Even Mild Cases of Covid-19 Pose Serious Risks to Brain Health

By Dr. Ziyad Al-Aly

From the very early days of the pandemic, “brain fog” emerged as a significant health condition that many experience after COVID-19.

Brain fog is a colloquial term that describes a state of mental sluggishness or lack of clarity and haziness that makes it difficult to concentrate, remember things and think clearly.

Fast-forward four years and there is now abundant evidence that being infected with SARS-CoV-2 – the virus that causes COVID-19 – can affect brain health in many ways.

In addition to brain fog, COVID-19 can lead to an array of problems, including headaches, seizure disorders, strokes, sleep problems, and tingling and paralysis of the nerves, as well as several mental health disorders.

A large and growing body of evidence amassed throughout the pandemic details the many ways that COVID-19 leaves an indelible mark on the brain. But the specific pathways by which the virus does so are still being elucidated, and curative treatments are nonexistent.

Now, two new studies published in the New England Journal of Medicine shed further light on the profound toll of COVID-19 on cognitive health.

I am a physician scientist, and I have been devoted to studying long COVID since early patient reports about this condition – even before the term “long COVID” was coined. I have testified before the U.S. Senate as an expert witness on long COVID and have published extensively on this topic.

Here are some of the most important studies to date documenting how COVID-19 affects brain health:

• Large epidemiological analyses showed that people who had COVID-19 were at an increased risk of cognitive deficits, such as memory problems.

• Imaging studies done in people before and after their COVID-19 infections show shrinkage of brain volume and altered brain structure after infection.

• A study of people with mild to moderate COVID-19 showed significant prolonged inflammation of the brain and changes that are commensurate with seven years of brain aging.

• Severe COVID-19 that requires hospitalization or intensive care may result in cognitive deficits and other brain damage that are equivalent to 20 years of aging.

• Laboratory experiments in human and mouse brain organoids designed to emulate changes in the human brain showed that SARS-CoV-2 infection triggers the fusion of brain cells. This effectively short-circuits brain electrical activity and compromises function.

• Autopsy studies of people who had severe COVID-19 but died months later from other causes showed that the virus was still present in brain tissue. This provides evidence that contrary to its name, SARS-CoV-2 is not only a respiratory virus, but it can also enter the brain in some individuals. But whether the persistence of the virus in brain tissue is driving some of the brain problems seen in people who have had COVID-19 is not yet clear.

• Studies show that even when the virus is mild and exclusively confined to the lungs, it can still provoke inflammation in the brain and impair brain cells’ ability to regenerate.

• COVID-19 can also disrupt the blood brain barrier, the shield that protects the nervous system – which is the control and command center of our bodies – making it “leaky.” Studies using imaging to assess the brains of people hospitalized with COVID-19 showed disrupted or leaky blood brain barriers in those who experienced brain fog.

• A large preliminary analysis pooling together data from 11 studies encompassing almost 1 million people with COVID-19 and more than 6 million uninfected individuals showed that COVID-19 increased the risk of development of new-onset dementia in people older than 60 years of age.

Autopsies have revealed devastating damage in the brains of people who died with COVID-19.

Drops in IQ

Most recently, a new study published in the New England Journal of Medicine assessed cognitive abilities such as memory, planning and spatial reasoning in nearly 113,000 people who had previously had COVID-19. The researchers found that those who had been infected had significant deficits in memory and executive task performance.

This decline was evident among those infected in the early phase of the pandemic and those infected when the delta and omicron variants were dominant. These findings show that the risk of cognitive decline did not abate as the pandemic virus evolved from the ancestral strain to omicron.

In the same study, those who had mild and resolved COVID-19 showed cognitive decline equivalent to a three-point loss of IQ. In comparison, those with unresolved persistent symptoms, such as people with persistent shortness of breath or fatigue, had a six-point loss in IQ. Those who had been admitted to the intensive care unit for COVID-19 had a nine-point loss in IQ. Reinfection with the virus contributed an additional two-point loss in IQ, as compared with no reinfection.

Generally the average IQ is about 100. An IQ above 130 indicates a highly gifted individual, while an IQ below 70 generally indicates a level of intellectual disability that may require significant societal support.

To put the finding of the New England Journal of Medicine study into perspective, I estimate that a three-point downward shift in IQ would increase the number of U.S. adults with an IQ less than 70 from 4.7 million to 7.5 million – an increase of 2.8 million adults with a level of cognitive impairment that requires significant societal support.

Another study in the same issue of the New England Journal of Medicine involved more than 100,000 Norwegians between March 2020 and April 2023. It documented worse memory function at several time points up to 36 months following a positive SARS-CoV-2 test.

Memory and Cognitive Decline

Taken together, these studies show that COVID-19 poses a serious risk to brain health, even in mild cases, and the effects are now being revealed at the population level.

A recent analysis of the U.S. Current Population Survey showed that after the start of the COVID-19 pandemic, an additional 1 million working-age Americans reported having “serious difficulty” remembering, concentrating or making decisions than at any time in the preceding 15 years. Most disconcertingly, this was mostly driven by younger adults between the ages of 18 to 44.

