Long COVID, also known as post-COVID conditions, can present with a wide range of symptoms that persist for weeks or months after the initial COVID-19 infection. The most common symptoms of long COVID include:

Neurological Symptoms

  • Headaches
  • Difficulty thinking or concentrating, often referred to as “brain fog”
  • Memory problems
  • Changes in smell or taste

Psychological Symptoms

  • Depression or anxiety
  • Mood changes

Other Symptoms

  • Fatigue or tiredness that interferes with daily life
  • Shortness of breath or difficulty breathing
  • Cough
  • Chest pain or heart palpitations
  • Sleep problems
  • Dizziness when standing up (orthostatic hypotension)
  • Joint or muscle pain
  • Fever
  • Stomach pain or other gastrointestinal issues
  • Changes in menstrual cycles

There is evidence of persistent inflammation in people with long COVID. This inflammation of blood vessels, brain tissues, and other organs is likely the cause of all of the above symptoms.

Receiving a COVID vaccination may prolong the symptoms of long-term COVID-19 in people who have already contracted COVID and now suffer from long COVID. However, vaccines seem to reduce the risk of severe COVID and long COVID.

Unfortunately, we do not have any proven therapies for long COVID. However, it is very important to make sure that nutritional deficiencies do not contribute to long COVID symptoms. I often find a deficiency of vitamin B12 and other B vitamins, vitamin D, magnesium, CoQ10, omega-3 fatty acids, zinc, and others. I recommend looking at your test results yourself since doctors may glance at the report and tell you everything is fine if nothing is flagged. The normal ranges for vitamins are too wide, and if you are at the bottom of the normal range, you are probably deficient. For example, vitamin B12 levels are considered normal between 200 and 1,200. Most neurologists will tell you that your level should be above 500. The same applies to RBC magnesium level – normal is 4.0 to 6.4, but you need to be above 5. Vitamin D should be well above 40, while 30 is still considered normal.

Another supplement I often recommend is NAC. A small study by Yale neurologists showed that 600 mg of NAC improved working memory, concentration, and executive functions. NAC helps the body produce glutathione, an important antioxidant. We sometimes give glutathione infusions along with other vitamins.

Supplements that reduce inflammation include ginger and turmeric extracts.

For brain fog and other neurological symptoms, we have had some success with transcranial magnetic stimulation (TMS). Other neurostimulation methods, such as tDCS, are also worth trying.

Some patients benefit from intravenous infusion of immune globulin, which is approved for some types of neuropathies.

Low-dose naltrexone (LDN) may also help, but no studies prove this.

Probiotics can help people with gastrointestinal symptoms.

Stimulants can be tried to treat fatigue and brain fog. They can also help with depression.

For headaches, we often give Botox injections.

Depression can be treated with antidepressants or TMS.

Some people respond well to physical therapy, acupuncture, herbs, meditation, cognitive-behavioral therapy, and other mind-body techniques.

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Chronic pain is known to alter the brain’s default mode network (DMN). The DMN is a group of interconnected brain regions activated when a person is not focused on the external world. Key DMN functions include mind wandering (daydreaming, thinking about the past or future, imagining scenarios), self-reflection (considering thoughts, feelings, and experiences), theory of mind (understanding others’ thoughts and intentions), and memory (retrieval and processing).

A recent study published in the journal Pain by German researchers investigated the relationship between chronic back pain and DMN alterations. The study, titled “Beyond the chronic pain stage: default mode network perturbation depends on years lived with back pain,” examined patients with chronic back pain (CBP), subacute back pain (SBP), and healthy controls using fMRI.

Results showed that the DMN is significantly altered in CBP patients compared to healthy individuals. Importantly, the degree of DMN disruption increased with the duration of pain, suggesting that the brain adapts to persistent pain over time. This adaptation is influenced by cognitive coping strategies or how individuals mentally manage their pain.

The study found that coping attitudes mediate the link between DMN changes and pain duration. This implies that how people think about and handle pain impacts their brain’s adaptation to it. Effective pain coping strategies could potentially lessen the negative effects of chronic pain on the brain, emphasizing the importance of psychological interventions like meditation, cognitive behavioral therapy (CBT), and acceptance-commitment therapy (ACT).

These findings also provide a scientific basis for treatments like transcranial magnetic stimulation (TMS) and other brain stimulation methods, which aim to restore normal brain connectivity, including DMN function.

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The FDA approved transcranial magnetic stimulation (TMS) to treat anxiety, depression, and OCD about 15 years ago. Most insurers cover this treatment. However, it remains highly underutilized.

A study just published by Dutch researchers in Psychiatry Online compared TMS with a third antidepressant in people who did not respond well to two different antidepressants.

Both treatments were combined with psychotherapy.

  • 89 people with depression who hadn’t improved with at least two previous treatments took part.

