Pain Research | Headache NewsBlog

Severe vitamin B12 deficiency can occur with normal blood levels of B12

By: Dr. Mauskop

15-10-2024

Alternative Therapies, Brain disorders, Migraine, Pain Research, Science of Migraine

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.

Disruption of brain networks by chronic pain can be prevented.

By: Dr. Mauskop

18-08-2024

Alternative Therapies, Brain disorders, Pain, Pain Research, Psychology of headaches

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.

Visit with the Nolan Williams’ TMS team at Stanford

By: Dr. Mauskop

24-04-2024

Alternative Therapies, Brain disorders, Chronic migraine, Head trauma, Headaches, Migraine, neurostimulation, New treatments, Pain, Pain Research, post-traumatic headache

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.

Pain relief from transcranial magnetic stimulation is possibly opioid-mediated

By: Dr. Mauskop

07-04-2024

Alternative Therapies, Brain disorders, Chronic migraine, Cluster headaches, Headaches, Headaches in children, Migraine, neurostimulation, New treatments, Pain, Pain Research, Science of Migraine

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.

TMS for medication overuse (rebound) headaches

By: Dr. Mauskop

28-01-2024

Alternative Therapies, Brain disorders, Chronic migraine, Head trauma, Headaches, Migraine, neurostimulation, New treatments, Pain, Pain Research, post-traumatic headache

Medication overuse or rebound headaches can occur as the result of excessive intake of caffeine, opioid analgesics, and short-acting barbiturate drug, butalbital (contained in Fioricet, Esgic and similar drugs). These three substances not only worsen migraine headaches, they are also addictive. Two of my patients with medication overuse headaches were able to stop the offending drugs with the help of repetitive transcranial magnetic stimulation (rTMS).

One patient, a 51-year-old man, had his migraines under control with Botox and infusions of eptinezumab (Vyepti) until he sustained a head injury with a skull fracture. His migraines worsened and he became disabled. A variety of therapies failed to reduce his pain. His pain was partially relieved by 60 mg of oxycodone a day, although he still was unable to work. After six weekly sessions of rTMS he was able to start reducing his oxycodone intake and after eight, he completely stopped it. He was able to return to work with the help of injections of fremanezumab (Ajovy).

Another patient, a 50-year-old woman, had been taking butalbital with caffeine and acetaminophen (Fioricet) for 20 years. The number of pills increased over time and for the previous several years, she had been taking 10 to 12 tablets every day. She was also receiving Botox injections, infusions of eptinezumab, and taking rizatriptan (Maxalt), 10 mg three times a day as well as 60 mg of nortriptyline, 12 mg of tizanidine nightly and atogepant, 60 mg. She had tried a wide variety of other treatments but was unable to reduce her Fioricet intake. Despite her persistent migraines, she was able to take care of her family. After three weekly sessions of rTMS she reduced her Fioricet intake to 3-4 a day, by the third month she was taking one a day, and after 6 months she was completely off it. She was also able to stop atogepant and tizanidine and reduced her nortriptyline to 25 mg.

In addition to helping relieve pain and migraines, rTMS has shown promise in the treatment of addiction, particularly in addressing withdrawal symptoms, depression, and cravings. While the use of rTMS for addiction is still relatively recent and not yet FDA-approved, some studies have demonstrated positive outcomes. For instance, a double-blind study showed that individuals receiving rTMS therapy for cocaine addiction had a higher rate of abstinence compared to those who received standard treatment. rTMS for addiction is still considered experimental, and more research is needed to fully understand its long-term effects and optimal treatment parameters.

We now offer transcranial magnetic stimulation (TMS) for migraines and other neurological conditions

By: Dr. Mauskop

20-01-2024

Alternative Therapies, Brain disorders, Chronic migraine, Head trauma, Headaches, Headaches in children, Migraine, Migraine in pregnancy, neurostimulation, New treatments, Pain, Pain Research, post-traumatic headache

Neurologists frequently find themselves managing patients resistant to standard treatments due to limited proven therapies for many neurological conditions. Some patients cannot tolerate or have contraindications to medications, particularly for such common disabling conditions like migraine and chronic pain.

