treated, just that it should be treated in ways that preserve the signaling that increases the blood supply.

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