Data from the European Union shows a similar trend – in 2022, 15% of people in the EU reported memory and concentration issues.

Looking ahead, it will be critical to identify who is most at risk. A better understanding is also needed of how these trends might affect the educational attainment of children and young adults and the economic productivity of working-age adults. And the extent to which these shifts will influence the epidemiology of dementia and Alzheimer’s disease is also not clear.

The growing body of research now confirms that COVID-19 should be considered a virus with a significant impact on the brain. The implications are far-reaching, from individuals experiencing cognitive struggles to the potential impact on populations and the economy.

Lifting the fog on the true causes behind these cognitive impairments, including brain fog, will require years if not decades of concerted efforts by researchers across the globe. And unfortunately, nearly everyone is a test case in this unprecedented global undertaking.

Ziyad Al-Aly, MD, is Chief of Research and Development at VA St. Louis Health Care System and a Senior Clinical Epidemiologist at Washington University in St. Louis.

Dr. Al-Aly’s laboratory was the first to produce evidence on the effects of vaccines on Long Covid, the health consequences of repeated infections with SARS-CoV-2, and the effect of antivirals on the short- and long-term outcomes of SARS-CoV-2 infection. He also co-chaired the Biden Administration committee that developed the National Research Action Plan for Long Covid.

This article originally appeared in The Conversation and is republished with permission.

Neuroplasticity: How the Brain ‘Rewires’ Itself

By Hilary Diefenbach, University of Colorado School of Medicine

High-profile sports like football and soccer have brought greater attention in recent years to concussions – the mildest form of traumatic brain injury.

Yet people often do not realize how common concussions are in everyday life, and seldom does the public hear about what happens in the aftermath of concussions – how long the road to recovery can be and what supports healing. Concussions are important to understand, not only for recovery, but also for the insights that the science of recovery can bring to brain health.

I am a speech language pathologist and an instructor in physical medicine and rehabilitation. I specialize in brain injury rehabilitation, with experience ranging from coma recovery to concussion care.

Treating problems tied to head injuries is complex. This is, in part, because it is not possible to directly examine the brain of a living person and because every brain injury is unique. Many aspects of health, both pre- and post-injury, affect recovery. In treating brain injuries, I work to translate this specialized science for each patient and their unique situation.

Brain Injuries Take Many Forms

While people commonly think of athletes when it comes to concussions, sports-related concussions are just one type of mild brain injury seen in health care practice. Concussions can also result from abusive head trauma, blast exposure, car accidents and falls.

The severity of a brain injury is diagnosed based on symptoms, brain imaging and a neurologic exam. Concussions are characterized by a lack of clear tissue damage seen on brain images like an MRI and by the length of time that a person loses consciousness – defined as between zero to 30 minutes.

In addition, a significant portion of concussions may not be identified or formally diagnosed at all. Even if you do not lose consciousness at the time of an injury, you could still have a concussion. Confusion, sensitivity to noise and lights and even changes to sleep and mood are common symptoms. But often, these signs may be misunderstood as signs of stress or shock during traumatic events, such as a car accident. Some people mistakenly assume that if they don’t lose consciousness, they haven’t experienced a concussion.

People who don’t feel that they have returned to normal after a concussion may need further treatment. Many report chronic symptoms that linger beyond the typical three-month recovery – a condition known as post-concussive syndrome. Around 10% of those who suffer a concussion experience post-concussive syndrome, although differences in how this problem is defined and recorded leads to highly variable estimates across studies.

So how does having a concussion affect the brain over time?

The links between concussion and dementias such as chronic traumatic encephalopathy, or, more generally, the relationship between a brain injury early in life and later brain diseases, are not yet clear. This uncertainty should not stop people from finding a path forward and taking strides to support their own brain health.

Brain ‘Detours’

After recovering from a brain injury, patients want to understand how to minimize further risk to their brain, which is all the more important since prior injury puts the brain at greater risk for further injuries.

Researchers and medical providers have learned that after injury the brain can change and “rewire” itself at a cellular level over the life span – a process called neuroplasticity. Brain cells, called neurons, join to form electrical pathways that power activity within the brain.

In addition to other repair processes, neuroplasticity supports damaged brain areas to reconnect injured routes or find “detours” to restore brain function. This means that in recovery, the brain can literally find a new way – or make one – to regain critical abilities.

Neuroplasticity also offers insight into why each brain injury is unique. Following a concussion, therapists focus on detailed evaluations and patient interviews to identify affected areas and to design an intervention.

While the general map of brain regions and their associated functions is standard, individual variability is common. Brain injuries from the same cause of injury, via similar force and intensity of impact and affecting the same location of the brain, can lead to very different symptoms in different people.

While the brain is fully developed by the time people reach their early 20s, neuroplasticity continues well beyond this point. Researchers have seen neuroplastic change during the life span in both the white and gray matter that form brain tissue. The remapping of brain pathways that occurs in late-life injuries, such as a stroke, is one strong piece of evidence to suggest there may be no specific “end date” to the brain’s capacity to restore its internal connections.