One promising treatment is transcranial magnetic stimulation (TMS). It is a proven procedure for anxiety, depression, obsessive-compulsive disorder (OCD), smoking cessation, and acute migraines. TMS utilizes magnetic fields to stimulate nerve cells in the brain that are underactive or reduce the excitability of overactive cells. TMS can change the flow of information between different parts of the brain in various neurological conditions. Published reports show the potential benefit of TMS in fibromyalgia, neuropathic pain, cluster headaches, facial pain, trigeminal and other neuralgias, back pain, insomnia, memory disorders, tinnitus, post-concussion syndrome, post-traumatic stress disorder (PTSD), restless leg syndrome, and long COVID. The evidence for the efficacy of TMS for these neurological disorders, however, is still limited.

Single-pulse TMS is approved by the FDA for the acute treatment of migraines with aura. The patient uses a portable device during the aura phase to self-administer a single pulse of TMS to the back of the head. This can abort the attack. Repetitive TMS (rTMS) has been studied for the prevention of migraines and other types of pain. It appears effective, but compared to depression trials, migraine studies were relatively small and the FDA has not cleared rTMS for the treatment of migraines. This means that insurance companies are not likely to pay for this “off-label” use of TMS.

rTMS is generally considered safe and well-tolerated, with side effects typically mild and temporary, including scalp discomfort, headaches, and facial twitching. More serious side effects like seizures and mania are very rare.

Before starting TMS, patients undergo a physical and mental health evaluation. The coil placement and dose are determined in the first session. During a TMS session, patients sit in a comfortable chair with earplugs. An electromagnetic coil is positioned near the scalp, delivering short magnetic pulses to specific brain regions involved in processing pain and other information. Patients feel and hear rapid tapping on their scalp that continues, on and off. Patients are awake and alert during the entire procedure. There are no limitations to activities before or after the treatment.

Treatment length varies from 20 to 45 minutes, depending on the stimulation pattern and number of sites stimulated. The frequency of treatments also varies – anywhere from daily for several weeks, to once a week. After the initial period of more frequent sessions, some patients require weekly or monthly sessions to maintain the effect. It may take a few weeks to see noticeable effects.

TMS is a good choice for people who have not responded to multiple standard therapies, people who do not want to take drugs, those who also suffer from depression and anxiety, and pregnant women. Sufficient evidence suggests that TMS is as safe in children as it is in adults, with studies indicating its effectiveness in treating depression in adolescents.

fMRI scan can establish the diagnosis of migraine

By: Dr. Mauskop

02-12-2023

Brain disorders, Chronic migraine, Headaches, Migraine, Pain, Pain Research, Science of Migraine

Neurologists diagnose migraine by the description of symptoms provided by the patient. We have not had an objective test to confirm that a person suffers from migraines.

A group of researchers led by Dr. Yiheng Tu in the department of psychiatry at Harvard Medical School developed an AI program that can diagnose migraine using fMRI (functional MRI) scanning. The AI program was first fed information on fMRIs of 116 individuals with migraines and then had this data compared to healthy controls.

The AI program had 93% sensitivity and 89% specificity. This means that it missed the diagnosis of migraine in only 7 out of 1oo patients and diagnosed migraine in 11% of patients who did not have it. These are very good numbers, but clearly, the method is not error-proof.

When they compared people with migraines to those with other types of pain, the sensitivity dropped to 78% and specificity, to 76%. This can be explained by the fact that similar functional changes in the brain probably occur with any type of pain.

A major obstacle to the wide use of fMRI scans is the cost. They are more expensive to perform than a regular MRI. Insurance companies are not likely to cover it since this is an experimental procedure. Another potential difficulty is that fMRI takes much longer to do than a regular MRI – an hour vs 20 minutes. During this time you have to lie inside a tube while trying not to move and hearing loud banging noises.

Anxiety may facilitate transformation of pain from acute to chronic

By: Dr. Mauskop

07-09-2023

Alternative Therapies, Brain disorders, Chronic migraine, Headaches, Migraine, Pain, Pain Research, Psychology of headaches, Science of Migraine

Our thoughts and emotions can impact the development of chronic pain. However, there haven’t been many studies exploring what causes pain to transition from being short-term (acute) to long-lasting (chronic).

