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Science of Migraine

Modern technology may help manage or even prevent pain before it becomes chronic. A recent study exploring the effects of repetitive transcranial magnetic stimulation (rTMS) on pain sensitivity offers some intriguing insights.

What is rTMS?

rTMS is a non-invasive method of brain stimulation. It involves sending magnetic pulses to specific areas of the brain through a coil placed on the scalp. This technique has been used to treat conditions like depression and chronic pain, but researchers are now looking at its potential to prevent pain. We used rTMS at the New York Headache Center to treat chronic migraine, other pain and neurological conditions that do not respond to usual treatment.

In a controlled experiment, researchers led by Nahian Chowdhury examined the role of rTMS in reducing future pain in healthy volunteers. The results were published in the latest issue of Pain, a journal of the International Association for the Study of Pain.

The subjects were divided into two groups:

Active rTMS Group: Received high-frequency rTMS to the area of the brain responsible for hand movements.

Sham rTMS Group: Received a fake treatment for comparison.

Both groups were then given an injection of nerve growth factor (NGF) into their jaw muscles, which causes prolonged pain similar to temporomandibular disorders (TMD), a condition causing jaw pain and dysfunction.

Results:

Pain Reduction: Participants who received active rTMS reported significantly less pain when chewing or yawning than the sham group. This effect was more pronounced in the early stages after the injection but persisted for days and weeks.

Brain Activity: The study found an increase in what’s known as peak alpha frequency (PAF) after rTMS, which is linked to lower pain sensitivity.

What Does This Mean for Pain Management?

Preventive Potential: This research suggests that rTMS could be used prophylactically to reduce pain sensitivity when pain is expected, like before surgery.

Future Directions: While promising, this study opens the door to further research into how rTMS can be optimized for pain control, potentially exploring different frequencies, duration, and areas of stimulation.

Pre-Surgery: rTMS might be used to reduce postoperative pain, potentially preventing the transition to chronic pain.

Chronic Pain Management: For those already dealing with chronic pain, understanding how brain activity changes with rTMS could lead to more effective treatments.

Conclusion

While we are still in the early stages, this study of rTMS offers hope for pain sufferers. It suggests a future where we might not only treat pain more effectively but also prevent it from becoming a long-term problem. This could revolutionize our approach to pain management, making it less about reducing and enduring pain and more about preventing it from taking root in the first place.

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“Dr. Mauskop,
Congratulations on hitting a new milestone – over 3800 citations of your articles! This places you in the top 5% for citations within the Doximity community.”
Some of the most cited articles:
– Intravenous Magnesium Sulphate Relieves Migraine Attacks in Patients with Low Serum Ionized Magnesium Levels: A Pilot Study
– Botulinum toxin type A for the prophylaxis of chronic daily headache: Subgroup analysis of patients not receiving other prophylactic medications: A randomized double-blind, placebo-controlled study
– Clinical Guidelines for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain
– Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study
– Foods and supplements in the management of migraine headaches.
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If you’re one of the millions of people who suffer from migraines, you might be worried about the long-term effects on your brain. Recent studies have suggested that people with migraines might be at higher risk for structural brain changes, such as damage to small vessels in the brain and shrinkage of the brain or brain atrophy.

A recent study published in Cephalalgia by Dutch researchers examined the connection between migraines and brain health in over 4,900 middle-aged and elderly people. The researchers used magnetic resonance imaging (MRI) to study the brains of the participants and assess any structural changes.

The study found that people with migraines were not any more likely to have structural brain changes than those without migraines. There were no significant differences between the two groups in terms of:

  • Total brain volume

  • Grey matter volume

  • White matter volume

  • White matter hyperintensity volume (a marker for small vessel disease)

  • Presence of lacunes (tiny holes in the brain)

  • Presence of cerebral microbleeds (small bleeds in the brain)

This study suggests that having migraines may not increase your risk of developing structural brain changes as you age. This is reassuring news for people who suffer from migraines and are concerned about the long-term effects on their brain health.

 

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Vitamin B12 deficiency is common in the elderly, vegetarians, people with diabetes, and other chronic conditions. This deficiency can cause neurological, psychiatric, hematological, and other symptoms. It can be a contributing factor to migraines, especially in people who experience visual auras.