Importantly, fuller density of brain cells is thought to create a buffer that is protective against damage due to injury and aging. This extra “bandwidth” is referred to as cognitive reserve. Broadly speaking, higher levels of baseline cognitive reserve have been linked to genetics, educational attainment and health factors.

Neuroplasticity is one process that research shows is critical to maintaining these reserves throughout life.

Building Brain Health

Cognitive reserve is crucial to brain health both before and after a concussion. Studies show that higher levels of cognitive reserve may lessen your risk for prolonged problems after a concussion.

In addition, injuries that occur during childhood and late life may present different challenges in recovery linked to the brain’s cognitive reserves and overall health. For this reason, screening tools for concussion often probe a person’s medical history prior to the event.

Keeping up cognitive reserves likely maintains healthy brain connections that can help us age better. Bilingualism, maintaining an active social life and even going to museums are linked with lower rates of dementia. These studies support that brain activity is good for brain health and it is triggered by many things, including thinking, learning and engaging with the world around us.

Just as there is no one-size-fits-all brain injury, there is also no single path toward brain health.

Advanced brain imaging to detect concussions is not available in standard clinical settings, so clinicians rarely have clear road maps for rehabilitation. But getting optimal sleep, avoiding excessive drinking or other toxic substances and leading a physically and mentally active life are core tenets of brain health.

Finally, the brain does not exist in isolation. Its health is connected to other parts of the body in many ways. Therefore, doctors recommend treating medical conditions that directly affect our brain health and that reduce brain aging, such as high blood pressure,sleep apnea,migraines and even hearing loss.

Brain health is unique to each person, and brain injury treatment depends on your individual lifestyle and health risks. Strategies to treat specific symptoms vary and should be designed with the help of medical specialists. But brain health and cognitive reserve provide a common direction for everyone. Living an active lifestyle – physically, mentally and socially – can drive neuroplasticity and maintain the brain.

Studies of healthy people offer insights into how individual brains are shaped through everyday activities. For instance, research finds that expert musicians have denser sound-processing regions in their brains. The brains of cab drivers have greater development of spatial memory areas. Even military fighter pilots have been shown to have denser tissue in regions connected to strategic thinking.

These startling discoveries teach us that what we do every day truly matters to brain health. For all of these reasons, brain researchers commonly use the phrase “neurons that fire together, wire together” to describe how the brain’s connections change shape associated with repeated patterns of the electrical firing of brain activity.

While many questions remain to be answered, it is well established that the brain can be shaped throughout life. With this knowledge in mind, we can tend to it with greater care.

Hilary Diefenbach, MA, is a licensed Speech Language Pathologist at the Marcus Institute for Brain Health and an Instructor at the University of Colorado School of Medicine. Hilary specializes in brain injury rehabilitation for adults.

This article originally appeared in The Conversation and is republished with permission.

Brain Changes Found in Patients with Long-Term Lyme Disease

By Pat Anson, PNN Editor

Researchers at Johns Hopkins University have documented changes in the brains of patients with post-treatment Lyme disease that may explain symptoms such as brain fog, memory loss and other cognitive issues. The finding could also have implications for patients with long covid, fibromyalgia, multiple sclerosis, chronic fatigue and other health conditions who have cognitive problems.    

Lyme disease is a bacterial illness spread by ticks that causes a rash, flu-like aches and fever, joint pain and fatigue. Most patients fully recover when treated early with antibiotics, but up to 20% of those with post-treatment Lyme disease (PTLD) have long-term symptoms, including depression, insomnia and cognitive difficulties. There is usually no clinical or laboratory evidence to explain their ongoing issues.

“Objective biologic measures of post-treatment Lyme symptoms typically can’t be identified using regular MRIs, CT scans, or blood tests,” says John Aucott, MD., director of the Johns Hopkins Lyme Disease Clinical Research Center.

Aucott and his colleagues recruited 12 PTLD patients and 18 people without a history of Lyme to undergo functional MRI (fMRI) scans while performing a short-term memory task. The scans allow investigators to track blood flow and other changes in the brain in real time.

Their findings, published in the journal PLOS ONE, suggest that cognitive difficulties in PTLD patients are linked to functional and structural changes in the “white matter” of the brain, which is crucial for processing and relaying information. The imaging tests revealed unusual activity in the frontal lobe, an area of the brain responsible for memory recall and concentration. Patients with post-treatment Lyme needed longer periods of time to complete the memory task.

“We saw certain areas in the frontal lobe under-activating and others that were over-activating, which was somewhat expected,” said lead author Cherie Marvel, PhD, an associate professor of neurology at Johns Hopkins.

“However, we didn’t see this same white matter activity in the group without post-treatment Lyme.”

To confirm their finding, researchers used another form of imaging called diffusion tensor imaging (DTI) on all 12 patients with Lyme and 12 of the non-Lyme participants. DTI detects the direction of water movement within brain tissue. Water was diffusing, or leaking, in the the same white matter regions identified in the fMRI.

Researchers believe the increased activity they saw in white matter may reflect an immune system response in the PTLD patients, which may also explain cognitive issues in patients with other chronic health conditions.

