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Brain disorders

A new study from Mayo Clinic researchers, published in The Journal of Headache and Pain, has examined the brain changes associated with acute post-traumatic headaches (PTH). These headaches can occur after a head injury or trauma and can be debilitating. The study involved 60 participants with acute PTH and 60 age-matched healthy controls. Using functional MRI (fMRI), the researchers found two key differences in the brains of PTH patients compared to healthy individuals.

Increased Iron Accumulation in Specific Brain Regions

First, the PTH patients showed higher levels of iron deposition in two brain areas: the left posterior cingulate and the bilateral cuneus regions. These areas are involved in various functions, including pain processing, attention, and visual processing. The accumulation of iron in these regions may disrupt normal brain function and contribute to the development and persistence of post-traumatic headaches.

Abnormal Functional Connectivity Patterns

Secondly, the researchers observed stronger functional connectivity between the bilateral cuneus (the visual processing area) and the right cerebellum (a region involved in motor control and coordination, and other functions) in PTH patients compared to healthy controls. Functional connectivity refers to the communication and synchronization between different brain regions. The abnormal connectivity patterns seen in PTH patients suggest disruptions in the brain networks responsible for processing sensory information, including pain signals.

Implications for Targeted Therapy

While these findings may have lacked utility in the past, they now have important implications for the treatment of post-traumatic headaches. We have been treating patients with repetitive transcranial magnetic stimulation (rTMS), a non-invasive technique that can modulate brain activity in specific regions. By stimulating the areas with abnormal connectivity, rTMS may help restore normal brain function and alleviate headache symptoms and other neurological and psychiatric symptoms. When possible, we perform fMRI scans on individual patients to identify the specific brain regions involved in their headache disorder. However, fMRI is still only a research tool, and when individual fMRI data is not available, studies like this one provide information on common brain changes associated with post-traumatic headaches that can be targeted with TMS.

 

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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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The famous Framingham Heart Study, spanning over 80 years from 1902 to 1985, looked at brain volumes across multiple generations of participants. The study analyzed MRI brain scans from 3,226 participants aged 45-74, born between the 1930s and 1970s. It found significant trends of larger brain volumes in several regions for individuals born in more recent decades:

– Intracranial volume, which represents the total brain size, was 6.6% greater in those born in the 1970s compared to the 1930s.

– Cerebral white matter volume, representing connections between brain cells, was 7.7% greater in the 1970s vs. 1930s cohort.

– Hippocampal volume, the area responsible for memory and other functions, was 5.7% larger in the 1970s compared to the 1930s.

– Cortical surface area, which correlates with the number of brain cells, was 14.9% greater in those born in the 1970s vs. 1930s.

The authors suggest these findings likely reflect improvements in early life factors over time, such as better nutrition, education, healthcare, and management of cardiovascular risk factors.

While the increase in brain size for any one individual is small, across entire populations, it can have a meaningful impact. Larger brain volumes are associated with higher cognitive abilities and resilience against degenerative neurological diseases like stroke, Parkinson’s, and Alzheimer’s.

So, the gradual increase in brain size over generations, even if subtle, may be contributing to higher average intelligence levels and lower rates of dementia in the population.

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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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A new study just published in Neurology showed that people taking proton pump inhibitors (PPIs) such as omeprazole (Prilosec) and esomeprazole (Nexium) have a 70% higher risk of having migraines or severe headaches. The risk was 40% higher with the use of H2 blockers such as famotidine (Pepcid) and 30% higher in those taking generic antacids.

The study analyzed data from 11,818 participants out of 31,127 in the National Health and Nutrition Examination Survey who were taking acid-suppressing drugs. Interestingly, those on H2 blockers had a higher migraine risk if they also had a higher intake of magnesium, though this finding was based on only 75 H2 blocker users, making it potentially unreliable.

The likely cause of the association between acid-suppressing drugs and headaches is the previously documented decrease in absorption of magnesium, vitamin B12, and other nutrients. PPIs have been also found to increase the risk of dementia.