If not treated, vitamin B12 deficiency can cause dementia, spinal cord damage, loss of vision, and permanent nerve damage. I check vitamin B12 levels in all of my patients. The blood test, however, is not always reliable. There are reports of severe deficiency with perfectly normal levels. This is why when a deficiency is suspected, additional tests are needed. These are homocysteine and methylmalonic acid levels. These tests can disclose the presence of a deficiency when vitamin B12 level is in the normal range.

To further complicate matters, a report by neurologists at UCSF described a patient with normal blood tests who nevertheless had a severe vitamin B12 deficiency in the brain. They discovered that this patient had antibodies to a receptor (CD320) that is necessary for the uptake of vitamin B12 from the blood into the brain across the blood-brain barrier. The spinal fluid of this patient completely lacked vitamin B12. Her presenting symptoms were difficulty speaking, unsteadiness, and tremor. She had no peripheral manifestations of vitamin B12 deficiency, only those related to the brain. She recovered with high doses of vitamin B12 supplementation and immunosuppressive therapy to reduce the amount of antibodies against the CD320 receptor.

The authors screened a few hundred patients with lupus, multiple sclerosis, and healthy controls. They found these antibodies in 6% of healthy controls, 6% of those with lupus without neurological symptoms, and 6% with multiple sclerosis. Antibodies were present in 21% of patients with lupus who had neurological symptoms.

This newly described condition is called autoimmune B12 central deficiency (ABCD). The role of these antibodies in healthy people is not clear. However, people with unexplained neurological symptoms should have a blood test for homocysteine, methylmalonic acid, and CD320 antibodies.

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The diagnosis of migraine still relies on the patient’s description of symptoms. We do not have an objective test to confirm the diagnosis.

Several studies using functional MRI (fMRI) attempted to identify people with migraines. A new study published by Korean doctors in The Journal of Headache and Pain used a different imaging technique to achieve this goal.

The researchers used diffusion MRI, a technique that focuses on the movement of water molecules within the brain’s tissues (fMRI measures blood flow to different areas of the brain). It is particularly useful for mapping the brain’s white matter tracts, which are the pathways that connect different brain regions.

47 patients with migraine were compared to 41 healthy controls

Significant differences were found in brain regions such as the orbitofrontal cortex, temporal pole, and sensory/motor areas.

Changes in connections between deeper brain structures (like the amygdala, accumbens, and caudate nuclei) were also noted.

Using machine learning, the researchers could distinguish between migraine patients and healthy individuals based on these brain connectivity features.

Hopefully, larger studies and easier access to advanced imaging techniques may eventually lead to an objective test of migraines. More importantly, identifying specific connectivity patterns may lead to more individualized treatments. These could be treatments with pharmaceuticals or neurostimulation techniques such as transcranial magnetic stimulation (TMS), which we use in our clinic.

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Given enough triggers, almost anyone can develop a migraine. There is a very good chance that even someone who has never had a migraine to become sleep-deprived, dehydrated, drunk, and stressed will develop a migraine headache. However, I have encountered people who told me that they have never had a headache and cannot even imagine what a headache would feel like.

Scientists have discovered why some people never get headaches. Researchers studied the DNA of nearly 64,000 people in Denmark, including about 3,000 who reported never having had a headache. The researchers found a specific area in a gene called ADARB2 that seems to protect against headaches. People with a certain variation in this gene were 20% more likely to be completely headache-free. ADARB2 is mostly active in the brain, particularly nerve cells that reduce brain activity. However, scientists don’t fully understand how this gene works yet.

While this discovery is exciting, more research is needed to confirm how ADARB2 helps prevent headaches. This study is the first to examine the genetics of being headache-free rather than focusing on what causes headaches. It opens up a new approach to understanding and potentially treating headache disorders.

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Candesartan ((Atacand) is a blood pressure medication in the class of angiotensin receptor blockers (ARBs). A recently published study involving 86 patients confirmed that candesartan can improve migraines. This was not a double-blind but rather an observational study, meaning that the results were not as reliable. However, the study is worth publicizing since candesartan is often overlooked as an effective migraine drug.

Here is more about candesartan from my previous post:

Candesartan was first shown to work for the prevention of migraine headaches in a 60-patient Norwegian trial published in JAMA in 2003. This was a double-blind crossover trial, which means that half of the patients were first placed on a placebo and then switched to candesartan and the second group started on candesartan and then were switched to placebo. This trial showed that when compared to placebo, 16 mg of candesartan resulted in a very significant reduction in mean number of days with headache, hours with headache, days with migraine, hours with migraine, headache severity index, level of disability, and days of sick leave. Candesartan was very well tolerated – there was no difference in side effects in patients taking the drug and those taking the placebo.