PLOS ONE

“Results reported here may have implications for other diseases in which white matter pathology has been demonstrated (e.g., multiple sclerosis) or in illnesses in which cognitive complaints follow disease onset,” researchers said. “The use of multimodal neuroimaging methods, like the ones used in the current study, may be a viable approach for obtaining information on brain function and structure to identify biomarkers of disease burden.”

Researchers say larger studies with more patients will be needed to confirm their findings, as well as long-term tracking of brain changes from the initial Lyme infection through development of PTLD.

Nearly 500,000 people are believed to get Lyme disease each year in the United States. Diagnoses of Lyme have soared over the past 15 years, according to a recent analysis of insurance claims that found Lyme cases rose 357% in rural areas and 65% in urban areas. The highest rates of Lyme were in New Jersey, Vermont, Maine, Rhode Island and Connecticut.

Study Finds Placebos Disrupt Pain Signals in Brain

By Pat Anson, PNN Editor

Much of the pain relief that a person gets from taking an analgesic medication is due to individual mindset, not the drug itself, according to new research that looks at how the human brain responds to a placebo.

The placebo effect is a well-documented but poorly understood condition in which a patient responds to a drug or treatment that is designed to have no therapeutic value. A 2018 study, for example, found that about half of patients who took a sugar pill they thought was an analgesic had a 30% reduction in pain – a level considered effective for an actual painkiller.    

To better understand how that is possible, researchers at Dartmouth University conducted a meta-analysis of 20 neuroimaging studies involving 603 healthy people who participated in placebo studies. Their findings, recently published in Nature Communications, showed that placebo treatments reduced pain-related activity in multiple areas of the brain.

"Our findings demonstrate that the participants who showed the most pain reduction with the placebo also showed the largest reductions in brain areas associated with pain construction," explains co-author Tor Wager, PhD, a Neuroscience Professor who is principal investigator of the Cognitive and Affective Neuroscience Lab at Dartmouth.

"We are still learning how the brain constructs pain experiences, but we know it's a mix of brain areas that process input from the body and those involved in motivation and decision-making. Placebo treatment reduced activity in areas involved in early pain signaling from the body, as well as motivational circuits not tied specifically to pain."

By examining brain images, researchers were able to identify the placebo effect in regions of the brain that process pain signals (nociception) and generate pain sensations.

They found that placebos strongly affect the thalamus, which processes sights, sounds and other types of sensory input; as well as the basal ganglia, which is important for motivation and pain-related activities.

Placebo treatments also reduced activity in the brain’s posterior insula, which is one of the areas involved in creating pain sensations. This suggests that placebos change the pathway for how pain is processed in the brain. 

"The placebo can affect what you do with the pain and how it motivates you, which could be a larger part of what's happening here," says Wager. "It's changing the circuitry that's important for motivation."

Previous research has found that placebos activate the brain’s prefrontal cortex, which triggers the release of natural, pain-relieving hormones that can block pain signals from being processed.

Researchers say placebo effects likely involve a combination of different brain reactions, depending on the placebo and people's predispositions. In other words, there is no uniformity in the placebo response because everyone is different.

"Our results suggest that placebo effects are not restricted solely to either sensory/nociceptive or cognitive/affective processes, but likely involves a combination of mechanisms that may differ depending on the placebo paradigm and other individual factors," said co-author Ulrike Bingel, PhD, a professor at the Center for Translational Neuro- and Behavioral Sciences at University Hospital Essen.

A 2016 study that looked at brain images of osteoarthritis patients found that about half had mid-frontal brain regions that had more connectivity with other parts of the brain, making them more likely to respond to the placebo effect. That could help could explain why some respond well to pain medication, while others do not.

How to Reduce Brain and Spinal Cord Inflammation

By Forest Tennant, PNN Columnist

Intractable pain syndrome (IPS) is constant pain with cardiovascular and endocrine dysfunction. IPS occurs when the initial cause of pain creates inflammation in the brain and spinal cord. This is called neuroinflammation.

Inflammation in the brain and spinal cord is what causes the worsening of IPS symptoms. Inflammation does its dirty work by burning out or damaging neurotransmitter systems such as dopamine, endorphin, cannabinoid, serotonin, and gaba aminobutyric acid (GABA). Common symptoms of neuroinflammation:

• Constant pain

• Fatigue

• Amotivation (Lack of motivation or purpose)

• Attention deficit

• Memory impairment

• Elevated blood pressure & pulse

• Social withdrawal

• Dietary change

• Weight gain

• Sugar craving

• Depression

Every person with IPS must attempt to control and reduce their brain and spinal cord inflammation. To reduce neuroinflammation, we recommend regular consumption of one or more of these non-prescription, natural herbal medicinal agents:

• Tumeric/Curcumin

• Ashwagandha

• Boswellia

• Palmitoyethanolamine (PEA)

• Traumeel

• Cannabidiol (CBD)

• Andrographis

You can take any of these on different days or several together, as long as you use at least one daily.