These acid-suppressing drugs are available without a prescription and people assume that they are safe. They are indeed safe when used for short periods of time. Once a person starts taking PPIs, they are very difficult to stop because stopping them often leads to a rebound of acid production. This sometimes makes heartburn worse than before a PPI was started. One way to try to stop them is to switch to an H2 blocker and then, to an antacid such as Gaviscon or Rolaids.

For those who require long-term PPI use, supplementing with magnesium, sublingual vitamin B12, and a multivitamin may help mitigate potential nutrient deficiencies. Vitamin B12 is often poorly absorbed and getting a monthly injection is more reliable. Some of our migraine patients, even some who are not on acid-suppressing drugs, also require monthly infusions of magnesium.

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Nolan Williams has been at the forefront of developing breakthrough TMS protocols for the treatment of depression and other psychiatric indications. It was very stimulating and informative to discuss techniques, protocols, indications, and research into TMS for various neurological and psychiatric indications with the members of Nolan Williams’ lab Greg Sahlem and Ika Kaloiani. Thank you for sharing your knowledge.

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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 study published in the current issue of JAMA Neurology examined the risk of stroke and myocardial infarction (heart attack) after starting a triptan. Triptans have been in use for over 30 years and include drugs such as sumatriptan (Imitrex), rizatriptan (Maxalt), and five others. In many countries, they are sold without a prescription. Danish researchers identified 429,612 individuals who redeemed their first prescription for a triptan.

Unlike all previous studies, they found a slight increase in the risk of stroke or heart attack. Surprisingly, in the abstract of this report, the authors present higher unadjusted numbers than in the discussion section. Of those 429,612 patients, 13 had a heart attack or a stroke within a week or two after they filled the prescription. This means that the risk is 1 in 30,000. Notably, patients who suffered from a stroke or heart attack were older than 60 and had risk factors for cardiovascular disease, such as hypertension, diabetes or previous heart attacks and strokes.

The authors concluded that their study supports the current US FDA recommendation that triptans should not be prescribed to patients with a history of coronary artery disease, transient ischemic attacks, or stroke. They also stated that their “findings do not raise concern” about triptan use in patients with low cardiovascular risk.

In a previous post, I mentioned a report that found NSAIDs such as ibuprofen, and naproxen to be more likely to cause major cardiovascular events than triptans in a ratio of 3.8 to 1. Fortunately, in high-risk patients, we can skip triptans and NSAIDs and use a new class of drugs to treat an acute migraine attack. CGRP antagonists do not increase the risk of cardiovascular events. These drugs are rimegepant (Nurtec), ubrogepant (Ubrelvy), and zavegepant (Zavzpret).

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A new study by Harvard researchers suggests that there is no connection between caffeine consumption and migraine headaches. I am not convinced. This study was small and had only 12 out of 97 participants consume 3-4 cups a day, while 65 consumed 1-2 cups and 20 consumed no caffeine. Statistics based on such small numbers are unreliable.

Most headache sufferers who drink large amounts of caffeine develop a caffeine-withdrawal headache when they don’t get their usual dose of caffeine on time.  My most dramatic case was that of a man who drank about 10 cups of coffee a day. He also set an alarm for 3 AM to have a cup of coffee. If he skipped that 3 AM cup, he would wake up with a debilitating migraine.

A double-blind caffeine withdrawal study published in the New England Journal of Medicine. It showed that 52% of people consuming an average of 2.5 cups of coffee developed a moderate or severe headache when caffeine was stopped.

Caffeine can play positive role in the treatment of migraine and tension-type headaches. It is considered to be an adjuvant analgesic and is included in over-the-counter and prescription drugs along with pain medications. It enhances pain relief produced by acetaminophen, aspirin, and other pain drugs.

The problem arises from excessive intake of caffeine. Two cups of coffee at breakfast, a cup of caffeinated soda at lunch, and a couple of Excedrin do not appear excessive until you consider the total amount of caffeine in these products. If you are prone to headaches, this amount may be sufficient to cause a headache, typically upon awakening in the morning.