In another trial, the researchers compared candesartan to placebo as well as to propranolol, which is an FDA-approved blood pressure drug for the prevention of migraines. This trial in 72 migraine sufferers compared 16 mg of candesartan with placebo and 160 mg of propranolol. Candesartan and propranolol were equally effective in reducing migraine days per month and both were significantly more effective than placebo.

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Functional MRI (fMRI) studies have shown that people with migraines have altered functional connectivity and activation patterns in pain-processing brain regions like the insula, thalamus, somatosensory cortex, as well as visual cortex. Some patients also have changes in the default mode and salience networks involved in attention and stimulus processing.

A study published this month by Chinese researchers in the Journal of Headache and Pain reports on connectivity changes in people with vestibular migraines.

They found abnormal resting-state functional connectivity in brain regions involved in multi-sensory and autonomic processing as well as impaired ocular motor control, pain modulation, and emotional regulation.

Until now, there has been little practical application for fMRI findings. However, with the help of Omniscient Neurotechnology, we have just started using fMRI data to better target our treatment with transcranial magnetic stimulation (TMS). TMS applied to motor and visual cortices has been reported to help relieve migraine headaches. We have also found it effective in a significant proportion of patients who did not respond to various other treatments. We have not yet accumulated enough data to determine if fMRI-guided TMS treatment is superior to TMS administered over a predetermined set of targets.

The main obstacle to wider use of TMS in clinical practice is the cost. TMS is approved by the FDA and is covered by insurance for the treatment of anxiety and depression, but not migraines or pain. fMRI is an expensive research tool and is also not covered by insurance. Hopefully, the NIH and other research foundations will provide the funds needed to study this promising treatment.

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Several studies have suggested that fish oil helps prevent migraine headaches. A new clinical trial by Taiwanese doctors provides the strongest evidence for this effect to date. The paper, A 12-week randomized double-blind clinical trial of eicosapentaenoic acid intervention in episodic migraine” was published this month in the journal Brain, Behavior, and Immunity.

Unlike previous studies, this one used a high dose of one of the two omega-3 fatty acids found in fish oil, eicosapentaenoic acid, or EPA. 70 people with episodic migraine participated in a 12-week trial.

One group of 35 people took 2 grams of fish oil daily, which contained 1.8 grams of EPA. The other group of 35 people took a placebo of 2 grams of soybean oil daily. The researchers tracked several measures related to migraine frequency, severity, disability, anxiety/depression, quality of life, and sleep quality before and after the 12 weeks. The results showed that the EPA group did significantly better than the placebo group on multiple measures:

 – They had 4.4 fewer monthly migraine days on average compared to 0.6 fewer days in the placebo group.

– They used acute migraine medication 1.3 fewer days compared to 0.1 more days in the placebo group.

– Their headache severity scores improved more than the placebo group.

– Their disability scores related to migraine improved more.

– Their anxiety and depression scores improved more.

– Their migraine-specific quality of life scores improved more.

Notably, women seemed to particularly benefit from taking the high-dose EPA supplement. Overall, the high dose of EPA from fish oil was able to significantly reduce migraine frequency and severity, improve psychological symptoms, and boost the quality of life for these episodic migraine patients over the 12 weeks. No major side effects were seen.

The cheapest and the highest quality product that will give you such a high amount of EPA is a prescription drug, icosapent ethyl (Vascepa). Most insurers will not cover it for migraines but a 60-day supply (120 capsules) will cost you $77, according to GoodRx.com. You do need a doctor to prescribe it to you.

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I will be speaking on nutritional supplements for migraines and an update on triptans on April 20, 2024.

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Repetitive transcranial magnetic stimulation (rTMS) is approved by the FDA for the treatment of depression and anxiety. We have been using it to treat migraine headaches and other neurological conditions that are not responsive to standard therapies. Improvement in headaches and pain may be at least in part due to improvement in depression. However, additional mechanisms play a role since we see patients who are not depressed but whose pain improves with rTMS.