  • They were randomly assigned to either TMS or a new antidepressant.

  • The treatment lasted eight weeks.

  • TMS involved 25 sessions of magnetic stimulation.

  • The medication group switched to a new antidepressant following standard guidelines.

The primary outcome measure was the degree of improvement in depression symptoms.

TMS was more effective than switching medications. More people responded well to MS (38% vs 15%) and more people’s depression went into remission with TMS (27% vs 5%).

TMS was better at improving symptoms of anxiety and lack of enjoyment (anhedonia)

Both treatments were equally effective for improving sleep, overthinking, and negative thought patterns. People’s expectations about their treatment were linked to how much their depression improved.

In conclusion, for people with depression that hasn’t responded well to a couple of medication attempts, TMS might be a more effective option than trying another antidepressant. The study also suggests that the choice between TMS and medication might depend on which specific symptoms a person struggles with most.

We started using TMS for people with migraine headaches if they do not respond to multiple standard therapies. About half of these patients respond well. However, we do not have large controlled trials to confirm that TMS effectively treats migraines.

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The use of focused ultrasound to treat brain disorders was one of the topics discussed at the 2024 NYC Neuromodulation Conference in NYC.

Coincidentally, a study on this topic was published last month by Jan Kubanek and his colleagues in Pain, the journal of the International Association for the Study of Pain: “Noninvasive targeted modulation of pain circuits with focused ultrasonic waves”.

Researchers developed a technique that targets the anterior cingulate cortex, a deep brain region involved in processing pain. By using focused ultrasound, this region can be modulated without surgery. This breakthrough has the potential to revolutionize pain management.

Twenty patients with chronic pain participated in a randomized crossover trial. They received two 40-minute sessions of either active or sham stimulation and were monitored for one week. The results were remarkable:

  • 60% of patients experienced a significant reduction in pain on day 1 and day 7 after active stimulation.
  • Sham stimulation only benefited 15% and 20% of patients, respectively.
  • Active stimulation reduced pain by 60.0% immediately after the intervention and by 43.0% and 33.0% on days 1 and 7.
  • Sham stimulation only reduced pain by 14.4%, 12.3%, and 6.6% on the same days.

The stimulation was well tolerated and the side effects were mild and resolved within 24 hours.

Since we have been using transcranial magnetic stimulation (TMS) to treat refractory migraines and other neurological conditions, it was good to read this part of the authors’ conclusion:

“The ultrasonic intervention is conceptually related to TMS applied to the motor cortex, which can provide improvements in chronic pain in certain groups of patients. The key difference is that ultrasonic waves can directly modulate the deep brain regions involved in chronic pain, including the anterior cingulate cortex. Transcranial magnetic stimulation is believed to modulate deep brain regions only indirectly, which may contribute to its variable response and the need for frequent re-administrations. Nonetheless, the effects of both modalities may be complementary, and their combined application may provide stronger effects than either approach alone.”

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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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Athletes have been using creatine supplementation for over 30 years. It seems to improve the energy supply to muscle tissues and increase fat-free mass. Creatine also supplies energy to nerve cells in the brain. Taking a creatine supplement increases the levels of creatine in muscles and the brain.

A review of six studies suggested that creatine improves short-term memory, intelligence, and reasoning. Creatine did not improve any cognitive abilities in young people. Vegetarians benefited more than non-vegetarians in memory tasks.

A study by Taiwanese researchers published in Cephalalgia showed reduced creatine levels in the thalamus (the pain-processing area in the brain) in patients with medication-overuse headaches.

Greek doctors published a report, Prevention of traumatic headache, dizziness and fatigue with creatine administration. A pilot study. They studied 39 patients who sustained a severe traumatic brain injury. There were 19 patients in the control group and 20 in the active group. The active group was given 0.4 g/kg of creatine. Treatment was administered within 4 hours of injury and was continued for 6 months. This treatment improved the duration of post-traumatic loss of memory, the duration of being on a respirator, and the duration of stay in an intensive care unit. They also showed improvement in headaches, dizziness, and fatigue. No side effects were reported.

Some studies suggest that creatine can improve bone health. Here is what WebMD says about creatine:

“While most people get low amounts of creatine by eating seafood and red meat, larger amounts are found in synthetic creatine supplements. Your pancreas and kidneys can also make around 1 gram of creatine each day. Creatine is one of your body’s natural energy sources.

Nearly 95% of the creatine in your body is stored in your skeletal muscles and is used during physical activity. As a dietary supplement, creatine is commonly used to improve exercise performance in athletes and older adults.”

There is not enough evidence to routinely recommend creatine for the treatment of migraine headaches. I do, however, recommend to my older patients taking 5 to 7  grams of creatine an hour before or after exercise.  I am 67 and do take it when I exercise.

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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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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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