 

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Because of my research and publications on magnesium, I was contacted by Nutrisense. This company helps people without diabetes improve their diet and “metabolic health”. They are interested in educating people about the role of magnesium, a very underappreciated mineral. The company offered me a free 2-week trial of their continuous glucose monitor (CGM). I have a healthy diet and normal weight so I was not sure that I could get any useful information. But I thought that some of my patients could benefit and wanted to see what they would experience.

CGM did provide some interesting observations. After exercise, I gulped down 12 oz of unsweetened coconut water. My glucose went up to 150, the upper limit of what is considered normal. I ate a golden delicious apple for a snack one afternoon. Healthy, isn’t it? My glucose level shot up to 165. The next day, I went to a birthday party for a 3-year-old and ate two slices of pizza, without toppings. The glucose level went up to 164. Another night, I had some sushi. The level was 169 (sushi rice is always cooked with sugar). Then, after dinner out with my family, we decided to have ice cream. I had two scoops with the good excuse of wanting to see how high my glucose would go. Surprisingly, it went up only to 151.

It is well known that eating protein and fat first will slow down the absorption of carbohydrates. This is why an apple, eaten between meals gave me a higher spike in sugar than two scoops of ice cream I ate after dinner. Any liquid form of sugar gets absorbed fast. So, you may want to avoid sweet drinks, including fruit juices. I found that getting feedback from the CGM helped modify my eating habits, mostly for the better. I may be less inclined to avoid desserts after dinner. However, additional calories do make me gain weight, so I will try to control myself.

A few caveats. Whenever I slept on the side where my CGM was attached, the glucose level appeared to drop to dangerous levels. This incorrect reading happens when compression restricts blood flow to the monitor. Occasionally, when exercising, I felt a poke from the needle of the CGM. And, after two weeks, my skin became a bit irritated by the sticky bandage that covered the CGM.

I may recommend CGM to my patients who get migraines when they are hungry and to those who are looking for additional help in losing weight. In addition to getting direct feedback about the impact of food on their sugar levels and those levels on their migraines, some patients may benefit from a consultation with a dietitian. Nutrisense can connect you with a dietitian.

My reactions to various foods were normal. Hunger is not one of my migraine triggers. However, many people with migraines have reactive hypoglycemia – an exaggerated response to carbohydrates. This means that when the blood glucose level spikes after a carbohydrate-rich meal, too much insulin is produced, and the glucose level drops below normal. This can be a migraine trigger. Even if migraine is not triggered, this can also make you sluggish and less productive. Skipping meals is also a known migraine trigger and the mechanism is similar – your blood glucose drops too low. There is also a strong correlation between weight and migraines – the heavier you are the more migraines you get. Women with polycystic ovarian syndrome (PCOS) are at a higher risk of having insulin resistance and developing diabetes.

The ideal diet is low in carbohydrates and high in protein. Three or four meals a day is the frequency that works best for most people. In general, the last meal should be at least two hours before bedtime. But there are exceptions.  For some, having a snack in the evening prevents morning or middle-of-the-night migraine.

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I am once again honored to participate in the annual meeting of the Headache Cooperative of the Northeast to be held March 7-9 at the Stamford Marriott Hotel and Spa in Stamford, CT.

You will get a chance to learn about the latest scientific breakthroughs from Rami Burstein, president of the International Headache Society. You will also hear from other prominent figures in the field, renowned for their pioneering work and extensive contributions over several decades – Drs. Steven Baskin, Elizabeth Loder, Thomas Ward, Morris Levin, Richard Lipton, Steven Silberstein, Allan Purdy, Alan Rapaport, Paul Rizzoli, Sait Ashina, and others.

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We use a neuronavigation system from Soterix (on the left) for precise targeting of transcranial magnetic stimulation (TMS). And we use the most advanced TMS machine from MagVenture (on the right) to treat chronic pain, migraines, fibromyalgia, and other neurological conditions.

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