A new study by Chinese and Australian researchers published in Pain suggests that opioid mechanisms (endorphins, encephalin, and other peptides) may underlie the mechanism of pain relief produced by rTMS.

This was a double-blind, placebo-controlled study. 45 healthy participants were randomized into 3 groups: one receiving rTMS over the primary motor cortex (M), dorsolateral prefrontal cortex (DLPFC), or sham stimulation. Experimental pain was induced by applying capsaicin (hot pepper extract) over the skin of the right hand followed by application of heat.

Participants received intravenous naloxone (an opioid receptor antagonist) or saline before the first rTMS session to block or allow opioid effects, respectively. After 90 minutes to allow naloxone metabolism, participants received a second rTMS session.

For the M1 group, naloxone abolished the analgesic effects of the first rTMS session compared to saline. Pain relief returned in the second session after naloxone was washed out of the body. For the DLPFC group, only the second prolonged rTMS session induced significant analgesia in the saline condition compared to naloxone. rTMS over M1 selectively increased plasma ?-endorphin levels, while rTMS over DLPFC increased encephalin levels.

The results suggest that opioid mechanisms mediate rTMS-induced analgesia. The specific opioid peptides and rTMS dosage requirements differ between M1 and DLPFC stimulation.

However, these results are far from definitive. The study was small and the study protocol was complicated (e.g. using a double dose of rTMS to DLPFC), which increases the likelihood of an error. Also, these results apply to conditions of acute pain. In patients with chronic pain and headaches, rTMS likely provides relief by improving network connectivity between different parts of the brain.

 

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A recent national survey called the “Harris Poll Migraine Report Card” provides insight into the profound impact migraine has on people’s lives, especially those dealing with frequent attacks and high acute medication use. The survey compared those currently experiencing high-frequency migraine (8 or more attack days per month) and using acute medication on 10 or more days per month, to those who previously had this pattern but now have reduced attack frequency and medication use.

Most respondents were first diagnosed with migraine or headache disorders in their mid-20s. However, despite meeting criteria for migraine, one-third did not self-identify as having migraine disease. This underscores how migraine is still underrecognized and misdiagnosed, with people often being mislabeled with terms like “stress headache.”

Regardless of diagnosis, the burden was clear – over 50% reported a negative impact on their overall quality of life. What’s more, at least half had experienced anxiety or depression, with almost half to over half saying migraine negatively affected their mental/emotional health. These findings align with prior research showing a significant burden can start at just 4 monthly migraine days.

In an attempt to improve their condition, most made lifestyle changes like stress management, limiting caffeine and improving diet. However, their treatment choices differed – those with more frequent migraine were more likely to use newer acute treatments like gepants, diclofenac and dihydroergotamine compared to the other group using more NSAIDs, triptans and ergotamines. The high-frequency group was also more inclined to try non-pharmacological options like supplements, marijuana, massage and physical therapy.

The use of prophylactic medications was low in both groups – about 15%. There are several potential reasons including lack of access to neurologists or even primary care doctors, lack of efficacy and side effects of existing drugs, and clinicians not encouraging the use of preventive medications.

The difference between these two groups could at least in part relate to the older age of the previous high-frequency group (mean age, 47 years vs 41), as age-related improvement can occur over time.

Interestingly, the high-frequency group had poorer optimization of their current acute treatments compared to those who previously experienced high frequency but reduced their attack frequency.

This brings the controversial issue of acute medication overuse into focus – does the suboptimal acute treatment lead to frequent use of medications, rather than the current widely accepted dogma that postulates that frequent use leads to more frequent headaches?

There is evidence that caffeine and opioid analgesics make headaches worse. The evidence for triptans and NSAIDs is based purely on correlational studies. Yes, I occasionally see patients improve when they stop or reduce their intake of NSAIDs or triptans. More often improvement comes from instituting effective preventive therapies along with lifestyle changes. NSAIDs have been proven to be effective for the prevention of migraine attacks and I have dozens of patients whose migraines are well-controlled with daily prophylactic or acute use of triptans. The safety of triptans is greater than that of NSAIDs and most prophylactic medications such as antidepressants and epilepsy drugs.

The concept of acute medication “overuse” may be unhelpful and stigmatizing, as it suggests frequent attacks are the patient’s fault rather than a disease manifestation. Optimizing acute treatments may naturally reduce the need for frequent medication use as attacks improve.

 

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