If the disorder that started your pain and IPS ends in “itis” -- arthritis, arachnoiditis, pancreatitis, cystitis, colitis or myositis -- you will also need a periodic (e.g., 1-2 times a week) low dose of a corticosteroid such as hydrocortisone, methylprednisolone, prednisone or dexamethasone.

Don’t rely on pain relievers alone. You must have an inflammation reduction component as part of your IPS treatment program.

Forest Tennant is retired from clinical practice but continues his research on intractable pain and arachnoiditis. This column is adapted from newsletters recently issued by the IPS Research and Education Project of the Tennant Foundation. Readers interested in subscribing to the newsletter can sign up by clicking here.

The Tennant Foundation has given financial support to Pain News Network and sponsors PNN’s Patient Resources section.  

Can We Forget About Chronic Pain?

By Ann Marie Gaudon, PNN Columnist

I recently came across a clinical report which describe two patients with a lengthy history of chronic pain severe enough to warrant opiate therapy. Both patients experienced sudden memory loss and forgot about their pain – literally.

Central sensitization is a process known to occur in the spinal cord and brain where if short-term acute pain is allowed to persist, then changes occur within the central nervous system which can lead to chronic or intractable pain.

That’s what happened to me. I have a diagnosis of a visceral pain syndrome, as opposed to a progressive pain condition. I experienced one vicious organ assault and after more than 30 years of it being healed, I remain in pain.

Other patients who have experienced painful trauma may relive painful episodes that evoke recurring memories -- they experience their pain over and over again. That is a classic symptom of post-traumatic stress disorder (PTSD). Think of a war veteran or survivor of sexual violence.

Either way, neurophysiologic changes which relate to learning, memory and pain can result in a maladaptive learning process which leaves one in chronic pain. These intricacies happen outside of conscious awareness. We are not aware of or in control of this dysfunctional process while it is occurring within our brain and spinal cord circuits.

Here is an overview of the two patients discussed in the report:

Patient #1

The first patient is a 47-year old female with complicated health problems. She had undergone multiple surgeries and treatment modalities for gastric ulcers, endometriosis, thyroid cancer, hypothyroidism, seizure disorder, malnutrition and chronic abdominal pain over 10 years.

Her pain was managed with high doses of opiate medications in various forms, including intravenous, transdermal and oral. During a complex 12-month hospital stay, she had at least five seizures and suffered memory loss so severe she could not remember her entire stay in the hospital.

She did eventually become fully alert and oriented to the present, but she no longer complained of her pain symptoms and no longer demonstrated a need for consistent pain medication.

Six months after discharge, the patient was living at home in stable condition and only occasionally using tramadol. She reported her symptoms as minimal and 1-2 on the pain scale. She still has no memory of many aspects of her long hospitalization.

Patient #2

A 57-year old male was described as a “highly functioning architect” with a 10-year history of low back and right extremity pain. He had undergone many unsuccessful treatments for pain, including surgery, and was being admitted to hospital to have an intrathecal pump surgically implanted for pain control. He was taking no less than nine medications for pain including high doses of opiate therapy.

Initially after the pump was placed, he reported having a partial reduction of pain in his leg. However, in the next six months he was requesting higher doses of intrathecal as well as oral opiates.

One month after this, the patient was in a minor motor vehicle accident where he did not lose consciousness, but inexplicably had partial memory loss. His physicians felt the accident was not the cause, as the memory loss symptoms occurred long afterward. The cause of the amnesia was unknown and tests including a brain MRI showed as normal.

The patient could not remember the names of his doctors, where he lived, what type of work he did, or why he had a pain pump implanted. He was weaned off opiates without any complaint of increased pain and subsequently had the pump removed at his request.

Eight months later, this patient was found minimally responsive in his home. It is not known what occurred, but there was a suspicion that he had fallen and incurred a head injury. The patient experienced profound memory loss, with no memory of who he was, his family members or his back pain.

His pain medications were discontinued with no complaint of pain, but he required placement in a long-term care home due to severe amnesia. Over the next two years, this patient regained partial memory, along with some back and leg pain. He has not requested or required opiate therapy.

Emotions, Pain and Memory

We know pain perception can be caused by nociceptive stimuli, yet we also know that emotional and psychological factors can increase our perception of pain. A complex play of nerve fibers which transmit messages to the brain and spinal cord suggest there is a relationship between emotions, pain and memory. The best evidence that memory plays a role in pain is that of phantom limb pain.

The two cases presented here suggest that memory may influence the perception of pain, and that amnesia can be accompanied by a loss of or significant reduction of pain in the absence of any physical factors.

Treatments that reduce “pain memories” in the brain and spinal cord, along with a focus on preventing pain to reduce or eliminate these memories, may someday have a more widespread role in the management of chronic pain. To have a treatment or ability to effectively erase a maladaptive pain memory leaves me with just three words:

Count me in.

Ann Marie Gaudon is a registered social worker and psychotherapist in the Waterloo region of Ontario, Canada with a specialty in chronic pain management. 

Ann Marie has been a chronic pain patient for over 30 years and works part-time as her health allows. For more information about her counseling services, visit her website.