Australian researchers conducted a study to investigate how our thought patterns, anxiety related to pain, and the tendency to avoid pain affect both acute and chronic pain. They conducted two studies for this purpose. In the first study, they interviewed 85 individuals experiencing long-term pain to understand their thoughts and emotions. In the second study, they observed 254 individuals who had recently started experiencing acute pain and followed up with them three months later.

In both studies, they examined interpretation bias using a word association task and assessed pain-related anxiety, pain avoidance, pain intensity, and how pain interfered with daily life. In both cases, they discovered that the way people think about pain was linked to how much it disrupted their daily lives. In the second study, they also found that people’s thought patterns about pain were connected to increased anxiety about pain. This heightened anxiety, in turn, made the pain more severe and disruptive after three months. While anxiety about pain also led people to try to avoid it, this avoidance behavior didn’t seem to affect the level of pain they experienced later on.

This research provides valuable insights into how pain can transition from acute to chronic. It suggests that our initial thoughts about pain might trigger anxiety related to pain, which can contribute to the pain persisting and becoming more troublesome over time. This finding could be crucial in developing strategies to prevent chronification of pain by addressing how people perceive and manage their anxiety about pain during its early stages. Cognitive-behavioral therapy, meditation, and other mind-body techniques could be some of such strategies.

Effects of observational learning on placebo responses, or why sham remedies seem to work so well

By: Dr. Mauskop

19-06-2023

Alternative Therapies, Brain disorders, Chronic migraine, Pain, Pain Research, Psychology of headaches

Many companies selling ineffective treatments for painful conditions manage to attract a large customer base by showcasing testimonials from satisfied customers. Recent research suggests that these individuals might genuinely benefit from hearing others express positive experiences.

A study published in the journal Pain, titled “Learning pain from others: a systematic review and meta-analysis of studies on placebo hypoalgesia and nocebo hyperalgesia induced by observational learning” explores the impact of observational learning on placebo and nocebo responses.

Placebo hypoalgesia refers to when a fake treatment (placebo) reduces pain, while nocebo hyperalgesia is when the placebo actually increases pain. Learning processes, such as classical conditioning and operant conditioning, have been shown to play a role in these effects. Verbal suggestions and observational learning from others also influence placebo and nocebo responses. However, the magnitude of these effects can vary depending on the specific learning process used.

This meta-analysis of 17 studies showed that observational learning can effectively modulate pain and pain expectancies. However, the magnitude of these effects varies across studies. Observing a model in person resulted in larger effects compared to observing a videotaped model. The analysis also suggested that placebo effects can be induced through observational learning, but nocebo effects were not consistently observed. Empathy, specifically the empathic concern component, was found to be associated with the magnitude of observational learning effects.

The article concludes that observational learning can indeed influence pain experience and pain expectancies. Further studies possibly could lead to methods to enhance the treatment effects of proven therapies.

Structural brain connectivity predicts pain

By: Dr. Mauskop

29-05-2023

Head trauma, Headaches, Migraine, Pain, Pain Research, post-traumatic headache

In a recent post, I mentioned a study in which researchers using functional MRI (fMRI) were able to link functional connectivity within the default mode network (DMN) and between DMN and executive control network (ECN) with the degree of disability in migraine patients.

In a new study published in the journal Pain, researchers examined the brains of patients with mild traumatic brain injury (mTBI) using fMRI imaging to understand the brain networks associated with early acute pain following a motor vehicle collision. Here are some key findings:

The properties of the brain’s white matter explained a significant portion of the variation in pain experienced after mTBI. This suggests that certain brain features make patients more likely to report higher levels of pain after the injury.
These white matter connections are associated with physiological and psychological characteristics related to pain sensitivity. The interactions between these connections and parameters of sensory testing and pain sensitivity can explain about one-third of the variability in pain.
The connectivity patterns in the brain’s white matter do not change over time, as observed up to a year after the injury. The same connectivity measures collected shortly after the injury and at six months post-injury can predict the level of pain reported by patients at the six-month mark.
The study further indicates that the strength of white matter connections in the sensorimotor, thalamic-cortical, and default-mode networks is associated with pain severity. These findings highlight the involvement of these brain networks in pain perception and suggest that connections within these networks can influence the experience of pain.

Over the past decade, scientists have been increasingly interested in functional connectivity, which is a way of finding networks in the brain that are related to particular activities, including resting. One of the most prominent networks is the default mode network.

The DMN is most active when the brain is at rest. When the brain is directed towards a task or goal, the default network deactivates. The DMN involves low-frequency oscillations of about one fluctuation per second.

The DMN is thought to be involved in a variety of cognitive functions, including self-awareness, social cognition, memory, thinking about the future, and daydreaming. The DMN is also thought to be involved in some psychiatric disorders, such as depression, post-traumatic stress disorder, obsessive-compulsive disorder, schizophrenia, and others.

The findings of this study suggest that the brain’s white matter networks plays an important role in pain perception, and that understanding these brain-pain relationships may lead to new treatments for pain in individuals with mTBI.

These brain networks are not fixed and we already have tools to improve their function. Meditation is one of the most effective and accessible such tools. Meditation has been shown to increase connectivity between different brain regions, including those involved in pain perception. It has also been shown to reduce the activity of pain-related brain regions. In addition to meditation, other things that people can do to improve the function of their brain networks and reduce pain include exercise and sleep.

How to reduce pain recollection

By: Dr. Mauskop

24-04-2023

Brain disorders, Headaches, Migraine, Pain, Pain Research, Psychology of headaches

A recent study published in the journal Pain showed that adding a non-painful stimulus at the end of a Pap smear can reduce pain recollection. The study, titled “Adding a Nonpainful End to Reduce Pain Recollection of Pap Smear Screening: A Randomized Controlled Trial,” was conducted by Taiwanese researchers and involved 266 women.

The study involved an intervention group that received a modified Pap test, where the operator kept the speculum still in the vagina for an additional 15 seconds after rotating it back, instead of immediately removing it. Participants in the modified Pap test group were unaware of this additional step, as they were behind a privacy curtain.

The outcomes of the study included recalled pain after Pap smear screening, real-time pain, and 1-year willingness to receive further Pap tests. Among 266 subjects, the modified Pap group experienced lower 5-minute recalled pain than the traditional Pap group on a 1 to 5 numeric scale and on a 0 to 10 visual analog scale. Subgroup analyses showed that these results were not affected by predicted pain, demographic, or socioeconomic characteristics, but it was more apparent in postmenopausal women. Additionally, the modified Pap test attenuated 1-year recalled pain on both pain scales and increased the 1-year willingness grade to receive further Pap tests.

This technique could potentially be applied to many other painful procedures, including Botox injections, blood draws, vaccine injections, dental procedures, and more.

Using AI to predict who will respond to placebo

By: Dr. Mauskop

16-04-2023

Headache medications, Headaches, Pain, Pain Research, Psychology of headaches

Placebo response is a bane of clinical trials but it can be very helpful in practice. A team of American and Canadian researchers used AI to help identify predictors of the placebo response. The results were recently published in Pain, under the title, Predicting placebo analgesia in patients with chronic pain using natural language processing: a preliminary validation study.

Since they used AI for their study, I thought it would be fitting to use ChatGPT to edit their abstract for the lay public.

Patients with chronic pain often experience significant pain relief from placebos (inert pills), and this effect can last for days or even weeks. However, it’s still unclear whether we can reliably predict who will respond to placebo and how to do so. Previous research has shown that people who respond well to placebos tend to talk about their pain and their life in a certain way. In this study, the researchers looked at whether these language patterns can predict who will respond to a placebo before they even receive the treatment, and whether we can distinguish between people who will respond to a placebo versus a real drug.

To do this, they analyzed language patterns from patients with chronic back pain who received a placebo in one study and used this information to build a language model that could predict who would respond to a placebo in a separate study. They found that this language model was able to predict, before treatment, which patients would respond well to a placebo in the second study. These patients reported an average of 30% pain relief from the placebo, while those predicted to be non-responders only experienced a 3% reduction in pain. However, the model was not able to predict who would respond to a real pain medication or who would recover without treatment, suggesting that it specifically predicts response to placebos.

Overall, this study suggests that we may be able to use language patterns to predict who will respond to placebos, which could help researchers design better clinical trials and improve patient care.