This column is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

Discovery of Brain Protein Could Lead to New Chronic Pain Treatments

By Pat Anson, PNN Editor

Researchers have identified a protein in the brain that appears to play a prominent role in the maintenance of long-term pain -- a discovery that could lead to new treatments that stop short-term acute pain from progressing to chronic pain.

The protein RGS4 (Regulator of G protein signaling 4) is found in brain circuits that process pathological pain, mood and motivation.

"Our research reveals that RGS4 actions contribute to the transition from acute and sub-acute pain to pathological pain states and to the maintenance of pain," says Venetia Zachariou, PhD, a professor in The Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai in New York City.

"Because chronic pain states affect numerous neurochemical processes and single-target drugs are unlikely to work, it's exciting to have discovered a multifunctional protein that can be targeted to disrupt the maintenance of pain."

In studies on genetically modified mice, Zachariou and her colleagues found that genetic inactivation of RGS4 did not affect acute pain, but it promoted recovery from nerve injuries, chemotherapy-induced neuropathy and peripheral inflammation. Mice lacking RGS4 developed all the expected symptoms of a nerve injury, but recovered within 3 weeks and returned to physical activity.

The transition from acute to chronic pain is accompanied by numerous adaptations in immune, glial and neuronal cells, many of which are still not well understood. Chronic pain patients experience a number of debilitating symptoms besides pain, such as sensory deficits, depression and loss of motivation

Researchers believe future drugs that target RGS4 could prevent acute pain from transitioning to chronic pain. Currently available medications for chronic pain only treat the symptoms – not the underlying condition – and have major side effects.

Dr. Zachariou's laboratory is conducting further investigation into the actions of RGS4 in the spinal cord and mood-regulating areas of the brain to better understand the mechanism by which the protein affects sensory and pain symptoms.

Their findings are published online in The Journal of Neuroscience.

Chronic Pain Accelerates Dementia

By Dr. Lynn Webster, PNN Columnist

In 2017, JAMA Internal Medicine published a study that found older people with chronic pain experience faster declines in memory and are more likely to develop dementia.  While prior research had shown a link between chronic pain and brain damage, this was one of the first studies to specifically suggest that chronic pain can cause dementia.

The authors reported that people aged 60 and over with persistent pain experienced a 9.2% more rapid decline in memory score when compared to people of the same age without chronic pain. This means that people with chronic pain may experience more difficulty in managing their finances, medications and social connections.

Dementia is a chronic condition of the brain that involves memory, personality and judgment. It is not a disease; it is a symptom of one or more diseases.

There are many types of dementia. Alzheimer’s disease is considered to be the most common.

Dementia usually worsens over time if the underlying disease remains static or progresses, as is the case with many chronic pain conditions.

There are an estimated 20 million Americans with high impact (the most severe) chronic pain who may be experiencing accelerated decline in cognition due to their pain. The amount of dementia appears to be associated with the severity and duration of chronic pain. Undertreated or untreated chronic pain may accelerate dementia.

Chronic pain affects an even larger percentage of elderly adults (one in three) than the general population. Since the prevalence of chronic pain increases with age, the probability of experiencing dementia increases as well. However, the reasons for that go beyond aging itself.

Seniors are more likely to take multiple medications that can contribute to mental confusion. On average, elderly people take five or more prescriptions. They may also use over-the-counter medications, which adds to potential drug-associated mental compromise.

Opioids, in particular, have been implicated in cognitive impairment. However, a study published in 2016 suggests there is no difference in cognitive decline between people on opioids and those on nonsteroidal anti-inflammatory drugs. The study's implication is that pain, not opioids, leads to cognitive impairment.

Brain Fog

Chronic pain appears to affect the function and structure of the hippocampus. This is the region of the brain that involves learning, memory, and emotional processing.

One explanation for the mental decline associated with chronic pain is that various areas of the brain compete for attention. Attentional impairment compromises memory by diverting attention to the areas of the brain processing pain. In effect, the brain is multi-tasking and favoring the processing of pain over cognition. This may, in part, explain the clinical phrase “brain fog.”

The Australian Broadcasting Company's "All in the Mind" website explains that pain damages the brain in several ways, including a change in the size of the thalamus and a decrease in the amount of a neurotransmitter (gamma-aminobutyric acid) the brain produces. In other words, chronic pain changes the brain structurally and functionally.

The prefrontal cortex is the part of the brain responsible for executive functions, such as cognition, social behavior, personality, and decision-making. It is also the part of the brain that modulates pain.

According to "All in the Mind," some researchers believe that chronic pain decreases the volume of the prefrontal cortex. Over time, brains damaged by pain lose the ability to handle pain — along with some of the personality attributes that make us who we are.

Brain Damage Can Be Reversed

The good news is that the brain damage caused by chronic pain can be reversed, at least to some extent. Unfortunately, the elderly are less likely to recover from dementia caused by chronic pain as compared with younger patients.

If pain is adequately treated, the brain may be able to regain its ability to function normally. A 2009 study of patients with chronic pain due to hip osteoarthritis showed reversal of brain changes when their pain was adequately treated. 

People who don’t have their acute pain managed are more likely to develop chronic pain. It is postulated that the changes in the brain that occur with chronic pain begin with the onset of acute pain. There is also some evidence that an individual’s genes may influence who is at greatest risk for developing brain damage from chronic pain and who is least likely to recover from it. 

Many people have criticized the concept of assessing pain as the 5th vital sign, and have called it a contributing factor for the opioid crisis. As I have said, pain may not be a vital sign, but it is vital that we assess it. Asking patients about their pain is critical to providing interventions that can mitigate the consequences of undertreated pain, including dementia. 

Lynn R. Webster, MD, is a vice president of scientific affairs for PRA Health Sciences and consults with the pharmaceutical industry. He is author of the award-winning book, “The Painful Truth,” and co-producer of the documentary, “It Hurts Until You Die.” You can find him on Twitter: @LynnRWebsterMD. 

The information in this column is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

Pain Companion: When Pain Hijacks Your Brain

By Sarah Anne Shockley, Columnist

I had a great inspiration for this article a couple of weeks ago and immediately forgot what it was. I exhausted myself, uselessly racking my brain for the idea I’d had. What was it I thought was so perfect to write for Pain News Network?

Several days went by with me trying to find the elusive idea. I couldn’t even figure out what it related to. It was as if it had completely left the universe and was utterly irretrievable. Gone without a trace.

Ever feel like that?

Studies have shown that chronic pain affects the brain, but most of us living with chronic pain don’t need researchers to tell us that. We live with brains that don’t seem to be firing on all cylinders every day. I don’t know if there is an official term for it, so I’m just calling it “Pain Brain.”

In this and my next column, I’ll discuss some of the ways in which Pain Brain affects our ability to cogitate -- and some practical ways I’ve found to live with it a little more gracefully and even to coax the brain back online.

Dealing with Blank Spaces        

Do you find yourself in the middle of a sentence and can’t remember what you were talking about? Sometimes can’t come up with the words for even the most common items like chair, book, pen? 

We worry that we might be getting Alzheimer’s and sometimes find ourselves very embarrassed when, in the midst of telling someone something important, our brains simply turn off.

We’re left with our mouths hanging open in mid-sentence, whatever we were just talking about an utter mystery to us. We draw a complete blank. Sometimes it’s just a word, but often it’s the whole concept. Just gone. This can be extremely disconcerting.                                    

I find, particularly when I’m tired, that I’m creating sentences with a whole lot of blank spaces in them. “Can you hand me the... the... the... the... you know, I mean, uh... the… the... the.....” You’ve probably done this too.            

Stop. Breathe. Relax. Laugh. Choose another word. Or just let it go and carry on without that word or even that idea. It’s not that your brain is dying, you’re in pain.            

I’ve found that it’s usually not all that helpful to exert a lot of energy to try and recapture the word I lost. I’ve found that my efforts usually don’t make a bit of difference. I can’t conjure up that exact word or thought no matter how hard I try - and I just wear myself out and get flustered.                   

Pushing your brain to get back into gear creates tension, and you don’t need any more of that. Trying to find the exact word leaves a longer silence in your conversation, and you get the deer-in-the-headlights look, and that’s when you begin to feel uncomfortable and embarrassed. You want to say, I’m not really stupid or senile or easily distracted, I used to be able to converse with the best of them!                   

Instead, just move on with the conversation. Usually, sooner or later, the words you need pop back in. Sometimes much later. Sometimes in the middle of the night. But that’s okay. If we can just be easy with it, it’s not that big of a deal. It’s usually more disconcerting for us than the person we’re talking with.

Dealing with Brain Freeze

There are times, however, when it’s more than a particular word that’s missing. For me, it’s often a total brain freeze. Everything comes to a screeching halt, usually in mid-sentence. I have no idea what I was just saying, what the topic of the conversation was, or what direction I was headed in.                  

It’s pretty strange, because you don’t lose the power of speech, you just have no idea what you’re talking about anymore. It’s like the part of your brain dealing with that specific subject goes on a coffee break in the middle of a sentence, leaving you kind of stunned by its complete lack of presence.

For friends and family members, you can make up a code word or phrase for when you’re feeling disconnected from your own brain. I often just say, Sorry, my brain just stopped. It’s short and to the point, and they’ve learned what it means. They either remind me of what we were talking about, or we move onto something else.                   

For other people who don’t know your situation, and if you find yourself embarrassed by your own stupefaction, you might try just changing the topic. It’s really strange, but the brain seems to be able to go somewhere else and work relatively well, just not where you wanted it to go at the moment.

You can also distract other people’s attention from your sudden silence by asking them a direct question such as, What were you saying a moment ago? Or simply, What do you think? If they have something they have to respond to, it usually diverts their attention from your blank stare.

If you refer to what they were saying indirectly, without having to remember exactly what it was they actually said, they will often fill in the blanks for you and help you back on track -- without you having to explain that your brain just stopped.

Living with Pain Brain can be challenging, but in my experience, those of us who struggle with it notice the blank spaces and lost words much more than anyone we’re conversing with.    

In my next column, we’ll talk about memory loss and lowered capacity to cogitate. I’ll have some suggestions for working with them as well.                                

Sarah Anne Shockley suffers from Thoracic Outlet Syndrome, a painful condition that affects the nerves and arteries in the upper chest. Sarah is the author of The Pain Companion: Everyday Wisdom for Living With and Moving Beyond Chronic Pain.

 Sarah also writes for her blog, The Pain Companion.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represent the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

How Chronic Pain Changes Mood and Motivation

By Pat Anson, Editor

Researchers in California have found the first biological evidence that chronic pain alters regions in the brain that regulate mood and motivation -- raising the risk of depression, anxiety and substance abuse.

In animal studies at UCLA and UC Irvine, researchers found that brain inflammation in rodents that was caused by chronic nerve pain led to accelerated growth and activation of immune cells called microglia. Those cells trigger chemical signals within the brain that restrict the release of dopamine, a neurotransmitter that helps control the brain's reward and pleasure centers.

"For over 20 years, scientists have been trying to unlock the mechanisms at work that connect opioid use, pain relief, depression and addiction," said Catherine Cahill, associate professor of anesthesiology & perioperative care at UCI, Christopher Evans of UCLA's Brain Research Institute. "Our findings represent a paradigm shift which has broad implications that are not restricted to the problem of pain and may translate to other disorders."

The study also revealed why opioid drugs such as morphine and cocaine may lose their effectiveness as animals transition from acute pain to chronic pain. Cahill and her colleagues learned that opioids fail to stimulate a dopamine response in mice and rats, resulting in impaired reward-motivated behavior.

Treating the rodents with a long-acting antibiotic called minocycline inhibited microglial activation, and restored dopamine release and reward-motivated behavior. That finding suggests that a similar approach could be used in treating chronic pain in humans.

"Our findings demonstrate that a peripheral nerve injury causes activated microglia within reward circuitry that result in disruption of dopaminergic signaling and reward behavior. These results have broad implications that are not restricted to the problem of pain, but are also relevant to affective disorders associated with disruption of reward circuitry," the study found.

The results of the five-year study appear online in the Journal of Neuroscience.

Cahill and her research team are now trying to establish that pain-derived changes in human brain circuitry can account for mood disorders.

"We have a drug compound that has the potential to normalize reward-like behavior," she said, "and subsequent clinical research could then employ imaging studies to identify how the same disruption in reward circuitry found in rodents occurs in chronic pain patients."

Researchers Say Brain Processes Pain Emotionally

By Pat Anson, Editor

Many chronic pain sufferers resent being told their pain is “all in your head” or that they’re being too emotional about their pain.

But tests conducted by German researchers suggest that the human brain begins to shift from sensory to emotional processing of pain after just a few minutes of painful stimuli.

Scientists at Technische Universität München (TUM) in Munich enrolled 41 people in a study to measure brain activity as they were exposed to painful heat stimulation of a hand. Participants wore a cap with 64 electrodes that measured nerve cell activity in the brain throughout the experiment. The electroencephalograms (EEGs) made it possible to pinpoint which nerve cells respond to pain.

Participants were then given painful heat stimuli to the hand for ten minutes, with the intensity of the heat varying throughout the experiment. The test subjects were asked to continuously assess the level of their pain on a scale of one to a hundred with the other hand using a slider.

"We were absolutely amazed by the results. After just a few minutes, the subjective perception of pain changed. For example, the subjects felt changes in pain when the objective stimulus remained unchanged. The sensation of pain became detached from the objective stimulus after just a few minutes," said Markus Ploner, MD, a professor for human pain research at the TUM School of Medicine.

Previous studies have shown that brief pain stimulation is predominantly processed by sensory areas of the brain that process signals from nerves in the skin. However, in the heat experiment with longer-lasting pain, the EEGs showed that emotional areas of the brain became active.

"If pain persists over a prolonged period of time, the associated brain activity shows that it changes from a pure perception process to a more emotional process. This realization is extremely interesting for the diagnosis and treatment of chronic pain where pain persists for months and years," explained Ploner.

A second experiment showed that it is not just the duration, but also the anticipation of pain that affects perception. Twenty test subjects were given different intensities of painful laser pulses on two areas of the back of the hand. The participants then verbally rated how strong they perceived the pain to be.

In a second round of testing, the subjects were again given the same stimuli, but this time with two creams applied to both hand areas. Although neither cream contained an analgesic, the subjects were told that one of the creams had a pain-relieving effect.

Researchers found the cream had a placebo effect.

"The subjects assessed the pain on the skin area with the allegedly pain-relieving cream as significantly lower than on the other area of skin," said Ploner.

In addition to feeling less pain, the EEGs showed that nerve cells triggered a different pattern of brain activity.

"Our results show how differently our brain processes the same pain stimuli. Systematically mapping and better understanding this complex neurological phenomenon of 'pain' in the brain is a big challenge, but is absolutely essential for improving therapeutic options for pain patients," added Ploner.